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PCI bests medical therapy for FFR grey zone stable angina
PARIS – Patients with stable angina and a fractional flow reserve (FFR) value in the grey zone of 0.75-0.81 experienced a significant reduction in myocardial ischemia and substantially greater quality of life improvement if they were randomized to percutaneous coronary intervention (PCI) plus optimal medical therapy than to optimal medical therapy alone in the Scottish Grey-zone FFR Study.
The Grey-zone FFR Study was a single-center, prospective, unblinded, randomized trial that included 100 patients with stable angina, single-vessel disease, and a fractional flow reserve in the grey zone of 0.75-0.81. While broad consensus exists that an FFR below 0.75 constitutes evidence of a hemodynamically significant coronary lesion warranting revascularization and an FFR greater than 0.80 indicates a lesion isn’t functionally significant and therefore PCI can safely be deferred, there has been uncertainty on what to do about lesions in the grey zone, which are frequently encountered in the cardiac catheterization laboratory.
“In my clinical practice, I tend to go ahead with PCI for patients in the grey zone if I felt it was clinically feasible and safe to do so, particularly if I was worried about their lesion morphology,” Barry Hennigan, MD, said in response to questions after presenting the results at the annual meeting of the European Association of Percutaneous Cardiovascular Interventions. “If it’s a proximal LAD [left anterior descending artery] lesion and it’s a grey zone patient, particularly if it’s a lesion morphology that you’re not comfortable with, I think you need to be very careful before you defer a case.”
The twin purposes of the Scottish study were to define the prevalence of major ischemia by stress MRI and invasive flow assessment via a pressure wire in grey zone patients – something which hadn’t been done before – and to determine if PCI deferral in such patients is appropriate in terms of symptom control. The primary outcome was change in angina severity at 3 months follow-up using the Seattle Angina Questionnaire (SAQ).
Scores on two of the five domains of the SAQ – anginal frequency and quality of life – were significantly improved in the PCI group. Anginal frequency scores improved by a mean of 20.58 points in the PCI plus optimal medical therapy (OMT) group, compared with a 9.39-point improvement with OMT alone. Quality of life scores improved by 24.04 points in the PCI group versus 9.39 points in controls, said Dr. Hennigan, an interventional cardiologist at the University of Glasgow and Golden Jubilee National Hospital. Scores in the other three SAQ domains – physical limitations, anginal stability, and treatment satisfaction – didn’t differ significantly between the two study arms, although consistently greater improvements were seen in the PCI group.
Baseline stress perfusion MRI as assessed by two blinded observers demonstrated that 17.4% of patients with stable angina and a grey zone FFR had major ischemia, while any ischemia – major or minor – was present in 24.4%. Follow-up scans at 3 months showed a roughly 50% reduction in the prevalence of ischemia in the PCI group, with 7.3% of treated patients still having major ischemia and 12.2% having any ischemia.
Also, 28% of participants had evidence of ischemia at baseline based upon their coronary flow reserve measurements and 8% had a hyperemic stenosis resistance measurement indicative of ischemia. So the FFR grey zone encompasses a range of cardiovascular risks.
In the PCI plus OMT group, 89% of patients (eight of nine) with baseline ischemia on stress MRI had a greater than 10-point improvement in quality of life scores on the SAQ at follow-up in contrast to 53% of patients without ischemia, which made for a statistically significant difference. An improvement of that magnitude is generally considered clinically meaningful. In contrast, in the OMT-only group, 9 of 14 patients with baseline ischemia (64.2%) had a greater than 10-point quality of life improvement, which wasn’t significantly different from the 45.5% improvement rate in patients with no ischemia.
The lessons? Grey zone patients who benefit most from prompt revascularization are those with demonstrable ischemia. In addition, roughly half of grey zone patients with stable angina will improve their quality of life scores by more than 10 points with OMT alone regardless of the presence of myocardial ischemia or not.
Dr. Hennigan was repeatedly asked how he reconciles the results of the grey zone study with those of the much-discussed ORBITA trial, the first and only randomized trial of real versus sham PCI in patients with stable angina. ORBITA didn’t find a significant quality of life advantage for real PCI over sham PCI.
“It is quite possible that a lot of the effect that we saw in our PCI group was placebo related,” he conceded. “However, we do have objective evidence that we reduced ischemia on MRI. Also, 29% of ORBITA patients had an FFR above 0.8, whereas nearly all our patients were below that threshold. So we perhaps had more prevalent ischemia than the ORBITA cohort.”
Also informative is a comparison of SAQ scores at follow-up in the sham PCI ORBITA control group versus the grey zone Scottish PCI group, Dr. Hennigan continued. The Scottish PCI group had a mean 20.6-point improvement in anginal frequency scores while on an average of 1.3 antianginal medications, compared with a 9.6-point improvement in ORBITA patients on 2.9 drugs. The grey zone group who got PCI plus OMT also had a mean 16.1-point improvement in the SAQ physical limitations domain, versus a 5.0-point improvement in the ORBITA controls.
The Grey-zone FFR Study was supported by the British Heart Foundation. Dr. Hennigan reported having no financial conflicts of interest.
PARIS – Patients with stable angina and a fractional flow reserve (FFR) value in the grey zone of 0.75-0.81 experienced a significant reduction in myocardial ischemia and substantially greater quality of life improvement if they were randomized to percutaneous coronary intervention (PCI) plus optimal medical therapy than to optimal medical therapy alone in the Scottish Grey-zone FFR Study.
The Grey-zone FFR Study was a single-center, prospective, unblinded, randomized trial that included 100 patients with stable angina, single-vessel disease, and a fractional flow reserve in the grey zone of 0.75-0.81. While broad consensus exists that an FFR below 0.75 constitutes evidence of a hemodynamically significant coronary lesion warranting revascularization and an FFR greater than 0.80 indicates a lesion isn’t functionally significant and therefore PCI can safely be deferred, there has been uncertainty on what to do about lesions in the grey zone, which are frequently encountered in the cardiac catheterization laboratory.
“In my clinical practice, I tend to go ahead with PCI for patients in the grey zone if I felt it was clinically feasible and safe to do so, particularly if I was worried about their lesion morphology,” Barry Hennigan, MD, said in response to questions after presenting the results at the annual meeting of the European Association of Percutaneous Cardiovascular Interventions. “If it’s a proximal LAD [left anterior descending artery] lesion and it’s a grey zone patient, particularly if it’s a lesion morphology that you’re not comfortable with, I think you need to be very careful before you defer a case.”
The twin purposes of the Scottish study were to define the prevalence of major ischemia by stress MRI and invasive flow assessment via a pressure wire in grey zone patients – something which hadn’t been done before – and to determine if PCI deferral in such patients is appropriate in terms of symptom control. The primary outcome was change in angina severity at 3 months follow-up using the Seattle Angina Questionnaire (SAQ).
Scores on two of the five domains of the SAQ – anginal frequency and quality of life – were significantly improved in the PCI group. Anginal frequency scores improved by a mean of 20.58 points in the PCI plus optimal medical therapy (OMT) group, compared with a 9.39-point improvement with OMT alone. Quality of life scores improved by 24.04 points in the PCI group versus 9.39 points in controls, said Dr. Hennigan, an interventional cardiologist at the University of Glasgow and Golden Jubilee National Hospital. Scores in the other three SAQ domains – physical limitations, anginal stability, and treatment satisfaction – didn’t differ significantly between the two study arms, although consistently greater improvements were seen in the PCI group.
Baseline stress perfusion MRI as assessed by two blinded observers demonstrated that 17.4% of patients with stable angina and a grey zone FFR had major ischemia, while any ischemia – major or minor – was present in 24.4%. Follow-up scans at 3 months showed a roughly 50% reduction in the prevalence of ischemia in the PCI group, with 7.3% of treated patients still having major ischemia and 12.2% having any ischemia.
Also, 28% of participants had evidence of ischemia at baseline based upon their coronary flow reserve measurements and 8% had a hyperemic stenosis resistance measurement indicative of ischemia. So the FFR grey zone encompasses a range of cardiovascular risks.
In the PCI plus OMT group, 89% of patients (eight of nine) with baseline ischemia on stress MRI had a greater than 10-point improvement in quality of life scores on the SAQ at follow-up in contrast to 53% of patients without ischemia, which made for a statistically significant difference. An improvement of that magnitude is generally considered clinically meaningful. In contrast, in the OMT-only group, 9 of 14 patients with baseline ischemia (64.2%) had a greater than 10-point quality of life improvement, which wasn’t significantly different from the 45.5% improvement rate in patients with no ischemia.
The lessons? Grey zone patients who benefit most from prompt revascularization are those with demonstrable ischemia. In addition, roughly half of grey zone patients with stable angina will improve their quality of life scores by more than 10 points with OMT alone regardless of the presence of myocardial ischemia or not.
Dr. Hennigan was repeatedly asked how he reconciles the results of the grey zone study with those of the much-discussed ORBITA trial, the first and only randomized trial of real versus sham PCI in patients with stable angina. ORBITA didn’t find a significant quality of life advantage for real PCI over sham PCI.
“It is quite possible that a lot of the effect that we saw in our PCI group was placebo related,” he conceded. “However, we do have objective evidence that we reduced ischemia on MRI. Also, 29% of ORBITA patients had an FFR above 0.8, whereas nearly all our patients were below that threshold. So we perhaps had more prevalent ischemia than the ORBITA cohort.”
Also informative is a comparison of SAQ scores at follow-up in the sham PCI ORBITA control group versus the grey zone Scottish PCI group, Dr. Hennigan continued. The Scottish PCI group had a mean 20.6-point improvement in anginal frequency scores while on an average of 1.3 antianginal medications, compared with a 9.6-point improvement in ORBITA patients on 2.9 drugs. The grey zone group who got PCI plus OMT also had a mean 16.1-point improvement in the SAQ physical limitations domain, versus a 5.0-point improvement in the ORBITA controls.
The Grey-zone FFR Study was supported by the British Heart Foundation. Dr. Hennigan reported having no financial conflicts of interest.
PARIS – Patients with stable angina and a fractional flow reserve (FFR) value in the grey zone of 0.75-0.81 experienced a significant reduction in myocardial ischemia and substantially greater quality of life improvement if they were randomized to percutaneous coronary intervention (PCI) plus optimal medical therapy than to optimal medical therapy alone in the Scottish Grey-zone FFR Study.
The Grey-zone FFR Study was a single-center, prospective, unblinded, randomized trial that included 100 patients with stable angina, single-vessel disease, and a fractional flow reserve in the grey zone of 0.75-0.81. While broad consensus exists that an FFR below 0.75 constitutes evidence of a hemodynamically significant coronary lesion warranting revascularization and an FFR greater than 0.80 indicates a lesion isn’t functionally significant and therefore PCI can safely be deferred, there has been uncertainty on what to do about lesions in the grey zone, which are frequently encountered in the cardiac catheterization laboratory.
“In my clinical practice, I tend to go ahead with PCI for patients in the grey zone if I felt it was clinically feasible and safe to do so, particularly if I was worried about their lesion morphology,” Barry Hennigan, MD, said in response to questions after presenting the results at the annual meeting of the European Association of Percutaneous Cardiovascular Interventions. “If it’s a proximal LAD [left anterior descending artery] lesion and it’s a grey zone patient, particularly if it’s a lesion morphology that you’re not comfortable with, I think you need to be very careful before you defer a case.”
The twin purposes of the Scottish study were to define the prevalence of major ischemia by stress MRI and invasive flow assessment via a pressure wire in grey zone patients – something which hadn’t been done before – and to determine if PCI deferral in such patients is appropriate in terms of symptom control. The primary outcome was change in angina severity at 3 months follow-up using the Seattle Angina Questionnaire (SAQ).
Scores on two of the five domains of the SAQ – anginal frequency and quality of life – were significantly improved in the PCI group. Anginal frequency scores improved by a mean of 20.58 points in the PCI plus optimal medical therapy (OMT) group, compared with a 9.39-point improvement with OMT alone. Quality of life scores improved by 24.04 points in the PCI group versus 9.39 points in controls, said Dr. Hennigan, an interventional cardiologist at the University of Glasgow and Golden Jubilee National Hospital. Scores in the other three SAQ domains – physical limitations, anginal stability, and treatment satisfaction – didn’t differ significantly between the two study arms, although consistently greater improvements were seen in the PCI group.
Baseline stress perfusion MRI as assessed by two blinded observers demonstrated that 17.4% of patients with stable angina and a grey zone FFR had major ischemia, while any ischemia – major or minor – was present in 24.4%. Follow-up scans at 3 months showed a roughly 50% reduction in the prevalence of ischemia in the PCI group, with 7.3% of treated patients still having major ischemia and 12.2% having any ischemia.
Also, 28% of participants had evidence of ischemia at baseline based upon their coronary flow reserve measurements and 8% had a hyperemic stenosis resistance measurement indicative of ischemia. So the FFR grey zone encompasses a range of cardiovascular risks.
In the PCI plus OMT group, 89% of patients (eight of nine) with baseline ischemia on stress MRI had a greater than 10-point improvement in quality of life scores on the SAQ at follow-up in contrast to 53% of patients without ischemia, which made for a statistically significant difference. An improvement of that magnitude is generally considered clinically meaningful. In contrast, in the OMT-only group, 9 of 14 patients with baseline ischemia (64.2%) had a greater than 10-point quality of life improvement, which wasn’t significantly different from the 45.5% improvement rate in patients with no ischemia.
The lessons? Grey zone patients who benefit most from prompt revascularization are those with demonstrable ischemia. In addition, roughly half of grey zone patients with stable angina will improve their quality of life scores by more than 10 points with OMT alone regardless of the presence of myocardial ischemia or not.
Dr. Hennigan was repeatedly asked how he reconciles the results of the grey zone study with those of the much-discussed ORBITA trial, the first and only randomized trial of real versus sham PCI in patients with stable angina. ORBITA didn’t find a significant quality of life advantage for real PCI over sham PCI.
“It is quite possible that a lot of the effect that we saw in our PCI group was placebo related,” he conceded. “However, we do have objective evidence that we reduced ischemia on MRI. Also, 29% of ORBITA patients had an FFR above 0.8, whereas nearly all our patients were below that threshold. So we perhaps had more prevalent ischemia than the ORBITA cohort.”
Also informative is a comparison of SAQ scores at follow-up in the sham PCI ORBITA control group versus the grey zone Scottish PCI group, Dr. Hennigan continued. The Scottish PCI group had a mean 20.6-point improvement in anginal frequency scores while on an average of 1.3 antianginal medications, compared with a 9.6-point improvement in ORBITA patients on 2.9 drugs. The grey zone group who got PCI plus OMT also had a mean 16.1-point improvement in the SAQ physical limitations domain, versus a 5.0-point improvement in the ORBITA controls.
The Grey-zone FFR Study was supported by the British Heart Foundation. Dr. Hennigan reported having no financial conflicts of interest.
REPORTING FROM EUROPCR 2018
Key clinical point:
Major finding: Patients with stable angina and a fractional flow reserve in the grey zone of 0.75-0.81 experienced a 50% reduction in objectively defined myocardial ischemia if they received percutaneous coronary intervention plus medical therapy, compared with medical therapy alone.
Study details: This single-center, prospective, open-label trial randomized 100 stable angina patients with a grey zone fractional flow reserve of 0.75-0.81 to percutaneous coronary intervention plus optimal medical therapy or optimal medical therapy alone.
Disclosures: The study was supported by the British Heart Foundation. The presenter reported having no financial conflicts.
Mindfulness Training for Migraine Gathers Steam
Reductions in headache days were similar between those receiving mindfulness training and those receiving pharmacologic prophylaxis.
SAN FRANCISCO—A brief course of mindfulness training for patients with chronic migraine after their withdrawal from overuse of acute migraine medications proved as effective as prophylactic medication over the course of 12 months of follow-up, said Frank Andrasik, PhD, and colleagues at the 60th Annual Scientific Meeting of the American Headache Society. 
“The effects of mindfulness by and large rivaled those of medication alone. Although [it was]not specifically assessed, patients commented that mindfulness did not have side effects and promoted greater involvement and adherence,” said Dr. Andrasik, Professor and Chair of the Department of Psychology and Director of the Center for Behavioral Medicine at the University of Memphis.
He noted that his study, which was published in the Journal of Headache Pain, is best considered exploratory because of its small size and nonrandomized design.
After five days of structured acute medication withdrawal in an outpatient day hospital setting, study participants were treated with either pharmacologic prophylaxis for migraine—most often using botulinum toxin—or a brief course in mindfulness training entailing six once-weekly 45-minute sessions plus home practice for seven to 10 minutes per day. “While this study design does not rise to level one randomized trial evidence, it does reflect real-world clinical practice, where patients often have a big say in choosing their treatment plan,” Dr. Andrasik observed.
At baseline, all 44 patients met diagnostic criteria for chronic migraine with associated acute medication overuse. They averaged 20.5 headache days per month, with 18.4 days of acute migraine medication use. At three, six, and 12 months of follow-up, the 22 patients in the mindfulness group averaged 8.3, 10.4, and 12.4 headache days per month, while the 22 on pharmacologic prophylaxis averaged 8.8, 11, and 8.6 headache days per month. Both groups averaged similar seven- to 10-day reductions in days of acute migraine medication use per month.
Using the widely accepted end point of at least a 50% reduction in headache days per month, 50% of the mindfulness-only group and 52.6% of the prophylactic medication-only group met that standard at 12 months of follow-up. Moreover, at 12 months, 65% of the mindfulness therapy group and 73.7% of the preventive medication group no longer met diagnostic criteria for chronic migraine.
The mindfulness protocol used in the study was based upon the popular mindfulness-based stress reduction program developed by Jon Kabat-Zinn, PhD, and colleagues in the mid 1980s.
Scores on the Migraine Disability Assessment (MIDAS) measure and the Beck Depression Inventory improved significantly and to a similar extent from baseline in both groups. In contrast, scores on the State-Trait Anxiety Inventory did not change significantly in either study arm.
Mindfulness for Migraine Is Still Emerging
Dr. Andrasik and session chair Elizabeth K. Seng, PhD, cautioned that despite solid evidence of efficacy for mindfulness training in the treatment of depression and several chronic pain disorders, mindfulness for treatment of migraine is still in its infancy. Large randomized, controlled clinical trials are ongoing or in the planning stages, and no results are available.
Dr. Seng, a Research Assistant Professor at Albert Einstein College of Medicine in New York, described mindfulness and acceptance as “third-wave” behavioral treatments for migraine. The first-wave therapies focused on fostering behavioral changes to reduce perceived stress to avoid triggering migraine attacks. Second-wave therapies involved interactions aimed at helping patients reframe maladaptive automatic thoughts to reduce stress stemming from the daily hassles of life.
“The focus in the first- and second-wave therapies is, ‘Change something and your life will be better. Change your behaviors, clean up your act, change your thoughts because your thoughts are not helping you, and thereby reduce stress and reduce migraine.’ These mindfulness therapies are incredibly different from that,” she explained.
Third-wave therapies are not directed toward changing daily stress or automatic thoughts; instead, they seek to change the patient’s relationship to them such that they no longer create barriers to engaging in life activities that the patient finds nourishing and meaningful. It is a matter of creating a willingness to experience pain to achieve worthwhile objectives, Dr. Seng explained.
Measuring Success
It is unclear that a reduction in migraine days—the traditional yardstick for therapeutic efficacy in migraine research—is the right primary outcome measure for third-wave therapies, according to the psychologist. “So far, our evidence would suggest that mindfulness-based therapies do not reduce migraine days as much as other behavioral treatments, but what they are doing is increasing migraine-related quality of life and reducing migraine-related disability to the same or possibly larger extent than our other behavioral treatments,” Dr. Seng said. “Maybe what these third-wave therapies are actually doing is impacting our cognitive and emotional functioning, and even if patients still experience similar levels of headache frequency, their reaction to those headache days no longer leads to suffering. That could be a clinically relevant outcome.”
Dr. Seng plans to formally study mindfulness therapies in a subgroup of migraine patients with high levels of depression. They might respond especially well, she hypothesized, since mindfulness was originally developed as a treatment for severe depression. “Patients who are depressed have a hard time overcoming barriers to engaging in nourishing life activities, and when they have a headache day, it is even worse. That is one of the things that is leading them to have migraine-related disability,” she said.
Dr. Andrasik, whose study was supported by the European Commission and an Italian research foundation, reported having no financial conflicts of interest regarding his presentation. Dr. Seng reported serving as a consultant to GlaxoSmithKline.
—Bruce Jancin
Suggested Reading
Grazzi L, Sansone E, Raggi A, et al. Mindfulness and pharmacological prophylaxis after withdrawal from medication overuse in patients with chronic migraine: an effectiveness trial with a one-year follow-up. J Headache Pain. 2017;18(1):15.
Kabat-Zinn J, Lipworth L, Burney R. The clinical use of mindfulness meditation for the self-regulation of chronic pain. J Behav Med. 1985;8(2):163-190.
Reductions in headache days were similar between those receiving mindfulness training and those receiving pharmacologic prophylaxis.
Reductions in headache days were similar between those receiving mindfulness training and those receiving pharmacologic prophylaxis.
SAN FRANCISCO—A brief course of mindfulness training for patients with chronic migraine after their withdrawal from overuse of acute migraine medications proved as effective as prophylactic medication over the course of 12 months of follow-up, said Frank Andrasik, PhD, and colleagues at the 60th Annual Scientific Meeting of the American Headache Society.
“The effects of mindfulness by and large rivaled those of medication alone. Although [it was]not specifically assessed, patients commented that mindfulness did not have side effects and promoted greater involvement and adherence,” said Dr. Andrasik, Professor and Chair of the Department of Psychology and Director of the Center for Behavioral Medicine at the University of Memphis.
He noted that his study, which was published in the Journal of Headache Pain, is best considered exploratory because of its small size and nonrandomized design.
After five days of structured acute medication withdrawal in an outpatient day hospital setting, study participants were treated with either pharmacologic prophylaxis for migraine—most often using botulinum toxin—or a brief course in mindfulness training entailing six once-weekly 45-minute sessions plus home practice for seven to 10 minutes per day. “While this study design does not rise to level one randomized trial evidence, it does reflect real-world clinical practice, where patients often have a big say in choosing their treatment plan,” Dr. Andrasik observed.
At baseline, all 44 patients met diagnostic criteria for chronic migraine with associated acute medication overuse. They averaged 20.5 headache days per month, with 18.4 days of acute migraine medication use. At three, six, and 12 months of follow-up, the 22 patients in the mindfulness group averaged 8.3, 10.4, and 12.4 headache days per month, while the 22 on pharmacologic prophylaxis averaged 8.8, 11, and 8.6 headache days per month. Both groups averaged similar seven- to 10-day reductions in days of acute migraine medication use per month.
Using the widely accepted end point of at least a 50% reduction in headache days per month, 50% of the mindfulness-only group and 52.6% of the prophylactic medication-only group met that standard at 12 months of follow-up. Moreover, at 12 months, 65% of the mindfulness therapy group and 73.7% of the preventive medication group no longer met diagnostic criteria for chronic migraine.
The mindfulness protocol used in the study was based upon the popular mindfulness-based stress reduction program developed by Jon Kabat-Zinn, PhD, and colleagues in the mid 1980s.
Scores on the Migraine Disability Assessment (MIDAS) measure and the Beck Depression Inventory improved significantly and to a similar extent from baseline in both groups. In contrast, scores on the State-Trait Anxiety Inventory did not change significantly in either study arm.
Mindfulness for Migraine Is Still Emerging
Dr. Andrasik and session chair Elizabeth K. Seng, PhD, cautioned that despite solid evidence of efficacy for mindfulness training in the treatment of depression and several chronic pain disorders, mindfulness for treatment of migraine is still in its infancy. Large randomized, controlled clinical trials are ongoing or in the planning stages, and no results are available.
Dr. Seng, a Research Assistant Professor at Albert Einstein College of Medicine in New York, described mindfulness and acceptance as “third-wave” behavioral treatments for migraine. The first-wave therapies focused on fostering behavioral changes to reduce perceived stress to avoid triggering migraine attacks. Second-wave therapies involved interactions aimed at helping patients reframe maladaptive automatic thoughts to reduce stress stemming from the daily hassles of life.
“The focus in the first- and second-wave therapies is, ‘Change something and your life will be better. Change your behaviors, clean up your act, change your thoughts because your thoughts are not helping you, and thereby reduce stress and reduce migraine.’ These mindfulness therapies are incredibly different from that,” she explained.
Third-wave therapies are not directed toward changing daily stress or automatic thoughts; instead, they seek to change the patient’s relationship to them such that they no longer create barriers to engaging in life activities that the patient finds nourishing and meaningful. It is a matter of creating a willingness to experience pain to achieve worthwhile objectives, Dr. Seng explained.
Measuring Success
It is unclear that a reduction in migraine days—the traditional yardstick for therapeutic efficacy in migraine research—is the right primary outcome measure for third-wave therapies, according to the psychologist. “So far, our evidence would suggest that mindfulness-based therapies do not reduce migraine days as much as other behavioral treatments, but what they are doing is increasing migraine-related quality of life and reducing migraine-related disability to the same or possibly larger extent than our other behavioral treatments,” Dr. Seng said. “Maybe what these third-wave therapies are actually doing is impacting our cognitive and emotional functioning, and even if patients still experience similar levels of headache frequency, their reaction to those headache days no longer leads to suffering. That could be a clinically relevant outcome.”
Dr. Seng plans to formally study mindfulness therapies in a subgroup of migraine patients with high levels of depression. They might respond especially well, she hypothesized, since mindfulness was originally developed as a treatment for severe depression. “Patients who are depressed have a hard time overcoming barriers to engaging in nourishing life activities, and when they have a headache day, it is even worse. That is one of the things that is leading them to have migraine-related disability,” she said.
Dr. Andrasik, whose study was supported by the European Commission and an Italian research foundation, reported having no financial conflicts of interest regarding his presentation. Dr. Seng reported serving as a consultant to GlaxoSmithKline.
—Bruce Jancin
Suggested Reading
Grazzi L, Sansone E, Raggi A, et al. Mindfulness and pharmacological prophylaxis after withdrawal from medication overuse in patients with chronic migraine: an effectiveness trial with a one-year follow-up. J Headache Pain. 2017;18(1):15.
Kabat-Zinn J, Lipworth L, Burney R. The clinical use of mindfulness meditation for the self-regulation of chronic pain. J Behav Med. 1985;8(2):163-190.
SAN FRANCISCO—A brief course of mindfulness training for patients with chronic migraine after their withdrawal from overuse of acute migraine medications proved as effective as prophylactic medication over the course of 12 months of follow-up, said Frank Andrasik, PhD, and colleagues at the 60th Annual Scientific Meeting of the American Headache Society.
“The effects of mindfulness by and large rivaled those of medication alone. Although [it was]not specifically assessed, patients commented that mindfulness did not have side effects and promoted greater involvement and adherence,” said Dr. Andrasik, Professor and Chair of the Department of Psychology and Director of the Center for Behavioral Medicine at the University of Memphis.
He noted that his study, which was published in the Journal of Headache Pain, is best considered exploratory because of its small size and nonrandomized design.
After five days of structured acute medication withdrawal in an outpatient day hospital setting, study participants were treated with either pharmacologic prophylaxis for migraine—most often using botulinum toxin—or a brief course in mindfulness training entailing six once-weekly 45-minute sessions plus home practice for seven to 10 minutes per day. “While this study design does not rise to level one randomized trial evidence, it does reflect real-world clinical practice, where patients often have a big say in choosing their treatment plan,” Dr. Andrasik observed.
At baseline, all 44 patients met diagnostic criteria for chronic migraine with associated acute medication overuse. They averaged 20.5 headache days per month, with 18.4 days of acute migraine medication use. At three, six, and 12 months of follow-up, the 22 patients in the mindfulness group averaged 8.3, 10.4, and 12.4 headache days per month, while the 22 on pharmacologic prophylaxis averaged 8.8, 11, and 8.6 headache days per month. Both groups averaged similar seven- to 10-day reductions in days of acute migraine medication use per month.
Using the widely accepted end point of at least a 50% reduction in headache days per month, 50% of the mindfulness-only group and 52.6% of the prophylactic medication-only group met that standard at 12 months of follow-up. Moreover, at 12 months, 65% of the mindfulness therapy group and 73.7% of the preventive medication group no longer met diagnostic criteria for chronic migraine.
The mindfulness protocol used in the study was based upon the popular mindfulness-based stress reduction program developed by Jon Kabat-Zinn, PhD, and colleagues in the mid 1980s.
Scores on the Migraine Disability Assessment (MIDAS) measure and the Beck Depression Inventory improved significantly and to a similar extent from baseline in both groups. In contrast, scores on the State-Trait Anxiety Inventory did not change significantly in either study arm.
Mindfulness for Migraine Is Still Emerging
Dr. Andrasik and session chair Elizabeth K. Seng, PhD, cautioned that despite solid evidence of efficacy for mindfulness training in the treatment of depression and several chronic pain disorders, mindfulness for treatment of migraine is still in its infancy. Large randomized, controlled clinical trials are ongoing or in the planning stages, and no results are available.
Dr. Seng, a Research Assistant Professor at Albert Einstein College of Medicine in New York, described mindfulness and acceptance as “third-wave” behavioral treatments for migraine. The first-wave therapies focused on fostering behavioral changes to reduce perceived stress to avoid triggering migraine attacks. Second-wave therapies involved interactions aimed at helping patients reframe maladaptive automatic thoughts to reduce stress stemming from the daily hassles of life.
“The focus in the first- and second-wave therapies is, ‘Change something and your life will be better. Change your behaviors, clean up your act, change your thoughts because your thoughts are not helping you, and thereby reduce stress and reduce migraine.’ These mindfulness therapies are incredibly different from that,” she explained.
Third-wave therapies are not directed toward changing daily stress or automatic thoughts; instead, they seek to change the patient’s relationship to them such that they no longer create barriers to engaging in life activities that the patient finds nourishing and meaningful. It is a matter of creating a willingness to experience pain to achieve worthwhile objectives, Dr. Seng explained.
Measuring Success
It is unclear that a reduction in migraine days—the traditional yardstick for therapeutic efficacy in migraine research—is the right primary outcome measure for third-wave therapies, according to the psychologist. “So far, our evidence would suggest that mindfulness-based therapies do not reduce migraine days as much as other behavioral treatments, but what they are doing is increasing migraine-related quality of life and reducing migraine-related disability to the same or possibly larger extent than our other behavioral treatments,” Dr. Seng said. “Maybe what these third-wave therapies are actually doing is impacting our cognitive and emotional functioning, and even if patients still experience similar levels of headache frequency, their reaction to those headache days no longer leads to suffering. That could be a clinically relevant outcome.”
Dr. Seng plans to formally study mindfulness therapies in a subgroup of migraine patients with high levels of depression. They might respond especially well, she hypothesized, since mindfulness was originally developed as a treatment for severe depression. “Patients who are depressed have a hard time overcoming barriers to engaging in nourishing life activities, and when they have a headache day, it is even worse. That is one of the things that is leading them to have migraine-related disability,” she said.
Dr. Andrasik, whose study was supported by the European Commission and an Italian research foundation, reported having no financial conflicts of interest regarding his presentation. Dr. Seng reported serving as a consultant to GlaxoSmithKline.
—Bruce Jancin
Suggested Reading
Grazzi L, Sansone E, Raggi A, et al. Mindfulness and pharmacological prophylaxis after withdrawal from medication overuse in patients with chronic migraine: an effectiveness trial with a one-year follow-up. J Headache Pain. 2017;18(1):15.
Kabat-Zinn J, Lipworth L, Burney R. The clinical use of mindfulness meditation for the self-regulation of chronic pain. J Behav Med. 1985;8(2):163-190.
Cardiovascular Health and Cognitive Decline: What Is the Connection?
Maintaining cardiovascular health may reduce white matter hyperintensities and decrease the risk of dementia.
Optimal measures of cardiovascular health are associated with brain health in adults, according to two studies published in the August 21 issue of JAMA.
In a French population-based cohort study, adults ages 65 and older with more cardiovascular health measures at ideal levels had a lower risk of dementia and lower rates of cognitive decline than did those with fewer optimal cardiovascular measures, such as blood pressure and physical activity.
In addition, a preliminary, cross-sectional study of younger adults found that the number of modifiable cardiovascular risk factors at recommended levels was associated with brain vessel structure and function and the number of white matter hyperintensities. 
“These two studies convey an immediately actionable message to clinicians, policy makers, and patients,” said Jeffrey L. Saver, MD, and Mary Cushman, MD, in an accompanying editorial. “Available evidence indicates that to achieve a lifetime of robust brain health free of dementia, it is never too early or too late to strive for attainment of ideal cardiovascular health.” Dr. Saver is a Professor of Neurology and Director of the Stroke Center at the University of California, Los Angeles. Dr. Cushman is a Professor of Medicine and Pathology at Larner College of Medicine at the University of Vermont in Burlington.
Cardiovascular Health in Older Age
Vascular dementia is the second most common neuropathologic basis of dementia, after Alzheimer’s disease, and “most cases of dementia arise from a combination of [Alzheimer’s disease] and cerebrovascular pathology,” the editorialists noted. Studies have suggested a connection between cardiovascular health and dementia, but the evidence is limited.
Cécilia Samieri, PhD, a Senior Researcher at the Bordeaux Population Health Research Center at the Université de Bordeaux in France, and colleagues studied people age 65 and older from Bordeaux, Dijon, and Montpellier, France, to examine the association between cardiovascular health level and risk of dementia and cognitive decline in older adults. 
The study included 6,626 people without a history of cardiovascular disease or dementia at baseline. Participants underwent in-person neuropsychologic testing between January 1999 and July 2016 and systematic detection of incident dementia. Participants had a mean age of 73.7, and 63.4% were women.
The investigators defined cardiovascular health using a seven-item tool from the American Heart Association (AHA). They determined the number of the AHA’s Life’s Simple Seven metrics that were at recommended levels (ie, nonsmoking, BMI < 25, regular physical activity, eating fish at least twice per week and fruits and vegetables at least three times per day, cholesterol < 200 mg/dL [untreated], fasting glucose < 100 mg/dL [untreated], and blood pressure < 120/80 mm Hg [untreated]).
Approximately 36.5% of the cohort had zero, one, or two optimal health metrics, 57.1% had three or four optimal health metrics, and 6.5% had five, six, or seven optimal health metrics.
During an average follow-up of 8.5 years, 745 participants developed dementia. Among participants with zero or one health metrics at optimal levels at baseline, the incidence rate of dementia was 1.76 per 100 person-years. Compared with this rate, the incidence rate per 100 person-years was 0.26 lower for participants with two optimal health metrics, 0.59 lower for participants with three optimal health metrics, 0.43 lower for participants with four optimal health metrics, 0.93 lower for participants with five optimal health metrics, and 0.96 lower for participants with six or seven optimal health metrics.
“In multivariable models, the hazard ratios for dementia were 0.90 per additional optimal metric,” the investigators said. “The study results support the recent recommendations of the AHA and the American Stroke Association for the promotion of the Life’s Simple Seven tool.”
Cerebrovascular Structure and Function in Young Adults
Wilby Williamson, BMBS
The researchers assessed patients’ cerebral vessel density, caliber, and tortuosity and brain white matter hyperintensity lesion count. In a subgroup of 52 participants, they assessed cerebral blood flow.
The researchers determined for each participant how many of eight modifiable risk factors were at recommended levels (ie, BMI < 25, highest tertile of cardiovascular fitness or physical activity, alcohol consumption < eight drinks per week, nonsmoker for more than six months, blood pressure on awake ambulatory monitoring < 130/80 mm Hg, a nonhypertensive diastolic response to exercise [ie, peak diastolic blood pressure < 90 mm Hg], total cholesterol < 200 mg/dL, and fasting glucose < 100 mg/dL).
On average, participants had six of the eight modifiable cardiovascular risk factors at recommended levels.
In multivariable models, cardiovascular risk factors were associated with cerebrovascular structure and the number of white matter hyperintensities. “For each additional modifiable risk factor categorized as healthy, vessel density was greater by 0.3 vessels/cm3, vessel caliber was greater by 8 μm, and white matter hyperintensity lesions were fewer by 1.6 lesions. Among the 52 participants with available data, cerebral blood flow varied with vessel density and was 2.5 mL/100 g/min higher for each healthier category of a modifiable risk factor,” Dr. Williamson and colleagues said.
The findings suggest that “some individuals may be starting to diverge to different risk trajectories for brain vascular health in early adulthood,” the researchers said. The study was exploratory, however, and follow-up studies are needed to determine the clinical significance of these findings, they said.
“The magnitude of changes was generally much less than would be expected to produce clinical symptoms such as cognitive impairment or gait difficulty,” said Drs. Saver and Cushman. The changes, however, “may portend more substantial abnormalities later in life,” they said. “Even during the late-life period, when septuagenarians become octogenarians, cardiovascular health is associated with substantial differences in cognitive trajectory and dementia onset.”
—Jake Remaly
Suggested Reading
Samieri C, Perier MC, Gaye B, et al. Association of cardiovascular health level in older age with cognitive decline and incident dementia. JAMA. 2018;320(7):657-664.
Saver JL, Cushman M. Striving for ideal cardiovascular and brain health: It is never too early or too late. JAMA. 2018; 320(7):645-647.
Williamson W, Lewandowski AJ, Forkert ND, et al. Association of cardiovascular risk factors with MRI indices of cerebrovascular structure and function and white matter hyperintensities in young adults. JAMA. 2018;320(7):665-673.
Maintaining cardiovascular health may reduce white matter hyperintensities and decrease the risk of dementia.
Maintaining cardiovascular health may reduce white matter hyperintensities and decrease the risk of dementia.
Optimal measures of cardiovascular health are associated with brain health in adults, according to two studies published in the August 21 issue of JAMA.
In a French population-based cohort study, adults ages 65 and older with more cardiovascular health measures at ideal levels had a lower risk of dementia and lower rates of cognitive decline than did those with fewer optimal cardiovascular measures, such as blood pressure and physical activity.
In addition, a preliminary, cross-sectional study of younger adults found that the number of modifiable cardiovascular risk factors at recommended levels was associated with brain vessel structure and function and the number of white matter hyperintensities.
“These two studies convey an immediately actionable message to clinicians, policy makers, and patients,” said Jeffrey L. Saver, MD, and Mary Cushman, MD, in an accompanying editorial. “Available evidence indicates that to achieve a lifetime of robust brain health free of dementia, it is never too early or too late to strive for attainment of ideal cardiovascular health.” Dr. Saver is a Professor of Neurology and Director of the Stroke Center at the University of California, Los Angeles. Dr. Cushman is a Professor of Medicine and Pathology at Larner College of Medicine at the University of Vermont in Burlington.
Cardiovascular Health in Older Age
Vascular dementia is the second most common neuropathologic basis of dementia, after Alzheimer’s disease, and “most cases of dementia arise from a combination of [Alzheimer’s disease] and cerebrovascular pathology,” the editorialists noted. Studies have suggested a connection between cardiovascular health and dementia, but the evidence is limited.
Cécilia Samieri, PhD, a Senior Researcher at the Bordeaux Population Health Research Center at the Université de Bordeaux in France, and colleagues studied people age 65 and older from Bordeaux, Dijon, and Montpellier, France, to examine the association between cardiovascular health level and risk of dementia and cognitive decline in older adults.
The study included 6,626 people without a history of cardiovascular disease or dementia at baseline. Participants underwent in-person neuropsychologic testing between January 1999 and July 2016 and systematic detection of incident dementia. Participants had a mean age of 73.7, and 63.4% were women.
The investigators defined cardiovascular health using a seven-item tool from the American Heart Association (AHA). They determined the number of the AHA’s Life’s Simple Seven metrics that were at recommended levels (ie, nonsmoking, BMI < 25, regular physical activity, eating fish at least twice per week and fruits and vegetables at least three times per day, cholesterol < 200 mg/dL [untreated], fasting glucose < 100 mg/dL [untreated], and blood pressure < 120/80 mm Hg [untreated]).
Approximately 36.5% of the cohort had zero, one, or two optimal health metrics, 57.1% had three or four optimal health metrics, and 6.5% had five, six, or seven optimal health metrics.
During an average follow-up of 8.5 years, 745 participants developed dementia. Among participants with zero or one health metrics at optimal levels at baseline, the incidence rate of dementia was 1.76 per 100 person-years. Compared with this rate, the incidence rate per 100 person-years was 0.26 lower for participants with two optimal health metrics, 0.59 lower for participants with three optimal health metrics, 0.43 lower for participants with four optimal health metrics, 0.93 lower for participants with five optimal health metrics, and 0.96 lower for participants with six or seven optimal health metrics.
“In multivariable models, the hazard ratios for dementia were 0.90 per additional optimal metric,” the investigators said. “The study results support the recent recommendations of the AHA and the American Stroke Association for the promotion of the Life’s Simple Seven tool.”
Cerebrovascular Structure and Function in Young Adults
Wilby Williamson, BMBS
The researchers assessed patients’ cerebral vessel density, caliber, and tortuosity and brain white matter hyperintensity lesion count. In a subgroup of 52 participants, they assessed cerebral blood flow.
The researchers determined for each participant how many of eight modifiable risk factors were at recommended levels (ie, BMI < 25, highest tertile of cardiovascular fitness or physical activity, alcohol consumption < eight drinks per week, nonsmoker for more than six months, blood pressure on awake ambulatory monitoring < 130/80 mm Hg, a nonhypertensive diastolic response to exercise [ie, peak diastolic blood pressure < 90 mm Hg], total cholesterol < 200 mg/dL, and fasting glucose < 100 mg/dL).
On average, participants had six of the eight modifiable cardiovascular risk factors at recommended levels.
In multivariable models, cardiovascular risk factors were associated with cerebrovascular structure and the number of white matter hyperintensities. “For each additional modifiable risk factor categorized as healthy, vessel density was greater by 0.3 vessels/cm3, vessel caliber was greater by 8 μm, and white matter hyperintensity lesions were fewer by 1.6 lesions. Among the 52 participants with available data, cerebral blood flow varied with vessel density and was 2.5 mL/100 g/min higher for each healthier category of a modifiable risk factor,” Dr. Williamson and colleagues said.
The findings suggest that “some individuals may be starting to diverge to different risk trajectories for brain vascular health in early adulthood,” the researchers said. The study was exploratory, however, and follow-up studies are needed to determine the clinical significance of these findings, they said.
“The magnitude of changes was generally much less than would be expected to produce clinical symptoms such as cognitive impairment or gait difficulty,” said Drs. Saver and Cushman. The changes, however, “may portend more substantial abnormalities later in life,” they said. “Even during the late-life period, when septuagenarians become octogenarians, cardiovascular health is associated with substantial differences in cognitive trajectory and dementia onset.”
—Jake Remaly
Suggested Reading
Samieri C, Perier MC, Gaye B, et al. Association of cardiovascular health level in older age with cognitive decline and incident dementia. JAMA. 2018;320(7):657-664.
Saver JL, Cushman M. Striving for ideal cardiovascular and brain health: It is never too early or too late. JAMA. 2018; 320(7):645-647.
Williamson W, Lewandowski AJ, Forkert ND, et al. Association of cardiovascular risk factors with MRI indices of cerebrovascular structure and function and white matter hyperintensities in young adults. JAMA. 2018;320(7):665-673.
Optimal measures of cardiovascular health are associated with brain health in adults, according to two studies published in the August 21 issue of JAMA.
In a French population-based cohort study, adults ages 65 and older with more cardiovascular health measures at ideal levels had a lower risk of dementia and lower rates of cognitive decline than did those with fewer optimal cardiovascular measures, such as blood pressure and physical activity.
In addition, a preliminary, cross-sectional study of younger adults found that the number of modifiable cardiovascular risk factors at recommended levels was associated with brain vessel structure and function and the number of white matter hyperintensities.
“These two studies convey an immediately actionable message to clinicians, policy makers, and patients,” said Jeffrey L. Saver, MD, and Mary Cushman, MD, in an accompanying editorial. “Available evidence indicates that to achieve a lifetime of robust brain health free of dementia, it is never too early or too late to strive for attainment of ideal cardiovascular health.” Dr. Saver is a Professor of Neurology and Director of the Stroke Center at the University of California, Los Angeles. Dr. Cushman is a Professor of Medicine and Pathology at Larner College of Medicine at the University of Vermont in Burlington.
Cardiovascular Health in Older Age
Vascular dementia is the second most common neuropathologic basis of dementia, after Alzheimer’s disease, and “most cases of dementia arise from a combination of [Alzheimer’s disease] and cerebrovascular pathology,” the editorialists noted. Studies have suggested a connection between cardiovascular health and dementia, but the evidence is limited.
Cécilia Samieri, PhD, a Senior Researcher at the Bordeaux Population Health Research Center at the Université de Bordeaux in France, and colleagues studied people age 65 and older from Bordeaux, Dijon, and Montpellier, France, to examine the association between cardiovascular health level and risk of dementia and cognitive decline in older adults.
The study included 6,626 people without a history of cardiovascular disease or dementia at baseline. Participants underwent in-person neuropsychologic testing between January 1999 and July 2016 and systematic detection of incident dementia. Participants had a mean age of 73.7, and 63.4% were women.
The investigators defined cardiovascular health using a seven-item tool from the American Heart Association (AHA). They determined the number of the AHA’s Life’s Simple Seven metrics that were at recommended levels (ie, nonsmoking, BMI < 25, regular physical activity, eating fish at least twice per week and fruits and vegetables at least three times per day, cholesterol < 200 mg/dL [untreated], fasting glucose < 100 mg/dL [untreated], and blood pressure < 120/80 mm Hg [untreated]).
Approximately 36.5% of the cohort had zero, one, or two optimal health metrics, 57.1% had three or four optimal health metrics, and 6.5% had five, six, or seven optimal health metrics.
During an average follow-up of 8.5 years, 745 participants developed dementia. Among participants with zero or one health metrics at optimal levels at baseline, the incidence rate of dementia was 1.76 per 100 person-years. Compared with this rate, the incidence rate per 100 person-years was 0.26 lower for participants with two optimal health metrics, 0.59 lower for participants with three optimal health metrics, 0.43 lower for participants with four optimal health metrics, 0.93 lower for participants with five optimal health metrics, and 0.96 lower for participants with six or seven optimal health metrics.
“In multivariable models, the hazard ratios for dementia were 0.90 per additional optimal metric,” the investigators said. “The study results support the recent recommendations of the AHA and the American Stroke Association for the promotion of the Life’s Simple Seven tool.”
Cerebrovascular Structure and Function in Young Adults
Wilby Williamson, BMBS
The researchers assessed patients’ cerebral vessel density, caliber, and tortuosity and brain white matter hyperintensity lesion count. In a subgroup of 52 participants, they assessed cerebral blood flow.
The researchers determined for each participant how many of eight modifiable risk factors were at recommended levels (ie, BMI < 25, highest tertile of cardiovascular fitness or physical activity, alcohol consumption < eight drinks per week, nonsmoker for more than six months, blood pressure on awake ambulatory monitoring < 130/80 mm Hg, a nonhypertensive diastolic response to exercise [ie, peak diastolic blood pressure < 90 mm Hg], total cholesterol < 200 mg/dL, and fasting glucose < 100 mg/dL).
On average, participants had six of the eight modifiable cardiovascular risk factors at recommended levels.
In multivariable models, cardiovascular risk factors were associated with cerebrovascular structure and the number of white matter hyperintensities. “For each additional modifiable risk factor categorized as healthy, vessel density was greater by 0.3 vessels/cm3, vessel caliber was greater by 8 μm, and white matter hyperintensity lesions were fewer by 1.6 lesions. Among the 52 participants with available data, cerebral blood flow varied with vessel density and was 2.5 mL/100 g/min higher for each healthier category of a modifiable risk factor,” Dr. Williamson and colleagues said.
The findings suggest that “some individuals may be starting to diverge to different risk trajectories for brain vascular health in early adulthood,” the researchers said. The study was exploratory, however, and follow-up studies are needed to determine the clinical significance of these findings, they said.
“The magnitude of changes was generally much less than would be expected to produce clinical symptoms such as cognitive impairment or gait difficulty,” said Drs. Saver and Cushman. The changes, however, “may portend more substantial abnormalities later in life,” they said. “Even during the late-life period, when septuagenarians become octogenarians, cardiovascular health is associated with substantial differences in cognitive trajectory and dementia onset.”
—Jake Remaly
Suggested Reading
Samieri C, Perier MC, Gaye B, et al. Association of cardiovascular health level in older age with cognitive decline and incident dementia. JAMA. 2018;320(7):657-664.
Saver JL, Cushman M. Striving for ideal cardiovascular and brain health: It is never too early or too late. JAMA. 2018; 320(7):645-647.
Williamson W, Lewandowski AJ, Forkert ND, et al. Association of cardiovascular risk factors with MRI indices of cerebrovascular structure and function and white matter hyperintensities in young adults. JAMA. 2018;320(7):665-673.
FDA approves oral dacomitinib for some metastatic NSCLC
The Food and Drug Administration has approved dacomitinib tablets (VIZIMPRO) for the first-line treatment of metastatic non-small cell lung cancer in patients with epidermal growth factor receptor (EGFR) exon 19 deletion or exon 21 L858R substitution mutations.
The second-generation, irreversible EGFR tyrosine kinase inhibitor (TKI) has a recommended dose of 45 mg once daily with or without food.
The approval is based on the randomized, active-controlled 452-patient ARCHER 1050 trial, in which the drug showed improvement in progression-free survival (PFS) versus gefitinib. The median PFS was 14.7 in the dacomitinib arm, compared with 9.2 months in the gefitinib arm (hazard ratio 0.59).
ARCHER 1050 trial participants had good performance status, no prior therapy for metastatic disease or recurrent disease and were disease-free for at least 12 months following systemic non-EGFR TKI-containing therapy. Dacomitinib and gefitinib were given once-daily at 45 mg and 250 mg oral doses, respectively, until disease progression or unacceptable toxicity.
No improvement was seen in overall response rate or overall survival with dacomitinib vs. gefitinib.
Of 394 patients who received dacomitinib, 27% experienced serious adverse reactions – most often diarrhea, rash, paronychia, stomatitis, decreased appetite, dry skin, decreased weight, alopecia, cough, and pruritus, according to the FDA. Those that most often lead to discontinuation were diarrhea and interstitial lung disease. Prescribing information for dacomitinib contains warnings and precautions for interstitial lung disease, diarrhea, and dermatologic adverse reactions.
The Food and Drug Administration has approved dacomitinib tablets (VIZIMPRO) for the first-line treatment of metastatic non-small cell lung cancer in patients with epidermal growth factor receptor (EGFR) exon 19 deletion or exon 21 L858R substitution mutations.
The second-generation, irreversible EGFR tyrosine kinase inhibitor (TKI) has a recommended dose of 45 mg once daily with or without food.
The approval is based on the randomized, active-controlled 452-patient ARCHER 1050 trial, in which the drug showed improvement in progression-free survival (PFS) versus gefitinib. The median PFS was 14.7 in the dacomitinib arm, compared with 9.2 months in the gefitinib arm (hazard ratio 0.59).
ARCHER 1050 trial participants had good performance status, no prior therapy for metastatic disease or recurrent disease and were disease-free for at least 12 months following systemic non-EGFR TKI-containing therapy. Dacomitinib and gefitinib were given once-daily at 45 mg and 250 mg oral doses, respectively, until disease progression or unacceptable toxicity.
No improvement was seen in overall response rate or overall survival with dacomitinib vs. gefitinib.
Of 394 patients who received dacomitinib, 27% experienced serious adverse reactions – most often diarrhea, rash, paronychia, stomatitis, decreased appetite, dry skin, decreased weight, alopecia, cough, and pruritus, according to the FDA. Those that most often lead to discontinuation were diarrhea and interstitial lung disease. Prescribing information for dacomitinib contains warnings and precautions for interstitial lung disease, diarrhea, and dermatologic adverse reactions.
The Food and Drug Administration has approved dacomitinib tablets (VIZIMPRO) for the first-line treatment of metastatic non-small cell lung cancer in patients with epidermal growth factor receptor (EGFR) exon 19 deletion or exon 21 L858R substitution mutations.
The second-generation, irreversible EGFR tyrosine kinase inhibitor (TKI) has a recommended dose of 45 mg once daily with or without food.
The approval is based on the randomized, active-controlled 452-patient ARCHER 1050 trial, in which the drug showed improvement in progression-free survival (PFS) versus gefitinib. The median PFS was 14.7 in the dacomitinib arm, compared with 9.2 months in the gefitinib arm (hazard ratio 0.59).
ARCHER 1050 trial participants had good performance status, no prior therapy for metastatic disease or recurrent disease and were disease-free for at least 12 months following systemic non-EGFR TKI-containing therapy. Dacomitinib and gefitinib were given once-daily at 45 mg and 250 mg oral doses, respectively, until disease progression or unacceptable toxicity.
No improvement was seen in overall response rate or overall survival with dacomitinib vs. gefitinib.
Of 394 patients who received dacomitinib, 27% experienced serious adverse reactions – most often diarrhea, rash, paronychia, stomatitis, decreased appetite, dry skin, decreased weight, alopecia, cough, and pruritus, according to the FDA. Those that most often lead to discontinuation were diarrhea and interstitial lung disease. Prescribing information for dacomitinib contains warnings and precautions for interstitial lung disease, diarrhea, and dermatologic adverse reactions.
PACIFIC trial: Durvalumab improves both OS and PFS in stage III NSCLC
TORONTO – The programmed death-ligand 1 (PD-L1) inhibitor durvalumab significantly improves overall survival in patients with stage III unresectable non–small-cell lung cancer without progression after chemoradiotherapy, according to updated results from the global phase 3 PACIFIC study.
The findings, presented at the World Conference on Lung Cancer, follow a prior report from the study showing improved progression-free survival (PFS) in durvalumab-treated patients (stratified hazard ratio, 0.52), and together these survival benefits mark the first major advance in this disease setting in decades,” Scott J. Antonia, MD, reported at the conference, sponsored by the International Association for the Study of Lung Cancer (IASLC).
“The fact is this is a new standard of care treatment for the patients with this disease,” he said, adding that “in all likelihood we are improving the cure rate for the patients with this disease.”
The findings were published simultaneously in the New England Journal of Medicine.
Overall survival at a median follow-up of 25.2 months in 473 patients randomized to receive durvalumab was significantly greater than among 236 who received placebo (stratified HR, 0.68; median survival not reached vs. 28.7 months in the groups, respectively), said Dr. Antonia of the H. Lee Moffitt Cancer Center and Research Institute, and professor of oncologic sciences at the University of South Florida, Tampa.
Durvalumab also improved overall survival in all prespecified subgroups, and PFS was similar to that in previous reports (stratified HR 0.51; median of 17.2 vs. 5.6 months with durvalumab and placebo, respectively), he said, noting that “interestingly, patients who were nonsmokers did benefit from durvalumab.”
This is notable because prior research suggests that never-smokers with advanced stage cancer have less of a chance of responding to immunotherapy (although they should still be offered immunotherapy), he explained.
“Also interestingly, it appears as if cisplatin was the better drug to use in the conventional therapy portion of the treatment,” he said.
Durvalumab also provided continued improvement vs. placebo in time to death or distant metastasis (stratified HR, 0.53), time to second progression (stratified HR, 0.58), time to first subsequent therapy or death (stratified HR, 0.58), and time to second subsequent therapy or death (stratified HR, 0.63).
Study subjects were patients with World Health Organization Performance Status scores of 0 or 1 with any PD-L1 tumor status, who received at least two cycles of conventional standard-of-care platinum-based chemoradiotherapy (CRT). They were randomized between May 2014 and April 2016 – at 1-42 days after CRT – to receive intravenous durvalumab at a dose of 10 mg/kg given intravenously every 2 weeks or placebo, and were stratified by age, gender, and smoking history.
Durvalumab was well tolerated; 30.5% and 26.1% of treatment and placebo patients, respectively, had grade 3/4 adverse events, and 15.4% and 9.8%, respectively, discontinued because of adverse events.
“There were no new safety signals with this longer follow-up,” Dr. Antonia said.
After study treatment ended, 41% and 54% in the groups, respectively, received additional anticancer therapy, and 8% and 22.4%, respectively, received additional immunotherapy, he noted.
The results are not only statistically significant, but clinically meaningful, and they offer new hope for patients with a disease that, in those who receive chemoradiotherapy, has a 3-year survival rate of only about 27%, he said.
During a press briefing at the conference, moderator Frances Shepherd, MD, a medical oncologist at Princess Margaret Cancer Centre in Toronto and a past president of the International Association for the Study of Lung Cancer, called the results “very exciting” given that this type of cancer represents about a third of all lung cancers and therefore affects an “enormous number of patients in Canada and globally.”
The PACIFIC trial was sponsored by AstraZeneca. Dr. Antonia reported being a speaker or advisory board member or receiving funding support from AstraZeneca and numerous other companies. Dr. Shepherd reported receiving honoraria and support from AstraZeneca and others. She is a speaker or advisory board member for Eli Lilly, AstraZeneca, and Merck, and she has ownership Interest in Eli Lilly and AstraZeneca.
SOURCE: Antonia S et al., WCLC 2018 Abstract PL02.01.
TORONTO – The programmed death-ligand 1 (PD-L1) inhibitor durvalumab significantly improves overall survival in patients with stage III unresectable non–small-cell lung cancer without progression after chemoradiotherapy, according to updated results from the global phase 3 PACIFIC study.
The findings, presented at the World Conference on Lung Cancer, follow a prior report from the study showing improved progression-free survival (PFS) in durvalumab-treated patients (stratified hazard ratio, 0.52), and together these survival benefits mark the first major advance in this disease setting in decades,” Scott J. Antonia, MD, reported at the conference, sponsored by the International Association for the Study of Lung Cancer (IASLC).
“The fact is this is a new standard of care treatment for the patients with this disease,” he said, adding that “in all likelihood we are improving the cure rate for the patients with this disease.”
The findings were published simultaneously in the New England Journal of Medicine.
Overall survival at a median follow-up of 25.2 months in 473 patients randomized to receive durvalumab was significantly greater than among 236 who received placebo (stratified HR, 0.68; median survival not reached vs. 28.7 months in the groups, respectively), said Dr. Antonia of the H. Lee Moffitt Cancer Center and Research Institute, and professor of oncologic sciences at the University of South Florida, Tampa.
Durvalumab also improved overall survival in all prespecified subgroups, and PFS was similar to that in previous reports (stratified HR 0.51; median of 17.2 vs. 5.6 months with durvalumab and placebo, respectively), he said, noting that “interestingly, patients who were nonsmokers did benefit from durvalumab.”
This is notable because prior research suggests that never-smokers with advanced stage cancer have less of a chance of responding to immunotherapy (although they should still be offered immunotherapy), he explained.
“Also interestingly, it appears as if cisplatin was the better drug to use in the conventional therapy portion of the treatment,” he said.
Durvalumab also provided continued improvement vs. placebo in time to death or distant metastasis (stratified HR, 0.53), time to second progression (stratified HR, 0.58), time to first subsequent therapy or death (stratified HR, 0.58), and time to second subsequent therapy or death (stratified HR, 0.63).
Study subjects were patients with World Health Organization Performance Status scores of 0 or 1 with any PD-L1 tumor status, who received at least two cycles of conventional standard-of-care platinum-based chemoradiotherapy (CRT). They were randomized between May 2014 and April 2016 – at 1-42 days after CRT – to receive intravenous durvalumab at a dose of 10 mg/kg given intravenously every 2 weeks or placebo, and were stratified by age, gender, and smoking history.
Durvalumab was well tolerated; 30.5% and 26.1% of treatment and placebo patients, respectively, had grade 3/4 adverse events, and 15.4% and 9.8%, respectively, discontinued because of adverse events.
“There were no new safety signals with this longer follow-up,” Dr. Antonia said.
After study treatment ended, 41% and 54% in the groups, respectively, received additional anticancer therapy, and 8% and 22.4%, respectively, received additional immunotherapy, he noted.
The results are not only statistically significant, but clinically meaningful, and they offer new hope for patients with a disease that, in those who receive chemoradiotherapy, has a 3-year survival rate of only about 27%, he said.
During a press briefing at the conference, moderator Frances Shepherd, MD, a medical oncologist at Princess Margaret Cancer Centre in Toronto and a past president of the International Association for the Study of Lung Cancer, called the results “very exciting” given that this type of cancer represents about a third of all lung cancers and therefore affects an “enormous number of patients in Canada and globally.”
The PACIFIC trial was sponsored by AstraZeneca. Dr. Antonia reported being a speaker or advisory board member or receiving funding support from AstraZeneca and numerous other companies. Dr. Shepherd reported receiving honoraria and support from AstraZeneca and others. She is a speaker or advisory board member for Eli Lilly, AstraZeneca, and Merck, and she has ownership Interest in Eli Lilly and AstraZeneca.
SOURCE: Antonia S et al., WCLC 2018 Abstract PL02.01.
TORONTO – The programmed death-ligand 1 (PD-L1) inhibitor durvalumab significantly improves overall survival in patients with stage III unresectable non–small-cell lung cancer without progression after chemoradiotherapy, according to updated results from the global phase 3 PACIFIC study.
The findings, presented at the World Conference on Lung Cancer, follow a prior report from the study showing improved progression-free survival (PFS) in durvalumab-treated patients (stratified hazard ratio, 0.52), and together these survival benefits mark the first major advance in this disease setting in decades,” Scott J. Antonia, MD, reported at the conference, sponsored by the International Association for the Study of Lung Cancer (IASLC).
“The fact is this is a new standard of care treatment for the patients with this disease,” he said, adding that “in all likelihood we are improving the cure rate for the patients with this disease.”
The findings were published simultaneously in the New England Journal of Medicine.
Overall survival at a median follow-up of 25.2 months in 473 patients randomized to receive durvalumab was significantly greater than among 236 who received placebo (stratified HR, 0.68; median survival not reached vs. 28.7 months in the groups, respectively), said Dr. Antonia of the H. Lee Moffitt Cancer Center and Research Institute, and professor of oncologic sciences at the University of South Florida, Tampa.
Durvalumab also improved overall survival in all prespecified subgroups, and PFS was similar to that in previous reports (stratified HR 0.51; median of 17.2 vs. 5.6 months with durvalumab and placebo, respectively), he said, noting that “interestingly, patients who were nonsmokers did benefit from durvalumab.”
This is notable because prior research suggests that never-smokers with advanced stage cancer have less of a chance of responding to immunotherapy (although they should still be offered immunotherapy), he explained.
“Also interestingly, it appears as if cisplatin was the better drug to use in the conventional therapy portion of the treatment,” he said.
Durvalumab also provided continued improvement vs. placebo in time to death or distant metastasis (stratified HR, 0.53), time to second progression (stratified HR, 0.58), time to first subsequent therapy or death (stratified HR, 0.58), and time to second subsequent therapy or death (stratified HR, 0.63).
Study subjects were patients with World Health Organization Performance Status scores of 0 or 1 with any PD-L1 tumor status, who received at least two cycles of conventional standard-of-care platinum-based chemoradiotherapy (CRT). They were randomized between May 2014 and April 2016 – at 1-42 days after CRT – to receive intravenous durvalumab at a dose of 10 mg/kg given intravenously every 2 weeks or placebo, and were stratified by age, gender, and smoking history.
Durvalumab was well tolerated; 30.5% and 26.1% of treatment and placebo patients, respectively, had grade 3/4 adverse events, and 15.4% and 9.8%, respectively, discontinued because of adverse events.
“There were no new safety signals with this longer follow-up,” Dr. Antonia said.
After study treatment ended, 41% and 54% in the groups, respectively, received additional anticancer therapy, and 8% and 22.4%, respectively, received additional immunotherapy, he noted.
The results are not only statistically significant, but clinically meaningful, and they offer new hope for patients with a disease that, in those who receive chemoradiotherapy, has a 3-year survival rate of only about 27%, he said.
During a press briefing at the conference, moderator Frances Shepherd, MD, a medical oncologist at Princess Margaret Cancer Centre in Toronto and a past president of the International Association for the Study of Lung Cancer, called the results “very exciting” given that this type of cancer represents about a third of all lung cancers and therefore affects an “enormous number of patients in Canada and globally.”
The PACIFIC trial was sponsored by AstraZeneca. Dr. Antonia reported being a speaker or advisory board member or receiving funding support from AstraZeneca and numerous other companies. Dr. Shepherd reported receiving honoraria and support from AstraZeneca and others. She is a speaker or advisory board member for Eli Lilly, AstraZeneca, and Merck, and she has ownership Interest in Eli Lilly and AstraZeneca.
SOURCE: Antonia S et al., WCLC 2018 Abstract PL02.01.
REPORTING FROM WCLC 2018
Key clinical point: Durvalumab improves survival in stage III unresectable NSCLC patients without progression after CRT.
Major finding: Median overall survival not reached vs. 28.7 months for durvalumab compared with placebo (stratified HR, 0.58).
Study details: The global, randomized, placebo-controlled phase 3 PACIFIC trial of 709 patients.
Disclosures: The PACIFIC trial was sponsored by AstraZeneca. Dr. Antonia reported being a speaker or advisory board member or receiving funding support from AstraZeneca and numerous other companies. Dr. Shepherd reported receiving honoraria and support from AstraZeneca and others. She is a speaker or advisory board member for Eli Lilly, AstraZeneca, and Merck, and she has ownership Interest in Eli Lilly and AstraZeneca.
Source: Antonia S et al. WCLC 2018 Abstract PL02.01.
Erythematous Verrucous Plaque on the Hand
The Diagnosis: Chromomycosis
Skin scrapings revealed brownish sclerotic bodies. A review of the skin biopsy performed 4 years prior showed florid pseudoepitheliomatous hyperplasia overlying dense mixed inflammatory infiltrates of predominantly granulomatous microabscesses in the dermis. Numerous sclerotic bodies were evident within multinucleated giant cells and scattered among epidermal and dermal microabscesses (Figure). Few atypical basal keratinocytes were noted, but frank pleomorphism and aberrant mitosis was absent.
Chromomycosis is a chronic subcutaneous fungal infection caused by pigmented (dematiaceous) fungi growing in soil, decaying vegetables, and rotting wood. Infection usually occurs via traumatic inoculation from splinters and thorns. Some of the agents responsible include Fonsecaea pedrosoi, Cladophialophora carrionii, and Phialophora verrucosa.1
Diverse cutaneous manifestations have been observed with 5 different clinical forms: nodules, verrucous hyperkeratotic plaques, cicatricial lesions with central sparing, scaly plaques, and tumoral (cauliflowerlike) lesions.2 Of these clinical presentations, verrucous hyperkeratotic plaques are the most common, as seen in our patient. However, this presentation is not exclusive to chromomycosis because many conditions appear similarly, including sporotrichosis, nontuberculous mycobacterial infection, tuberculosis verrucosa cutis, and squamous cell carcinoma (SCC). The presence of small ulcerations may appear as the black dots seen on the plaques of chromomycosis, distinguishing chromomycosis from other conditions. Although this feature may be a fundamental clue for diagnosis, it should be emphasized that in many occasions, clinical differences between chromomycosis and its differentials are subtle. A study involving 9 patients with chromomycosis reported that only 1 was given the initial diagnosis of mycosis. Six patients initially were diagnosed with cutaneous malignancies, 1 patient with viral warts, and another patient with ganglion.3 Therefore, unless there is a high index of suspicion, these conditions may easily be mistaken for others by clinicians who are unfamiliar with their presentations, particularly in the setting of a busy clinic.
Chromomycosis routinely is diagnosed based on histologic examination and culture. Apart from sclerotic bodies, other histopathologic features include an inflammatory infiltrate characterized by neutrophilic microabscesses, multinucleated cells, fibrosis, acanthosis, papillomatosis, hyperkeratosis, and pseudoepitheliomatous hyperplasia (PEH).2 Pseudoepitheliomatous hyperplasia is an exaggerated proliferation of the epidermis, usually secondary to chronic inflammatory skin conditions.4 Because most verrucous lesions are thought to be neoplastic and carcinomas more commonly are seen and expected in dermatopathology, PEH can sometimes be mistaken for SCC. At times, the squamous epithelium of PEH can appear infiltrative, giving the illusion of well-differentiated SCC.5 However, absence of marked cellular atypia and abnormal mitotic activity should suggest otherwise. Thorough scrutiny for a concomitant infective process is necessary to avoid the overdiagnosis of SCC. Special stains for infectious agents such as periodic acid-Schiff and Grocott-Gomori methenamine-silver for fungal spores and Ziehl-Neelsen for acid-fast bacilli may reveal infectious organisms. Multilevel sections of deeper levels also may be essential to uncover sparse organisms.6
There is no standard treatment of chromomycosis. Some treatment options are available based on few open clinical studies and expert opinions. Systemic antifungals such as itraconazole or terbinafine most commonly are used with 15% to 80% cure rates.7 In invasive refractory cases, a combination of itraconazole and terbinafine has been employed as salvage therapy. Recently, the use of newer azoles such as posaconazole is favored due to its expanded-spectrum profile along with better pharmacodynamics and pharmacokinetic profile versus itraconazole. Physical methods such as cryotherapy, heat therapy, laser therapy, and photodynamic therapy frequently are practiced in conjunction with systemic antifungal therapy.8 Surgical procedures such as photocoagulation, Mohs micrographic surgery, and curettage sometimes are recommended for smaller well-defined lesions. Amputation, however, is rarely ever indicated, as there rarely is deep tissue involvement.2
Our case highlights the importance of clinicopathologic correlation in diagnosing squamous epithelial lesions. A high index of clinical suspicion and a wider list of differential diagnoses of verrucous plaques are necessary to minimize pitfalls in diagnosing lesions with squamous proliferation and therefore reduces the need for unnecessary interventions.
- Queiroz-Telles F, Esterre P, Perez-Blanco M, et al. Chromoblastomycosis: an overview of clinical manifestations, diagnosis and treatment. Med Mycol. 2009;47:3-15.
- Krzyściak PM, Pindycka-Piaszczyńska M, Piaszczyński M. Chromoblastomycosis. Postepy Dermatol Allergol. 2014;31:310-321.
- Jayalakshmi P, Looi LM, Soo-Hoo TS. Chromoblastomycosis in Malaysia. Mycopathologica. 1990;109:27-31.
- Zayour M, Lazova R. Pseudoepitheliomatous hyperplasia: a review. Am J Dermatopathol. 2011;33:112-126.
- El-Khoury J, Kibbi AG, Abbas O. Mucocutaneous pseudoepitheliomatous hyperplasia: a review. Am J Dermatopathol. 2012;34:165-175.
- Tan KB, Tan SH, Aw DC, et al. Simulators of squamous cell carcinoma of the skin: diagnostic challenges on small biopsies and clinicopathological correlation [published online June 25, 2013]. J Skin Cancer. 2013;2013:752864.
- Queiroz-Telles F, Santos DW. Challenges in the therapy of chromoblastomycosis. Mycopathologia. 2013;175:477-488.
- Queiroz-Telles F, de Hoog S, Santos DW, et al. Chromoblastomycosis. Clin Microbiol Rev. 2017;30:233-276.
The Diagnosis: Chromomycosis
Skin scrapings revealed brownish sclerotic bodies. A review of the skin biopsy performed 4 years prior showed florid pseudoepitheliomatous hyperplasia overlying dense mixed inflammatory infiltrates of predominantly granulomatous microabscesses in the dermis. Numerous sclerotic bodies were evident within multinucleated giant cells and scattered among epidermal and dermal microabscesses (Figure). Few atypical basal keratinocytes were noted, but frank pleomorphism and aberrant mitosis was absent.
Chromomycosis is a chronic subcutaneous fungal infection caused by pigmented (dematiaceous) fungi growing in soil, decaying vegetables, and rotting wood. Infection usually occurs via traumatic inoculation from splinters and thorns. Some of the agents responsible include Fonsecaea pedrosoi, Cladophialophora carrionii, and Phialophora verrucosa.1
Diverse cutaneous manifestations have been observed with 5 different clinical forms: nodules, verrucous hyperkeratotic plaques, cicatricial lesions with central sparing, scaly plaques, and tumoral (cauliflowerlike) lesions.2 Of these clinical presentations, verrucous hyperkeratotic plaques are the most common, as seen in our patient. However, this presentation is not exclusive to chromomycosis because many conditions appear similarly, including sporotrichosis, nontuberculous mycobacterial infection, tuberculosis verrucosa cutis, and squamous cell carcinoma (SCC). The presence of small ulcerations may appear as the black dots seen on the plaques of chromomycosis, distinguishing chromomycosis from other conditions. Although this feature may be a fundamental clue for diagnosis, it should be emphasized that in many occasions, clinical differences between chromomycosis and its differentials are subtle. A study involving 9 patients with chromomycosis reported that only 1 was given the initial diagnosis of mycosis. Six patients initially were diagnosed with cutaneous malignancies, 1 patient with viral warts, and another patient with ganglion.3 Therefore, unless there is a high index of suspicion, these conditions may easily be mistaken for others by clinicians who are unfamiliar with their presentations, particularly in the setting of a busy clinic.
Chromomycosis routinely is diagnosed based on histologic examination and culture. Apart from sclerotic bodies, other histopathologic features include an inflammatory infiltrate characterized by neutrophilic microabscesses, multinucleated cells, fibrosis, acanthosis, papillomatosis, hyperkeratosis, and pseudoepitheliomatous hyperplasia (PEH).2 Pseudoepitheliomatous hyperplasia is an exaggerated proliferation of the epidermis, usually secondary to chronic inflammatory skin conditions.4 Because most verrucous lesions are thought to be neoplastic and carcinomas more commonly are seen and expected in dermatopathology, PEH can sometimes be mistaken for SCC. At times, the squamous epithelium of PEH can appear infiltrative, giving the illusion of well-differentiated SCC.5 However, absence of marked cellular atypia and abnormal mitotic activity should suggest otherwise. Thorough scrutiny for a concomitant infective process is necessary to avoid the overdiagnosis of SCC. Special stains for infectious agents such as periodic acid-Schiff and Grocott-Gomori methenamine-silver for fungal spores and Ziehl-Neelsen for acid-fast bacilli may reveal infectious organisms. Multilevel sections of deeper levels also may be essential to uncover sparse organisms.6
There is no standard treatment of chromomycosis. Some treatment options are available based on few open clinical studies and expert opinions. Systemic antifungals such as itraconazole or terbinafine most commonly are used with 15% to 80% cure rates.7 In invasive refractory cases, a combination of itraconazole and terbinafine has been employed as salvage therapy. Recently, the use of newer azoles such as posaconazole is favored due to its expanded-spectrum profile along with better pharmacodynamics and pharmacokinetic profile versus itraconazole. Physical methods such as cryotherapy, heat therapy, laser therapy, and photodynamic therapy frequently are practiced in conjunction with systemic antifungal therapy.8 Surgical procedures such as photocoagulation, Mohs micrographic surgery, and curettage sometimes are recommended for smaller well-defined lesions. Amputation, however, is rarely ever indicated, as there rarely is deep tissue involvement.2
Our case highlights the importance of clinicopathologic correlation in diagnosing squamous epithelial lesions. A high index of clinical suspicion and a wider list of differential diagnoses of verrucous plaques are necessary to minimize pitfalls in diagnosing lesions with squamous proliferation and therefore reduces the need for unnecessary interventions.
The Diagnosis: Chromomycosis
Skin scrapings revealed brownish sclerotic bodies. A review of the skin biopsy performed 4 years prior showed florid pseudoepitheliomatous hyperplasia overlying dense mixed inflammatory infiltrates of predominantly granulomatous microabscesses in the dermis. Numerous sclerotic bodies were evident within multinucleated giant cells and scattered among epidermal and dermal microabscesses (Figure). Few atypical basal keratinocytes were noted, but frank pleomorphism and aberrant mitosis was absent.
Chromomycosis is a chronic subcutaneous fungal infection caused by pigmented (dematiaceous) fungi growing in soil, decaying vegetables, and rotting wood. Infection usually occurs via traumatic inoculation from splinters and thorns. Some of the agents responsible include Fonsecaea pedrosoi, Cladophialophora carrionii, and Phialophora verrucosa.1
Diverse cutaneous manifestations have been observed with 5 different clinical forms: nodules, verrucous hyperkeratotic plaques, cicatricial lesions with central sparing, scaly plaques, and tumoral (cauliflowerlike) lesions.2 Of these clinical presentations, verrucous hyperkeratotic plaques are the most common, as seen in our patient. However, this presentation is not exclusive to chromomycosis because many conditions appear similarly, including sporotrichosis, nontuberculous mycobacterial infection, tuberculosis verrucosa cutis, and squamous cell carcinoma (SCC). The presence of small ulcerations may appear as the black dots seen on the plaques of chromomycosis, distinguishing chromomycosis from other conditions. Although this feature may be a fundamental clue for diagnosis, it should be emphasized that in many occasions, clinical differences between chromomycosis and its differentials are subtle. A study involving 9 patients with chromomycosis reported that only 1 was given the initial diagnosis of mycosis. Six patients initially were diagnosed with cutaneous malignancies, 1 patient with viral warts, and another patient with ganglion.3 Therefore, unless there is a high index of suspicion, these conditions may easily be mistaken for others by clinicians who are unfamiliar with their presentations, particularly in the setting of a busy clinic.
Chromomycosis routinely is diagnosed based on histologic examination and culture. Apart from sclerotic bodies, other histopathologic features include an inflammatory infiltrate characterized by neutrophilic microabscesses, multinucleated cells, fibrosis, acanthosis, papillomatosis, hyperkeratosis, and pseudoepitheliomatous hyperplasia (PEH).2 Pseudoepitheliomatous hyperplasia is an exaggerated proliferation of the epidermis, usually secondary to chronic inflammatory skin conditions.4 Because most verrucous lesions are thought to be neoplastic and carcinomas more commonly are seen and expected in dermatopathology, PEH can sometimes be mistaken for SCC. At times, the squamous epithelium of PEH can appear infiltrative, giving the illusion of well-differentiated SCC.5 However, absence of marked cellular atypia and abnormal mitotic activity should suggest otherwise. Thorough scrutiny for a concomitant infective process is necessary to avoid the overdiagnosis of SCC. Special stains for infectious agents such as periodic acid-Schiff and Grocott-Gomori methenamine-silver for fungal spores and Ziehl-Neelsen for acid-fast bacilli may reveal infectious organisms. Multilevel sections of deeper levels also may be essential to uncover sparse organisms.6
There is no standard treatment of chromomycosis. Some treatment options are available based on few open clinical studies and expert opinions. Systemic antifungals such as itraconazole or terbinafine most commonly are used with 15% to 80% cure rates.7 In invasive refractory cases, a combination of itraconazole and terbinafine has been employed as salvage therapy. Recently, the use of newer azoles such as posaconazole is favored due to its expanded-spectrum profile along with better pharmacodynamics and pharmacokinetic profile versus itraconazole. Physical methods such as cryotherapy, heat therapy, laser therapy, and photodynamic therapy frequently are practiced in conjunction with systemic antifungal therapy.8 Surgical procedures such as photocoagulation, Mohs micrographic surgery, and curettage sometimes are recommended for smaller well-defined lesions. Amputation, however, is rarely ever indicated, as there rarely is deep tissue involvement.2
Our case highlights the importance of clinicopathologic correlation in diagnosing squamous epithelial lesions. A high index of clinical suspicion and a wider list of differential diagnoses of verrucous plaques are necessary to minimize pitfalls in diagnosing lesions with squamous proliferation and therefore reduces the need for unnecessary interventions.
- Queiroz-Telles F, Esterre P, Perez-Blanco M, et al. Chromoblastomycosis: an overview of clinical manifestations, diagnosis and treatment. Med Mycol. 2009;47:3-15.
- Krzyściak PM, Pindycka-Piaszczyńska M, Piaszczyński M. Chromoblastomycosis. Postepy Dermatol Allergol. 2014;31:310-321.
- Jayalakshmi P, Looi LM, Soo-Hoo TS. Chromoblastomycosis in Malaysia. Mycopathologica. 1990;109:27-31.
- Zayour M, Lazova R. Pseudoepitheliomatous hyperplasia: a review. Am J Dermatopathol. 2011;33:112-126.
- El-Khoury J, Kibbi AG, Abbas O. Mucocutaneous pseudoepitheliomatous hyperplasia: a review. Am J Dermatopathol. 2012;34:165-175.
- Tan KB, Tan SH, Aw DC, et al. Simulators of squamous cell carcinoma of the skin: diagnostic challenges on small biopsies and clinicopathological correlation [published online June 25, 2013]. J Skin Cancer. 2013;2013:752864.
- Queiroz-Telles F, Santos DW. Challenges in the therapy of chromoblastomycosis. Mycopathologia. 2013;175:477-488.
- Queiroz-Telles F, de Hoog S, Santos DW, et al. Chromoblastomycosis. Clin Microbiol Rev. 2017;30:233-276.
- Queiroz-Telles F, Esterre P, Perez-Blanco M, et al. Chromoblastomycosis: an overview of clinical manifestations, diagnosis and treatment. Med Mycol. 2009;47:3-15.
- Krzyściak PM, Pindycka-Piaszczyńska M, Piaszczyński M. Chromoblastomycosis. Postepy Dermatol Allergol. 2014;31:310-321.
- Jayalakshmi P, Looi LM, Soo-Hoo TS. Chromoblastomycosis in Malaysia. Mycopathologica. 1990;109:27-31.
- Zayour M, Lazova R. Pseudoepitheliomatous hyperplasia: a review. Am J Dermatopathol. 2011;33:112-126.
- El-Khoury J, Kibbi AG, Abbas O. Mucocutaneous pseudoepitheliomatous hyperplasia: a review. Am J Dermatopathol. 2012;34:165-175.
- Tan KB, Tan SH, Aw DC, et al. Simulators of squamous cell carcinoma of the skin: diagnostic challenges on small biopsies and clinicopathological correlation [published online June 25, 2013]. J Skin Cancer. 2013;2013:752864.
- Queiroz-Telles F, Santos DW. Challenges in the therapy of chromoblastomycosis. Mycopathologia. 2013;175:477-488.
- Queiroz-Telles F, de Hoog S, Santos DW, et al. Chromoblastomycosis. Clin Microbiol Rev. 2017;30:233-276.
A 75-year-old retired farmer presented with an erythematous verrucous plaque on the dorsal aspect of the left hand of 4 years' duration. Superficial biopsies from the lesion 4 years prior to presentation revealed pseudoepitheliomatous hyperplasia suggestive of squamous cell carcinoma, which led to the excision of the lesion along with 2 digits of the left hand. Despite surgery, the lesions promptly recurred and continued to progress. Physical examination revealed a verrucous plaque with crusting and small ulcerations (black dots) over the extensor aspect of the left hand and forearm.
Identifying and Treating CNS Vasculitis
Often difficult to diagnose, CNS vasculitis is a serious condition that can be treated effectively if addressed early.
HILTON HEAD, SC—Vasculitis is a general term for a group of uncommon diseases involving inflammation of blood vessels, which can lead to the occlusion or destruction of the vessels and to ischemia of the tissues supplied by those vessels. CNS vasculitis can be a primary disease or occur secondary to infections or as part of a systemic vasculitis or systemic inflammatory (eg, rheumatologic) disease. Without prompt diagnosis and treatment, patients are at high risk of permanent neurologic disability or death, according to a presentation at the 41st Annual Contemporary Clinical Neurology Symposium. 
If diagnosed and treated early, CNS vasculitis has a good prognosis, but delayed intervention can result in severe morbidity or mortality, said Siddharama Pawate, MD, Associate Professor of Neurology at the Vanderbilt University Medical Center in Nashville. “You have to do extensive workups sometimes before you can make a diagnosis,” he said, citing the need for neurology, rheumatology, and infectious disease input. “Investigations include serologic testing, CSF analysis, MRI, and brain biopsy.”
Rare But With a High Risk of Morbidity
The 2012 International Chapel Hill Consensus Conference on the Nomenclature of Vasculitis adopted an extensive list of names for the numerous manifestations of vasculitis. These include the following:
• Large-vessel vasculitis (eg, giant cell arteritis [GCA])
• Medium-vessel vasculitis (eg, polyarteritis nodosa)
• Small-vessel vasculitis (eg, microscopic polyangiitis and granulomatosis with polyangiitis [Wegener’s granulomatosis])
• Variable-vessel vasculitis (eg, Behçet’s disease)
• Single-organ vasculitis (eg, primary CNS vasculitis)
• Vasculitis associated with systemic disease (eg, rheumatoid vasculitis)
• Vasculitis associated with probable etiology (eg, hepatitis B virus-associated or cancer-associated vasculitis).
CNS vasculitis may be grouped into two larger categories—infectious CNS vasculitis and immune-mediated CNS vasculitis. Dr. Pawate provided a brief overview of infectious causes of vasculitis including bacteria, mycobacteria, varicella-zoster, fungi, and neurocysticercosis, but devoted the main part of his presentation to the latter of the two categories, including a focus on primary CNS vasculitis (PCNSV), which is also known as primary angiitis of the CNS (PACNS). Dr. Pawate offered an analysis of what is entailed in the recognition, diagnosis, and treatment of CNS vasculitis in general and its immune-mediated variants more specifically.
CNS vasculitis may occur as part of a broader systemic vasculitis. GCA is a medical emergency that can cause permanent visual loss if not diagnosed and treated early. Vision loss occurs most often due to anterior ischemic optic neuropathy but also central retinal artery occlusion and posterior ischemic optic neuropathy. The American College of Rheumatology criteria for GCA diagnosis include three of the five following core features: age 50 or older at onset, new-onset headaches, temporal artery abnormality, elevated erythrocyte sedimentation rate of at least 50 mm/h, and abnormal temporal artery biopsy. High-dose steroids should be started if there is suspicion, without waiting for biopsy results. Recently, the anti-IL6 monoclonal antibody tocilizumab was approved by the FDA as a treatment for GCA. Granulomatosis with polyangiitis most often causes peripheral neuropathy, but can cause a small or medium vessel CNS vasculitis. Eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome) is characterized by the triad of asthma, hypereosinophilia, and necrotizing vasculitis, usually in that order. CNS involvement is common as part of the vasculitis. CNS vasculitis may also be seen in Behçet’s disease manifesting as dural sinus thrombosis and arterial occlusion or aneurysm.
In systemic lupus erythematosus, vasculitis has a prevalence ranging between 11% and 36%, but CNS involvement is much less common. Case reports of CNS vasculitis in patients with rheumatoid arthritis are rare.
Primary CNS Vasculitis
Primary CNS vasculitis causes inflammation of mostly small- to medium-sized leptomeningeal and parenchymal arterial vessels. It is rare—a 2007 retrospective analysis by Salvarani et al of 101 cases estimated the average annual incidence to be 2.4 cases per one million person-years. Onset tends to occur in middle age, with a median age at diagnosis of 50 and a similar frequency in males and females.
Clinical presentation of PCNSV can be acute, subacute, chronic, or recurrent. Depending on the area of the brain or spinal cord that is affected, patients can present with a wide variety of neurologic complaints. Headache is the most common symptom—found in 50% to 78% of patients—followed by altered cognition and persistent neurologic deficits. Stroke and transient ischemic attack involving multiple vascular areas occur in 30% to 50% of patients.
The diagnostic gold standard for PCNSV is brain parenchymal/leptomeningeal biopsy. The most common diagnoses are granulomatous angiitis of the CNS (58%), lymphocytic PACNS (28%), and necrotizing vasculitis (14%). More than 90% of patients have abnormalities on MRI, and the most common imaging findings are cortical and subcortical infarcts, leptomeningeal enhancement, intracranial hemorrhage, and areas of increased signal on FLAIR and T2-weighted sequences. It has been increasingly recognized that differential diagnosis for PCNSV should include reversible cerebral vasoconstriction syndrome (RCVS), which is characterized by reversible multifocal narrowing of the cerebral arteries—typically preceded by sudden, severe thunderclap headaches with or without associated neurologic deficits. RCVS typically resolves in approximately 12 weeks.
Regarding treatment for PCNSV, Dr. Pawate recommended starting with high-dose steroids—eg, IV methylprednisolone, 1,000 mg daily for five days, with a prolonged oral prednisone taper starting at 1 mg/kg/day—and six to nine months of IV cyclophosphamide pulse therapy, 500–750 mg/m2 every two to four weeks for more severe cases. Case studies have shown rituximab and mycophenolate to be effective. “I had one patient initially on cyclophosphamide for six months who we [then] maintained on mycophenolate for five years and then stopped immunosuppression,” Dr. Pawate said. “She did quite well.”
—Fred Balzac
Suggested Reading
Abdel Razek AA, Alvarez H, Bagg S, et al. Imaging spectrum of CNS vasculitis. Radiographics. 2014;34(4):873-894.
Chow FC, Marra CM, Cho TA. Cerebrovascular disease in central nervous system infections. Semin Neurol. 2011;31(3):286-306.
Hajj-Ali RA, Calabrese LH. Diagnosis and classification of central nervous system vasculitis. J Autoimmun. 2014;48-49:149-152.
Jennette JC, Falk RJ, Bacon PA, et al. 2012 revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides. Arthritis Rheum. 2013;65(1):1-11.
Salvarani C, Brown RD Jr, Calamia KT, et al. Primary central nervous system vasculitis: analysis of 101 patients. Ann Neurol. 2007;62(5):442-451.
Scolding NJ. Central nervous system vasculitis. Semin Immunopathol. 2009;31(4):527-536.
Often difficult to diagnose, CNS vasculitis is a serious condition that can be treated effectively if addressed early.
Often difficult to diagnose, CNS vasculitis is a serious condition that can be treated effectively if addressed early.
HILTON HEAD, SC—Vasculitis is a general term for a group of uncommon diseases involving inflammation of blood vessels, which can lead to the occlusion or destruction of the vessels and to ischemia of the tissues supplied by those vessels. CNS vasculitis can be a primary disease or occur secondary to infections or as part of a systemic vasculitis or systemic inflammatory (eg, rheumatologic) disease. Without prompt diagnosis and treatment, patients are at high risk of permanent neurologic disability or death, according to a presentation at the 41st Annual Contemporary Clinical Neurology Symposium.
If diagnosed and treated early, CNS vasculitis has a good prognosis, but delayed intervention can result in severe morbidity or mortality, said Siddharama Pawate, MD, Associate Professor of Neurology at the Vanderbilt University Medical Center in Nashville. “You have to do extensive workups sometimes before you can make a diagnosis,” he said, citing the need for neurology, rheumatology, and infectious disease input. “Investigations include serologic testing, CSF analysis, MRI, and brain biopsy.”
Rare But With a High Risk of Morbidity
The 2012 International Chapel Hill Consensus Conference on the Nomenclature of Vasculitis adopted an extensive list of names for the numerous manifestations of vasculitis. These include the following:
• Large-vessel vasculitis (eg, giant cell arteritis [GCA])
• Medium-vessel vasculitis (eg, polyarteritis nodosa)
• Small-vessel vasculitis (eg, microscopic polyangiitis and granulomatosis with polyangiitis [Wegener’s granulomatosis])
• Variable-vessel vasculitis (eg, Behçet’s disease)
• Single-organ vasculitis (eg, primary CNS vasculitis)
• Vasculitis associated with systemic disease (eg, rheumatoid vasculitis)
• Vasculitis associated with probable etiology (eg, hepatitis B virus-associated or cancer-associated vasculitis).
CNS vasculitis may be grouped into two larger categories—infectious CNS vasculitis and immune-mediated CNS vasculitis. Dr. Pawate provided a brief overview of infectious causes of vasculitis including bacteria, mycobacteria, varicella-zoster, fungi, and neurocysticercosis, but devoted the main part of his presentation to the latter of the two categories, including a focus on primary CNS vasculitis (PCNSV), which is also known as primary angiitis of the CNS (PACNS). Dr. Pawate offered an analysis of what is entailed in the recognition, diagnosis, and treatment of CNS vasculitis in general and its immune-mediated variants more specifically.
CNS vasculitis may occur as part of a broader systemic vasculitis. GCA is a medical emergency that can cause permanent visual loss if not diagnosed and treated early. Vision loss occurs most often due to anterior ischemic optic neuropathy but also central retinal artery occlusion and posterior ischemic optic neuropathy. The American College of Rheumatology criteria for GCA diagnosis include three of the five following core features: age 50 or older at onset, new-onset headaches, temporal artery abnormality, elevated erythrocyte sedimentation rate of at least 50 mm/h, and abnormal temporal artery biopsy. High-dose steroids should be started if there is suspicion, without waiting for biopsy results. Recently, the anti-IL6 monoclonal antibody tocilizumab was approved by the FDA as a treatment for GCA. Granulomatosis with polyangiitis most often causes peripheral neuropathy, but can cause a small or medium vessel CNS vasculitis. Eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome) is characterized by the triad of asthma, hypereosinophilia, and necrotizing vasculitis, usually in that order. CNS involvement is common as part of the vasculitis. CNS vasculitis may also be seen in Behçet’s disease manifesting as dural sinus thrombosis and arterial occlusion or aneurysm.
In systemic lupus erythematosus, vasculitis has a prevalence ranging between 11% and 36%, but CNS involvement is much less common. Case reports of CNS vasculitis in patients with rheumatoid arthritis are rare.
Primary CNS Vasculitis
Primary CNS vasculitis causes inflammation of mostly small- to medium-sized leptomeningeal and parenchymal arterial vessels. It is rare—a 2007 retrospective analysis by Salvarani et al of 101 cases estimated the average annual incidence to be 2.4 cases per one million person-years. Onset tends to occur in middle age, with a median age at diagnosis of 50 and a similar frequency in males and females.
Clinical presentation of PCNSV can be acute, subacute, chronic, or recurrent. Depending on the area of the brain or spinal cord that is affected, patients can present with a wide variety of neurologic complaints. Headache is the most common symptom—found in 50% to 78% of patients—followed by altered cognition and persistent neurologic deficits. Stroke and transient ischemic attack involving multiple vascular areas occur in 30% to 50% of patients.
The diagnostic gold standard for PCNSV is brain parenchymal/leptomeningeal biopsy. The most common diagnoses are granulomatous angiitis of the CNS (58%), lymphocytic PACNS (28%), and necrotizing vasculitis (14%). More than 90% of patients have abnormalities on MRI, and the most common imaging findings are cortical and subcortical infarcts, leptomeningeal enhancement, intracranial hemorrhage, and areas of increased signal on FLAIR and T2-weighted sequences. It has been increasingly recognized that differential diagnosis for PCNSV should include reversible cerebral vasoconstriction syndrome (RCVS), which is characterized by reversible multifocal narrowing of the cerebral arteries—typically preceded by sudden, severe thunderclap headaches with or without associated neurologic deficits. RCVS typically resolves in approximately 12 weeks.
Regarding treatment for PCNSV, Dr. Pawate recommended starting with high-dose steroids—eg, IV methylprednisolone, 1,000 mg daily for five days, with a prolonged oral prednisone taper starting at 1 mg/kg/day—and six to nine months of IV cyclophosphamide pulse therapy, 500–750 mg/m2 every two to four weeks for more severe cases. Case studies have shown rituximab and mycophenolate to be effective. “I had one patient initially on cyclophosphamide for six months who we [then] maintained on mycophenolate for five years and then stopped immunosuppression,” Dr. Pawate said. “She did quite well.”
—Fred Balzac
Suggested Reading
Abdel Razek AA, Alvarez H, Bagg S, et al. Imaging spectrum of CNS vasculitis. Radiographics. 2014;34(4):873-894.
Chow FC, Marra CM, Cho TA. Cerebrovascular disease in central nervous system infections. Semin Neurol. 2011;31(3):286-306.
Hajj-Ali RA, Calabrese LH. Diagnosis and classification of central nervous system vasculitis. J Autoimmun. 2014;48-49:149-152.
Jennette JC, Falk RJ, Bacon PA, et al. 2012 revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides. Arthritis Rheum. 2013;65(1):1-11.
Salvarani C, Brown RD Jr, Calamia KT, et al. Primary central nervous system vasculitis: analysis of 101 patients. Ann Neurol. 2007;62(5):442-451.
Scolding NJ. Central nervous system vasculitis. Semin Immunopathol. 2009;31(4):527-536.
HILTON HEAD, SC—Vasculitis is a general term for a group of uncommon diseases involving inflammation of blood vessels, which can lead to the occlusion or destruction of the vessels and to ischemia of the tissues supplied by those vessels. CNS vasculitis can be a primary disease or occur secondary to infections or as part of a systemic vasculitis or systemic inflammatory (eg, rheumatologic) disease. Without prompt diagnosis and treatment, patients are at high risk of permanent neurologic disability or death, according to a presentation at the 41st Annual Contemporary Clinical Neurology Symposium.
If diagnosed and treated early, CNS vasculitis has a good prognosis, but delayed intervention can result in severe morbidity or mortality, said Siddharama Pawate, MD, Associate Professor of Neurology at the Vanderbilt University Medical Center in Nashville. “You have to do extensive workups sometimes before you can make a diagnosis,” he said, citing the need for neurology, rheumatology, and infectious disease input. “Investigations include serologic testing, CSF analysis, MRI, and brain biopsy.”
Rare But With a High Risk of Morbidity
The 2012 International Chapel Hill Consensus Conference on the Nomenclature of Vasculitis adopted an extensive list of names for the numerous manifestations of vasculitis. These include the following:
• Large-vessel vasculitis (eg, giant cell arteritis [GCA])
• Medium-vessel vasculitis (eg, polyarteritis nodosa)
• Small-vessel vasculitis (eg, microscopic polyangiitis and granulomatosis with polyangiitis [Wegener’s granulomatosis])
• Variable-vessel vasculitis (eg, Behçet’s disease)
• Single-organ vasculitis (eg, primary CNS vasculitis)
• Vasculitis associated with systemic disease (eg, rheumatoid vasculitis)
• Vasculitis associated with probable etiology (eg, hepatitis B virus-associated or cancer-associated vasculitis).
CNS vasculitis may be grouped into two larger categories—infectious CNS vasculitis and immune-mediated CNS vasculitis. Dr. Pawate provided a brief overview of infectious causes of vasculitis including bacteria, mycobacteria, varicella-zoster, fungi, and neurocysticercosis, but devoted the main part of his presentation to the latter of the two categories, including a focus on primary CNS vasculitis (PCNSV), which is also known as primary angiitis of the CNS (PACNS). Dr. Pawate offered an analysis of what is entailed in the recognition, diagnosis, and treatment of CNS vasculitis in general and its immune-mediated variants more specifically.
CNS vasculitis may occur as part of a broader systemic vasculitis. GCA is a medical emergency that can cause permanent visual loss if not diagnosed and treated early. Vision loss occurs most often due to anterior ischemic optic neuropathy but also central retinal artery occlusion and posterior ischemic optic neuropathy. The American College of Rheumatology criteria for GCA diagnosis include three of the five following core features: age 50 or older at onset, new-onset headaches, temporal artery abnormality, elevated erythrocyte sedimentation rate of at least 50 mm/h, and abnormal temporal artery biopsy. High-dose steroids should be started if there is suspicion, without waiting for biopsy results. Recently, the anti-IL6 monoclonal antibody tocilizumab was approved by the FDA as a treatment for GCA. Granulomatosis with polyangiitis most often causes peripheral neuropathy, but can cause a small or medium vessel CNS vasculitis. Eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome) is characterized by the triad of asthma, hypereosinophilia, and necrotizing vasculitis, usually in that order. CNS involvement is common as part of the vasculitis. CNS vasculitis may also be seen in Behçet’s disease manifesting as dural sinus thrombosis and arterial occlusion or aneurysm.
In systemic lupus erythematosus, vasculitis has a prevalence ranging between 11% and 36%, but CNS involvement is much less common. Case reports of CNS vasculitis in patients with rheumatoid arthritis are rare.
Primary CNS Vasculitis
Primary CNS vasculitis causes inflammation of mostly small- to medium-sized leptomeningeal and parenchymal arterial vessels. It is rare—a 2007 retrospective analysis by Salvarani et al of 101 cases estimated the average annual incidence to be 2.4 cases per one million person-years. Onset tends to occur in middle age, with a median age at diagnosis of 50 and a similar frequency in males and females.
Clinical presentation of PCNSV can be acute, subacute, chronic, or recurrent. Depending on the area of the brain or spinal cord that is affected, patients can present with a wide variety of neurologic complaints. Headache is the most common symptom—found in 50% to 78% of patients—followed by altered cognition and persistent neurologic deficits. Stroke and transient ischemic attack involving multiple vascular areas occur in 30% to 50% of patients.
The diagnostic gold standard for PCNSV is brain parenchymal/leptomeningeal biopsy. The most common diagnoses are granulomatous angiitis of the CNS (58%), lymphocytic PACNS (28%), and necrotizing vasculitis (14%). More than 90% of patients have abnormalities on MRI, and the most common imaging findings are cortical and subcortical infarcts, leptomeningeal enhancement, intracranial hemorrhage, and areas of increased signal on FLAIR and T2-weighted sequences. It has been increasingly recognized that differential diagnosis for PCNSV should include reversible cerebral vasoconstriction syndrome (RCVS), which is characterized by reversible multifocal narrowing of the cerebral arteries—typically preceded by sudden, severe thunderclap headaches with or without associated neurologic deficits. RCVS typically resolves in approximately 12 weeks.
Regarding treatment for PCNSV, Dr. Pawate recommended starting with high-dose steroids—eg, IV methylprednisolone, 1,000 mg daily for five days, with a prolonged oral prednisone taper starting at 1 mg/kg/day—and six to nine months of IV cyclophosphamide pulse therapy, 500–750 mg/m2 every two to four weeks for more severe cases. Case studies have shown rituximab and mycophenolate to be effective. “I had one patient initially on cyclophosphamide for six months who we [then] maintained on mycophenolate for five years and then stopped immunosuppression,” Dr. Pawate said. “She did quite well.”
—Fred Balzac
Suggested Reading
Abdel Razek AA, Alvarez H, Bagg S, et al. Imaging spectrum of CNS vasculitis. Radiographics. 2014;34(4):873-894.
Chow FC, Marra CM, Cho TA. Cerebrovascular disease in central nervous system infections. Semin Neurol. 2011;31(3):286-306.
Hajj-Ali RA, Calabrese LH. Diagnosis and classification of central nervous system vasculitis. J Autoimmun. 2014;48-49:149-152.
Jennette JC, Falk RJ, Bacon PA, et al. 2012 revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides. Arthritis Rheum. 2013;65(1):1-11.
Salvarani C, Brown RD Jr, Calamia KT, et al. Primary central nervous system vasculitis: analysis of 101 patients. Ann Neurol. 2007;62(5):442-451.
Scolding NJ. Central nervous system vasculitis. Semin Immunopathol. 2009;31(4):527-536.
How to Correct a Misdiagnosis of MS
Build rapport with patients and recognize that they may be emotionally and financially invested in the diagnosis, one neurologist suggests.
HILTON HEAD, SC—Given the lack of a definitive diagnostic test for multiple sclerosis (MS), diagnosing the disease can prove difficult. When considering symptoms, signs, and MRI findings that are suggestive of MS, clinicians must rely on their clinical judgment and experience, skillful interpretation of tests, and knowledge of and willingness to consider alternative diagnoses. Because of the subjective judgments involved and the many conditions that may mimic MS, it is not surprising that physicians sometimes misdiagnose MS, said Harold Moses, MD, at Vanderbilt University’s 41st Annual Contemporary Clinical Neurology Symposium. 
A study by Solomon et al suggests ways to reduce the likelihood of misdiagnosis, said Dr. Moses, Associate Professor of Neurology at Vanderbilt University in Nashville. “Neurologists should … avoid overreliance on MRI changes as the principal support for an MS diagnosis,” he said. “Nonspecific or atypical MRI findings should be interpreted cautiously. A diagnosis of MS should not be made or reinforced in patients with psychiatric conditions without evidence for MS.”
For patients with emotional distress and psychologically based functional disability who do not meet diagnostic criteria for MS, a diagnosis of MS should be avoided. When MS remains a possibility, the patient should be informed of that fact and followed with clinical assessment and, if appropriate, MRI, Dr. Moses added. “Neurologists should be open in admitting and discussing uncertainty with patients,” he said. “It’s important to be honest in … indicating the need for further testing or observation over time. When emotional factors are thought to contribute [to a patient’s symptoms], treatments should be directed at these issues concurrently.”
First, Do No Harm
Psychiatrists and other therapists may be able to help patients when the diagnosis remains an open question. “MS disease-modifying drugs should be prescribed only for patients who have definitive evidence for MS or for those who present with classical clinically isolated syndromes—optic neuritis, transverse myelitis, and brainstem events—accompanied by appropriate changes on MRI,” Dr. Moses said.
Challenging cases include asymptomatic patients with MRI findings; patients with a first occurrence of symptoms, especially when the presentation is atypical; and patients with mimics of MS, such as vasculitis. Neurologists should be vigilant to identify mimics, particularly because these conditions may be treatable. The presence of psychiatric illness also may create challenging clinical scenarios.
“Psychologic and psychiatric factors may be present, but that patient may still have MS…. The question is, how do you tease out why that person is not doing well—that discordance, if you will, between how their MRI and exam are versus how they feel and how they are functioning.”
A Survey of Specialists
Solomon et al conducted a cross-sectional, internet-based survey of 242 MS specialists. Of the 50.4% of physicians who responded, 95% reported evaluating within the past year at least one patient who had been diagnosed with MS but who they felt strongly did not have the disease. More than 90% of respondents reported the use of disease-modifying therapy (DMT) in a proportion of these patients, and 94% found clinical encounters with these patients to be of an equal or greater challenge than making a new diagnosis of MS. A smaller proportion of respondents (14%) reported that, in some cases, they withheld telling a patient their opinion that the patient did not have MS.
As the study’s authors observed, evidence of therapeutic benefit from early initiation of DMT in patients with MS generates a sense of urgency to diagnose the disease early and begin therapy, Dr. Moses said. However, misdiagnosis in many cases may have resulted from—in place of prudent clinical and laboratory monitoring—an overreliance on MRI findings in patients with syndromes for which established MS diagnostic imaging criteria have not been validated. “Ultimately, MS remains a clinical diagnosis,” said Dr. Moses. “You use an MRI as an adjunct to help you confirm a diagnosis.”
Misdiagnosis of MS can cause serious harm. For example, conditions such as neuromyelitis optica and cervical spondylosis can lead to irreversible disability if unrecognized and inappropriately treated. Use of DMT in patients without MS exposes them to unnecessary health risks and financial costs. Dr. Moses cited the case of a 45-year-old woman who probably did not have MS but whose treatment with interferon beta-1a likely resulted in her going on dialysis. “These drugs are not benign,” he said. “[Such an outcome] is a very rare thing, but keep in mind that if a patient does not have MS, he or she should not be on MS therapy.”
Invested in the Diagnosis
As discussed by Boissy and Ford, neurologists may be inclined to use a medically inaccurate label, such as “a touch of MS,” “mild MS,” “benign MS,” or “MS by history,” when talking with patients who have received a misdiagnosis of MS, Dr. Moses said. Patients who have attributed psychogenic symptoms to misdiagnosed MS often resist a psychogenic explanation. In addition, they may be invested physically, emotionally, and financially in the diagnosis of MS—making treatment challenging for clinicians, Dr. Moses said.
Therapeutic mislabeling raises ethical issues, however. Mislabeling may expose patients to risky therapies, lead to an inappropriate use of resources, compromise the credibility of the clinician, and cause psychologic harm to the patient.
Neurologists would do better to consider scheduling multiple visits to explore psychogenic factors, as well as the patient’s fears and emotions, with the aim of developing a rapport and encouraging appropriate evaluations, Dr. Moses said. “If physicians endorse an inaccurate diagnosis, this undoubtedly conflicts with their professional obligations for truth telling, avoiding harming patients, … acting in the patient’s best interest, and stewardship of medical resources,” he said.
—Fred Balzac
Suggested Reading
Boissy AR, Ford PJ. A touch of MS: therapeutic mislabeling. Neurology. 2012;78(24):1981-1985.
Solomon AJ, Bourdette DN, Cross AH, et al. The contemporary spectrum of multiple sclerosis misdiagnosis: a multicenter study. Neurology. 2016;87(13):1393-1399.
Solomon AJ, Klein EP, Bourdette D. “Undiagnosing” multiple sclerosis: the challenge of misdiagnosis in MS. Neurology. 2012;78(24):1986-1991.
Build rapport with patients and recognize that they may be emotionally and financially invested in the diagnosis, one neurologist suggests.
Build rapport with patients and recognize that they may be emotionally and financially invested in the diagnosis, one neurologist suggests.
HILTON HEAD, SC—Given the lack of a definitive diagnostic test for multiple sclerosis (MS), diagnosing the disease can prove difficult. When considering symptoms, signs, and MRI findings that are suggestive of MS, clinicians must rely on their clinical judgment and experience, skillful interpretation of tests, and knowledge of and willingness to consider alternative diagnoses. Because of the subjective judgments involved and the many conditions that may mimic MS, it is not surprising that physicians sometimes misdiagnose MS, said Harold Moses, MD, at Vanderbilt University’s 41st Annual Contemporary Clinical Neurology Symposium.
A study by Solomon et al suggests ways to reduce the likelihood of misdiagnosis, said Dr. Moses, Associate Professor of Neurology at Vanderbilt University in Nashville. “Neurologists should … avoid overreliance on MRI changes as the principal support for an MS diagnosis,” he said. “Nonspecific or atypical MRI findings should be interpreted cautiously. A diagnosis of MS should not be made or reinforced in patients with psychiatric conditions without evidence for MS.”
For patients with emotional distress and psychologically based functional disability who do not meet diagnostic criteria for MS, a diagnosis of MS should be avoided. When MS remains a possibility, the patient should be informed of that fact and followed with clinical assessment and, if appropriate, MRI, Dr. Moses added. “Neurologists should be open in admitting and discussing uncertainty with patients,” he said. “It’s important to be honest in … indicating the need for further testing or observation over time. When emotional factors are thought to contribute [to a patient’s symptoms], treatments should be directed at these issues concurrently.”
First, Do No Harm
Psychiatrists and other therapists may be able to help patients when the diagnosis remains an open question. “MS disease-modifying drugs should be prescribed only for patients who have definitive evidence for MS or for those who present with classical clinically isolated syndromes—optic neuritis, transverse myelitis, and brainstem events—accompanied by appropriate changes on MRI,” Dr. Moses said.
Challenging cases include asymptomatic patients with MRI findings; patients with a first occurrence of symptoms, especially when the presentation is atypical; and patients with mimics of MS, such as vasculitis. Neurologists should be vigilant to identify mimics, particularly because these conditions may be treatable. The presence of psychiatric illness also may create challenging clinical scenarios.
“Psychologic and psychiatric factors may be present, but that patient may still have MS…. The question is, how do you tease out why that person is not doing well—that discordance, if you will, between how their MRI and exam are versus how they feel and how they are functioning.”
A Survey of Specialists
Solomon et al conducted a cross-sectional, internet-based survey of 242 MS specialists. Of the 50.4% of physicians who responded, 95% reported evaluating within the past year at least one patient who had been diagnosed with MS but who they felt strongly did not have the disease. More than 90% of respondents reported the use of disease-modifying therapy (DMT) in a proportion of these patients, and 94% found clinical encounters with these patients to be of an equal or greater challenge than making a new diagnosis of MS. A smaller proportion of respondents (14%) reported that, in some cases, they withheld telling a patient their opinion that the patient did not have MS.
As the study’s authors observed, evidence of therapeutic benefit from early initiation of DMT in patients with MS generates a sense of urgency to diagnose the disease early and begin therapy, Dr. Moses said. However, misdiagnosis in many cases may have resulted from—in place of prudent clinical and laboratory monitoring—an overreliance on MRI findings in patients with syndromes for which established MS diagnostic imaging criteria have not been validated. “Ultimately, MS remains a clinical diagnosis,” said Dr. Moses. “You use an MRI as an adjunct to help you confirm a diagnosis.”
Misdiagnosis of MS can cause serious harm. For example, conditions such as neuromyelitis optica and cervical spondylosis can lead to irreversible disability if unrecognized and inappropriately treated. Use of DMT in patients without MS exposes them to unnecessary health risks and financial costs. Dr. Moses cited the case of a 45-year-old woman who probably did not have MS but whose treatment with interferon beta-1a likely resulted in her going on dialysis. “These drugs are not benign,” he said. “[Such an outcome] is a very rare thing, but keep in mind that if a patient does not have MS, he or she should not be on MS therapy.”
Invested in the Diagnosis
As discussed by Boissy and Ford, neurologists may be inclined to use a medically inaccurate label, such as “a touch of MS,” “mild MS,” “benign MS,” or “MS by history,” when talking with patients who have received a misdiagnosis of MS, Dr. Moses said. Patients who have attributed psychogenic symptoms to misdiagnosed MS often resist a psychogenic explanation. In addition, they may be invested physically, emotionally, and financially in the diagnosis of MS—making treatment challenging for clinicians, Dr. Moses said.
Therapeutic mislabeling raises ethical issues, however. Mislabeling may expose patients to risky therapies, lead to an inappropriate use of resources, compromise the credibility of the clinician, and cause psychologic harm to the patient.
Neurologists would do better to consider scheduling multiple visits to explore psychogenic factors, as well as the patient’s fears and emotions, with the aim of developing a rapport and encouraging appropriate evaluations, Dr. Moses said. “If physicians endorse an inaccurate diagnosis, this undoubtedly conflicts with their professional obligations for truth telling, avoiding harming patients, … acting in the patient’s best interest, and stewardship of medical resources,” he said.
—Fred Balzac
Suggested Reading
Boissy AR, Ford PJ. A touch of MS: therapeutic mislabeling. Neurology. 2012;78(24):1981-1985.
Solomon AJ, Bourdette DN, Cross AH, et al. The contemporary spectrum of multiple sclerosis misdiagnosis: a multicenter study. Neurology. 2016;87(13):1393-1399.
Solomon AJ, Klein EP, Bourdette D. “Undiagnosing” multiple sclerosis: the challenge of misdiagnosis in MS. Neurology. 2012;78(24):1986-1991.
HILTON HEAD, SC—Given the lack of a definitive diagnostic test for multiple sclerosis (MS), diagnosing the disease can prove difficult. When considering symptoms, signs, and MRI findings that are suggestive of MS, clinicians must rely on their clinical judgment and experience, skillful interpretation of tests, and knowledge of and willingness to consider alternative diagnoses. Because of the subjective judgments involved and the many conditions that may mimic MS, it is not surprising that physicians sometimes misdiagnose MS, said Harold Moses, MD, at Vanderbilt University’s 41st Annual Contemporary Clinical Neurology Symposium.
A study by Solomon et al suggests ways to reduce the likelihood of misdiagnosis, said Dr. Moses, Associate Professor of Neurology at Vanderbilt University in Nashville. “Neurologists should … avoid overreliance on MRI changes as the principal support for an MS diagnosis,” he said. “Nonspecific or atypical MRI findings should be interpreted cautiously. A diagnosis of MS should not be made or reinforced in patients with psychiatric conditions without evidence for MS.”
For patients with emotional distress and psychologically based functional disability who do not meet diagnostic criteria for MS, a diagnosis of MS should be avoided. When MS remains a possibility, the patient should be informed of that fact and followed with clinical assessment and, if appropriate, MRI, Dr. Moses added. “Neurologists should be open in admitting and discussing uncertainty with patients,” he said. “It’s important to be honest in … indicating the need for further testing or observation over time. When emotional factors are thought to contribute [to a patient’s symptoms], treatments should be directed at these issues concurrently.”
First, Do No Harm
Psychiatrists and other therapists may be able to help patients when the diagnosis remains an open question. “MS disease-modifying drugs should be prescribed only for patients who have definitive evidence for MS or for those who present with classical clinically isolated syndromes—optic neuritis, transverse myelitis, and brainstem events—accompanied by appropriate changes on MRI,” Dr. Moses said.
Challenging cases include asymptomatic patients with MRI findings; patients with a first occurrence of symptoms, especially when the presentation is atypical; and patients with mimics of MS, such as vasculitis. Neurologists should be vigilant to identify mimics, particularly because these conditions may be treatable. The presence of psychiatric illness also may create challenging clinical scenarios.
“Psychologic and psychiatric factors may be present, but that patient may still have MS…. The question is, how do you tease out why that person is not doing well—that discordance, if you will, between how their MRI and exam are versus how they feel and how they are functioning.”
A Survey of Specialists
Solomon et al conducted a cross-sectional, internet-based survey of 242 MS specialists. Of the 50.4% of physicians who responded, 95% reported evaluating within the past year at least one patient who had been diagnosed with MS but who they felt strongly did not have the disease. More than 90% of respondents reported the use of disease-modifying therapy (DMT) in a proportion of these patients, and 94% found clinical encounters with these patients to be of an equal or greater challenge than making a new diagnosis of MS. A smaller proportion of respondents (14%) reported that, in some cases, they withheld telling a patient their opinion that the patient did not have MS.
As the study’s authors observed, evidence of therapeutic benefit from early initiation of DMT in patients with MS generates a sense of urgency to diagnose the disease early and begin therapy, Dr. Moses said. However, misdiagnosis in many cases may have resulted from—in place of prudent clinical and laboratory monitoring—an overreliance on MRI findings in patients with syndromes for which established MS diagnostic imaging criteria have not been validated. “Ultimately, MS remains a clinical diagnosis,” said Dr. Moses. “You use an MRI as an adjunct to help you confirm a diagnosis.”
Misdiagnosis of MS can cause serious harm. For example, conditions such as neuromyelitis optica and cervical spondylosis can lead to irreversible disability if unrecognized and inappropriately treated. Use of DMT in patients without MS exposes them to unnecessary health risks and financial costs. Dr. Moses cited the case of a 45-year-old woman who probably did not have MS but whose treatment with interferon beta-1a likely resulted in her going on dialysis. “These drugs are not benign,” he said. “[Such an outcome] is a very rare thing, but keep in mind that if a patient does not have MS, he or she should not be on MS therapy.”
Invested in the Diagnosis
As discussed by Boissy and Ford, neurologists may be inclined to use a medically inaccurate label, such as “a touch of MS,” “mild MS,” “benign MS,” or “MS by history,” when talking with patients who have received a misdiagnosis of MS, Dr. Moses said. Patients who have attributed psychogenic symptoms to misdiagnosed MS often resist a psychogenic explanation. In addition, they may be invested physically, emotionally, and financially in the diagnosis of MS—making treatment challenging for clinicians, Dr. Moses said.
Therapeutic mislabeling raises ethical issues, however. Mislabeling may expose patients to risky therapies, lead to an inappropriate use of resources, compromise the credibility of the clinician, and cause psychologic harm to the patient.
Neurologists would do better to consider scheduling multiple visits to explore psychogenic factors, as well as the patient’s fears and emotions, with the aim of developing a rapport and encouraging appropriate evaluations, Dr. Moses said. “If physicians endorse an inaccurate diagnosis, this undoubtedly conflicts with their professional obligations for truth telling, avoiding harming patients, … acting in the patient’s best interest, and stewardship of medical resources,” he said.
—Fred Balzac
Suggested Reading
Boissy AR, Ford PJ. A touch of MS: therapeutic mislabeling. Neurology. 2012;78(24):1981-1985.
Solomon AJ, Bourdette DN, Cross AH, et al. The contemporary spectrum of multiple sclerosis misdiagnosis: a multicenter study. Neurology. 2016;87(13):1393-1399.
Solomon AJ, Klein EP, Bourdette D. “Undiagnosing” multiple sclerosis: the challenge of misdiagnosis in MS. Neurology. 2012;78(24):1986-1991.
Study Examines Dementia Epidemiology in the LGB Population
Among older adults who are lesbian, gay, or bisexual, depression nearly triples the risk of dementia.
CHICAGO—The first large-scale analysis of dementia prevalence among sexual minorities found a rate of 8% in adults age 60 or older who are lesbian, gay, or bisexual (LGB), according to research presented at AAIC 2018.
The crude dementia prevalence was lower than the 9% prevalence among a heterosexual comparator group. Subjects in the LGB group, however, were younger, more likely to be male, and more likely to have a college education, compared with subjects in the heterosexual group, said Jason Flatt, PhD. 
The analysis of a large California health care database is the first step in learning more about dementia in this diverse population, said Dr. Flatt, Assistant Professor at the Institute for Health & Aging at the University of California, San Francisco.
A Gap in the Literature
Between two million and three million people age 60 or older in the United States identify as LGB. “With the continued aging of our entire population, we expect this number to increase to about six million by 2040,” Dr. Flatt said. “Given the gaps in collection of sexual orientation and gender identification, we have not been able to look at this issue before.”
Sexual minorities may face unique dementia risks. They are less likely to marry and have children than are heterosexuals, and twice as likely to live alone. “They often have little or no caregiver support, and are likely to have experienced stigma, discrimination, trauma, and high lifelong stress,” he said. These experiences make the LGB population less likely to seek out medical care. “All of these things impact health over the life course,” he said.
To examine the prevalence of dementia and potential risk factors in a sample of LGB older adults, Dr. Flatt and his colleagues analyzed data from the Kaiser Permanente Research Program on Genes, Environment, and Health. Their study examined dementia prevalence and comorbidities among 4,337 LGB subjects and 195,264 heterosexual subjects aged 60 or older. Dementia diagnoses occurred between 1996 and 2015, and the mean follow-up time was nine years. A quarter of the LGB sample identified as lesbian, 37% identified as gay men, and 38% identified as bisexual. Depression was more common in the LGB group (35% vs 28%), as was posttraumatic stress disorder (1.9% vs 1%). Both are well-documented risk factors for dementia.
The LGB group had a younger mean age, compared with the heterosexual group (69 vs 71). In addition, a greater percentage of LGB subjects identified as male (63% vs 44%) and had a college education (62% vs 40%).
Other risk factors such as hypertension, stroke, and heart disease did not significantly differ between the groups. Dr. Flatt and his associates plan to examine midlife obesity, physical inactivity, and low educational attainment in a future analysis.
Depression Nearly Tripled the Risk
A dementia diagnosis occurred in 343 subjects (7.9%) in the LGB group and in 18,060 subjects (9.2%) in the heterosexual group.
Higher education did not seem to be as protective in the LGB population, Dr. Flatt said.
In a regression analysis that adjusted for age and education, depression almost tripled the risk of dementia among sexual minorities (odds ratio, 2.7). Depression was also a significant dementia risk factor for heterosexual subjects (odds ratio, 2.5).
These initial findings highlight the need for more research into this population, Dr. Flatt said.
“We need to provide more LGB-affirming health care services, and this means training health care providers to meet these needs,” he said. Such efforts might include improved community outreach that could result in earlier detection and treatment, as well as training medical staff to provide more culturally sensitive care.
—Michele G. Sullivan
Among older adults who are lesbian, gay, or bisexual, depression nearly triples the risk of dementia.
Among older adults who are lesbian, gay, or bisexual, depression nearly triples the risk of dementia.
CHICAGO—The first large-scale analysis of dementia prevalence among sexual minorities found a rate of 8% in adults age 60 or older who are lesbian, gay, or bisexual (LGB), according to research presented at AAIC 2018.
The crude dementia prevalence was lower than the 9% prevalence among a heterosexual comparator group. Subjects in the LGB group, however, were younger, more likely to be male, and more likely to have a college education, compared with subjects in the heterosexual group, said Jason Flatt, PhD.
The analysis of a large California health care database is the first step in learning more about dementia in this diverse population, said Dr. Flatt, Assistant Professor at the Institute for Health & Aging at the University of California, San Francisco.
A Gap in the Literature
Between two million and three million people age 60 or older in the United States identify as LGB. “With the continued aging of our entire population, we expect this number to increase to about six million by 2040,” Dr. Flatt said. “Given the gaps in collection of sexual orientation and gender identification, we have not been able to look at this issue before.”
Sexual minorities may face unique dementia risks. They are less likely to marry and have children than are heterosexuals, and twice as likely to live alone. “They often have little or no caregiver support, and are likely to have experienced stigma, discrimination, trauma, and high lifelong stress,” he said. These experiences make the LGB population less likely to seek out medical care. “All of these things impact health over the life course,” he said.
To examine the prevalence of dementia and potential risk factors in a sample of LGB older adults, Dr. Flatt and his colleagues analyzed data from the Kaiser Permanente Research Program on Genes, Environment, and Health. Their study examined dementia prevalence and comorbidities among 4,337 LGB subjects and 195,264 heterosexual subjects aged 60 or older. Dementia diagnoses occurred between 1996 and 2015, and the mean follow-up time was nine years. A quarter of the LGB sample identified as lesbian, 37% identified as gay men, and 38% identified as bisexual. Depression was more common in the LGB group (35% vs 28%), as was posttraumatic stress disorder (1.9% vs 1%). Both are well-documented risk factors for dementia.
The LGB group had a younger mean age, compared with the heterosexual group (69 vs 71). In addition, a greater percentage of LGB subjects identified as male (63% vs 44%) and had a college education (62% vs 40%).
Other risk factors such as hypertension, stroke, and heart disease did not significantly differ between the groups. Dr. Flatt and his associates plan to examine midlife obesity, physical inactivity, and low educational attainment in a future analysis.
Depression Nearly Tripled the Risk
A dementia diagnosis occurred in 343 subjects (7.9%) in the LGB group and in 18,060 subjects (9.2%) in the heterosexual group.
Higher education did not seem to be as protective in the LGB population, Dr. Flatt said.
In a regression analysis that adjusted for age and education, depression almost tripled the risk of dementia among sexual minorities (odds ratio, 2.7). Depression was also a significant dementia risk factor for heterosexual subjects (odds ratio, 2.5).
These initial findings highlight the need for more research into this population, Dr. Flatt said.
“We need to provide more LGB-affirming health care services, and this means training health care providers to meet these needs,” he said. Such efforts might include improved community outreach that could result in earlier detection and treatment, as well as training medical staff to provide more culturally sensitive care.
—Michele G. Sullivan
CHICAGO—The first large-scale analysis of dementia prevalence among sexual minorities found a rate of 8% in adults age 60 or older who are lesbian, gay, or bisexual (LGB), according to research presented at AAIC 2018.
The crude dementia prevalence was lower than the 9% prevalence among a heterosexual comparator group. Subjects in the LGB group, however, were younger, more likely to be male, and more likely to have a college education, compared with subjects in the heterosexual group, said Jason Flatt, PhD.
The analysis of a large California health care database is the first step in learning more about dementia in this diverse population, said Dr. Flatt, Assistant Professor at the Institute for Health & Aging at the University of California, San Francisco.
A Gap in the Literature
Between two million and three million people age 60 or older in the United States identify as LGB. “With the continued aging of our entire population, we expect this number to increase to about six million by 2040,” Dr. Flatt said. “Given the gaps in collection of sexual orientation and gender identification, we have not been able to look at this issue before.”
Sexual minorities may face unique dementia risks. They are less likely to marry and have children than are heterosexuals, and twice as likely to live alone. “They often have little or no caregiver support, and are likely to have experienced stigma, discrimination, trauma, and high lifelong stress,” he said. These experiences make the LGB population less likely to seek out medical care. “All of these things impact health over the life course,” he said.
To examine the prevalence of dementia and potential risk factors in a sample of LGB older adults, Dr. Flatt and his colleagues analyzed data from the Kaiser Permanente Research Program on Genes, Environment, and Health. Their study examined dementia prevalence and comorbidities among 4,337 LGB subjects and 195,264 heterosexual subjects aged 60 or older. Dementia diagnoses occurred between 1996 and 2015, and the mean follow-up time was nine years. A quarter of the LGB sample identified as lesbian, 37% identified as gay men, and 38% identified as bisexual. Depression was more common in the LGB group (35% vs 28%), as was posttraumatic stress disorder (1.9% vs 1%). Both are well-documented risk factors for dementia.
The LGB group had a younger mean age, compared with the heterosexual group (69 vs 71). In addition, a greater percentage of LGB subjects identified as male (63% vs 44%) and had a college education (62% vs 40%).
Other risk factors such as hypertension, stroke, and heart disease did not significantly differ between the groups. Dr. Flatt and his associates plan to examine midlife obesity, physical inactivity, and low educational attainment in a future analysis.
Depression Nearly Tripled the Risk
A dementia diagnosis occurred in 343 subjects (7.9%) in the LGB group and in 18,060 subjects (9.2%) in the heterosexual group.
Higher education did not seem to be as protective in the LGB population, Dr. Flatt said.
In a regression analysis that adjusted for age and education, depression almost tripled the risk of dementia among sexual minorities (odds ratio, 2.7). Depression was also a significant dementia risk factor for heterosexual subjects (odds ratio, 2.5).
These initial findings highlight the need for more research into this population, Dr. Flatt said.
“We need to provide more LGB-affirming health care services, and this means training health care providers to meet these needs,” he said. Such efforts might include improved community outreach that could result in earlier detection and treatment, as well as training medical staff to provide more culturally sensitive care.
—Michele G. Sullivan
Alan M. Rapoport, MD, on Medication Overuse Headache
Neurology Reviews recently shared two poll questions with our Facebook followers about treatment medication overuse headache (MOH). I was very interested to see the results of our poll. While the number of responses was somewhat low, we do get some sense of what respondents are saying. In this commentary, I will first tell you my perspective on the answers and then we will see what some other headache specialists say about the answers to these questions.
Poll Results:
Can MOH be treated with preventive medications without detoxification?
33 votes
YES, 39%
NO, 61%
Can MOH be treated with the new preventive medications (the monoclonal antibodies to CGRP ligand or receptor) without detoxification?
26 votes
YES, 38%
NO, 62%
My Commentary:
Let me explain in more detail my thoughts on the first question, “Can MOH be treated with preventive medications without detoxification?”
If a patient had the diagnosis of MOH – meaning 15 or more headache days per month for at least 3 months, with use of stronger medications (triptans, ergots, opiates, butalbital-containing medications) for 10 days per month or milder treatment (aspirin, acetaminophen, nonsteroidal anti-inflammatory drugs [NSAIDs]) for 15 days per month – can they improve by being put on a traditional preventive medication without intentionally reducing their overused acute medications by a detoxification protocol ordered by a doctor or nurse?
Only 39% of our audience said yes. Yet some studies have shown that patients placed on onabotulinumtoxinA or topiramate might improve without them going through a detoxification of the overused medications. As a physician, I would suggest simultaneously decreasing in their acute medications. I think in some cases this approach creates additional improvement and makes the patient feel better. It would be better for their quality of life, as well as for their kidneys and possibly even their brains.
Here are my thoughts on the second question, “Can MOH be treated with the new preventive medications (the monoclonal antibodies to CGRP ligand or receptor), without detoxification?”
If a patient has MOH, can you expect them to improve after being placed on 1 of the 4 monoclonal antibodies to CGRP ligand or its receptor – all of which are either recently approved or currently in development – without suggesting that they decrease their overused acute care medications? Note that erenumab (Aimovig-aaoe) has been approved by the FDA and marketed as of the time of this writing; we expect 2 more products to be approved very soon.
Almost an identical percentage of our audience (38%) said yes. There is evidence in published clinical trials that those patients given these new medications did about as well with or without the presence of MOH, and both groups did better than the placebo patients. Note that most trials prohibited overuse of opiates and butalbital.
I am a firm believer of detoxifying patients from their overused over-the-counter (OTC) or prescription medications. I believe that opiates and butalbital-containing medications, when overused, are worse for patients than OTCs, NSAIDs, ergot and triptans, but all of these can cause MOH. There are many studies showing that both inpatient and outpatient detoxification alone can really help. However, it is difficult to detoxify patients and some refuse to try this approach.
So, what should we do as physicians? If a patient has MOH, I educate them, try to detoxify them slowly on an outpatient basis, and if I feel it will help, start them on a preventive medication, even before the detoxification begins so they can reach therapeutic levels. In the future, will I use one of the standard preventives, approved or off-label, for migraine prevention (beta blockers, topiramate and other anticonvulsants, antidepressants, angiotensin receptor blockers, onabotulinumtoxinA and others)? It remains to be seen. I am leaning towards the anti CGRP ligand and receptor monoclonal antibodies and preventive small molecule oral CGRP receptor blockers. While that might be enough to start with, I will continue explaining to my patients why they should actively begin a slow detoxification.
Let us see what some headache specialists said about both questions.
Robert Cowan, MD, FAAN:
There have been studies that show migraine can improve without the discontinuation of medication overuse. But that is not what the question asks. The question as posed is whether MOH can be treated with a preventive medication without detoxification. Since the diagnosis of MOH has, in the past, required the cessation of overuse leading to an improvement in the underlying headache, then technically, the answer would be “no.” But that being said, there is ample evidence that the number of headache days/months and other measures of headache can, in fact, improve with the introduction of a preventive, along with other measures such as lifestyle modification. The other ambiguity in the question has to do with what is meant by “detoxification.” Is this a hospital-based detox, or is a gradual decrease in the offending medicine in combination with the addition of a preventive, still considered “detoxification?” Also, does the response imply a sequential relationship between the detoxification and initiation of the preventive? Without further clarification, this response ratio to the question is very difficult to interpret.
There is animal data that suggests acute migraine medications may promote MOH in susceptible individuals through CGRP-dependent mechanisms and anti-CGRP antibodies may be useful for the MOH (Cephalalgia. 2017;37(6):560-570. doi: 10.1177/0333102416650702). While there are no published CGRP antibody studies that did not exclude MOH patients to my knowledge, an abstract by Silberstein et al at the recent AHS Scientific Meeting reported decreased use of overused medication with fremanazumab (Headache. 2018;58(S2):76-78).
Ira Turner, MD
There is clear data to suggest that it is not necessary to detoxify these patients before starting preventive therapy. This is true for the older and newer medications. In fact, not only do these preventive therapies still work in the presence of medication overuse, but they also help to reduce medication overuse. The one caveat that must be mentioned is that this may not apply to opiate overuse. Opiate over-users were excluded from these studies.
While it is of course our goal to reduce and stop acute medication overuse, it should not be done at the expense of delaying preventive therapy. In fact, it is desirable to do both simultaneously. This applies to oral preventive medications, botulinum toxin and CGRP monoclonal antibodies.
In view of this well-established data, it was quite surprising to me to see the results of the 2 polls cited. It seems as if we still have a lot of educating to do regarding migraine prevention in general and with medication overuse in migraine in particular.
Stewart Tepper, MD
Dr. Tepper did not have time to comment, but suggested we show you an abstract presented at the recent AHS meeting. It shows that erenumab-aaoe helps patients with MOH who have not been detoxified (Headache. 2018;58(S2):160-162).
###
Please write to us at Neurology Reviews Migraine Resource Center ([email protected]) with your opinions.
Alan M. Rapoport, MD
Editor-in-Chief
Migraine Resource Center
Clinical Professor of Neurology
The David Geffen School of Medicine at UCLA
Los Angeles, California
Neurology Reviews recently shared two poll questions with our Facebook followers about treatment medication overuse headache (MOH). I was very interested to see the results of our poll. While the number of responses was somewhat low, we do get some sense of what respondents are saying. In this commentary, I will first tell you my perspective on the answers and then we will see what some other headache specialists say about the answers to these questions.
Poll Results:
Can MOH be treated with preventive medications without detoxification?
33 votes
YES, 39%
NO, 61%
Can MOH be treated with the new preventive medications (the monoclonal antibodies to CGRP ligand or receptor) without detoxification?
26 votes
YES, 38%
NO, 62%
My Commentary:
Let me explain in more detail my thoughts on the first question, “Can MOH be treated with preventive medications without detoxification?”
If a patient had the diagnosis of MOH – meaning 15 or more headache days per month for at least 3 months, with use of stronger medications (triptans, ergots, opiates, butalbital-containing medications) for 10 days per month or milder treatment (aspirin, acetaminophen, nonsteroidal anti-inflammatory drugs [NSAIDs]) for 15 days per month – can they improve by being put on a traditional preventive medication without intentionally reducing their overused acute medications by a detoxification protocol ordered by a doctor or nurse?
Only 39% of our audience said yes. Yet some studies have shown that patients placed on onabotulinumtoxinA or topiramate might improve without them going through a detoxification of the overused medications. As a physician, I would suggest simultaneously decreasing in their acute medications. I think in some cases this approach creates additional improvement and makes the patient feel better. It would be better for their quality of life, as well as for their kidneys and possibly even their brains.
Here are my thoughts on the second question, “Can MOH be treated with the new preventive medications (the monoclonal antibodies to CGRP ligand or receptor), without detoxification?”
If a patient has MOH, can you expect them to improve after being placed on 1 of the 4 monoclonal antibodies to CGRP ligand or its receptor – all of which are either recently approved or currently in development – without suggesting that they decrease their overused acute care medications? Note that erenumab (Aimovig-aaoe) has been approved by the FDA and marketed as of the time of this writing; we expect 2 more products to be approved very soon.
Almost an identical percentage of our audience (38%) said yes. There is evidence in published clinical trials that those patients given these new medications did about as well with or without the presence of MOH, and both groups did better than the placebo patients. Note that most trials prohibited overuse of opiates and butalbital.
I am a firm believer of detoxifying patients from their overused over-the-counter (OTC) or prescription medications. I believe that opiates and butalbital-containing medications, when overused, are worse for patients than OTCs, NSAIDs, ergot and triptans, but all of these can cause MOH. There are many studies showing that both inpatient and outpatient detoxification alone can really help. However, it is difficult to detoxify patients and some refuse to try this approach.
So, what should we do as physicians? If a patient has MOH, I educate them, try to detoxify them slowly on an outpatient basis, and if I feel it will help, start them on a preventive medication, even before the detoxification begins so they can reach therapeutic levels. In the future, will I use one of the standard preventives, approved or off-label, for migraine prevention (beta blockers, topiramate and other anticonvulsants, antidepressants, angiotensin receptor blockers, onabotulinumtoxinA and others)? It remains to be seen. I am leaning towards the anti CGRP ligand and receptor monoclonal antibodies and preventive small molecule oral CGRP receptor blockers. While that might be enough to start with, I will continue explaining to my patients why they should actively begin a slow detoxification.
Let us see what some headache specialists said about both questions.
Robert Cowan, MD, FAAN:
There have been studies that show migraine can improve without the discontinuation of medication overuse. But that is not what the question asks. The question as posed is whether MOH can be treated with a preventive medication without detoxification. Since the diagnosis of MOH has, in the past, required the cessation of overuse leading to an improvement in the underlying headache, then technically, the answer would be “no.” But that being said, there is ample evidence that the number of headache days/months and other measures of headache can, in fact, improve with the introduction of a preventive, along with other measures such as lifestyle modification. The other ambiguity in the question has to do with what is meant by “detoxification.” Is this a hospital-based detox, or is a gradual decrease in the offending medicine in combination with the addition of a preventive, still considered “detoxification?” Also, does the response imply a sequential relationship between the detoxification and initiation of the preventive? Without further clarification, this response ratio to the question is very difficult to interpret.
There is animal data that suggests acute migraine medications may promote MOH in susceptible individuals through CGRP-dependent mechanisms and anti-CGRP antibodies may be useful for the MOH (Cephalalgia. 2017;37(6):560-570. doi: 10.1177/0333102416650702). While there are no published CGRP antibody studies that did not exclude MOH patients to my knowledge, an abstract by Silberstein et al at the recent AHS Scientific Meeting reported decreased use of overused medication with fremanazumab (Headache. 2018;58(S2):76-78).
Ira Turner, MD
There is clear data to suggest that it is not necessary to detoxify these patients before starting preventive therapy. This is true for the older and newer medications. In fact, not only do these preventive therapies still work in the presence of medication overuse, but they also help to reduce medication overuse. The one caveat that must be mentioned is that this may not apply to opiate overuse. Opiate over-users were excluded from these studies.
While it is of course our goal to reduce and stop acute medication overuse, it should not be done at the expense of delaying preventive therapy. In fact, it is desirable to do both simultaneously. This applies to oral preventive medications, botulinum toxin and CGRP monoclonal antibodies.
In view of this well-established data, it was quite surprising to me to see the results of the 2 polls cited. It seems as if we still have a lot of educating to do regarding migraine prevention in general and with medication overuse in migraine in particular.
Stewart Tepper, MD
Dr. Tepper did not have time to comment, but suggested we show you an abstract presented at the recent AHS meeting. It shows that erenumab-aaoe helps patients with MOH who have not been detoxified (Headache. 2018;58(S2):160-162).
###
Please write to us at Neurology Reviews Migraine Resource Center ([email protected]) with your opinions.
Alan M. Rapoport, MD
Editor-in-Chief
Migraine Resource Center
Clinical Professor of Neurology
The David Geffen School of Medicine at UCLA
Los Angeles, California
Neurology Reviews recently shared two poll questions with our Facebook followers about treatment medication overuse headache (MOH). I was very interested to see the results of our poll. While the number of responses was somewhat low, we do get some sense of what respondents are saying. In this commentary, I will first tell you my perspective on the answers and then we will see what some other headache specialists say about the answers to these questions.
Poll Results:
Can MOH be treated with preventive medications without detoxification?
33 votes
YES, 39%
NO, 61%
Can MOH be treated with the new preventive medications (the monoclonal antibodies to CGRP ligand or receptor) without detoxification?
26 votes
YES, 38%
NO, 62%
My Commentary:
Let me explain in more detail my thoughts on the first question, “Can MOH be treated with preventive medications without detoxification?”
If a patient had the diagnosis of MOH – meaning 15 or more headache days per month for at least 3 months, with use of stronger medications (triptans, ergots, opiates, butalbital-containing medications) for 10 days per month or milder treatment (aspirin, acetaminophen, nonsteroidal anti-inflammatory drugs [NSAIDs]) for 15 days per month – can they improve by being put on a traditional preventive medication without intentionally reducing their overused acute medications by a detoxification protocol ordered by a doctor or nurse?
Only 39% of our audience said yes. Yet some studies have shown that patients placed on onabotulinumtoxinA or topiramate might improve without them going through a detoxification of the overused medications. As a physician, I would suggest simultaneously decreasing in their acute medications. I think in some cases this approach creates additional improvement and makes the patient feel better. It would be better for their quality of life, as well as for their kidneys and possibly even their brains.
Here are my thoughts on the second question, “Can MOH be treated with the new preventive medications (the monoclonal antibodies to CGRP ligand or receptor), without detoxification?”
If a patient has MOH, can you expect them to improve after being placed on 1 of the 4 monoclonal antibodies to CGRP ligand or its receptor – all of which are either recently approved or currently in development – without suggesting that they decrease their overused acute care medications? Note that erenumab (Aimovig-aaoe) has been approved by the FDA and marketed as of the time of this writing; we expect 2 more products to be approved very soon.
Almost an identical percentage of our audience (38%) said yes. There is evidence in published clinical trials that those patients given these new medications did about as well with or without the presence of MOH, and both groups did better than the placebo patients. Note that most trials prohibited overuse of opiates and butalbital.
I am a firm believer of detoxifying patients from their overused over-the-counter (OTC) or prescription medications. I believe that opiates and butalbital-containing medications, when overused, are worse for patients than OTCs, NSAIDs, ergot and triptans, but all of these can cause MOH. There are many studies showing that both inpatient and outpatient detoxification alone can really help. However, it is difficult to detoxify patients and some refuse to try this approach.
So, what should we do as physicians? If a patient has MOH, I educate them, try to detoxify them slowly on an outpatient basis, and if I feel it will help, start them on a preventive medication, even before the detoxification begins so they can reach therapeutic levels. In the future, will I use one of the standard preventives, approved or off-label, for migraine prevention (beta blockers, topiramate and other anticonvulsants, antidepressants, angiotensin receptor blockers, onabotulinumtoxinA and others)? It remains to be seen. I am leaning towards the anti CGRP ligand and receptor monoclonal antibodies and preventive small molecule oral CGRP receptor blockers. While that might be enough to start with, I will continue explaining to my patients why they should actively begin a slow detoxification.
Let us see what some headache specialists said about both questions.
Robert Cowan, MD, FAAN:
There have been studies that show migraine can improve without the discontinuation of medication overuse. But that is not what the question asks. The question as posed is whether MOH can be treated with a preventive medication without detoxification. Since the diagnosis of MOH has, in the past, required the cessation of overuse leading to an improvement in the underlying headache, then technically, the answer would be “no.” But that being said, there is ample evidence that the number of headache days/months and other measures of headache can, in fact, improve with the introduction of a preventive, along with other measures such as lifestyle modification. The other ambiguity in the question has to do with what is meant by “detoxification.” Is this a hospital-based detox, or is a gradual decrease in the offending medicine in combination with the addition of a preventive, still considered “detoxification?” Also, does the response imply a sequential relationship between the detoxification and initiation of the preventive? Without further clarification, this response ratio to the question is very difficult to interpret.
There is animal data that suggests acute migraine medications may promote MOH in susceptible individuals through CGRP-dependent mechanisms and anti-CGRP antibodies may be useful for the MOH (Cephalalgia. 2017;37(6):560-570. doi: 10.1177/0333102416650702). While there are no published CGRP antibody studies that did not exclude MOH patients to my knowledge, an abstract by Silberstein et al at the recent AHS Scientific Meeting reported decreased use of overused medication with fremanazumab (Headache. 2018;58(S2):76-78).
Ira Turner, MD
There is clear data to suggest that it is not necessary to detoxify these patients before starting preventive therapy. This is true for the older and newer medications. In fact, not only do these preventive therapies still work in the presence of medication overuse, but they also help to reduce medication overuse. The one caveat that must be mentioned is that this may not apply to opiate overuse. Opiate over-users were excluded from these studies.
While it is of course our goal to reduce and stop acute medication overuse, it should not be done at the expense of delaying preventive therapy. In fact, it is desirable to do both simultaneously. This applies to oral preventive medications, botulinum toxin and CGRP monoclonal antibodies.
In view of this well-established data, it was quite surprising to me to see the results of the 2 polls cited. It seems as if we still have a lot of educating to do regarding migraine prevention in general and with medication overuse in migraine in particular.
Stewart Tepper, MD
Dr. Tepper did not have time to comment, but suggested we show you an abstract presented at the recent AHS meeting. It shows that erenumab-aaoe helps patients with MOH who have not been detoxified (Headache. 2018;58(S2):160-162).
###
Please write to us at Neurology Reviews Migraine Resource Center ([email protected]) with your opinions.
Alan M. Rapoport, MD
Editor-in-Chief
Migraine Resource Center
Clinical Professor of Neurology
The David Geffen School of Medicine at UCLA
Los Angeles, California