Literature Review

The long-term neurologic symptoms such as “brain fog” experienced by some patients with COVID-19 may be caused by a unique pathology – the occlusion of brain capillaries by large megakaryocyte cells, a new report suggests.

The authors report five separate post-mortem cases from patients who died with COVID-19 in which large cells resembling megakaryocytes were identified in cortical capillaries. Immunohistochemistry subsequently confirmed their megakaryocyte identity.

They point out that the finding is of interest as – to their knowledge – megakaryocytes have not been found in the brain before.

The observations are described in a research letter published online Feb. 12 in JAMA Neurology.
 

Bone marrow cells in the brain

Lead author David Nauen, MD, PhD, a neuropathologist from Johns Hopkins University, Baltimore, reported that he identified these cells in the first analysis of post-mortem brain tissue from a patient who had COVID-19.

“Some other viruses cause changes in the brain such as encephalopathy, and as neurologic symptoms are often reported in COVID-19, I was curious to see if similar effects were seen in brain post-mortem samples from patients who had died with the infection,” Dr. Nauen said.

On his first analysis of the brain tissue of a patient who had COVID-19, Dr. Nauen saw no evidence of viral encephalitis, but he observed some “unusually large” cells in the brain capillaries.

“I was taken aback; I couldn’t figure out what they were. Then I realized these cells were megakaryocytes from the bone marrow. I have never seen these cells in the brain before. I asked several colleagues and none of them had either. After extensive literature searches, I could find no evidence of megakaryocytes being in the brain,” Dr. Nauen noted.

Megakaryocytes, he explained, are “very large cells, and the brain capillaries are very small – just large enough to let red blood cells and lymphocytes pass through. To see these very large cells in such vessels is extremely unusual. It looks like they are causing occlusions.”  

By occluding flow through individual capillaries, these large cells could cause ischemic alteration in a distinct pattern, potentially resulting in an atypical form of neurologic impairment, the authors suggest.

“This might alter the hemodynamics and put pressure on other vessels, possibly contributing to the increased risk of stroke that has been reported in COVID-19,” Dr. Nauen said. None of the samples he examined came from patients with COVID-19 who had had a stroke, he reported.

Other than the presence of megakaryocytes in the capillaries, the brain looked normal, he said. He has now examined samples from 15 brains of patients who had COVID-19 and megakaryocytes have been found in the brain capillaries in five cases.
 

New neurologic complication

Classic encephalitis found with other viruses has not been reported in brain post-mortem examinations from patients who had COVID-19, Dr. Nauen noted. “The cognitive issues such as grogginess associated with COVID-19 would indicate problems with the cortex but that hasn’t been documented. This occlusion of a multitude of tiny vessels by megalokaryocytes may offer some explanation of the cognitive issues. This is a new kind of vascular insult seen on pathology, and suggests a new kind of neurologic complication,” he added.

The big question is what these megakaryocytes are doing in the brain.

“Megakaryocytes are bone marrow cells. They are not immune cells. Their job is to produce platelets to help the blood clot. They are not normally found outside the bone marrow, but they have been reported in other organs in COVID-19 patients.

“But the big puzzle associated with finding them in the brain is how they get through the very fine network of blood vessels in the lungs. The geometry just doesn’t work. We don’t know which part of the COVID inflammatory response makes this happen,” said Dr. Nauen.

The authors suggest one possibility is that altered endothelial or other signaling is recruiting megakaryocytes into the circulation and somehow permitting them to pass through the lungs.

“We need to try and understand if there is anything distinctive about these megakaryocytes – which proteins are they expressing that may explain why they are behaving in such an unusual way,” said Dr. Nauen.

Noting that many patients with severe COVID-19 have problems with clotting, and megakaryocytes are part of the clotting system, he speculated that some sort of aberrant message is being sent to these cells.

“It is notable that we found megakaryocytes in cortical capillaries in 33% of cases examined. Because the standard brain autopsy sections taken sampled at random [are] only a minute portion of the cortical volume, finding these cells suggests the total burden could be considerable,” the authors wrote.

Dr. Nauen added that to his knowledge, this is the first report of such observations, and the next step is to look for similar findings in larger sample sizes.

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

The long-term neurologic symptoms such as “brain fog” experienced by some patients with COVID-19 may be caused by a unique pathology – the occlusion of brain capillaries by large megakaryocyte cells, a new report suggests.

The authors report five separate post-mortem cases from patients who died with COVID-19 in which large cells resembling megakaryocytes were identified in cortical capillaries. Immunohistochemistry subsequently confirmed their megakaryocyte identity.

They point out that the finding is of interest as – to their knowledge – megakaryocytes have not been found in the brain before.

The observations are described in a research letter published online Feb. 12 in JAMA Neurology.
 

Bone marrow cells in the brain

Lead author David Nauen, MD, PhD, a neuropathologist from Johns Hopkins University, Baltimore, reported that he identified these cells in the first analysis of post-mortem brain tissue from a patient who had COVID-19.

“Some other viruses cause changes in the brain such as encephalopathy, and as neurologic symptoms are often reported in COVID-19, I was curious to see if similar effects were seen in brain post-mortem samples from patients who had died with the infection,” Dr. Nauen said.

On his first analysis of the brain tissue of a patient who had COVID-19, Dr. Nauen saw no evidence of viral encephalitis, but he observed some “unusually large” cells in the brain capillaries.

“I was taken aback; I couldn’t figure out what they were. Then I realized these cells were megakaryocytes from the bone marrow. I have never seen these cells in the brain before. I asked several colleagues and none of them had either. After extensive literature searches, I could find no evidence of megakaryocytes being in the brain,” Dr. Nauen noted.

Megakaryocytes, he explained, are “very large cells, and the brain capillaries are very small – just large enough to let red blood cells and lymphocytes pass through. To see these very large cells in such vessels is extremely unusual. It looks like they are causing occlusions.”  

By occluding flow through individual capillaries, these large cells could cause ischemic alteration in a distinct pattern, potentially resulting in an atypical form of neurologic impairment, the authors suggest.

“This might alter the hemodynamics and put pressure on other vessels, possibly contributing to the increased risk of stroke that has been reported in COVID-19,” Dr. Nauen said. None of the samples he examined came from patients with COVID-19 who had had a stroke, he reported.

Other than the presence of megakaryocytes in the capillaries, the brain looked normal, he said. He has now examined samples from 15 brains of patients who had COVID-19 and megakaryocytes have been found in the brain capillaries in five cases.
 

New neurologic complication

Classic encephalitis found with other viruses has not been reported in brain post-mortem examinations from patients who had COVID-19, Dr. Nauen noted. “The cognitive issues such as grogginess associated with COVID-19 would indicate problems with the cortex but that hasn’t been documented. This occlusion of a multitude of tiny vessels by megalokaryocytes may offer some explanation of the cognitive issues. This is a new kind of vascular insult seen on pathology, and suggests a new kind of neurologic complication,” he added.

The big question is what these megakaryocytes are doing in the brain.

“Megakaryocytes are bone marrow cells. They are not immune cells. Their job is to produce platelets to help the blood clot. They are not normally found outside the bone marrow, but they have been reported in other organs in COVID-19 patients.

“But the big puzzle associated with finding them in the brain is how they get through the very fine network of blood vessels in the lungs. The geometry just doesn’t work. We don’t know which part of the COVID inflammatory response makes this happen,” said Dr. Nauen.

The authors suggest one possibility is that altered endothelial or other signaling is recruiting megakaryocytes into the circulation and somehow permitting them to pass through the lungs.

“We need to try and understand if there is anything distinctive about these megakaryocytes – which proteins are they expressing that may explain why they are behaving in such an unusual way,” said Dr. Nauen.

Noting that many patients with severe COVID-19 have problems with clotting, and megakaryocytes are part of the clotting system, he speculated that some sort of aberrant message is being sent to these cells.

“It is notable that we found megakaryocytes in cortical capillaries in 33% of cases examined. Because the standard brain autopsy sections taken sampled at random [are] only a minute portion of the cortical volume, finding these cells suggests the total burden could be considerable,” the authors wrote.

Dr. Nauen added that to his knowledge, this is the first report of such observations, and the next step is to look for similar findings in larger sample sizes.

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

The long-term neurologic symptoms such as “brain fog” experienced by some patients with COVID-19 may be caused by a unique pathology – the occlusion of brain capillaries by large megakaryocyte cells, a new report suggests.

The authors report five separate post-mortem cases from patients who died with COVID-19 in which large cells resembling megakaryocytes were identified in cortical capillaries. Immunohistochemistry subsequently confirmed their megakaryocyte identity.

They point out that the finding is of interest as – to their knowledge – megakaryocytes have not been found in the brain before.

The observations are described in a research letter published online Feb. 12 in JAMA Neurology.
 

Bone marrow cells in the brain

Lead author David Nauen, MD, PhD, a neuropathologist from Johns Hopkins University, Baltimore, reported that he identified these cells in the first analysis of post-mortem brain tissue from a patient who had COVID-19.

“Some other viruses cause changes in the brain such as encephalopathy, and as neurologic symptoms are often reported in COVID-19, I was curious to see if similar effects were seen in brain post-mortem samples from patients who had died with the infection,” Dr. Nauen said.

On his first analysis of the brain tissue of a patient who had COVID-19, Dr. Nauen saw no evidence of viral encephalitis, but he observed some “unusually large” cells in the brain capillaries.

“I was taken aback; I couldn’t figure out what they were. Then I realized these cells were megakaryocytes from the bone marrow. I have never seen these cells in the brain before. I asked several colleagues and none of them had either. After extensive literature searches, I could find no evidence of megakaryocytes being in the brain,” Dr. Nauen noted.

Megakaryocytes, he explained, are “very large cells, and the brain capillaries are very small – just large enough to let red blood cells and lymphocytes pass through. To see these very large cells in such vessels is extremely unusual. It looks like they are causing occlusions.”  

By occluding flow through individual capillaries, these large cells could cause ischemic alteration in a distinct pattern, potentially resulting in an atypical form of neurologic impairment, the authors suggest.

“This might alter the hemodynamics and put pressure on other vessels, possibly contributing to the increased risk of stroke that has been reported in COVID-19,” Dr. Nauen said. None of the samples he examined came from patients with COVID-19 who had had a stroke, he reported.

Other than the presence of megakaryocytes in the capillaries, the brain looked normal, he said. He has now examined samples from 15 brains of patients who had COVID-19 and megakaryocytes have been found in the brain capillaries in five cases.
 

New neurologic complication

Classic encephalitis found with other viruses has not been reported in brain post-mortem examinations from patients who had COVID-19, Dr. Nauen noted. “The cognitive issues such as grogginess associated with COVID-19 would indicate problems with the cortex but that hasn’t been documented. This occlusion of a multitude of tiny vessels by megalokaryocytes may offer some explanation of the cognitive issues. This is a new kind of vascular insult seen on pathology, and suggests a new kind of neurologic complication,” he added.

The big question is what these megakaryocytes are doing in the brain.

“Megakaryocytes are bone marrow cells. They are not immune cells. Their job is to produce platelets to help the blood clot. They are not normally found outside the bone marrow, but they have been reported in other organs in COVID-19 patients.

“But the big puzzle associated with finding them in the brain is how they get through the very fine network of blood vessels in the lungs. The geometry just doesn’t work. We don’t know which part of the COVID inflammatory response makes this happen,” said Dr. Nauen.

The authors suggest one possibility is that altered endothelial or other signaling is recruiting megakaryocytes into the circulation and somehow permitting them to pass through the lungs.

“We need to try and understand if there is anything distinctive about these megakaryocytes – which proteins are they expressing that may explain why they are behaving in such an unusual way,” said Dr. Nauen.

Noting that many patients with severe COVID-19 have problems with clotting, and megakaryocytes are part of the clotting system, he speculated that some sort of aberrant message is being sent to these cells.

“It is notable that we found megakaryocytes in cortical capillaries in 33% of cases examined. Because the standard brain autopsy sections taken sampled at random [are] only a minute portion of the cortical volume, finding these cells suggests the total burden could be considerable,” the authors wrote.

Dr. Nauen added that to his knowledge, this is the first report of such observations, and the next step is to look for similar findings in larger sample sizes.

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

Patients with cluster headache face a double whammy: Physicians too often fail to recognize it, and their condition is among the most severe and debilitating among headache types. In fact, a new survey of patients with cluster headache shows that they rank the pain as worse than most other painful experiences in life, including childbirth, passing of kidney stones, and pancreatitis, among others.

The study’s comparison of cluster headaches to other common painful experiences can help nonsufferers relate to the experience, said Larry Schor, PhD, a coauthor of the paper. “Headache is a terrible word. Bee stings sting, burns burn. [A cluster headache] doesn’t ache. It’s a piercing intensity like you just can’t believe,” said Dr. Schor, professor of psychology at the University of West Georgia, Carrollton, and a cluster headache patient since he first experienced an attack at the age of 21.

The study was published in the January 2021 issue of Headache.

Ranking cluster headaches as worse than experiences such as childbirth or kidney stones is “kind of eye opening, and helps to describe the experience in terms that more people can relate to. I think it helps to share the experience of cluster headache more broadly, because we’re in a situation where cluster headache remains underfunded, and we don’t have enough treatments for it. I think one way to overcome that is to spread awareness of what this problem is, and the impact it has on human life,” said Rashmi Halker Singh, MD, associate professor of neurology at the Mayo Clinic in Scottsdale, Ariz., and deputy editor of Headache. She was not involved in the study.

Dr. Schor called for physicians to consider cluster headache an emergency, because of the severity of pain and also the potential for suicidality. Treatments remain comparatively sparse, but high-flow oxygen can help some patients, and intranasal or intravenous triptans can treat acute pain. In 2018, the Food and Drug Administration approved galcanezumab (Eli Lilly) for prevention of episodic cluster headaches.

But cluster headaches are often misdiagnosed. For many patients, it takes more than a year or even as long as 5 years to get an accurate diagnosis, according to Dr. Schor. Women may be particularly vulnerable to misdiagnosis, because migraines are more common in women. It doesn’t help that many neurologists are taught that cluster headache is primarily a male disease. “Because that idea is so ingrained, I think a lot of women who have cluster headache are probably missed and told they have migraine instead. There are a lot of women who have cluster headache, and that gender difference might not be as big a difference as we were initially taught. We need to do a better job of recognizing cluster headache to better understand what the true prevalence is,” said Dr. Halker Singh.

She noted that patients with side-locked headache should be evaluated for cluster headache, and asked how long the pain lasts in the absence of medication. “Also ask about the presence of cranial autonomic symptoms, and if they occur in the context of headache pain, and if they are side-locked to the side of the headache. Those are important questions that can tease out cluster headache from other conditions,” said Dr. Halker Singh.

For the survey, the researchers asked 1,604 patients with cluster headache patients to rate pain on a scale of 1 to 10. Cluster headache ranked highest at 9.7, then labor pain (7.2), pancreatitis (7.0), and nephrolithiasis (6.9). Cluster headache pain was ranked at 10.0 by 72.1% of respondents. Those reporting maximal pain or were more likely to have cranial autonomic features in comparison with patients who reported less pain, including conjunctival injection or lacrimation (91% versus 85%), eyelid edema (77% versus 66%), forehead/facial sweating (60% versus 49%), fullness in the ear (47% versus 35%), and miosis or ptosis (85% versus 75%). They had more frequent attacks (4.0 versus 3.5 per day), higher Hopelessness Depression Symptom Questionnaire scores (24.5 versus 21.1), and reduced effectiveness of calcium channel blockers (2.2 versus 2.5 on a 5-point Likert scale). They were more often female (34% versus 24%). (P < .001 for all).

The study received funding from Autonomic Technologies and Cluster Busters. Dr. Schor and Dr. Halker Singh had no relevant financial disclosures.

Patients with cluster headache face a double whammy: Physicians too often fail to recognize it, and their condition is among the most severe and debilitating among headache types. In fact, a new survey of patients with cluster headache shows that they rank the pain as worse than most other painful experiences in life, including childbirth, passing of kidney stones, and pancreatitis, among others.

The study’s comparison of cluster headaches to other common painful experiences can help nonsufferers relate to the experience, said Larry Schor, PhD, a coauthor of the paper. “Headache is a terrible word. Bee stings sting, burns burn. [A cluster headache] doesn’t ache. It’s a piercing intensity like you just can’t believe,” said Dr. Schor, professor of psychology at the University of West Georgia, Carrollton, and a cluster headache patient since he first experienced an attack at the age of 21.

The study was published in the January 2021 issue of Headache.

Ranking cluster headaches as worse than experiences such as childbirth or kidney stones is “kind of eye opening, and helps to describe the experience in terms that more people can relate to. I think it helps to share the experience of cluster headache more broadly, because we’re in a situation where cluster headache remains underfunded, and we don’t have enough treatments for it. I think one way to overcome that is to spread awareness of what this problem is, and the impact it has on human life,” said Rashmi Halker Singh, MD, associate professor of neurology at the Mayo Clinic in Scottsdale, Ariz., and deputy editor of Headache. She was not involved in the study.

Dr. Schor called for physicians to consider cluster headache an emergency, because of the severity of pain and also the potential for suicidality. Treatments remain comparatively sparse, but high-flow oxygen can help some patients, and intranasal or intravenous triptans can treat acute pain. In 2018, the Food and Drug Administration approved galcanezumab (Eli Lilly) for prevention of episodic cluster headaches.

But cluster headaches are often misdiagnosed. For many patients, it takes more than a year or even as long as 5 years to get an accurate diagnosis, according to Dr. Schor. Women may be particularly vulnerable to misdiagnosis, because migraines are more common in women. It doesn’t help that many neurologists are taught that cluster headache is primarily a male disease. “Because that idea is so ingrained, I think a lot of women who have cluster headache are probably missed and told they have migraine instead. There are a lot of women who have cluster headache, and that gender difference might not be as big a difference as we were initially taught. We need to do a better job of recognizing cluster headache to better understand what the true prevalence is,” said Dr. Halker Singh.

She noted that patients with side-locked headache should be evaluated for cluster headache, and asked how long the pain lasts in the absence of medication. “Also ask about the presence of cranial autonomic symptoms, and if they occur in the context of headache pain, and if they are side-locked to the side of the headache. Those are important questions that can tease out cluster headache from other conditions,” said Dr. Halker Singh.

For the survey, the researchers asked 1,604 patients with cluster headache patients to rate pain on a scale of 1 to 10. Cluster headache ranked highest at 9.7, then labor pain (7.2), pancreatitis (7.0), and nephrolithiasis (6.9). Cluster headache pain was ranked at 10.0 by 72.1% of respondents. Those reporting maximal pain or were more likely to have cranial autonomic features in comparison with patients who reported less pain, including conjunctival injection or lacrimation (91% versus 85%), eyelid edema (77% versus 66%), forehead/facial sweating (60% versus 49%), fullness in the ear (47% versus 35%), and miosis or ptosis (85% versus 75%). They had more frequent attacks (4.0 versus 3.5 per day), higher Hopelessness Depression Symptom Questionnaire scores (24.5 versus 21.1), and reduced effectiveness of calcium channel blockers (2.2 versus 2.5 on a 5-point Likert scale). They were more often female (34% versus 24%). (P < .001 for all).

The study received funding from Autonomic Technologies and Cluster Busters. Dr. Schor and Dr. Halker Singh had no relevant financial disclosures.

Patients with cluster headache face a double whammy: Physicians too often fail to recognize it, and their condition is among the most severe and debilitating among headache types. In fact, a new survey of patients with cluster headache shows that they rank the pain as worse than most other painful experiences in life, including childbirth, passing of kidney stones, and pancreatitis, among others.

The study’s comparison of cluster headaches to other common painful experiences can help nonsufferers relate to the experience, said Larry Schor, PhD, a coauthor of the paper. “Headache is a terrible word. Bee stings sting, burns burn. [A cluster headache] doesn’t ache. It’s a piercing intensity like you just can’t believe,” said Dr. Schor, professor of psychology at the University of West Georgia, Carrollton, and a cluster headache patient since he first experienced an attack at the age of 21.

The study was published in the January 2021 issue of Headache.

Ranking cluster headaches as worse than experiences such as childbirth or kidney stones is “kind of eye opening, and helps to describe the experience in terms that more people can relate to. I think it helps to share the experience of cluster headache more broadly, because we’re in a situation where cluster headache remains underfunded, and we don’t have enough treatments for it. I think one way to overcome that is to spread awareness of what this problem is, and the impact it has on human life,” said Rashmi Halker Singh, MD, associate professor of neurology at the Mayo Clinic in Scottsdale, Ariz., and deputy editor of Headache. She was not involved in the study.

Dr. Schor called for physicians to consider cluster headache an emergency, because of the severity of pain and also the potential for suicidality. Treatments remain comparatively sparse, but high-flow oxygen can help some patients, and intranasal or intravenous triptans can treat acute pain. In 2018, the Food and Drug Administration approved galcanezumab (Eli Lilly) for prevention of episodic cluster headaches.

But cluster headaches are often misdiagnosed. For many patients, it takes more than a year or even as long as 5 years to get an accurate diagnosis, according to Dr. Schor. Women may be particularly vulnerable to misdiagnosis, because migraines are more common in women. It doesn’t help that many neurologists are taught that cluster headache is primarily a male disease. “Because that idea is so ingrained, I think a lot of women who have cluster headache are probably missed and told they have migraine instead. There are a lot of women who have cluster headache, and that gender difference might not be as big a difference as we were initially taught. We need to do a better job of recognizing cluster headache to better understand what the true prevalence is,” said Dr. Halker Singh.

She noted that patients with side-locked headache should be evaluated for cluster headache, and asked how long the pain lasts in the absence of medication. “Also ask about the presence of cranial autonomic symptoms, and if they occur in the context of headache pain, and if they are side-locked to the side of the headache. Those are important questions that can tease out cluster headache from other conditions,” said Dr. Halker Singh.

For the survey, the researchers asked 1,604 patients with cluster headache patients to rate pain on a scale of 1 to 10. Cluster headache ranked highest at 9.7, then labor pain (7.2), pancreatitis (7.0), and nephrolithiasis (6.9). Cluster headache pain was ranked at 10.0 by 72.1% of respondents. Those reporting maximal pain or were more likely to have cranial autonomic features in comparison with patients who reported less pain, including conjunctival injection or lacrimation (91% versus 85%), eyelid edema (77% versus 66%), forehead/facial sweating (60% versus 49%), fullness in the ear (47% versus 35%), and miosis or ptosis (85% versus 75%). They had more frequent attacks (4.0 versus 3.5 per day), higher Hopelessness Depression Symptom Questionnaire scores (24.5 versus 21.1), and reduced effectiveness of calcium channel blockers (2.2 versus 2.5 on a 5-point Likert scale). They were more often female (34% versus 24%). (P < .001 for all).

The study received funding from Autonomic Technologies and Cluster Busters. Dr. Schor and Dr. Halker Singh had no relevant financial disclosures.

Certain drugs currently used to treat benign prostatic hyperplasia (BPH) may provide neuroprotection and delay or prevent the onset of Parkinson’s disease, new research suggests. Treatment of BPH with terazosin (Hytrin), doxazosin (Cardura), or alfuzosin (Uroxatral), all of which enhance glycolysis, was associated with a lower risk of developing Parkinson’s disease than patients taking a drug used for the same indication, tamsulosin (Flomax), which does not affect glycolysis.

“If giving someone terazosin or similar medications truly reduces their risk of disease, these results could have significant clinical implications for neurologists,” said lead author Jacob E. Simmering, PhD, assistant professor of internal medicine at the University of Iowa, Iowa City.

There are few reliable neuroprotective treatments for Parkinson’s disease, he said. “We can manage some of the symptoms, but we can’t stop it from progressing. If a randomized trial finds the same result, this will provide a new option to slow progression of Parkinson’s disease.”

The pathogenesis of Parkinson’s disease is heterogeneous, however, and not all patients may benefit from glycolysis-enhancing drugs, the investigators noted. Future research will be needed to identify potential candidates for this treatment, and clarify the effects of these drugs, they wrote.

The findings were published online Feb. 1, 2021, in JAMA Neurology.
 

Time-dependent effects

The major risk factor for Parkinson’s disease is age, which is associated with impaired energy metabolism. Glycolysis is decreased among patients with Parkinson’s disease, yet impaired energy metabolism has not been investigated widely as a pathogenic factor in the disease, the authors wrote.

Studies have indicated that terazosin increases the activity of an enzyme important in glycolysis. Doxazosin and alfuzosin have a similar mechanism of action and enhance energy metabolism. Tamsulosin, a structurally unrelated drug, has the same mechanism of action as the other three drugs, but does not enhance energy metabolism.

In this report, the researchers investigated the hypothesis that patients who received therapy with terazosin, doxazosin, or alfuzosin would have a lower risk of developing Parkinson’s disease than patients receiving tamsulosin. To do that, they used health care utilization data from Denmark and the United States, including the Danish National Prescription Registry, the Danish National Patient Registry, the Danish Civil Registration System, and the Truven Health Analytics MarketScan database.

The investigators searched the records for patients who filled prescriptions for any of the four drugs of interest. They excluded any patients who developed Parkinson’s disease within 1 year of starting medication. Because use of these drugs is rare among women, they included only men in their analysis.

They looked at patient outcomes beginning at 1 year after the initiation of treatment. They also required patients to fill at least two prescriptions before the beginning of follow-up. Patients who switched from tamsulosin to any of the other drugs, or vice versa, were excluded from analysis.

The investigators used propensity-score matching to ensure that patients in the tamsulosin and terazosin/doxazosin/alfuzosin groups were similar in terms of their other potential risk factors. The primary outcome was the development of Parkinson’s disease.

They identified 52,365 propensity score–matched pairs in the Danish registries and 94,883 pairs in the Truven database. The mean age was 67.9 years in the Danish registries and 63.8 years in the Truven database, and follow-up was approximately 5 years and 3 years respectively. Baseline covariates were well balanced between cohorts.

Among Danish patients, those who took terazosin, doxazosin, or alfuzosin had a lower risk of developing Parkinson’s disease versus those who took tamsulosin (hazard ratio, 0.88). Similarly, patients in the Truven database who took terazosin, doxazosin, or alfuzosin had a lower risk of developing Parkinson’s disease than those who took tamsulosin (HR, 0.63).

In both cohorts, the risk for Parkinson’s disease among patients receiving terazosin, doxazosin, or alfuzosin, compared with those receiving tamsulosin, decreased with increasing numbers of prescriptions filled. Long-term treatment with any of the three glycolysis-enhancing drugs was associated with greater risk reduction in the Danish (HR, 0.79) and Truven (HR, 0.46) cohorts versus tamsulosin.

Differences in case definitions, which may reflect how Parkinson’s disease was managed, complicate comparisons between the Danish and Truven cohorts, said Dr. Simmering. Another challenge is the source of the data. “The Truven data set was derived from insurance claims from people with private insurance or Medicare supplemental plans,” he said. “This group is quite large but may not be representative of everyone in the United States. We would also only be able to follow people while they were on one insurance plan. If they switched coverage to a company that doesn’t contribute data, we would lose them.”

The Danish database, however, includes all residents of Denmark. Only people who left the country were lost to follow-up.

The results support the hypothesis that increasing energy in cells slows disease progression, Dr. Simmering added. “There are a few conditions, mostly REM sleep disorders, that are associated with future diagnosis of Parkinson’s disease. Right now, we don’t have anything to offer people at elevated risk of Parkinson’s disease that might prevent the disease. If a controlled trial finds that terazosin slows or prevents Parkinson’s disease, we would have something truly protective to offer these patients.”
 

Biomarker needed

Commenting on the results, Alberto J. Espay, MD, MSc, professor of neurology at the University of Cincinnati Academic Health Center, was cautious. “These findings are of unclear applicability to any particular patient without a biomarker for a deficit of glycolysis that these drugs are presumed to affect,” Dr. Espay said. “Hence, there is no feasible or warranted change in practice as a result of this study.”

Pathogenic mechanisms are heterogeneous among patients with Parkinson’s disease, Dr. Espay added. “We will need to understand who among the large biological universe of Parkinson’s patients may have impaired energy metabolism as a pathogenic mechanism to be selected for a future clinical trial evaluating terazosin, doxazosin, or alfuzosin as a potential disease-modifying intervention.”

Parkinson’s disease is not one disease, but a group of disorders with unique biological abnormalities, said Dr. Espay. “We know so much about ‘Parkinson’s disease’ and next to nothing about the biology of individuals with Parkinson’s disease.”

This situation has enabled the development of symptomatic treatments, such as dopaminergic therapies, but failed to yield disease-modifying treatments, he said.

The University of Iowa contributed funds for this study. Dr. Simmering has received pilot funding from the University of Iowa Institute for Clinical and Translational Science. He had no conflicts of interest to disclose. Dr. Espay disclosed no relevant financial relationships.  

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

Certain drugs currently used to treat benign prostatic hyperplasia (BPH) may provide neuroprotection and delay or prevent the onset of Parkinson’s disease, new research suggests. Treatment of BPH with terazosin (Hytrin), doxazosin (Cardura), or alfuzosin (Uroxatral), all of which enhance glycolysis, was associated with a lower risk of developing Parkinson’s disease than patients taking a drug used for the same indication, tamsulosin (Flomax), which does not affect glycolysis.

“If giving someone terazosin or similar medications truly reduces their risk of disease, these results could have significant clinical implications for neurologists,” said lead author Jacob E. Simmering, PhD, assistant professor of internal medicine at the University of Iowa, Iowa City.

There are few reliable neuroprotective treatments for Parkinson’s disease, he said. “We can manage some of the symptoms, but we can’t stop it from progressing. If a randomized trial finds the same result, this will provide a new option to slow progression of Parkinson’s disease.”

The pathogenesis of Parkinson’s disease is heterogeneous, however, and not all patients may benefit from glycolysis-enhancing drugs, the investigators noted. Future research will be needed to identify potential candidates for this treatment, and clarify the effects of these drugs, they wrote.

The findings were published online Feb. 1, 2021, in JAMA Neurology.
 

Time-dependent effects

The major risk factor for Parkinson’s disease is age, which is associated with impaired energy metabolism. Glycolysis is decreased among patients with Parkinson’s disease, yet impaired energy metabolism has not been investigated widely as a pathogenic factor in the disease, the authors wrote.

Studies have indicated that terazosin increases the activity of an enzyme important in glycolysis. Doxazosin and alfuzosin have a similar mechanism of action and enhance energy metabolism. Tamsulosin, a structurally unrelated drug, has the same mechanism of action as the other three drugs, but does not enhance energy metabolism.

In this report, the researchers investigated the hypothesis that patients who received therapy with terazosin, doxazosin, or alfuzosin would have a lower risk of developing Parkinson’s disease than patients receiving tamsulosin. To do that, they used health care utilization data from Denmark and the United States, including the Danish National Prescription Registry, the Danish National Patient Registry, the Danish Civil Registration System, and the Truven Health Analytics MarketScan database.

The investigators searched the records for patients who filled prescriptions for any of the four drugs of interest. They excluded any patients who developed Parkinson’s disease within 1 year of starting medication. Because use of these drugs is rare among women, they included only men in their analysis.

They looked at patient outcomes beginning at 1 year after the initiation of treatment. They also required patients to fill at least two prescriptions before the beginning of follow-up. Patients who switched from tamsulosin to any of the other drugs, or vice versa, were excluded from analysis.

The investigators used propensity-score matching to ensure that patients in the tamsulosin and terazosin/doxazosin/alfuzosin groups were similar in terms of their other potential risk factors. The primary outcome was the development of Parkinson’s disease.

They identified 52,365 propensity score–matched pairs in the Danish registries and 94,883 pairs in the Truven database. The mean age was 67.9 years in the Danish registries and 63.8 years in the Truven database, and follow-up was approximately 5 years and 3 years respectively. Baseline covariates were well balanced between cohorts.

Among Danish patients, those who took terazosin, doxazosin, or alfuzosin had a lower risk of developing Parkinson’s disease versus those who took tamsulosin (hazard ratio, 0.88). Similarly, patients in the Truven database who took terazosin, doxazosin, or alfuzosin had a lower risk of developing Parkinson’s disease than those who took tamsulosin (HR, 0.63).

In both cohorts, the risk for Parkinson’s disease among patients receiving terazosin, doxazosin, or alfuzosin, compared with those receiving tamsulosin, decreased with increasing numbers of prescriptions filled. Long-term treatment with any of the three glycolysis-enhancing drugs was associated with greater risk reduction in the Danish (HR, 0.79) and Truven (HR, 0.46) cohorts versus tamsulosin.

Differences in case definitions, which may reflect how Parkinson’s disease was managed, complicate comparisons between the Danish and Truven cohorts, said Dr. Simmering. Another challenge is the source of the data. “The Truven data set was derived from insurance claims from people with private insurance or Medicare supplemental plans,” he said. “This group is quite large but may not be representative of everyone in the United States. We would also only be able to follow people while they were on one insurance plan. If they switched coverage to a company that doesn’t contribute data, we would lose them.”

The Danish database, however, includes all residents of Denmark. Only people who left the country were lost to follow-up.

The results support the hypothesis that increasing energy in cells slows disease progression, Dr. Simmering added. “There are a few conditions, mostly REM sleep disorders, that are associated with future diagnosis of Parkinson’s disease. Right now, we don’t have anything to offer people at elevated risk of Parkinson’s disease that might prevent the disease. If a controlled trial finds that terazosin slows or prevents Parkinson’s disease, we would have something truly protective to offer these patients.”
 

Biomarker needed

Commenting on the results, Alberto J. Espay, MD, MSc, professor of neurology at the University of Cincinnati Academic Health Center, was cautious. “These findings are of unclear applicability to any particular patient without a biomarker for a deficit of glycolysis that these drugs are presumed to affect,” Dr. Espay said. “Hence, there is no feasible or warranted change in practice as a result of this study.”

Pathogenic mechanisms are heterogeneous among patients with Parkinson’s disease, Dr. Espay added. “We will need to understand who among the large biological universe of Parkinson’s patients may have impaired energy metabolism as a pathogenic mechanism to be selected for a future clinical trial evaluating terazosin, doxazosin, or alfuzosin as a potential disease-modifying intervention.”

Parkinson’s disease is not one disease, but a group of disorders with unique biological abnormalities, said Dr. Espay. “We know so much about ‘Parkinson’s disease’ and next to nothing about the biology of individuals with Parkinson’s disease.”

This situation has enabled the development of symptomatic treatments, such as dopaminergic therapies, but failed to yield disease-modifying treatments, he said.

The University of Iowa contributed funds for this study. Dr. Simmering has received pilot funding from the University of Iowa Institute for Clinical and Translational Science. He had no conflicts of interest to disclose. Dr. Espay disclosed no relevant financial relationships.  

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

Certain drugs currently used to treat benign prostatic hyperplasia (BPH) may provide neuroprotection and delay or prevent the onset of Parkinson’s disease, new research suggests. Treatment of BPH with terazosin (Hytrin), doxazosin (Cardura), or alfuzosin (Uroxatral), all of which enhance glycolysis, was associated with a lower risk of developing Parkinson’s disease than patients taking a drug used for the same indication, tamsulosin (Flomax), which does not affect glycolysis.

“If giving someone terazosin or similar medications truly reduces their risk of disease, these results could have significant clinical implications for neurologists,” said lead author Jacob E. Simmering, PhD, assistant professor of internal medicine at the University of Iowa, Iowa City.

There are few reliable neuroprotective treatments for Parkinson’s disease, he said. “We can manage some of the symptoms, but we can’t stop it from progressing. If a randomized trial finds the same result, this will provide a new option to slow progression of Parkinson’s disease.”

The pathogenesis of Parkinson’s disease is heterogeneous, however, and not all patients may benefit from glycolysis-enhancing drugs, the investigators noted. Future research will be needed to identify potential candidates for this treatment, and clarify the effects of these drugs, they wrote.

The findings were published online Feb. 1, 2021, in JAMA Neurology.
 

Time-dependent effects

The major risk factor for Parkinson’s disease is age, which is associated with impaired energy metabolism. Glycolysis is decreased among patients with Parkinson’s disease, yet impaired energy metabolism has not been investigated widely as a pathogenic factor in the disease, the authors wrote.

Studies have indicated that terazosin increases the activity of an enzyme important in glycolysis. Doxazosin and alfuzosin have a similar mechanism of action and enhance energy metabolism. Tamsulosin, a structurally unrelated drug, has the same mechanism of action as the other three drugs, but does not enhance energy metabolism.

In this report, the researchers investigated the hypothesis that patients who received therapy with terazosin, doxazosin, or alfuzosin would have a lower risk of developing Parkinson’s disease than patients receiving tamsulosin. To do that, they used health care utilization data from Denmark and the United States, including the Danish National Prescription Registry, the Danish National Patient Registry, the Danish Civil Registration System, and the Truven Health Analytics MarketScan database.

The investigators searched the records for patients who filled prescriptions for any of the four drugs of interest. They excluded any patients who developed Parkinson’s disease within 1 year of starting medication. Because use of these drugs is rare among women, they included only men in their analysis.

They looked at patient outcomes beginning at 1 year after the initiation of treatment. They also required patients to fill at least two prescriptions before the beginning of follow-up. Patients who switched from tamsulosin to any of the other drugs, or vice versa, were excluded from analysis.

The investigators used propensity-score matching to ensure that patients in the tamsulosin and terazosin/doxazosin/alfuzosin groups were similar in terms of their other potential risk factors. The primary outcome was the development of Parkinson’s disease.

They identified 52,365 propensity score–matched pairs in the Danish registries and 94,883 pairs in the Truven database. The mean age was 67.9 years in the Danish registries and 63.8 years in the Truven database, and follow-up was approximately 5 years and 3 years respectively. Baseline covariates were well balanced between cohorts.

Among Danish patients, those who took terazosin, doxazosin, or alfuzosin had a lower risk of developing Parkinson’s disease versus those who took tamsulosin (hazard ratio, 0.88). Similarly, patients in the Truven database who took terazosin, doxazosin, or alfuzosin had a lower risk of developing Parkinson’s disease than those who took tamsulosin (HR, 0.63).

In both cohorts, the risk for Parkinson’s disease among patients receiving terazosin, doxazosin, or alfuzosin, compared with those receiving tamsulosin, decreased with increasing numbers of prescriptions filled. Long-term treatment with any of the three glycolysis-enhancing drugs was associated with greater risk reduction in the Danish (HR, 0.79) and Truven (HR, 0.46) cohorts versus tamsulosin.

Differences in case definitions, which may reflect how Parkinson’s disease was managed, complicate comparisons between the Danish and Truven cohorts, said Dr. Simmering. Another challenge is the source of the data. “The Truven data set was derived from insurance claims from people with private insurance or Medicare supplemental plans,” he said. “This group is quite large but may not be representative of everyone in the United States. We would also only be able to follow people while they were on one insurance plan. If they switched coverage to a company that doesn’t contribute data, we would lose them.”

The Danish database, however, includes all residents of Denmark. Only people who left the country were lost to follow-up.

The results support the hypothesis that increasing energy in cells slows disease progression, Dr. Simmering added. “There are a few conditions, mostly REM sleep disorders, that are associated with future diagnosis of Parkinson’s disease. Right now, we don’t have anything to offer people at elevated risk of Parkinson’s disease that might prevent the disease. If a controlled trial finds that terazosin slows or prevents Parkinson’s disease, we would have something truly protective to offer these patients.”
 

Biomarker needed

Commenting on the results, Alberto J. Espay, MD, MSc, professor of neurology at the University of Cincinnati Academic Health Center, was cautious. “These findings are of unclear applicability to any particular patient without a biomarker for a deficit of glycolysis that these drugs are presumed to affect,” Dr. Espay said. “Hence, there is no feasible or warranted change in practice as a result of this study.”

Pathogenic mechanisms are heterogeneous among patients with Parkinson’s disease, Dr. Espay added. “We will need to understand who among the large biological universe of Parkinson’s patients may have impaired energy metabolism as a pathogenic mechanism to be selected for a future clinical trial evaluating terazosin, doxazosin, or alfuzosin as a potential disease-modifying intervention.”

Parkinson’s disease is not one disease, but a group of disorders with unique biological abnormalities, said Dr. Espay. “We know so much about ‘Parkinson’s disease’ and next to nothing about the biology of individuals with Parkinson’s disease.”

This situation has enabled the development of symptomatic treatments, such as dopaminergic therapies, but failed to yield disease-modifying treatments, he said.

The University of Iowa contributed funds for this study. Dr. Simmering has received pilot funding from the University of Iowa Institute for Clinical and Translational Science. He had no conflicts of interest to disclose. Dr. Espay disclosed no relevant financial relationships.  

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

Among patients with migraine who use prescription medications, the increasing use of prescription opioids is associated with chronic migraine, more severe disability, and anxiety and depression, according to an analysis published in the January issue of Headache . The use of prescription opioids also is associated with treatment-related variables such as poor acute treatment optimization and treatment in a pain clinic. The results indicate the continued need to educate patients and clinicians about the potential risks of opioids for migraineurs, according to the researchers.

A review of MAST data

Dr. Lipton and colleagues set out to identify the variables associated with the frequency of opioid use in people with migraine. Among the variables that they sought to examine were demographic characteristics, comorbidities, headache characteristics, medication use, and patterns of health care use. Dr. Lipton’s group hypothesized that migraine-related severity and burden would increase with increasing frequency of opioid use.

To conduct their research, the investigators examined data from the MAST study, a nationwide sample of American adults with migraine. They focused specifically on participants who reported receiving prescription acute medications. Participants eligible for this analysis reported 3 or more headache days in the previous 3 months and at least 1 monthly headache day in the previous month. In all, 15,133 participants met these criteria.

Dr. Lipton and colleagues categorized participants into four groups based on their frequency of opioid use. The groups had no opioid use, 3 or fewer monthly days of opioid use, 4 to 9 monthly days of opioid use, and 10 or more days of monthly opioid use. The last category is consistent with the International Classification of Headache Disorders-3 criteria for overuse of opioids in migraine.

At baseline, MAST participants provided information about variables such as gender, age, marital status, smoking status, education, and income. Participants also reported how many times in the previous 6 months they had visited a primary care doctor, a neurologist, a headache specialist, or a pain specialist. Dr. Lipton’s group calculated monthly headache days using the number of days during the previous 3 months affected by headache. The Migraine Disability Assessment (MIDAS) questionnaire was used to measure headache-related disability. The four-item Patient Health Questionnaire (PHQ-4) was used to screen for anxiety and depression, and the Migraine Treatment Optimization Questionnaire (mTOQ-4) evaluated participants’ treatment optimization.
 

Men predominated among opioid users

The investigators included 4,701 MAST participants in their analysis. The population’s mean age was 45 years, and 71.6% of participants were women. Of the entire sample, 67.5% reported no opioid use, and 32.5% reported opioid use. Of the total study population, 18.7% of patients took opioids 3 or fewer days per month, 6.5% took opioids 4 to 9 days per month, and 7.3% took opioids on 10 or more days per month.

Opioid users did not differ from nonusers on race or marital status. Men were overrepresented among all groups of opioid users, however. In addition, opioid use was more prevalent among participants with fewer than 4 years of college education (34.9%) than among participants with 4 or more years of college (30.8%). The proportion of participants with fewer than 4 years of college increased with increasing monthly opioid use. Furthermore, opioid use increased with decreasing household income. As opioid use increased, rates of employment decreased. Approximately 33% of the entire sample were obese, and the proportion of obese participants increased with increasing days per month of opioid use.

The most frequent setting during the previous 6 months for participants seeking care was primary care (49.7%). The next most frequent setting was neurology units (20.9%), pain clinics (8.3%), and headache clinics (7.7%). The prevalence of opioid use was 37.5% among participants with primary care visits, 37.3% among participants with neurologist visits, 43.0% among participants with headache clinic visits, and 53.5% with pain clinic visits.

About 15% of the population had chronic migraine. The prevalence of chronic migraine increased with increasing frequency of opioid use. About 49% of the sample had allodynia, and the prevalence of allodynia increased with increasing frequency of opioid use. Overall, disability was moderate to severe in 57.3% of participants. Participants who used opioids on 3 or fewer days per month had the lowest prevalence of moderate to severe disability (50.2%), and participants who used opioids on 10 or more days per month had the highest prevalence of moderate to severe disability (83.8%).

Approximately 21% of participants had anxiety or depression. The lowest prevalence of anxiety or depression was among participants who took opioids on 3 or fewer days per month (17.4%), and the highest prevalence was among participants who took opioids on 10 or more days per month (43.2%). About 39% of the population had very poor to poor treatment optimization. Among opioid nonusers, 35.6% had very poor to poor treatment optimization, and 59.4% of participants who used opioids on 10 or more days per month had very poor to poor treatment optimization.

Dr. Lipton and colleagues also examined the study population’s use of triptans. Overall, 51.5% of participants reported taking triptans. The prevalence of triptan use was highest among participants who did not use opioids (64.1%) and lowest among participants who used opioids on 3 or fewer days per month (20.5%). Triptan use increased as monthly days of opioid use increased.
 

Pain clinics and opioid prescription

“In the general population, women are more likely to receive opioids than men,” said Dr. Lipton. “This [finding] could reflect, in part, that women have more pain disorders than men and are more likely to seek medical care for pain than men.” In the current study, however, men with migraine were more likely to receive opioid prescriptions than were women with migraine. One potential explanation for this finding is that men with migraine are less likely to receive a migraine diagnosis, which might attenuate opioid prescribing, than women with migraine. “It may be that opioids are perceived to be serious drugs for serious pain, and that some physicians may be more likely to prescribe opioids to men because the disorder is taken more seriously in men than women,” said Dr. Lipton.

The observation that opioids were more likely to be prescribed for people treated in pain clinics “is consistent with my understanding of practice patterns,” he added. “Generally, neurologists strive to find effective acute treatment alternatives to opioids. The emergence of [drug classes known as] gepants and ditans provides a helpful set of alternatives to tritpans.”

Dr. Lipton and his colleagues plan further research into the treatment of migraineurs. “In a claims analysis, we showed that when people with migraine fail a triptan, they are most likely to get an opioid as their next drug,” he said. “Reasonable [clinicians] might disagree on the next step. The next step, in the absence of contraindications, could be a different oral triptan, a nonoral triptan, or a gepant or ditan. We are planning a randomized trial to probe this question.”
 

Why are opioids still being used?

The study’s reliance on patients’ self-report and its retrospective design are two of its weaknesses, said Alan M. Rapoport, MD, clinical professor of neurology at the University of California, Los Angeles, and editor-in-chief of Neurology Reviews. One strength, however, is that the stratified sampling methodology produced a study population that accurately reflects the demographic characteristics of the U.S. adult population, he added. Another strength is the investigators’ examination of opioid use by patient characteristics such as marital status, education, income, obesity, and smoking.

Given the harmful effects of opioids in migraine, it is hard to understand why as much as one-third of study participants using acute care medication for migraine were using opioids, said Dr. Rapoport. Using opioids for the acute treatment of migraine attacks often indicates inadequate treatment optimization, which leads to ongoing headache. As a consequence, patients may take more medication, which can increase headache frequency and lead to diagnoses of chronic migraine and medication overuse headache. Although the study found an association between the increased use of opioids and decreased household income and increased unemployment, smoking, and obesity, “it is not possible to assign causality to any of these associations, even though some would argue that decreased socioeconomic status was somehow related to more headache, disability, obesity, smoking, and unemployment,” he added.

“The paper suggests that future research should look at the risk factors for use of opioids and should determine if depression is a risk factor for or a consequence of opioid use,” said Dr. Rapoport. “Interventional studies designed to improve the acute care of migraine attacks might be able to reduce the use of opioids. I have not used opioids or butalbital-containing medication in my office for many years.”

This study was funded and sponsored by Dr. Reddy’s Laboratories group of companies, Princeton, N.J. Dr. Lipton has received grant support from the National Institutes of Health, the National Headache Foundation, and the Migraine Research Fund. He serves as a consultant, serves as an advisory board member, or has received honoraria from Alder, Allergan, American Headache Society, Autonomic Technologies, Biohaven, Dr. Reddy’s Laboratories, Eli Lilly, eNeura Therapeutics, Merck, Novartis, Pfizer, and Teva, Inc. He receives royalties from Wolff’s Headache, 8th Edition (New York: Oxford University Press, 2009) and holds stock options in eNeura Therapeutics and Biohaven.

SOURCE: Lipton RB, et al. Headache. https://doi.org/10.1111/head.14018. 2020;61(1):103-16.

Among patients with migraine who use prescription medications, the increasing use of prescription opioids is associated with chronic migraine, more severe disability, and anxiety and depression, according to an analysis published in the January issue of Headache . The use of prescription opioids also is associated with treatment-related variables such as poor acute treatment optimization and treatment in a pain clinic. The results indicate the continued need to educate patients and clinicians about the potential risks of opioids for migraineurs, according to the researchers.

A review of MAST data

Dr. Lipton and colleagues set out to identify the variables associated with the frequency of opioid use in people with migraine. Among the variables that they sought to examine were demographic characteristics, comorbidities, headache characteristics, medication use, and patterns of health care use. Dr. Lipton’s group hypothesized that migraine-related severity and burden would increase with increasing frequency of opioid use.

To conduct their research, the investigators examined data from the MAST study, a nationwide sample of American adults with migraine. They focused specifically on participants who reported receiving prescription acute medications. Participants eligible for this analysis reported 3 or more headache days in the previous 3 months and at least 1 monthly headache day in the previous month. In all, 15,133 participants met these criteria.

Dr. Lipton and colleagues categorized participants into four groups based on their frequency of opioid use. The groups had no opioid use, 3 or fewer monthly days of opioid use, 4 to 9 monthly days of opioid use, and 10 or more days of monthly opioid use. The last category is consistent with the International Classification of Headache Disorders-3 criteria for overuse of opioids in migraine.

At baseline, MAST participants provided information about variables such as gender, age, marital status, smoking status, education, and income. Participants also reported how many times in the previous 6 months they had visited a primary care doctor, a neurologist, a headache specialist, or a pain specialist. Dr. Lipton’s group calculated monthly headache days using the number of days during the previous 3 months affected by headache. The Migraine Disability Assessment (MIDAS) questionnaire was used to measure headache-related disability. The four-item Patient Health Questionnaire (PHQ-4) was used to screen for anxiety and depression, and the Migraine Treatment Optimization Questionnaire (mTOQ-4) evaluated participants’ treatment optimization.
 

Men predominated among opioid users

The investigators included 4,701 MAST participants in their analysis. The population’s mean age was 45 years, and 71.6% of participants were women. Of the entire sample, 67.5% reported no opioid use, and 32.5% reported opioid use. Of the total study population, 18.7% of patients took opioids 3 or fewer days per month, 6.5% took opioids 4 to 9 days per month, and 7.3% took opioids on 10 or more days per month.

Opioid users did not differ from nonusers on race or marital status. Men were overrepresented among all groups of opioid users, however. In addition, opioid use was more prevalent among participants with fewer than 4 years of college education (34.9%) than among participants with 4 or more years of college (30.8%). The proportion of participants with fewer than 4 years of college increased with increasing monthly opioid use. Furthermore, opioid use increased with decreasing household income. As opioid use increased, rates of employment decreased. Approximately 33% of the entire sample were obese, and the proportion of obese participants increased with increasing days per month of opioid use.

The most frequent setting during the previous 6 months for participants seeking care was primary care (49.7%). The next most frequent setting was neurology units (20.9%), pain clinics (8.3%), and headache clinics (7.7%). The prevalence of opioid use was 37.5% among participants with primary care visits, 37.3% among participants with neurologist visits, 43.0% among participants with headache clinic visits, and 53.5% with pain clinic visits.

About 15% of the population had chronic migraine. The prevalence of chronic migraine increased with increasing frequency of opioid use. About 49% of the sample had allodynia, and the prevalence of allodynia increased with increasing frequency of opioid use. Overall, disability was moderate to severe in 57.3% of participants. Participants who used opioids on 3 or fewer days per month had the lowest prevalence of moderate to severe disability (50.2%), and participants who used opioids on 10 or more days per month had the highest prevalence of moderate to severe disability (83.8%).

Approximately 21% of participants had anxiety or depression. The lowest prevalence of anxiety or depression was among participants who took opioids on 3 or fewer days per month (17.4%), and the highest prevalence was among participants who took opioids on 10 or more days per month (43.2%). About 39% of the population had very poor to poor treatment optimization. Among opioid nonusers, 35.6% had very poor to poor treatment optimization, and 59.4% of participants who used opioids on 10 or more days per month had very poor to poor treatment optimization.

Dr. Lipton and colleagues also examined the study population’s use of triptans. Overall, 51.5% of participants reported taking triptans. The prevalence of triptan use was highest among participants who did not use opioids (64.1%) and lowest among participants who used opioids on 3 or fewer days per month (20.5%). Triptan use increased as monthly days of opioid use increased.
 

Pain clinics and opioid prescription

“In the general population, women are more likely to receive opioids than men,” said Dr. Lipton. “This [finding] could reflect, in part, that women have more pain disorders than men and are more likely to seek medical care for pain than men.” In the current study, however, men with migraine were more likely to receive opioid prescriptions than were women with migraine. One potential explanation for this finding is that men with migraine are less likely to receive a migraine diagnosis, which might attenuate opioid prescribing, than women with migraine. “It may be that opioids are perceived to be serious drugs for serious pain, and that some physicians may be more likely to prescribe opioids to men because the disorder is taken more seriously in men than women,” said Dr. Lipton.

The observation that opioids were more likely to be prescribed for people treated in pain clinics “is consistent with my understanding of practice patterns,” he added. “Generally, neurologists strive to find effective acute treatment alternatives to opioids. The emergence of [drug classes known as] gepants and ditans provides a helpful set of alternatives to tritpans.”

Dr. Lipton and his colleagues plan further research into the treatment of migraineurs. “In a claims analysis, we showed that when people with migraine fail a triptan, they are most likely to get an opioid as their next drug,” he said. “Reasonable [clinicians] might disagree on the next step. The next step, in the absence of contraindications, could be a different oral triptan, a nonoral triptan, or a gepant or ditan. We are planning a randomized trial to probe this question.”
 

Why are opioids still being used?

The study’s reliance on patients’ self-report and its retrospective design are two of its weaknesses, said Alan M. Rapoport, MD, clinical professor of neurology at the University of California, Los Angeles, and editor-in-chief of Neurology Reviews. One strength, however, is that the stratified sampling methodology produced a study population that accurately reflects the demographic characteristics of the U.S. adult population, he added. Another strength is the investigators’ examination of opioid use by patient characteristics such as marital status, education, income, obesity, and smoking.

Given the harmful effects of opioids in migraine, it is hard to understand why as much as one-third of study participants using acute care medication for migraine were using opioids, said Dr. Rapoport. Using opioids for the acute treatment of migraine attacks often indicates inadequate treatment optimization, which leads to ongoing headache. As a consequence, patients may take more medication, which can increase headache frequency and lead to diagnoses of chronic migraine and medication overuse headache. Although the study found an association between the increased use of opioids and decreased household income and increased unemployment, smoking, and obesity, “it is not possible to assign causality to any of these associations, even though some would argue that decreased socioeconomic status was somehow related to more headache, disability, obesity, smoking, and unemployment,” he added.

“The paper suggests that future research should look at the risk factors for use of opioids and should determine if depression is a risk factor for or a consequence of opioid use,” said Dr. Rapoport. “Interventional studies designed to improve the acute care of migraine attacks might be able to reduce the use of opioids. I have not used opioids or butalbital-containing medication in my office for many years.”

This study was funded and sponsored by Dr. Reddy’s Laboratories group of companies, Princeton, N.J. Dr. Lipton has received grant support from the National Institutes of Health, the National Headache Foundation, and the Migraine Research Fund. He serves as a consultant, serves as an advisory board member, or has received honoraria from Alder, Allergan, American Headache Society, Autonomic Technologies, Biohaven, Dr. Reddy’s Laboratories, Eli Lilly, eNeura Therapeutics, Merck, Novartis, Pfizer, and Teva, Inc. He receives royalties from Wolff’s Headache, 8th Edition (New York: Oxford University Press, 2009) and holds stock options in eNeura Therapeutics and Biohaven.

SOURCE: Lipton RB, et al. Headache. https://doi.org/10.1111/head.14018. 2020;61(1):103-16.

Among patients with migraine who use prescription medications, the increasing use of prescription opioids is associated with chronic migraine, more severe disability, and anxiety and depression, according to an analysis published in the January issue of Headache . The use of prescription opioids also is associated with treatment-related variables such as poor acute treatment optimization and treatment in a pain clinic. The results indicate the continued need to educate patients and clinicians about the potential risks of opioids for migraineurs, according to the researchers.

A review of MAST data

Dr. Lipton and colleagues set out to identify the variables associated with the frequency of opioid use in people with migraine. Among the variables that they sought to examine were demographic characteristics, comorbidities, headache characteristics, medication use, and patterns of health care use. Dr. Lipton’s group hypothesized that migraine-related severity and burden would increase with increasing frequency of opioid use.

To conduct their research, the investigators examined data from the MAST study, a nationwide sample of American adults with migraine. They focused specifically on participants who reported receiving prescription acute medications. Participants eligible for this analysis reported 3 or more headache days in the previous 3 months and at least 1 monthly headache day in the previous month. In all, 15,133 participants met these criteria.

Dr. Lipton and colleagues categorized participants into four groups based on their frequency of opioid use. The groups had no opioid use, 3 or fewer monthly days of opioid use, 4 to 9 monthly days of opioid use, and 10 or more days of monthly opioid use. The last category is consistent with the International Classification of Headache Disorders-3 criteria for overuse of opioids in migraine.

At baseline, MAST participants provided information about variables such as gender, age, marital status, smoking status, education, and income. Participants also reported how many times in the previous 6 months they had visited a primary care doctor, a neurologist, a headache specialist, or a pain specialist. Dr. Lipton’s group calculated monthly headache days using the number of days during the previous 3 months affected by headache. The Migraine Disability Assessment (MIDAS) questionnaire was used to measure headache-related disability. The four-item Patient Health Questionnaire (PHQ-4) was used to screen for anxiety and depression, and the Migraine Treatment Optimization Questionnaire (mTOQ-4) evaluated participants’ treatment optimization.
 

Men predominated among opioid users

The investigators included 4,701 MAST participants in their analysis. The population’s mean age was 45 years, and 71.6% of participants were women. Of the entire sample, 67.5% reported no opioid use, and 32.5% reported opioid use. Of the total study population, 18.7% of patients took opioids 3 or fewer days per month, 6.5% took opioids 4 to 9 days per month, and 7.3% took opioids on 10 or more days per month.

Opioid users did not differ from nonusers on race or marital status. Men were overrepresented among all groups of opioid users, however. In addition, opioid use was more prevalent among participants with fewer than 4 years of college education (34.9%) than among participants with 4 or more years of college (30.8%). The proportion of participants with fewer than 4 years of college increased with increasing monthly opioid use. Furthermore, opioid use increased with decreasing household income. As opioid use increased, rates of employment decreased. Approximately 33% of the entire sample were obese, and the proportion of obese participants increased with increasing days per month of opioid use.

The most frequent setting during the previous 6 months for participants seeking care was primary care (49.7%). The next most frequent setting was neurology units (20.9%), pain clinics (8.3%), and headache clinics (7.7%). The prevalence of opioid use was 37.5% among participants with primary care visits, 37.3% among participants with neurologist visits, 43.0% among participants with headache clinic visits, and 53.5% with pain clinic visits.

About 15% of the population had chronic migraine. The prevalence of chronic migraine increased with increasing frequency of opioid use. About 49% of the sample had allodynia, and the prevalence of allodynia increased with increasing frequency of opioid use. Overall, disability was moderate to severe in 57.3% of participants. Participants who used opioids on 3 or fewer days per month had the lowest prevalence of moderate to severe disability (50.2%), and participants who used opioids on 10 or more days per month had the highest prevalence of moderate to severe disability (83.8%).

Approximately 21% of participants had anxiety or depression. The lowest prevalence of anxiety or depression was among participants who took opioids on 3 or fewer days per month (17.4%), and the highest prevalence was among participants who took opioids on 10 or more days per month (43.2%). About 39% of the population had very poor to poor treatment optimization. Among opioid nonusers, 35.6% had very poor to poor treatment optimization, and 59.4% of participants who used opioids on 10 or more days per month had very poor to poor treatment optimization.

Dr. Lipton and colleagues also examined the study population’s use of triptans. Overall, 51.5% of participants reported taking triptans. The prevalence of triptan use was highest among participants who did not use opioids (64.1%) and lowest among participants who used opioids on 3 or fewer days per month (20.5%). Triptan use increased as monthly days of opioid use increased.
 

Pain clinics and opioid prescription

“In the general population, women are more likely to receive opioids than men,” said Dr. Lipton. “This [finding] could reflect, in part, that women have more pain disorders than men and are more likely to seek medical care for pain than men.” In the current study, however, men with migraine were more likely to receive opioid prescriptions than were women with migraine. One potential explanation for this finding is that men with migraine are less likely to receive a migraine diagnosis, which might attenuate opioid prescribing, than women with migraine. “It may be that opioids are perceived to be serious drugs for serious pain, and that some physicians may be more likely to prescribe opioids to men because the disorder is taken more seriously in men than women,” said Dr. Lipton.

The observation that opioids were more likely to be prescribed for people treated in pain clinics “is consistent with my understanding of practice patterns,” he added. “Generally, neurologists strive to find effective acute treatment alternatives to opioids. The emergence of [drug classes known as] gepants and ditans provides a helpful set of alternatives to tritpans.”

Dr. Lipton and his colleagues plan further research into the treatment of migraineurs. “In a claims analysis, we showed that when people with migraine fail a triptan, they are most likely to get an opioid as their next drug,” he said. “Reasonable [clinicians] might disagree on the next step. The next step, in the absence of contraindications, could be a different oral triptan, a nonoral triptan, or a gepant or ditan. We are planning a randomized trial to probe this question.”
 

Why are opioids still being used?

The study’s reliance on patients’ self-report and its retrospective design are two of its weaknesses, said Alan M. Rapoport, MD, clinical professor of neurology at the University of California, Los Angeles, and editor-in-chief of Neurology Reviews. One strength, however, is that the stratified sampling methodology produced a study population that accurately reflects the demographic characteristics of the U.S. adult population, he added. Another strength is the investigators’ examination of opioid use by patient characteristics such as marital status, education, income, obesity, and smoking.

Given the harmful effects of opioids in migraine, it is hard to understand why as much as one-third of study participants using acute care medication for migraine were using opioids, said Dr. Rapoport. Using opioids for the acute treatment of migraine attacks often indicates inadequate treatment optimization, which leads to ongoing headache. As a consequence, patients may take more medication, which can increase headache frequency and lead to diagnoses of chronic migraine and medication overuse headache. Although the study found an association between the increased use of opioids and decreased household income and increased unemployment, smoking, and obesity, “it is not possible to assign causality to any of these associations, even though some would argue that decreased socioeconomic status was somehow related to more headache, disability, obesity, smoking, and unemployment,” he added.

“The paper suggests that future research should look at the risk factors for use of opioids and should determine if depression is a risk factor for or a consequence of opioid use,” said Dr. Rapoport. “Interventional studies designed to improve the acute care of migraine attacks might be able to reduce the use of opioids. I have not used opioids or butalbital-containing medication in my office for many years.”

This study was funded and sponsored by Dr. Reddy’s Laboratories group of companies, Princeton, N.J. Dr. Lipton has received grant support from the National Institutes of Health, the National Headache Foundation, and the Migraine Research Fund. He serves as a consultant, serves as an advisory board member, or has received honoraria from Alder, Allergan, American Headache Society, Autonomic Technologies, Biohaven, Dr. Reddy’s Laboratories, Eli Lilly, eNeura Therapeutics, Merck, Novartis, Pfizer, and Teva, Inc. He receives royalties from Wolff’s Headache, 8th Edition (New York: Oxford University Press, 2009) and holds stock options in eNeura Therapeutics and Biohaven.

SOURCE: Lipton RB, et al. Headache. https://doi.org/10.1111/head.14018. 2020;61(1):103-16.

A meta-analysis of two randomized studies evaluating patent foramen ovale (PFO) closure as a treatment strategy for migraine has shown significant benefits in several key endpoints, prompting the authors to conclude the approach warrants reevaluation.
 

The pooled analysis of patient-level data from the PRIMA and PREMIUM studies, both of which evaluated the Amplatzer PFO Occluder device (Abbott Vascular), showed that PFO closure significantly reduced the mean number of monthly migraine days and monthly migraine attacks and resulted in a greater number of patients who experienced complete migraine cessation.

The study, led by Mohammad K. Mojadidi, MD, Virginia Commonwealth University, Richmond, was published online in the Journal of the American College of Cardiology on Feb. 8, 2021.

Commenting on the article, the coauthor of an accompanying editorial, Zubair Ahmed, MD, of the Cleveland Clinic said the meta-analysis gave some useful new information but is not enough to recommend PFO closure routinely for patients with migraine.

“This meta-analysis looked at different endpoints that are more relevant to current clinical practice than those in the two original studies, and the results show that we shouldn’t rule out PFO closure as a treatment strategy for some migraine patients,” Dr. Ahmed stated. “But we’re still not sure exactly which patients are most likely to benefit from this approach, and we need additional studies to gain more understanding on that.”

The study authors noted that there is an established link between the presence of PFO and migraine, especially migraine with aura. In observational studies of PFO closure for cryptogenic stroke, the vast majority of patients who also had migraine reported a more than 50% reduction in migraine days per month after PFO closure.

However, two recent randomized clinical trials evaluating the Amplatzer PFO Occluder device for reducing the frequency and duration of episodic migraine headaches did not meet their respective primary endpoints, although they did show significant benefit of PFO closure in most of their secondary endpoints.

The current meta-analysis pooled individual participant data from the two trials to increase the power to detect the effect of percutaneous PFO closure for treating patients with episodic migraine compared with medical therapy alone.

In the two studies including a total of 337 patients, 176 were randomized to PFO closure and 161 to medical treatment only. At 12 months, three of the four efficacy endpoints evaluated in the meta-analysis were significantly reduced in the PFO-closure group. These were mean reduction of monthly migraine days (–3.1 days vs. –1.9 days; P = .02), mean reduction of monthly migraine attacks (–2.0 vs. –1.4; P = .01), and number of patients who experienced complete cessation of migraine (9% vs. 0.7%; P < .001).

The responder rate, defined as more than a 50% reduction in migraine attacks, showed a trend towards an increase in the PFO-closure group but did not achieve statistical significance (38% vs. 29%; P = .13).  

For the safety analysis, nine procedure-related and four device-related adverse events occurred in 245 patients who eventually received devices. All events were transient and resolved.
 

Better effect in patients with aura

Patients with migraine with aura, in particular frequent aura, had a significantly greater reduction in migraine days and a higher incidence of complete migraine cessation following PFO closure versus no closure, the authors reported.

In those without aura, PFO closure did not significantly reduce migraine days or improve complete headache cessation. However, some patients without aura did respond to PFO closure, which was statistically significant for reduction of migraine attacks (–2.0 vs. –1.0; P = .03).

“The interaction between the brain that is susceptible to migraine and the plethora of potential triggers is complex. A PFO may be the potential pathway for a variety of chemical triggers, such as serotonin from platelets, and although less frequent, some people with migraine without aura may trigger their migraine through this mechanism,” the researchers suggested. This hypothesis will be tested in the RELIEF trial, which is now being planned.

In the accompanying editorial, Dr. Ahmed and coauthor Robert J. Sommer, MD, Columbia University Medical Center, New York, pointed out that the meta-analysis demonstrates benefit of PFO closure in the migraine population for the first time.

“Moreover, the investigators defined a population of patients who may benefit most from PFO closure, those with migraine with frequent aura, suggesting that these may be different physiologically than other migraine subtypes. The analysis also places the PRIMA and PREMIUM outcomes in the context of endpoints that are more practical and are more commonly assessed in current clinical trials,” the editorialists noted.
 

Many unanswered questions

But the editorialists highlighted several significant limitations of the analysis, including “pooling of patient cohorts, methods, and outcome measures that might not be entirely comparable,” which they say could have introduced bias.

They also pointed out that the underlying pathophysiological mechanism linking migraine symptoms to PFO remains unknown. They explain that the mechanism is thought to involve the right-to-left passage of systemic venous blood, with some component – which would normally be eliminated or reduced on passage through the pulmonary vasculature – reaching the cerebral circulation via the PFO in supranormal concentrations and acting as a trigger for migraine activity in patients with susceptible brains.

But not all patients with migraine who have PFO benefit from PFO closure, they noted, and therefore presumably have PFO-unrelated migraines. There is no verified way to distinguish between these two groups at present.

“Once we learn to identify the subset of migraine patients in whom PFOs are actually causal of headache symptoms, screening and treatment of PFO for migraine can become a reality,” they wrote.

Although the meta-analysis is a step in the right direction, “it is not a home run,” Dr. Ahmed elaborated. “This was a post hoc analysis of two studies, neither of which showed significant benefits on their primary endpoints. That weakens the findings somewhat.”

He added: “At present, PFO closure is not routinely recommended as a migraine treatment strategy as we haven’t been sure which patients are most likely to benefit. And while this meta-analysis suggests patients with aura may be more likely to benefit, one quarter of patients without aura in the PREMIUM trial responded to PFO closure, so it’s not just about aura.

“There are still many unanswered questions.

“I don’t think the new information from this meta-analysis is enough to persuade me to change my practice, but it is a small building block in the overall picture and suggests this may be a suitable strategy for some patients in future,” he concluded.

The study had no outside funding. Participant-level data were provided by Abbott. Several coauthors were on the steering committee for the PREMIUM or PRIMA trials. Dr. Ahmed reported receiving consulting fees from, Amgen, AbbVie, electroCore, and Eli Lilly; serving on advisory boards for Amgen and Supernus; serving as a speaker for AbbVie; and receiving funding for an investigator-initiated trial from Teva and Eli Lilly.

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

A meta-analysis of two randomized studies evaluating patent foramen ovale (PFO) closure as a treatment strategy for migraine has shown significant benefits in several key endpoints, prompting the authors to conclude the approach warrants reevaluation.
 

The pooled analysis of patient-level data from the PRIMA and PREMIUM studies, both of which evaluated the Amplatzer PFO Occluder device (Abbott Vascular), showed that PFO closure significantly reduced the mean number of monthly migraine days and monthly migraine attacks and resulted in a greater number of patients who experienced complete migraine cessation.

The study, led by Mohammad K. Mojadidi, MD, Virginia Commonwealth University, Richmond, was published online in the Journal of the American College of Cardiology on Feb. 8, 2021.

Commenting on the article, the coauthor of an accompanying editorial, Zubair Ahmed, MD, of the Cleveland Clinic said the meta-analysis gave some useful new information but is not enough to recommend PFO closure routinely for patients with migraine.

“This meta-analysis looked at different endpoints that are more relevant to current clinical practice than those in the two original studies, and the results show that we shouldn’t rule out PFO closure as a treatment strategy for some migraine patients,” Dr. Ahmed stated. “But we’re still not sure exactly which patients are most likely to benefit from this approach, and we need additional studies to gain more understanding on that.”

The study authors noted that there is an established link between the presence of PFO and migraine, especially migraine with aura. In observational studies of PFO closure for cryptogenic stroke, the vast majority of patients who also had migraine reported a more than 50% reduction in migraine days per month after PFO closure.

However, two recent randomized clinical trials evaluating the Amplatzer PFO Occluder device for reducing the frequency and duration of episodic migraine headaches did not meet their respective primary endpoints, although they did show significant benefit of PFO closure in most of their secondary endpoints.

The current meta-analysis pooled individual participant data from the two trials to increase the power to detect the effect of percutaneous PFO closure for treating patients with episodic migraine compared with medical therapy alone.

In the two studies including a total of 337 patients, 176 were randomized to PFO closure and 161 to medical treatment only. At 12 months, three of the four efficacy endpoints evaluated in the meta-analysis were significantly reduced in the PFO-closure group. These were mean reduction of monthly migraine days (–3.1 days vs. –1.9 days; P = .02), mean reduction of monthly migraine attacks (–2.0 vs. –1.4; P = .01), and number of patients who experienced complete cessation of migraine (9% vs. 0.7%; P < .001).

The responder rate, defined as more than a 50% reduction in migraine attacks, showed a trend towards an increase in the PFO-closure group but did not achieve statistical significance (38% vs. 29%; P = .13).  

For the safety analysis, nine procedure-related and four device-related adverse events occurred in 245 patients who eventually received devices. All events were transient and resolved.
 

Better effect in patients with aura

Patients with migraine with aura, in particular frequent aura, had a significantly greater reduction in migraine days and a higher incidence of complete migraine cessation following PFO closure versus no closure, the authors reported.

In those without aura, PFO closure did not significantly reduce migraine days or improve complete headache cessation. However, some patients without aura did respond to PFO closure, which was statistically significant for reduction of migraine attacks (–2.0 vs. –1.0; P = .03).

“The interaction between the brain that is susceptible to migraine and the plethora of potential triggers is complex. A PFO may be the potential pathway for a variety of chemical triggers, such as serotonin from platelets, and although less frequent, some people with migraine without aura may trigger their migraine through this mechanism,” the researchers suggested. This hypothesis will be tested in the RELIEF trial, which is now being planned.

In the accompanying editorial, Dr. Ahmed and coauthor Robert J. Sommer, MD, Columbia University Medical Center, New York, pointed out that the meta-analysis demonstrates benefit of PFO closure in the migraine population for the first time.

“Moreover, the investigators defined a population of patients who may benefit most from PFO closure, those with migraine with frequent aura, suggesting that these may be different physiologically than other migraine subtypes. The analysis also places the PRIMA and PREMIUM outcomes in the context of endpoints that are more practical and are more commonly assessed in current clinical trials,” the editorialists noted.
 

Many unanswered questions

But the editorialists highlighted several significant limitations of the analysis, including “pooling of patient cohorts, methods, and outcome measures that might not be entirely comparable,” which they say could have introduced bias.

They also pointed out that the underlying pathophysiological mechanism linking migraine symptoms to PFO remains unknown. They explain that the mechanism is thought to involve the right-to-left passage of systemic venous blood, with some component – which would normally be eliminated or reduced on passage through the pulmonary vasculature – reaching the cerebral circulation via the PFO in supranormal concentrations and acting as a trigger for migraine activity in patients with susceptible brains.

But not all patients with migraine who have PFO benefit from PFO closure, they noted, and therefore presumably have PFO-unrelated migraines. There is no verified way to distinguish between these two groups at present.

“Once we learn to identify the subset of migraine patients in whom PFOs are actually causal of headache symptoms, screening and treatment of PFO for migraine can become a reality,” they wrote.

Although the meta-analysis is a step in the right direction, “it is not a home run,” Dr. Ahmed elaborated. “This was a post hoc analysis of two studies, neither of which showed significant benefits on their primary endpoints. That weakens the findings somewhat.”

He added: “At present, PFO closure is not routinely recommended as a migraine treatment strategy as we haven’t been sure which patients are most likely to benefit. And while this meta-analysis suggests patients with aura may be more likely to benefit, one quarter of patients without aura in the PREMIUM trial responded to PFO closure, so it’s not just about aura.

“There are still many unanswered questions.

“I don’t think the new information from this meta-analysis is enough to persuade me to change my practice, but it is a small building block in the overall picture and suggests this may be a suitable strategy for some patients in future,” he concluded.

The study had no outside funding. Participant-level data were provided by Abbott. Several coauthors were on the steering committee for the PREMIUM or PRIMA trials. Dr. Ahmed reported receiving consulting fees from, Amgen, AbbVie, electroCore, and Eli Lilly; serving on advisory boards for Amgen and Supernus; serving as a speaker for AbbVie; and receiving funding for an investigator-initiated trial from Teva and Eli Lilly.

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

A meta-analysis of two randomized studies evaluating patent foramen ovale (PFO) closure as a treatment strategy for migraine has shown significant benefits in several key endpoints, prompting the authors to conclude the approach warrants reevaluation.
 

The pooled analysis of patient-level data from the PRIMA and PREMIUM studies, both of which evaluated the Amplatzer PFO Occluder device (Abbott Vascular), showed that PFO closure significantly reduced the mean number of monthly migraine days and monthly migraine attacks and resulted in a greater number of patients who experienced complete migraine cessation.

The study, led by Mohammad K. Mojadidi, MD, Virginia Commonwealth University, Richmond, was published online in the Journal of the American College of Cardiology on Feb. 8, 2021.

Commenting on the article, the coauthor of an accompanying editorial, Zubair Ahmed, MD, of the Cleveland Clinic said the meta-analysis gave some useful new information but is not enough to recommend PFO closure routinely for patients with migraine.

“This meta-analysis looked at different endpoints that are more relevant to current clinical practice than those in the two original studies, and the results show that we shouldn’t rule out PFO closure as a treatment strategy for some migraine patients,” Dr. Ahmed stated. “But we’re still not sure exactly which patients are most likely to benefit from this approach, and we need additional studies to gain more understanding on that.”

The study authors noted that there is an established link between the presence of PFO and migraine, especially migraine with aura. In observational studies of PFO closure for cryptogenic stroke, the vast majority of patients who also had migraine reported a more than 50% reduction in migraine days per month after PFO closure.

However, two recent randomized clinical trials evaluating the Amplatzer PFO Occluder device for reducing the frequency and duration of episodic migraine headaches did not meet their respective primary endpoints, although they did show significant benefit of PFO closure in most of their secondary endpoints.

The current meta-analysis pooled individual participant data from the two trials to increase the power to detect the effect of percutaneous PFO closure for treating patients with episodic migraine compared with medical therapy alone.

In the two studies including a total of 337 patients, 176 were randomized to PFO closure and 161 to medical treatment only. At 12 months, three of the four efficacy endpoints evaluated in the meta-analysis were significantly reduced in the PFO-closure group. These were mean reduction of monthly migraine days (–3.1 days vs. –1.9 days; P = .02), mean reduction of monthly migraine attacks (–2.0 vs. –1.4; P = .01), and number of patients who experienced complete cessation of migraine (9% vs. 0.7%; P < .001).

The responder rate, defined as more than a 50% reduction in migraine attacks, showed a trend towards an increase in the PFO-closure group but did not achieve statistical significance (38% vs. 29%; P = .13).  

For the safety analysis, nine procedure-related and four device-related adverse events occurred in 245 patients who eventually received devices. All events were transient and resolved.
 

Better effect in patients with aura

Patients with migraine with aura, in particular frequent aura, had a significantly greater reduction in migraine days and a higher incidence of complete migraine cessation following PFO closure versus no closure, the authors reported.

In those without aura, PFO closure did not significantly reduce migraine days or improve complete headache cessation. However, some patients without aura did respond to PFO closure, which was statistically significant for reduction of migraine attacks (–2.0 vs. –1.0; P = .03).

“The interaction between the brain that is susceptible to migraine and the plethora of potential triggers is complex. A PFO may be the potential pathway for a variety of chemical triggers, such as serotonin from platelets, and although less frequent, some people with migraine without aura may trigger their migraine through this mechanism,” the researchers suggested. This hypothesis will be tested in the RELIEF trial, which is now being planned.

In the accompanying editorial, Dr. Ahmed and coauthor Robert J. Sommer, MD, Columbia University Medical Center, New York, pointed out that the meta-analysis demonstrates benefit of PFO closure in the migraine population for the first time.

“Moreover, the investigators defined a population of patients who may benefit most from PFO closure, those with migraine with frequent aura, suggesting that these may be different physiologically than other migraine subtypes. The analysis also places the PRIMA and PREMIUM outcomes in the context of endpoints that are more practical and are more commonly assessed in current clinical trials,” the editorialists noted.
 

Many unanswered questions

But the editorialists highlighted several significant limitations of the analysis, including “pooling of patient cohorts, methods, and outcome measures that might not be entirely comparable,” which they say could have introduced bias.

They also pointed out that the underlying pathophysiological mechanism linking migraine symptoms to PFO remains unknown. They explain that the mechanism is thought to involve the right-to-left passage of systemic venous blood, with some component – which would normally be eliminated or reduced on passage through the pulmonary vasculature – reaching the cerebral circulation via the PFO in supranormal concentrations and acting as a trigger for migraine activity in patients with susceptible brains.

But not all patients with migraine who have PFO benefit from PFO closure, they noted, and therefore presumably have PFO-unrelated migraines. There is no verified way to distinguish between these two groups at present.

“Once we learn to identify the subset of migraine patients in whom PFOs are actually causal of headache symptoms, screening and treatment of PFO for migraine can become a reality,” they wrote.

Although the meta-analysis is a step in the right direction, “it is not a home run,” Dr. Ahmed elaborated. “This was a post hoc analysis of two studies, neither of which showed significant benefits on their primary endpoints. That weakens the findings somewhat.”

He added: “At present, PFO closure is not routinely recommended as a migraine treatment strategy as we haven’t been sure which patients are most likely to benefit. And while this meta-analysis suggests patients with aura may be more likely to benefit, one quarter of patients without aura in the PREMIUM trial responded to PFO closure, so it’s not just about aura.

“There are still many unanswered questions.

“I don’t think the new information from this meta-analysis is enough to persuade me to change my practice, but it is a small building block in the overall picture and suggests this may be a suitable strategy for some patients in future,” he concluded.

The study had no outside funding. Participant-level data were provided by Abbott. Several coauthors were on the steering committee for the PREMIUM or PRIMA trials. Dr. Ahmed reported receiving consulting fees from, Amgen, AbbVie, electroCore, and Eli Lilly; serving on advisory boards for Amgen and Supernus; serving as a speaker for AbbVie; and receiving funding for an investigator-initiated trial from Teva and Eli Lilly.

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

Multiple sclerosis (MS) may not pose a higher risk for complications in pregnant women, according to a new study published online Feb. 3 in Neurology Clinical Practice. While pregnancy and childbirth are not regarded as conditions that engender high-risk pregnancy in the MS population, previous studies evaluating the effects of MS on pregnancy and parturition have yet to fully elucidate some outcomes for pregnant women and their babies in multiple sclerosis.

“Women with multiple sclerosis may be understandably concerned about the risk of pregnancy,” said Melinda Magyari, MD, PhD, a consultant at the University of Copenhagen. “While previous research has shown there is no higher risk of birth defect for babies born to women with MS, we wanted to find out if women with MS are at risk for a variety of pregnancy complications.”

MS is regarded as a progressive, neurological disease mediated by the immune system that demands careful consideration of numerous situations and life changes including family planning. The MS population is overwhelmingly female, as women account for three out of every four cases of MS. The majority of these women range from 20 to 40 years of age at the time of being diagnosed with MS. Despite the unknown risks of pregnancy-related complications and various perinatal complications in this patient population, women who have MS are not discouraged from conceiving.
 

Assessing pregnancy outcomes

This nationwide, population-based, cross-sectional study evaluated the pregnancies of 2,930 women with MS between Jan. 1, 1997, and Dec. 31, 2016, registered in the Danish Multiple Sclerosis Registry. The researchers compared pregnancy-related and prenatal outcomes to a 5% random sample of 56,958 randomly-selected pregnant women from Denmark’s general population who did not have MS. They found no differences in the risks associated with several pregnancy-related complications (e.g., preeclampsia, gestational diabetes, or placental complications), emergency Cesarean section (C-section), instrumental delivery, stillbirth, preterm birth, or congenital malformation. Apgar scores were low in both groups. A composite of various biometrics in newborns such as reflexes, muscle tone, and heart rate immediately following birth, the Apgar score is used to help assess the neonatal health, with a value of less than 7 considered low. Here, preterm birth is defined as delivery occurring before 37 weeks of gestation, and stillbirth describes a fetus born dead after 22 weeks of gestation.

Women in the MS cohort were more likely to have elective C-sections (odds ratio, 2.89 [95% confidence interval, 1.65-2.16]), induced labor (OR, 1.15 [95%CI, 1.01-1.31]) and have babies with low birth weight based on their gestational age (OR, 1.29 [95% CI, 1.04-1.60]). Nearly 30% of babies born in the cohort (n = 851) were born to mothers who had received disease-modifying therapy (DMT). Neonates exposed to DMT weighed an average of 116 g less than babies born to mothers who had not received DMT (3,378 g vs. 3,494 g) with a slightly lower gestational age (39 weeks as opposed to 40 weeks). However, babies born to mothers with MS were less likely to show signs of asphyxia (OR, 0.87 [95% CI, 0.78-0.97]) than the comparison cohort.

“We found overall, their pregnancies were just as healthy as those of the moms without MS,” Dr. Magyari said.
 

Comprehensive data

Denmark’s health care system has two key features that make it an attractive setting in which to conduct such a study – the first being its universal health care. The second advantage is that the country enacted several health registries in the 1970s and 1980s that enable the collection of more comprehensive data. For example, the Danish National Patient Register is a population-based registry that spans the entire nation, facilitating epidemiological research with what the study’s authors describe as “high generalizability.” Providing additional insights regarding the patient story helps add context to pregnancy and outcomes. Among the data collected on the women studied were demographics, contact information, and abortions, both spontaneous and medically induced. The country uses other databases and registries to capture additional data. For example, the Register of Legally Induced Abortions provides data regarding the context of medically induced abortions. In contrast, the Danish Medical Birth Registry provides context regarding specified variables regarding women’s pregnancies, delivery, and perinatal outcomes. Finally, the population’s education register offers information regarding patients’ educational history.

A key strength of this study is that the long duration of follow-up data from the Danish Medical Birth Registry, along with its comprehensive data collection, eliminates recall bias. Universal access to health care also improves the generalizability of data. A limitation of the study is its lack of data on maternal smoking and its effects on low gestational weights. The study also has some data gaps, including body mass index information missing from a large portion of the cohort. Finally, the sample size of newborns born to mothers who had received DMT therapy within the last 6 months of gestation was too underpowered to stratify based on first on first-line or second-line treatment.

Dr. Magyari served on scientific advisory boards for Biogen, Sanofi, Teva, Roche, Novartis, and Merck. She has also received honoraria for lecturing from Biogen, Merck, Novartis, Sanofi, Genzyme, and has received research support and support for congress participation from Biogen, Genzyme, Teva, Roche, Merck, and Novartis. Coauthors disclosed various fees received from Merck, Novartis, Biogen, Roche, Sanofi Genzyme, and Teva.

Multiple sclerosis (MS) may not pose a higher risk for complications in pregnant women, according to a new study published online Feb. 3 in Neurology Clinical Practice. While pregnancy and childbirth are not regarded as conditions that engender high-risk pregnancy in the MS population, previous studies evaluating the effects of MS on pregnancy and parturition have yet to fully elucidate some outcomes for pregnant women and their babies in multiple sclerosis.

“Women with multiple sclerosis may be understandably concerned about the risk of pregnancy,” said Melinda Magyari, MD, PhD, a consultant at the University of Copenhagen. “While previous research has shown there is no higher risk of birth defect for babies born to women with MS, we wanted to find out if women with MS are at risk for a variety of pregnancy complications.”

MS is regarded as a progressive, neurological disease mediated by the immune system that demands careful consideration of numerous situations and life changes including family planning. The MS population is overwhelmingly female, as women account for three out of every four cases of MS. The majority of these women range from 20 to 40 years of age at the time of being diagnosed with MS. Despite the unknown risks of pregnancy-related complications and various perinatal complications in this patient population, women who have MS are not discouraged from conceiving.
 

Assessing pregnancy outcomes

This nationwide, population-based, cross-sectional study evaluated the pregnancies of 2,930 women with MS between Jan. 1, 1997, and Dec. 31, 2016, registered in the Danish Multiple Sclerosis Registry. The researchers compared pregnancy-related and prenatal outcomes to a 5% random sample of 56,958 randomly-selected pregnant women from Denmark’s general population who did not have MS. They found no differences in the risks associated with several pregnancy-related complications (e.g., preeclampsia, gestational diabetes, or placental complications), emergency Cesarean section (C-section), instrumental delivery, stillbirth, preterm birth, or congenital malformation. Apgar scores were low in both groups. A composite of various biometrics in newborns such as reflexes, muscle tone, and heart rate immediately following birth, the Apgar score is used to help assess the neonatal health, with a value of less than 7 considered low. Here, preterm birth is defined as delivery occurring before 37 weeks of gestation, and stillbirth describes a fetus born dead after 22 weeks of gestation.

Women in the MS cohort were more likely to have elective C-sections (odds ratio, 2.89 [95% confidence interval, 1.65-2.16]), induced labor (OR, 1.15 [95%CI, 1.01-1.31]) and have babies with low birth weight based on their gestational age (OR, 1.29 [95% CI, 1.04-1.60]). Nearly 30% of babies born in the cohort (n = 851) were born to mothers who had received disease-modifying therapy (DMT). Neonates exposed to DMT weighed an average of 116 g less than babies born to mothers who had not received DMT (3,378 g vs. 3,494 g) with a slightly lower gestational age (39 weeks as opposed to 40 weeks). However, babies born to mothers with MS were less likely to show signs of asphyxia (OR, 0.87 [95% CI, 0.78-0.97]) than the comparison cohort.

“We found overall, their pregnancies were just as healthy as those of the moms without MS,” Dr. Magyari said.
 

Comprehensive data

Denmark’s health care system has two key features that make it an attractive setting in which to conduct such a study – the first being its universal health care. The second advantage is that the country enacted several health registries in the 1970s and 1980s that enable the collection of more comprehensive data. For example, the Danish National Patient Register is a population-based registry that spans the entire nation, facilitating epidemiological research with what the study’s authors describe as “high generalizability.” Providing additional insights regarding the patient story helps add context to pregnancy and outcomes. Among the data collected on the women studied were demographics, contact information, and abortions, both spontaneous and medically induced. The country uses other databases and registries to capture additional data. For example, the Register of Legally Induced Abortions provides data regarding the context of medically induced abortions. In contrast, the Danish Medical Birth Registry provides context regarding specified variables regarding women’s pregnancies, delivery, and perinatal outcomes. Finally, the population’s education register offers information regarding patients’ educational history.

A key strength of this study is that the long duration of follow-up data from the Danish Medical Birth Registry, along with its comprehensive data collection, eliminates recall bias. Universal access to health care also improves the generalizability of data. A limitation of the study is its lack of data on maternal smoking and its effects on low gestational weights. The study also has some data gaps, including body mass index information missing from a large portion of the cohort. Finally, the sample size of newborns born to mothers who had received DMT therapy within the last 6 months of gestation was too underpowered to stratify based on first on first-line or second-line treatment.

Dr. Magyari served on scientific advisory boards for Biogen, Sanofi, Teva, Roche, Novartis, and Merck. She has also received honoraria for lecturing from Biogen, Merck, Novartis, Sanofi, Genzyme, and has received research support and support for congress participation from Biogen, Genzyme, Teva, Roche, Merck, and Novartis. Coauthors disclosed various fees received from Merck, Novartis, Biogen, Roche, Sanofi Genzyme, and Teva.

Multiple sclerosis (MS) may not pose a higher risk for complications in pregnant women, according to a new study published online Feb. 3 in Neurology Clinical Practice. While pregnancy and childbirth are not regarded as conditions that engender high-risk pregnancy in the MS population, previous studies evaluating the effects of MS on pregnancy and parturition have yet to fully elucidate some outcomes for pregnant women and their babies in multiple sclerosis.

“Women with multiple sclerosis may be understandably concerned about the risk of pregnancy,” said Melinda Magyari, MD, PhD, a consultant at the University of Copenhagen. “While previous research has shown there is no higher risk of birth defect for babies born to women with MS, we wanted to find out if women with MS are at risk for a variety of pregnancy complications.”

MS is regarded as a progressive, neurological disease mediated by the immune system that demands careful consideration of numerous situations and life changes including family planning. The MS population is overwhelmingly female, as women account for three out of every four cases of MS. The majority of these women range from 20 to 40 years of age at the time of being diagnosed with MS. Despite the unknown risks of pregnancy-related complications and various perinatal complications in this patient population, women who have MS are not discouraged from conceiving.
 

Assessing pregnancy outcomes

This nationwide, population-based, cross-sectional study evaluated the pregnancies of 2,930 women with MS between Jan. 1, 1997, and Dec. 31, 2016, registered in the Danish Multiple Sclerosis Registry. The researchers compared pregnancy-related and prenatal outcomes to a 5% random sample of 56,958 randomly-selected pregnant women from Denmark’s general population who did not have MS. They found no differences in the risks associated with several pregnancy-related complications (e.g., preeclampsia, gestational diabetes, or placental complications), emergency Cesarean section (C-section), instrumental delivery, stillbirth, preterm birth, or congenital malformation. Apgar scores were low in both groups. A composite of various biometrics in newborns such as reflexes, muscle tone, and heart rate immediately following birth, the Apgar score is used to help assess the neonatal health, with a value of less than 7 considered low. Here, preterm birth is defined as delivery occurring before 37 weeks of gestation, and stillbirth describes a fetus born dead after 22 weeks of gestation.

Women in the MS cohort were more likely to have elective C-sections (odds ratio, 2.89 [95% confidence interval, 1.65-2.16]), induced labor (OR, 1.15 [95%CI, 1.01-1.31]) and have babies with low birth weight based on their gestational age (OR, 1.29 [95% CI, 1.04-1.60]). Nearly 30% of babies born in the cohort (n = 851) were born to mothers who had received disease-modifying therapy (DMT). Neonates exposed to DMT weighed an average of 116 g less than babies born to mothers who had not received DMT (3,378 g vs. 3,494 g) with a slightly lower gestational age (39 weeks as opposed to 40 weeks). However, babies born to mothers with MS were less likely to show signs of asphyxia (OR, 0.87 [95% CI, 0.78-0.97]) than the comparison cohort.

“We found overall, their pregnancies were just as healthy as those of the moms without MS,” Dr. Magyari said.
 

Comprehensive data

Denmark’s health care system has two key features that make it an attractive setting in which to conduct such a study – the first being its universal health care. The second advantage is that the country enacted several health registries in the 1970s and 1980s that enable the collection of more comprehensive data. For example, the Danish National Patient Register is a population-based registry that spans the entire nation, facilitating epidemiological research with what the study’s authors describe as “high generalizability.” Providing additional insights regarding the patient story helps add context to pregnancy and outcomes. Among the data collected on the women studied were demographics, contact information, and abortions, both spontaneous and medically induced. The country uses other databases and registries to capture additional data. For example, the Register of Legally Induced Abortions provides data regarding the context of medically induced abortions. In contrast, the Danish Medical Birth Registry provides context regarding specified variables regarding women’s pregnancies, delivery, and perinatal outcomes. Finally, the population’s education register offers information regarding patients’ educational history.

A key strength of this study is that the long duration of follow-up data from the Danish Medical Birth Registry, along with its comprehensive data collection, eliminates recall bias. Universal access to health care also improves the generalizability of data. A limitation of the study is its lack of data on maternal smoking and its effects on low gestational weights. The study also has some data gaps, including body mass index information missing from a large portion of the cohort. Finally, the sample size of newborns born to mothers who had received DMT therapy within the last 6 months of gestation was too underpowered to stratify based on first on first-line or second-line treatment.

Dr. Magyari served on scientific advisory boards for Biogen, Sanofi, Teva, Roche, Novartis, and Merck. She has also received honoraria for lecturing from Biogen, Merck, Novartis, Sanofi, Genzyme, and has received research support and support for congress participation from Biogen, Genzyme, Teva, Roche, Merck, and Novartis. Coauthors disclosed various fees received from Merck, Novartis, Biogen, Roche, Sanofi Genzyme, and Teva.

Adverse cognitive and psychiatric effects seen associated with the investigational Alzheimer’s drug atabecestat were reversed within 6 months of treatment cessation, according to follow-up results from a truncated clinical trial.

A blinded, placebo-controlled, manufacturer-sponsored trial that had randomized 557 patients with preclinical Alzheimer’s disease to 25 mg daily oral atabecestat, 5 mg atabecestat, or placebo, was halted in 2018 over concerns about liver toxicity. The main outcome measure of the trial was change on the Alzheimer’s Disease Cooperative Study Preclinical Alzheimer Cognitive Composite, while two other scales were used to assess cognitive function and neuropsychological status.

A preliminary analysis found the higher dose of the atabecestat to significantly worsen subjects’ cognition starting at around 3 months of treatment, compared with placebo. Treatment with atabecestat was also seen associated with higher incidence of neuropsychiatric adverse events, including anxiety and depression.

In their follow-up study published Jan. 19, 2021 in JAMA Neurology (doi: 10.1001/jamaneurol.2020.4857), Reisa Sperling, MD, of Brigham and Women’s Hospital, Boston, and colleagues reported that the cognitive worsening and neuropsychiatric adverse effects seen linked to atabecestat treatment reverted to baseline levels within 6 months of halting treatment. Most of the worsening seen in the study was associated with episodic memory tasks, including “list learning, story memory, list recognition, story recall, and figure recall,” Dr. Sperling and colleagues found.

Atabecestat was also associated with “dose-related and duration-related decreases in whole-brain volume, compared with placebo treatment,” the investigators reported. Brain volume loss has been seen in trials of other beta-secretase (BACE) inhibitors and shown with one, umibecestat, to be reversible after stopping treatment.

Dr. Sperling and colleagues acknowledged as a major limitation of their study that just over a third of the cohort received another cognitive composite score after baseline. “The observation that cognitive worsening and neuropsychiatric-related [adverse events] recovered following discontinuation of atabecestat is encouraging but needs replication, given that the observation period after stopping treatment was variable and not preplanned,” the investigators wrote in their analysis. After a median exposure of 21 weeks to the study drug or placebo, subjects were followed off treatment for a median 15 weeks.
 

Questions surround BACE inhibitors

Development of atabecestat has been discontinued along with others in its class of agents, known as BACE inhibitors, which target an enzyme that initiates production of amyloid-beta, the plaque-forming peptide that is considered a driver of Alzheimer’s disease. In the past few years a number of BACE inhibitors have been shown in trials to worsen cognition in a dose-dependent way, compared with placebo. The reasons for these effects are still unknown.

Dr. Sperling and colleagues concluded that, if BACE investigators like atabecestat are to be studied anew, it must be at low doses, with more modest enzyme inhibition, and alongside careful safety and cognitive monitoring.

While no BACE inhibitor is currently in the pipeline for Alzheimer’s – trials of these agents have been stopped for futility or toxicity –Paul Aisen, MD of the University of Southern California, Los Angeles, and a coauthor of Dr. Sperling and colleagues’ study, commented that it was important that clinical investigation of BACE inhibitors continue. 

“This drug class is optimal to correct the metabolic dysregulation that is likely a primary root cause” of Alzheimer’s disease, Dr. Aisen said in an interview. “Evidence from trials such as this suggest that the cognitive toxicity of BACE inhibitors is dose related, nonprogressive, and reversible. We should now focus on establishing the safety of relatively low-dose BACE inhibition so that such regimens can be tested in AD trials.”
 

Research should continue

Robert Vassar, PhD, of Northwestern University, Chicago, who was not a coauthor on the study, also expressed a desire for BACE inhibitor research to continue.

“It is my view that the cognitive worsening of atabecestat and the other BACE inhibitors was caused by overinhibition of the enzyme related to functions of certain BACE substrates in the brain,” Dr. Vassar commented. “A major question is whether a lower dose of BACE inhibitor – achieving about 30% inhibition – could be safe and lower amyloid-beta enough to delay onset in people still without symptoms. The good news of this study is that the atabecestat-related cognitive worsening is reversible, leaving open the possibility of low-dose prevention trials.”

Dr. Vassar noted that, with both doses of atabecestat, Dr. Sperling and colleagues did not see changes in neurofilament light or total tau, two biomarkers of neurodegeneration, but did report decreases in phosphorylated tau (p181 tau), a marker of disease progression, compared with placebo.

“This indicates that atabecestat did not cause neurodegeneration and in fact moved p181 tau in the beneficial direction for Alzheimer’s disease. Perhaps if it were not for the liver toxicity, the trial may have been completed and other Alzheimer’s disease biomarkers may have changed in the beneficial direction as well,” Dr. Vassar said.

Dr. Sperling and colleagues’ study was sponsored by Janssen, the manufacturer of atabecestat. Dr. Sperling disclosed receiving research funding from Janssen and other drug makers, while nearly all the study’s coauthors reported being directly employed by the sponsor or receiving industry funding. Dr. Aisen disclosed personal fees from several manufacturers and past fees from the sponsor. Dr. Vassar disclosed consulting and other financial relationships with biotechnology companies that did not include this study’s sponsor.

Adverse cognitive and psychiatric effects seen associated with the investigational Alzheimer’s drug atabecestat were reversed within 6 months of treatment cessation, according to follow-up results from a truncated clinical trial.

A blinded, placebo-controlled, manufacturer-sponsored trial that had randomized 557 patients with preclinical Alzheimer’s disease to 25 mg daily oral atabecestat, 5 mg atabecestat, or placebo, was halted in 2018 over concerns about liver toxicity. The main outcome measure of the trial was change on the Alzheimer’s Disease Cooperative Study Preclinical Alzheimer Cognitive Composite, while two other scales were used to assess cognitive function and neuropsychological status.

A preliminary analysis found the higher dose of the atabecestat to significantly worsen subjects’ cognition starting at around 3 months of treatment, compared with placebo. Treatment with atabecestat was also seen associated with higher incidence of neuropsychiatric adverse events, including anxiety and depression.

In their follow-up study published Jan. 19, 2021 in JAMA Neurology (doi: 10.1001/jamaneurol.2020.4857), Reisa Sperling, MD, of Brigham and Women’s Hospital, Boston, and colleagues reported that the cognitive worsening and neuropsychiatric adverse effects seen linked to atabecestat treatment reverted to baseline levels within 6 months of halting treatment. Most of the worsening seen in the study was associated with episodic memory tasks, including “list learning, story memory, list recognition, story recall, and figure recall,” Dr. Sperling and colleagues found.

Atabecestat was also associated with “dose-related and duration-related decreases in whole-brain volume, compared with placebo treatment,” the investigators reported. Brain volume loss has been seen in trials of other beta-secretase (BACE) inhibitors and shown with one, umibecestat, to be reversible after stopping treatment.

Dr. Sperling and colleagues acknowledged as a major limitation of their study that just over a third of the cohort received another cognitive composite score after baseline. “The observation that cognitive worsening and neuropsychiatric-related [adverse events] recovered following discontinuation of atabecestat is encouraging but needs replication, given that the observation period after stopping treatment was variable and not preplanned,” the investigators wrote in their analysis. After a median exposure of 21 weeks to the study drug or placebo, subjects were followed off treatment for a median 15 weeks.
 

Questions surround BACE inhibitors

Development of atabecestat has been discontinued along with others in its class of agents, known as BACE inhibitors, which target an enzyme that initiates production of amyloid-beta, the plaque-forming peptide that is considered a driver of Alzheimer’s disease. In the past few years a number of BACE inhibitors have been shown in trials to worsen cognition in a dose-dependent way, compared with placebo. The reasons for these effects are still unknown.

Dr. Sperling and colleagues concluded that, if BACE investigators like atabecestat are to be studied anew, it must be at low doses, with more modest enzyme inhibition, and alongside careful safety and cognitive monitoring.

While no BACE inhibitor is currently in the pipeline for Alzheimer’s – trials of these agents have been stopped for futility or toxicity –Paul Aisen, MD of the University of Southern California, Los Angeles, and a coauthor of Dr. Sperling and colleagues’ study, commented that it was important that clinical investigation of BACE inhibitors continue. 

“This drug class is optimal to correct the metabolic dysregulation that is likely a primary root cause” of Alzheimer’s disease, Dr. Aisen said in an interview. “Evidence from trials such as this suggest that the cognitive toxicity of BACE inhibitors is dose related, nonprogressive, and reversible. We should now focus on establishing the safety of relatively low-dose BACE inhibition so that such regimens can be tested in AD trials.”
 

Research should continue

Robert Vassar, PhD, of Northwestern University, Chicago, who was not a coauthor on the study, also expressed a desire for BACE inhibitor research to continue.

“It is my view that the cognitive worsening of atabecestat and the other BACE inhibitors was caused by overinhibition of the enzyme related to functions of certain BACE substrates in the brain,” Dr. Vassar commented. “A major question is whether a lower dose of BACE inhibitor – achieving about 30% inhibition – could be safe and lower amyloid-beta enough to delay onset in people still without symptoms. The good news of this study is that the atabecestat-related cognitive worsening is reversible, leaving open the possibility of low-dose prevention trials.”

Dr. Vassar noted that, with both doses of atabecestat, Dr. Sperling and colleagues did not see changes in neurofilament light or total tau, two biomarkers of neurodegeneration, but did report decreases in phosphorylated tau (p181 tau), a marker of disease progression, compared with placebo.

“This indicates that atabecestat did not cause neurodegeneration and in fact moved p181 tau in the beneficial direction for Alzheimer’s disease. Perhaps if it were not for the liver toxicity, the trial may have been completed and other Alzheimer’s disease biomarkers may have changed in the beneficial direction as well,” Dr. Vassar said.

Dr. Sperling and colleagues’ study was sponsored by Janssen, the manufacturer of atabecestat. Dr. Sperling disclosed receiving research funding from Janssen and other drug makers, while nearly all the study’s coauthors reported being directly employed by the sponsor or receiving industry funding. Dr. Aisen disclosed personal fees from several manufacturers and past fees from the sponsor. Dr. Vassar disclosed consulting and other financial relationships with biotechnology companies that did not include this study’s sponsor.

Adverse cognitive and psychiatric effects seen associated with the investigational Alzheimer’s drug atabecestat were reversed within 6 months of treatment cessation, according to follow-up results from a truncated clinical trial.

A blinded, placebo-controlled, manufacturer-sponsored trial that had randomized 557 patients with preclinical Alzheimer’s disease to 25 mg daily oral atabecestat, 5 mg atabecestat, or placebo, was halted in 2018 over concerns about liver toxicity. The main outcome measure of the trial was change on the Alzheimer’s Disease Cooperative Study Preclinical Alzheimer Cognitive Composite, while two other scales were used to assess cognitive function and neuropsychological status.

A preliminary analysis found the higher dose of the atabecestat to significantly worsen subjects’ cognition starting at around 3 months of treatment, compared with placebo. Treatment with atabecestat was also seen associated with higher incidence of neuropsychiatric adverse events, including anxiety and depression.

In their follow-up study published Jan. 19, 2021 in JAMA Neurology (doi: 10.1001/jamaneurol.2020.4857), Reisa Sperling, MD, of Brigham and Women’s Hospital, Boston, and colleagues reported that the cognitive worsening and neuropsychiatric adverse effects seen linked to atabecestat treatment reverted to baseline levels within 6 months of halting treatment. Most of the worsening seen in the study was associated with episodic memory tasks, including “list learning, story memory, list recognition, story recall, and figure recall,” Dr. Sperling and colleagues found.

Atabecestat was also associated with “dose-related and duration-related decreases in whole-brain volume, compared with placebo treatment,” the investigators reported. Brain volume loss has been seen in trials of other beta-secretase (BACE) inhibitors and shown with one, umibecestat, to be reversible after stopping treatment.

Dr. Sperling and colleagues acknowledged as a major limitation of their study that just over a third of the cohort received another cognitive composite score after baseline. “The observation that cognitive worsening and neuropsychiatric-related [adverse events] recovered following discontinuation of atabecestat is encouraging but needs replication, given that the observation period after stopping treatment was variable and not preplanned,” the investigators wrote in their analysis. After a median exposure of 21 weeks to the study drug or placebo, subjects were followed off treatment for a median 15 weeks.
 

Questions surround BACE inhibitors

Development of atabecestat has been discontinued along with others in its class of agents, known as BACE inhibitors, which target an enzyme that initiates production of amyloid-beta, the plaque-forming peptide that is considered a driver of Alzheimer’s disease. In the past few years a number of BACE inhibitors have been shown in trials to worsen cognition in a dose-dependent way, compared with placebo. The reasons for these effects are still unknown.

Dr. Sperling and colleagues concluded that, if BACE investigators like atabecestat are to be studied anew, it must be at low doses, with more modest enzyme inhibition, and alongside careful safety and cognitive monitoring.

While no BACE inhibitor is currently in the pipeline for Alzheimer’s – trials of these agents have been stopped for futility or toxicity –Paul Aisen, MD of the University of Southern California, Los Angeles, and a coauthor of Dr. Sperling and colleagues’ study, commented that it was important that clinical investigation of BACE inhibitors continue. 

“This drug class is optimal to correct the metabolic dysregulation that is likely a primary root cause” of Alzheimer’s disease, Dr. Aisen said in an interview. “Evidence from trials such as this suggest that the cognitive toxicity of BACE inhibitors is dose related, nonprogressive, and reversible. We should now focus on establishing the safety of relatively low-dose BACE inhibition so that such regimens can be tested in AD trials.”
 

Research should continue

Robert Vassar, PhD, of Northwestern University, Chicago, who was not a coauthor on the study, also expressed a desire for BACE inhibitor research to continue.

“It is my view that the cognitive worsening of atabecestat and the other BACE inhibitors was caused by overinhibition of the enzyme related to functions of certain BACE substrates in the brain,” Dr. Vassar commented. “A major question is whether a lower dose of BACE inhibitor – achieving about 30% inhibition – could be safe and lower amyloid-beta enough to delay onset in people still without symptoms. The good news of this study is that the atabecestat-related cognitive worsening is reversible, leaving open the possibility of low-dose prevention trials.”

Dr. Vassar noted that, with both doses of atabecestat, Dr. Sperling and colleagues did not see changes in neurofilament light or total tau, two biomarkers of neurodegeneration, but did report decreases in phosphorylated tau (p181 tau), a marker of disease progression, compared with placebo.

“This indicates that atabecestat did not cause neurodegeneration and in fact moved p181 tau in the beneficial direction for Alzheimer’s disease. Perhaps if it were not for the liver toxicity, the trial may have been completed and other Alzheimer’s disease biomarkers may have changed in the beneficial direction as well,” Dr. Vassar said.

Dr. Sperling and colleagues’ study was sponsored by Janssen, the manufacturer of atabecestat. Dr. Sperling disclosed receiving research funding from Janssen and other drug makers, while nearly all the study’s coauthors reported being directly employed by the sponsor or receiving industry funding. Dr. Aisen disclosed personal fees from several manufacturers and past fees from the sponsor. Dr. Vassar disclosed consulting and other financial relationships with biotechnology companies that did not include this study’s sponsor.

Clinical trials enrolling patients with progressive multiple sclerosis (MS) commonly use the Expanded Disability Status Scale (EDSS), an instrument that looks at impairment across several different functional domains, as a primary outcome measure. But results from a new analysis of trial data suggest that the EDSS, in use since 1983, may be a noisier or more variation-prone measure of MS disease progression than two other widely used measures: the timed 25-foot walk and the 9-hole peg test.

For their research, published in the Jan. 5 issue of Neurology, Marcus W. Koch, MD, PhD, of the department of neurosciences at Hotchkiss Brain Institute at the University of Calgary (Alta.) and colleagues looked at data from the placebo arms of two randomized trials that collectively enrolled nearly 700 patients with secondary progressive MS (SPMS). The trials were similar in terms of baseline patient characteristics and level of disability.
 

Comparing three outcome measures

The investigators compared disability progression and improvement across each of the three instruments and their combinations. Because improvement is understood to occur only rarely in untreated secondary progressive MS, most improvement picked up in the placebo arm of a trial is assumed to be noise from random variation or measurement error.

Dr. Koch and colleagues found that the EDSS showed higher rates of improvement than the other tests. The EDSS also showed the smallest differences between progression and improvement among the three instruments, with improvement rate over time increasing in parallel with disability progression rates. With the other two tests, improvement rates remained low – at 10% or less – while disability was seen steadily increasing over time.

The results, the investigators wrote in their analysis, suggest that the timed 25-foot walk and 9-hole peg test are the more reliable outcome measures. The reason “may simply lie in the fact that both the timed 25-foot walk and 9-hole peg test are objective and quantitative interval-scaled measures while the EDSS is a graded categorical measure.” As primary outcome measures in clinical trials, “the lower noise of the timed 25-foot walk and 9-hole peg test may make them preferable over the EDSS,” Dr. Koch and colleagues concluded. The investigators noted that a 2019 analysis of different MS disability scales across more than 13,000 patients in 14 trials did not find such stark differences – but that the patients in the pooled trials had less disability at baseline (median EDSS score of 2.5, compared with 6.0 for the two trials in Dr. Koch and colleagues’ study). This suggests, the investigators wrote, “that the timed 25-foot walk and 9-hole peg test may be more useful outcomes in patients with a progressive disease course and with greater baseline disability.”
 

‘Considerable implications’ for the design of future clinical trials

In an accompanying editorial, Tomas Kalincik, MD, PhD, of the University of Melbourne, along with colleagues in Italy and Britain, praised Dr. Koch and colleagues’ study as having “considerable implications for the design of future clinical trials because detecting a treatment effect on an outcome that is subject to large measurement error is difficult.” Most trials in progressive MS use change in EDSS score as their primary or key secondary outcomes. “However, as the authors elegantly show, other, more reliable clinical outcomes are needed. As we are revisiting our biological hypotheses for treatment of progressive MS, perhaps the time has come that we should also revisit the instruments that we use to examine their efficacy.”

The editorialists allowed for the possibility that something besides noise or measurement error could be responsible for the disparities seen across the instruments. “An alternative interpretation of the presented results could be that recovery of neurologic function is more common in SPMS than what we had previously thought and that EDSS is more sensitive to its detection than the other two measures,” they wrote.

Dr. Koch and colleagues’ study received no outside funding. Dr. Koch disclosed consulting fees and other financial support from several drug manufacturers, and three coauthors also disclosed financial relationships with pharmaceutical companies. All three editorial writers disclosed similar relationships.

Clinical trials enrolling patients with progressive multiple sclerosis (MS) commonly use the Expanded Disability Status Scale (EDSS), an instrument that looks at impairment across several different functional domains, as a primary outcome measure. But results from a new analysis of trial data suggest that the EDSS, in use since 1983, may be a noisier or more variation-prone measure of MS disease progression than two other widely used measures: the timed 25-foot walk and the 9-hole peg test.

For their research, published in the Jan. 5 issue of Neurology, Marcus W. Koch, MD, PhD, of the department of neurosciences at Hotchkiss Brain Institute at the University of Calgary (Alta.) and colleagues looked at data from the placebo arms of two randomized trials that collectively enrolled nearly 700 patients with secondary progressive MS (SPMS). The trials were similar in terms of baseline patient characteristics and level of disability.
 

Comparing three outcome measures

The investigators compared disability progression and improvement across each of the three instruments and their combinations. Because improvement is understood to occur only rarely in untreated secondary progressive MS, most improvement picked up in the placebo arm of a trial is assumed to be noise from random variation or measurement error.

Dr. Koch and colleagues found that the EDSS showed higher rates of improvement than the other tests. The EDSS also showed the smallest differences between progression and improvement among the three instruments, with improvement rate over time increasing in parallel with disability progression rates. With the other two tests, improvement rates remained low – at 10% or less – while disability was seen steadily increasing over time.

The results, the investigators wrote in their analysis, suggest that the timed 25-foot walk and 9-hole peg test are the more reliable outcome measures. The reason “may simply lie in the fact that both the timed 25-foot walk and 9-hole peg test are objective and quantitative interval-scaled measures while the EDSS is a graded categorical measure.” As primary outcome measures in clinical trials, “the lower noise of the timed 25-foot walk and 9-hole peg test may make them preferable over the EDSS,” Dr. Koch and colleagues concluded. The investigators noted that a 2019 analysis of different MS disability scales across more than 13,000 patients in 14 trials did not find such stark differences – but that the patients in the pooled trials had less disability at baseline (median EDSS score of 2.5, compared with 6.0 for the two trials in Dr. Koch and colleagues’ study). This suggests, the investigators wrote, “that the timed 25-foot walk and 9-hole peg test may be more useful outcomes in patients with a progressive disease course and with greater baseline disability.”
 

‘Considerable implications’ for the design of future clinical trials

In an accompanying editorial, Tomas Kalincik, MD, PhD, of the University of Melbourne, along with colleagues in Italy and Britain, praised Dr. Koch and colleagues’ study as having “considerable implications for the design of future clinical trials because detecting a treatment effect on an outcome that is subject to large measurement error is difficult.” Most trials in progressive MS use change in EDSS score as their primary or key secondary outcomes. “However, as the authors elegantly show, other, more reliable clinical outcomes are needed. As we are revisiting our biological hypotheses for treatment of progressive MS, perhaps the time has come that we should also revisit the instruments that we use to examine their efficacy.”

The editorialists allowed for the possibility that something besides noise or measurement error could be responsible for the disparities seen across the instruments. “An alternative interpretation of the presented results could be that recovery of neurologic function is more common in SPMS than what we had previously thought and that EDSS is more sensitive to its detection than the other two measures,” they wrote.

Dr. Koch and colleagues’ study received no outside funding. Dr. Koch disclosed consulting fees and other financial support from several drug manufacturers, and three coauthors also disclosed financial relationships with pharmaceutical companies. All three editorial writers disclosed similar relationships.

Clinical trials enrolling patients with progressive multiple sclerosis (MS) commonly use the Expanded Disability Status Scale (EDSS), an instrument that looks at impairment across several different functional domains, as a primary outcome measure. But results from a new analysis of trial data suggest that the EDSS, in use since 1983, may be a noisier or more variation-prone measure of MS disease progression than two other widely used measures: the timed 25-foot walk and the 9-hole peg test.

For their research, published in the Jan. 5 issue of Neurology, Marcus W. Koch, MD, PhD, of the department of neurosciences at Hotchkiss Brain Institute at the University of Calgary (Alta.) and colleagues looked at data from the placebo arms of two randomized trials that collectively enrolled nearly 700 patients with secondary progressive MS (SPMS). The trials were similar in terms of baseline patient characteristics and level of disability.
 

Comparing three outcome measures

The investigators compared disability progression and improvement across each of the three instruments and their combinations. Because improvement is understood to occur only rarely in untreated secondary progressive MS, most improvement picked up in the placebo arm of a trial is assumed to be noise from random variation or measurement error.

Dr. Koch and colleagues found that the EDSS showed higher rates of improvement than the other tests. The EDSS also showed the smallest differences between progression and improvement among the three instruments, with improvement rate over time increasing in parallel with disability progression rates. With the other two tests, improvement rates remained low – at 10% or less – while disability was seen steadily increasing over time.

The results, the investigators wrote in their analysis, suggest that the timed 25-foot walk and 9-hole peg test are the more reliable outcome measures. The reason “may simply lie in the fact that both the timed 25-foot walk and 9-hole peg test are objective and quantitative interval-scaled measures while the EDSS is a graded categorical measure.” As primary outcome measures in clinical trials, “the lower noise of the timed 25-foot walk and 9-hole peg test may make them preferable over the EDSS,” Dr. Koch and colleagues concluded. The investigators noted that a 2019 analysis of different MS disability scales across more than 13,000 patients in 14 trials did not find such stark differences – but that the patients in the pooled trials had less disability at baseline (median EDSS score of 2.5, compared with 6.0 for the two trials in Dr. Koch and colleagues’ study). This suggests, the investigators wrote, “that the timed 25-foot walk and 9-hole peg test may be more useful outcomes in patients with a progressive disease course and with greater baseline disability.”
 

‘Considerable implications’ for the design of future clinical trials

In an accompanying editorial, Tomas Kalincik, MD, PhD, of the University of Melbourne, along with colleagues in Italy and Britain, praised Dr. Koch and colleagues’ study as having “considerable implications for the design of future clinical trials because detecting a treatment effect on an outcome that is subject to large measurement error is difficult.” Most trials in progressive MS use change in EDSS score as their primary or key secondary outcomes. “However, as the authors elegantly show, other, more reliable clinical outcomes are needed. As we are revisiting our biological hypotheses for treatment of progressive MS, perhaps the time has come that we should also revisit the instruments that we use to examine their efficacy.”

The editorialists allowed for the possibility that something besides noise or measurement error could be responsible for the disparities seen across the instruments. “An alternative interpretation of the presented results could be that recovery of neurologic function is more common in SPMS than what we had previously thought and that EDSS is more sensitive to its detection than the other two measures,” they wrote.

Dr. Koch and colleagues’ study received no outside funding. Dr. Koch disclosed consulting fees and other financial support from several drug manufacturers, and three coauthors also disclosed financial relationships with pharmaceutical companies. All three editorial writers disclosed similar relationships.

The incidence of idiopathic intracranial hypertension (IIH) – characterized by increased cerebrospinal fluid (CSF) pressure – is rising considerably, corresponding to population increases in body mass index (BMI), a new study has shown. “The condition is associated with a high rate of health care utilization, so the increasing incidence has important implications for health care professionals and policy makers in addressing the associated comorbidities,” said senior author William Owen Pickrell, PhD, Swansea University (Wales).

The study was published online Jan. 20 in Neurology.

IIH is a condition of unknown etiology that is strongly associated with obesity, the researchers noted. Predominantly affecting women of childbearing age, it causes chronic disabling headaches, visual disturbance, and in a minority of patients, permanent visual loss. The definitive management is weight loss, but a minority of patients require surgery to preserve vision.

People with IIH potentially have high rates of health care utilization, multiple specialist consultations, diagnostic tests, CSF diversion procedures, and complications related to CSF diversion surgery.  
 

Population study in Wales

Given that there is a paucity of data regarding the epidemiology, health care utilization, and outcomes of people with IIH, Dr. Pickrell and colleagues conducted the current retrospective cohort study, which aimed to determine the temporal trends of IIH incidence and prevalence in Wales and health care utilization associated with IIH. They also investigated the effects of socioeconomic deprivation and obesity on IIH epidemiology.

For the study, they used and validated primary and secondary care IIH diagnostic codes within the Secure Anonymised Information Linkage data bank, which is part of the national e-health records research infrastructure for Wales, to ascertain IIH cases and controls between 2003 and 2017. In total, 35 million patient-years of data were analyzed. Information was recorded on body mass index, deprivation quintile, CSF diversion surgery, and unscheduled hospital admissions in case and control cohorts.

“This is the first time the diagnostic codes for this condition have been validated. This is important as it is critical if we are studying a condition to know that the individuals we are studying actually have that condition,” Dr. Pickrell commented. “We were able to establish that the diagnostic codes were 92% sensitive and 87% specific – that’s pretty good.”

Results showed a significant increase in IIH incidence and prevalence in Wales. The prevalence of IIH in Wales increased sixfold from 12/100,000 in 2003 to 76/100,000 in 2017, and the incidence of IIH increased threefold from 2.3/100,000 per year in 2003 to 7.8/100,000 per year in 2017. This corresponded with increases in obesity rates: 29% of the population was obese in 2003, compared with 40% in 2017.
 

Reasons for the increase

“The considerable increase in IIH incidence is multifactorial but likely predominately due to rising obesity rates,” the authors noted. “The worldwide prevalence of obesity nearly tripled between 1975 and 2016 and therefore these results also have global relevance.”

The increase in IIH incidence may also be attributable to increased IIH diagnosis rates because of raised awareness of the condition and greater use of digital fundoscopy at routine optometry appointments, they suggested.

“We found a strong association between increasing BMI, sex (being female), and IIH. Around 85% of our IIH cohort were female, similar to other studies, and we also found a significant association with increased deprivation and IIH, particularly in women,” the authors reported.

IIH is associated with increasing deprivation in women even after adjusting for obesity suggesting additional etiologic factors associated with deprivation apart from BMI; this effect was not seen in men, pointing to sex-specific drivers for IIH, they added.

The results also show that individuals with IIH have increased rates of unscheduled health care utilization compared with a matched-control cohort. The rate ratio for unscheduled hospital admissions in the IIH cohort, compared with controls was 5.28.

“A considerable proportion of this excess in unscheduled hospital admissions occurs at the time of diagnosis and can be explained by the need for urgent investigation of papilloedema with brain imaging and spinal fluid analysis. However, there is also a considerable excess in unscheduled hospital admissions up to 2 years after diagnosis,” the authors reported.

They suggested that these admissions are likely to be for severe headache, and they say there is some scope to reduce emergency admissions through better management of headache, patient education, and rapid access to outpatient specialist advice.

They also pointed out that the rate of unscheduled admissions is higher in the IIH cohort in the 3 years leading up to diagnosis, suggesting an opportunity for earlier diagnosis and earlier intervention.

In their study population, 8% of patients with IIH received CSF diversion procedures a mean of 1.3 years after diagnosis, and these patients showed significantly increased unscheduled health care admission rates, compared with IIH patients who had not undergone such procedures.

“There are frequent complications with the shunts after surgery, which causes a high revision rate,” Dr. Pickrell commented. In this study, 40% of patients undergoing CSF diversion needed at least one CSF shunt revision procedure.

The study was supported by the Brain Repair and Intracranial Neurotherapeutics unit, Wales Gene Park, Health Data Research UK, Engineering and Physical Sciences Research Council, Economic and Social Research Council, Department of Health and Social Care (England), Chief Scientist Office of the Scottish Government Health and Social Care Directorates, Health and Social Care Research and Development Division (Wales), Public Health Agency (Northern Ireland), British Heart Foundation, and Wellcome Trust. The authors reported no relevant financial relationships.

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

The incidence of idiopathic intracranial hypertension (IIH) – characterized by increased cerebrospinal fluid (CSF) pressure – is rising considerably, corresponding to population increases in body mass index (BMI), a new study has shown. “The condition is associated with a high rate of health care utilization, so the increasing incidence has important implications for health care professionals and policy makers in addressing the associated comorbidities,” said senior author William Owen Pickrell, PhD, Swansea University (Wales).

The study was published online Jan. 20 in Neurology.

IIH is a condition of unknown etiology that is strongly associated with obesity, the researchers noted. Predominantly affecting women of childbearing age, it causes chronic disabling headaches, visual disturbance, and in a minority of patients, permanent visual loss. The definitive management is weight loss, but a minority of patients require surgery to preserve vision.

People with IIH potentially have high rates of health care utilization, multiple specialist consultations, diagnostic tests, CSF diversion procedures, and complications related to CSF diversion surgery.  
 

Population study in Wales

Given that there is a paucity of data regarding the epidemiology, health care utilization, and outcomes of people with IIH, Dr. Pickrell and colleagues conducted the current retrospective cohort study, which aimed to determine the temporal trends of IIH incidence and prevalence in Wales and health care utilization associated with IIH. They also investigated the effects of socioeconomic deprivation and obesity on IIH epidemiology.

For the study, they used and validated primary and secondary care IIH diagnostic codes within the Secure Anonymised Information Linkage data bank, which is part of the national e-health records research infrastructure for Wales, to ascertain IIH cases and controls between 2003 and 2017. In total, 35 million patient-years of data were analyzed. Information was recorded on body mass index, deprivation quintile, CSF diversion surgery, and unscheduled hospital admissions in case and control cohorts.

“This is the first time the diagnostic codes for this condition have been validated. This is important as it is critical if we are studying a condition to know that the individuals we are studying actually have that condition,” Dr. Pickrell commented. “We were able to establish that the diagnostic codes were 92% sensitive and 87% specific – that’s pretty good.”

Results showed a significant increase in IIH incidence and prevalence in Wales. The prevalence of IIH in Wales increased sixfold from 12/100,000 in 2003 to 76/100,000 in 2017, and the incidence of IIH increased threefold from 2.3/100,000 per year in 2003 to 7.8/100,000 per year in 2017. This corresponded with increases in obesity rates: 29% of the population was obese in 2003, compared with 40% in 2017.
 

Reasons for the increase

“The considerable increase in IIH incidence is multifactorial but likely predominately due to rising obesity rates,” the authors noted. “The worldwide prevalence of obesity nearly tripled between 1975 and 2016 and therefore these results also have global relevance.”

The increase in IIH incidence may also be attributable to increased IIH diagnosis rates because of raised awareness of the condition and greater use of digital fundoscopy at routine optometry appointments, they suggested.

“We found a strong association between increasing BMI, sex (being female), and IIH. Around 85% of our IIH cohort were female, similar to other studies, and we also found a significant association with increased deprivation and IIH, particularly in women,” the authors reported.

IIH is associated with increasing deprivation in women even after adjusting for obesity suggesting additional etiologic factors associated with deprivation apart from BMI; this effect was not seen in men, pointing to sex-specific drivers for IIH, they added.

The results also show that individuals with IIH have increased rates of unscheduled health care utilization compared with a matched-control cohort. The rate ratio for unscheduled hospital admissions in the IIH cohort, compared with controls was 5.28.

“A considerable proportion of this excess in unscheduled hospital admissions occurs at the time of diagnosis and can be explained by the need for urgent investigation of papilloedema with brain imaging and spinal fluid analysis. However, there is also a considerable excess in unscheduled hospital admissions up to 2 years after diagnosis,” the authors reported.

They suggested that these admissions are likely to be for severe headache, and they say there is some scope to reduce emergency admissions through better management of headache, patient education, and rapid access to outpatient specialist advice.

They also pointed out that the rate of unscheduled admissions is higher in the IIH cohort in the 3 years leading up to diagnosis, suggesting an opportunity for earlier diagnosis and earlier intervention.

In their study population, 8% of patients with IIH received CSF diversion procedures a mean of 1.3 years after diagnosis, and these patients showed significantly increased unscheduled health care admission rates, compared with IIH patients who had not undergone such procedures.

“There are frequent complications with the shunts after surgery, which causes a high revision rate,” Dr. Pickrell commented. In this study, 40% of patients undergoing CSF diversion needed at least one CSF shunt revision procedure.

The study was supported by the Brain Repair and Intracranial Neurotherapeutics unit, Wales Gene Park, Health Data Research UK, Engineering and Physical Sciences Research Council, Economic and Social Research Council, Department of Health and Social Care (England), Chief Scientist Office of the Scottish Government Health and Social Care Directorates, Health and Social Care Research and Development Division (Wales), Public Health Agency (Northern Ireland), British Heart Foundation, and Wellcome Trust. The authors reported no relevant financial relationships.

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

The incidence of idiopathic intracranial hypertension (IIH) – characterized by increased cerebrospinal fluid (CSF) pressure – is rising considerably, corresponding to population increases in body mass index (BMI), a new study has shown. “The condition is associated with a high rate of health care utilization, so the increasing incidence has important implications for health care professionals and policy makers in addressing the associated comorbidities,” said senior author William Owen Pickrell, PhD, Swansea University (Wales).

The study was published online Jan. 20 in Neurology.

IIH is a condition of unknown etiology that is strongly associated with obesity, the researchers noted. Predominantly affecting women of childbearing age, it causes chronic disabling headaches, visual disturbance, and in a minority of patients, permanent visual loss. The definitive management is weight loss, but a minority of patients require surgery to preserve vision.

People with IIH potentially have high rates of health care utilization, multiple specialist consultations, diagnostic tests, CSF diversion procedures, and complications related to CSF diversion surgery.  
 

Population study in Wales

Given that there is a paucity of data regarding the epidemiology, health care utilization, and outcomes of people with IIH, Dr. Pickrell and colleagues conducted the current retrospective cohort study, which aimed to determine the temporal trends of IIH incidence and prevalence in Wales and health care utilization associated with IIH. They also investigated the effects of socioeconomic deprivation and obesity on IIH epidemiology.

For the study, they used and validated primary and secondary care IIH diagnostic codes within the Secure Anonymised Information Linkage data bank, which is part of the national e-health records research infrastructure for Wales, to ascertain IIH cases and controls between 2003 and 2017. In total, 35 million patient-years of data were analyzed. Information was recorded on body mass index, deprivation quintile, CSF diversion surgery, and unscheduled hospital admissions in case and control cohorts.

“This is the first time the diagnostic codes for this condition have been validated. This is important as it is critical if we are studying a condition to know that the individuals we are studying actually have that condition,” Dr. Pickrell commented. “We were able to establish that the diagnostic codes were 92% sensitive and 87% specific – that’s pretty good.”

Results showed a significant increase in IIH incidence and prevalence in Wales. The prevalence of IIH in Wales increased sixfold from 12/100,000 in 2003 to 76/100,000 in 2017, and the incidence of IIH increased threefold from 2.3/100,000 per year in 2003 to 7.8/100,000 per year in 2017. This corresponded with increases in obesity rates: 29% of the population was obese in 2003, compared with 40% in 2017.
 

Reasons for the increase

“The considerable increase in IIH incidence is multifactorial but likely predominately due to rising obesity rates,” the authors noted. “The worldwide prevalence of obesity nearly tripled between 1975 and 2016 and therefore these results also have global relevance.”

The increase in IIH incidence may also be attributable to increased IIH diagnosis rates because of raised awareness of the condition and greater use of digital fundoscopy at routine optometry appointments, they suggested.

“We found a strong association between increasing BMI, sex (being female), and IIH. Around 85% of our IIH cohort were female, similar to other studies, and we also found a significant association with increased deprivation and IIH, particularly in women,” the authors reported.

IIH is associated with increasing deprivation in women even after adjusting for obesity suggesting additional etiologic factors associated with deprivation apart from BMI; this effect was not seen in men, pointing to sex-specific drivers for IIH, they added.

The results also show that individuals with IIH have increased rates of unscheduled health care utilization compared with a matched-control cohort. The rate ratio for unscheduled hospital admissions in the IIH cohort, compared with controls was 5.28.

“A considerable proportion of this excess in unscheduled hospital admissions occurs at the time of diagnosis and can be explained by the need for urgent investigation of papilloedema with brain imaging and spinal fluid analysis. However, there is also a considerable excess in unscheduled hospital admissions up to 2 years after diagnosis,” the authors reported.

They suggested that these admissions are likely to be for severe headache, and they say there is some scope to reduce emergency admissions through better management of headache, patient education, and rapid access to outpatient specialist advice.

They also pointed out that the rate of unscheduled admissions is higher in the IIH cohort in the 3 years leading up to diagnosis, suggesting an opportunity for earlier diagnosis and earlier intervention.

In their study population, 8% of patients with IIH received CSF diversion procedures a mean of 1.3 years after diagnosis, and these patients showed significantly increased unscheduled health care admission rates, compared with IIH patients who had not undergone such procedures.

“There are frequent complications with the shunts after surgery, which causes a high revision rate,” Dr. Pickrell commented. In this study, 40% of patients undergoing CSF diversion needed at least one CSF shunt revision procedure.

The study was supported by the Brain Repair and Intracranial Neurotherapeutics unit, Wales Gene Park, Health Data Research UK, Engineering and Physical Sciences Research Council, Economic and Social Research Council, Department of Health and Social Care (England), Chief Scientist Office of the Scottish Government Health and Social Care Directorates, Health and Social Care Research and Development Division (Wales), Public Health Agency (Northern Ireland), British Heart Foundation, and Wellcome Trust. The authors reported no relevant financial relationships.

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

The benefits of autologous hematopoietic stem cell transplant (AHSCT) for patients with multiple sclerosis (MS) persist for more than 10 years in the majority of patents, new data show. The study reports on 210 Italian patients who underwent AHSCT between 2007 and 2019. Among the entire study cohort, 79.5% of patients had not experienced worsening of disability at 5 years, and 65.5% had not experienced it at 10 years.

Patients with relapsing remitting MS had better results, with 85.5% experiencing no worsening of disability at 5 years, and 71.3% at 10 years. Among patients with progressive MS, 71.0% showed no worsening of disability at 5 years, and 57.2% at 10 years.

“This is the longest follow-up of AHSCT in MS patients so far to be reported,” said study author Matilde Inglese, MD, University of Genoa (Italy). “We have shown AHSCT to be highly effective to prevent long-term disability worsening in most treated patients.”

The study was published online Jan. 20 in Neurology.

“We suggest that AHSCT should be considered as a treatment strategy for MS not responding to conventional therapy,” the authors concluded.

The study had no control group, so a direct comparison is not possible. Nevertheless, Dr. Inglese said she believed these results are better than those that would be achieved with disease-modifying drug therapy for similar patients.

“The best patient candidates for this procedure are those with highly active multiple sclerosis who are not responsive to high-efficacy drugs, such as alemtuzumab or ocrelizumab,” Dr. Inglese commented. “Younger patients with an aggressive form of relapsing remitting MS tend to do the best, although patients with progressive forms of MS who still have active lesions on MRI also benefit.”
 

Renewing the immune system

The transplant procedure involves giving high-dose cyclophosphamide to stimulate mobilization of bone marrow stem cells, which are collected from peripheral blood. Patients then undergo intense immunosuppression with a cocktail of drugs to remove the autoreactive T cells, and the stem cells, which are not autoreactive, are reinfused.

“We are effectively renewing the immune system,” Dr. Inglese said. “While it is not correct to call it a cure, as we are not eliminating the etiology of the disease, it is the closest to complete suppression of the disease that we can get.”

Other results from the study show that among patients with relapsing remitting MS, rates of relapse-free survival were 78.1% at 5 years and 63.5% at 10 years.

Better results were achieved for patients who received the BEAM+ATG conditioning regimen for immunosuppression. That regimen includes carmustine, cytosine-arabinoside, etoposide, and melphalan, followed by rabbit antithymocyte globulin. Among patients with relapsing remitting disease who were treated with this protocol, rates of relapse-free survival were 86.4% at 5 years and 77.0% at 10 years.

For patients with relapsing remitting MS, the probability of achieving NEDA-3 status (no evidence of disease activity, including the absence of clinical relapses, disability worsening, and MRI inflammatory activity) was 62.2% at 5 years and 40.5% at 10 years.

Among those patients with relapsing remitting MS who received the BEAM+ATG conditioning protocol, NEDA-3 status was achieved in 67.7% at 5 years and in 54.9% at 10 years.

Three deaths occurred within 100 days following AHSCT (1.4% of the entire study population). One patient developed pulmonary thromboembolism, received fibrinolytic treatment, and died 48 hours later after intracranial hemorrhage. The second patient experienced engraftment failure and died 24 days after transplant because of an opportunistic infection. The third patient died 1 month after transplant from Wernicke-like encephalopathy. All the patients who died received the BEAM+ATG conditioning regimen. No transplant-related deaths occurred in patients who underwent transplant after 2007.

Dr. Inglese noted that the mortality rate associated with AHSCT has been greatly reduced in recent years. “We are seeing a very low mortality rate – about 0.3% – thanks to improvements in the procedure and better patient selection. This seems acceptable, given that we are treating patients with very aggressive disease who have a high risk of becoming significantly disabled relatively early in life,” she commented.

However, it is vitally important that the procedure be conducted in a specialized center with a highly experienced multidisciplinary team, she stressed.

In the Neurology article, the authors concluded: “Although patients with RRMS [relapsing remitting MS] are those who benefit the most from transplant, AHSCT has been also shown to prevent disability worsening in a large proportion of patients with active progressive MS.

“The BEAM+ATG conditioning protocol, although associated with a higher transplant mortality rate, was associated with a more pronounced suppression of clinical relapses and MRI inflammatory activity, allowing complete disease control in a higher proportion of patients,” they wrote.
 

Potent and durable efficacy, with caveats

Commenting on these latest findings, Jeffrey A. Cohen, MD, of the Mellen Center for Multiple Sclerosis at the Cleveland Clinic, said: “AHSCT appears to have potent and durable efficacy in MS but is associated with significant risk and cost.”

The patients who are most likely to benefit are young and have experienced the onset of disease relatively recently. They are still ambulatory with highly active MS and have experienced recent clinical relapses and/or MRI lesion activity, and such activity continues despite disease-modifying therapy, Dr. Cohen noted. He added that “AHSCT is a reasonable option for such patients who have essentially failed the available disease-modifying therapy options.”

He pointed out that the key question is where AHSCT belongs in the overall MS algorithm relative to other high-efficacy therapies. “We need to know whether it should be used more broadly rather than as a last resort.”

To address that question, several randomized trials comparing AHSCT with high-efficacy disease-modifying therapy are in progress, including the National Institutes of Health–sponsored BEAT-MS trial in the United States (for which Dr. Cohen is the lead investigator) and four European trials – NET-MS (for which Dr. Inglese is the lead investigator), STAR-MS, RAM-MS, and COAST-MS.

The current study was partially funded and supported by the Italian Multiple Sclerosis Foundation. Dr. Inglese disclosed no relevant financial relationships.

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

The benefits of autologous hematopoietic stem cell transplant (AHSCT) for patients with multiple sclerosis (MS) persist for more than 10 years in the majority of patents, new data show. The study reports on 210 Italian patients who underwent AHSCT between 2007 and 2019. Among the entire study cohort, 79.5% of patients had not experienced worsening of disability at 5 years, and 65.5% had not experienced it at 10 years.

Patients with relapsing remitting MS had better results, with 85.5% experiencing no worsening of disability at 5 years, and 71.3% at 10 years. Among patients with progressive MS, 71.0% showed no worsening of disability at 5 years, and 57.2% at 10 years.

“This is the longest follow-up of AHSCT in MS patients so far to be reported,” said study author Matilde Inglese, MD, University of Genoa (Italy). “We have shown AHSCT to be highly effective to prevent long-term disability worsening in most treated patients.”

The study was published online Jan. 20 in Neurology.

“We suggest that AHSCT should be considered as a treatment strategy for MS not responding to conventional therapy,” the authors concluded.

The study had no control group, so a direct comparison is not possible. Nevertheless, Dr. Inglese said she believed these results are better than those that would be achieved with disease-modifying drug therapy for similar patients.

“The best patient candidates for this procedure are those with highly active multiple sclerosis who are not responsive to high-efficacy drugs, such as alemtuzumab or ocrelizumab,” Dr. Inglese commented. “Younger patients with an aggressive form of relapsing remitting MS tend to do the best, although patients with progressive forms of MS who still have active lesions on MRI also benefit.”
 

Renewing the immune system

The transplant procedure involves giving high-dose cyclophosphamide to stimulate mobilization of bone marrow stem cells, which are collected from peripheral blood. Patients then undergo intense immunosuppression with a cocktail of drugs to remove the autoreactive T cells, and the stem cells, which are not autoreactive, are reinfused.

“We are effectively renewing the immune system,” Dr. Inglese said. “While it is not correct to call it a cure, as we are not eliminating the etiology of the disease, it is the closest to complete suppression of the disease that we can get.”

Other results from the study show that among patients with relapsing remitting MS, rates of relapse-free survival were 78.1% at 5 years and 63.5% at 10 years.

Better results were achieved for patients who received the BEAM+ATG conditioning regimen for immunosuppression. That regimen includes carmustine, cytosine-arabinoside, etoposide, and melphalan, followed by rabbit antithymocyte globulin. Among patients with relapsing remitting disease who were treated with this protocol, rates of relapse-free survival were 86.4% at 5 years and 77.0% at 10 years.

For patients with relapsing remitting MS, the probability of achieving NEDA-3 status (no evidence of disease activity, including the absence of clinical relapses, disability worsening, and MRI inflammatory activity) was 62.2% at 5 years and 40.5% at 10 years.

Among those patients with relapsing remitting MS who received the BEAM+ATG conditioning protocol, NEDA-3 status was achieved in 67.7% at 5 years and in 54.9% at 10 years.

Three deaths occurred within 100 days following AHSCT (1.4% of the entire study population). One patient developed pulmonary thromboembolism, received fibrinolytic treatment, and died 48 hours later after intracranial hemorrhage. The second patient experienced engraftment failure and died 24 days after transplant because of an opportunistic infection. The third patient died 1 month after transplant from Wernicke-like encephalopathy. All the patients who died received the BEAM+ATG conditioning regimen. No transplant-related deaths occurred in patients who underwent transplant after 2007.

Dr. Inglese noted that the mortality rate associated with AHSCT has been greatly reduced in recent years. “We are seeing a very low mortality rate – about 0.3% – thanks to improvements in the procedure and better patient selection. This seems acceptable, given that we are treating patients with very aggressive disease who have a high risk of becoming significantly disabled relatively early in life,” she commented.

However, it is vitally important that the procedure be conducted in a specialized center with a highly experienced multidisciplinary team, she stressed.

In the Neurology article, the authors concluded: “Although patients with RRMS [relapsing remitting MS] are those who benefit the most from transplant, AHSCT has been also shown to prevent disability worsening in a large proportion of patients with active progressive MS.

“The BEAM+ATG conditioning protocol, although associated with a higher transplant mortality rate, was associated with a more pronounced suppression of clinical relapses and MRI inflammatory activity, allowing complete disease control in a higher proportion of patients,” they wrote.
 

Potent and durable efficacy, with caveats

Commenting on these latest findings, Jeffrey A. Cohen, MD, of the Mellen Center for Multiple Sclerosis at the Cleveland Clinic, said: “AHSCT appears to have potent and durable efficacy in MS but is associated with significant risk and cost.”

The patients who are most likely to benefit are young and have experienced the onset of disease relatively recently. They are still ambulatory with highly active MS and have experienced recent clinical relapses and/or MRI lesion activity, and such activity continues despite disease-modifying therapy, Dr. Cohen noted. He added that “AHSCT is a reasonable option for such patients who have essentially failed the available disease-modifying therapy options.”

He pointed out that the key question is where AHSCT belongs in the overall MS algorithm relative to other high-efficacy therapies. “We need to know whether it should be used more broadly rather than as a last resort.”

To address that question, several randomized trials comparing AHSCT with high-efficacy disease-modifying therapy are in progress, including the National Institutes of Health–sponsored BEAT-MS trial in the United States (for which Dr. Cohen is the lead investigator) and four European trials – NET-MS (for which Dr. Inglese is the lead investigator), STAR-MS, RAM-MS, and COAST-MS.

The current study was partially funded and supported by the Italian Multiple Sclerosis Foundation. Dr. Inglese disclosed no relevant financial relationships.

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

The benefits of autologous hematopoietic stem cell transplant (AHSCT) for patients with multiple sclerosis (MS) persist for more than 10 years in the majority of patents, new data show. The study reports on 210 Italian patients who underwent AHSCT between 2007 and 2019. Among the entire study cohort, 79.5% of patients had not experienced worsening of disability at 5 years, and 65.5% had not experienced it at 10 years.

Patients with relapsing remitting MS had better results, with 85.5% experiencing no worsening of disability at 5 years, and 71.3% at 10 years. Among patients with progressive MS, 71.0% showed no worsening of disability at 5 years, and 57.2% at 10 years.

“This is the longest follow-up of AHSCT in MS patients so far to be reported,” said study author Matilde Inglese, MD, University of Genoa (Italy). “We have shown AHSCT to be highly effective to prevent long-term disability worsening in most treated patients.”

The study was published online Jan. 20 in Neurology.

“We suggest that AHSCT should be considered as a treatment strategy for MS not responding to conventional therapy,” the authors concluded.

The study had no control group, so a direct comparison is not possible. Nevertheless, Dr. Inglese said she believed these results are better than those that would be achieved with disease-modifying drug therapy for similar patients.

“The best patient candidates for this procedure are those with highly active multiple sclerosis who are not responsive to high-efficacy drugs, such as alemtuzumab or ocrelizumab,” Dr. Inglese commented. “Younger patients with an aggressive form of relapsing remitting MS tend to do the best, although patients with progressive forms of MS who still have active lesions on MRI also benefit.”
 

Renewing the immune system

The transplant procedure involves giving high-dose cyclophosphamide to stimulate mobilization of bone marrow stem cells, which are collected from peripheral blood. Patients then undergo intense immunosuppression with a cocktail of drugs to remove the autoreactive T cells, and the stem cells, which are not autoreactive, are reinfused.

“We are effectively renewing the immune system,” Dr. Inglese said. “While it is not correct to call it a cure, as we are not eliminating the etiology of the disease, it is the closest to complete suppression of the disease that we can get.”

Other results from the study show that among patients with relapsing remitting MS, rates of relapse-free survival were 78.1% at 5 years and 63.5% at 10 years.

Better results were achieved for patients who received the BEAM+ATG conditioning regimen for immunosuppression. That regimen includes carmustine, cytosine-arabinoside, etoposide, and melphalan, followed by rabbit antithymocyte globulin. Among patients with relapsing remitting disease who were treated with this protocol, rates of relapse-free survival were 86.4% at 5 years and 77.0% at 10 years.

For patients with relapsing remitting MS, the probability of achieving NEDA-3 status (no evidence of disease activity, including the absence of clinical relapses, disability worsening, and MRI inflammatory activity) was 62.2% at 5 years and 40.5% at 10 years.

Among those patients with relapsing remitting MS who received the BEAM+ATG conditioning protocol, NEDA-3 status was achieved in 67.7% at 5 years and in 54.9% at 10 years.

Three deaths occurred within 100 days following AHSCT (1.4% of the entire study population). One patient developed pulmonary thromboembolism, received fibrinolytic treatment, and died 48 hours later after intracranial hemorrhage. The second patient experienced engraftment failure and died 24 days after transplant because of an opportunistic infection. The third patient died 1 month after transplant from Wernicke-like encephalopathy. All the patients who died received the BEAM+ATG conditioning regimen. No transplant-related deaths occurred in patients who underwent transplant after 2007.

Dr. Inglese noted that the mortality rate associated with AHSCT has been greatly reduced in recent years. “We are seeing a very low mortality rate – about 0.3% – thanks to improvements in the procedure and better patient selection. This seems acceptable, given that we are treating patients with very aggressive disease who have a high risk of becoming significantly disabled relatively early in life,” she commented.

However, it is vitally important that the procedure be conducted in a specialized center with a highly experienced multidisciplinary team, she stressed.

In the Neurology article, the authors concluded: “Although patients with RRMS [relapsing remitting MS] are those who benefit the most from transplant, AHSCT has been also shown to prevent disability worsening in a large proportion of patients with active progressive MS.

“The BEAM+ATG conditioning protocol, although associated with a higher transplant mortality rate, was associated with a more pronounced suppression of clinical relapses and MRI inflammatory activity, allowing complete disease control in a higher proportion of patients,” they wrote.
 

Potent and durable efficacy, with caveats

Commenting on these latest findings, Jeffrey A. Cohen, MD, of the Mellen Center for Multiple Sclerosis at the Cleveland Clinic, said: “AHSCT appears to have potent and durable efficacy in MS but is associated with significant risk and cost.”

The patients who are most likely to benefit are young and have experienced the onset of disease relatively recently. They are still ambulatory with highly active MS and have experienced recent clinical relapses and/or MRI lesion activity, and such activity continues despite disease-modifying therapy, Dr. Cohen noted. He added that “AHSCT is a reasonable option for such patients who have essentially failed the available disease-modifying therapy options.”

He pointed out that the key question is where AHSCT belongs in the overall MS algorithm relative to other high-efficacy therapies. “We need to know whether it should be used more broadly rather than as a last resort.”

To address that question, several randomized trials comparing AHSCT with high-efficacy disease-modifying therapy are in progress, including the National Institutes of Health–sponsored BEAT-MS trial in the United States (for which Dr. Cohen is the lead investigator) and four European trials – NET-MS (for which Dr. Inglese is the lead investigator), STAR-MS, RAM-MS, and COAST-MS.

The current study was partially funded and supported by the Italian Multiple Sclerosis Foundation. Dr. Inglese disclosed no relevant financial relationships.

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