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The findings of a new randomized trial support the rapid tapering of prednisone in patients with generalized myasthenia gravis requiring combined corticosteroid and azathioprine therapy. The trial showed that the conventional slow tapering regimen enabled discontinuation of prednisone earlier than previously reported but the new rapid-tapering regimen enabled an even faster discontinuation.

Noting that although both regimens led to a comparable myasthenia gravis status and prednisone dose at 15 months, the authors stated: “We think that the reduction of the cumulative dose over a year (equivalent to 5 mg/day) is a clinically relevant reduction, since the risk of complications is proportional to the daily or cumulative doses of prednisone.

“Our results warrant testing of a more rapid-tapering regimen in a future trial. In the meantime, our trial provides useful information on how prednisone tapering could be managed in patients with generalized myasthenia gravis treated with azathioprine,” they concluded.

The trial was published online Feb. 8 in JAMA Neurology.

Myasthenia gravis is a disorder of neuromuscular transmission, resulting from autoantibodies to components of the neuromuscular junction, most commonly the acetylcholine receptor. The incidence ranges from 0.3 to 2.8 per 100,000, and it is estimated to affect more than 700,000 people worldwide.

The authors of the current paper, led by Tarek Sharshar, MD, PhD, Groupe Hospitalier Universitaire, Paris, explained that many patients whose symptoms are not controlled by cholinesterase inhibitors are treated with corticosteroids and an immunosuppressant, usually azathioprine. No specific dosing protocol for prednisone has been validated, but it is commonly gradually increased to 0.75 mg/kg on alternate days and reduced progressively when minimal manifestation status (MMS; no symptoms or functional limitations) is reached.  

They noted that this regimen leads to high and prolonged corticosteroid treatment – often for several years – with the mean daily prednisone dose exceeding 30 mg/day at 15 months and 20 mg/day at 36 months. As long-term use of corticosteroids is often associated with significant complications, reducing or even discontinuing prednisone treatment without destabilizing myasthenia gravis is therefore a therapeutic goal.


 

Evaluating dosage regimens

To investigate whether different dosage regimens could help wean patients with generalized myasthenia gravis from corticosteroid therapy without compromising efficacy, the researchers conducted this study in which the current recommended regimen was compared with an approach using higher initial corticosteroid doses followed by rapid tapering.

In the conventional slow-tapering group (control group), prednisone was given on alternate days, starting at a dose of 10 mg then increased by increments of 10 mg every 2 days up to 1.5 mg/kg on alternate days without exceeding 100 mg. This dose was maintained until MMS was reached and then reduced by 10 mg every 2 weeks until a dosage of 40 mg was reached, with subsequent slowing of the taper to 5 mg monthly. If MMS was not maintained, the alternate-day prednisone dose was increased by 10 mg every 2 weeks until MMS was restored, and the tapering resumed 4 weeks later.

In the new rapid-tapering group, oral prednisone was immediately started at 0.75 mg/kg per day, and this was followed by an earlier and rapid decrease once improved myasthenia gravis status was attained. Three different tapering schedules were applied dependent on the improvement status of the patient.

First, If the patient reached MMS at 1 month, the dose of prednisone was reduced by 0.1 mg/kg every 10 days up to 0.45 mg/kg per day, then 0.05 mg/kg every 10 days up to 0.25 mg/kg per day, then in decrements of 1 mg by adjusting the duration of the decrements according to the participant’s weight with the aim of achieving complete cessation of corticosteroid therapy within 18-20 weeks for this third stage of tapering.

Second, if the state of MMS was not reached at 1 month but the participant had improved, a slower tapering was conducted, with the dosage reduced in a similar way to the first instance but with each reduction introduced every 20 days. If the participant reached MMS during this tapering process, the tapering of prednisone was similar to the sequence described in the first group.

Third, if MMS was not reached and the participant had not improved, the initial dose was maintained for the first 3 months; beyond that time, a decrease in the prednisone dose was undertaken as in the second group to a minimum dose of 0.25 mg/kg per day, after which the prednisone dose was not reduced further. If the patient improved, the tapering of prednisone followed the sequence described in the second category.

Reductions in prednisone dose could be accelerated in the case of severe prednisone adverse effects, according to the prescriber’s decision.

In the event of a myasthenia gravis exacerbation, the patient was hospitalized and the dose of prednisone was routinely doubled, or for a more moderate aggravation, the dose was increased to the previous dose recommended in the tapering regimen.

Azathioprine, up to a maximum dose of 3 mg/kg per day, was prescribed for all participants. In all, 117 patients were randomly assigned, and 113 completed the study.

The primary outcome was the proportion of participants having reached MMS without prednisone at 12 months and having not relapsed or taken prednisone between months 12 and 15. This was achieved by significantly more patients in the rapid-tapering group (39% vs. 9%; risk ratio, 3.61; P < .001).

Rapid tapering allowed sparing of a mean of 1,898 mg of prednisone over 1 year (5.3 mg/day) per patient.

The rate of myasthenia gravis exacerbation or worsening did not differ significantly between the two groups, nor did the use of plasmapheresis or IVIG or the doses of azathioprine.

The overall number of serious adverse events did not differ significantly between the two groups (slow tapering, 22% vs. rapid-tapering, 36%; P = .15).

The researchers said it is possible that prednisone tapering would differ with another immunosuppressive agent but as azathioprine is the first-line immunosuppressant usually recommended, these results are relevant for a large proportion of patients.

They said the better outcome of the intervention group could have been related to one or more of four differences in prednisone administration: An immediate high dose versus a slow increase of the prednisone dose; daily versus alternate-day dosing; earlier tapering initiation; and faster tapering. However, the structure of the study did not allow identification of which of these factors was responsible.

“Researching the best prednisone-tapering scheme is not only a major issue for patients with myasthenia gravis but also for other autoimmune or inflammatory diseases, because validated prednisone-tapering regimens are scarce,” the authors said.

The rapid tapering of prednisone therapy appears to be feasible, beneficial, and safe in patients with generalized myasthenia gravis and “warrants testing in other autoimmune diseases,” they added.
 

Particularly relevant to late-onset disease

Commenting on the study, Raffi Topakian, MD, Klinikum Wels-Grieskirchen, Wels, Austria, said the results showed that in patients with moderate to severe generalized myasthenia gravis requiring high-dose prednisone, azathioprine, a widely used immunosuppressant, may have a quicker steroid-sparing effect than previously thought, and that rapid steroid tapering can be achieved safely, resulting in a reduction of the cumulative steroid dose over a year despite higher initial doses.

Dr. Topakian, who was not involved with the research, pointed out that the median age was advanced (around 56 years), and the benefit of a regimen that leads to a reduction of the cumulative steroid dose over a year may be disproportionately larger for older, sicker patients with many comorbidities who are at considerably higher risk for a prednisone-induced increase in cardiovascular complications, osteoporotic fractures, and gastrointestinal bleeding. 

“The study findings are particularly relevant for the management of late-onset myasthenia gravis (when first symptoms start after age 45-50 years), which is being encountered more frequently over the past years,” he said.

“But the holy grail of myasthenia gravis treatment has not been found yet,” Dr. Topakian noted. “Disappointingly, rapid tapering of steroids (compared to slow tapering) resulted in a reduction of the cumulative steroid dose only, but was not associated with better myasthenia gravis functional status or lower doses of steroids at 15 months. To my view, this finding points to the limited immunosuppressive efficacy of azathioprine.”

He added that the study findings should not be extrapolated to patients with mild presentations or to those with muscle-specific kinase myasthenia gravis.

Dr. Sharshar disclosed no relevant financial relationships. Disclosures for the study coauthors appear in the original article.
 

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

The findings of a new randomized trial support the rapid tapering of prednisone in patients with generalized myasthenia gravis requiring combined corticosteroid and azathioprine therapy. The trial showed that the conventional slow tapering regimen enabled discontinuation of prednisone earlier than previously reported but the new rapid-tapering regimen enabled an even faster discontinuation.

Noting that although both regimens led to a comparable myasthenia gravis status and prednisone dose at 15 months, the authors stated: “We think that the reduction of the cumulative dose over a year (equivalent to 5 mg/day) is a clinically relevant reduction, since the risk of complications is proportional to the daily or cumulative doses of prednisone.

“Our results warrant testing of a more rapid-tapering regimen in a future trial. In the meantime, our trial provides useful information on how prednisone tapering could be managed in patients with generalized myasthenia gravis treated with azathioprine,” they concluded.

The trial was published online Feb. 8 in JAMA Neurology.

Myasthenia gravis is a disorder of neuromuscular transmission, resulting from autoantibodies to components of the neuromuscular junction, most commonly the acetylcholine receptor. The incidence ranges from 0.3 to 2.8 per 100,000, and it is estimated to affect more than 700,000 people worldwide.

The authors of the current paper, led by Tarek Sharshar, MD, PhD, Groupe Hospitalier Universitaire, Paris, explained that many patients whose symptoms are not controlled by cholinesterase inhibitors are treated with corticosteroids and an immunosuppressant, usually azathioprine. No specific dosing protocol for prednisone has been validated, but it is commonly gradually increased to 0.75 mg/kg on alternate days and reduced progressively when minimal manifestation status (MMS; no symptoms or functional limitations) is reached.  

They noted that this regimen leads to high and prolonged corticosteroid treatment – often for several years – with the mean daily prednisone dose exceeding 30 mg/day at 15 months and 20 mg/day at 36 months. As long-term use of corticosteroids is often associated with significant complications, reducing or even discontinuing prednisone treatment without destabilizing myasthenia gravis is therefore a therapeutic goal.


 

Evaluating dosage regimens

To investigate whether different dosage regimens could help wean patients with generalized myasthenia gravis from corticosteroid therapy without compromising efficacy, the researchers conducted this study in which the current recommended regimen was compared with an approach using higher initial corticosteroid doses followed by rapid tapering.

In the conventional slow-tapering group (control group), prednisone was given on alternate days, starting at a dose of 10 mg then increased by increments of 10 mg every 2 days up to 1.5 mg/kg on alternate days without exceeding 100 mg. This dose was maintained until MMS was reached and then reduced by 10 mg every 2 weeks until a dosage of 40 mg was reached, with subsequent slowing of the taper to 5 mg monthly. If MMS was not maintained, the alternate-day prednisone dose was increased by 10 mg every 2 weeks until MMS was restored, and the tapering resumed 4 weeks later.

In the new rapid-tapering group, oral prednisone was immediately started at 0.75 mg/kg per day, and this was followed by an earlier and rapid decrease once improved myasthenia gravis status was attained. Three different tapering schedules were applied dependent on the improvement status of the patient.

First, If the patient reached MMS at 1 month, the dose of prednisone was reduced by 0.1 mg/kg every 10 days up to 0.45 mg/kg per day, then 0.05 mg/kg every 10 days up to 0.25 mg/kg per day, then in decrements of 1 mg by adjusting the duration of the decrements according to the participant’s weight with the aim of achieving complete cessation of corticosteroid therapy within 18-20 weeks for this third stage of tapering.

Second, if the state of MMS was not reached at 1 month but the participant had improved, a slower tapering was conducted, with the dosage reduced in a similar way to the first instance but with each reduction introduced every 20 days. If the participant reached MMS during this tapering process, the tapering of prednisone was similar to the sequence described in the first group.

Third, if MMS was not reached and the participant had not improved, the initial dose was maintained for the first 3 months; beyond that time, a decrease in the prednisone dose was undertaken as in the second group to a minimum dose of 0.25 mg/kg per day, after which the prednisone dose was not reduced further. If the patient improved, the tapering of prednisone followed the sequence described in the second category.

Reductions in prednisone dose could be accelerated in the case of severe prednisone adverse effects, according to the prescriber’s decision.

In the event of a myasthenia gravis exacerbation, the patient was hospitalized and the dose of prednisone was routinely doubled, or for a more moderate aggravation, the dose was increased to the previous dose recommended in the tapering regimen.

Azathioprine, up to a maximum dose of 3 mg/kg per day, was prescribed for all participants. In all, 117 patients were randomly assigned, and 113 completed the study.

The primary outcome was the proportion of participants having reached MMS without prednisone at 12 months and having not relapsed or taken prednisone between months 12 and 15. This was achieved by significantly more patients in the rapid-tapering group (39% vs. 9%; risk ratio, 3.61; P < .001).

Rapid tapering allowed sparing of a mean of 1,898 mg of prednisone over 1 year (5.3 mg/day) per patient.

The rate of myasthenia gravis exacerbation or worsening did not differ significantly between the two groups, nor did the use of plasmapheresis or IVIG or the doses of azathioprine.

The overall number of serious adverse events did not differ significantly between the two groups (slow tapering, 22% vs. rapid-tapering, 36%; P = .15).

The researchers said it is possible that prednisone tapering would differ with another immunosuppressive agent but as azathioprine is the first-line immunosuppressant usually recommended, these results are relevant for a large proportion of patients.

They said the better outcome of the intervention group could have been related to one or more of four differences in prednisone administration: An immediate high dose versus a slow increase of the prednisone dose; daily versus alternate-day dosing; earlier tapering initiation; and faster tapering. However, the structure of the study did not allow identification of which of these factors was responsible.

“Researching the best prednisone-tapering scheme is not only a major issue for patients with myasthenia gravis but also for other autoimmune or inflammatory diseases, because validated prednisone-tapering regimens are scarce,” the authors said.

The rapid tapering of prednisone therapy appears to be feasible, beneficial, and safe in patients with generalized myasthenia gravis and “warrants testing in other autoimmune diseases,” they added.
 

Particularly relevant to late-onset disease

Commenting on the study, Raffi Topakian, MD, Klinikum Wels-Grieskirchen, Wels, Austria, said the results showed that in patients with moderate to severe generalized myasthenia gravis requiring high-dose prednisone, azathioprine, a widely used immunosuppressant, may have a quicker steroid-sparing effect than previously thought, and that rapid steroid tapering can be achieved safely, resulting in a reduction of the cumulative steroid dose over a year despite higher initial doses.

Dr. Topakian, who was not involved with the research, pointed out that the median age was advanced (around 56 years), and the benefit of a regimen that leads to a reduction of the cumulative steroid dose over a year may be disproportionately larger for older, sicker patients with many comorbidities who are at considerably higher risk for a prednisone-induced increase in cardiovascular complications, osteoporotic fractures, and gastrointestinal bleeding. 

“The study findings are particularly relevant for the management of late-onset myasthenia gravis (when first symptoms start after age 45-50 years), which is being encountered more frequently over the past years,” he said.

“But the holy grail of myasthenia gravis treatment has not been found yet,” Dr. Topakian noted. “Disappointingly, rapid tapering of steroids (compared to slow tapering) resulted in a reduction of the cumulative steroid dose only, but was not associated with better myasthenia gravis functional status or lower doses of steroids at 15 months. To my view, this finding points to the limited immunosuppressive efficacy of azathioprine.”

He added that the study findings should not be extrapolated to patients with mild presentations or to those with muscle-specific kinase myasthenia gravis.

Dr. Sharshar disclosed no relevant financial relationships. Disclosures for the study coauthors appear in the original article.
 

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

The findings of a new randomized trial support the rapid tapering of prednisone in patients with generalized myasthenia gravis requiring combined corticosteroid and azathioprine therapy. The trial showed that the conventional slow tapering regimen enabled discontinuation of prednisone earlier than previously reported but the new rapid-tapering regimen enabled an even faster discontinuation.

Noting that although both regimens led to a comparable myasthenia gravis status and prednisone dose at 15 months, the authors stated: “We think that the reduction of the cumulative dose over a year (equivalent to 5 mg/day) is a clinically relevant reduction, since the risk of complications is proportional to the daily or cumulative doses of prednisone.

“Our results warrant testing of a more rapid-tapering regimen in a future trial. In the meantime, our trial provides useful information on how prednisone tapering could be managed in patients with generalized myasthenia gravis treated with azathioprine,” they concluded.

The trial was published online Feb. 8 in JAMA Neurology.

Myasthenia gravis is a disorder of neuromuscular transmission, resulting from autoantibodies to components of the neuromuscular junction, most commonly the acetylcholine receptor. The incidence ranges from 0.3 to 2.8 per 100,000, and it is estimated to affect more than 700,000 people worldwide.

The authors of the current paper, led by Tarek Sharshar, MD, PhD, Groupe Hospitalier Universitaire, Paris, explained that many patients whose symptoms are not controlled by cholinesterase inhibitors are treated with corticosteroids and an immunosuppressant, usually azathioprine. No specific dosing protocol for prednisone has been validated, but it is commonly gradually increased to 0.75 mg/kg on alternate days and reduced progressively when minimal manifestation status (MMS; no symptoms or functional limitations) is reached.  

They noted that this regimen leads to high and prolonged corticosteroid treatment – often for several years – with the mean daily prednisone dose exceeding 30 mg/day at 15 months and 20 mg/day at 36 months. As long-term use of corticosteroids is often associated with significant complications, reducing or even discontinuing prednisone treatment without destabilizing myasthenia gravis is therefore a therapeutic goal.


 

Evaluating dosage regimens

To investigate whether different dosage regimens could help wean patients with generalized myasthenia gravis from corticosteroid therapy without compromising efficacy, the researchers conducted this study in which the current recommended regimen was compared with an approach using higher initial corticosteroid doses followed by rapid tapering.

In the conventional slow-tapering group (control group), prednisone was given on alternate days, starting at a dose of 10 mg then increased by increments of 10 mg every 2 days up to 1.5 mg/kg on alternate days without exceeding 100 mg. This dose was maintained until MMS was reached and then reduced by 10 mg every 2 weeks until a dosage of 40 mg was reached, with subsequent slowing of the taper to 5 mg monthly. If MMS was not maintained, the alternate-day prednisone dose was increased by 10 mg every 2 weeks until MMS was restored, and the tapering resumed 4 weeks later.

In the new rapid-tapering group, oral prednisone was immediately started at 0.75 mg/kg per day, and this was followed by an earlier and rapid decrease once improved myasthenia gravis status was attained. Three different tapering schedules were applied dependent on the improvement status of the patient.

First, If the patient reached MMS at 1 month, the dose of prednisone was reduced by 0.1 mg/kg every 10 days up to 0.45 mg/kg per day, then 0.05 mg/kg every 10 days up to 0.25 mg/kg per day, then in decrements of 1 mg by adjusting the duration of the decrements according to the participant’s weight with the aim of achieving complete cessation of corticosteroid therapy within 18-20 weeks for this third stage of tapering.

Second, if the state of MMS was not reached at 1 month but the participant had improved, a slower tapering was conducted, with the dosage reduced in a similar way to the first instance but with each reduction introduced every 20 days. If the participant reached MMS during this tapering process, the tapering of prednisone was similar to the sequence described in the first group.

Third, if MMS was not reached and the participant had not improved, the initial dose was maintained for the first 3 months; beyond that time, a decrease in the prednisone dose was undertaken as in the second group to a minimum dose of 0.25 mg/kg per day, after which the prednisone dose was not reduced further. If the patient improved, the tapering of prednisone followed the sequence described in the second category.

Reductions in prednisone dose could be accelerated in the case of severe prednisone adverse effects, according to the prescriber’s decision.

In the event of a myasthenia gravis exacerbation, the patient was hospitalized and the dose of prednisone was routinely doubled, or for a more moderate aggravation, the dose was increased to the previous dose recommended in the tapering regimen.

Azathioprine, up to a maximum dose of 3 mg/kg per day, was prescribed for all participants. In all, 117 patients were randomly assigned, and 113 completed the study.

The primary outcome was the proportion of participants having reached MMS without prednisone at 12 months and having not relapsed or taken prednisone between months 12 and 15. This was achieved by significantly more patients in the rapid-tapering group (39% vs. 9%; risk ratio, 3.61; P < .001).

Rapid tapering allowed sparing of a mean of 1,898 mg of prednisone over 1 year (5.3 mg/day) per patient.

The rate of myasthenia gravis exacerbation or worsening did not differ significantly between the two groups, nor did the use of plasmapheresis or IVIG or the doses of azathioprine.

The overall number of serious adverse events did not differ significantly between the two groups (slow tapering, 22% vs. rapid-tapering, 36%; P = .15).

The researchers said it is possible that prednisone tapering would differ with another immunosuppressive agent but as azathioprine is the first-line immunosuppressant usually recommended, these results are relevant for a large proportion of patients.

They said the better outcome of the intervention group could have been related to one or more of four differences in prednisone administration: An immediate high dose versus a slow increase of the prednisone dose; daily versus alternate-day dosing; earlier tapering initiation; and faster tapering. However, the structure of the study did not allow identification of which of these factors was responsible.

“Researching the best prednisone-tapering scheme is not only a major issue for patients with myasthenia gravis but also for other autoimmune or inflammatory diseases, because validated prednisone-tapering regimens are scarce,” the authors said.

The rapid tapering of prednisone therapy appears to be feasible, beneficial, and safe in patients with generalized myasthenia gravis and “warrants testing in other autoimmune diseases,” they added.
 

Particularly relevant to late-onset disease

Commenting on the study, Raffi Topakian, MD, Klinikum Wels-Grieskirchen, Wels, Austria, said the results showed that in patients with moderate to severe generalized myasthenia gravis requiring high-dose prednisone, azathioprine, a widely used immunosuppressant, may have a quicker steroid-sparing effect than previously thought, and that rapid steroid tapering can be achieved safely, resulting in a reduction of the cumulative steroid dose over a year despite higher initial doses.

Dr. Topakian, who was not involved with the research, pointed out that the median age was advanced (around 56 years), and the benefit of a regimen that leads to a reduction of the cumulative steroid dose over a year may be disproportionately larger for older, sicker patients with many comorbidities who are at considerably higher risk for a prednisone-induced increase in cardiovascular complications, osteoporotic fractures, and gastrointestinal bleeding. 

“The study findings are particularly relevant for the management of late-onset myasthenia gravis (when first symptoms start after age 45-50 years), which is being encountered more frequently over the past years,” he said.

“But the holy grail of myasthenia gravis treatment has not been found yet,” Dr. Topakian noted. “Disappointingly, rapid tapering of steroids (compared to slow tapering) resulted in a reduction of the cumulative steroid dose only, but was not associated with better myasthenia gravis functional status or lower doses of steroids at 15 months. To my view, this finding points to the limited immunosuppressive efficacy of azathioprine.”

He added that the study findings should not be extrapolated to patients with mild presentations or to those with muscle-specific kinase myasthenia gravis.

Dr. Sharshar disclosed no relevant financial relationships. Disclosures for the study coauthors appear in the original article.
 

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

Of four surgical procedures for breast cancer that have been determined to be of low value because they yield no meaningful clinical benefit, two continue to be utilized. In fact, the use of two of these procedures has increased in the United States, new research shows.

“This is the first study to [evaluate] all four of the low-value breast cancer procedures at the same time and try to draw some conclusions on practice patterns across facilities,” said senior author Lesly A. Dossett, MD, MPH, Center for Health Outcomes and Policy, the University of Michigan, Ann Arbor.

The two low-value procedures that have increased in use are contralateral prophylactic mastectomy for average-risk women with unilateral cancer and sentinel lymph node biopsy for clinically node-negative women aged 70 years and older with hormone receptor–positive (HR+) cancer.

“This suggests that formal efforts to reduce low value care through dissemination of guidelines, education of patients or providers, or alignment of incentives will be necessary to achieve full deimplementation,” she told this news organization.

The researchers emphasize that the providing of services that have no clinically meaningful benefit is a national epidemic, costing the United States more than $100 billion dollars annually.

These trends are notable and likely reflect a broad range of factors, commented Katharine Yao, MD, chief of the division of surgical oncology at the NorthShore University HealthSystem, Evanston, Ill.

“I think the better message here is not so much that facilities are doing too many low-value procedures but more that these procedures are still being performed, and the trends show increased rates over the years – why is that?”

“Perhaps there are other factors here we need to explore: why do these procedures persist, and why, despite the Choosing Wisely campaign, [do] they continue to increase?” she said in an interview. “Maybe there is something we can learn here about patient and physician preferences that perhaps we should be paying more attention to.”

The study was published on Feb. 3 in JAMA Surgery.

For the analysis, Dr. Dossett and her colleagues evaluated surgical data from the National Cancer Database. They examined data from more than 1,500 surgical facilities and from surgeries involving 920,256 women in the United States who were diagnosed with breast cancer between 2004 and 2016.

The team focused on four procedures that have been determined to be of low value by Choosing Wisely, a campaign of the American Board of Internal Medicine Foundation, on the basis of recommendations of the American College of Surgeons, the Society for Surgical Oncology, and the American Society for Breast Surgeons.

The results show that, for two of the four low-value procedures, use declined significantly over the study period. These two procedures were axillary lymph node dissection for limited nodal disease, for patients undergoing lumpectomy and radiotherapy, and lumpectomy re-excision for patients whose surgical margins were close but were negative for invasive cancer.

Axillary lymph node dissection declined from 63% in 2004 to 14% in 2016. The steepest reduction was seen soon after data from the Z0011 study were published in 2010. The rates for this procedure halved in the following year, from 62% in 2010 to 31% in 2011 (P < .001).

Likewise, reoperation rates after lumpectomy dropped from 19% in 2004 to 15% in 2016. The sharpest decline, from 18% in 2013 to 16% in 2014, corresponded to the publishing of the SSO/ASTRO consensus statement, which designated a negative margin as having “no tumor on ink.”

Two of the four low-value procedures increased in use during the study period.

Rates of contralateral prophylactic mastectomy increased nearly 2.5-fold among women with unilateral breast cancer undergoing mastectomy, from 11% in 2004 to 26% in 2016, despite SSO guidelines issued in 2007 recommending that the procedure not be used for women at average risk.

In addition, rates of sentinel lymph node biopsy among women aged 70 years and older with clinically node-negative HR+ breast cancer increased from 78% in 2004 to 87% in 2012. There was no significant decline in the use of this procedure, even after the CALGB 9343 trial from the Cancer and Leukemia Group B showed no survival benefit in 2013.
 

Patterns at hospitals vary

The authors of the study also examined hospital factors, which can heavily influence choice of procedure.

These results showed that the greatest reductions of the low-value breast cancer procedures occurred at academic research programs and high-volume surgical facilities. Elsewhere, the rates varied widely.

Interfacility rates of axillary lymph node dissection ranged from 7% to 47%; lumpectomy reoperation rates ranged from 3% to 62%; contralateral prophylactic mastectomy rates ranged from 9% to 67%; and sentinel lymph node biopsy rates ranged from 25% to 97%.

Being an outlier for use of one procedure did not necessarily translate to nonconformity for others. Factors such as a hospital’s volume of breast cancer cases or the type of facility did not appear to influence rates of axillary lymph node dissection or lumpectomy reoperation.

However, the rates of contralateral prophylactic mastectomy were significantly higher in high-volume centers and integrated network cancer programs, compared with community cancer programs (23% vs. 2%; P < .001).

Dr. Dossett said the lack of consistency was somewhat unexpected.

“We expected we would find some facilities were constantly good or bad at deimplementation or that there would be stronger associations between certain facility characteristics and performance,” she said. “That really wasn’t the case, and most facilities had mixed performance.”
 

Evidence may or may not influence trends

The authors speculate on why the low-value designation is in some cases being ignored.

The evidence regarding the risk for lymphedema related to axillary lymph node dissection procedure appears to have helped reduce its use, they note.

However, surgeons have been much less convinced of benefits in omitting sentinel lymph node biopsy, either because they are unfamiliar with the recommendations to avoid the procedure, or they may feel the procedure adds only minimal time and risk to a patient’s operation, the authors explain.

Patients may be convinced to opt to omit sentinel lymph node biopsy if they are properly counseled regarding the risks and benefits of the procedure, Dr. Dossett commented.

Dr. Yao added that, for elderly patients, age can play an important role in sentinel node biopsy.

“Patients’ life expectancy has increased over the years, and node status may impact adjuvant therapy decisions for these patients, even chemotherapy decisions,” she said.

Pressure to continue to perform contralateral prophylactic mastectomy is believed to be significantly patient driven, Dr. Dossett noted.

“I ultimately think the best way to reduce contralateral prophylactic mastectomy is to encourage women with small cancers to undergo breast-conserving surgery, i.e., lumpectomy, instead of mastectomy,” she explained.

“Once the decision for mastectomy is made, there is often a great deal of momentum towards a contralateral prophylactic mastectomy.”

“Contralateral prophylactic mastectomy is a personal preference that many surgeons are willing to do for their patients,” Dr. Yao explained.

“Although no survival benefit has been demonstrated for this procedure, patients find many other benefits that have nothing to do with survival.”

The authors and Dr. Yao have disclosed no relevant financial relationships.

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

Of four surgical procedures for breast cancer that have been determined to be of low value because they yield no meaningful clinical benefit, two continue to be utilized. In fact, the use of two of these procedures has increased in the United States, new research shows.

“This is the first study to [evaluate] all four of the low-value breast cancer procedures at the same time and try to draw some conclusions on practice patterns across facilities,” said senior author Lesly A. Dossett, MD, MPH, Center for Health Outcomes and Policy, the University of Michigan, Ann Arbor.

The two low-value procedures that have increased in use are contralateral prophylactic mastectomy for average-risk women with unilateral cancer and sentinel lymph node biopsy for clinically node-negative women aged 70 years and older with hormone receptor–positive (HR+) cancer.

“This suggests that formal efforts to reduce low value care through dissemination of guidelines, education of patients or providers, or alignment of incentives will be necessary to achieve full deimplementation,” she told this news organization.

The researchers emphasize that the providing of services that have no clinically meaningful benefit is a national epidemic, costing the United States more than $100 billion dollars annually.

These trends are notable and likely reflect a broad range of factors, commented Katharine Yao, MD, chief of the division of surgical oncology at the NorthShore University HealthSystem, Evanston, Ill.

“I think the better message here is not so much that facilities are doing too many low-value procedures but more that these procedures are still being performed, and the trends show increased rates over the years – why is that?”

“Perhaps there are other factors here we need to explore: why do these procedures persist, and why, despite the Choosing Wisely campaign, [do] they continue to increase?” she said in an interview. “Maybe there is something we can learn here about patient and physician preferences that perhaps we should be paying more attention to.”

The study was published on Feb. 3 in JAMA Surgery.

For the analysis, Dr. Dossett and her colleagues evaluated surgical data from the National Cancer Database. They examined data from more than 1,500 surgical facilities and from surgeries involving 920,256 women in the United States who were diagnosed with breast cancer between 2004 and 2016.

The team focused on four procedures that have been determined to be of low value by Choosing Wisely, a campaign of the American Board of Internal Medicine Foundation, on the basis of recommendations of the American College of Surgeons, the Society for Surgical Oncology, and the American Society for Breast Surgeons.

The results show that, for two of the four low-value procedures, use declined significantly over the study period. These two procedures were axillary lymph node dissection for limited nodal disease, for patients undergoing lumpectomy and radiotherapy, and lumpectomy re-excision for patients whose surgical margins were close but were negative for invasive cancer.

Axillary lymph node dissection declined from 63% in 2004 to 14% in 2016. The steepest reduction was seen soon after data from the Z0011 study were published in 2010. The rates for this procedure halved in the following year, from 62% in 2010 to 31% in 2011 (P < .001).

Likewise, reoperation rates after lumpectomy dropped from 19% in 2004 to 15% in 2016. The sharpest decline, from 18% in 2013 to 16% in 2014, corresponded to the publishing of the SSO/ASTRO consensus statement, which designated a negative margin as having “no tumor on ink.”

Two of the four low-value procedures increased in use during the study period.

Rates of contralateral prophylactic mastectomy increased nearly 2.5-fold among women with unilateral breast cancer undergoing mastectomy, from 11% in 2004 to 26% in 2016, despite SSO guidelines issued in 2007 recommending that the procedure not be used for women at average risk.

In addition, rates of sentinel lymph node biopsy among women aged 70 years and older with clinically node-negative HR+ breast cancer increased from 78% in 2004 to 87% in 2012. There was no significant decline in the use of this procedure, even after the CALGB 9343 trial from the Cancer and Leukemia Group B showed no survival benefit in 2013.
 

Patterns at hospitals vary

The authors of the study also examined hospital factors, which can heavily influence choice of procedure.

These results showed that the greatest reductions of the low-value breast cancer procedures occurred at academic research programs and high-volume surgical facilities. Elsewhere, the rates varied widely.

Interfacility rates of axillary lymph node dissection ranged from 7% to 47%; lumpectomy reoperation rates ranged from 3% to 62%; contralateral prophylactic mastectomy rates ranged from 9% to 67%; and sentinel lymph node biopsy rates ranged from 25% to 97%.

Being an outlier for use of one procedure did not necessarily translate to nonconformity for others. Factors such as a hospital’s volume of breast cancer cases or the type of facility did not appear to influence rates of axillary lymph node dissection or lumpectomy reoperation.

However, the rates of contralateral prophylactic mastectomy were significantly higher in high-volume centers and integrated network cancer programs, compared with community cancer programs (23% vs. 2%; P < .001).

Dr. Dossett said the lack of consistency was somewhat unexpected.

“We expected we would find some facilities were constantly good or bad at deimplementation or that there would be stronger associations between certain facility characteristics and performance,” she said. “That really wasn’t the case, and most facilities had mixed performance.”
 

Evidence may or may not influence trends

The authors speculate on why the low-value designation is in some cases being ignored.

The evidence regarding the risk for lymphedema related to axillary lymph node dissection procedure appears to have helped reduce its use, they note.

However, surgeons have been much less convinced of benefits in omitting sentinel lymph node biopsy, either because they are unfamiliar with the recommendations to avoid the procedure, or they may feel the procedure adds only minimal time and risk to a patient’s operation, the authors explain.

Patients may be convinced to opt to omit sentinel lymph node biopsy if they are properly counseled regarding the risks and benefits of the procedure, Dr. Dossett commented.

Dr. Yao added that, for elderly patients, age can play an important role in sentinel node biopsy.

“Patients’ life expectancy has increased over the years, and node status may impact adjuvant therapy decisions for these patients, even chemotherapy decisions,” she said.

Pressure to continue to perform contralateral prophylactic mastectomy is believed to be significantly patient driven, Dr. Dossett noted.

“I ultimately think the best way to reduce contralateral prophylactic mastectomy is to encourage women with small cancers to undergo breast-conserving surgery, i.e., lumpectomy, instead of mastectomy,” she explained.

“Once the decision for mastectomy is made, there is often a great deal of momentum towards a contralateral prophylactic mastectomy.”

“Contralateral prophylactic mastectomy is a personal preference that many surgeons are willing to do for their patients,” Dr. Yao explained.

“Although no survival benefit has been demonstrated for this procedure, patients find many other benefits that have nothing to do with survival.”

The authors and Dr. Yao have disclosed no relevant financial relationships.

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

Of four surgical procedures for breast cancer that have been determined to be of low value because they yield no meaningful clinical benefit, two continue to be utilized. In fact, the use of two of these procedures has increased in the United States, new research shows.

“This is the first study to [evaluate] all four of the low-value breast cancer procedures at the same time and try to draw some conclusions on practice patterns across facilities,” said senior author Lesly A. Dossett, MD, MPH, Center for Health Outcomes and Policy, the University of Michigan, Ann Arbor.

The two low-value procedures that have increased in use are contralateral prophylactic mastectomy for average-risk women with unilateral cancer and sentinel lymph node biopsy for clinically node-negative women aged 70 years and older with hormone receptor–positive (HR+) cancer.

“This suggests that formal efforts to reduce low value care through dissemination of guidelines, education of patients or providers, or alignment of incentives will be necessary to achieve full deimplementation,” she told this news organization.

The researchers emphasize that the providing of services that have no clinically meaningful benefit is a national epidemic, costing the United States more than $100 billion dollars annually.

These trends are notable and likely reflect a broad range of factors, commented Katharine Yao, MD, chief of the division of surgical oncology at the NorthShore University HealthSystem, Evanston, Ill.

“I think the better message here is not so much that facilities are doing too many low-value procedures but more that these procedures are still being performed, and the trends show increased rates over the years – why is that?”

“Perhaps there are other factors here we need to explore: why do these procedures persist, and why, despite the Choosing Wisely campaign, [do] they continue to increase?” she said in an interview. “Maybe there is something we can learn here about patient and physician preferences that perhaps we should be paying more attention to.”

The study was published on Feb. 3 in JAMA Surgery.

For the analysis, Dr. Dossett and her colleagues evaluated surgical data from the National Cancer Database. They examined data from more than 1,500 surgical facilities and from surgeries involving 920,256 women in the United States who were diagnosed with breast cancer between 2004 and 2016.

The team focused on four procedures that have been determined to be of low value by Choosing Wisely, a campaign of the American Board of Internal Medicine Foundation, on the basis of recommendations of the American College of Surgeons, the Society for Surgical Oncology, and the American Society for Breast Surgeons.

The results show that, for two of the four low-value procedures, use declined significantly over the study period. These two procedures were axillary lymph node dissection for limited nodal disease, for patients undergoing lumpectomy and radiotherapy, and lumpectomy re-excision for patients whose surgical margins were close but were negative for invasive cancer.

Axillary lymph node dissection declined from 63% in 2004 to 14% in 2016. The steepest reduction was seen soon after data from the Z0011 study were published in 2010. The rates for this procedure halved in the following year, from 62% in 2010 to 31% in 2011 (P < .001).

Likewise, reoperation rates after lumpectomy dropped from 19% in 2004 to 15% in 2016. The sharpest decline, from 18% in 2013 to 16% in 2014, corresponded to the publishing of the SSO/ASTRO consensus statement, which designated a negative margin as having “no tumor on ink.”

Two of the four low-value procedures increased in use during the study period.

Rates of contralateral prophylactic mastectomy increased nearly 2.5-fold among women with unilateral breast cancer undergoing mastectomy, from 11% in 2004 to 26% in 2016, despite SSO guidelines issued in 2007 recommending that the procedure not be used for women at average risk.

In addition, rates of sentinel lymph node biopsy among women aged 70 years and older with clinically node-negative HR+ breast cancer increased from 78% in 2004 to 87% in 2012. There was no significant decline in the use of this procedure, even after the CALGB 9343 trial from the Cancer and Leukemia Group B showed no survival benefit in 2013.
 

Patterns at hospitals vary

The authors of the study also examined hospital factors, which can heavily influence choice of procedure.

These results showed that the greatest reductions of the low-value breast cancer procedures occurred at academic research programs and high-volume surgical facilities. Elsewhere, the rates varied widely.

Interfacility rates of axillary lymph node dissection ranged from 7% to 47%; lumpectomy reoperation rates ranged from 3% to 62%; contralateral prophylactic mastectomy rates ranged from 9% to 67%; and sentinel lymph node biopsy rates ranged from 25% to 97%.

Being an outlier for use of one procedure did not necessarily translate to nonconformity for others. Factors such as a hospital’s volume of breast cancer cases or the type of facility did not appear to influence rates of axillary lymph node dissection or lumpectomy reoperation.

However, the rates of contralateral prophylactic mastectomy were significantly higher in high-volume centers and integrated network cancer programs, compared with community cancer programs (23% vs. 2%; P < .001).

Dr. Dossett said the lack of consistency was somewhat unexpected.

“We expected we would find some facilities were constantly good or bad at deimplementation or that there would be stronger associations between certain facility characteristics and performance,” she said. “That really wasn’t the case, and most facilities had mixed performance.”
 

Evidence may or may not influence trends

The authors speculate on why the low-value designation is in some cases being ignored.

The evidence regarding the risk for lymphedema related to axillary lymph node dissection procedure appears to have helped reduce its use, they note.

However, surgeons have been much less convinced of benefits in omitting sentinel lymph node biopsy, either because they are unfamiliar with the recommendations to avoid the procedure, or they may feel the procedure adds only minimal time and risk to a patient’s operation, the authors explain.

Patients may be convinced to opt to omit sentinel lymph node biopsy if they are properly counseled regarding the risks and benefits of the procedure, Dr. Dossett commented.

Dr. Yao added that, for elderly patients, age can play an important role in sentinel node biopsy.

“Patients’ life expectancy has increased over the years, and node status may impact adjuvant therapy decisions for these patients, even chemotherapy decisions,” she said.

Pressure to continue to perform contralateral prophylactic mastectomy is believed to be significantly patient driven, Dr. Dossett noted.

“I ultimately think the best way to reduce contralateral prophylactic mastectomy is to encourage women with small cancers to undergo breast-conserving surgery, i.e., lumpectomy, instead of mastectomy,” she explained.

“Once the decision for mastectomy is made, there is often a great deal of momentum towards a contralateral prophylactic mastectomy.”

“Contralateral prophylactic mastectomy is a personal preference that many surgeons are willing to do for their patients,” Dr. Yao explained.

“Although no survival benefit has been demonstrated for this procedure, patients find many other benefits that have nothing to do with survival.”

The authors and Dr. Yao have disclosed no relevant financial relationships.

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

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

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

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

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

Bone marrow cells in the brain

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

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

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

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

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

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

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

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

New neurologic complication

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Bone marrow cells in the brain

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

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

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

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

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

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

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

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

New neurologic complication

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Bone marrow cells in the brain

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

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

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

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

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

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

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

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

New neurologic complication

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

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

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

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

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

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

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

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

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

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

Research has shown that, compared with their urban counterparts, rural cancer patients have higher cancer-related mortality and other negative treatment outcomes.

Among other explanations, the disparity has been attributed to lower education and income levels, medical and behavioral risk factors, differences in health literacy, and lower confidence in the medical system among rural residents (JCO Oncol Pract. 2020 Jul;16(7):422-30).

The COVID-19 and Oncology Patient Experience Consortium

Ms. Daniels explained that the COVID-19 and Oncology Patient Experience (COPES) Consortium was created to investigate various aspects of the patient experience during the pandemic. Three cancer centers – Moffitt Cancer Center, Huntsman Cancer Institute, and the Sylvester Comprehensive Cancer Center – participate in COPES.

At Huntsman, investigators studied social and health behaviors of cancer patients to assess whether there was a difference between those from rural and urban areas. The researchers looked at the impact of the pandemic on psychosocial outcomes, preventive measures patients implemented, and their perceptions of the risk of SARS-CoV-2 infection.

The team’s hypothesis was that rural patients might be more vulnerable than urban patients to the effects of social isolation, emotional distress, and health-adverse behaviors, but the investigators noted that there has been no prior research on the topic.
 

Assessing behaviors, attitudes, and outcomes

Between August and September 2020, the researchers surveyed 1,328 adult cancer patients who had visited Huntsman in the previous 4 years and who were enrolled in Huntsman’s Total Cancer Care or Precision Exercise Prescription studies.

Patients completed questionnaires that encompassed demographic and clinical factors, employment status, health behaviors, and infection preventive measures. Questionnaires were provided in electronic, paper, or phone-based formats. Information regarding age, race, ethnicity, and tumor stage was abstracted from Huntsman’s electronic health record.

Modifications in daily life and social interaction were assessed on a 5-point scale. Changes in exercise habits and alcohol consumption were assessed on a 3-point scale. Infection mitigation measures (the use of face masks and hand sanitizer) and perceptions about the likelihood of SARS-CoV-2 infection were measured.

The rural-urban community area codes system, which classifies U.S. census tracts by measures of population density, urbanization, and daily commuting, was utilized to categorize patients into rural and urban residences.
 

Characteristics of urban and rural cancer patients

There were 997 urban and 331 rural participants. The mean age was 60.1 years in the urban population and 62.6 years in the rural population (P = .01). There were no urban-rural differences in sex, ethnicity, cancer stage, or body mass index.

More urban than rural participants were employed full- or part-time (45% vs. 37%; P = .045). The rural counties had more patients who were not currently employed, primarily due to retirement (77% vs. 69% urban; P < .001).

“No health insurance coverage” was reported by 2% of urban and 4% of rural participants (P = .009), and 85% of all patients reported “good” to “excellent” overall health. Cancer patients in rural counties were significantly more likely to have ever smoked (37% vs. 25% urban; P = .001). In addition, alcohol consumption in the previous year was higher in rural patients. “Every day to less than once monthly” alcohol usage was reported by 44% of urban and 60% of rural patients (P < .001).
 

Changes in daily life and health-related behavior during the pandemic

Urban patients were more likely to report changes in their daily lives due to the pandemic. Specifically, 35% of urban patients and 26% of rural patients said the pandemic had changed their daily life “a lot” (P = .001).

However, there were no major differences between urban and rural patients when it came to changes in social interaction in the past month or feeling lonely in the past month (P = .45 and P = .88, respectively). Similarly, there were no significant differences for changes in alcohol consumption between the groups (P = .90).

Changes in exercise habits due to the pandemic were more common among patients in urban counties (51% vs. 39% rural; P < .001), though similar percentages of patients reported exercising less (44% urban vs. 45% rural) or more frequently (24% urban vs. 20% rural).

In terms of infection mitigation measures, urban patients were more likely to use face masks “very often” (83% vs. 66% rural; P < .001), while hand sanitizer was used “very often” among 66% of urban and 57% of rural participants (P = .05).

Urban participants were more likely than were their rural counterparts to think themselves “somewhat” or “very” likely to develop COVID-19 (22% vs. 14%; P = .04).

It might be short-sighted for oncology and public health specialists to be dismissive of differences in infection mitigation behaviors and perceptions of vulnerability to SARS-CoV-2 infection. Those behaviors and perceptions of risk could lead to lower vaccination rates in rural areas. If that occurs, there would be major negative consequences for the long-term health of rural communities and their medically vulnerable residents.
 

Future directions

Although the first 6 months of the COVID-19 pandemic had disparate effects on cancer patients living in rural and urban counties, the reasons for the disparities are complex and not easily explained by this study.

It is possible that sequential administration of the survey during the pandemic would have uncovered greater variances in attitude and health-related behaviors.

As Ms. Daniels noted, when the survey was performed, Utah had not experienced a high frequency of COVID-19 cases. Furthermore, different levels of restrictions were implemented on a county-by-county basis, potentially influencing patients’ behaviors, psychosocial adjustment, and perceptions of risk.

In addition, there may have been differences in unmeasured endpoints (infection rates, medical care utilization via telemedicine, hospitalization rates, late effects, and mortality) between the urban and rural populations.

As the investigators concluded, further research is needed to better characterize the pandemic’s short- and long-term effects on cancer patients in rural and urban settings and appropriate interventions. Such studies may yield insights into the various facets of the well-documented “rural health gap” in cancer outcomes and interventions that could narrow the gap in spheres beyond the COVID-19 pandemic.

Ms. Daniels reported having no relevant disclosures.
 

Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers, as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.

Research has shown that, compared with their urban counterparts, rural cancer patients have higher cancer-related mortality and other negative treatment outcomes.

Among other explanations, the disparity has been attributed to lower education and income levels, medical and behavioral risk factors, differences in health literacy, and lower confidence in the medical system among rural residents (JCO Oncol Pract. 2020 Jul;16(7):422-30).

The COVID-19 and Oncology Patient Experience Consortium

Ms. Daniels explained that the COVID-19 and Oncology Patient Experience (COPES) Consortium was created to investigate various aspects of the patient experience during the pandemic. Three cancer centers – Moffitt Cancer Center, Huntsman Cancer Institute, and the Sylvester Comprehensive Cancer Center – participate in COPES.

At Huntsman, investigators studied social and health behaviors of cancer patients to assess whether there was a difference between those from rural and urban areas. The researchers looked at the impact of the pandemic on psychosocial outcomes, preventive measures patients implemented, and their perceptions of the risk of SARS-CoV-2 infection.

The team’s hypothesis was that rural patients might be more vulnerable than urban patients to the effects of social isolation, emotional distress, and health-adverse behaviors, but the investigators noted that there has been no prior research on the topic.
 

Assessing behaviors, attitudes, and outcomes

Between August and September 2020, the researchers surveyed 1,328 adult cancer patients who had visited Huntsman in the previous 4 years and who were enrolled in Huntsman’s Total Cancer Care or Precision Exercise Prescription studies.

Patients completed questionnaires that encompassed demographic and clinical factors, employment status, health behaviors, and infection preventive measures. Questionnaires were provided in electronic, paper, or phone-based formats. Information regarding age, race, ethnicity, and tumor stage was abstracted from Huntsman’s electronic health record.

Modifications in daily life and social interaction were assessed on a 5-point scale. Changes in exercise habits and alcohol consumption were assessed on a 3-point scale. Infection mitigation measures (the use of face masks and hand sanitizer) and perceptions about the likelihood of SARS-CoV-2 infection were measured.

The rural-urban community area codes system, which classifies U.S. census tracts by measures of population density, urbanization, and daily commuting, was utilized to categorize patients into rural and urban residences.
 

Characteristics of urban and rural cancer patients

There were 997 urban and 331 rural participants. The mean age was 60.1 years in the urban population and 62.6 years in the rural population (P = .01). There were no urban-rural differences in sex, ethnicity, cancer stage, or body mass index.

More urban than rural participants were employed full- or part-time (45% vs. 37%; P = .045). The rural counties had more patients who were not currently employed, primarily due to retirement (77% vs. 69% urban; P < .001).

“No health insurance coverage” was reported by 2% of urban and 4% of rural participants (P = .009), and 85% of all patients reported “good” to “excellent” overall health. Cancer patients in rural counties were significantly more likely to have ever smoked (37% vs. 25% urban; P = .001). In addition, alcohol consumption in the previous year was higher in rural patients. “Every day to less than once monthly” alcohol usage was reported by 44% of urban and 60% of rural patients (P < .001).
 

Changes in daily life and health-related behavior during the pandemic

Urban patients were more likely to report changes in their daily lives due to the pandemic. Specifically, 35% of urban patients and 26% of rural patients said the pandemic had changed their daily life “a lot” (P = .001).

However, there were no major differences between urban and rural patients when it came to changes in social interaction in the past month or feeling lonely in the past month (P = .45 and P = .88, respectively). Similarly, there were no significant differences for changes in alcohol consumption between the groups (P = .90).

Changes in exercise habits due to the pandemic were more common among patients in urban counties (51% vs. 39% rural; P < .001), though similar percentages of patients reported exercising less (44% urban vs. 45% rural) or more frequently (24% urban vs. 20% rural).

In terms of infection mitigation measures, urban patients were more likely to use face masks “very often” (83% vs. 66% rural; P < .001), while hand sanitizer was used “very often” among 66% of urban and 57% of rural participants (P = .05).

Urban participants were more likely than were their rural counterparts to think themselves “somewhat” or “very” likely to develop COVID-19 (22% vs. 14%; P = .04).

It might be short-sighted for oncology and public health specialists to be dismissive of differences in infection mitigation behaviors and perceptions of vulnerability to SARS-CoV-2 infection. Those behaviors and perceptions of risk could lead to lower vaccination rates in rural areas. If that occurs, there would be major negative consequences for the long-term health of rural communities and their medically vulnerable residents.
 

Future directions

Although the first 6 months of the COVID-19 pandemic had disparate effects on cancer patients living in rural and urban counties, the reasons for the disparities are complex and not easily explained by this study.

It is possible that sequential administration of the survey during the pandemic would have uncovered greater variances in attitude and health-related behaviors.

As Ms. Daniels noted, when the survey was performed, Utah had not experienced a high frequency of COVID-19 cases. Furthermore, different levels of restrictions were implemented on a county-by-county basis, potentially influencing patients’ behaviors, psychosocial adjustment, and perceptions of risk.

In addition, there may have been differences in unmeasured endpoints (infection rates, medical care utilization via telemedicine, hospitalization rates, late effects, and mortality) between the urban and rural populations.

As the investigators concluded, further research is needed to better characterize the pandemic’s short- and long-term effects on cancer patients in rural and urban settings and appropriate interventions. Such studies may yield insights into the various facets of the well-documented “rural health gap” in cancer outcomes and interventions that could narrow the gap in spheres beyond the COVID-19 pandemic.

Ms. Daniels reported having no relevant disclosures.
 

Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers, as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.

Research has shown that, compared with their urban counterparts, rural cancer patients have higher cancer-related mortality and other negative treatment outcomes.

Among other explanations, the disparity has been attributed to lower education and income levels, medical and behavioral risk factors, differences in health literacy, and lower confidence in the medical system among rural residents (JCO Oncol Pract. 2020 Jul;16(7):422-30).

The COVID-19 and Oncology Patient Experience Consortium

Ms. Daniels explained that the COVID-19 and Oncology Patient Experience (COPES) Consortium was created to investigate various aspects of the patient experience during the pandemic. Three cancer centers – Moffitt Cancer Center, Huntsman Cancer Institute, and the Sylvester Comprehensive Cancer Center – participate in COPES.

At Huntsman, investigators studied social and health behaviors of cancer patients to assess whether there was a difference between those from rural and urban areas. The researchers looked at the impact of the pandemic on psychosocial outcomes, preventive measures patients implemented, and their perceptions of the risk of SARS-CoV-2 infection.

The team’s hypothesis was that rural patients might be more vulnerable than urban patients to the effects of social isolation, emotional distress, and health-adverse behaviors, but the investigators noted that there has been no prior research on the topic.
 

Assessing behaviors, attitudes, and outcomes

Between August and September 2020, the researchers surveyed 1,328 adult cancer patients who had visited Huntsman in the previous 4 years and who were enrolled in Huntsman’s Total Cancer Care or Precision Exercise Prescription studies.

Patients completed questionnaires that encompassed demographic and clinical factors, employment status, health behaviors, and infection preventive measures. Questionnaires were provided in electronic, paper, or phone-based formats. Information regarding age, race, ethnicity, and tumor stage was abstracted from Huntsman’s electronic health record.

Modifications in daily life and social interaction were assessed on a 5-point scale. Changes in exercise habits and alcohol consumption were assessed on a 3-point scale. Infection mitigation measures (the use of face masks and hand sanitizer) and perceptions about the likelihood of SARS-CoV-2 infection were measured.

The rural-urban community area codes system, which classifies U.S. census tracts by measures of population density, urbanization, and daily commuting, was utilized to categorize patients into rural and urban residences.
 

Characteristics of urban and rural cancer patients

There were 997 urban and 331 rural participants. The mean age was 60.1 years in the urban population and 62.6 years in the rural population (P = .01). There were no urban-rural differences in sex, ethnicity, cancer stage, or body mass index.

More urban than rural participants were employed full- or part-time (45% vs. 37%; P = .045). The rural counties had more patients who were not currently employed, primarily due to retirement (77% vs. 69% urban; P < .001).

“No health insurance coverage” was reported by 2% of urban and 4% of rural participants (P = .009), and 85% of all patients reported “good” to “excellent” overall health. Cancer patients in rural counties were significantly more likely to have ever smoked (37% vs. 25% urban; P = .001). In addition, alcohol consumption in the previous year was higher in rural patients. “Every day to less than once monthly” alcohol usage was reported by 44% of urban and 60% of rural patients (P < .001).
 

Changes in daily life and health-related behavior during the pandemic

Urban patients were more likely to report changes in their daily lives due to the pandemic. Specifically, 35% of urban patients and 26% of rural patients said the pandemic had changed their daily life “a lot” (P = .001).

However, there were no major differences between urban and rural patients when it came to changes in social interaction in the past month or feeling lonely in the past month (P = .45 and P = .88, respectively). Similarly, there were no significant differences for changes in alcohol consumption between the groups (P = .90).

Changes in exercise habits due to the pandemic were more common among patients in urban counties (51% vs. 39% rural; P < .001), though similar percentages of patients reported exercising less (44% urban vs. 45% rural) or more frequently (24% urban vs. 20% rural).

In terms of infection mitigation measures, urban patients were more likely to use face masks “very often” (83% vs. 66% rural; P < .001), while hand sanitizer was used “very often” among 66% of urban and 57% of rural participants (P = .05).

Urban participants were more likely than were their rural counterparts to think themselves “somewhat” or “very” likely to develop COVID-19 (22% vs. 14%; P = .04).

It might be short-sighted for oncology and public health specialists to be dismissive of differences in infection mitigation behaviors and perceptions of vulnerability to SARS-CoV-2 infection. Those behaviors and perceptions of risk could lead to lower vaccination rates in rural areas. If that occurs, there would be major negative consequences for the long-term health of rural communities and their medically vulnerable residents.
 

Future directions

Although the first 6 months of the COVID-19 pandemic had disparate effects on cancer patients living in rural and urban counties, the reasons for the disparities are complex and not easily explained by this study.

It is possible that sequential administration of the survey during the pandemic would have uncovered greater variances in attitude and health-related behaviors.

As Ms. Daniels noted, when the survey was performed, Utah had not experienced a high frequency of COVID-19 cases. Furthermore, different levels of restrictions were implemented on a county-by-county basis, potentially influencing patients’ behaviors, psychosocial adjustment, and perceptions of risk.

In addition, there may have been differences in unmeasured endpoints (infection rates, medical care utilization via telemedicine, hospitalization rates, late effects, and mortality) between the urban and rural populations.

As the investigators concluded, further research is needed to better characterize the pandemic’s short- and long-term effects on cancer patients in rural and urban settings and appropriate interventions. Such studies may yield insights into the various facets of the well-documented “rural health gap” in cancer outcomes and interventions that could narrow the gap in spheres beyond the COVID-19 pandemic.

Ms. Daniels reported having no relevant disclosures.
 

Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers, as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.

Although coronavirus 19 disease (COVID-19), caused by severe acute respiratory coronavirus 2, is characterized by symptoms that primarily impact the respiratory system, many patients experience neurological manifestations, with headache among leading complaints. Moreover, headache symptoms, including migraine-like headache, can last long after patients recover from COVID-19. 

Last November, in an interview with 60 Minutes,  Sadie Nagamootoo described her experience. “There are days when I do nothing and cannot get out of bed. The migraines are 10 times worse than a flu headache.”

To help individuals like Nagamootoo and others who experience headache as a result of COVID-19, it is important to understand the data that are emerging and how to incorporate them into practice. Following are answers to important questions that can guide front-line neurologists and other clinicians who are practicing during the pandemic.

Why is headache a symptom of COVID-19? It should come as no surprise that patients with COVID-19 can experience headache. Peng reminds us, in a November 2020 editorial in Cephalalgia, that headache is a common symptom in individuals with acute respiratory disease, representing a physiological response to acute infection. Headache is often the primary reason patients seek treatment. 

How is headache associated with COVID-19? It is too early to know with certainty the mechanisms underlying COVID-19 headache, but a possible explanation—according to Uygun and colleagues, writing in the The Journal of Headache and Pain—is that the virus directly invades trigeminal nerve endings in the nasal and oral cavities. 

How does headache tend to present in COVID-19? Patricia Pozo-Rosich, MD, PhD, presented on this topic at the American Headache Society’s 2020 Virtual Annual Scientific Meeting in June. In a recent interview with Neurology Reviews,  Dr. Pozo-Rosich, head of the Headache & Craniofacial Pain Unit at Vall d’Hebron University Hospital, Barcelona, Spain, noted that “headache seems to have 2 different presentations: 1) migraine-like characteristics that are severe, disabling, and usually start before other COVID symptoms and 2) tension-type headache characteristics, which usually start together with the rest of COVID symptoms.”

Are there symptoms that tend to occur more frequently in patients with COVID-19 and headache? Caronna and colleagues recently published an analysis in Cephalalgia of 130 individuals with COVID-19, showing that loss of smell and/or taste occurred in more than half of patients with headache, compared with fewer than 20% of those without headache. This finding is notable because it has been frequently reported in case reports of patients with COVID-19 and headache.

What does the presence of headache indicate about COVID-19 prognosis? The good news for individuals with COVID-19 who experience headache is that the duration of their COVID-19 illness might very well be shorter. In the Caronna study, COVID-19 duration in individuals with headache was, on average, 1 week shorter (24 days) than in those without headache symptoms (31 days).  “We don’t know why,” said Dr. Pozo-Rosich, who is one of the study’s authors. She hypothesizes that it is because of a balance between neuroinflammation and systemic inflammation. “Having an extraordinary initial reaction at the nasal cavity might protect us from having greater systemic inflammation.”

What is the cause of headache from COVID-19? Bolay and colleagues reported in Headache in Spring 2020 that patients developed new-onset, moderate-to-severe, bilateral pulsating or pressing headache toward the frontal area and forehead during the viral phase of disease. The virus activates peripheral trigeminal nerve endings directly or through vasculopathy and/or increased circulating pro-inflammatory cytokines.

What else is important to be aware of regarding headache evolution in individuals with COVID-19? The bad news for many of these individuals is that, although their COVID-19 illness might dissipate more quickly, headaches could linger. Moreover, many will be experiencing chronic headache for the first time in their life. Caronna reported that that one third of follow-up patients who reported headache were experiencing persistent disabling headache daily after 6 weeks, and more than half had no history of recurrent headache.

What is the recommended treatment for headache associated with COVID-19? Dr. Pozo-Rosich recommends starting with a nonsteroidal anti-inflammatory medication. Eventually, steroids might be indicated, “especially if the disease progresses.”

It is important for neurologists to be aware of new-onset headache associated with anosmia early in the disease. Test for the virus in such a patient; hopefully, their course will be shorter, milder, and non-respiratory.

Although coronavirus 19 disease (COVID-19), caused by severe acute respiratory coronavirus 2, is characterized by symptoms that primarily impact the respiratory system, many patients experience neurological manifestations, with headache among leading complaints. Moreover, headache symptoms, including migraine-like headache, can last long after patients recover from COVID-19. 

Last November, in an interview with 60 Minutes,  Sadie Nagamootoo described her experience. “There are days when I do nothing and cannot get out of bed. The migraines are 10 times worse than a flu headache.”

To help individuals like Nagamootoo and others who experience headache as a result of COVID-19, it is important to understand the data that are emerging and how to incorporate them into practice. Following are answers to important questions that can guide front-line neurologists and other clinicians who are practicing during the pandemic.

Why is headache a symptom of COVID-19? It should come as no surprise that patients with COVID-19 can experience headache. Peng reminds us, in a November 2020 editorial in Cephalalgia, that headache is a common symptom in individuals with acute respiratory disease, representing a physiological response to acute infection. Headache is often the primary reason patients seek treatment. 

How is headache associated with COVID-19? It is too early to know with certainty the mechanisms underlying COVID-19 headache, but a possible explanation—according to Uygun and colleagues, writing in the The Journal of Headache and Pain—is that the virus directly invades trigeminal nerve endings in the nasal and oral cavities. 

How does headache tend to present in COVID-19? Patricia Pozo-Rosich, MD, PhD, presented on this topic at the American Headache Society’s 2020 Virtual Annual Scientific Meeting in June. In a recent interview with Neurology Reviews,  Dr. Pozo-Rosich, head of the Headache & Craniofacial Pain Unit at Vall d’Hebron University Hospital, Barcelona, Spain, noted that “headache seems to have 2 different presentations: 1) migraine-like characteristics that are severe, disabling, and usually start before other COVID symptoms and 2) tension-type headache characteristics, which usually start together with the rest of COVID symptoms.”

Are there symptoms that tend to occur more frequently in patients with COVID-19 and headache? Caronna and colleagues recently published an analysis in Cephalalgia of 130 individuals with COVID-19, showing that loss of smell and/or taste occurred in more than half of patients with headache, compared with fewer than 20% of those without headache. This finding is notable because it has been frequently reported in case reports of patients with COVID-19 and headache.

What does the presence of headache indicate about COVID-19 prognosis? The good news for individuals with COVID-19 who experience headache is that the duration of their COVID-19 illness might very well be shorter. In the Caronna study, COVID-19 duration in individuals with headache was, on average, 1 week shorter (24 days) than in those without headache symptoms (31 days).  “We don’t know why,” said Dr. Pozo-Rosich, who is one of the study’s authors. She hypothesizes that it is because of a balance between neuroinflammation and systemic inflammation. “Having an extraordinary initial reaction at the nasal cavity might protect us from having greater systemic inflammation.”

What is the cause of headache from COVID-19? Bolay and colleagues reported in Headache in Spring 2020 that patients developed new-onset, moderate-to-severe, bilateral pulsating or pressing headache toward the frontal area and forehead during the viral phase of disease. The virus activates peripheral trigeminal nerve endings directly or through vasculopathy and/or increased circulating pro-inflammatory cytokines.

What else is important to be aware of regarding headache evolution in individuals with COVID-19? The bad news for many of these individuals is that, although their COVID-19 illness might dissipate more quickly, headaches could linger. Moreover, many will be experiencing chronic headache for the first time in their life. Caronna reported that that one third of follow-up patients who reported headache were experiencing persistent disabling headache daily after 6 weeks, and more than half had no history of recurrent headache.

What is the recommended treatment for headache associated with COVID-19? Dr. Pozo-Rosich recommends starting with a nonsteroidal anti-inflammatory medication. Eventually, steroids might be indicated, “especially if the disease progresses.”

It is important for neurologists to be aware of new-onset headache associated with anosmia early in the disease. Test for the virus in such a patient; hopefully, their course will be shorter, milder, and non-respiratory.

Although coronavirus 19 disease (COVID-19), caused by severe acute respiratory coronavirus 2, is characterized by symptoms that primarily impact the respiratory system, many patients experience neurological manifestations, with headache among leading complaints. Moreover, headache symptoms, including migraine-like headache, can last long after patients recover from COVID-19. 

Last November, in an interview with 60 Minutes,  Sadie Nagamootoo described her experience. “There are days when I do nothing and cannot get out of bed. The migraines are 10 times worse than a flu headache.”

To help individuals like Nagamootoo and others who experience headache as a result of COVID-19, it is important to understand the data that are emerging and how to incorporate them into practice. Following are answers to important questions that can guide front-line neurologists and other clinicians who are practicing during the pandemic.

Why is headache a symptom of COVID-19? It should come as no surprise that patients with COVID-19 can experience headache. Peng reminds us, in a November 2020 editorial in Cephalalgia, that headache is a common symptom in individuals with acute respiratory disease, representing a physiological response to acute infection. Headache is often the primary reason patients seek treatment. 

How is headache associated with COVID-19? It is too early to know with certainty the mechanisms underlying COVID-19 headache, but a possible explanation—according to Uygun and colleagues, writing in the The Journal of Headache and Pain—is that the virus directly invades trigeminal nerve endings in the nasal and oral cavities. 

How does headache tend to present in COVID-19? Patricia Pozo-Rosich, MD, PhD, presented on this topic at the American Headache Society’s 2020 Virtual Annual Scientific Meeting in June. In a recent interview with Neurology Reviews,  Dr. Pozo-Rosich, head of the Headache & Craniofacial Pain Unit at Vall d’Hebron University Hospital, Barcelona, Spain, noted that “headache seems to have 2 different presentations: 1) migraine-like characteristics that are severe, disabling, and usually start before other COVID symptoms and 2) tension-type headache characteristics, which usually start together with the rest of COVID symptoms.”

Are there symptoms that tend to occur more frequently in patients with COVID-19 and headache? Caronna and colleagues recently published an analysis in Cephalalgia of 130 individuals with COVID-19, showing that loss of smell and/or taste occurred in more than half of patients with headache, compared with fewer than 20% of those without headache. This finding is notable because it has been frequently reported in case reports of patients with COVID-19 and headache.

What does the presence of headache indicate about COVID-19 prognosis? The good news for individuals with COVID-19 who experience headache is that the duration of their COVID-19 illness might very well be shorter. In the Caronna study, COVID-19 duration in individuals with headache was, on average, 1 week shorter (24 days) than in those without headache symptoms (31 days).  “We don’t know why,” said Dr. Pozo-Rosich, who is one of the study’s authors. She hypothesizes that it is because of a balance between neuroinflammation and systemic inflammation. “Having an extraordinary initial reaction at the nasal cavity might protect us from having greater systemic inflammation.”

What is the cause of headache from COVID-19? Bolay and colleagues reported in Headache in Spring 2020 that patients developed new-onset, moderate-to-severe, bilateral pulsating or pressing headache toward the frontal area and forehead during the viral phase of disease. The virus activates peripheral trigeminal nerve endings directly or through vasculopathy and/or increased circulating pro-inflammatory cytokines.

What else is important to be aware of regarding headache evolution in individuals with COVID-19? The bad news for many of these individuals is that, although their COVID-19 illness might dissipate more quickly, headaches could linger. Moreover, many will be experiencing chronic headache for the first time in their life. Caronna reported that that one third of follow-up patients who reported headache were experiencing persistent disabling headache daily after 6 weeks, and more than half had no history of recurrent headache.

What is the recommended treatment for headache associated with COVID-19? Dr. Pozo-Rosich recommends starting with a nonsteroidal anti-inflammatory medication. Eventually, steroids might be indicated, “especially if the disease progresses.”

It is important for neurologists to be aware of new-onset headache associated with anosmia early in the disease. Test for the virus in such a patient; hopefully, their course will be shorter, milder, and non-respiratory.

The U.S. Preventive Services Task Force is planning to update its breast cancer screening guidelines, which were last issued in 2016. For transparency, it has released the draft research plan it will use for formulating the update, and this draft plan is open for comment until Feb. 17.

However, an expert in breast screening has taken issue with the whole plan.

Daniel Kopans, MD, professor of radiology at Harvard Medical School and founder of the Breast Imaging Division at Massachusetts General Hospital, Boston, argues that previous USPSTF guidelines on breast cancer screening “have been based on flawed analyses of scientific data” and the research plan, as outlined, perpetuates this.

He has also objected, yet again, to the USPSTF panel not having any experts in breast screening on the panel.

Writing in a commentary on Aunt Minnie, a radiology website, he warns about the dangers of not listening to experts: “The COVID-19 pandemic has demonstrated the tragic consequences that result from ignoring science, evidence, and the analysis and advice of experts while being guided by inexpert advice.”
 

Controversy over previous guidelines

The current USPSTF guidelines on breast cancer screening, which were issued in 2016, were largely unchanged from the previous guidelines that had been issued in 2009. They recommended mammography screening every 2 years for women 50-74 years of age but said that women aged 40-49 should make individual decisions about screening in partnership with their doctors.

The guidance on younger women was met with severe criticism from many experts, as previously reported by this news organization, and the every-2-year interval has also been questioned.

The American College of Radiology and Society of Breast Imaging both recommend annual mammograms starting at age 40.

In the update the USPSTF is now planning, it has an opportunity to “revisit the group’s flawed decision in 2009” about not recommending screening for women in their 40s, argues Dr. Kopans.  

But to do that, a number of factors need to be addressed to present a fair and impartial review of the science and evidence in favor of breast screening, he continues, while worrying the draft plan, as currently outlined, will not do so.

One big problem, he argues, is that USPSTF, in its draft plan, has not included statistical models from the U.S. National Cancer Institute and Cancer Intervention and Surveillance Modeling Network to project the potential outcomes of various screening protocols. These NCI/CISNET models all predict that the most lives are saved by annual screening starting at age 40, he points out.

Without these models, the USPSTF will be “guessing in their predictions,” he argues.

Second, even though a reduction in advanced-stage disease is a potentially useful “surrogate endpoint,” Dr. Kopans points out that it is still crucial to remember that women diagnosed at all stages of breast cancer die of the disease. “It has been shown that reducing the size of cancers within stages is also a major benefit from screening that reduces deaths,” he says.

Third, he contends in his commentary that there is a “false claim that the background incidence of breast cancer has not increased over time.” Dr. Kopans says this has been the primary source of misinformation that has been used to promote “the false concepts of massive overdiagnosis” as well as a “false claim that there has not been a reduction in advanced cancers.”

To emphasize his point, Dr. Kopans explains that data clearly demonstrate that the baseline incidence of breast cancer has steadily risen by 1%-1.3% per year, going back at least 80 years. This increase predates screening, which didn’t really begin until the mid-1980s.

“If the correct increasing baseline is used, not only is there no apparent ‘overdiagnosis’ of invasive cancers, but it appears that there has been a major reduction in the incidence of invasive cancers,” he writes. “By using the correct baseline incidence and extrapolation, it is also clear that there has been a major reduction in the rate of advanced cancers.”

To date, there have not been any randomized controlled trials comparing screening intervals (for example, annual vs. every second or third year). But based on the CISNET models, Dr. Kopans emphasized that annual screening is estimated to provide the greatest reduction in deaths. “All women ages 40-74 should be encouraged to be screened every year,” he says.

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

The U.S. Preventive Services Task Force is planning to update its breast cancer screening guidelines, which were last issued in 2016. For transparency, it has released the draft research plan it will use for formulating the update, and this draft plan is open for comment until Feb. 17.

However, an expert in breast screening has taken issue with the whole plan.

Daniel Kopans, MD, professor of radiology at Harvard Medical School and founder of the Breast Imaging Division at Massachusetts General Hospital, Boston, argues that previous USPSTF guidelines on breast cancer screening “have been based on flawed analyses of scientific data” and the research plan, as outlined, perpetuates this.

He has also objected, yet again, to the USPSTF panel not having any experts in breast screening on the panel.

Writing in a commentary on Aunt Minnie, a radiology website, he warns about the dangers of not listening to experts: “The COVID-19 pandemic has demonstrated the tragic consequences that result from ignoring science, evidence, and the analysis and advice of experts while being guided by inexpert advice.”
 

Controversy over previous guidelines

The current USPSTF guidelines on breast cancer screening, which were issued in 2016, were largely unchanged from the previous guidelines that had been issued in 2009. They recommended mammography screening every 2 years for women 50-74 years of age but said that women aged 40-49 should make individual decisions about screening in partnership with their doctors.

The guidance on younger women was met with severe criticism from many experts, as previously reported by this news organization, and the every-2-year interval has also been questioned.

The American College of Radiology and Society of Breast Imaging both recommend annual mammograms starting at age 40.

In the update the USPSTF is now planning, it has an opportunity to “revisit the group’s flawed decision in 2009” about not recommending screening for women in their 40s, argues Dr. Kopans.  

But to do that, a number of factors need to be addressed to present a fair and impartial review of the science and evidence in favor of breast screening, he continues, while worrying the draft plan, as currently outlined, will not do so.

One big problem, he argues, is that USPSTF, in its draft plan, has not included statistical models from the U.S. National Cancer Institute and Cancer Intervention and Surveillance Modeling Network to project the potential outcomes of various screening protocols. These NCI/CISNET models all predict that the most lives are saved by annual screening starting at age 40, he points out.

Without these models, the USPSTF will be “guessing in their predictions,” he argues.

Second, even though a reduction in advanced-stage disease is a potentially useful “surrogate endpoint,” Dr. Kopans points out that it is still crucial to remember that women diagnosed at all stages of breast cancer die of the disease. “It has been shown that reducing the size of cancers within stages is also a major benefit from screening that reduces deaths,” he says.

Third, he contends in his commentary that there is a “false claim that the background incidence of breast cancer has not increased over time.” Dr. Kopans says this has been the primary source of misinformation that has been used to promote “the false concepts of massive overdiagnosis” as well as a “false claim that there has not been a reduction in advanced cancers.”

To emphasize his point, Dr. Kopans explains that data clearly demonstrate that the baseline incidence of breast cancer has steadily risen by 1%-1.3% per year, going back at least 80 years. This increase predates screening, which didn’t really begin until the mid-1980s.

“If the correct increasing baseline is used, not only is there no apparent ‘overdiagnosis’ of invasive cancers, but it appears that there has been a major reduction in the incidence of invasive cancers,” he writes. “By using the correct baseline incidence and extrapolation, it is also clear that there has been a major reduction in the rate of advanced cancers.”

To date, there have not been any randomized controlled trials comparing screening intervals (for example, annual vs. every second or third year). But based on the CISNET models, Dr. Kopans emphasized that annual screening is estimated to provide the greatest reduction in deaths. “All women ages 40-74 should be encouraged to be screened every year,” he says.

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

The U.S. Preventive Services Task Force is planning to update its breast cancer screening guidelines, which were last issued in 2016. For transparency, it has released the draft research plan it will use for formulating the update, and this draft plan is open for comment until Feb. 17.

However, an expert in breast screening has taken issue with the whole plan.

Daniel Kopans, MD, professor of radiology at Harvard Medical School and founder of the Breast Imaging Division at Massachusetts General Hospital, Boston, argues that previous USPSTF guidelines on breast cancer screening “have been based on flawed analyses of scientific data” and the research plan, as outlined, perpetuates this.

He has also objected, yet again, to the USPSTF panel not having any experts in breast screening on the panel.

Writing in a commentary on Aunt Minnie, a radiology website, he warns about the dangers of not listening to experts: “The COVID-19 pandemic has demonstrated the tragic consequences that result from ignoring science, evidence, and the analysis and advice of experts while being guided by inexpert advice.”
 

Controversy over previous guidelines

The current USPSTF guidelines on breast cancer screening, which were issued in 2016, were largely unchanged from the previous guidelines that had been issued in 2009. They recommended mammography screening every 2 years for women 50-74 years of age but said that women aged 40-49 should make individual decisions about screening in partnership with their doctors.

The guidance on younger women was met with severe criticism from many experts, as previously reported by this news organization, and the every-2-year interval has also been questioned.

The American College of Radiology and Society of Breast Imaging both recommend annual mammograms starting at age 40.

In the update the USPSTF is now planning, it has an opportunity to “revisit the group’s flawed decision in 2009” about not recommending screening for women in their 40s, argues Dr. Kopans.  

But to do that, a number of factors need to be addressed to present a fair and impartial review of the science and evidence in favor of breast screening, he continues, while worrying the draft plan, as currently outlined, will not do so.

One big problem, he argues, is that USPSTF, in its draft plan, has not included statistical models from the U.S. National Cancer Institute and Cancer Intervention and Surveillance Modeling Network to project the potential outcomes of various screening protocols. These NCI/CISNET models all predict that the most lives are saved by annual screening starting at age 40, he points out.

Without these models, the USPSTF will be “guessing in their predictions,” he argues.

Second, even though a reduction in advanced-stage disease is a potentially useful “surrogate endpoint,” Dr. Kopans points out that it is still crucial to remember that women diagnosed at all stages of breast cancer die of the disease. “It has been shown that reducing the size of cancers within stages is also a major benefit from screening that reduces deaths,” he says.

Third, he contends in his commentary that there is a “false claim that the background incidence of breast cancer has not increased over time.” Dr. Kopans says this has been the primary source of misinformation that has been used to promote “the false concepts of massive overdiagnosis” as well as a “false claim that there has not been a reduction in advanced cancers.”

To emphasize his point, Dr. Kopans explains that data clearly demonstrate that the baseline incidence of breast cancer has steadily risen by 1%-1.3% per year, going back at least 80 years. This increase predates screening, which didn’t really begin until the mid-1980s.

“If the correct increasing baseline is used, not only is there no apparent ‘overdiagnosis’ of invasive cancers, but it appears that there has been a major reduction in the incidence of invasive cancers,” he writes. “By using the correct baseline incidence and extrapolation, it is also clear that there has been a major reduction in the rate of advanced cancers.”

To date, there have not been any randomized controlled trials comparing screening intervals (for example, annual vs. every second or third year). But based on the CISNET models, Dr. Kopans emphasized that annual screening is estimated to provide the greatest reduction in deaths. “All women ages 40-74 should be encouraged to be screened every year,” he says.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Time-dependent effects

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

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

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

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

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

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

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

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

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

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

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

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

Biomarker needed

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

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

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

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

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

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

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

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

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

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

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

Time-dependent effects

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

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

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

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

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

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

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

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

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

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

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

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

Biomarker needed

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

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

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

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

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

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

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

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

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

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

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

Time-dependent effects

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

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

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

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

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

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

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

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

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

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

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

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

Biomarker needed

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

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

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

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

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

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

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

A review of MAST data

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

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

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

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

Men predominated among opioid users

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

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

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

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

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

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

Pain clinics and opioid prescription

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

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

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

Why are opioids still being used?

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

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

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

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

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

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

A review of MAST data

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

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

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

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

Men predominated among opioid users

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

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

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

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

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

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

Pain clinics and opioid prescription

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

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

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

Why are opioids still being used?

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

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

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

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

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

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

A review of MAST data

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

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

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

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

Men predominated among opioid users

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

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

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

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

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

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

Pain clinics and opioid prescription

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

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

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

Why are opioids still being used?

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Better effect in patients with aura

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

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

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

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

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

Many unanswered questions

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

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

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

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

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

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

“There are still many unanswered questions.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Better effect in patients with aura

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

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

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

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

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

Many unanswered questions

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

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

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

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

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

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

“There are still many unanswered questions.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Better effect in patients with aura

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

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

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

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

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

Many unanswered questions

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

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

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

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

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

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

“There are still many unanswered questions.

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

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

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