MDedge Neurology

TOPLINE: 

Dual antiplatelet therapy (DAPT) with clopidogrel-aspirin given within 72 hours of a mild ischemic stroke or a high-risk transient ischemic attack (TIA) shows a greater risk reduction for new stroke than aspirin alone, although with a higher bleeding risk.

METHODOLOGY:

• The INSPIRES, a double-blind, placebo-controlled trial, involved patients with mild ischemic stroke or high-risk TIA of presumed atherosclerotic cause who had not undergone thrombolysis or thrombectomy.
• A total of 6100 patients were randomly assigned to receive clopidogrel plus aspirin or matching clopidogrel placebo plus aspirin within 72 hours after symptom onset.
• The occurrence of any new stroke (ischemic or hemorrhagic) within 90 days was the primary efficacy outcome.
• The primary safety outcome was moderate to severe bleeding, also assessed within 90 days.

TAKEAWAY:

• Within 24 hours of symptom onset, 12.8% of patients were assigned to each treatment group, and the remaining 87.2% were assigned within the time window of 24-72 hours.
• (7.3% vs 9.2%; marginal estimated hazard ratio [HR], 0.79; P =.008).
• The risk of a composite cardiovascular event and ischemic stroke were also 20%-25% lower with aspirin-clopidogrel combo vs aspirin alone.
• Moderate to severe bleeding was low in both groups (<1%), but the risk was double in patients who received DAPT vs aspirin alone (HR, 2.08; P =.03).

IN PRACTICE:

In an accompanying editorial, Anthony S. Kim, MD from the UCSF Weill Institute for Neurosciences, Department of Neurology, University of California, San Francisco, commented, “The current trial provides evidence to support expanding the time window for dual antiplatelet therapy to 72 hours.” He also warned against administering DAPT to “patients with heightened bleeding risks, such as those with a history of cerebral or systemic hemorrhage.”

SOURCE:

Yilong Wang, MD, PhD, who held positions in the Department of Neurology, Beijing Tiantan Hospital, and several other institutions, was the corresponding author of this study. This study was published online December 28 in the New England Journal of Medicine.

LIMITATIONS:

• Patients with stroke of presumed cardioembolic origin, those with moderate or severe stroke, and those who had undergone thrombolysis or thrombectomy were excluded from this study.
• Of the enrolled participants, 98.5% belonged to the Han Chinese ethnic group.

DISCLOSURES:

This study was supported by grants from the National Natural Science Foundation of China, the National Key R&D Program of China, and other sources. Some authors declared receiving grants or contracts or serving as consultants in various sources.

A version of this article appeared on Medscape.com.

TOPLINE: 

Dual antiplatelet therapy (DAPT) with clopidogrel-aspirin given within 72 hours of a mild ischemic stroke or a high-risk transient ischemic attack (TIA) shows a greater risk reduction for new stroke than aspirin alone, although with a higher bleeding risk.

METHODOLOGY:

• The INSPIRES, a double-blind, placebo-controlled trial, involved patients with mild ischemic stroke or high-risk TIA of presumed atherosclerotic cause who had not undergone thrombolysis or thrombectomy.
• A total of 6100 patients were randomly assigned to receive clopidogrel plus aspirin or matching clopidogrel placebo plus aspirin within 72 hours after symptom onset.
• The occurrence of any new stroke (ischemic or hemorrhagic) within 90 days was the primary efficacy outcome.
• The primary safety outcome was moderate to severe bleeding, also assessed within 90 days.

TAKEAWAY:

• Within 24 hours of symptom onset, 12.8% of patients were assigned to each treatment group, and the remaining 87.2% were assigned within the time window of 24-72 hours.
• (7.3% vs 9.2%; marginal estimated hazard ratio [HR], 0.79; P =.008).
• The risk of a composite cardiovascular event and ischemic stroke were also 20%-25% lower with aspirin-clopidogrel combo vs aspirin alone.
• Moderate to severe bleeding was low in both groups (<1%), but the risk was double in patients who received DAPT vs aspirin alone (HR, 2.08; P =.03).

IN PRACTICE:

In an accompanying editorial, Anthony S. Kim, MD from the UCSF Weill Institute for Neurosciences, Department of Neurology, University of California, San Francisco, commented, “The current trial provides evidence to support expanding the time window for dual antiplatelet therapy to 72 hours.” He also warned against administering DAPT to “patients with heightened bleeding risks, such as those with a history of cerebral or systemic hemorrhage.”

SOURCE:

Yilong Wang, MD, PhD, who held positions in the Department of Neurology, Beijing Tiantan Hospital, and several other institutions, was the corresponding author of this study. This study was published online December 28 in the New England Journal of Medicine.

LIMITATIONS:

• Patients with stroke of presumed cardioembolic origin, those with moderate or severe stroke, and those who had undergone thrombolysis or thrombectomy were excluded from this study.
• Of the enrolled participants, 98.5% belonged to the Han Chinese ethnic group.

DISCLOSURES:

This study was supported by grants from the National Natural Science Foundation of China, the National Key R&D Program of China, and other sources. Some authors declared receiving grants or contracts or serving as consultants in various sources.

A version of this article appeared on Medscape.com.

TOPLINE: 

Dual antiplatelet therapy (DAPT) with clopidogrel-aspirin given within 72 hours of a mild ischemic stroke or a high-risk transient ischemic attack (TIA) shows a greater risk reduction for new stroke than aspirin alone, although with a higher bleeding risk.

METHODOLOGY:

• The INSPIRES, a double-blind, placebo-controlled trial, involved patients with mild ischemic stroke or high-risk TIA of presumed atherosclerotic cause who had not undergone thrombolysis or thrombectomy.
• A total of 6100 patients were randomly assigned to receive clopidogrel plus aspirin or matching clopidogrel placebo plus aspirin within 72 hours after symptom onset.
• The occurrence of any new stroke (ischemic or hemorrhagic) within 90 days was the primary efficacy outcome.
• The primary safety outcome was moderate to severe bleeding, also assessed within 90 days.

TAKEAWAY:

• Within 24 hours of symptom onset, 12.8% of patients were assigned to each treatment group, and the remaining 87.2% were assigned within the time window of 24-72 hours.
• (7.3% vs 9.2%; marginal estimated hazard ratio [HR], 0.79; P =.008).
• The risk of a composite cardiovascular event and ischemic stroke were also 20%-25% lower with aspirin-clopidogrel combo vs aspirin alone.
• Moderate to severe bleeding was low in both groups (<1%), but the risk was double in patients who received DAPT vs aspirin alone (HR, 2.08; P =.03).

IN PRACTICE:

In an accompanying editorial, Anthony S. Kim, MD from the UCSF Weill Institute for Neurosciences, Department of Neurology, University of California, San Francisco, commented, “The current trial provides evidence to support expanding the time window for dual antiplatelet therapy to 72 hours.” He also warned against administering DAPT to “patients with heightened bleeding risks, such as those with a history of cerebral or systemic hemorrhage.”

SOURCE:

Yilong Wang, MD, PhD, who held positions in the Department of Neurology, Beijing Tiantan Hospital, and several other institutions, was the corresponding author of this study. This study was published online December 28 in the New England Journal of Medicine.

LIMITATIONS:

• Patients with stroke of presumed cardioembolic origin, those with moderate or severe stroke, and those who had undergone thrombolysis or thrombectomy were excluded from this study.
• Of the enrolled participants, 98.5% belonged to the Han Chinese ethnic group.

DISCLOSURES:

This study was supported by grants from the National Natural Science Foundation of China, the National Key R&D Program of China, and other sources. Some authors declared receiving grants or contracts or serving as consultants in various sources.

A version of this article appeared on Medscape.com.

Claiming that both cosmetic and therapeutic uses of Botox and related products can lead to systemic iatrogenic botulism, Public Citizen is asking the Food and Drug Administration (FDA) to strengthen warnings on the labeling of all approved botulinum toxin products.

The nonprofit watchdog group successfully petitioned the FDA in 2008 to require a warning for Botox and related products regarding the risk of distant spread of the toxin. In its latest petition to the agency, it says that the injectables need additional warnings about the possibility of iatrogenic botulism with initial and repeated doses and that individuals who contract the condition may need botulinum antitoxin to avert temporary muscle paralysis, hospitalization, and death.

The current warning does not contain any information about the potential need for antitoxin and downplays the need for giving antitoxin in the settings of excessive dosing, accidental injection, and oral ingestion, said Public Citizen.

“Our petition is based on clear postmarketing evidence that refutes industry propaganda claiming that Botox and related drugs are ‘always safe’ and that no ‘definitive’ cases of botulism have occurred with recommended doses,” Azza AbuDagga, PhD, health services researcher at Public Citizen’s Health Research Group, said in a statement.

Public Citizen said that using data from the FDA’s Adverse Event Reporting System (FAERS), it found 5414 reports of serious outcomes from botulinum toxin products from January 1989 through March 2021. Almost 22% involved cosmetic indications and about 78% involved therapeutic indications.

Of the 5414 reports, 121 (2%) specified botulism as an adverse reaction; 89 involved therapeutic uses of a botulinum toxin products, and 32 involved cosmetic uses. Many of those 121 reports involved doses within the recommended range for the indication, according to Public Citizen.

The group is also asking the FDA to remove what it calls misleading promotional statements in the labeling of Botox and Botox Cosmetic and from the medication guides for those products. The labels state that there have been “no definitive serious adverse event reports of distant spread of toxin effect” with either the cosmetic use or for use in treating chronic migraine, severe underarm sweating, blepharospasm, or strabismus. These statements do not appear in similar labeling in other countries, such as Canada and the United Kingdom, said Public Citizen.

“The FDA needs to implement our two requested actions quickly to warn the public in unambiguous terms about the risk of botulism associated with the use of Botox and related drugs,” Dr. AbuDagga said in the Public Citizen statement. “This will allow health care professionals and patients to make more informed decisions about the benefit-risk profile of these widely used drugs.”

The Public Citizen petition would apply to all seven approved botulinum toxin biological products: abobotulinumtoxinA (Dysport), daxibotulinumtoxinA-lanm (Daxxify), incobotulinumtoxinA (Xeomin), onabotulinumtoxinA (Botox, Botox Cosmetic), prabotulinumtoxinA-xvfs (Jeuveau) and rimabotulinumtoxinB (Myobloc).

An FDA spokesperson said the agency is reviewing the citizen petition, and that generally the agency does not comment on pending petitions. “When we respond to the petition, we will respond directly to the petitioner and post the response in the designated agency docket,” the spokesperson told this news organization. At press time, Botox manufacturer AbbVie had not responded to a request for a comment.

Botulinum toxin is the most-used product for nonsurgical cosmetic procedures, according to the International Society of Aesthetic Plastic Surgery (ISAPS). The ISAPS reported that there were more than 7 million botulinum toxin procedures performed by plastic surgeons worldwide in 2021.

The American Society of Plastic Surgery reported that its members performed 4.4 million Botox procedures in 2020, while the American Society of Dermatologic Surgery (ASDS) said its members performed 2.3 million wrinkle-relaxing procedures in 2019, a 60% increase since 2012.

Claiming that both cosmetic and therapeutic uses of Botox and related products can lead to systemic iatrogenic botulism, Public Citizen is asking the Food and Drug Administration (FDA) to strengthen warnings on the labeling of all approved botulinum toxin products.

The nonprofit watchdog group successfully petitioned the FDA in 2008 to require a warning for Botox and related products regarding the risk of distant spread of the toxin. In its latest petition to the agency, it says that the injectables need additional warnings about the possibility of iatrogenic botulism with initial and repeated doses and that individuals who contract the condition may need botulinum antitoxin to avert temporary muscle paralysis, hospitalization, and death.

The current warning does not contain any information about the potential need for antitoxin and downplays the need for giving antitoxin in the settings of excessive dosing, accidental injection, and oral ingestion, said Public Citizen.

“Our petition is based on clear postmarketing evidence that refutes industry propaganda claiming that Botox and related drugs are ‘always safe’ and that no ‘definitive’ cases of botulism have occurred with recommended doses,” Azza AbuDagga, PhD, health services researcher at Public Citizen’s Health Research Group, said in a statement.

Public Citizen said that using data from the FDA’s Adverse Event Reporting System (FAERS), it found 5414 reports of serious outcomes from botulinum toxin products from January 1989 through March 2021. Almost 22% involved cosmetic indications and about 78% involved therapeutic indications.

Of the 5414 reports, 121 (2%) specified botulism as an adverse reaction; 89 involved therapeutic uses of a botulinum toxin products, and 32 involved cosmetic uses. Many of those 121 reports involved doses within the recommended range for the indication, according to Public Citizen.

The group is also asking the FDA to remove what it calls misleading promotional statements in the labeling of Botox and Botox Cosmetic and from the medication guides for those products. The labels state that there have been “no definitive serious adverse event reports of distant spread of toxin effect” with either the cosmetic use or for use in treating chronic migraine, severe underarm sweating, blepharospasm, or strabismus. These statements do not appear in similar labeling in other countries, such as Canada and the United Kingdom, said Public Citizen.

“The FDA needs to implement our two requested actions quickly to warn the public in unambiguous terms about the risk of botulism associated with the use of Botox and related drugs,” Dr. AbuDagga said in the Public Citizen statement. “This will allow health care professionals and patients to make more informed decisions about the benefit-risk profile of these widely used drugs.”

The Public Citizen petition would apply to all seven approved botulinum toxin biological products: abobotulinumtoxinA (Dysport), daxibotulinumtoxinA-lanm (Daxxify), incobotulinumtoxinA (Xeomin), onabotulinumtoxinA (Botox, Botox Cosmetic), prabotulinumtoxinA-xvfs (Jeuveau) and rimabotulinumtoxinB (Myobloc).

An FDA spokesperson said the agency is reviewing the citizen petition, and that generally the agency does not comment on pending petitions. “When we respond to the petition, we will respond directly to the petitioner and post the response in the designated agency docket,” the spokesperson told this news organization. At press time, Botox manufacturer AbbVie had not responded to a request for a comment.

Botulinum toxin is the most-used product for nonsurgical cosmetic procedures, according to the International Society of Aesthetic Plastic Surgery (ISAPS). The ISAPS reported that there were more than 7 million botulinum toxin procedures performed by plastic surgeons worldwide in 2021.

The American Society of Plastic Surgery reported that its members performed 4.4 million Botox procedures in 2020, while the American Society of Dermatologic Surgery (ASDS) said its members performed 2.3 million wrinkle-relaxing procedures in 2019, a 60% increase since 2012.

Claiming that both cosmetic and therapeutic uses of Botox and related products can lead to systemic iatrogenic botulism, Public Citizen is asking the Food and Drug Administration (FDA) to strengthen warnings on the labeling of all approved botulinum toxin products.

The nonprofit watchdog group successfully petitioned the FDA in 2008 to require a warning for Botox and related products regarding the risk of distant spread of the toxin. In its latest petition to the agency, it says that the injectables need additional warnings about the possibility of iatrogenic botulism with initial and repeated doses and that individuals who contract the condition may need botulinum antitoxin to avert temporary muscle paralysis, hospitalization, and death.

The current warning does not contain any information about the potential need for antitoxin and downplays the need for giving antitoxin in the settings of excessive dosing, accidental injection, and oral ingestion, said Public Citizen.

“Our petition is based on clear postmarketing evidence that refutes industry propaganda claiming that Botox and related drugs are ‘always safe’ and that no ‘definitive’ cases of botulism have occurred with recommended doses,” Azza AbuDagga, PhD, health services researcher at Public Citizen’s Health Research Group, said in a statement.

Public Citizen said that using data from the FDA’s Adverse Event Reporting System (FAERS), it found 5414 reports of serious outcomes from botulinum toxin products from January 1989 through March 2021. Almost 22% involved cosmetic indications and about 78% involved therapeutic indications.

Of the 5414 reports, 121 (2%) specified botulism as an adverse reaction; 89 involved therapeutic uses of a botulinum toxin products, and 32 involved cosmetic uses. Many of those 121 reports involved doses within the recommended range for the indication, according to Public Citizen.

The group is also asking the FDA to remove what it calls misleading promotional statements in the labeling of Botox and Botox Cosmetic and from the medication guides for those products. The labels state that there have been “no definitive serious adverse event reports of distant spread of toxin effect” with either the cosmetic use or for use in treating chronic migraine, severe underarm sweating, blepharospasm, or strabismus. These statements do not appear in similar labeling in other countries, such as Canada and the United Kingdom, said Public Citizen.

“The FDA needs to implement our two requested actions quickly to warn the public in unambiguous terms about the risk of botulism associated with the use of Botox and related drugs,” Dr. AbuDagga said in the Public Citizen statement. “This will allow health care professionals and patients to make more informed decisions about the benefit-risk profile of these widely used drugs.”

The Public Citizen petition would apply to all seven approved botulinum toxin biological products: abobotulinumtoxinA (Dysport), daxibotulinumtoxinA-lanm (Daxxify), incobotulinumtoxinA (Xeomin), onabotulinumtoxinA (Botox, Botox Cosmetic), prabotulinumtoxinA-xvfs (Jeuveau) and rimabotulinumtoxinB (Myobloc).

An FDA spokesperson said the agency is reviewing the citizen petition, and that generally the agency does not comment on pending petitions. “When we respond to the petition, we will respond directly to the petitioner and post the response in the designated agency docket,” the spokesperson told this news organization. At press time, Botox manufacturer AbbVie had not responded to a request for a comment.

Botulinum toxin is the most-used product for nonsurgical cosmetic procedures, according to the International Society of Aesthetic Plastic Surgery (ISAPS). The ISAPS reported that there were more than 7 million botulinum toxin procedures performed by plastic surgeons worldwide in 2021.

The American Society of Plastic Surgery reported that its members performed 4.4 million Botox procedures in 2020, while the American Society of Dermatologic Surgery (ASDS) said its members performed 2.3 million wrinkle-relaxing procedures in 2019, a 60% increase since 2012.

A new study that incorporated optical coherence tomography angiography (OCTA) has identified significant differences in retinal perfusion and macular anatomy during migraine attacks. Together, these changes could one day represent migraine biomarkers, authors say. The study was published online in Headache.

“We’re always looking for a biological marker for migraine,” said Alan M. Rapoport, MD, a clinical professor of neurology in the David Geffen School of Medicine at the University of California Los Angeles and past president of the International Headache Society. Researchers have identified many parameters that make people more likely to experience migraine, he said, but there remains no smoking gun. “We do not yet have a diagnostic test.”

Investigators have long been examining ocular vascular supply, added Dr. Rapoport, who was not involved with the study, because the eyes, visual system of the brain, and migraine are closely related. “But no one has ever figured out that one could use anything related to the eye as a definitive diagnostic test. This study was interesting because researchers used a very advanced technique to see if there are changes in the vascular supply to the eyeball during migraine.”
 

During Attacks

Study investigators prospectively enrolled 37 patients diagnosed with migraine with aura (MA), 30 with migraine without aura (MO), and 20 healthy controls. All subjects underwent macular OCTA for interictal analysis. A total of 20 patients with migraine (12 with MA and 8 with MO) underwent repeat scans during migraine attacks, and 5 control patients had repeat scans.

Compared with interictal measurements, significant parafoveal reductions in vessel flux index, an indicator of retinal perfusion, occurred in both the MA and MO groups during migraine attacks: –7% (95% CI, –10% to –4%; P = .006) and –7% (95% CI, –10% to –3%; P = .016), respectively, versus controls (2%, 95% CI, –3% to 7%).

The fact that migraine attacks resulted in reduced blood supply to the retinal region responsible for central vision is intriguing, said Dr. Rapoport, because sufficient reductions in blood supply there could result in blurred vision or other visual difficulties that might be mistaken for a true aura. “Many patients describe blurred vision related to their migraine headaches which do not usually qualify for an aura diagnosis,” he said.

Diagnostic criteria for MA, which afflicts around one third of people with migraine, include visual aberrations lasting at least 5 minutes and no more than 60 minutes. Visual aberrations average about 20-25 minutes, said Dr. Rapoport. “And we don’t usually accept blurred vision.” For most people who experience ictal blurred vision, he added, the phenomenon only lasts a short time and is not considered an aura.

More typical visual manifestations of MA include zigzag lines in an overall crescent shape that may blink, have bright edges, grow and shrink in size, and/or move across the visual field; patients also may have blind spots or distortions (e.g. far away vision, smaller or larger vision, or kaleidoscopic fractured vision). Nevertheless, said Dr. Rapoport, the study may shed light on why some people experiencing a migraine attack may suffer a brief bout of blurred vision and mistakenly report experiencing an aura.
 

Between Attacks

Comparing the two migraine groups interictally showed statistically significant differences in macular structure and function. Compared with the MO cohort, the MA cohort had higher circularity (mean [SD] 0.686 [0.088] vs. 0.629 [0.120] MO, P = .004), as well as a 13% (SD ± 10%, P = .003) lower foveal vessel flux index. “Not only is perfusion lower in both types of migraine during the attack,” said Dr. Rapoport, “but between attacks, people with MA had a lower blood supply to the retina than those who had MO.”

Unilateral Migraine

In a subset of patients (14 with MA and 12 with MO) whose headaches occurred unilaterally, investigators found retinal vascular parameters consistent with greater perfusion in the ipsilateral eye versus the contralateral eye. The significance of these findings remains unclear, Dr. Rapoport said, because circulatory findings revealed by CAT or MRI scans of patients with unilateral headaches are often normal or involve complex changes or mild edema on the side of the headache. The visual cortex on either side receives input from both eyes, he added.

Study Limitations

Authors acknowledged several study shortcomings. Most notably, COVID-19 restrictions resulted in a small sample size, and several patients (excluded from analysis) failed to return for repeat scans during migraine attacks. The study included patients with migraine attacks of varying frequency, and a handful of patients used acute rescue medications before undergoing ictal scans.

“If a future study corrected all these shortcomings,” Dr. Rapoport said, “the results might be more impressive and even more significant.” Based on these results alone, he said, it would be premature to pronounce OCTA-derived measurements of retinal perfusion and related parameters as future migraine biomarkers.

“But it’s a good start. If this hasn’t been done before, in quite this way, this is a very interesting study which, when repeated, should lead to even more significant findings.”

For now, the paper should remind practicing neurologists to dig deeper when patients complain of visual problems during migraine attacks. “It might be blurred vision for just 3 minutes,” he said. “Some patients may be calling it an aura, or the doctor may be thinking it is an aura because they’re not digging for further information in the history. We may now have a window into decreased retinal perfusion during a migraine attack and why some patients have blurred vision.”

The study was funded by the Amgen and the Baldwin Foundation. Dr. Rapoport is editor-in-chief of Neurology Reviews but reports no relevant relationships with the funders of this research.

A new study that incorporated optical coherence tomography angiography (OCTA) has identified significant differences in retinal perfusion and macular anatomy during migraine attacks. Together, these changes could one day represent migraine biomarkers, authors say. The study was published online in Headache.

“We’re always looking for a biological marker for migraine,” said Alan M. Rapoport, MD, a clinical professor of neurology in the David Geffen School of Medicine at the University of California Los Angeles and past president of the International Headache Society. Researchers have identified many parameters that make people more likely to experience migraine, he said, but there remains no smoking gun. “We do not yet have a diagnostic test.”

Investigators have long been examining ocular vascular supply, added Dr. Rapoport, who was not involved with the study, because the eyes, visual system of the brain, and migraine are closely related. “But no one has ever figured out that one could use anything related to the eye as a definitive diagnostic test. This study was interesting because researchers used a very advanced technique to see if there are changes in the vascular supply to the eyeball during migraine.”
 

During Attacks

Study investigators prospectively enrolled 37 patients diagnosed with migraine with aura (MA), 30 with migraine without aura (MO), and 20 healthy controls. All subjects underwent macular OCTA for interictal analysis. A total of 20 patients with migraine (12 with MA and 8 with MO) underwent repeat scans during migraine attacks, and 5 control patients had repeat scans.

Compared with interictal measurements, significant parafoveal reductions in vessel flux index, an indicator of retinal perfusion, occurred in both the MA and MO groups during migraine attacks: –7% (95% CI, –10% to –4%; P = .006) and –7% (95% CI, –10% to –3%; P = .016), respectively, versus controls (2%, 95% CI, –3% to 7%).

The fact that migraine attacks resulted in reduced blood supply to the retinal region responsible for central vision is intriguing, said Dr. Rapoport, because sufficient reductions in blood supply there could result in blurred vision or other visual difficulties that might be mistaken for a true aura. “Many patients describe blurred vision related to their migraine headaches which do not usually qualify for an aura diagnosis,” he said.

Diagnostic criteria for MA, which afflicts around one third of people with migraine, include visual aberrations lasting at least 5 minutes and no more than 60 minutes. Visual aberrations average about 20-25 minutes, said Dr. Rapoport. “And we don’t usually accept blurred vision.” For most people who experience ictal blurred vision, he added, the phenomenon only lasts a short time and is not considered an aura.

More typical visual manifestations of MA include zigzag lines in an overall crescent shape that may blink, have bright edges, grow and shrink in size, and/or move across the visual field; patients also may have blind spots or distortions (e.g. far away vision, smaller or larger vision, or kaleidoscopic fractured vision). Nevertheless, said Dr. Rapoport, the study may shed light on why some people experiencing a migraine attack may suffer a brief bout of blurred vision and mistakenly report experiencing an aura.
 

Between Attacks

Comparing the two migraine groups interictally showed statistically significant differences in macular structure and function. Compared with the MO cohort, the MA cohort had higher circularity (mean [SD] 0.686 [0.088] vs. 0.629 [0.120] MO, P = .004), as well as a 13% (SD ± 10%, P = .003) lower foveal vessel flux index. “Not only is perfusion lower in both types of migraine during the attack,” said Dr. Rapoport, “but between attacks, people with MA had a lower blood supply to the retina than those who had MO.”

Unilateral Migraine

In a subset of patients (14 with MA and 12 with MO) whose headaches occurred unilaterally, investigators found retinal vascular parameters consistent with greater perfusion in the ipsilateral eye versus the contralateral eye. The significance of these findings remains unclear, Dr. Rapoport said, because circulatory findings revealed by CAT or MRI scans of patients with unilateral headaches are often normal or involve complex changes or mild edema on the side of the headache. The visual cortex on either side receives input from both eyes, he added.

Study Limitations

Authors acknowledged several study shortcomings. Most notably, COVID-19 restrictions resulted in a small sample size, and several patients (excluded from analysis) failed to return for repeat scans during migraine attacks. The study included patients with migraine attacks of varying frequency, and a handful of patients used acute rescue medications before undergoing ictal scans.

“If a future study corrected all these shortcomings,” Dr. Rapoport said, “the results might be more impressive and even more significant.” Based on these results alone, he said, it would be premature to pronounce OCTA-derived measurements of retinal perfusion and related parameters as future migraine biomarkers.

“But it’s a good start. If this hasn’t been done before, in quite this way, this is a very interesting study which, when repeated, should lead to even more significant findings.”

For now, the paper should remind practicing neurologists to dig deeper when patients complain of visual problems during migraine attacks. “It might be blurred vision for just 3 minutes,” he said. “Some patients may be calling it an aura, or the doctor may be thinking it is an aura because they’re not digging for further information in the history. We may now have a window into decreased retinal perfusion during a migraine attack and why some patients have blurred vision.”

The study was funded by the Amgen and the Baldwin Foundation. Dr. Rapoport is editor-in-chief of Neurology Reviews but reports no relevant relationships with the funders of this research.

A new study that incorporated optical coherence tomography angiography (OCTA) has identified significant differences in retinal perfusion and macular anatomy during migraine attacks. Together, these changes could one day represent migraine biomarkers, authors say. The study was published online in Headache.

“We’re always looking for a biological marker for migraine,” said Alan M. Rapoport, MD, a clinical professor of neurology in the David Geffen School of Medicine at the University of California Los Angeles and past president of the International Headache Society. Researchers have identified many parameters that make people more likely to experience migraine, he said, but there remains no smoking gun. “We do not yet have a diagnostic test.”

Investigators have long been examining ocular vascular supply, added Dr. Rapoport, who was not involved with the study, because the eyes, visual system of the brain, and migraine are closely related. “But no one has ever figured out that one could use anything related to the eye as a definitive diagnostic test. This study was interesting because researchers used a very advanced technique to see if there are changes in the vascular supply to the eyeball during migraine.”
 

During Attacks

Study investigators prospectively enrolled 37 patients diagnosed with migraine with aura (MA), 30 with migraine without aura (MO), and 20 healthy controls. All subjects underwent macular OCTA for interictal analysis. A total of 20 patients with migraine (12 with MA and 8 with MO) underwent repeat scans during migraine attacks, and 5 control patients had repeat scans.

Compared with interictal measurements, significant parafoveal reductions in vessel flux index, an indicator of retinal perfusion, occurred in both the MA and MO groups during migraine attacks: –7% (95% CI, –10% to –4%; P = .006) and –7% (95% CI, –10% to –3%; P = .016), respectively, versus controls (2%, 95% CI, –3% to 7%).

The fact that migraine attacks resulted in reduced blood supply to the retinal region responsible for central vision is intriguing, said Dr. Rapoport, because sufficient reductions in blood supply there could result in blurred vision or other visual difficulties that might be mistaken for a true aura. “Many patients describe blurred vision related to their migraine headaches which do not usually qualify for an aura diagnosis,” he said.

Diagnostic criteria for MA, which afflicts around one third of people with migraine, include visual aberrations lasting at least 5 minutes and no more than 60 minutes. Visual aberrations average about 20-25 minutes, said Dr. Rapoport. “And we don’t usually accept blurred vision.” For most people who experience ictal blurred vision, he added, the phenomenon only lasts a short time and is not considered an aura.

More typical visual manifestations of MA include zigzag lines in an overall crescent shape that may blink, have bright edges, grow and shrink in size, and/or move across the visual field; patients also may have blind spots or distortions (e.g. far away vision, smaller or larger vision, or kaleidoscopic fractured vision). Nevertheless, said Dr. Rapoport, the study may shed light on why some people experiencing a migraine attack may suffer a brief bout of blurred vision and mistakenly report experiencing an aura.
 

Between Attacks

Comparing the two migraine groups interictally showed statistically significant differences in macular structure and function. Compared with the MO cohort, the MA cohort had higher circularity (mean [SD] 0.686 [0.088] vs. 0.629 [0.120] MO, P = .004), as well as a 13% (SD ± 10%, P = .003) lower foveal vessel flux index. “Not only is perfusion lower in both types of migraine during the attack,” said Dr. Rapoport, “but between attacks, people with MA had a lower blood supply to the retina than those who had MO.”

Unilateral Migraine

In a subset of patients (14 with MA and 12 with MO) whose headaches occurred unilaterally, investigators found retinal vascular parameters consistent with greater perfusion in the ipsilateral eye versus the contralateral eye. The significance of these findings remains unclear, Dr. Rapoport said, because circulatory findings revealed by CAT or MRI scans of patients with unilateral headaches are often normal or involve complex changes or mild edema on the side of the headache. The visual cortex on either side receives input from both eyes, he added.

Study Limitations

Authors acknowledged several study shortcomings. Most notably, COVID-19 restrictions resulted in a small sample size, and several patients (excluded from analysis) failed to return for repeat scans during migraine attacks. The study included patients with migraine attacks of varying frequency, and a handful of patients used acute rescue medications before undergoing ictal scans.

“If a future study corrected all these shortcomings,” Dr. Rapoport said, “the results might be more impressive and even more significant.” Based on these results alone, he said, it would be premature to pronounce OCTA-derived measurements of retinal perfusion and related parameters as future migraine biomarkers.

“But it’s a good start. If this hasn’t been done before, in quite this way, this is a very interesting study which, when repeated, should lead to even more significant findings.”

For now, the paper should remind practicing neurologists to dig deeper when patients complain of visual problems during migraine attacks. “It might be blurred vision for just 3 minutes,” he said. “Some patients may be calling it an aura, or the doctor may be thinking it is an aura because they’re not digging for further information in the history. We may now have a window into decreased retinal perfusion during a migraine attack and why some patients have blurred vision.”

The study was funded by the Amgen and the Baldwin Foundation. Dr. Rapoport is editor-in-chief of Neurology Reviews but reports no relevant relationships with the funders of this research.

Christmas, like New Year’s Day, Thanksgiving, birthdays, and anniversaries, is one of those times that we use to mark where we were and how far we’ve come.

I’m in a mixed marriage, so we celebrate both Hanukkah and Christmas. Twenty-five years ago I was a newly minted attending neurologist, not even 6 months out of fellowship.

My wife was pregnant with our first child and had invited my Jewish family over for Christmas dinner. This was our first December in our first house and she wanted to do something special for them.

Being the low person on the totem pole, it was my first Christmas on call, covering for myself and two other neurologists.

So I was driving. A lot. My wife was on her own to get things ready, and I was hoping to be home for dinner.

It was, as always seems to be the case with holidays, quite busy. I was up long before dawn to start, driving a circular route to cover four hospitals scattered around Phoenix. At least the roads were empty.

At some point the planned pattern breaks down as new consults and urgent patient status changes happen. You try to start by going from A to B to C to D for rounds, but within a few hours I was going from A to B to C, then back to A, then D, then B, then A again, and so on. All the while I was returning patient calls. Wash, rinse, repeat.

At some point I dialed my wife to see how she was doing and she gave me a list of last-minute things she needed picked up (which included some dairy products and more Christmas lights for her tree). I found a small store that was still open. For the rest of my day on call a grocery bag full of dairy products was carried from hospital to hospital with me, being put in the doctor’s lounge refrigerator with my name on it (this is Phoenix, even in winter you can’t leave it in the car). This added another trip from C back to A when I realized I’d left the groceries there.

I got home a few minutes before my family came over, after 14-15 hours of driving between hospitals. I was putting up the new lights when they came in. Fortunately I wasn’t called back in that night, and turned things over to my call partners in the morning.

Now? Since early 2020 my hospital days are behind me. My kids have their own lives, jobs, and school, but still all came over to see us.

I didn’t have to leave the house. I spent most of the day in a robe and pajamas, working at my desk on this and that, sometimes wandering to another table to futz with my current jigsaw puzzle or chat with my kids or go soak in my hot tub.

In 1998 I weighed 50 pounds less (still working on losing it), had no kids, or dogs. Now I’m in another house, have three grown kids, and in the interim have enjoyed seven awesome dogs (currently only one). My wife still invited my family over for Christmas dinner, but now it’s my mom and uncle. My dad and aunt are gone.

The changes are mostly good, though, as with all passages of time there is sadness and loss. When all is said and done I wouldn’t have done much differently even if I could.

I’m lucky, and I know it. Regardless of what you celebrate, it’s a good time to take stock of your blessings. To quote Sheryl Crow, “It’s not having what you want, it’s wanting what you’ve got.”

Happy New Year to all.
 

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

Christmas, like New Year’s Day, Thanksgiving, birthdays, and anniversaries, is one of those times that we use to mark where we were and how far we’ve come.

I’m in a mixed marriage, so we celebrate both Hanukkah and Christmas. Twenty-five years ago I was a newly minted attending neurologist, not even 6 months out of fellowship.

My wife was pregnant with our first child and had invited my Jewish family over for Christmas dinner. This was our first December in our first house and she wanted to do something special for them.

Being the low person on the totem pole, it was my first Christmas on call, covering for myself and two other neurologists.

So I was driving. A lot. My wife was on her own to get things ready, and I was hoping to be home for dinner.

It was, as always seems to be the case with holidays, quite busy. I was up long before dawn to start, driving a circular route to cover four hospitals scattered around Phoenix. At least the roads were empty.

At some point the planned pattern breaks down as new consults and urgent patient status changes happen. You try to start by going from A to B to C to D for rounds, but within a few hours I was going from A to B to C, then back to A, then D, then B, then A again, and so on. All the while I was returning patient calls. Wash, rinse, repeat.

At some point I dialed my wife to see how she was doing and she gave me a list of last-minute things she needed picked up (which included some dairy products and more Christmas lights for her tree). I found a small store that was still open. For the rest of my day on call a grocery bag full of dairy products was carried from hospital to hospital with me, being put in the doctor’s lounge refrigerator with my name on it (this is Phoenix, even in winter you can’t leave it in the car). This added another trip from C back to A when I realized I’d left the groceries there.

I got home a few minutes before my family came over, after 14-15 hours of driving between hospitals. I was putting up the new lights when they came in. Fortunately I wasn’t called back in that night, and turned things over to my call partners in the morning.

Now? Since early 2020 my hospital days are behind me. My kids have their own lives, jobs, and school, but still all came over to see us.

I didn’t have to leave the house. I spent most of the day in a robe and pajamas, working at my desk on this and that, sometimes wandering to another table to futz with my current jigsaw puzzle or chat with my kids or go soak in my hot tub.

In 1998 I weighed 50 pounds less (still working on losing it), had no kids, or dogs. Now I’m in another house, have three grown kids, and in the interim have enjoyed seven awesome dogs (currently only one). My wife still invited my family over for Christmas dinner, but now it’s my mom and uncle. My dad and aunt are gone.

The changes are mostly good, though, as with all passages of time there is sadness and loss. When all is said and done I wouldn’t have done much differently even if I could.

I’m lucky, and I know it. Regardless of what you celebrate, it’s a good time to take stock of your blessings. To quote Sheryl Crow, “It’s not having what you want, it’s wanting what you’ve got.”

Happy New Year to all.
 

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

Christmas, like New Year’s Day, Thanksgiving, birthdays, and anniversaries, is one of those times that we use to mark where we were and how far we’ve come.

I’m in a mixed marriage, so we celebrate both Hanukkah and Christmas. Twenty-five years ago I was a newly minted attending neurologist, not even 6 months out of fellowship.

My wife was pregnant with our first child and had invited my Jewish family over for Christmas dinner. This was our first December in our first house and she wanted to do something special for them.

Being the low person on the totem pole, it was my first Christmas on call, covering for myself and two other neurologists.

So I was driving. A lot. My wife was on her own to get things ready, and I was hoping to be home for dinner.

It was, as always seems to be the case with holidays, quite busy. I was up long before dawn to start, driving a circular route to cover four hospitals scattered around Phoenix. At least the roads were empty.

At some point the planned pattern breaks down as new consults and urgent patient status changes happen. You try to start by going from A to B to C to D for rounds, but within a few hours I was going from A to B to C, then back to A, then D, then B, then A again, and so on. All the while I was returning patient calls. Wash, rinse, repeat.

At some point I dialed my wife to see how she was doing and she gave me a list of last-minute things she needed picked up (which included some dairy products and more Christmas lights for her tree). I found a small store that was still open. For the rest of my day on call a grocery bag full of dairy products was carried from hospital to hospital with me, being put in the doctor’s lounge refrigerator with my name on it (this is Phoenix, even in winter you can’t leave it in the car). This added another trip from C back to A when I realized I’d left the groceries there.

I got home a few minutes before my family came over, after 14-15 hours of driving between hospitals. I was putting up the new lights when they came in. Fortunately I wasn’t called back in that night, and turned things over to my call partners in the morning.

Now? Since early 2020 my hospital days are behind me. My kids have their own lives, jobs, and school, but still all came over to see us.

I didn’t have to leave the house. I spent most of the day in a robe and pajamas, working at my desk on this and that, sometimes wandering to another table to futz with my current jigsaw puzzle or chat with my kids or go soak in my hot tub.

In 1998 I weighed 50 pounds less (still working on losing it), had no kids, or dogs. Now I’m in another house, have three grown kids, and in the interim have enjoyed seven awesome dogs (currently only one). My wife still invited my family over for Christmas dinner, but now it’s my mom and uncle. My dad and aunt are gone.

The changes are mostly good, though, as with all passages of time there is sadness and loss. When all is said and done I wouldn’t have done much differently even if I could.

I’m lucky, and I know it. Regardless of what you celebrate, it’s a good time to take stock of your blessings. To quote Sheryl Crow, “It’s not having what you want, it’s wanting what you’ve got.”

Happy New Year to all.
 

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

Neuroinflammation expert Jarred Younger, PhD, disputes a recent study commentary calling for clinicians to stop prescribing low-dose naltrexone for people with fibromyalgia.

Naltrexone is a nonselective µ-opioid receptor antagonist approved by the US Food and Drug Administration (FDA) at doses of 50-100 mg/day to treat opioid and alcohol dependence. Lower doses, typically 1-5 mg, can produce an analgesic effect via antagonism of receptors on microglial cells that lead to neuroinflammation. The low-dose version, available at compounding pharmacies, is not FDA-approved, but for many years it has been used off-label to treat fibromyalgia and related conditions.

Results from earlier small clinical trials have conflicted, but two conducted by Dr. Younger using doses of 4.5 mg/day showed benefit in reducing pain and other fibromyalgia symptoms. However, a new study from Denmark on 6 mg low-dose naltrexone versus placebo among 99 women with fibromyalgia demonstrated no significant difference in the primary outcome of change in pain intensity from baseline to 12 weeks.

On the other hand, there was a significant improvement in memory, and there were no differences in adverse events or safety, the authors reported in The Lancet Rheumatology.

Nonetheless, an accompanying commentary called the study a “resoundingly negative trial” and advised that while off-label use of low-dose naltrexone could continue for patients already taking it, clinicians should not initiate it for patients who have not previously used it, pending additional data.

Dr. Younger, director of the Neuroinflammation, Pain and Fatigue Laboratory at the University of Alabama, Birmingham, was speaking on December 13, 2023, at a National Institutes of Health meeting about myalgic encephalomyelitis/chronic fatigue syndrome about the potential use of low-dose naltrexone for that patient population. He had checked the literature in preparation for his talk and saw the new study, which had just been published December 5, 2023. 

During his talk, Dr. Younger said, “It looks like the study was very well done, and all the decisions made sense to me, so I don’t doubt the quality of their data or the statistics.”

But as for the commentary, he said, “I strongly disagree, and I believe the physicians at this conference strongly disagree with that as well. I know plenty of physicians who would say that is not good advice because this drug is so helpful for so many people.”

Indeed, Anthony L. Komaroff, MD, who heard Dr. Younger’s talk but hadn’t seen the new study, told this news organization that he is a “fan” of low-dose naltrexone based on his own experience with one patient who had a “clearly beneficial response” and that of other clinicians he’s spoken with about it. “My colleagues say it doesn’t work for everyone because the disease is so heterogeneous ... but it definitely works for some patients.”

Dr. Younger noted that the proportion of people in the Danish study who reported a clinically significant, that is 30% reduction, in pain scores was 45% versus 28% with placebo, not far from the 50% he found in his studies. “If they’d had 40 to 60 more people, they would have had statistically significant difference,” Dr. Younger said.

Indeed, the authors themselves pointed this out in their discussion, noting, “Our study was not powered to detect a significant difference regarding responder indices ... Subgroups of patients with fibromyalgia might respond differently to low-dose naltrexone treatment, and we intend to conduct a responder analysis based on levels of inflammatory biomarkers and specific biomarkers of glial activation, hypothesising that an inflammatory subgroup might benefit from the treatment. Results will be published in subsequent papers.”

The commentary authors responded to that, saying that they “appreciate” the intention to conduct that subgroup analysis, but that it is “probable that the current sample size will preclude robust statistical comparisons but could be a step to generate hypotheses.”

Those authors noted that a systematic review has described both pro-inflammatory (tumor necrosis factor, interleukin [IL]-6, and IL-8) and anti-inflammatory (IL-10) cytokines as peripheral inflammatory biomarkers in patients with fibromyalgia. “The specific peripheral biomarkers of glial activation are yet to be identified. The neuroinflammation hypothesis of fibromyalgia could be supported if a reduction of central nervous system inflammation would predict improvement of fibromyalgia symptoms. Subsequent work in this area is eagerly awaited.”

In the meantime, Dr. Younger said, “I do not think this should stop us from looking at low-dose naltrexone [or that] we shouldn’t try it. I’ve talked to over a thousand people over the last 10 years. It would be a very bad thing to give up on low-dose naltrexone now.”

Dr. Younger’s work is funded by the National Institutes of Health, Department of Defense, SolveME, the American Fibromyalgia Association, and ME Research UK. Komaroff has no disclosures.

A version of this article appeared on Medscape.com.

Neuroinflammation expert Jarred Younger, PhD, disputes a recent study commentary calling for clinicians to stop prescribing low-dose naltrexone for people with fibromyalgia.

Naltrexone is a nonselective µ-opioid receptor antagonist approved by the US Food and Drug Administration (FDA) at doses of 50-100 mg/day to treat opioid and alcohol dependence. Lower doses, typically 1-5 mg, can produce an analgesic effect via antagonism of receptors on microglial cells that lead to neuroinflammation. The low-dose version, available at compounding pharmacies, is not FDA-approved, but for many years it has been used off-label to treat fibromyalgia and related conditions.

Results from earlier small clinical trials have conflicted, but two conducted by Dr. Younger using doses of 4.5 mg/day showed benefit in reducing pain and other fibromyalgia symptoms. However, a new study from Denmark on 6 mg low-dose naltrexone versus placebo among 99 women with fibromyalgia demonstrated no significant difference in the primary outcome of change in pain intensity from baseline to 12 weeks.

On the other hand, there was a significant improvement in memory, and there were no differences in adverse events or safety, the authors reported in The Lancet Rheumatology.

Nonetheless, an accompanying commentary called the study a “resoundingly negative trial” and advised that while off-label use of low-dose naltrexone could continue for patients already taking it, clinicians should not initiate it for patients who have not previously used it, pending additional data.

Dr. Younger, director of the Neuroinflammation, Pain and Fatigue Laboratory at the University of Alabama, Birmingham, was speaking on December 13, 2023, at a National Institutes of Health meeting about myalgic encephalomyelitis/chronic fatigue syndrome about the potential use of low-dose naltrexone for that patient population. He had checked the literature in preparation for his talk and saw the new study, which had just been published December 5, 2023. 

During his talk, Dr. Younger said, “It looks like the study was very well done, and all the decisions made sense to me, so I don’t doubt the quality of their data or the statistics.”

But as for the commentary, he said, “I strongly disagree, and I believe the physicians at this conference strongly disagree with that as well. I know plenty of physicians who would say that is not good advice because this drug is so helpful for so many people.”

Indeed, Anthony L. Komaroff, MD, who heard Dr. Younger’s talk but hadn’t seen the new study, told this news organization that he is a “fan” of low-dose naltrexone based on his own experience with one patient who had a “clearly beneficial response” and that of other clinicians he’s spoken with about it. “My colleagues say it doesn’t work for everyone because the disease is so heterogeneous ... but it definitely works for some patients.”

Dr. Younger noted that the proportion of people in the Danish study who reported a clinically significant, that is 30% reduction, in pain scores was 45% versus 28% with placebo, not far from the 50% he found in his studies. “If they’d had 40 to 60 more people, they would have had statistically significant difference,” Dr. Younger said.

Indeed, the authors themselves pointed this out in their discussion, noting, “Our study was not powered to detect a significant difference regarding responder indices ... Subgroups of patients with fibromyalgia might respond differently to low-dose naltrexone treatment, and we intend to conduct a responder analysis based on levels of inflammatory biomarkers and specific biomarkers of glial activation, hypothesising that an inflammatory subgroup might benefit from the treatment. Results will be published in subsequent papers.”

The commentary authors responded to that, saying that they “appreciate” the intention to conduct that subgroup analysis, but that it is “probable that the current sample size will preclude robust statistical comparisons but could be a step to generate hypotheses.”

Those authors noted that a systematic review has described both pro-inflammatory (tumor necrosis factor, interleukin [IL]-6, and IL-8) and anti-inflammatory (IL-10) cytokines as peripheral inflammatory biomarkers in patients with fibromyalgia. “The specific peripheral biomarkers of glial activation are yet to be identified. The neuroinflammation hypothesis of fibromyalgia could be supported if a reduction of central nervous system inflammation would predict improvement of fibromyalgia symptoms. Subsequent work in this area is eagerly awaited.”

In the meantime, Dr. Younger said, “I do not think this should stop us from looking at low-dose naltrexone [or that] we shouldn’t try it. I’ve talked to over a thousand people over the last 10 years. It would be a very bad thing to give up on low-dose naltrexone now.”

Dr. Younger’s work is funded by the National Institutes of Health, Department of Defense, SolveME, the American Fibromyalgia Association, and ME Research UK. Komaroff has no disclosures.

A version of this article appeared on Medscape.com.

Neuroinflammation expert Jarred Younger, PhD, disputes a recent study commentary calling for clinicians to stop prescribing low-dose naltrexone for people with fibromyalgia.

Naltrexone is a nonselective µ-opioid receptor antagonist approved by the US Food and Drug Administration (FDA) at doses of 50-100 mg/day to treat opioid and alcohol dependence. Lower doses, typically 1-5 mg, can produce an analgesic effect via antagonism of receptors on microglial cells that lead to neuroinflammation. The low-dose version, available at compounding pharmacies, is not FDA-approved, but for many years it has been used off-label to treat fibromyalgia and related conditions.

Results from earlier small clinical trials have conflicted, but two conducted by Dr. Younger using doses of 4.5 mg/day showed benefit in reducing pain and other fibromyalgia symptoms. However, a new study from Denmark on 6 mg low-dose naltrexone versus placebo among 99 women with fibromyalgia demonstrated no significant difference in the primary outcome of change in pain intensity from baseline to 12 weeks.

On the other hand, there was a significant improvement in memory, and there were no differences in adverse events or safety, the authors reported in The Lancet Rheumatology.

Nonetheless, an accompanying commentary called the study a “resoundingly negative trial” and advised that while off-label use of low-dose naltrexone could continue for patients already taking it, clinicians should not initiate it for patients who have not previously used it, pending additional data.

Dr. Younger, director of the Neuroinflammation, Pain and Fatigue Laboratory at the University of Alabama, Birmingham, was speaking on December 13, 2023, at a National Institutes of Health meeting about myalgic encephalomyelitis/chronic fatigue syndrome about the potential use of low-dose naltrexone for that patient population. He had checked the literature in preparation for his talk and saw the new study, which had just been published December 5, 2023. 

During his talk, Dr. Younger said, “It looks like the study was very well done, and all the decisions made sense to me, so I don’t doubt the quality of their data or the statistics.”

But as for the commentary, he said, “I strongly disagree, and I believe the physicians at this conference strongly disagree with that as well. I know plenty of physicians who would say that is not good advice because this drug is so helpful for so many people.”

Indeed, Anthony L. Komaroff, MD, who heard Dr. Younger’s talk but hadn’t seen the new study, told this news organization that he is a “fan” of low-dose naltrexone based on his own experience with one patient who had a “clearly beneficial response” and that of other clinicians he’s spoken with about it. “My colleagues say it doesn’t work for everyone because the disease is so heterogeneous ... but it definitely works for some patients.”

Dr. Younger noted that the proportion of people in the Danish study who reported a clinically significant, that is 30% reduction, in pain scores was 45% versus 28% with placebo, not far from the 50% he found in his studies. “If they’d had 40 to 60 more people, they would have had statistically significant difference,” Dr. Younger said.

Indeed, the authors themselves pointed this out in their discussion, noting, “Our study was not powered to detect a significant difference regarding responder indices ... Subgroups of patients with fibromyalgia might respond differently to low-dose naltrexone treatment, and we intend to conduct a responder analysis based on levels of inflammatory biomarkers and specific biomarkers of glial activation, hypothesising that an inflammatory subgroup might benefit from the treatment. Results will be published in subsequent papers.”

The commentary authors responded to that, saying that they “appreciate” the intention to conduct that subgroup analysis, but that it is “probable that the current sample size will preclude robust statistical comparisons but could be a step to generate hypotheses.”

Those authors noted that a systematic review has described both pro-inflammatory (tumor necrosis factor, interleukin [IL]-6, and IL-8) and anti-inflammatory (IL-10) cytokines as peripheral inflammatory biomarkers in patients with fibromyalgia. “The specific peripheral biomarkers of glial activation are yet to be identified. The neuroinflammation hypothesis of fibromyalgia could be supported if a reduction of central nervous system inflammation would predict improvement of fibromyalgia symptoms. Subsequent work in this area is eagerly awaited.”

In the meantime, Dr. Younger said, “I do not think this should stop us from looking at low-dose naltrexone [or that] we shouldn’t try it. I’ve talked to over a thousand people over the last 10 years. It would be a very bad thing to give up on low-dose naltrexone now.”

Dr. Younger’s work is funded by the National Institutes of Health, Department of Defense, SolveME, the American Fibromyalgia Association, and ME Research UK. Komaroff has no disclosures.

A version of this article appeared on Medscape.com.

BETHESDA, MD — New research into the mechanisms underlying myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and long COVID is aimed at identifying potential approaches to treatment of the two overlapping illnesses.

According to a new data brief from the National Center for Health Statistics, in 2021-2022, 1.3% of US adults had ME/CFS, a complex, multisystem illness characterized by activity-limiting fatigue, worsening of symptoms after exertion, unrefreshing sleep, and other symptoms.

A 2-day conference, Advancing ME/CFS Research: Identifying Targets for Potential Intervention and Learning from Long COVID, was held in December 12-13 on the main campus of the US National Institutes of Health (NIH) and was livestreamed. The last such meeting, also featuring results from NIH-funded research, was held in April 2019.

“Things have changed since 2019 ... The idea of this meeting is to try and identify pathways that will be treatable and druggable and really make an impact for patients based on the things that we’ve learned over the last number of years and including, fortunately or unfortunately, the huge number of people who are suffering from long COVID, where the symptoms overlap so much with those who have been suffering for a long time with ME/CFS,” said Conference Chair Joe Breen, PhD, of the National Institute of Allergy and Infectious Diseases.

As in 2019, the meeting was preceded by a day of research presentations from young investigators, some of whom also presented their findings at the main meeting. New this year were four “lived experience” speakers who described their physical, emotional, and financial struggles with ME/CFS or long COVID. Two of them presented virtually because they were too ill to travel.

Social worker and patient advocate Terri Wilder of Minneapolis, Minnesota, reported some feedback she received on social media after she asked people with ME/CFS about their priorities for the research and clinical communities.

Among the top responses were the need to recognize and study the phenomenon of “post-exertional malaise” and to stop recommending exercise for people with these illnesses, to accelerate research to find effective treatments, and to put an end to stigma around the condition. “People don’t believe us when we tell them we’re sick, people make fun of us, misperceptions persist,” Wilder said.

One person commented, “[Clinicians] shouldn’t be afraid to try off-label meds with us if needed. There may be some secondary effects, but they are better options than us taking our own lives because we can’t stand the suffering.”

Research areas covered at the conference included immunology, virology, metabolism, gene regulation, and neurology of both ME/CFS and long COVID, as well as the latest findings regarding the overlap between the two conditions.
 

Oxidative Stress in Both ME/CFS and Long COVID: A Role for Metformin?

Mark M. Davis, PhD, professor and director of the Institute for Immunity, Transplantation, and Infection at Stanford University, Palo Alto, California, summarized published data suggesting that oxidative stress is a shared characteristic of both ME/CFS and long COVID. Most cellular reactive oxygen species (ROS) are produced in the cell’s mitochondria, and T-cell activation is ROS-dependent.

Women in particular with ME/CFS show high ROS levels with consistent T-cell hyperproliferation, “which can be suppressed with specific drugs such as metformin. This raises the prospect of optimizing drug treatment and drug discovery with a simple in vitro assay of the effects on a patient’s lymphocytes,” Dr. Davis said. He also cited a study suggesting that metformin may help prevent long COVID.

Asked to comment on that, longtime ME/CFS researcher Anthony L. Komaroff, MD, of Harvard University, Cambridge, Massachusetts, cautioned that although metformin is used safely by millions of people with type 2 diabetes worldwide, it’s possible that some people with ME/CFS may be more likely to experience its known adverse effects such as lactic acidosis.

To repurpose metformin or any other already-marketed drugs for ME/CFS and/or long COVID, Dr. Komaroff said, “We should entertain treatment trials.” However, as he and many others lamented at the conference, funding for off-patent drugs often isn’t forthcoming.
 

Addressing the Microbiome, Innate Immunity

W. Ian Lipkin, MD, of Columbia University, New York, NY, was one of two speakers who discussed the role of disruptions in the microbiome and innate immunity in ME/CFS. He presented data suggesting that “dysregulation of the gut microbiome in ME/CFS may interfere with butyrate production, resulting in inflammation and porosity to bacteria and bacterial products that trigger innate immunity.”

Dr. Lipkin highlighted a “really intriguing” paper in which exogenous administration of interleukin 37 (IL-37), a naturally occurring inhibitor of inflammation, reversed the decrease in exercise performance observed during inflammation-induced fatigue and increased exercise performance, both in mice.

“Although we do not fully understand the pathophysiology of ME/CFS, it is not premature to consider randomized clinical trials of pro- and pre-biotics that address dysbiosis as well as drugs that modify innate immune responses such as poly (I:C) and IL-37,” Dr. Lipkin said.
 

Alleviating Endoplasmic Reticulum (ER) Stress: A Strategy to Increase Energy?

Paul M. Hwang, MD, PhD, from the Cardiovascular Branch of the National Heart, Lung, and Blood Institute, Bethesda, Maryland, described work that he and his colleagues recently published around a case of a 38-year-old woman with Li-Fraumeni syndrome, a genetic early-onset cancer, who also had extensive fatigue, exercise intolerance, and post-exertional malaise that began after she contracted mononucleosis as a teenager.

Testing revealed that her cells had increased expression of Wiskott-Aldrich Syndrome Protein Family Member 3 (WASF3), a “top candidate” gene found to be associated with ME/CFS in a bioinformatics study published more than a decade ago. Moreover, immunoblotting of deidentified skeletal muscle biopsy samples obtained from patients with postinfectious ME/CFS also revealed significantly increased WASF3 levels.

Hwang and colleagues showed in mice that ER stress–induced WASF3 protein localizes to mitochondria and disrupts respiratory supercomplex assembly, leading to decreased oxygen consumption and exercise endurance.

However, use of the investigational protein phosphatase 1 inhibitor salubrinal in the female patient’s cells inhibited the ER stress, which in turn decreased WASF3 expression and improved mitochondrial supercomplex formation and respiration, “suggesting a treatment strategy in ME/CFS,” Dr. Hwang said.
 

Neurovascular Dysregulation During Exercise: A Role for Pyridostigmine?

David M. Systrom, MD, a pulmonary and critical care medicine specialist at the Brigham and Women’s Hospital, Boston, Massachusetts, gave an update of his work investigating neurovascular dysregulation during exercise in both ME/CFS and long COVID using invasive cardiopulmonary testing.

In a 2021 publication, Dr. Systrom and his colleagues identified the mechanism of “preload failure,” or lower filling pressures of blood in the heart chambers because of insufficient vein constriction and reduced return of blood to the right side of the heart in people with ME/CFS, compared with healthy controls.

Subsequently, in a randomized trial of 45 patients with ME/CFS, Systrom and his colleagues published in November 2022, use of the cholinesterase inhibitor pyridostigmine, currently approved for treating myasthenia gravis and related conditions, improved peak Vo2 by increasing cardiac output and filling pressures.

Now, Dr. Systrom’s team is conducting a randomized trial comparing 60 mg pyridostigmine with or without low-dose naltrexone (LDN) vs placebo in 160 patients with ME/CFS for 3 months. Metabolomic, transcriptomic, proteomic, and other assessments will be conducted on urine and blood samples. Participants will also wear devices that measure steps, sleep, heart rate, and other metrics.

Komaroff cautioned that pyridostigmine, too, has potential adverse effects. “I’m not sure pyridostigmine is ready for prime time ... It’s a drug developed for a very different purpose ... Now will it hold up in a larger trial, and will there be any side effects that turn up in larger studies? It’s not unreasonable to study.”
 

Brain Inflammation: Measuring and Treating It

Hannah F. Bues, clinical research coordinator at Massachusetts General Hospital, Boston, presented data now in preprint (ie, not yet peer-reviewed) in which researchers used [11C]PBR28 PET neuroimaging, a marker of neuroinflammation, to compare 12 individuals with long COVID vs 43 healthy controls. They found significantly increased neuroinflammation in several different brain regions in the long COVID group compared with controls.

Samples of peripheral blood plasma also showed significant correlations between neuroinflammation and circulating analytes related to vascular dysfunction. This work is ongoing in both long COVID and pre-COVID ME/CFS populations, Bues said.

Jarred Younger, PhD, of the Neuroinflammation, Pain, and Fatigue Laboratory at the University of Alabama, Birmingham, also gave an update of his ongoing work demonstrating significant brain inflammation seen in neuroimaging of people with ME/CFS compared with healthy controls.

Dr. Younger has been investigating the use of LDN for pain in fibromyalgia. Anecdotally, there have been reports of fatigue reduction with LDN in ME/CFS.

Dr. Younger conducted a post hoc analysis of his previous trial of LDN for 12 weeks in 30 patients with fibromyalgia. Of those, 16 met older CFS criteria. There was a significant reduction in their fatigue severity, with P <.0001 from baseline and P < .009 compared with placebo. The P values were high because the data included daily symptom reports. The average fatigue reduction was 25%.

“It wasn’t a study designed for ME/CFS, but I think it’s compelling evidence and enough with the other types of data we have to say we need to do a proper clinical trial of low-dose naltrexone in ME/CFS now,” Dr. Younger said.
 

‘We Need to Do Something’ About the Underfunding

Another NIH-funded ME/CFS researcher, Maureen Hanson, PhD, of Cornell University, Ithaca, NY, noted that the NIH currently funds ME/CFS research at about $13 million compared with $1.15 billion for the Researching COVID to Enhance Recovery Initiative granted to NIH by Congress for “post-acute sequelae of SARS-CoV-2 (PASC)” in 2021 “because of the urgency of studying this. Most of us here are well aware of the underfunding of ME/CFS relative to the burden of illness,” she said.

Current 2024 funding for AIDS research is $3294 million. “There are 1.2 million individuals living with HIV in the United States, and there are over 3 million who are barely living with ME/CFS in the United States. We need to do something about this ... It’s certainly possible that future funding for PASC is now going to disappear,” Dr. Hanson cautioned.

Wilder, the patient advocate, reminded the audience that “There is a cohort of people with ME who got sick in the 1980s and 1990s in the prime of their life ... They have dreamed of a day when there would be a major announcement that a treatment has been discovered to take away the suffering of this disease ... They keep waiting and waiting, year after year, missing more and more of their lives with each passing day ... We’re all depending on you.”

Dr. Systrom has received funding from the Solve ME/CFS Initiative, Department of Defense, and Open Medicine Foundation. Dr. Younger’s work is funded by the NIH, Department of Defense, SolveME, the American Fibromyalgia Association, and ME Research UK. Dr. Lipkin and Dr. Hanson receive NIH funding. Dr. Komaroff has no disclosures.
 

A version of this article appeared on Medscape.com.

BETHESDA, MD — New research into the mechanisms underlying myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and long COVID is aimed at identifying potential approaches to treatment of the two overlapping illnesses.

According to a new data brief from the National Center for Health Statistics, in 2021-2022, 1.3% of US adults had ME/CFS, a complex, multisystem illness characterized by activity-limiting fatigue, worsening of symptoms after exertion, unrefreshing sleep, and other symptoms.

A 2-day conference, Advancing ME/CFS Research: Identifying Targets for Potential Intervention and Learning from Long COVID, was held in December 12-13 on the main campus of the US National Institutes of Health (NIH) and was livestreamed. The last such meeting, also featuring results from NIH-funded research, was held in April 2019.

“Things have changed since 2019 ... The idea of this meeting is to try and identify pathways that will be treatable and druggable and really make an impact for patients based on the things that we’ve learned over the last number of years and including, fortunately or unfortunately, the huge number of people who are suffering from long COVID, where the symptoms overlap so much with those who have been suffering for a long time with ME/CFS,” said Conference Chair Joe Breen, PhD, of the National Institute of Allergy and Infectious Diseases.

As in 2019, the meeting was preceded by a day of research presentations from young investigators, some of whom also presented their findings at the main meeting. New this year were four “lived experience” speakers who described their physical, emotional, and financial struggles with ME/CFS or long COVID. Two of them presented virtually because they were too ill to travel.

Social worker and patient advocate Terri Wilder of Minneapolis, Minnesota, reported some feedback she received on social media after she asked people with ME/CFS about their priorities for the research and clinical communities.

Among the top responses were the need to recognize and study the phenomenon of “post-exertional malaise” and to stop recommending exercise for people with these illnesses, to accelerate research to find effective treatments, and to put an end to stigma around the condition. “People don’t believe us when we tell them we’re sick, people make fun of us, misperceptions persist,” Wilder said.

One person commented, “[Clinicians] shouldn’t be afraid to try off-label meds with us if needed. There may be some secondary effects, but they are better options than us taking our own lives because we can’t stand the suffering.”

Research areas covered at the conference included immunology, virology, metabolism, gene regulation, and neurology of both ME/CFS and long COVID, as well as the latest findings regarding the overlap between the two conditions.
 

Oxidative Stress in Both ME/CFS and Long COVID: A Role for Metformin?

Mark M. Davis, PhD, professor and director of the Institute for Immunity, Transplantation, and Infection at Stanford University, Palo Alto, California, summarized published data suggesting that oxidative stress is a shared characteristic of both ME/CFS and long COVID. Most cellular reactive oxygen species (ROS) are produced in the cell’s mitochondria, and T-cell activation is ROS-dependent.

Women in particular with ME/CFS show high ROS levels with consistent T-cell hyperproliferation, “which can be suppressed with specific drugs such as metformin. This raises the prospect of optimizing drug treatment and drug discovery with a simple in vitro assay of the effects on a patient’s lymphocytes,” Dr. Davis said. He also cited a study suggesting that metformin may help prevent long COVID.

Asked to comment on that, longtime ME/CFS researcher Anthony L. Komaroff, MD, of Harvard University, Cambridge, Massachusetts, cautioned that although metformin is used safely by millions of people with type 2 diabetes worldwide, it’s possible that some people with ME/CFS may be more likely to experience its known adverse effects such as lactic acidosis.

To repurpose metformin or any other already-marketed drugs for ME/CFS and/or long COVID, Dr. Komaroff said, “We should entertain treatment trials.” However, as he and many others lamented at the conference, funding for off-patent drugs often isn’t forthcoming.
 

Addressing the Microbiome, Innate Immunity

W. Ian Lipkin, MD, of Columbia University, New York, NY, was one of two speakers who discussed the role of disruptions in the microbiome and innate immunity in ME/CFS. He presented data suggesting that “dysregulation of the gut microbiome in ME/CFS may interfere with butyrate production, resulting in inflammation and porosity to bacteria and bacterial products that trigger innate immunity.”

Dr. Lipkin highlighted a “really intriguing” paper in which exogenous administration of interleukin 37 (IL-37), a naturally occurring inhibitor of inflammation, reversed the decrease in exercise performance observed during inflammation-induced fatigue and increased exercise performance, both in mice.

“Although we do not fully understand the pathophysiology of ME/CFS, it is not premature to consider randomized clinical trials of pro- and pre-biotics that address dysbiosis as well as drugs that modify innate immune responses such as poly (I:C) and IL-37,” Dr. Lipkin said.
 

Alleviating Endoplasmic Reticulum (ER) Stress: A Strategy to Increase Energy?

Paul M. Hwang, MD, PhD, from the Cardiovascular Branch of the National Heart, Lung, and Blood Institute, Bethesda, Maryland, described work that he and his colleagues recently published around a case of a 38-year-old woman with Li-Fraumeni syndrome, a genetic early-onset cancer, who also had extensive fatigue, exercise intolerance, and post-exertional malaise that began after she contracted mononucleosis as a teenager.

Testing revealed that her cells had increased expression of Wiskott-Aldrich Syndrome Protein Family Member 3 (WASF3), a “top candidate” gene found to be associated with ME/CFS in a bioinformatics study published more than a decade ago. Moreover, immunoblotting of deidentified skeletal muscle biopsy samples obtained from patients with postinfectious ME/CFS also revealed significantly increased WASF3 levels.

Hwang and colleagues showed in mice that ER stress–induced WASF3 protein localizes to mitochondria and disrupts respiratory supercomplex assembly, leading to decreased oxygen consumption and exercise endurance.

However, use of the investigational protein phosphatase 1 inhibitor salubrinal in the female patient’s cells inhibited the ER stress, which in turn decreased WASF3 expression and improved mitochondrial supercomplex formation and respiration, “suggesting a treatment strategy in ME/CFS,” Dr. Hwang said.
 

Neurovascular Dysregulation During Exercise: A Role for Pyridostigmine?

David M. Systrom, MD, a pulmonary and critical care medicine specialist at the Brigham and Women’s Hospital, Boston, Massachusetts, gave an update of his work investigating neurovascular dysregulation during exercise in both ME/CFS and long COVID using invasive cardiopulmonary testing.

In a 2021 publication, Dr. Systrom and his colleagues identified the mechanism of “preload failure,” or lower filling pressures of blood in the heart chambers because of insufficient vein constriction and reduced return of blood to the right side of the heart in people with ME/CFS, compared with healthy controls.

Subsequently, in a randomized trial of 45 patients with ME/CFS, Systrom and his colleagues published in November 2022, use of the cholinesterase inhibitor pyridostigmine, currently approved for treating myasthenia gravis and related conditions, improved peak Vo2 by increasing cardiac output and filling pressures.

Now, Dr. Systrom’s team is conducting a randomized trial comparing 60 mg pyridostigmine with or without low-dose naltrexone (LDN) vs placebo in 160 patients with ME/CFS for 3 months. Metabolomic, transcriptomic, proteomic, and other assessments will be conducted on urine and blood samples. Participants will also wear devices that measure steps, sleep, heart rate, and other metrics.

Komaroff cautioned that pyridostigmine, too, has potential adverse effects. “I’m not sure pyridostigmine is ready for prime time ... It’s a drug developed for a very different purpose ... Now will it hold up in a larger trial, and will there be any side effects that turn up in larger studies? It’s not unreasonable to study.”
 

Brain Inflammation: Measuring and Treating It

Hannah F. Bues, clinical research coordinator at Massachusetts General Hospital, Boston, presented data now in preprint (ie, not yet peer-reviewed) in which researchers used [11C]PBR28 PET neuroimaging, a marker of neuroinflammation, to compare 12 individuals with long COVID vs 43 healthy controls. They found significantly increased neuroinflammation in several different brain regions in the long COVID group compared with controls.

Samples of peripheral blood plasma also showed significant correlations between neuroinflammation and circulating analytes related to vascular dysfunction. This work is ongoing in both long COVID and pre-COVID ME/CFS populations, Bues said.

Jarred Younger, PhD, of the Neuroinflammation, Pain, and Fatigue Laboratory at the University of Alabama, Birmingham, also gave an update of his ongoing work demonstrating significant brain inflammation seen in neuroimaging of people with ME/CFS compared with healthy controls.

Dr. Younger has been investigating the use of LDN for pain in fibromyalgia. Anecdotally, there have been reports of fatigue reduction with LDN in ME/CFS.

Dr. Younger conducted a post hoc analysis of his previous trial of LDN for 12 weeks in 30 patients with fibromyalgia. Of those, 16 met older CFS criteria. There was a significant reduction in their fatigue severity, with P <.0001 from baseline and P < .009 compared with placebo. The P values were high because the data included daily symptom reports. The average fatigue reduction was 25%.

“It wasn’t a study designed for ME/CFS, but I think it’s compelling evidence and enough with the other types of data we have to say we need to do a proper clinical trial of low-dose naltrexone in ME/CFS now,” Dr. Younger said.
 

‘We Need to Do Something’ About the Underfunding

Another NIH-funded ME/CFS researcher, Maureen Hanson, PhD, of Cornell University, Ithaca, NY, noted that the NIH currently funds ME/CFS research at about $13 million compared with $1.15 billion for the Researching COVID to Enhance Recovery Initiative granted to NIH by Congress for “post-acute sequelae of SARS-CoV-2 (PASC)” in 2021 “because of the urgency of studying this. Most of us here are well aware of the underfunding of ME/CFS relative to the burden of illness,” she said.

Current 2024 funding for AIDS research is $3294 million. “There are 1.2 million individuals living with HIV in the United States, and there are over 3 million who are barely living with ME/CFS in the United States. We need to do something about this ... It’s certainly possible that future funding for PASC is now going to disappear,” Dr. Hanson cautioned.

Wilder, the patient advocate, reminded the audience that “There is a cohort of people with ME who got sick in the 1980s and 1990s in the prime of their life ... They have dreamed of a day when there would be a major announcement that a treatment has been discovered to take away the suffering of this disease ... They keep waiting and waiting, year after year, missing more and more of their lives with each passing day ... We’re all depending on you.”

Dr. Systrom has received funding from the Solve ME/CFS Initiative, Department of Defense, and Open Medicine Foundation. Dr. Younger’s work is funded by the NIH, Department of Defense, SolveME, the American Fibromyalgia Association, and ME Research UK. Dr. Lipkin and Dr. Hanson receive NIH funding. Dr. Komaroff has no disclosures.
 

A version of this article appeared on Medscape.com.

BETHESDA, MD — New research into the mechanisms underlying myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and long COVID is aimed at identifying potential approaches to treatment of the two overlapping illnesses.

According to a new data brief from the National Center for Health Statistics, in 2021-2022, 1.3% of US adults had ME/CFS, a complex, multisystem illness characterized by activity-limiting fatigue, worsening of symptoms after exertion, unrefreshing sleep, and other symptoms.

A 2-day conference, Advancing ME/CFS Research: Identifying Targets for Potential Intervention and Learning from Long COVID, was held in December 12-13 on the main campus of the US National Institutes of Health (NIH) and was livestreamed. The last such meeting, also featuring results from NIH-funded research, was held in April 2019.

“Things have changed since 2019 ... The idea of this meeting is to try and identify pathways that will be treatable and druggable and really make an impact for patients based on the things that we’ve learned over the last number of years and including, fortunately or unfortunately, the huge number of people who are suffering from long COVID, where the symptoms overlap so much with those who have been suffering for a long time with ME/CFS,” said Conference Chair Joe Breen, PhD, of the National Institute of Allergy and Infectious Diseases.

As in 2019, the meeting was preceded by a day of research presentations from young investigators, some of whom also presented their findings at the main meeting. New this year were four “lived experience” speakers who described their physical, emotional, and financial struggles with ME/CFS or long COVID. Two of them presented virtually because they were too ill to travel.

Social worker and patient advocate Terri Wilder of Minneapolis, Minnesota, reported some feedback she received on social media after she asked people with ME/CFS about their priorities for the research and clinical communities.

Among the top responses were the need to recognize and study the phenomenon of “post-exertional malaise” and to stop recommending exercise for people with these illnesses, to accelerate research to find effective treatments, and to put an end to stigma around the condition. “People don’t believe us when we tell them we’re sick, people make fun of us, misperceptions persist,” Wilder said.

One person commented, “[Clinicians] shouldn’t be afraid to try off-label meds with us if needed. There may be some secondary effects, but they are better options than us taking our own lives because we can’t stand the suffering.”

Research areas covered at the conference included immunology, virology, metabolism, gene regulation, and neurology of both ME/CFS and long COVID, as well as the latest findings regarding the overlap between the two conditions.
 

Oxidative Stress in Both ME/CFS and Long COVID: A Role for Metformin?

Mark M. Davis, PhD, professor and director of the Institute for Immunity, Transplantation, and Infection at Stanford University, Palo Alto, California, summarized published data suggesting that oxidative stress is a shared characteristic of both ME/CFS and long COVID. Most cellular reactive oxygen species (ROS) are produced in the cell’s mitochondria, and T-cell activation is ROS-dependent.

Women in particular with ME/CFS show high ROS levels with consistent T-cell hyperproliferation, “which can be suppressed with specific drugs such as metformin. This raises the prospect of optimizing drug treatment and drug discovery with a simple in vitro assay of the effects on a patient’s lymphocytes,” Dr. Davis said. He also cited a study suggesting that metformin may help prevent long COVID.

Asked to comment on that, longtime ME/CFS researcher Anthony L. Komaroff, MD, of Harvard University, Cambridge, Massachusetts, cautioned that although metformin is used safely by millions of people with type 2 diabetes worldwide, it’s possible that some people with ME/CFS may be more likely to experience its known adverse effects such as lactic acidosis.

To repurpose metformin or any other already-marketed drugs for ME/CFS and/or long COVID, Dr. Komaroff said, “We should entertain treatment trials.” However, as he and many others lamented at the conference, funding for off-patent drugs often isn’t forthcoming.
 

Addressing the Microbiome, Innate Immunity

W. Ian Lipkin, MD, of Columbia University, New York, NY, was one of two speakers who discussed the role of disruptions in the microbiome and innate immunity in ME/CFS. He presented data suggesting that “dysregulation of the gut microbiome in ME/CFS may interfere with butyrate production, resulting in inflammation and porosity to bacteria and bacterial products that trigger innate immunity.”

Dr. Lipkin highlighted a “really intriguing” paper in which exogenous administration of interleukin 37 (IL-37), a naturally occurring inhibitor of inflammation, reversed the decrease in exercise performance observed during inflammation-induced fatigue and increased exercise performance, both in mice.

“Although we do not fully understand the pathophysiology of ME/CFS, it is not premature to consider randomized clinical trials of pro- and pre-biotics that address dysbiosis as well as drugs that modify innate immune responses such as poly (I:C) and IL-37,” Dr. Lipkin said.
 

Alleviating Endoplasmic Reticulum (ER) Stress: A Strategy to Increase Energy?

Paul M. Hwang, MD, PhD, from the Cardiovascular Branch of the National Heart, Lung, and Blood Institute, Bethesda, Maryland, described work that he and his colleagues recently published around a case of a 38-year-old woman with Li-Fraumeni syndrome, a genetic early-onset cancer, who also had extensive fatigue, exercise intolerance, and post-exertional malaise that began after she contracted mononucleosis as a teenager.

Testing revealed that her cells had increased expression of Wiskott-Aldrich Syndrome Protein Family Member 3 (WASF3), a “top candidate” gene found to be associated with ME/CFS in a bioinformatics study published more than a decade ago. Moreover, immunoblotting of deidentified skeletal muscle biopsy samples obtained from patients with postinfectious ME/CFS also revealed significantly increased WASF3 levels.

Hwang and colleagues showed in mice that ER stress–induced WASF3 protein localizes to mitochondria and disrupts respiratory supercomplex assembly, leading to decreased oxygen consumption and exercise endurance.

However, use of the investigational protein phosphatase 1 inhibitor salubrinal in the female patient’s cells inhibited the ER stress, which in turn decreased WASF3 expression and improved mitochondrial supercomplex formation and respiration, “suggesting a treatment strategy in ME/CFS,” Dr. Hwang said.
 

Neurovascular Dysregulation During Exercise: A Role for Pyridostigmine?

David M. Systrom, MD, a pulmonary and critical care medicine specialist at the Brigham and Women’s Hospital, Boston, Massachusetts, gave an update of his work investigating neurovascular dysregulation during exercise in both ME/CFS and long COVID using invasive cardiopulmonary testing.

In a 2021 publication, Dr. Systrom and his colleagues identified the mechanism of “preload failure,” or lower filling pressures of blood in the heart chambers because of insufficient vein constriction and reduced return of blood to the right side of the heart in people with ME/CFS, compared with healthy controls.

Subsequently, in a randomized trial of 45 patients with ME/CFS, Systrom and his colleagues published in November 2022, use of the cholinesterase inhibitor pyridostigmine, currently approved for treating myasthenia gravis and related conditions, improved peak Vo2 by increasing cardiac output and filling pressures.

Now, Dr. Systrom’s team is conducting a randomized trial comparing 60 mg pyridostigmine with or without low-dose naltrexone (LDN) vs placebo in 160 patients with ME/CFS for 3 months. Metabolomic, transcriptomic, proteomic, and other assessments will be conducted on urine and blood samples. Participants will also wear devices that measure steps, sleep, heart rate, and other metrics.

Komaroff cautioned that pyridostigmine, too, has potential adverse effects. “I’m not sure pyridostigmine is ready for prime time ... It’s a drug developed for a very different purpose ... Now will it hold up in a larger trial, and will there be any side effects that turn up in larger studies? It’s not unreasonable to study.”
 

Brain Inflammation: Measuring and Treating It

Hannah F. Bues, clinical research coordinator at Massachusetts General Hospital, Boston, presented data now in preprint (ie, not yet peer-reviewed) in which researchers used [11C]PBR28 PET neuroimaging, a marker of neuroinflammation, to compare 12 individuals with long COVID vs 43 healthy controls. They found significantly increased neuroinflammation in several different brain regions in the long COVID group compared with controls.

Samples of peripheral blood plasma also showed significant correlations between neuroinflammation and circulating analytes related to vascular dysfunction. This work is ongoing in both long COVID and pre-COVID ME/CFS populations, Bues said.

Jarred Younger, PhD, of the Neuroinflammation, Pain, and Fatigue Laboratory at the University of Alabama, Birmingham, also gave an update of his ongoing work demonstrating significant brain inflammation seen in neuroimaging of people with ME/CFS compared with healthy controls.

Dr. Younger has been investigating the use of LDN for pain in fibromyalgia. Anecdotally, there have been reports of fatigue reduction with LDN in ME/CFS.

Dr. Younger conducted a post hoc analysis of his previous trial of LDN for 12 weeks in 30 patients with fibromyalgia. Of those, 16 met older CFS criteria. There was a significant reduction in their fatigue severity, with P <.0001 from baseline and P < .009 compared with placebo. The P values were high because the data included daily symptom reports. The average fatigue reduction was 25%.

“It wasn’t a study designed for ME/CFS, but I think it’s compelling evidence and enough with the other types of data we have to say we need to do a proper clinical trial of low-dose naltrexone in ME/CFS now,” Dr. Younger said.
 

‘We Need to Do Something’ About the Underfunding

Another NIH-funded ME/CFS researcher, Maureen Hanson, PhD, of Cornell University, Ithaca, NY, noted that the NIH currently funds ME/CFS research at about $13 million compared with $1.15 billion for the Researching COVID to Enhance Recovery Initiative granted to NIH by Congress for “post-acute sequelae of SARS-CoV-2 (PASC)” in 2021 “because of the urgency of studying this. Most of us here are well aware of the underfunding of ME/CFS relative to the burden of illness,” she said.

Current 2024 funding for AIDS research is $3294 million. “There are 1.2 million individuals living with HIV in the United States, and there are over 3 million who are barely living with ME/CFS in the United States. We need to do something about this ... It’s certainly possible that future funding for PASC is now going to disappear,” Dr. Hanson cautioned.

Wilder, the patient advocate, reminded the audience that “There is a cohort of people with ME who got sick in the 1980s and 1990s in the prime of their life ... They have dreamed of a day when there would be a major announcement that a treatment has been discovered to take away the suffering of this disease ... They keep waiting and waiting, year after year, missing more and more of their lives with each passing day ... We’re all depending on you.”

Dr. Systrom has received funding from the Solve ME/CFS Initiative, Department of Defense, and Open Medicine Foundation. Dr. Younger’s work is funded by the NIH, Department of Defense, SolveME, the American Fibromyalgia Association, and ME Research UK. Dr. Lipkin and Dr. Hanson receive NIH funding. Dr. Komaroff has no disclosures.
 

A version of this article appeared on Medscape.com.

TOPLINE:

Regular moderate to vigorous physical activity predicts larger brain size in key regions, including gray and white matter and the hippocampus, new data suggest. 

METHODOLOGY: 

• The potential neuroprotective effects of regular physical activity on brain structure are unclear despite reported links between physical activity and reduced dementia risk. 
• To investigate, researchers analyzed MRI brain scans from 10,125 healthy adults (mean age, 53 years; 52% male) who self-reported their level of physical activity.
• Moderate to vigorous physical activities, defined as those increasing respiration and pulse rate for at least 10 continuous minutes, was modeled with brain volumes, adjusting for covariates.
• The threshold for defining physically active (vs nonactive) adults was intentionally set at 2.5 days per week, a level far lower than current guidelines.

TAKEAWAY:

• Three quarters of the cohort reported engaging in moderate to vigorous physical activity approximately 4 days per week. 
• Physically active adults tended to be younger, with a higher proportion of White individuals, and with lower rates of hypertension and type 2 diabetes. 
• After adjusting for multiple factors, increased days of moderate to vigorous activity correlated with larger normalized brain volume in multiple regions including total gray matter; white matter; hippocampus; and frontal, parietal, and occipital lobes. 

IN PRACTICE: 

“We found that even moderate levels of physical activity, such as taking fewer than 4,000 steps a day, can have a positive effect on brain health. This is much less than the often-suggested 10,000 steps, making it a more achievable goal for many people,” co-author David Merrill, MD, with Pacific Brain Health Center, Santa Monica, California, said in a statement. 

SOURCE: 

The study, with first author Cyrus A. Raji, MD, PhD, Washington University School of Medicine, St. Louis, was published online in the Journal of Alzheimer’s Disease.

LIMITATIONS: 

Participants self-reported physical activity in the past 2 weeks, which does not reflect a lifetime of activity levels. The correlation identified between physical activity and brain volumes may not be solely attributable to physical activity alone. 

DISCLOSURES: 

The study received funding from several health centers and foundations. Dr. Raji consults for Brainreader ApS, Neurevolution LLC, Apollo Health, Voxelwise Imaging Technology, and Pacific Neuroscience Foundation and is an editorial board member of the Journal of Alzheimer’s Disease but was not involved in the peer-review process.

A version of this article appeared on Medscape.com.

TOPLINE:

Regular moderate to vigorous physical activity predicts larger brain size in key regions, including gray and white matter and the hippocampus, new data suggest. 

METHODOLOGY: 

• The potential neuroprotective effects of regular physical activity on brain structure are unclear despite reported links between physical activity and reduced dementia risk. 
• To investigate, researchers analyzed MRI brain scans from 10,125 healthy adults (mean age, 53 years; 52% male) who self-reported their level of physical activity.
• Moderate to vigorous physical activities, defined as those increasing respiration and pulse rate for at least 10 continuous minutes, was modeled with brain volumes, adjusting for covariates.
• The threshold for defining physically active (vs nonactive) adults was intentionally set at 2.5 days per week, a level far lower than current guidelines.

TAKEAWAY:

• Three quarters of the cohort reported engaging in moderate to vigorous physical activity approximately 4 days per week. 
• Physically active adults tended to be younger, with a higher proportion of White individuals, and with lower rates of hypertension and type 2 diabetes. 
• After adjusting for multiple factors, increased days of moderate to vigorous activity correlated with larger normalized brain volume in multiple regions including total gray matter; white matter; hippocampus; and frontal, parietal, and occipital lobes. 

IN PRACTICE: 

“We found that even moderate levels of physical activity, such as taking fewer than 4,000 steps a day, can have a positive effect on brain health. This is much less than the often-suggested 10,000 steps, making it a more achievable goal for many people,” co-author David Merrill, MD, with Pacific Brain Health Center, Santa Monica, California, said in a statement. 

SOURCE: 

The study, with first author Cyrus A. Raji, MD, PhD, Washington University School of Medicine, St. Louis, was published online in the Journal of Alzheimer’s Disease.

LIMITATIONS: 

Participants self-reported physical activity in the past 2 weeks, which does not reflect a lifetime of activity levels. The correlation identified between physical activity and brain volumes may not be solely attributable to physical activity alone. 

DISCLOSURES: 

The study received funding from several health centers and foundations. Dr. Raji consults for Brainreader ApS, Neurevolution LLC, Apollo Health, Voxelwise Imaging Technology, and Pacific Neuroscience Foundation and is an editorial board member of the Journal of Alzheimer’s Disease but was not involved in the peer-review process.

A version of this article appeared on Medscape.com.

TOPLINE:

Regular moderate to vigorous physical activity predicts larger brain size in key regions, including gray and white matter and the hippocampus, new data suggest. 

METHODOLOGY: 

• The potential neuroprotective effects of regular physical activity on brain structure are unclear despite reported links between physical activity and reduced dementia risk. 
• To investigate, researchers analyzed MRI brain scans from 10,125 healthy adults (mean age, 53 years; 52% male) who self-reported their level of physical activity.
• Moderate to vigorous physical activities, defined as those increasing respiration and pulse rate for at least 10 continuous minutes, was modeled with brain volumes, adjusting for covariates.
• The threshold for defining physically active (vs nonactive) adults was intentionally set at 2.5 days per week, a level far lower than current guidelines.

TAKEAWAY:

• Three quarters of the cohort reported engaging in moderate to vigorous physical activity approximately 4 days per week. 
• Physically active adults tended to be younger, with a higher proportion of White individuals, and with lower rates of hypertension and type 2 diabetes. 
• After adjusting for multiple factors, increased days of moderate to vigorous activity correlated with larger normalized brain volume in multiple regions including total gray matter; white matter; hippocampus; and frontal, parietal, and occipital lobes. 

IN PRACTICE: 

“We found that even moderate levels of physical activity, such as taking fewer than 4,000 steps a day, can have a positive effect on brain health. This is much less than the often-suggested 10,000 steps, making it a more achievable goal for many people,” co-author David Merrill, MD, with Pacific Brain Health Center, Santa Monica, California, said in a statement. 

SOURCE: 

The study, with first author Cyrus A. Raji, MD, PhD, Washington University School of Medicine, St. Louis, was published online in the Journal of Alzheimer’s Disease.

LIMITATIONS: 

Participants self-reported physical activity in the past 2 weeks, which does not reflect a lifetime of activity levels. The correlation identified between physical activity and brain volumes may not be solely attributable to physical activity alone. 

DISCLOSURES: 

The study received funding from several health centers and foundations. Dr. Raji consults for Brainreader ApS, Neurevolution LLC, Apollo Health, Voxelwise Imaging Technology, and Pacific Neuroscience Foundation and is an editorial board member of the Journal of Alzheimer’s Disease but was not involved in the peer-review process.

A version of this article appeared on Medscape.com.

TOPLINE:

Patients aged 50 years or older with clinically apparent Helicobacter pylori infection (CAHPI) have an 11% increased risk for Alzheimer’s disease (AD), results of a large and lengthy population-based study suggest.

METHODOLOGY: 

• Researchers identified all cases with a first-time diagnosis of AD and matched each AD case to up to 40 AD-free control cases on the basis of age, sex, cohort entry date, and duration of follow-up.
• The exposure of interest was CAHPI, defined based on an algorithm using clinical guidelines and recommendations on the management of H pylori (HP) infection, with researchers focusing on infected individuals presenting with symptoms or developing serious complications from the infection.
• Researchers performed several sensitivity analyses, which included repeating the primary analysis using alternate lag periods, restricting the cohort to participants with AD (not vascular, alcoholic, and unspecified dementia), and using salmonellosis, an infection not previously associated with AD, as a negative control exposure.

TAKEAWAY: 

• Compared with no exposure to CAHPI, exposure to CAHPI was associated with a moderately increased risk for AD (odds ratio [OR], 1.11; 95% CI, 1.01-1.21), with no major effect modification by demographics or socioeconomic status.
• The increased risk peaked 7.3-10.8 years after CAHPI onset (OR, 1.24; 95% CI, 1.05-1.47) before decreasing.
• Sensitivity analyses yielded findings that were overall consistent with those of the primary analysis.
• The analysis with salmonellosis as a negative control exposure showed no association with the risk for AD (OR, 1.03; 95% CI, 0.82-1.29).

IN PRACTICE:

“These results support the notion of HP infection as a potential modifiable risk factor of AD” and “pave the way for future randomized controlled trials that would assess the impact and cost-effectiveness of population-based targeted interventions such as individualized HP eradication programs, on the development of AD,” the authors write.

SOURCE:

The study was conducted by Antonios Douros, Department of Medicine, and Department of Epidemiology, Biostatistics, and Occupational Health, McGill University, Montreal, Quebec, Canada, and colleagues. It was published online in Alzheimer’s & Dementia.

LIMITATIONS:

Given the observational nature of the study, residual confounding is possible. Because the exposure definition was on the basis of CAHPI recorded by general practitioners, exposure misclassification due to symptomatic patients not seeking primary care is possible, as is outcome misclassification. The authors can’t rule out the possibility of an association between asymptomatic H pylori infection and AD risk.

DISCLOSURES:

The study received funding from the Canadian Institutes of Health Research. Douros has no relevant conflicts of interest; see paper for disclosures of other authors.

Pauline Anderson has disclosed no relevant financial relationships.

A version of this article appeared on Medscape.com.

TOPLINE:

Patients aged 50 years or older with clinically apparent Helicobacter pylori infection (CAHPI) have an 11% increased risk for Alzheimer’s disease (AD), results of a large and lengthy population-based study suggest.

METHODOLOGY: 

• Researchers identified all cases with a first-time diagnosis of AD and matched each AD case to up to 40 AD-free control cases on the basis of age, sex, cohort entry date, and duration of follow-up.
• The exposure of interest was CAHPI, defined based on an algorithm using clinical guidelines and recommendations on the management of H pylori (HP) infection, with researchers focusing on infected individuals presenting with symptoms or developing serious complications from the infection.
• Researchers performed several sensitivity analyses, which included repeating the primary analysis using alternate lag periods, restricting the cohort to participants with AD (not vascular, alcoholic, and unspecified dementia), and using salmonellosis, an infection not previously associated with AD, as a negative control exposure.

TAKEAWAY: 

• Compared with no exposure to CAHPI, exposure to CAHPI was associated with a moderately increased risk for AD (odds ratio [OR], 1.11; 95% CI, 1.01-1.21), with no major effect modification by demographics or socioeconomic status.
• The increased risk peaked 7.3-10.8 years after CAHPI onset (OR, 1.24; 95% CI, 1.05-1.47) before decreasing.
• Sensitivity analyses yielded findings that were overall consistent with those of the primary analysis.
• The analysis with salmonellosis as a negative control exposure showed no association with the risk for AD (OR, 1.03; 95% CI, 0.82-1.29).

IN PRACTICE:

“These results support the notion of HP infection as a potential modifiable risk factor of AD” and “pave the way for future randomized controlled trials that would assess the impact and cost-effectiveness of population-based targeted interventions such as individualized HP eradication programs, on the development of AD,” the authors write.

SOURCE:

The study was conducted by Antonios Douros, Department of Medicine, and Department of Epidemiology, Biostatistics, and Occupational Health, McGill University, Montreal, Quebec, Canada, and colleagues. It was published online in Alzheimer’s & Dementia.

LIMITATIONS:

Given the observational nature of the study, residual confounding is possible. Because the exposure definition was on the basis of CAHPI recorded by general practitioners, exposure misclassification due to symptomatic patients not seeking primary care is possible, as is outcome misclassification. The authors can’t rule out the possibility of an association between asymptomatic H pylori infection and AD risk.

DISCLOSURES:

The study received funding from the Canadian Institutes of Health Research. Douros has no relevant conflicts of interest; see paper for disclosures of other authors.

Pauline Anderson has disclosed no relevant financial relationships.

A version of this article appeared on Medscape.com.

TOPLINE:

Patients aged 50 years or older with clinically apparent Helicobacter pylori infection (CAHPI) have an 11% increased risk for Alzheimer’s disease (AD), results of a large and lengthy population-based study suggest.

METHODOLOGY: 

• Researchers identified all cases with a first-time diagnosis of AD and matched each AD case to up to 40 AD-free control cases on the basis of age, sex, cohort entry date, and duration of follow-up.
• The exposure of interest was CAHPI, defined based on an algorithm using clinical guidelines and recommendations on the management of H pylori (HP) infection, with researchers focusing on infected individuals presenting with symptoms or developing serious complications from the infection.
• Researchers performed several sensitivity analyses, which included repeating the primary analysis using alternate lag periods, restricting the cohort to participants with AD (not vascular, alcoholic, and unspecified dementia), and using salmonellosis, an infection not previously associated with AD, as a negative control exposure.

TAKEAWAY: 

• Compared with no exposure to CAHPI, exposure to CAHPI was associated with a moderately increased risk for AD (odds ratio [OR], 1.11; 95% CI, 1.01-1.21), with no major effect modification by demographics or socioeconomic status.
• The increased risk peaked 7.3-10.8 years after CAHPI onset (OR, 1.24; 95% CI, 1.05-1.47) before decreasing.
• Sensitivity analyses yielded findings that were overall consistent with those of the primary analysis.
• The analysis with salmonellosis as a negative control exposure showed no association with the risk for AD (OR, 1.03; 95% CI, 0.82-1.29).

IN PRACTICE:

“These results support the notion of HP infection as a potential modifiable risk factor of AD” and “pave the way for future randomized controlled trials that would assess the impact and cost-effectiveness of population-based targeted interventions such as individualized HP eradication programs, on the development of AD,” the authors write.

SOURCE:

The study was conducted by Antonios Douros, Department of Medicine, and Department of Epidemiology, Biostatistics, and Occupational Health, McGill University, Montreal, Quebec, Canada, and colleagues. It was published online in Alzheimer’s & Dementia.

LIMITATIONS:

Given the observational nature of the study, residual confounding is possible. Because the exposure definition was on the basis of CAHPI recorded by general practitioners, exposure misclassification due to symptomatic patients not seeking primary care is possible, as is outcome misclassification. The authors can’t rule out the possibility of an association between asymptomatic H pylori infection and AD risk.

DISCLOSURES:

The study received funding from the Canadian Institutes of Health Research. Douros has no relevant conflicts of interest; see paper for disclosures of other authors.

Pauline Anderson has disclosed no relevant financial relationships.

A version of this article appeared on Medscape.com.

Selecting a treatment plan to deal with acute migraine attacks can be like putting together a toolkit of possible therapies, individualized for each patient, one expert said.

The toolkit should comprise reliable treatments that patients know are going to work and that act quickly, allowing them to get back to functioning normally in their daily lives, said Jessica Ailani, MD, during a talk at the 17th European Headache Congress held recently in Barcelona, Spain. 

“Everyone with migraine needs acute treatment,” Dr. Ailani, who is a clinical professor of neurology at MedStar Georgetown University Hospital and director of the Georgetown Headache Center, Washington, DC, noted. “Sometimes we can reduce acute treatment with preventative agents, but some disability will remain, so we have to focus on good acute treatment, and this becomes more complex if a person has a lot of comorbidities, which is common in older patients.” 

In selecting suitable treatments for migraine, consideration has to be given to the patient profile, any other conditions they have, speed of onset of the migraine attack, length of the attack, associated symptoms, and side effects of the medications, she said. 
 

A Complex Case

As an example, Dr. Ailani described the process she used to treat one of her patients who had frequent severe migraines and other issues causing difficult decisions when selecting medications — a woman in her late 60s with several other comorbidities.

“This is the kind of case I see on a daily basis and which keeps me up at night,” she said. “Many times in clinical practice, we see complex cases like this, and through the course of a year, we may try every treatment option we have in a patient like this.”

On the first presentation, the patient had a chronic migraine with severe headaches every day. She had a history of previous cervical discectomy with fusion surgery; uncontrolled hypertension, for which she was taking an angiotensin blocker; high cholesterol, for which she was taking a statin; and diabetes with an A1c of 8. She did not smoke or drink alcohol, exercised moderately, and her body mass index was in a good range. 

“Before a patient ever sees a doctor for their migraine, they will have already tried a lot of different things. Most people are already using NSAIDs and acetaminophen, the most commonly used treatments for acute migraine,” Dr. Ailani explains.

Her patient was taking a triptan and the barbiturate, butalbital. Dr. Ailani notes that the triptan is very effective, but in the United States, they are not available over the counter, and the patient is only allowed nine doses per month on her insurance, so she was supplementing with butalbital. 

Over the course of a year, Dr. Ailani got her off the butalbital and started her on onabotulinum toxin A for migraine prevention, which reduced her headache days to about 15 per month (8 severe). She then added the anti-calcitonin gene-related peptide (CGRP) monoclonal antibody, galcanezumab, as another preventative, which further reduced the headache days down to 8-10 days per month (all migraine). 

The attacks are rapid onset and can last multiple days. They come with photophobia and phonophobia and cause her to be bedridden, she noted. 

“I was still worried about this frequency of headache and the fact she was using a triptan for acute treatment when she had uncontrolled hypertension and other cardiovascular risk factors, Dr. Ailani commented. 

She explained that triptans are generally not used in individuals aged over 65 years because of a lack of data in this age group. They are also contraindicated in patients with cardiovascular (CV) disease, and caution is advised in patients with CV risk factors. Noting that migraine is an independent risk factor for stroke in healthy individuals, and this patient already had three other major risk factors for stroke, Dr. Ailani said she did not think a triptan was the best option. 

When triptans do not work, Dr. Ailani said she thinks about dihydroergotamine, which she describes as “a great drug for long-lasting migraine” as it tends to have a sustained response. But it also has vasoconstrictive effects and can increase blood pressure, so it was not suitable for this patient. 

CV risk is also an issue with nonsteroidal anti-inflammatory drugs (NSAIDs), one of the staple treatments for acute migraine.

“NSAIDs are available over the counter, inexpensive, quite effective, and have minimal immediate side effects,” Dr. Ailani said. But long-term adverse events include CV events, particularly in those who already have CV risk factors, and it is now thought that NSAIDs actually carry more CV risk than triptans.

She noted that out of all the NSAIDs, celecoxib carries the lowest CV risk, and in the United States, it is available as a liquid formulation. There is also a study of ketorolac nasal spray showing it to be as effective as sumatriptan nasal spray for acute migraine.

As her patient was still going to the emergency room (ER) quite frequently at this point, Dr. Ailani prescribed ketorolac nasal spray as an emergency rescue medication, which did help to reduce ER visits but did not solve the acute treatment problem.

The next option she tried was the CGRP antagonists or “gepants” because of their good tolerability.

Because her patient had long attacks, Dr. Ailani said her first choice gepant was rimegepant as it has a long half-life.

She noted that in patients who have frequent migraine attacks (> 6 migraine days per month), using rimegepant as needed has been shown to lead to migraine frequency declining over time. “This shows that if we treat acute attacks properly, we can minimize the risk of chronic migraine.”

She pointed out that if a patient has prodrome that is easy to identify or has short attacks, ubrogepant may be a good option, having shown effectiveness in preventing or reducing the onset of the headache in the recently reported PRODROME trial when given the day before migraine starts.

Then there is also zavegepant, which is available as a nasal spray, so it is a good option for patients with nausea and vomiting. Dr. Ailani suggested that zavegepant as a third-generation gepant may be worth trying in patients who have tried the other gepants, as it is a different type of molecule.

For this patient, neither rimegepant nor ubrogepant worked. “We tried treating in the prodrome, when the pain was starting, adding to other treatments, but she is not a ‘gepant’ responder. We have yet to try zavegepant,” she said.

The next consideration was lasmiditan. “This patient is a triptan responder and lasmiditan is a 5HT1 agonist, so it makes sense to try this. Also, it doesn’t have a vasoconstrictor effect as it doesn’t work on the blood vessels, so it is safe for patients with high blood pressure,” Dr. Ailani noted.

She pointed out, however, that lasmiditan has become a rescue medication in her practice because of side effect issues such as dizziness and sleepiness.

But Dr. Ailani said she has learned how to use the medication to minimize the side effects, by increasing the dose slowly and advising patients to take it later in the day.

“We start with 50 mg for a few doses then increase to 100 mg. This seems to build tolerability.”

Her patient has found good relief from lasmiditan 100 mg, but she can’t take it during the day as it makes her sleepy.

As a last resort, Dr. Ailani went back to metoclopramide, which she described as “a tried and tested old-time drug.”

While this does not make the patient sleepy, it has other adverse effects limiting the frequency of its use, she noted. “I ask her to try to limit it to twice a week, and this has been pretty effective. She can function when she uses it.” 

Dr. Ailani also points out that neuromodulation should be in everyone’s tool kit. “So, we added an external combined occipital and trigeminal (eCOT device) neurostimulation device.”

The patient’s tool kit now looks like this:

• Neuromodulation device and meditation at first sign of an attack.
• Add metoclopramide 10 mg and acetaminophen 1000 mg.
• If the attack lasts into the second day, add lasmiditan 100 mg in the evening of the second day (limit 8 days a month).
• If the patient has a sudden onset severe migraine with nausea and vomiting that might make her go to the ER, add in ketorolac nasal spray (not > 5 days per month).

Dr. Ailani noted that other patients will need different toolkits, and in most cases, it is recommended to think about “situational prevention” for times when migraine attacks are predictable, which may include air travel, high-stress times (holidays, etc.), occasions when alcohol will be consumed, and at times of certain weather triggers.

Dr. Ailani disclosed no relevant financial relationships.

A version of this article appeared on Medscape.com.

Selecting a treatment plan to deal with acute migraine attacks can be like putting together a toolkit of possible therapies, individualized for each patient, one expert said.

The toolkit should comprise reliable treatments that patients know are going to work and that act quickly, allowing them to get back to functioning normally in their daily lives, said Jessica Ailani, MD, during a talk at the 17th European Headache Congress held recently in Barcelona, Spain. 

“Everyone with migraine needs acute treatment,” Dr. Ailani, who is a clinical professor of neurology at MedStar Georgetown University Hospital and director of the Georgetown Headache Center, Washington, DC, noted. “Sometimes we can reduce acute treatment with preventative agents, but some disability will remain, so we have to focus on good acute treatment, and this becomes more complex if a person has a lot of comorbidities, which is common in older patients.” 

In selecting suitable treatments for migraine, consideration has to be given to the patient profile, any other conditions they have, speed of onset of the migraine attack, length of the attack, associated symptoms, and side effects of the medications, she said. 
 

A Complex Case

As an example, Dr. Ailani described the process she used to treat one of her patients who had frequent severe migraines and other issues causing difficult decisions when selecting medications — a woman in her late 60s with several other comorbidities.

“This is the kind of case I see on a daily basis and which keeps me up at night,” she said. “Many times in clinical practice, we see complex cases like this, and through the course of a year, we may try every treatment option we have in a patient like this.”

On the first presentation, the patient had a chronic migraine with severe headaches every day. She had a history of previous cervical discectomy with fusion surgery; uncontrolled hypertension, for which she was taking an angiotensin blocker; high cholesterol, for which she was taking a statin; and diabetes with an A1c of 8. She did not smoke or drink alcohol, exercised moderately, and her body mass index was in a good range. 

“Before a patient ever sees a doctor for their migraine, they will have already tried a lot of different things. Most people are already using NSAIDs and acetaminophen, the most commonly used treatments for acute migraine,” Dr. Ailani explains.

Her patient was taking a triptan and the barbiturate, butalbital. Dr. Ailani notes that the triptan is very effective, but in the United States, they are not available over the counter, and the patient is only allowed nine doses per month on her insurance, so she was supplementing with butalbital. 

Over the course of a year, Dr. Ailani got her off the butalbital and started her on onabotulinum toxin A for migraine prevention, which reduced her headache days to about 15 per month (8 severe). She then added the anti-calcitonin gene-related peptide (CGRP) monoclonal antibody, galcanezumab, as another preventative, which further reduced the headache days down to 8-10 days per month (all migraine). 

The attacks are rapid onset and can last multiple days. They come with photophobia and phonophobia and cause her to be bedridden, she noted. 

“I was still worried about this frequency of headache and the fact she was using a triptan for acute treatment when she had uncontrolled hypertension and other cardiovascular risk factors, Dr. Ailani commented. 

She explained that triptans are generally not used in individuals aged over 65 years because of a lack of data in this age group. They are also contraindicated in patients with cardiovascular (CV) disease, and caution is advised in patients with CV risk factors. Noting that migraine is an independent risk factor for stroke in healthy individuals, and this patient already had three other major risk factors for stroke, Dr. Ailani said she did not think a triptan was the best option. 

When triptans do not work, Dr. Ailani said she thinks about dihydroergotamine, which she describes as “a great drug for long-lasting migraine” as it tends to have a sustained response. But it also has vasoconstrictive effects and can increase blood pressure, so it was not suitable for this patient. 

CV risk is also an issue with nonsteroidal anti-inflammatory drugs (NSAIDs), one of the staple treatments for acute migraine.

“NSAIDs are available over the counter, inexpensive, quite effective, and have minimal immediate side effects,” Dr. Ailani said. But long-term adverse events include CV events, particularly in those who already have CV risk factors, and it is now thought that NSAIDs actually carry more CV risk than triptans.

She noted that out of all the NSAIDs, celecoxib carries the lowest CV risk, and in the United States, it is available as a liquid formulation. There is also a study of ketorolac nasal spray showing it to be as effective as sumatriptan nasal spray for acute migraine.

As her patient was still going to the emergency room (ER) quite frequently at this point, Dr. Ailani prescribed ketorolac nasal spray as an emergency rescue medication, which did help to reduce ER visits but did not solve the acute treatment problem.

The next option she tried was the CGRP antagonists or “gepants” because of their good tolerability.

Because her patient had long attacks, Dr. Ailani said her first choice gepant was rimegepant as it has a long half-life.

She noted that in patients who have frequent migraine attacks (> 6 migraine days per month), using rimegepant as needed has been shown to lead to migraine frequency declining over time. “This shows that if we treat acute attacks properly, we can minimize the risk of chronic migraine.”

She pointed out that if a patient has prodrome that is easy to identify or has short attacks, ubrogepant may be a good option, having shown effectiveness in preventing or reducing the onset of the headache in the recently reported PRODROME trial when given the day before migraine starts.

Then there is also zavegepant, which is available as a nasal spray, so it is a good option for patients with nausea and vomiting. Dr. Ailani suggested that zavegepant as a third-generation gepant may be worth trying in patients who have tried the other gepants, as it is a different type of molecule.

For this patient, neither rimegepant nor ubrogepant worked. “We tried treating in the prodrome, when the pain was starting, adding to other treatments, but she is not a ‘gepant’ responder. We have yet to try zavegepant,” she said.

The next consideration was lasmiditan. “This patient is a triptan responder and lasmiditan is a 5HT1 agonist, so it makes sense to try this. Also, it doesn’t have a vasoconstrictor effect as it doesn’t work on the blood vessels, so it is safe for patients with high blood pressure,” Dr. Ailani noted.

She pointed out, however, that lasmiditan has become a rescue medication in her practice because of side effect issues such as dizziness and sleepiness.

But Dr. Ailani said she has learned how to use the medication to minimize the side effects, by increasing the dose slowly and advising patients to take it later in the day.

“We start with 50 mg for a few doses then increase to 100 mg. This seems to build tolerability.”

Her patient has found good relief from lasmiditan 100 mg, but she can’t take it during the day as it makes her sleepy.

As a last resort, Dr. Ailani went back to metoclopramide, which she described as “a tried and tested old-time drug.”

While this does not make the patient sleepy, it has other adverse effects limiting the frequency of its use, she noted. “I ask her to try to limit it to twice a week, and this has been pretty effective. She can function when she uses it.” 

Dr. Ailani also points out that neuromodulation should be in everyone’s tool kit. “So, we added an external combined occipital and trigeminal (eCOT device) neurostimulation device.”

The patient’s tool kit now looks like this:

• Neuromodulation device and meditation at first sign of an attack.
• Add metoclopramide 10 mg and acetaminophen 1000 mg.
• If the attack lasts into the second day, add lasmiditan 100 mg in the evening of the second day (limit 8 days a month).
• If the patient has a sudden onset severe migraine with nausea and vomiting that might make her go to the ER, add in ketorolac nasal spray (not > 5 days per month).

Dr. Ailani noted that other patients will need different toolkits, and in most cases, it is recommended to think about “situational prevention” for times when migraine attacks are predictable, which may include air travel, high-stress times (holidays, etc.), occasions when alcohol will be consumed, and at times of certain weather triggers.

Dr. Ailani disclosed no relevant financial relationships.

A version of this article appeared on Medscape.com.

Selecting a treatment plan to deal with acute migraine attacks can be like putting together a toolkit of possible therapies, individualized for each patient, one expert said.

The toolkit should comprise reliable treatments that patients know are going to work and that act quickly, allowing them to get back to functioning normally in their daily lives, said Jessica Ailani, MD, during a talk at the 17th European Headache Congress held recently in Barcelona, Spain. 

“Everyone with migraine needs acute treatment,” Dr. Ailani, who is a clinical professor of neurology at MedStar Georgetown University Hospital and director of the Georgetown Headache Center, Washington, DC, noted. “Sometimes we can reduce acute treatment with preventative agents, but some disability will remain, so we have to focus on good acute treatment, and this becomes more complex if a person has a lot of comorbidities, which is common in older patients.” 

In selecting suitable treatments for migraine, consideration has to be given to the patient profile, any other conditions they have, speed of onset of the migraine attack, length of the attack, associated symptoms, and side effects of the medications, she said. 
 

A Complex Case

As an example, Dr. Ailani described the process she used to treat one of her patients who had frequent severe migraines and other issues causing difficult decisions when selecting medications — a woman in her late 60s with several other comorbidities.

“This is the kind of case I see on a daily basis and which keeps me up at night,” she said. “Many times in clinical practice, we see complex cases like this, and through the course of a year, we may try every treatment option we have in a patient like this.”

On the first presentation, the patient had a chronic migraine with severe headaches every day. She had a history of previous cervical discectomy with fusion surgery; uncontrolled hypertension, for which she was taking an angiotensin blocker; high cholesterol, for which she was taking a statin; and diabetes with an A1c of 8. She did not smoke or drink alcohol, exercised moderately, and her body mass index was in a good range. 

“Before a patient ever sees a doctor for their migraine, they will have already tried a lot of different things. Most people are already using NSAIDs and acetaminophen, the most commonly used treatments for acute migraine,” Dr. Ailani explains.

Her patient was taking a triptan and the barbiturate, butalbital. Dr. Ailani notes that the triptan is very effective, but in the United States, they are not available over the counter, and the patient is only allowed nine doses per month on her insurance, so she was supplementing with butalbital. 

Over the course of a year, Dr. Ailani got her off the butalbital and started her on onabotulinum toxin A for migraine prevention, which reduced her headache days to about 15 per month (8 severe). She then added the anti-calcitonin gene-related peptide (CGRP) monoclonal antibody, galcanezumab, as another preventative, which further reduced the headache days down to 8-10 days per month (all migraine). 

The attacks are rapid onset and can last multiple days. They come with photophobia and phonophobia and cause her to be bedridden, she noted. 

“I was still worried about this frequency of headache and the fact she was using a triptan for acute treatment when she had uncontrolled hypertension and other cardiovascular risk factors, Dr. Ailani commented. 

She explained that triptans are generally not used in individuals aged over 65 years because of a lack of data in this age group. They are also contraindicated in patients with cardiovascular (CV) disease, and caution is advised in patients with CV risk factors. Noting that migraine is an independent risk factor for stroke in healthy individuals, and this patient already had three other major risk factors for stroke, Dr. Ailani said she did not think a triptan was the best option. 

When triptans do not work, Dr. Ailani said she thinks about dihydroergotamine, which she describes as “a great drug for long-lasting migraine” as it tends to have a sustained response. But it also has vasoconstrictive effects and can increase blood pressure, so it was not suitable for this patient. 

CV risk is also an issue with nonsteroidal anti-inflammatory drugs (NSAIDs), one of the staple treatments for acute migraine.

“NSAIDs are available over the counter, inexpensive, quite effective, and have minimal immediate side effects,” Dr. Ailani said. But long-term adverse events include CV events, particularly in those who already have CV risk factors, and it is now thought that NSAIDs actually carry more CV risk than triptans.

She noted that out of all the NSAIDs, celecoxib carries the lowest CV risk, and in the United States, it is available as a liquid formulation. There is also a study of ketorolac nasal spray showing it to be as effective as sumatriptan nasal spray for acute migraine.

As her patient was still going to the emergency room (ER) quite frequently at this point, Dr. Ailani prescribed ketorolac nasal spray as an emergency rescue medication, which did help to reduce ER visits but did not solve the acute treatment problem.

The next option she tried was the CGRP antagonists or “gepants” because of their good tolerability.

Because her patient had long attacks, Dr. Ailani said her first choice gepant was rimegepant as it has a long half-life.

She noted that in patients who have frequent migraine attacks (> 6 migraine days per month), using rimegepant as needed has been shown to lead to migraine frequency declining over time. “This shows that if we treat acute attacks properly, we can minimize the risk of chronic migraine.”

She pointed out that if a patient has prodrome that is easy to identify or has short attacks, ubrogepant may be a good option, having shown effectiveness in preventing or reducing the onset of the headache in the recently reported PRODROME trial when given the day before migraine starts.

Then there is also zavegepant, which is available as a nasal spray, so it is a good option for patients with nausea and vomiting. Dr. Ailani suggested that zavegepant as a third-generation gepant may be worth trying in patients who have tried the other gepants, as it is a different type of molecule.

For this patient, neither rimegepant nor ubrogepant worked. “We tried treating in the prodrome, when the pain was starting, adding to other treatments, but she is not a ‘gepant’ responder. We have yet to try zavegepant,” she said.

The next consideration was lasmiditan. “This patient is a triptan responder and lasmiditan is a 5HT1 agonist, so it makes sense to try this. Also, it doesn’t have a vasoconstrictor effect as it doesn’t work on the blood vessels, so it is safe for patients with high blood pressure,” Dr. Ailani noted.

She pointed out, however, that lasmiditan has become a rescue medication in her practice because of side effect issues such as dizziness and sleepiness.

But Dr. Ailani said she has learned how to use the medication to minimize the side effects, by increasing the dose slowly and advising patients to take it later in the day.

“We start with 50 mg for a few doses then increase to 100 mg. This seems to build tolerability.”

Her patient has found good relief from lasmiditan 100 mg, but she can’t take it during the day as it makes her sleepy.

As a last resort, Dr. Ailani went back to metoclopramide, which she described as “a tried and tested old-time drug.”

While this does not make the patient sleepy, it has other adverse effects limiting the frequency of its use, she noted. “I ask her to try to limit it to twice a week, and this has been pretty effective. She can function when she uses it.” 

Dr. Ailani also points out that neuromodulation should be in everyone’s tool kit. “So, we added an external combined occipital and trigeminal (eCOT device) neurostimulation device.”

The patient’s tool kit now looks like this:

• Neuromodulation device and meditation at first sign of an attack.
• Add metoclopramide 10 mg and acetaminophen 1000 mg.
• If the attack lasts into the second day, add lasmiditan 100 mg in the evening of the second day (limit 8 days a month).
• If the patient has a sudden onset severe migraine with nausea and vomiting that might make her go to the ER, add in ketorolac nasal spray (not > 5 days per month).

Dr. Ailani noted that other patients will need different toolkits, and in most cases, it is recommended to think about “situational prevention” for times when migraine attacks are predictable, which may include air travel, high-stress times (holidays, etc.), occasions when alcohol will be consumed, and at times of certain weather triggers.

Dr. Ailani disclosed no relevant financial relationships.

A version of this article appeared on Medscape.com.

A new federal rule opens the door for physicians in California and Texas to take advantage of student loan forgiveness, possibly bringing much-needed relief to those with cumbersome debt loads after repayments resumed last month. However, the timing is critical, as some doctors may need to consolidate their loans by December 31 to remain eligible.

Updated guidelines for the Public Service Loan Forgiveness Program (PSLF) took effect in July, expanding the number of potential borrowers who could have their federal student loan balances wiped clean after working full time in a government or nonprofit role and making 120 monthly loan payments.

But loan forgiveness also hinges on having the correct employment type and requires applicants to be a “direct hire” of the organization. State laws in California and Texas prohibit nonprofit hospitals and health care entities from directly hiring physicians — a loophole that has barred doctors in those locations from applying.

Both states’ medical and hospital associations worked with the US Department of Education (DOE) to offer an exception. California and Texas physicians can now satisfy the employment type condition by having a written contract or medical staff privileges with a nonprofit hospital or facility, even if the physician is part of a for-profit sole proprietorship, partnership, or medical group.

Eligible loans cannot be in default and must have been received through the Direct Loan Program, which includes Parent PLUS loans. Doctors with non-qualifying student loans, such as Federal Family Education Loans, can become PSLF-eligible and have past time worked counted toward the requirements if they consolidate into a direct loan by December 31.

The California Medical Association (CMA) has an online guide to help doctors and employers navigate the new rules.

The change comes just in time because California and Texas need to expand their physician workforces by tens of thousands over the next decade. “This program will allow us to retain and recruit new physicians to our states to address our growing physician shortages and access to care challenges for the patients who need us most,” Texas Medical Association president Rick W. Snyder II, MD, said in a statement.

Physicians should use the PSLF Help Tool to complete the forgiveness application, said Ashley Harrington, senior advisor at the DOE. During a free on-demand webinar hosted by CMA, she said the form has been streamlined and will ask applicants to list the nonprofit entity where they provide care, its employer identification number, the length of time worked there, and the average hours worked per week. The employer must sign to certify the physician’s reported hours.

Ideally, physicians should submit a PSLF form annually or each time they change jobs, but they can also wait until the end of the 10 years to submit the form, said Ms. Harrington.

With the average medical education loan debt exceeding $200,000, CMA president Donaldo Hernandez, MD, said the rule will ensure low-income and minority students can consider medical careers.

California family medicine physician Ashley Paydar, DO, said that she has already applied for PSLF and found the process relatively easy. While she awaits final approval, she’s planning for the future. “Loan forgiveness will allow me to do a fellowship and save for my children›s college so they can pursue higher education without the debt,” she said.

Still, employers have no legal obligation to certify physicians’ hours, and many may express hesitation as they try to understand the new guidelines, said Long Do, JD, partner at Athene Law in San Francisco and speaker during the webinar. He urged physicians to have patience when working through the application process.

A version of this article appeared on Medscape.com.

A new federal rule opens the door for physicians in California and Texas to take advantage of student loan forgiveness, possibly bringing much-needed relief to those with cumbersome debt loads after repayments resumed last month. However, the timing is critical, as some doctors may need to consolidate their loans by December 31 to remain eligible.

Updated guidelines for the Public Service Loan Forgiveness Program (PSLF) took effect in July, expanding the number of potential borrowers who could have their federal student loan balances wiped clean after working full time in a government or nonprofit role and making 120 monthly loan payments.

But loan forgiveness also hinges on having the correct employment type and requires applicants to be a “direct hire” of the organization. State laws in California and Texas prohibit nonprofit hospitals and health care entities from directly hiring physicians — a loophole that has barred doctors in those locations from applying.

Both states’ medical and hospital associations worked with the US Department of Education (DOE) to offer an exception. California and Texas physicians can now satisfy the employment type condition by having a written contract or medical staff privileges with a nonprofit hospital or facility, even if the physician is part of a for-profit sole proprietorship, partnership, or medical group.

Eligible loans cannot be in default and must have been received through the Direct Loan Program, which includes Parent PLUS loans. Doctors with non-qualifying student loans, such as Federal Family Education Loans, can become PSLF-eligible and have past time worked counted toward the requirements if they consolidate into a direct loan by December 31.

The California Medical Association (CMA) has an online guide to help doctors and employers navigate the new rules.

The change comes just in time because California and Texas need to expand their physician workforces by tens of thousands over the next decade. “This program will allow us to retain and recruit new physicians to our states to address our growing physician shortages and access to care challenges for the patients who need us most,” Texas Medical Association president Rick W. Snyder II, MD, said in a statement.

Physicians should use the PSLF Help Tool to complete the forgiveness application, said Ashley Harrington, senior advisor at the DOE. During a free on-demand webinar hosted by CMA, she said the form has been streamlined and will ask applicants to list the nonprofit entity where they provide care, its employer identification number, the length of time worked there, and the average hours worked per week. The employer must sign to certify the physician’s reported hours.

Ideally, physicians should submit a PSLF form annually or each time they change jobs, but they can also wait until the end of the 10 years to submit the form, said Ms. Harrington.

With the average medical education loan debt exceeding $200,000, CMA president Donaldo Hernandez, MD, said the rule will ensure low-income and minority students can consider medical careers.

California family medicine physician Ashley Paydar, DO, said that she has already applied for PSLF and found the process relatively easy. While she awaits final approval, she’s planning for the future. “Loan forgiveness will allow me to do a fellowship and save for my children›s college so they can pursue higher education without the debt,” she said.

Still, employers have no legal obligation to certify physicians’ hours, and many may express hesitation as they try to understand the new guidelines, said Long Do, JD, partner at Athene Law in San Francisco and speaker during the webinar. He urged physicians to have patience when working through the application process.

A version of this article appeared on Medscape.com.

A new federal rule opens the door for physicians in California and Texas to take advantage of student loan forgiveness, possibly bringing much-needed relief to those with cumbersome debt loads after repayments resumed last month. However, the timing is critical, as some doctors may need to consolidate their loans by December 31 to remain eligible.

Updated guidelines for the Public Service Loan Forgiveness Program (PSLF) took effect in July, expanding the number of potential borrowers who could have their federal student loan balances wiped clean after working full time in a government or nonprofit role and making 120 monthly loan payments.

But loan forgiveness also hinges on having the correct employment type and requires applicants to be a “direct hire” of the organization. State laws in California and Texas prohibit nonprofit hospitals and health care entities from directly hiring physicians — a loophole that has barred doctors in those locations from applying.

Both states’ medical and hospital associations worked with the US Department of Education (DOE) to offer an exception. California and Texas physicians can now satisfy the employment type condition by having a written contract or medical staff privileges with a nonprofit hospital or facility, even if the physician is part of a for-profit sole proprietorship, partnership, or medical group.

Eligible loans cannot be in default and must have been received through the Direct Loan Program, which includes Parent PLUS loans. Doctors with non-qualifying student loans, such as Federal Family Education Loans, can become PSLF-eligible and have past time worked counted toward the requirements if they consolidate into a direct loan by December 31.

The California Medical Association (CMA) has an online guide to help doctors and employers navigate the new rules.

The change comes just in time because California and Texas need to expand their physician workforces by tens of thousands over the next decade. “This program will allow us to retain and recruit new physicians to our states to address our growing physician shortages and access to care challenges for the patients who need us most,” Texas Medical Association president Rick W. Snyder II, MD, said in a statement.

Physicians should use the PSLF Help Tool to complete the forgiveness application, said Ashley Harrington, senior advisor at the DOE. During a free on-demand webinar hosted by CMA, she said the form has been streamlined and will ask applicants to list the nonprofit entity where they provide care, its employer identification number, the length of time worked there, and the average hours worked per week. The employer must sign to certify the physician’s reported hours.

Ideally, physicians should submit a PSLF form annually or each time they change jobs, but they can also wait until the end of the 10 years to submit the form, said Ms. Harrington.

With the average medical education loan debt exceeding $200,000, CMA president Donaldo Hernandez, MD, said the rule will ensure low-income and minority students can consider medical careers.

California family medicine physician Ashley Paydar, DO, said that she has already applied for PSLF and found the process relatively easy. While she awaits final approval, she’s planning for the future. “Loan forgiveness will allow me to do a fellowship and save for my children›s college so they can pursue higher education without the debt,” she said.

Still, employers have no legal obligation to certify physicians’ hours, and many may express hesitation as they try to understand the new guidelines, said Long Do, JD, partner at Athene Law in San Francisco and speaker during the webinar. He urged physicians to have patience when working through the application process.

A version of this article appeared on Medscape.com.