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First drug for MET+ NSCLC shows high response rates
conclude investigators of the pivotal trial that led to the drug’s approval.
Responses were seen in all patients regardless of how many previous drugs they had been treated with, although responses were particularly pronounced among patients who were treatment naive.
Capmatinib and a companion assay received FDA approval in May 2020 for the treatment of adults with metastatic NSCLC harboring MET exon 14–skipping mutations.
These MET mutations occur in 3%-4% of NSCLC patients. MET amplifications occur in 1%-6% of NSCLC patients. They have been associated with poor response to chemotherapy and immunotherapy.
“Prior to this approval, there weren’t any approved therapies for this group of patients,” noted Edward Garon, MD, associate professor of hematology and oncology at the University of California, Los Angeles, who led the pivotal trial.
“There are several drugs that have been used off label for MET exon 14 skipping mutations, but none with an indication for it,” he said in an interview.
Garon emphasized that capmatinib was particularly robust for patients who had not received prior therapy, although he added that it was also very effective for those who had been previously treated.
“The drug has been approved and it is available, and we have already written prescriptions for it at our clinic,” said Dr. Garon, “although, at our clinic, the majority of patients using it were part of the [pivotal] clinical trial.”
That trial is the phase 2 GEOMETRY mono-1 study. Results from the study were presented at a meeting earlier this year and have now been published in the New England Journal of Medicine.
It was conducted in a cohort of 364 patients with advanced NSCLC. Patients were stratified into five cohorts and two expansion cohorts, which were assigned according to MET status and previous lines of therapy. Across cohorts 1 through 5, a total of 97 patients had a MET exon 14–skipping mutation, and 210 had MET amplification. All patients were treated with capmatinib 400 mg twice daily.
Among patients with a MET exon 14 skipping mutation, an overall response was observed in 41% of previously treated patients and in 68% of those who had not previously been treated.
“That is a very high response rate, and clearly this drug is targeting this mutation,” said Fred Hirsch, MD, PhD, executive director, Center for Thoracic Oncology, Mount Sinai Health System, New York, who was approached for comment. “It’s very active, and you don’t get those responses with chemotherapy.”
The median duration of response was 9.7 months among previously treated patients and 12.6 months among those who were treatment naive. Median progression-free survival (PFS) was 5.4 months and 12.4 months, respectively.
In the cohort of patients with MET amplification, the overall response was 12% among those whose tumor tissue had a gene copy number of 6-9. The overall response rate was 9% among those with a gene copy number of 4 or 5, and it was 7% among those with a gene copy number of less than 4.
Median PFS was 2.7 months for patients whose tumor tissue had a gene copy number of 6-9 and in those with a gene copy number of 4 or 5. PFS rose to 3.6 months for patients with a gene copy number of less than 4.
The most frequently reported adverse events were peripheral edema (in 51%) and nausea (in 45%). These events were mostly of grade 1 or 2. Treatment-related serious adverse events occurred in 13% of patients. The incidence was lower in the groups with shorter duration of exposure. Treatment was discontinued in 11% of patients (consistent across cohorts) because of adverse events.
Dr. Hirsch commented that the results for patients with NSCLC and brain metastases were particularly noteworthy. “Brain metastases are, unfortunately, a common problem in patients with lung cancer,” he said. “Now, we have a drug that is effective for MET mutation and CNS involvement and can penetrate the blood-brain barrier, and this is a very encouraging situation.”
He pointed out that 7 of 13 patients with brain metastases responded to treatment with capmatinib. “Four patients have a complete response, and that is very encouraging,” said Dr. Hirsch. “This is clearly a deal-breaker in my opinion.”
The future is bright
Dr. Hirsch noted that the evidence supporting capmatinib is strong, even though a larger prospective study with a control group is lacking. “If we have a patient with this mutation, and knowing that there is a drug with a response rate of 68%, that is a good reason to try the drug up front. The data are sufficient that it should be offered to the patient, even without a control group.”
Capmatinib is the latest of many targeted drugs that have been launched in recent years, and several immunotherapies are also now available for treatment of this disease. These new therapies are making this a “very encouraging time in lung cancer,” Dr. Hirsch commented.
“We are seeing long-term survival, and, eventually, we may start seeing potential cures for some patients,” he said. “But at the very least, we are seeing very good long-term results with many of these targeted therapies, and we are continuing to learn more about resistant mechanisms. I can’t wait to see future in the field.”
The study was funded by Novartis Pharmaceuticals. Dr. Garon reports consulting or advisory roles with Dracen and research funding (institutional) from Merck, Genentech, AstraZeneca, Novartis, Lilly, Bristol-Myers Squibb, Mirati Therapeutics, Dynavax, Iovance Biotherapeutics, and Neon Therapeutics. His coauthors have disclosed numerous relationships with industry, as listed in the original article. Dr. Hirsch has disclosed no relevant financial relationships.
This article first appeared on Medscape.com.
conclude investigators of the pivotal trial that led to the drug’s approval.
Responses were seen in all patients regardless of how many previous drugs they had been treated with, although responses were particularly pronounced among patients who were treatment naive.
Capmatinib and a companion assay received FDA approval in May 2020 for the treatment of adults with metastatic NSCLC harboring MET exon 14–skipping mutations.
These MET mutations occur in 3%-4% of NSCLC patients. MET amplifications occur in 1%-6% of NSCLC patients. They have been associated with poor response to chemotherapy and immunotherapy.
“Prior to this approval, there weren’t any approved therapies for this group of patients,” noted Edward Garon, MD, associate professor of hematology and oncology at the University of California, Los Angeles, who led the pivotal trial.
“There are several drugs that have been used off label for MET exon 14 skipping mutations, but none with an indication for it,” he said in an interview.
Garon emphasized that capmatinib was particularly robust for patients who had not received prior therapy, although he added that it was also very effective for those who had been previously treated.
“The drug has been approved and it is available, and we have already written prescriptions for it at our clinic,” said Dr. Garon, “although, at our clinic, the majority of patients using it were part of the [pivotal] clinical trial.”
That trial is the phase 2 GEOMETRY mono-1 study. Results from the study were presented at a meeting earlier this year and have now been published in the New England Journal of Medicine.
It was conducted in a cohort of 364 patients with advanced NSCLC. Patients were stratified into five cohorts and two expansion cohorts, which were assigned according to MET status and previous lines of therapy. Across cohorts 1 through 5, a total of 97 patients had a MET exon 14–skipping mutation, and 210 had MET amplification. All patients were treated with capmatinib 400 mg twice daily.
Among patients with a MET exon 14 skipping mutation, an overall response was observed in 41% of previously treated patients and in 68% of those who had not previously been treated.
“That is a very high response rate, and clearly this drug is targeting this mutation,” said Fred Hirsch, MD, PhD, executive director, Center for Thoracic Oncology, Mount Sinai Health System, New York, who was approached for comment. “It’s very active, and you don’t get those responses with chemotherapy.”
The median duration of response was 9.7 months among previously treated patients and 12.6 months among those who were treatment naive. Median progression-free survival (PFS) was 5.4 months and 12.4 months, respectively.
In the cohort of patients with MET amplification, the overall response was 12% among those whose tumor tissue had a gene copy number of 6-9. The overall response rate was 9% among those with a gene copy number of 4 or 5, and it was 7% among those with a gene copy number of less than 4.
Median PFS was 2.7 months for patients whose tumor tissue had a gene copy number of 6-9 and in those with a gene copy number of 4 or 5. PFS rose to 3.6 months for patients with a gene copy number of less than 4.
The most frequently reported adverse events were peripheral edema (in 51%) and nausea (in 45%). These events were mostly of grade 1 or 2. Treatment-related serious adverse events occurred in 13% of patients. The incidence was lower in the groups with shorter duration of exposure. Treatment was discontinued in 11% of patients (consistent across cohorts) because of adverse events.
Dr. Hirsch commented that the results for patients with NSCLC and brain metastases were particularly noteworthy. “Brain metastases are, unfortunately, a common problem in patients with lung cancer,” he said. “Now, we have a drug that is effective for MET mutation and CNS involvement and can penetrate the blood-brain barrier, and this is a very encouraging situation.”
He pointed out that 7 of 13 patients with brain metastases responded to treatment with capmatinib. “Four patients have a complete response, and that is very encouraging,” said Dr. Hirsch. “This is clearly a deal-breaker in my opinion.”
The future is bright
Dr. Hirsch noted that the evidence supporting capmatinib is strong, even though a larger prospective study with a control group is lacking. “If we have a patient with this mutation, and knowing that there is a drug with a response rate of 68%, that is a good reason to try the drug up front. The data are sufficient that it should be offered to the patient, even without a control group.”
Capmatinib is the latest of many targeted drugs that have been launched in recent years, and several immunotherapies are also now available for treatment of this disease. These new therapies are making this a “very encouraging time in lung cancer,” Dr. Hirsch commented.
“We are seeing long-term survival, and, eventually, we may start seeing potential cures for some patients,” he said. “But at the very least, we are seeing very good long-term results with many of these targeted therapies, and we are continuing to learn more about resistant mechanisms. I can’t wait to see future in the field.”
The study was funded by Novartis Pharmaceuticals. Dr. Garon reports consulting or advisory roles with Dracen and research funding (institutional) from Merck, Genentech, AstraZeneca, Novartis, Lilly, Bristol-Myers Squibb, Mirati Therapeutics, Dynavax, Iovance Biotherapeutics, and Neon Therapeutics. His coauthors have disclosed numerous relationships with industry, as listed in the original article. Dr. Hirsch has disclosed no relevant financial relationships.
This article first appeared on Medscape.com.
conclude investigators of the pivotal trial that led to the drug’s approval.
Responses were seen in all patients regardless of how many previous drugs they had been treated with, although responses were particularly pronounced among patients who were treatment naive.
Capmatinib and a companion assay received FDA approval in May 2020 for the treatment of adults with metastatic NSCLC harboring MET exon 14–skipping mutations.
These MET mutations occur in 3%-4% of NSCLC patients. MET amplifications occur in 1%-6% of NSCLC patients. They have been associated with poor response to chemotherapy and immunotherapy.
“Prior to this approval, there weren’t any approved therapies for this group of patients,” noted Edward Garon, MD, associate professor of hematology and oncology at the University of California, Los Angeles, who led the pivotal trial.
“There are several drugs that have been used off label for MET exon 14 skipping mutations, but none with an indication for it,” he said in an interview.
Garon emphasized that capmatinib was particularly robust for patients who had not received prior therapy, although he added that it was also very effective for those who had been previously treated.
“The drug has been approved and it is available, and we have already written prescriptions for it at our clinic,” said Dr. Garon, “although, at our clinic, the majority of patients using it were part of the [pivotal] clinical trial.”
That trial is the phase 2 GEOMETRY mono-1 study. Results from the study were presented at a meeting earlier this year and have now been published in the New England Journal of Medicine.
It was conducted in a cohort of 364 patients with advanced NSCLC. Patients were stratified into five cohorts and two expansion cohorts, which were assigned according to MET status and previous lines of therapy. Across cohorts 1 through 5, a total of 97 patients had a MET exon 14–skipping mutation, and 210 had MET amplification. All patients were treated with capmatinib 400 mg twice daily.
Among patients with a MET exon 14 skipping mutation, an overall response was observed in 41% of previously treated patients and in 68% of those who had not previously been treated.
“That is a very high response rate, and clearly this drug is targeting this mutation,” said Fred Hirsch, MD, PhD, executive director, Center for Thoracic Oncology, Mount Sinai Health System, New York, who was approached for comment. “It’s very active, and you don’t get those responses with chemotherapy.”
The median duration of response was 9.7 months among previously treated patients and 12.6 months among those who were treatment naive. Median progression-free survival (PFS) was 5.4 months and 12.4 months, respectively.
In the cohort of patients with MET amplification, the overall response was 12% among those whose tumor tissue had a gene copy number of 6-9. The overall response rate was 9% among those with a gene copy number of 4 or 5, and it was 7% among those with a gene copy number of less than 4.
Median PFS was 2.7 months for patients whose tumor tissue had a gene copy number of 6-9 and in those with a gene copy number of 4 or 5. PFS rose to 3.6 months for patients with a gene copy number of less than 4.
The most frequently reported adverse events were peripheral edema (in 51%) and nausea (in 45%). These events were mostly of grade 1 or 2. Treatment-related serious adverse events occurred in 13% of patients. The incidence was lower in the groups with shorter duration of exposure. Treatment was discontinued in 11% of patients (consistent across cohorts) because of adverse events.
Dr. Hirsch commented that the results for patients with NSCLC and brain metastases were particularly noteworthy. “Brain metastases are, unfortunately, a common problem in patients with lung cancer,” he said. “Now, we have a drug that is effective for MET mutation and CNS involvement and can penetrate the blood-brain barrier, and this is a very encouraging situation.”
He pointed out that 7 of 13 patients with brain metastases responded to treatment with capmatinib. “Four patients have a complete response, and that is very encouraging,” said Dr. Hirsch. “This is clearly a deal-breaker in my opinion.”
The future is bright
Dr. Hirsch noted that the evidence supporting capmatinib is strong, even though a larger prospective study with a control group is lacking. “If we have a patient with this mutation, and knowing that there is a drug with a response rate of 68%, that is a good reason to try the drug up front. The data are sufficient that it should be offered to the patient, even without a control group.”
Capmatinib is the latest of many targeted drugs that have been launched in recent years, and several immunotherapies are also now available for treatment of this disease. These new therapies are making this a “very encouraging time in lung cancer,” Dr. Hirsch commented.
“We are seeing long-term survival, and, eventually, we may start seeing potential cures for some patients,” he said. “But at the very least, we are seeing very good long-term results with many of these targeted therapies, and we are continuing to learn more about resistant mechanisms. I can’t wait to see future in the field.”
The study was funded by Novartis Pharmaceuticals. Dr. Garon reports consulting or advisory roles with Dracen and research funding (institutional) from Merck, Genentech, AstraZeneca, Novartis, Lilly, Bristol-Myers Squibb, Mirati Therapeutics, Dynavax, Iovance Biotherapeutics, and Neon Therapeutics. His coauthors have disclosed numerous relationships with industry, as listed in the original article. Dr. Hirsch has disclosed no relevant financial relationships.
This article first appeared on Medscape.com.
Hair dye and cancer study ‘offers some reassurance’
Findings limited to White women in United States
The largest study of its kind has found no positive association between personal use of permanent hair dye and the risk for most cancers and cancer mortality.
The findings come from the Nurses’ Health Study, an ongoing prospective cohort study of more than 117,000 women who have been followed for 36 years and who did not have cancer at baseline.
The findings were published online on September 2 in the BMJ.
The results “offer some reassurance against concerns that personal use of permanent hair dyes might be associated with increased cancer risk or mortality,” write the investigators, with first author Yin Zhang, PhD, of Harvard Medical School, Boston.
The findings, which are limited to White women in the United States, indicate correlation, not causation, the authors emphasize.
Nevertheless, the researchers found an increased risk for some cancers among hair dye users, especially with greater cumulative dose (200 or more uses during the study period). The risk was increased for basal cell carcinoma, breast cancer (specifically, estrogen receptor negative [ER–], progesterone receptor negative [PR–], and hormone receptor negative [ER–, PR–]), and ovarian cancer.
A British expert not involved in the study dismissed these findings. “The reported associations are very weak, and, given the number of associations reported in this manuscript, they are very likely to be chance findings,” commented Paul Pharoah, PhD, professor of cancer epidemiology at the University of Cambridge (England).
“For the cancers where an increase in risk is reported, the results are not compelling. Even if they were real findings, the associations may not be cause-and-effect, and, even if they were causal associations, the magnitude of the effects are so small that any risk would be trivial.
“In short, none of the findings reported in this manuscript suggest that women who use hair dye are putting themselves at increased risk of cancer,” he stated.
A U.S. researcher who has previously coauthored a study suggesting an association between hair dye and breast cancer agreed that the increases in risk reported in this current study are “small.” But they are “of interest,” especially for breast and ovarian cancer, said Alexandra White, PhD, of the National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, N.C.
Hair dyes include compounds that “are not just potential carcinogens but also act as endocrine disruptors,” she said in an interview.
“In both breast and ovarian cancer, we know that hormones play an important part in the etiology ... so it’s biologically plausible that you would see [these associations in the current study],” added Dr. White, who was approached for comment.
However, she added that, even with the “modest” 20%-28% increase in the relative risk for certain breast cancers linked to a heavy cumulative dose of dyes in the current study, “there doesn’t seem to be any strong association with any cancer type.”
But she also pointed out that the most outstanding risk association was among ER–/PR– breast cancers, which are the “most aggressive and difficult to treat,” and thus the new findings are “important.”
Dr. White is the lead author of a 2019 study that received a lot of media attention because it rang an alarm bell about hair dyes and breast cancer risk.
That study concluded that ever using permanent hair dye or hair straighteners was associated with a higher risk for breast cancer than never using them and that this higher risk was especially associated with Black women. However, the study participants were from the prospective Sister Study. The participants in that study had no history of breast cancer, but they each had at least one sister who did. This family history of breast cancer may represent selection bias.
With changes in the 1980s, even safer now?
The study of hair dyes and cancer has “major public health implications” because the use of hair dye is widespread, Dr. Zhang and colleagues write in their article. They estimate that 50% to 80% of women and 10% of men aged 40 years and older in the United States and Europe use hair dye.
Permanent hair dyes “pose the greatest potential concern,” they stated, adding that these account for approximately 80% of hair dyes used in the United States and Europe and an even higher percentage in Asia.
The International Agency for Research on Cancer classifies occupational exposure to hair dyes as probably carcinogenic, but the carcinogenicity resulting from personal use of hair dyes is not classifiable – thus, there is no warning about at-home usage.
Notably, there was “a huge and very important” change in hair dye ingredients in the 1980s after the Food and Drug Administration warned about some chemicals in permanent hair dyes and the cosmetic industry altered their formulas, lead author Dr. Zhang said.
However, the researchers could not analyze use before and after the changes because not enough women reported first use of permanent hair dye after 1980 (only 1890 of 117,200 participants).
“We could expect that the current ingredients should make it safer,” Dr. Zhang said.
Study details
The researchers report that ever-users of permanent hair dyes had no significant increases in risk for solid cancers (n = 20,805; hazard ratio, 0.98, 95% confidence interval, 0.96-1.01) or hematopoietic cancers overall (n = 1,807; HR, 1.00; 95% CI, 0.91-1.10) compared with nonusers.
Additionally, ever-users did not have an increased risk for most specific cancers or cancer-related death (n = 4,860; HR, 0.96; 95% CI, 0.91-1.02).
As noted above, there were some exceptions.
Basal cell carcinoma risk was slightly increased for ever-users (n = 22,560; HR, 1.05; 95% CI, 1.02-1.08). Cumulative dose (a calculation of duration and frequency) was positively associated with risk for ER– breast cancer, PR– breast cancer, ER–/PR– breast cancer, and ovarian cancer, with risk rising in accordance with the total amount of dye.
Notably, at a cumulative dose of ≥200 uses, there was a 20% increase in the relative risk for ER- breast cancer (n = 1521; HR, 1.20; 95% CI, 1.02-1.41; P value for trend, .03). At the same cumulative dose, there was a 28% increase in the relative risk for ER-/PR- breast cancer (n = 1287; HR, 1.28, 95% CI, 1.08-1.52; P value for trend, .006).
In addition, an increased risk for Hodgkin lymphoma was observed, but only for women with naturally dark hair (the calculation was based on 70 women, 24 of whom had dark hair).
In a press statement, senior author Eva Schernhammer, PhD, of Harvard and the Medical University of Vienna, said the results “justify further prospective validation.”
She also explained that there are many variables to consider in this research, including different populations and countries, different susceptibility genotypes, different exposure settings (personal use vs. occupational exposure), and different colors of the permanent hair dyes used (dark dyes vs. light dyes).
Geographic location is a particularly important variable, suggested the study authors.
They pointed out that Europe, but not the United States, banned some individual hair dye ingredients that were considered carcinogenic during both the 1980s and 2000s. One country has even tighter oversight: “The most restrictive regulation of hair dyes exists in Japan, where cosmetic products are considered equivalent to drugs.”
The study was funded by the Centers for Disease Control and Prevention and the National Institute for Occupational Safety and Health. The study authors and Dr. White have disclosed no relevant financial relationships.
This article first appeared on Medscape.com.
Findings limited to White women in United States
Findings limited to White women in United States
The largest study of its kind has found no positive association between personal use of permanent hair dye and the risk for most cancers and cancer mortality.
The findings come from the Nurses’ Health Study, an ongoing prospective cohort study of more than 117,000 women who have been followed for 36 years and who did not have cancer at baseline.
The findings were published online on September 2 in the BMJ.
The results “offer some reassurance against concerns that personal use of permanent hair dyes might be associated with increased cancer risk or mortality,” write the investigators, with first author Yin Zhang, PhD, of Harvard Medical School, Boston.
The findings, which are limited to White women in the United States, indicate correlation, not causation, the authors emphasize.
Nevertheless, the researchers found an increased risk for some cancers among hair dye users, especially with greater cumulative dose (200 or more uses during the study period). The risk was increased for basal cell carcinoma, breast cancer (specifically, estrogen receptor negative [ER–], progesterone receptor negative [PR–], and hormone receptor negative [ER–, PR–]), and ovarian cancer.
A British expert not involved in the study dismissed these findings. “The reported associations are very weak, and, given the number of associations reported in this manuscript, they are very likely to be chance findings,” commented Paul Pharoah, PhD, professor of cancer epidemiology at the University of Cambridge (England).
“For the cancers where an increase in risk is reported, the results are not compelling. Even if they were real findings, the associations may not be cause-and-effect, and, even if they were causal associations, the magnitude of the effects are so small that any risk would be trivial.
“In short, none of the findings reported in this manuscript suggest that women who use hair dye are putting themselves at increased risk of cancer,” he stated.
A U.S. researcher who has previously coauthored a study suggesting an association between hair dye and breast cancer agreed that the increases in risk reported in this current study are “small.” But they are “of interest,” especially for breast and ovarian cancer, said Alexandra White, PhD, of the National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, N.C.
Hair dyes include compounds that “are not just potential carcinogens but also act as endocrine disruptors,” she said in an interview.
“In both breast and ovarian cancer, we know that hormones play an important part in the etiology ... so it’s biologically plausible that you would see [these associations in the current study],” added Dr. White, who was approached for comment.
However, she added that, even with the “modest” 20%-28% increase in the relative risk for certain breast cancers linked to a heavy cumulative dose of dyes in the current study, “there doesn’t seem to be any strong association with any cancer type.”
But she also pointed out that the most outstanding risk association was among ER–/PR– breast cancers, which are the “most aggressive and difficult to treat,” and thus the new findings are “important.”
Dr. White is the lead author of a 2019 study that received a lot of media attention because it rang an alarm bell about hair dyes and breast cancer risk.
That study concluded that ever using permanent hair dye or hair straighteners was associated with a higher risk for breast cancer than never using them and that this higher risk was especially associated with Black women. However, the study participants were from the prospective Sister Study. The participants in that study had no history of breast cancer, but they each had at least one sister who did. This family history of breast cancer may represent selection bias.
With changes in the 1980s, even safer now?
The study of hair dyes and cancer has “major public health implications” because the use of hair dye is widespread, Dr. Zhang and colleagues write in their article. They estimate that 50% to 80% of women and 10% of men aged 40 years and older in the United States and Europe use hair dye.
Permanent hair dyes “pose the greatest potential concern,” they stated, adding that these account for approximately 80% of hair dyes used in the United States and Europe and an even higher percentage in Asia.
The International Agency for Research on Cancer classifies occupational exposure to hair dyes as probably carcinogenic, but the carcinogenicity resulting from personal use of hair dyes is not classifiable – thus, there is no warning about at-home usage.
Notably, there was “a huge and very important” change in hair dye ingredients in the 1980s after the Food and Drug Administration warned about some chemicals in permanent hair dyes and the cosmetic industry altered their formulas, lead author Dr. Zhang said.
However, the researchers could not analyze use before and after the changes because not enough women reported first use of permanent hair dye after 1980 (only 1890 of 117,200 participants).
“We could expect that the current ingredients should make it safer,” Dr. Zhang said.
Study details
The researchers report that ever-users of permanent hair dyes had no significant increases in risk for solid cancers (n = 20,805; hazard ratio, 0.98, 95% confidence interval, 0.96-1.01) or hematopoietic cancers overall (n = 1,807; HR, 1.00; 95% CI, 0.91-1.10) compared with nonusers.
Additionally, ever-users did not have an increased risk for most specific cancers or cancer-related death (n = 4,860; HR, 0.96; 95% CI, 0.91-1.02).
As noted above, there were some exceptions.
Basal cell carcinoma risk was slightly increased for ever-users (n = 22,560; HR, 1.05; 95% CI, 1.02-1.08). Cumulative dose (a calculation of duration and frequency) was positively associated with risk for ER– breast cancer, PR– breast cancer, ER–/PR– breast cancer, and ovarian cancer, with risk rising in accordance with the total amount of dye.
Notably, at a cumulative dose of ≥200 uses, there was a 20% increase in the relative risk for ER- breast cancer (n = 1521; HR, 1.20; 95% CI, 1.02-1.41; P value for trend, .03). At the same cumulative dose, there was a 28% increase in the relative risk for ER-/PR- breast cancer (n = 1287; HR, 1.28, 95% CI, 1.08-1.52; P value for trend, .006).
In addition, an increased risk for Hodgkin lymphoma was observed, but only for women with naturally dark hair (the calculation was based on 70 women, 24 of whom had dark hair).
In a press statement, senior author Eva Schernhammer, PhD, of Harvard and the Medical University of Vienna, said the results “justify further prospective validation.”
She also explained that there are many variables to consider in this research, including different populations and countries, different susceptibility genotypes, different exposure settings (personal use vs. occupational exposure), and different colors of the permanent hair dyes used (dark dyes vs. light dyes).
Geographic location is a particularly important variable, suggested the study authors.
They pointed out that Europe, but not the United States, banned some individual hair dye ingredients that were considered carcinogenic during both the 1980s and 2000s. One country has even tighter oversight: “The most restrictive regulation of hair dyes exists in Japan, where cosmetic products are considered equivalent to drugs.”
The study was funded by the Centers for Disease Control and Prevention and the National Institute for Occupational Safety and Health. The study authors and Dr. White have disclosed no relevant financial relationships.
This article first appeared on Medscape.com.
The largest study of its kind has found no positive association between personal use of permanent hair dye and the risk for most cancers and cancer mortality.
The findings come from the Nurses’ Health Study, an ongoing prospective cohort study of more than 117,000 women who have been followed for 36 years and who did not have cancer at baseline.
The findings were published online on September 2 in the BMJ.
The results “offer some reassurance against concerns that personal use of permanent hair dyes might be associated with increased cancer risk or mortality,” write the investigators, with first author Yin Zhang, PhD, of Harvard Medical School, Boston.
The findings, which are limited to White women in the United States, indicate correlation, not causation, the authors emphasize.
Nevertheless, the researchers found an increased risk for some cancers among hair dye users, especially with greater cumulative dose (200 or more uses during the study period). The risk was increased for basal cell carcinoma, breast cancer (specifically, estrogen receptor negative [ER–], progesterone receptor negative [PR–], and hormone receptor negative [ER–, PR–]), and ovarian cancer.
A British expert not involved in the study dismissed these findings. “The reported associations are very weak, and, given the number of associations reported in this manuscript, they are very likely to be chance findings,” commented Paul Pharoah, PhD, professor of cancer epidemiology at the University of Cambridge (England).
“For the cancers where an increase in risk is reported, the results are not compelling. Even if they were real findings, the associations may not be cause-and-effect, and, even if they were causal associations, the magnitude of the effects are so small that any risk would be trivial.
“In short, none of the findings reported in this manuscript suggest that women who use hair dye are putting themselves at increased risk of cancer,” he stated.
A U.S. researcher who has previously coauthored a study suggesting an association between hair dye and breast cancer agreed that the increases in risk reported in this current study are “small.” But they are “of interest,” especially for breast and ovarian cancer, said Alexandra White, PhD, of the National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, N.C.
Hair dyes include compounds that “are not just potential carcinogens but also act as endocrine disruptors,” she said in an interview.
“In both breast and ovarian cancer, we know that hormones play an important part in the etiology ... so it’s biologically plausible that you would see [these associations in the current study],” added Dr. White, who was approached for comment.
However, she added that, even with the “modest” 20%-28% increase in the relative risk for certain breast cancers linked to a heavy cumulative dose of dyes in the current study, “there doesn’t seem to be any strong association with any cancer type.”
But she also pointed out that the most outstanding risk association was among ER–/PR– breast cancers, which are the “most aggressive and difficult to treat,” and thus the new findings are “important.”
Dr. White is the lead author of a 2019 study that received a lot of media attention because it rang an alarm bell about hair dyes and breast cancer risk.
That study concluded that ever using permanent hair dye or hair straighteners was associated with a higher risk for breast cancer than never using them and that this higher risk was especially associated with Black women. However, the study participants were from the prospective Sister Study. The participants in that study had no history of breast cancer, but they each had at least one sister who did. This family history of breast cancer may represent selection bias.
With changes in the 1980s, even safer now?
The study of hair dyes and cancer has “major public health implications” because the use of hair dye is widespread, Dr. Zhang and colleagues write in their article. They estimate that 50% to 80% of women and 10% of men aged 40 years and older in the United States and Europe use hair dye.
Permanent hair dyes “pose the greatest potential concern,” they stated, adding that these account for approximately 80% of hair dyes used in the United States and Europe and an even higher percentage in Asia.
The International Agency for Research on Cancer classifies occupational exposure to hair dyes as probably carcinogenic, but the carcinogenicity resulting from personal use of hair dyes is not classifiable – thus, there is no warning about at-home usage.
Notably, there was “a huge and very important” change in hair dye ingredients in the 1980s after the Food and Drug Administration warned about some chemicals in permanent hair dyes and the cosmetic industry altered their formulas, lead author Dr. Zhang said.
However, the researchers could not analyze use before and after the changes because not enough women reported first use of permanent hair dye after 1980 (only 1890 of 117,200 participants).
“We could expect that the current ingredients should make it safer,” Dr. Zhang said.
Study details
The researchers report that ever-users of permanent hair dyes had no significant increases in risk for solid cancers (n = 20,805; hazard ratio, 0.98, 95% confidence interval, 0.96-1.01) or hematopoietic cancers overall (n = 1,807; HR, 1.00; 95% CI, 0.91-1.10) compared with nonusers.
Additionally, ever-users did not have an increased risk for most specific cancers or cancer-related death (n = 4,860; HR, 0.96; 95% CI, 0.91-1.02).
As noted above, there were some exceptions.
Basal cell carcinoma risk was slightly increased for ever-users (n = 22,560; HR, 1.05; 95% CI, 1.02-1.08). Cumulative dose (a calculation of duration and frequency) was positively associated with risk for ER– breast cancer, PR– breast cancer, ER–/PR– breast cancer, and ovarian cancer, with risk rising in accordance with the total amount of dye.
Notably, at a cumulative dose of ≥200 uses, there was a 20% increase in the relative risk for ER- breast cancer (n = 1521; HR, 1.20; 95% CI, 1.02-1.41; P value for trend, .03). At the same cumulative dose, there was a 28% increase in the relative risk for ER-/PR- breast cancer (n = 1287; HR, 1.28, 95% CI, 1.08-1.52; P value for trend, .006).
In addition, an increased risk for Hodgkin lymphoma was observed, but only for women with naturally dark hair (the calculation was based on 70 women, 24 of whom had dark hair).
In a press statement, senior author Eva Schernhammer, PhD, of Harvard and the Medical University of Vienna, said the results “justify further prospective validation.”
She also explained that there are many variables to consider in this research, including different populations and countries, different susceptibility genotypes, different exposure settings (personal use vs. occupational exposure), and different colors of the permanent hair dyes used (dark dyes vs. light dyes).
Geographic location is a particularly important variable, suggested the study authors.
They pointed out that Europe, but not the United States, banned some individual hair dye ingredients that were considered carcinogenic during both the 1980s and 2000s. One country has even tighter oversight: “The most restrictive regulation of hair dyes exists in Japan, where cosmetic products are considered equivalent to drugs.”
The study was funded by the Centers for Disease Control and Prevention and the National Institute for Occupational Safety and Health. The study authors and Dr. White have disclosed no relevant financial relationships.
This article first appeared on Medscape.com.
Chronicles of Cancer: A history of mammography, part 2
The push and pull of social forces
Science and technology emerge from and are shaped by social forces outside the laboratory and clinic. This is an essential fact of most new medical technology. In the Chronicles of Cancer series, part 1 of the story of mammography focused on the technological determinants of its development and use. Part 2 will focus on some of the social forces that shaped the development of mammography.
“Few medical issues have been as controversial – or as political, at least in the United States – as the role of mammographic screening for breast cancer,” according to Donald A. Berry, PhD, a biostatistician at the University of Texas MD Anderson Cancer Center, Houston.1
In fact, technology aside, the history of mammography has been and remains rife with controversy on the one side and vigorous promotion on the other, all enmeshed within the War on Cancer, corporate and professional interests, and the women’s rights movement’s growing issues with what was seen as a patriarchal medical establishment.
Today the issue of conflicts of interest are paramount in any discussion of new medical developments, from the early preclinical stages to ultimate deployment. Then, as now, professional and advocacy societies had a profound influence on government and social decision-making, but in that earlier, more trusting era, buoyed by the amazing changes that technology was bringing to everyday life and an unshakable commitment to and belief in “progress,” science and the medical community held a far more effective sway over the beliefs and behavior of the general population.
Women’s health observed
Although the main focus of the women’s movement with regard to breast cancer was a struggle against the common practice of routine radical mastectomies and a push toward breast-conserving surgeries, the issue of preventive care and screening with regard to women’s health was also a major concern.
Regarding mammography, early enthusiasm in the medical community and among the general public was profound. In 1969, Robert Egan described how mammography had a “certain magic appeal.” The patient, he continued, “feels something special is being done for her.” Women whose cancers had been discovered on a mammogram praised radiologists as heroes who had saved their lives.2
In that era, however, beyond the confines of the doctor’s office, mammography and breast cancer remained topics not discussed among the public at large, despite efforts by the American Cancer Society to change this.
ACS weighs in
Various groups had been promoting the benefits of breast self-examination since the 1930s, and in 1947, the American Cancer Society launched an awareness campaign, “Look for a Lump or Thickening in the Breast,” instructing women to perform a monthly breast self-exam. Between self-examination and clinical breast examinations in physicians’ offices, the ACS believed that smaller and more treatable breast cancers could be discovered.
In 1972, the ACS, working with the National Cancer Institute (NCI), inaugurated the Breast Cancer Detection Demonstration Project (BCDDP), which planned to screen over a quarter of a million American women for breast cancer. The initiative was a direct outgrowth of the National Cancer Act of 1971,3 the key legislation of the War on Cancer, promoted by President Richard Nixon in his State of the Union address in 1971 and responsible for the creation of the National Cancer Institute.
Arthur I. Holleb, MD, ACS senior vice president for medical affairs and research, announced that, “[T]he time has come for the American Cancer Society to mount a massive program on mammography just as we did with the Pap test,”2 according to Barron Lerner, MD, whose book “The Breast Cancer Wars” provides a history of the long-term controversies involved.4
The Pap test, widely promulgated in the 1950s and 1960s, had produced a decline in mortality from cervical cancer.
Regardless of the lack of data on effectiveness at earlier ages, the ACS chose to include women as young as 35 in the BCDDP in order “to inculcate them with ‘good health habits’ ” and “to make our screenee want to return periodically and to want to act as a missionary to bring other women into the screening process.”2
Celebrity status matters
All of the elements of a social revolution in the use of mammography were in place in the late 1960s, but the final triggers to raise social consciousness were the cases of several high-profile female celebrities. In 1973, beloved former child star Shirley Temple Black revealed her breast cancer diagnosis and mastectomy in an era when public discussion of cancer – especially breast cancer – was rare.4
But it wasn’t until 1974 that public awareness and media coverage exploded, sparked by the impact of First Lady Betty Ford’s outspokenness on her own experience of breast cancer. “In obituaries prior to the 1950s and 1960s, women who died from breast cancer were often listed as dying from ‘a prolonged disease’ or ‘a woman’s disease,’ ” according to Tasha Dubriwny, PhD, now an associate professor of communication and women’s and gender studies at Texas A&M University, College Station, when interviewed by the American Association for Cancer Research.5Betty Ford openly addressed her breast cancer diagnosis and treatment and became a prominent advocate for early screening, transforming the landscape of breast cancer awareness. And although Betty Ford’s diagnosis was based on clinical examination rather than mammography, its boost to overall screening was indisputable.
“Within weeks [after Betty Ford’s announcement] thousands of women who had been reluctant to examine their breasts inundated cancer screening centers,” according to a 1987 article in the New York Times.6 Among these women was Happy Rockefeller, the wife of Vice President Nelson A. Rockefeller. Happy Rockefeller also found that she had breast cancer upon screening, and with Betty Ford would become another icon thereafter for breast cancer screening.
“Ford’s lesson for other women was straightforward: Get a mammogram, which she had not done. The American Cancer Society and National Cancer Institute had recently mounted a demonstration project to promote the detection of breast cancer as early as possible, when it was presumed to be more curable. The degree to which women embraced Ford’s message became clear through the famous ‘Betty Ford blip.’ So many women got breast examinations and mammograms for the first time after Ford’s announcement that the actual incidence of breast cancer in the United States went up by 15 percent.”4
In a 1975 address to the American Cancer Society, Betty Ford said: “One day I appeared to be fine and the next day I was in the hospital for a mastectomy. It made me realize how many women in the country could be in the same situation. That realization made me decide to discuss my breast cancer operation openly, because I thought of all the lives in jeopardy. My experience and frank discussion of breast cancer did prompt many women to learn about self-examination, regular checkups, and such detection techniques as mammography. These are so important. I just cannot stress enough how necessary it is for women to take an active interest in their own health and body.”7
ACS guidelines evolve
It wasn’t until 1976 that the ACS issued its first major guidelines for mammography screening. The ACS suggested mammograms may be called for in women aged 35-39 if there was a personal history of breast cancer, and between ages 40 and 49 if their mother or sisters had a history of breast cancer. Women aged 50 years and older could have yearly screening. Thereafter, the use of mammography was encouraged more and more with each new set of recommendations.8
Between 1980 and 1982, these guidelines expanded to advising a baseline mammogram for women aged 35-39 years; that women consult with their physician between ages 40 and 49; and that women over 50 have a yearly mammogram.
Between 1983 and 1991, the recommendations were for a baseline mammogram for women aged 35-39 years; a mammogram every 1-2 years for women aged 40-49; and yearly mammograms for women aged 50 and up. The baseline mammogram recommendation was dropped in 1992.
Between 1997 and 2015, the stakes were upped, and women aged 40-49 years were now recommended to have yearly mammograms, as were still all women aged 50 years and older.
In October 2015, the ACS changed their recommendation to say that women aged 40-44 years should have the choice of initiating mammogram screening, and that the risks and benefits of doing so should be discussed with their physicians. Women aged 45 years and older were still recommended for yearly mammogram screening. That recommendation stands today.
Controversies arise over risk/benefit
The technology was not, however, universally embraced. “By the late 1970s, mammography had diffused much more widely but had become a source of tremendous controversy. On the one hand, advocates of the technology enthusiastically touted its ability to detect smaller, more curable cancers. On the other hand, critics asked whether breast x-rays, particularly for women aged 50 and younger, actually caused more harm than benefit.”2
In addition, meta-analyses of the nine major screening trials conducted between 1965 and 1991 indicated that the reduced breast cancer mortality with screening was dependent on age. In particular, the results for women aged 40-49 years and 50-59 years showed only borderline statistical significance, and they varied depending on how cases were accrued in individual trials.
“Assuming that differences actually exist, the absolute breast cancer mortality reduction per 10,000 women screened for 10 years ranged from 3 for age 39-49 years; 5-8 for age 50-59 years; and 12-21 for age 60=69 years,” according to a review by the U.S. Preventive Services Task Force.9
The estimates for the group aged 70-74 years were limited by low numbers of events in trials that had smaller numbers of women in this age group.
Age has continued to be a major factor in determining the cost/benefit of routine mammography screening, with the American College of Physicians stating in its 2019 guidelines, “The potential harms outweigh the benefits in most women aged 40 to 49 years,” and adding, “In average-risk women aged 75 years or older or in women with a life expectancy of 10 years or less, clinicians should discontinue screening for breast cancer.”10
A Cochrane Report from 2013 was equally critical: “If we assume that screening reduces breast cancer mortality by 15% after 13 years of follow-up and that overdiagnosis and overtreatment is at 30%, it means that for every 2,000 women invited for screening throughout 10 years, one will avoid dying of breast cancer and 10 healthy women, who would not have been diagnosed if there had not been screening, will be treated unnecessarily. Furthermore, more than 200 women will experience important psychological distress including anxiety and uncertainty for years because of false positive findings.”11
Conflicting voices exist
These reports advising a more nuanced evaluation of the benefits of mammography, however, were received with skepticism from doctors committed to the vision of breast cancer screening and convinced by anecdotal evidence in their own practices.
These reports were also in direct contradiction to recommendations made in 1997 by the National Cancer Institute, which recommended screening mammograms every 3 years for women aged 40-49 years at average risk of breast cancer.
Such scientific vacillation has contributed to a love/hate relationship with mammography in the mainstream media, fueling new controversies with regard to breast cancer screening, sometimes as much driven by public suspicion and political advocacy as by scientific evolution.
Vocal opponents of universal mammography screening arose throughout the years, and even the cases of Betty Ford and Happy Rockefeller have been called into question as iconic demonstrations of the effectiveness of screening. And although not directly linked to the issue of screening, the rebellion against the routine use of radical mastectomies, a technique pioneered by Halsted in 1894 and in continuing use into the modern era, sparked outrage in women’s rights activists who saw it as evidence of a patriarchal medical establishment making arbitrary decisions concerning women’s bodies. For example, feminist and breast cancer activist Rose Kushner argued against the unnecessary disfigurement of women’s bodies and urged the use and development of less drastic techniques, including partial mastectomies and lumpectomies as viable choices. And these choices were increasingly supported by the medical community as safe and effective alternatives for many patients.12
A 2015 paper in the Journal of the Royal Society of Medicine was bluntly titled “Mammography screening is harmful and should be abandoned.”13 According to the author, who was the editor of the 2013 Cochrane Report, “I believe that if screening had been a drug, it would have been withdrawn from the market long ago.” And the popular press has not been shy at weighing in on the controversy, driven, in part, by the lack of consensus and continually changing guidelines, with major publications such as U.S. News and World Report, the Washington Post, and others addressing the issue over the years. And even public advocacy groups such as the Susan G. Komen organization14 are supporting the more modern professional guidelines in taking a more nuanced approach to the discussion of risks and benefits for individual women.
In 2014, the Swiss Medical Board, a nationally appointed body, recommended that new mammography screening programs should not be instituted in that country and that limits be placed on current programs because of the imbalance between risks and benefits of mammography screening.15 And a study done in Australia in 2020 agreed, stating, “Using data of 30% overdiagnosis of women aged 50 to 69 years in the NSW [New South Wales] BreastScreen program in 2012, we calculated an Australian ratio of harm of overdiagnosis to benefit (breast cancer deaths avoided) of 15:1 and recommended stopping the invitation to screening.”16
Conclusion
If nothing else, the history of mammography shows that the interconnection of social factors with the rise of a medical technology can have profound impacts on patient care. Technology developed by men for women became a touchstone of resentment in a world ever more aware of sex and gender biases in everything from the conduct of clinical trials to the care (or lack thereof) of women with heart disease. Tied for so many years to a radically disfiguring and drastic form of surgery that affected what many felt to be a hallmark and representation of womanhood1,17 mammography also carried the weight of both the real and imaginary fears of radiation exposure.
Well into its development, the technology still found itself under intense public scrutiny, and was enmeshed in a continual media circus, with ping-ponging discussions of risk/benefit in the scientific literature fueling complaints by many of the dominance of a patriarchal medical community over women’s bodies.
With guidelines for mammography still evolving, questions still remaining, and new technologies such as digital imaging falling short in their hoped-for promise, the story remains unfinished, and the future still uncertain. One thing remains clear, however: In the right circumstances, with the right patient population, and properly executed, mammography has saved lives when tied to effective, early treatment, whatever its flaws and failings. This truth goes hand in hand with another reality: It may have also contributed to considerable unanticipated harm through overdiagnosis and overtreatment.
Overall, the history of mammography is a cautionary tale for the entire medical community and for the development of new medical technologies. The push-pull of the demand for progress to save lives and the slowness and often inconclusiveness of scientific studies that validate new technologies create gray areas, where social determinants and professional interests vie in an information vacuum for control of the narrative of risks vs. benefits.
The story of mammography is not yet concluded, and may never be, especially given the unlikelihood of conducting the massive randomized clinical trials that would be needed to settle the issue. It is more likely to remain controversial, at least until the technology of mammography becomes obsolete, replaced by something new and different, which will likely start the push-pull cycle all over again.
And regardless of the risks and benefits of mammography screening, the issue of treatment once breast cancer is identified is perhaps one of more overwhelming import.
References
1. Berry, DA. The Breast. 2013;22[Supplement 2]:S73-S76.
2. Lerner, BH. “To See Today With the Eyes of Tomorrow: A History of Screening Mammography.” Background paper for the Institute of Medicine report Mammography and Beyond: Developing Technologies for the Early Detection of Breast Cancer. 2001.
3. NCI website. The National Cancer Act of 1971. www.cancer.gov/about-nci/overview/history/national-cancer-act-1971.
4. Lerner BH. The Huffington Post, Sep. 26, 2014.
5. Wu C. Cancer Today. 2012;2(3): Sep. 27.
6. “”The New York Times. Oct. 17, 1987.
7. Ford B. Remarks to the American Cancer Society. 1975.
8. The American Cancer Society website. History of ACS Recommendations for the Early Detection of Cancer in People Without Symptoms.
9. Nelson HD et al. Screening for Breast Cancer: A Systematic Review to Update the 2009 U.S. Preventive Services Task Force Recommendation. 2016; Evidence Syntheses, No. 124; pp.29-49.
10. Qasseem A et al. Annals of Internal Medicine. 2019;170(8):547-60.
11. Gotzsche PC et al. Cochrane Report 2013.
12. Lerner, BH. West J Med. May 2001;174(5):362-5.
13. Gotzsche PC. J R Soc Med. 2015;108(9): 341-5.
14. Susan G. Komen website. Weighing the Benefits and Risks of Mammography.
15. Biller-Andorno N et al. N Engl J Med 2014;370:1965-7.
16. Burton R et al. JAMA Netw Open. 2020;3(6):e208249.
17. Webb C et al. Plast Surg. 2019;27(1):49-53.
Mark Lesney is the editor of Hematology News and the managing editor of MDedge.com/IDPractioner. He has a PhD in plant virology and a PhD in the history of science, with a focus on the history of biotechnology and medicine. He has worked as a writer/editor for the American Chemical Society, and has served as an adjunct assistant professor in the department of biochemistry and molecular & cellular biology at Georgetown University, Washington.
The push and pull of social forces
The push and pull of social forces
Science and technology emerge from and are shaped by social forces outside the laboratory and clinic. This is an essential fact of most new medical technology. In the Chronicles of Cancer series, part 1 of the story of mammography focused on the technological determinants of its development and use. Part 2 will focus on some of the social forces that shaped the development of mammography.
“Few medical issues have been as controversial – or as political, at least in the United States – as the role of mammographic screening for breast cancer,” according to Donald A. Berry, PhD, a biostatistician at the University of Texas MD Anderson Cancer Center, Houston.1
In fact, technology aside, the history of mammography has been and remains rife with controversy on the one side and vigorous promotion on the other, all enmeshed within the War on Cancer, corporate and professional interests, and the women’s rights movement’s growing issues with what was seen as a patriarchal medical establishment.
Today the issue of conflicts of interest are paramount in any discussion of new medical developments, from the early preclinical stages to ultimate deployment. Then, as now, professional and advocacy societies had a profound influence on government and social decision-making, but in that earlier, more trusting era, buoyed by the amazing changes that technology was bringing to everyday life and an unshakable commitment to and belief in “progress,” science and the medical community held a far more effective sway over the beliefs and behavior of the general population.
Women’s health observed
Although the main focus of the women’s movement with regard to breast cancer was a struggle against the common practice of routine radical mastectomies and a push toward breast-conserving surgeries, the issue of preventive care and screening with regard to women’s health was also a major concern.
Regarding mammography, early enthusiasm in the medical community and among the general public was profound. In 1969, Robert Egan described how mammography had a “certain magic appeal.” The patient, he continued, “feels something special is being done for her.” Women whose cancers had been discovered on a mammogram praised radiologists as heroes who had saved their lives.2
In that era, however, beyond the confines of the doctor’s office, mammography and breast cancer remained topics not discussed among the public at large, despite efforts by the American Cancer Society to change this.
ACS weighs in
Various groups had been promoting the benefits of breast self-examination since the 1930s, and in 1947, the American Cancer Society launched an awareness campaign, “Look for a Lump or Thickening in the Breast,” instructing women to perform a monthly breast self-exam. Between self-examination and clinical breast examinations in physicians’ offices, the ACS believed that smaller and more treatable breast cancers could be discovered.
In 1972, the ACS, working with the National Cancer Institute (NCI), inaugurated the Breast Cancer Detection Demonstration Project (BCDDP), which planned to screen over a quarter of a million American women for breast cancer. The initiative was a direct outgrowth of the National Cancer Act of 1971,3 the key legislation of the War on Cancer, promoted by President Richard Nixon in his State of the Union address in 1971 and responsible for the creation of the National Cancer Institute.
Arthur I. Holleb, MD, ACS senior vice president for medical affairs and research, announced that, “[T]he time has come for the American Cancer Society to mount a massive program on mammography just as we did with the Pap test,”2 according to Barron Lerner, MD, whose book “The Breast Cancer Wars” provides a history of the long-term controversies involved.4
The Pap test, widely promulgated in the 1950s and 1960s, had produced a decline in mortality from cervical cancer.
Regardless of the lack of data on effectiveness at earlier ages, the ACS chose to include women as young as 35 in the BCDDP in order “to inculcate them with ‘good health habits’ ” and “to make our screenee want to return periodically and to want to act as a missionary to bring other women into the screening process.”2
Celebrity status matters
All of the elements of a social revolution in the use of mammography were in place in the late 1960s, but the final triggers to raise social consciousness were the cases of several high-profile female celebrities. In 1973, beloved former child star Shirley Temple Black revealed her breast cancer diagnosis and mastectomy in an era when public discussion of cancer – especially breast cancer – was rare.4
But it wasn’t until 1974 that public awareness and media coverage exploded, sparked by the impact of First Lady Betty Ford’s outspokenness on her own experience of breast cancer. “In obituaries prior to the 1950s and 1960s, women who died from breast cancer were often listed as dying from ‘a prolonged disease’ or ‘a woman’s disease,’ ” according to Tasha Dubriwny, PhD, now an associate professor of communication and women’s and gender studies at Texas A&M University, College Station, when interviewed by the American Association for Cancer Research.5Betty Ford openly addressed her breast cancer diagnosis and treatment and became a prominent advocate for early screening, transforming the landscape of breast cancer awareness. And although Betty Ford’s diagnosis was based on clinical examination rather than mammography, its boost to overall screening was indisputable.
“Within weeks [after Betty Ford’s announcement] thousands of women who had been reluctant to examine their breasts inundated cancer screening centers,” according to a 1987 article in the New York Times.6 Among these women was Happy Rockefeller, the wife of Vice President Nelson A. Rockefeller. Happy Rockefeller also found that she had breast cancer upon screening, and with Betty Ford would become another icon thereafter for breast cancer screening.
“Ford’s lesson for other women was straightforward: Get a mammogram, which she had not done. The American Cancer Society and National Cancer Institute had recently mounted a demonstration project to promote the detection of breast cancer as early as possible, when it was presumed to be more curable. The degree to which women embraced Ford’s message became clear through the famous ‘Betty Ford blip.’ So many women got breast examinations and mammograms for the first time after Ford’s announcement that the actual incidence of breast cancer in the United States went up by 15 percent.”4
In a 1975 address to the American Cancer Society, Betty Ford said: “One day I appeared to be fine and the next day I was in the hospital for a mastectomy. It made me realize how many women in the country could be in the same situation. That realization made me decide to discuss my breast cancer operation openly, because I thought of all the lives in jeopardy. My experience and frank discussion of breast cancer did prompt many women to learn about self-examination, regular checkups, and such detection techniques as mammography. These are so important. I just cannot stress enough how necessary it is for women to take an active interest in their own health and body.”7
ACS guidelines evolve
It wasn’t until 1976 that the ACS issued its first major guidelines for mammography screening. The ACS suggested mammograms may be called for in women aged 35-39 if there was a personal history of breast cancer, and between ages 40 and 49 if their mother or sisters had a history of breast cancer. Women aged 50 years and older could have yearly screening. Thereafter, the use of mammography was encouraged more and more with each new set of recommendations.8
Between 1980 and 1982, these guidelines expanded to advising a baseline mammogram for women aged 35-39 years; that women consult with their physician between ages 40 and 49; and that women over 50 have a yearly mammogram.
Between 1983 and 1991, the recommendations were for a baseline mammogram for women aged 35-39 years; a mammogram every 1-2 years for women aged 40-49; and yearly mammograms for women aged 50 and up. The baseline mammogram recommendation was dropped in 1992.
Between 1997 and 2015, the stakes were upped, and women aged 40-49 years were now recommended to have yearly mammograms, as were still all women aged 50 years and older.
In October 2015, the ACS changed their recommendation to say that women aged 40-44 years should have the choice of initiating mammogram screening, and that the risks and benefits of doing so should be discussed with their physicians. Women aged 45 years and older were still recommended for yearly mammogram screening. That recommendation stands today.
Controversies arise over risk/benefit
The technology was not, however, universally embraced. “By the late 1970s, mammography had diffused much more widely but had become a source of tremendous controversy. On the one hand, advocates of the technology enthusiastically touted its ability to detect smaller, more curable cancers. On the other hand, critics asked whether breast x-rays, particularly for women aged 50 and younger, actually caused more harm than benefit.”2
In addition, meta-analyses of the nine major screening trials conducted between 1965 and 1991 indicated that the reduced breast cancer mortality with screening was dependent on age. In particular, the results for women aged 40-49 years and 50-59 years showed only borderline statistical significance, and they varied depending on how cases were accrued in individual trials.
“Assuming that differences actually exist, the absolute breast cancer mortality reduction per 10,000 women screened for 10 years ranged from 3 for age 39-49 years; 5-8 for age 50-59 years; and 12-21 for age 60=69 years,” according to a review by the U.S. Preventive Services Task Force.9
The estimates for the group aged 70-74 years were limited by low numbers of events in trials that had smaller numbers of women in this age group.
Age has continued to be a major factor in determining the cost/benefit of routine mammography screening, with the American College of Physicians stating in its 2019 guidelines, “The potential harms outweigh the benefits in most women aged 40 to 49 years,” and adding, “In average-risk women aged 75 years or older or in women with a life expectancy of 10 years or less, clinicians should discontinue screening for breast cancer.”10
A Cochrane Report from 2013 was equally critical: “If we assume that screening reduces breast cancer mortality by 15% after 13 years of follow-up and that overdiagnosis and overtreatment is at 30%, it means that for every 2,000 women invited for screening throughout 10 years, one will avoid dying of breast cancer and 10 healthy women, who would not have been diagnosed if there had not been screening, will be treated unnecessarily. Furthermore, more than 200 women will experience important psychological distress including anxiety and uncertainty for years because of false positive findings.”11
Conflicting voices exist
These reports advising a more nuanced evaluation of the benefits of mammography, however, were received with skepticism from doctors committed to the vision of breast cancer screening and convinced by anecdotal evidence in their own practices.
These reports were also in direct contradiction to recommendations made in 1997 by the National Cancer Institute, which recommended screening mammograms every 3 years for women aged 40-49 years at average risk of breast cancer.
Such scientific vacillation has contributed to a love/hate relationship with mammography in the mainstream media, fueling new controversies with regard to breast cancer screening, sometimes as much driven by public suspicion and political advocacy as by scientific evolution.
Vocal opponents of universal mammography screening arose throughout the years, and even the cases of Betty Ford and Happy Rockefeller have been called into question as iconic demonstrations of the effectiveness of screening. And although not directly linked to the issue of screening, the rebellion against the routine use of radical mastectomies, a technique pioneered by Halsted in 1894 and in continuing use into the modern era, sparked outrage in women’s rights activists who saw it as evidence of a patriarchal medical establishment making arbitrary decisions concerning women’s bodies. For example, feminist and breast cancer activist Rose Kushner argued against the unnecessary disfigurement of women’s bodies and urged the use and development of less drastic techniques, including partial mastectomies and lumpectomies as viable choices. And these choices were increasingly supported by the medical community as safe and effective alternatives for many patients.12
A 2015 paper in the Journal of the Royal Society of Medicine was bluntly titled “Mammography screening is harmful and should be abandoned.”13 According to the author, who was the editor of the 2013 Cochrane Report, “I believe that if screening had been a drug, it would have been withdrawn from the market long ago.” And the popular press has not been shy at weighing in on the controversy, driven, in part, by the lack of consensus and continually changing guidelines, with major publications such as U.S. News and World Report, the Washington Post, and others addressing the issue over the years. And even public advocacy groups such as the Susan G. Komen organization14 are supporting the more modern professional guidelines in taking a more nuanced approach to the discussion of risks and benefits for individual women.
In 2014, the Swiss Medical Board, a nationally appointed body, recommended that new mammography screening programs should not be instituted in that country and that limits be placed on current programs because of the imbalance between risks and benefits of mammography screening.15 And a study done in Australia in 2020 agreed, stating, “Using data of 30% overdiagnosis of women aged 50 to 69 years in the NSW [New South Wales] BreastScreen program in 2012, we calculated an Australian ratio of harm of overdiagnosis to benefit (breast cancer deaths avoided) of 15:1 and recommended stopping the invitation to screening.”16
Conclusion
If nothing else, the history of mammography shows that the interconnection of social factors with the rise of a medical technology can have profound impacts on patient care. Technology developed by men for women became a touchstone of resentment in a world ever more aware of sex and gender biases in everything from the conduct of clinical trials to the care (or lack thereof) of women with heart disease. Tied for so many years to a radically disfiguring and drastic form of surgery that affected what many felt to be a hallmark and representation of womanhood1,17 mammography also carried the weight of both the real and imaginary fears of radiation exposure.
Well into its development, the technology still found itself under intense public scrutiny, and was enmeshed in a continual media circus, with ping-ponging discussions of risk/benefit in the scientific literature fueling complaints by many of the dominance of a patriarchal medical community over women’s bodies.
With guidelines for mammography still evolving, questions still remaining, and new technologies such as digital imaging falling short in their hoped-for promise, the story remains unfinished, and the future still uncertain. One thing remains clear, however: In the right circumstances, with the right patient population, and properly executed, mammography has saved lives when tied to effective, early treatment, whatever its flaws and failings. This truth goes hand in hand with another reality: It may have also contributed to considerable unanticipated harm through overdiagnosis and overtreatment.
Overall, the history of mammography is a cautionary tale for the entire medical community and for the development of new medical technologies. The push-pull of the demand for progress to save lives and the slowness and often inconclusiveness of scientific studies that validate new technologies create gray areas, where social determinants and professional interests vie in an information vacuum for control of the narrative of risks vs. benefits.
The story of mammography is not yet concluded, and may never be, especially given the unlikelihood of conducting the massive randomized clinical trials that would be needed to settle the issue. It is more likely to remain controversial, at least until the technology of mammography becomes obsolete, replaced by something new and different, which will likely start the push-pull cycle all over again.
And regardless of the risks and benefits of mammography screening, the issue of treatment once breast cancer is identified is perhaps one of more overwhelming import.
References
1. Berry, DA. The Breast. 2013;22[Supplement 2]:S73-S76.
2. Lerner, BH. “To See Today With the Eyes of Tomorrow: A History of Screening Mammography.” Background paper for the Institute of Medicine report Mammography and Beyond: Developing Technologies for the Early Detection of Breast Cancer. 2001.
3. NCI website. The National Cancer Act of 1971. www.cancer.gov/about-nci/overview/history/national-cancer-act-1971.
4. Lerner BH. The Huffington Post, Sep. 26, 2014.
5. Wu C. Cancer Today. 2012;2(3): Sep. 27.
6. “”The New York Times. Oct. 17, 1987.
7. Ford B. Remarks to the American Cancer Society. 1975.
8. The American Cancer Society website. History of ACS Recommendations for the Early Detection of Cancer in People Without Symptoms.
9. Nelson HD et al. Screening for Breast Cancer: A Systematic Review to Update the 2009 U.S. Preventive Services Task Force Recommendation. 2016; Evidence Syntheses, No. 124; pp.29-49.
10. Qasseem A et al. Annals of Internal Medicine. 2019;170(8):547-60.
11. Gotzsche PC et al. Cochrane Report 2013.
12. Lerner, BH. West J Med. May 2001;174(5):362-5.
13. Gotzsche PC. J R Soc Med. 2015;108(9): 341-5.
14. Susan G. Komen website. Weighing the Benefits and Risks of Mammography.
15. Biller-Andorno N et al. N Engl J Med 2014;370:1965-7.
16. Burton R et al. JAMA Netw Open. 2020;3(6):e208249.
17. Webb C et al. Plast Surg. 2019;27(1):49-53.
Mark Lesney is the editor of Hematology News and the managing editor of MDedge.com/IDPractioner. He has a PhD in plant virology and a PhD in the history of science, with a focus on the history of biotechnology and medicine. He has worked as a writer/editor for the American Chemical Society, and has served as an adjunct assistant professor in the department of biochemistry and molecular & cellular biology at Georgetown University, Washington.
Science and technology emerge from and are shaped by social forces outside the laboratory and clinic. This is an essential fact of most new medical technology. In the Chronicles of Cancer series, part 1 of the story of mammography focused on the technological determinants of its development and use. Part 2 will focus on some of the social forces that shaped the development of mammography.
“Few medical issues have been as controversial – or as political, at least in the United States – as the role of mammographic screening for breast cancer,” according to Donald A. Berry, PhD, a biostatistician at the University of Texas MD Anderson Cancer Center, Houston.1
In fact, technology aside, the history of mammography has been and remains rife with controversy on the one side and vigorous promotion on the other, all enmeshed within the War on Cancer, corporate and professional interests, and the women’s rights movement’s growing issues with what was seen as a patriarchal medical establishment.
Today the issue of conflicts of interest are paramount in any discussion of new medical developments, from the early preclinical stages to ultimate deployment. Then, as now, professional and advocacy societies had a profound influence on government and social decision-making, but in that earlier, more trusting era, buoyed by the amazing changes that technology was bringing to everyday life and an unshakable commitment to and belief in “progress,” science and the medical community held a far more effective sway over the beliefs and behavior of the general population.
Women’s health observed
Although the main focus of the women’s movement with regard to breast cancer was a struggle against the common practice of routine radical mastectomies and a push toward breast-conserving surgeries, the issue of preventive care and screening with regard to women’s health was also a major concern.
Regarding mammography, early enthusiasm in the medical community and among the general public was profound. In 1969, Robert Egan described how mammography had a “certain magic appeal.” The patient, he continued, “feels something special is being done for her.” Women whose cancers had been discovered on a mammogram praised radiologists as heroes who had saved their lives.2
In that era, however, beyond the confines of the doctor’s office, mammography and breast cancer remained topics not discussed among the public at large, despite efforts by the American Cancer Society to change this.
ACS weighs in
Various groups had been promoting the benefits of breast self-examination since the 1930s, and in 1947, the American Cancer Society launched an awareness campaign, “Look for a Lump or Thickening in the Breast,” instructing women to perform a monthly breast self-exam. Between self-examination and clinical breast examinations in physicians’ offices, the ACS believed that smaller and more treatable breast cancers could be discovered.
In 1972, the ACS, working with the National Cancer Institute (NCI), inaugurated the Breast Cancer Detection Demonstration Project (BCDDP), which planned to screen over a quarter of a million American women for breast cancer. The initiative was a direct outgrowth of the National Cancer Act of 1971,3 the key legislation of the War on Cancer, promoted by President Richard Nixon in his State of the Union address in 1971 and responsible for the creation of the National Cancer Institute.
Arthur I. Holleb, MD, ACS senior vice president for medical affairs and research, announced that, “[T]he time has come for the American Cancer Society to mount a massive program on mammography just as we did with the Pap test,”2 according to Barron Lerner, MD, whose book “The Breast Cancer Wars” provides a history of the long-term controversies involved.4
The Pap test, widely promulgated in the 1950s and 1960s, had produced a decline in mortality from cervical cancer.
Regardless of the lack of data on effectiveness at earlier ages, the ACS chose to include women as young as 35 in the BCDDP in order “to inculcate them with ‘good health habits’ ” and “to make our screenee want to return periodically and to want to act as a missionary to bring other women into the screening process.”2
Celebrity status matters
All of the elements of a social revolution in the use of mammography were in place in the late 1960s, but the final triggers to raise social consciousness were the cases of several high-profile female celebrities. In 1973, beloved former child star Shirley Temple Black revealed her breast cancer diagnosis and mastectomy in an era when public discussion of cancer – especially breast cancer – was rare.4
But it wasn’t until 1974 that public awareness and media coverage exploded, sparked by the impact of First Lady Betty Ford’s outspokenness on her own experience of breast cancer. “In obituaries prior to the 1950s and 1960s, women who died from breast cancer were often listed as dying from ‘a prolonged disease’ or ‘a woman’s disease,’ ” according to Tasha Dubriwny, PhD, now an associate professor of communication and women’s and gender studies at Texas A&M University, College Station, when interviewed by the American Association for Cancer Research.5Betty Ford openly addressed her breast cancer diagnosis and treatment and became a prominent advocate for early screening, transforming the landscape of breast cancer awareness. And although Betty Ford’s diagnosis was based on clinical examination rather than mammography, its boost to overall screening was indisputable.
“Within weeks [after Betty Ford’s announcement] thousands of women who had been reluctant to examine their breasts inundated cancer screening centers,” according to a 1987 article in the New York Times.6 Among these women was Happy Rockefeller, the wife of Vice President Nelson A. Rockefeller. Happy Rockefeller also found that she had breast cancer upon screening, and with Betty Ford would become another icon thereafter for breast cancer screening.
“Ford’s lesson for other women was straightforward: Get a mammogram, which she had not done. The American Cancer Society and National Cancer Institute had recently mounted a demonstration project to promote the detection of breast cancer as early as possible, when it was presumed to be more curable. The degree to which women embraced Ford’s message became clear through the famous ‘Betty Ford blip.’ So many women got breast examinations and mammograms for the first time after Ford’s announcement that the actual incidence of breast cancer in the United States went up by 15 percent.”4
In a 1975 address to the American Cancer Society, Betty Ford said: “One day I appeared to be fine and the next day I was in the hospital for a mastectomy. It made me realize how many women in the country could be in the same situation. That realization made me decide to discuss my breast cancer operation openly, because I thought of all the lives in jeopardy. My experience and frank discussion of breast cancer did prompt many women to learn about self-examination, regular checkups, and such detection techniques as mammography. These are so important. I just cannot stress enough how necessary it is for women to take an active interest in their own health and body.”7
ACS guidelines evolve
It wasn’t until 1976 that the ACS issued its first major guidelines for mammography screening. The ACS suggested mammograms may be called for in women aged 35-39 if there was a personal history of breast cancer, and between ages 40 and 49 if their mother or sisters had a history of breast cancer. Women aged 50 years and older could have yearly screening. Thereafter, the use of mammography was encouraged more and more with each new set of recommendations.8
Between 1980 and 1982, these guidelines expanded to advising a baseline mammogram for women aged 35-39 years; that women consult with their physician between ages 40 and 49; and that women over 50 have a yearly mammogram.
Between 1983 and 1991, the recommendations were for a baseline mammogram for women aged 35-39 years; a mammogram every 1-2 years for women aged 40-49; and yearly mammograms for women aged 50 and up. The baseline mammogram recommendation was dropped in 1992.
Between 1997 and 2015, the stakes were upped, and women aged 40-49 years were now recommended to have yearly mammograms, as were still all women aged 50 years and older.
In October 2015, the ACS changed their recommendation to say that women aged 40-44 years should have the choice of initiating mammogram screening, and that the risks and benefits of doing so should be discussed with their physicians. Women aged 45 years and older were still recommended for yearly mammogram screening. That recommendation stands today.
Controversies arise over risk/benefit
The technology was not, however, universally embraced. “By the late 1970s, mammography had diffused much more widely but had become a source of tremendous controversy. On the one hand, advocates of the technology enthusiastically touted its ability to detect smaller, more curable cancers. On the other hand, critics asked whether breast x-rays, particularly for women aged 50 and younger, actually caused more harm than benefit.”2
In addition, meta-analyses of the nine major screening trials conducted between 1965 and 1991 indicated that the reduced breast cancer mortality with screening was dependent on age. In particular, the results for women aged 40-49 years and 50-59 years showed only borderline statistical significance, and they varied depending on how cases were accrued in individual trials.
“Assuming that differences actually exist, the absolute breast cancer mortality reduction per 10,000 women screened for 10 years ranged from 3 for age 39-49 years; 5-8 for age 50-59 years; and 12-21 for age 60=69 years,” according to a review by the U.S. Preventive Services Task Force.9
The estimates for the group aged 70-74 years were limited by low numbers of events in trials that had smaller numbers of women in this age group.
Age has continued to be a major factor in determining the cost/benefit of routine mammography screening, with the American College of Physicians stating in its 2019 guidelines, “The potential harms outweigh the benefits in most women aged 40 to 49 years,” and adding, “In average-risk women aged 75 years or older or in women with a life expectancy of 10 years or less, clinicians should discontinue screening for breast cancer.”10
A Cochrane Report from 2013 was equally critical: “If we assume that screening reduces breast cancer mortality by 15% after 13 years of follow-up and that overdiagnosis and overtreatment is at 30%, it means that for every 2,000 women invited for screening throughout 10 years, one will avoid dying of breast cancer and 10 healthy women, who would not have been diagnosed if there had not been screening, will be treated unnecessarily. Furthermore, more than 200 women will experience important psychological distress including anxiety and uncertainty for years because of false positive findings.”11
Conflicting voices exist
These reports advising a more nuanced evaluation of the benefits of mammography, however, were received with skepticism from doctors committed to the vision of breast cancer screening and convinced by anecdotal evidence in their own practices.
These reports were also in direct contradiction to recommendations made in 1997 by the National Cancer Institute, which recommended screening mammograms every 3 years for women aged 40-49 years at average risk of breast cancer.
Such scientific vacillation has contributed to a love/hate relationship with mammography in the mainstream media, fueling new controversies with regard to breast cancer screening, sometimes as much driven by public suspicion and political advocacy as by scientific evolution.
Vocal opponents of universal mammography screening arose throughout the years, and even the cases of Betty Ford and Happy Rockefeller have been called into question as iconic demonstrations of the effectiveness of screening. And although not directly linked to the issue of screening, the rebellion against the routine use of radical mastectomies, a technique pioneered by Halsted in 1894 and in continuing use into the modern era, sparked outrage in women’s rights activists who saw it as evidence of a patriarchal medical establishment making arbitrary decisions concerning women’s bodies. For example, feminist and breast cancer activist Rose Kushner argued against the unnecessary disfigurement of women’s bodies and urged the use and development of less drastic techniques, including partial mastectomies and lumpectomies as viable choices. And these choices were increasingly supported by the medical community as safe and effective alternatives for many patients.12
A 2015 paper in the Journal of the Royal Society of Medicine was bluntly titled “Mammography screening is harmful and should be abandoned.”13 According to the author, who was the editor of the 2013 Cochrane Report, “I believe that if screening had been a drug, it would have been withdrawn from the market long ago.” And the popular press has not been shy at weighing in on the controversy, driven, in part, by the lack of consensus and continually changing guidelines, with major publications such as U.S. News and World Report, the Washington Post, and others addressing the issue over the years. And even public advocacy groups such as the Susan G. Komen organization14 are supporting the more modern professional guidelines in taking a more nuanced approach to the discussion of risks and benefits for individual women.
In 2014, the Swiss Medical Board, a nationally appointed body, recommended that new mammography screening programs should not be instituted in that country and that limits be placed on current programs because of the imbalance between risks and benefits of mammography screening.15 And a study done in Australia in 2020 agreed, stating, “Using data of 30% overdiagnosis of women aged 50 to 69 years in the NSW [New South Wales] BreastScreen program in 2012, we calculated an Australian ratio of harm of overdiagnosis to benefit (breast cancer deaths avoided) of 15:1 and recommended stopping the invitation to screening.”16
Conclusion
If nothing else, the history of mammography shows that the interconnection of social factors with the rise of a medical technology can have profound impacts on patient care. Technology developed by men for women became a touchstone of resentment in a world ever more aware of sex and gender biases in everything from the conduct of clinical trials to the care (or lack thereof) of women with heart disease. Tied for so many years to a radically disfiguring and drastic form of surgery that affected what many felt to be a hallmark and representation of womanhood1,17 mammography also carried the weight of both the real and imaginary fears of radiation exposure.
Well into its development, the technology still found itself under intense public scrutiny, and was enmeshed in a continual media circus, with ping-ponging discussions of risk/benefit in the scientific literature fueling complaints by many of the dominance of a patriarchal medical community over women’s bodies.
With guidelines for mammography still evolving, questions still remaining, and new technologies such as digital imaging falling short in their hoped-for promise, the story remains unfinished, and the future still uncertain. One thing remains clear, however: In the right circumstances, with the right patient population, and properly executed, mammography has saved lives when tied to effective, early treatment, whatever its flaws and failings. This truth goes hand in hand with another reality: It may have also contributed to considerable unanticipated harm through overdiagnosis and overtreatment.
Overall, the history of mammography is a cautionary tale for the entire medical community and for the development of new medical technologies. The push-pull of the demand for progress to save lives and the slowness and often inconclusiveness of scientific studies that validate new technologies create gray areas, where social determinants and professional interests vie in an information vacuum for control of the narrative of risks vs. benefits.
The story of mammography is not yet concluded, and may never be, especially given the unlikelihood of conducting the massive randomized clinical trials that would be needed to settle the issue. It is more likely to remain controversial, at least until the technology of mammography becomes obsolete, replaced by something new and different, which will likely start the push-pull cycle all over again.
And regardless of the risks and benefits of mammography screening, the issue of treatment once breast cancer is identified is perhaps one of more overwhelming import.
References
1. Berry, DA. The Breast. 2013;22[Supplement 2]:S73-S76.
2. Lerner, BH. “To See Today With the Eyes of Tomorrow: A History of Screening Mammography.” Background paper for the Institute of Medicine report Mammography and Beyond: Developing Technologies for the Early Detection of Breast Cancer. 2001.
3. NCI website. The National Cancer Act of 1971. www.cancer.gov/about-nci/overview/history/national-cancer-act-1971.
4. Lerner BH. The Huffington Post, Sep. 26, 2014.
5. Wu C. Cancer Today. 2012;2(3): Sep. 27.
6. “”The New York Times. Oct. 17, 1987.
7. Ford B. Remarks to the American Cancer Society. 1975.
8. The American Cancer Society website. History of ACS Recommendations for the Early Detection of Cancer in People Without Symptoms.
9. Nelson HD et al. Screening for Breast Cancer: A Systematic Review to Update the 2009 U.S. Preventive Services Task Force Recommendation. 2016; Evidence Syntheses, No. 124; pp.29-49.
10. Qasseem A et al. Annals of Internal Medicine. 2019;170(8):547-60.
11. Gotzsche PC et al. Cochrane Report 2013.
12. Lerner, BH. West J Med. May 2001;174(5):362-5.
13. Gotzsche PC. J R Soc Med. 2015;108(9): 341-5.
14. Susan G. Komen website. Weighing the Benefits and Risks of Mammography.
15. Biller-Andorno N et al. N Engl J Med 2014;370:1965-7.
16. Burton R et al. JAMA Netw Open. 2020;3(6):e208249.
17. Webb C et al. Plast Surg. 2019;27(1):49-53.
Mark Lesney is the editor of Hematology News and the managing editor of MDedge.com/IDPractioner. He has a PhD in plant virology and a PhD in the history of science, with a focus on the history of biotechnology and medicine. He has worked as a writer/editor for the American Chemical Society, and has served as an adjunct assistant professor in the department of biochemistry and molecular & cellular biology at Georgetown University, Washington.
Blood biomarkers could help predict when athletes recover from concussions
, according to a new study of collegiate athletes and recovery time. “Although preliminary, the current results highlight the potential role of biomarkers in tracking neuronal recovery, which may be associated with duration of [return to sport],” wrote Cassandra L. Pattinson, PhD, of the University of Queensland, Brisbane, Australia, and the National Institutes of Health, Bethesda, Md., along with coauthors. The study was published in JAMA Network Open.
To determine if three specific blood biomarkers – total tau protein, glial fibrillary acidic protein (GFAP), and neurofilament light chain protein (NfL) – can help predict when athletes should return from sports-related concussions, a multicenter, prospective diagnostic study was launched and led by the Advanced Research Core (ARC) of the Concussion Assessment, Research, and Education (CARE) Consortium. The consortium is a joint effort of the National Collegiate Athletics Association (NCAA) and the U.S. Department of Defense.
From among the CARE ARC database, researchers evaluated 127 eligible student athletes who had experienced a sports-related concussion, underwent clinical testing and blood collection before and after their injuries, and returned to their sports. Their average age was 18.9 years old, 76% were men, and 65% were White. Biomarker levels were measured from nonfasting blood samples via ultrasensitive single molecule array technology. As current NCAA guidelines indicate that most athletes will be asymptomatic roughly 2 weeks after a concussion, the study used 14 days as a cutoff period.
Among the 127 athletes, the median return-to-sport time was 14 days; 65 returned to their sports in less than 14 days while 62 returned to their sports in 14 days or more. According to the study’s linear mixed models, athletes with a return-to-sport time of 14 days or longer had significantly higher total tau levels at 24-48 hours post injury (mean difference –0.51 pg/mL, 95% confidence interval, –0.88 to –0.14; P = .008) and when symptoms had resolved (mean difference –0.71 pg/mL, 95% CI, –1.09 to –0.34; P < .001) compared with athletes with a return-to-sport time of less than 14 days. Athletes who returned in 14 days or more also had comparatively lower levels of GFAP postinjury than did those who returned in under 14 days (4.39 pg/mL versus 4.72 pg/mL; P = .04).
Preliminary steps toward an appropriate point-of-care test
“This particular study is one of several emerging studies on what these biomarkers look like,” Brian W. Hainline, MD, chief medical officer of the NCAA, said in an interview. “It’s all still very preliminary – you couldn’t make policy changes based on what we have – but the data is accumulating. Ultimately, we should be able to perform a multivariate analysis of all the different objective biomarkers, looking at repetitive head impact exposure, looking at imaging, looking at these blood-based biomarkers. Then you can say, ‘OK, what can we do? Can we actually predict recovery, who is likely or less likely to do well?’ ”
“It’s not realistic to be taking blood samples all the time,” said Dr. Hainline, who was not involved in the study. “Another goal, once we know which biomarkers are valuable, is to convert to a point-of-care test. You get a finger prick or even a salivary test and we get the result immediately; that’s the direction that all of this is heading. But first, we have to lay out the groundwork. We envision a day, in the not too distant future, where we can get this information much more quickly.”
The authors acknowledged their study’s limitations, including an inability to standardize the time of biomarker collection and the fact that they analyzed a “relatively small number of athletes” who met their specific criteria. That said, they emphasized that their work is based on “the largest prospective sample of sports-related concussions in athletes to date” and that they “anticipate that we will be able to continue to gather a more representative sample” in the future to better generalize to the larger collegiate community.
The study was supported by the Grand Alliance Concussion Assessment, Research, and Education Consortium, which was funded in part by the NCAA and the Department of Defense. The authors disclosed receiving grants and travel reimbursements from – or working as advisers or consultants for – various organizations, college programs, and sports leagues.
SOURCE: Pattinson CL, et al. JAMA Netw Open. 2020 Aug 27. doi: 10.1001/jamanetworkopen.2020.13191.
, according to a new study of collegiate athletes and recovery time. “Although preliminary, the current results highlight the potential role of biomarkers in tracking neuronal recovery, which may be associated with duration of [return to sport],” wrote Cassandra L. Pattinson, PhD, of the University of Queensland, Brisbane, Australia, and the National Institutes of Health, Bethesda, Md., along with coauthors. The study was published in JAMA Network Open.
To determine if three specific blood biomarkers – total tau protein, glial fibrillary acidic protein (GFAP), and neurofilament light chain protein (NfL) – can help predict when athletes should return from sports-related concussions, a multicenter, prospective diagnostic study was launched and led by the Advanced Research Core (ARC) of the Concussion Assessment, Research, and Education (CARE) Consortium. The consortium is a joint effort of the National Collegiate Athletics Association (NCAA) and the U.S. Department of Defense.
From among the CARE ARC database, researchers evaluated 127 eligible student athletes who had experienced a sports-related concussion, underwent clinical testing and blood collection before and after their injuries, and returned to their sports. Their average age was 18.9 years old, 76% were men, and 65% were White. Biomarker levels were measured from nonfasting blood samples via ultrasensitive single molecule array technology. As current NCAA guidelines indicate that most athletes will be asymptomatic roughly 2 weeks after a concussion, the study used 14 days as a cutoff period.
Among the 127 athletes, the median return-to-sport time was 14 days; 65 returned to their sports in less than 14 days while 62 returned to their sports in 14 days or more. According to the study’s linear mixed models, athletes with a return-to-sport time of 14 days or longer had significantly higher total tau levels at 24-48 hours post injury (mean difference –0.51 pg/mL, 95% confidence interval, –0.88 to –0.14; P = .008) and when symptoms had resolved (mean difference –0.71 pg/mL, 95% CI, –1.09 to –0.34; P < .001) compared with athletes with a return-to-sport time of less than 14 days. Athletes who returned in 14 days or more also had comparatively lower levels of GFAP postinjury than did those who returned in under 14 days (4.39 pg/mL versus 4.72 pg/mL; P = .04).
Preliminary steps toward an appropriate point-of-care test
“This particular study is one of several emerging studies on what these biomarkers look like,” Brian W. Hainline, MD, chief medical officer of the NCAA, said in an interview. “It’s all still very preliminary – you couldn’t make policy changes based on what we have – but the data is accumulating. Ultimately, we should be able to perform a multivariate analysis of all the different objective biomarkers, looking at repetitive head impact exposure, looking at imaging, looking at these blood-based biomarkers. Then you can say, ‘OK, what can we do? Can we actually predict recovery, who is likely or less likely to do well?’ ”
“It’s not realistic to be taking blood samples all the time,” said Dr. Hainline, who was not involved in the study. “Another goal, once we know which biomarkers are valuable, is to convert to a point-of-care test. You get a finger prick or even a salivary test and we get the result immediately; that’s the direction that all of this is heading. But first, we have to lay out the groundwork. We envision a day, in the not too distant future, where we can get this information much more quickly.”
The authors acknowledged their study’s limitations, including an inability to standardize the time of biomarker collection and the fact that they analyzed a “relatively small number of athletes” who met their specific criteria. That said, they emphasized that their work is based on “the largest prospective sample of sports-related concussions in athletes to date” and that they “anticipate that we will be able to continue to gather a more representative sample” in the future to better generalize to the larger collegiate community.
The study was supported by the Grand Alliance Concussion Assessment, Research, and Education Consortium, which was funded in part by the NCAA and the Department of Defense. The authors disclosed receiving grants and travel reimbursements from – or working as advisers or consultants for – various organizations, college programs, and sports leagues.
SOURCE: Pattinson CL, et al. JAMA Netw Open. 2020 Aug 27. doi: 10.1001/jamanetworkopen.2020.13191.
, according to a new study of collegiate athletes and recovery time. “Although preliminary, the current results highlight the potential role of biomarkers in tracking neuronal recovery, which may be associated with duration of [return to sport],” wrote Cassandra L. Pattinson, PhD, of the University of Queensland, Brisbane, Australia, and the National Institutes of Health, Bethesda, Md., along with coauthors. The study was published in JAMA Network Open.
To determine if three specific blood biomarkers – total tau protein, glial fibrillary acidic protein (GFAP), and neurofilament light chain protein (NfL) – can help predict when athletes should return from sports-related concussions, a multicenter, prospective diagnostic study was launched and led by the Advanced Research Core (ARC) of the Concussion Assessment, Research, and Education (CARE) Consortium. The consortium is a joint effort of the National Collegiate Athletics Association (NCAA) and the U.S. Department of Defense.
From among the CARE ARC database, researchers evaluated 127 eligible student athletes who had experienced a sports-related concussion, underwent clinical testing and blood collection before and after their injuries, and returned to their sports. Their average age was 18.9 years old, 76% were men, and 65% were White. Biomarker levels were measured from nonfasting blood samples via ultrasensitive single molecule array technology. As current NCAA guidelines indicate that most athletes will be asymptomatic roughly 2 weeks after a concussion, the study used 14 days as a cutoff period.
Among the 127 athletes, the median return-to-sport time was 14 days; 65 returned to their sports in less than 14 days while 62 returned to their sports in 14 days or more. According to the study’s linear mixed models, athletes with a return-to-sport time of 14 days or longer had significantly higher total tau levels at 24-48 hours post injury (mean difference –0.51 pg/mL, 95% confidence interval, –0.88 to –0.14; P = .008) and when symptoms had resolved (mean difference –0.71 pg/mL, 95% CI, –1.09 to –0.34; P < .001) compared with athletes with a return-to-sport time of less than 14 days. Athletes who returned in 14 days or more also had comparatively lower levels of GFAP postinjury than did those who returned in under 14 days (4.39 pg/mL versus 4.72 pg/mL; P = .04).
Preliminary steps toward an appropriate point-of-care test
“This particular study is one of several emerging studies on what these biomarkers look like,” Brian W. Hainline, MD, chief medical officer of the NCAA, said in an interview. “It’s all still very preliminary – you couldn’t make policy changes based on what we have – but the data is accumulating. Ultimately, we should be able to perform a multivariate analysis of all the different objective biomarkers, looking at repetitive head impact exposure, looking at imaging, looking at these blood-based biomarkers. Then you can say, ‘OK, what can we do? Can we actually predict recovery, who is likely or less likely to do well?’ ”
“It’s not realistic to be taking blood samples all the time,” said Dr. Hainline, who was not involved in the study. “Another goal, once we know which biomarkers are valuable, is to convert to a point-of-care test. You get a finger prick or even a salivary test and we get the result immediately; that’s the direction that all of this is heading. But first, we have to lay out the groundwork. We envision a day, in the not too distant future, where we can get this information much more quickly.”
The authors acknowledged their study’s limitations, including an inability to standardize the time of biomarker collection and the fact that they analyzed a “relatively small number of athletes” who met their specific criteria. That said, they emphasized that their work is based on “the largest prospective sample of sports-related concussions in athletes to date” and that they “anticipate that we will be able to continue to gather a more representative sample” in the future to better generalize to the larger collegiate community.
The study was supported by the Grand Alliance Concussion Assessment, Research, and Education Consortium, which was funded in part by the NCAA and the Department of Defense. The authors disclosed receiving grants and travel reimbursements from – or working as advisers or consultants for – various organizations, college programs, and sports leagues.
SOURCE: Pattinson CL, et al. JAMA Netw Open. 2020 Aug 27. doi: 10.1001/jamanetworkopen.2020.13191.
FROM JAMA NETWORK OPEN
New schizophrenia treatment guideline released
The American Psychiatric Association has released a new evidence-based practice guideline for the treatment of schizophrenia.
The guideline focuses on assessment and treatment planning, which are integral to patient-centered care, and includes recommendations regarding pharmacotherapy, with particular focus on clozapine, as well as previously recommended and new psychosocial interventions.
“Our intention was to make recommendations to treat the whole person and take into account their family and other significant people in their lives,” George Keepers, MD, chair of the guideline writing group, said in an interview.
‘State-of-the-art methodology’
Dr. Keepers, professor of psychiatry at Oregon Health and Science University, Portland, explained the rigorous process that informs the current guideline, which was “based not solely on expert consensus but was preceded by an evidence-based review of the literature that was then discussed, digested, and distilled into specific recommendations.”
Many current recommendations are “similar to previous recommendations, but there are a few important differences,” he said.
Two experts in schizophrenia who were not involved in guideline authorship praised it for its usefulness and methodology.
Philip D. Harvey, PhD, Leonard M. Miller Professor of Psychiatry and Behavioral Sciences, University of Miami, said in an interview that the guideline “clarified the typical treatment algorithm from first episode to treatment resistance [which is] very clearly laid out for the first time.”
Christoph Correll, MD, professor of psychiatry and molecular medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, N.Y., said in an interview that the guideline “followed state-of-the-art methodology.”
First steps
The guideline recommends beginning with assessment of the patient and determination of the treatment plan.
Patients should be “treated with an antipsychotic medication and monitored for effectiveness and side effects.” Even after the patient’s symptoms have improved, antipsychotic treatment should continue.
For patients whose symptoms have improved, treatment should continue with the same antipsychotic and should not be switched.
“The problem we’re addressing in this recommendation is that patients are often treated with an effective medication and then forced, by circumstances or their insurance company, to switch to another that may not be effective for them, resulting in unnecessary relapses of the illness,” said Dr. Keepers.
“ and do what’s in the best interest of the patient,” he said.
“The guideline called out that antipsychotics that are effective and tolerated should be continued, without specifying a duration of treatment, thereby indicating indirectly that there is no clear end of the recommendation for ongoing maintenance treatment in individuals with schizophrenia,” said Dr. Correll.
Clozapine underutilized
The guideline highlights the role of clozapine and recommends its use for patients with treatment-resistant schizophrenia and those at risk for suicide. Clozapine is also recommended for patients at “substantial” risk for aggressive behavior, regardless of other treatments.
“Clozapine is underutilized for treatment of schizophrenia in the U.S. and a number of other countries, but it is a really important treatment for patients who don’t respond to other antipsychotic agents,” said Dr. Keepers.
“With this recommendation, we hope that more patients will wind up receiving the medication and benefiting from it,” he added.
In addition, patients should receive treatment with a long-acting injectable antipsychotic “if they prefer such treatment or if they have a history of poor or uncertain adherence” (level of evidence, 2B).
The guideline authors “are recommending long-acting injectable medications for people who want them, not just people with poor prior adherence, which is a critical step,” said Dr. Harvey, director of the division of psychology at the University of Miami.
Managing antipsychotic side effects
The guideline offers recommendations for patients experiencing antipsychotic-induced side effects.
VMAT2s, which represent a “class of drugs that have become available since the last schizophrenia guidelines, are effective in tardive dyskinesia. It is important that patients with tardive dyskinesia have access to these drugs because they do work,” Dr. Keepers said.
Adequate funding needed
Recommended psychosocial interventions include treatment in a specialty care program for patients with schizophrenia who are experiencing a first episode of psychosis, use of cognitive-behavioral therapy for psychosis, psychoeducation, and supported employment services (2B).
“We reviewed very good data showing that patients who receive these services are more likely to be able to be employed and less likely to be rehospitalized or have a relapse,” Dr. Keepers observed.
In addition, patients with schizophrenia should receive assertive community treatment interventions if there is a “history of poor engagement with services leading to frequent relapse or social disruption.”
Family interventions are recommended for patients who have ongoing contact with their families (2B), and patients should also receive interventions “aimed at developing self-management skills and enhancing person-oriented recovery.” They should receive cognitive remediation, social skills training, and supportive psychotherapy.
Dr. Keepers pointed to “major barriers” to providing some of these psychosocial treatments. “They are beyond the scope of someone in an individual private practice situation, so they need to be delivered within the context of treatment programs that are either publicly or privately based,” he said.
“Psychiatrists can and do work closely with community and mental health centers, psychologists, and social workers who can provide these kinds of treatments,” but “many [treatments] require specialized skills and training before they can be offered, and there is a shortage of personnel to deliver them,” he noted.
“Both the national and state governments have not provided adequate funding for treatment of individuals with this condition [schizophrenia],” he added.
Dr. Keepers reports no relevant financial relationships. The other authors’ disclosures are listed in the original article. Dr. Harvey reports no relevant financial relationships. Dr. Correll disclosed ties to Acadia, Alkermes, Allergan, Angelini, Axsome, Gedeon Richter, Gerson Lehrman Group, Indivior, IntraCellular Therapies, Janssen/J&J, LB Pharma, Lundbeck, MedAvante-ProPhase, Medscape, Merck, Mylan, Neurocrine, Noven, Otsuka, Pfizer, Recordati, Rovi, Servier, Sumitomo Dainippon, Sunovion, Supernus, Takeda, and Teva. He has received grant support from Janssen and Takeda. He is also a stock option holder of LB Pharma.
A version of this article originally appeared on Medscape.com.
The American Psychiatric Association has released a new evidence-based practice guideline for the treatment of schizophrenia.
The guideline focuses on assessment and treatment planning, which are integral to patient-centered care, and includes recommendations regarding pharmacotherapy, with particular focus on clozapine, as well as previously recommended and new psychosocial interventions.
“Our intention was to make recommendations to treat the whole person and take into account their family and other significant people in their lives,” George Keepers, MD, chair of the guideline writing group, said in an interview.
‘State-of-the-art methodology’
Dr. Keepers, professor of psychiatry at Oregon Health and Science University, Portland, explained the rigorous process that informs the current guideline, which was “based not solely on expert consensus but was preceded by an evidence-based review of the literature that was then discussed, digested, and distilled into specific recommendations.”
Many current recommendations are “similar to previous recommendations, but there are a few important differences,” he said.
Two experts in schizophrenia who were not involved in guideline authorship praised it for its usefulness and methodology.
Philip D. Harvey, PhD, Leonard M. Miller Professor of Psychiatry and Behavioral Sciences, University of Miami, said in an interview that the guideline “clarified the typical treatment algorithm from first episode to treatment resistance [which is] very clearly laid out for the first time.”
Christoph Correll, MD, professor of psychiatry and molecular medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, N.Y., said in an interview that the guideline “followed state-of-the-art methodology.”
First steps
The guideline recommends beginning with assessment of the patient and determination of the treatment plan.
Patients should be “treated with an antipsychotic medication and monitored for effectiveness and side effects.” Even after the patient’s symptoms have improved, antipsychotic treatment should continue.
For patients whose symptoms have improved, treatment should continue with the same antipsychotic and should not be switched.
“The problem we’re addressing in this recommendation is that patients are often treated with an effective medication and then forced, by circumstances or their insurance company, to switch to another that may not be effective for them, resulting in unnecessary relapses of the illness,” said Dr. Keepers.
“ and do what’s in the best interest of the patient,” he said.
“The guideline called out that antipsychotics that are effective and tolerated should be continued, without specifying a duration of treatment, thereby indicating indirectly that there is no clear end of the recommendation for ongoing maintenance treatment in individuals with schizophrenia,” said Dr. Correll.
Clozapine underutilized
The guideline highlights the role of clozapine and recommends its use for patients with treatment-resistant schizophrenia and those at risk for suicide. Clozapine is also recommended for patients at “substantial” risk for aggressive behavior, regardless of other treatments.
“Clozapine is underutilized for treatment of schizophrenia in the U.S. and a number of other countries, but it is a really important treatment for patients who don’t respond to other antipsychotic agents,” said Dr. Keepers.
“With this recommendation, we hope that more patients will wind up receiving the medication and benefiting from it,” he added.
In addition, patients should receive treatment with a long-acting injectable antipsychotic “if they prefer such treatment or if they have a history of poor or uncertain adherence” (level of evidence, 2B).
The guideline authors “are recommending long-acting injectable medications for people who want them, not just people with poor prior adherence, which is a critical step,” said Dr. Harvey, director of the division of psychology at the University of Miami.
Managing antipsychotic side effects
The guideline offers recommendations for patients experiencing antipsychotic-induced side effects.
VMAT2s, which represent a “class of drugs that have become available since the last schizophrenia guidelines, are effective in tardive dyskinesia. It is important that patients with tardive dyskinesia have access to these drugs because they do work,” Dr. Keepers said.
Adequate funding needed
Recommended psychosocial interventions include treatment in a specialty care program for patients with schizophrenia who are experiencing a first episode of psychosis, use of cognitive-behavioral therapy for psychosis, psychoeducation, and supported employment services (2B).
“We reviewed very good data showing that patients who receive these services are more likely to be able to be employed and less likely to be rehospitalized or have a relapse,” Dr. Keepers observed.
In addition, patients with schizophrenia should receive assertive community treatment interventions if there is a “history of poor engagement with services leading to frequent relapse or social disruption.”
Family interventions are recommended for patients who have ongoing contact with their families (2B), and patients should also receive interventions “aimed at developing self-management skills and enhancing person-oriented recovery.” They should receive cognitive remediation, social skills training, and supportive psychotherapy.
Dr. Keepers pointed to “major barriers” to providing some of these psychosocial treatments. “They are beyond the scope of someone in an individual private practice situation, so they need to be delivered within the context of treatment programs that are either publicly or privately based,” he said.
“Psychiatrists can and do work closely with community and mental health centers, psychologists, and social workers who can provide these kinds of treatments,” but “many [treatments] require specialized skills and training before they can be offered, and there is a shortage of personnel to deliver them,” he noted.
“Both the national and state governments have not provided adequate funding for treatment of individuals with this condition [schizophrenia],” he added.
Dr. Keepers reports no relevant financial relationships. The other authors’ disclosures are listed in the original article. Dr. Harvey reports no relevant financial relationships. Dr. Correll disclosed ties to Acadia, Alkermes, Allergan, Angelini, Axsome, Gedeon Richter, Gerson Lehrman Group, Indivior, IntraCellular Therapies, Janssen/J&J, LB Pharma, Lundbeck, MedAvante-ProPhase, Medscape, Merck, Mylan, Neurocrine, Noven, Otsuka, Pfizer, Recordati, Rovi, Servier, Sumitomo Dainippon, Sunovion, Supernus, Takeda, and Teva. He has received grant support from Janssen and Takeda. He is also a stock option holder of LB Pharma.
A version of this article originally appeared on Medscape.com.
The American Psychiatric Association has released a new evidence-based practice guideline for the treatment of schizophrenia.
The guideline focuses on assessment and treatment planning, which are integral to patient-centered care, and includes recommendations regarding pharmacotherapy, with particular focus on clozapine, as well as previously recommended and new psychosocial interventions.
“Our intention was to make recommendations to treat the whole person and take into account their family and other significant people in their lives,” George Keepers, MD, chair of the guideline writing group, said in an interview.
‘State-of-the-art methodology’
Dr. Keepers, professor of psychiatry at Oregon Health and Science University, Portland, explained the rigorous process that informs the current guideline, which was “based not solely on expert consensus but was preceded by an evidence-based review of the literature that was then discussed, digested, and distilled into specific recommendations.”
Many current recommendations are “similar to previous recommendations, but there are a few important differences,” he said.
Two experts in schizophrenia who were not involved in guideline authorship praised it for its usefulness and methodology.
Philip D. Harvey, PhD, Leonard M. Miller Professor of Psychiatry and Behavioral Sciences, University of Miami, said in an interview that the guideline “clarified the typical treatment algorithm from first episode to treatment resistance [which is] very clearly laid out for the first time.”
Christoph Correll, MD, professor of psychiatry and molecular medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, N.Y., said in an interview that the guideline “followed state-of-the-art methodology.”
First steps
The guideline recommends beginning with assessment of the patient and determination of the treatment plan.
Patients should be “treated with an antipsychotic medication and monitored for effectiveness and side effects.” Even after the patient’s symptoms have improved, antipsychotic treatment should continue.
For patients whose symptoms have improved, treatment should continue with the same antipsychotic and should not be switched.
“The problem we’re addressing in this recommendation is that patients are often treated with an effective medication and then forced, by circumstances or their insurance company, to switch to another that may not be effective for them, resulting in unnecessary relapses of the illness,” said Dr. Keepers.
“ and do what’s in the best interest of the patient,” he said.
“The guideline called out that antipsychotics that are effective and tolerated should be continued, without specifying a duration of treatment, thereby indicating indirectly that there is no clear end of the recommendation for ongoing maintenance treatment in individuals with schizophrenia,” said Dr. Correll.
Clozapine underutilized
The guideline highlights the role of clozapine and recommends its use for patients with treatment-resistant schizophrenia and those at risk for suicide. Clozapine is also recommended for patients at “substantial” risk for aggressive behavior, regardless of other treatments.
“Clozapine is underutilized for treatment of schizophrenia in the U.S. and a number of other countries, but it is a really important treatment for patients who don’t respond to other antipsychotic agents,” said Dr. Keepers.
“With this recommendation, we hope that more patients will wind up receiving the medication and benefiting from it,” he added.
In addition, patients should receive treatment with a long-acting injectable antipsychotic “if they prefer such treatment or if they have a history of poor or uncertain adherence” (level of evidence, 2B).
The guideline authors “are recommending long-acting injectable medications for people who want them, not just people with poor prior adherence, which is a critical step,” said Dr. Harvey, director of the division of psychology at the University of Miami.
Managing antipsychotic side effects
The guideline offers recommendations for patients experiencing antipsychotic-induced side effects.
VMAT2s, which represent a “class of drugs that have become available since the last schizophrenia guidelines, are effective in tardive dyskinesia. It is important that patients with tardive dyskinesia have access to these drugs because they do work,” Dr. Keepers said.
Adequate funding needed
Recommended psychosocial interventions include treatment in a specialty care program for patients with schizophrenia who are experiencing a first episode of psychosis, use of cognitive-behavioral therapy for psychosis, psychoeducation, and supported employment services (2B).
“We reviewed very good data showing that patients who receive these services are more likely to be able to be employed and less likely to be rehospitalized or have a relapse,” Dr. Keepers observed.
In addition, patients with schizophrenia should receive assertive community treatment interventions if there is a “history of poor engagement with services leading to frequent relapse or social disruption.”
Family interventions are recommended for patients who have ongoing contact with their families (2B), and patients should also receive interventions “aimed at developing self-management skills and enhancing person-oriented recovery.” They should receive cognitive remediation, social skills training, and supportive psychotherapy.
Dr. Keepers pointed to “major barriers” to providing some of these psychosocial treatments. “They are beyond the scope of someone in an individual private practice situation, so they need to be delivered within the context of treatment programs that are either publicly or privately based,” he said.
“Psychiatrists can and do work closely with community and mental health centers, psychologists, and social workers who can provide these kinds of treatments,” but “many [treatments] require specialized skills and training before they can be offered, and there is a shortage of personnel to deliver them,” he noted.
“Both the national and state governments have not provided adequate funding for treatment of individuals with this condition [schizophrenia],” he added.
Dr. Keepers reports no relevant financial relationships. The other authors’ disclosures are listed in the original article. Dr. Harvey reports no relevant financial relationships. Dr. Correll disclosed ties to Acadia, Alkermes, Allergan, Angelini, Axsome, Gedeon Richter, Gerson Lehrman Group, Indivior, IntraCellular Therapies, Janssen/J&J, LB Pharma, Lundbeck, MedAvante-ProPhase, Medscape, Merck, Mylan, Neurocrine, Noven, Otsuka, Pfizer, Recordati, Rovi, Servier, Sumitomo Dainippon, Sunovion, Supernus, Takeda, and Teva. He has received grant support from Janssen and Takeda. He is also a stock option holder of LB Pharma.
A version of this article originally appeared on Medscape.com.
Gene signature may improve prognostication in ovarian cancer
according to a study published in Annals of Oncology.
“Gene expression signature tests for prognosis are available for other cancers, such as breast cancer, and these help with treatment decisions, but no such tests are available for ovarian cancer,” senior investigator Susan J. Ramus, PhD, of Lowy Cancer Research Centre, University of NSW Sydney, commented in an interview.
Dr. Ramus and associates developed and validated their 101-gene expression signature using pretreatment tumor tissue from 3,769 women with high-grade serous ovarian cancer treated on 21 studies.
The investigators found this signature, called OTTA-SPOT (Ovarian Tumor Tissue Analysis Consortium–Stratified Prognosis of Ovarian Tumors), performed well at stratifying women according to overall survival. Median overall survival times ranged from about 2 years for patients in the top quintile of scores to more than 9 years for patients in the bottom quintile.
Moreover, OTTA-SPOT significantly improved prognostication when added to age and stage.
“This tumor test works on formalin-fixed, paraffin-embedded tumors, as collected routinely in clinical practice,” Dr. Ramus noted. “Women predicted to have poor survival using current treatments could be included in clinical trials to rapidly get alternative treatment. Many of the genes included in this test are targets of known drugs, so this information could lead to alternative targeted treatments.
“This test is not ready for routine clinical care yet,” she added. “The next step would be to include this signature as part of a clinical trial. If patients predicted to have poor survival are given alternative treatments that improve their survival, then the test could be included in treatment decisions.”
Study details
Dr. Ramus and colleagues began this work by measuring tumor expression of 513 genes selected via meta-analysis. The team then developed a gene expression assay and a prognostic signature for overall survival, which they trained on tumors from 2,702 women in 15 studies and validated on an independent set of tumors from 1,067 women in 6 studies.
In analyses adjusted for covariates, expression levels of 276 genes were associated with overall survival. The signature with the best prognostic performance contained 101 genes that were enriched in pathways having treatment implications, such as pathways involved in immune response, mitosis, and homologous recombination repair.
Adding the signature to age and stage alone improved prediction of 2- and 5-year overall survival. The area under the curve increased from 0.61 to 0.69 for 2-year overall survival and from 0.62 to 0.75 for 5-year overall survival (with nonoverlapping 95% confidence intervals for 5-year survival).
Each standard deviation increase in the gene expression score was associated with a more than doubling of the risk of death (hazard ratio, 2.35; P < .001).
The median overall survival by gene expression score quintile was 9.5 years for patients in the first quintile, 5.4 years for patients in the second, 3.8 years for patients in the third, 3.2 years for patients in the fourth, and 2.3 years for patients in the fifth.
This study was funded by the National Institutes of Health/National Cancer Institute, the Canadian Institutes for Health Research, and the Department of Defense Ovarian Cancer Research Program. Some of the authors disclosed financial relationships with a range of companies. Dr. Ramus disclosed no conflicts of interest.
SOURCE: Millstein J et al. Ann Oncol. 2020 Sep;31(9):1240-50.
according to a study published in Annals of Oncology.
“Gene expression signature tests for prognosis are available for other cancers, such as breast cancer, and these help with treatment decisions, but no such tests are available for ovarian cancer,” senior investigator Susan J. Ramus, PhD, of Lowy Cancer Research Centre, University of NSW Sydney, commented in an interview.
Dr. Ramus and associates developed and validated their 101-gene expression signature using pretreatment tumor tissue from 3,769 women with high-grade serous ovarian cancer treated on 21 studies.
The investigators found this signature, called OTTA-SPOT (Ovarian Tumor Tissue Analysis Consortium–Stratified Prognosis of Ovarian Tumors), performed well at stratifying women according to overall survival. Median overall survival times ranged from about 2 years for patients in the top quintile of scores to more than 9 years for patients in the bottom quintile.
Moreover, OTTA-SPOT significantly improved prognostication when added to age and stage.
“This tumor test works on formalin-fixed, paraffin-embedded tumors, as collected routinely in clinical practice,” Dr. Ramus noted. “Women predicted to have poor survival using current treatments could be included in clinical trials to rapidly get alternative treatment. Many of the genes included in this test are targets of known drugs, so this information could lead to alternative targeted treatments.
“This test is not ready for routine clinical care yet,” she added. “The next step would be to include this signature as part of a clinical trial. If patients predicted to have poor survival are given alternative treatments that improve their survival, then the test could be included in treatment decisions.”
Study details
Dr. Ramus and colleagues began this work by measuring tumor expression of 513 genes selected via meta-analysis. The team then developed a gene expression assay and a prognostic signature for overall survival, which they trained on tumors from 2,702 women in 15 studies and validated on an independent set of tumors from 1,067 women in 6 studies.
In analyses adjusted for covariates, expression levels of 276 genes were associated with overall survival. The signature with the best prognostic performance contained 101 genes that were enriched in pathways having treatment implications, such as pathways involved in immune response, mitosis, and homologous recombination repair.
Adding the signature to age and stage alone improved prediction of 2- and 5-year overall survival. The area under the curve increased from 0.61 to 0.69 for 2-year overall survival and from 0.62 to 0.75 for 5-year overall survival (with nonoverlapping 95% confidence intervals for 5-year survival).
Each standard deviation increase in the gene expression score was associated with a more than doubling of the risk of death (hazard ratio, 2.35; P < .001).
The median overall survival by gene expression score quintile was 9.5 years for patients in the first quintile, 5.4 years for patients in the second, 3.8 years for patients in the third, 3.2 years for patients in the fourth, and 2.3 years for patients in the fifth.
This study was funded by the National Institutes of Health/National Cancer Institute, the Canadian Institutes for Health Research, and the Department of Defense Ovarian Cancer Research Program. Some of the authors disclosed financial relationships with a range of companies. Dr. Ramus disclosed no conflicts of interest.
SOURCE: Millstein J et al. Ann Oncol. 2020 Sep;31(9):1240-50.
according to a study published in Annals of Oncology.
“Gene expression signature tests for prognosis are available for other cancers, such as breast cancer, and these help with treatment decisions, but no such tests are available for ovarian cancer,” senior investigator Susan J. Ramus, PhD, of Lowy Cancer Research Centre, University of NSW Sydney, commented in an interview.
Dr. Ramus and associates developed and validated their 101-gene expression signature using pretreatment tumor tissue from 3,769 women with high-grade serous ovarian cancer treated on 21 studies.
The investigators found this signature, called OTTA-SPOT (Ovarian Tumor Tissue Analysis Consortium–Stratified Prognosis of Ovarian Tumors), performed well at stratifying women according to overall survival. Median overall survival times ranged from about 2 years for patients in the top quintile of scores to more than 9 years for patients in the bottom quintile.
Moreover, OTTA-SPOT significantly improved prognostication when added to age and stage.
“This tumor test works on formalin-fixed, paraffin-embedded tumors, as collected routinely in clinical practice,” Dr. Ramus noted. “Women predicted to have poor survival using current treatments could be included in clinical trials to rapidly get alternative treatment. Many of the genes included in this test are targets of known drugs, so this information could lead to alternative targeted treatments.
“This test is not ready for routine clinical care yet,” she added. “The next step would be to include this signature as part of a clinical trial. If patients predicted to have poor survival are given alternative treatments that improve their survival, then the test could be included in treatment decisions.”
Study details
Dr. Ramus and colleagues began this work by measuring tumor expression of 513 genes selected via meta-analysis. The team then developed a gene expression assay and a prognostic signature for overall survival, which they trained on tumors from 2,702 women in 15 studies and validated on an independent set of tumors from 1,067 women in 6 studies.
In analyses adjusted for covariates, expression levels of 276 genes were associated with overall survival. The signature with the best prognostic performance contained 101 genes that were enriched in pathways having treatment implications, such as pathways involved in immune response, mitosis, and homologous recombination repair.
Adding the signature to age and stage alone improved prediction of 2- and 5-year overall survival. The area under the curve increased from 0.61 to 0.69 for 2-year overall survival and from 0.62 to 0.75 for 5-year overall survival (with nonoverlapping 95% confidence intervals for 5-year survival).
Each standard deviation increase in the gene expression score was associated with a more than doubling of the risk of death (hazard ratio, 2.35; P < .001).
The median overall survival by gene expression score quintile was 9.5 years for patients in the first quintile, 5.4 years for patients in the second, 3.8 years for patients in the third, 3.2 years for patients in the fourth, and 2.3 years for patients in the fifth.
This study was funded by the National Institutes of Health/National Cancer Institute, the Canadian Institutes for Health Research, and the Department of Defense Ovarian Cancer Research Program. Some of the authors disclosed financial relationships with a range of companies. Dr. Ramus disclosed no conflicts of interest.
SOURCE: Millstein J et al. Ann Oncol. 2020 Sep;31(9):1240-50.
FROM ANNALS OF ONCOLOGY
Hyperpigmentation of the Tongue
The Diagnosis: Addison Disease in the Context of Polyglandular Autoimmune Syndrome Type 2
The patient’s hormone levels as well as distinct clinical features led to a diagnosis of Addison disease in the context of polyglandular autoimmune syndrome type 2 (PAS-2). Approximately 50% of PAS-2 cases are familiar, and different modes of inheritance—autosomal recessive, autosomal dominant, and polygenic—have been reported. Women are affected up to 3 times more often than men.1,2 The age of onset ranges from infancy to late adulthood, with most cases occurring in early adulthood. Primary adrenal insufficiency (Addison disease) is the principal manifestation of PAS-2. It appears in approximately 50% of patients, occurring simultaneously with autoimmune thyroid disease or diabetes mellitus in 20% of patients and following them in 30% of patients.1,2 Autoimmune thyroid diseases such as chronic autoimmune thyroiditis and occasionally Graves disease as well as type 1 diabetes mellitus also are common. Polyglandular autoimmune syndrome type 2 with primary adrenal insufficiency and autoimmune thyroid disease was formerly referred to as Schmidt syndrome.3 It must be differentiated from polyglandular autoimmune syndrome type 1, a rare condition that also is referred to as autoimmune polyendocrinopathycandidiasis-ectodermal dystrophy syndrome.1,3 As with any other cause of adrenal insufficiency, the treatment involves hormone replacement therapy up to normal levels and then tapering according to stress levels (ie, surgery or infections that require a dose increase). Our patient was diagnosed according to hormone levels and clinical features and was started on 30 mg daily of hydrocortisone and 50 μg daily of levothyroxine. No improvement in her condition was noted after 6 months of treatment. The patient is still under yearly follow-up, and the mucous hyperpigmentation faded approximately 6 months after hormonal homeostasis was achieved.
Peutz-Jeghers syndrome is inherited in an autosomal-dominant fashion. It is characterized by multiple hamartomatous polyps in the gastrointestinal tract, mucocutaneous pigmentation, and an increased risk for gastrointestinal and nongastrointestinal cancer. Mucocutaneous pigmented macules most commonly occur on the lips and perioral region, buccal mucosa, and the palms and soles. However, mucocutaneous pigmentation usually occurs during the first 1 to 2 years of life, increases in size and number over the ensuing years, and usually fades after puberty.4
Laugier-Hunziker syndrome is an acquired benign disorder presenting in adults with lentigines on the lips and buccal mucosa. It frequently is accompaniedby longitudinal melanonychia, macular pigmentation of the genitals, and involvement of the palms and soles. The diagnosis of Laugier-Hunziker syndrome is one of exclusion and is made after ruling out other causes of oral and labial hyperpigmentation, including physiologic pigmentation seen in darker-skinned individuals as well as inherited diseases associated with lentiginosis, requiring complete physical examination, endoscopy, and colonscopy.5
A wide variety of drugs and chemicals can lead to diffuse cutaneous hyperpigmentation. Increased production of melanin and/or the deposition of drug complexes or metals in the dermis is responsible for the skin discoloration. Drugs that most often cause hyperpigmentation on mucosal surfaces are hydroxychloroquine, minocycline, nicotine, silver, and some chemotherapy agents. The hyperpigmentation usually resolves with discontinuation of the offending agent, but the course may be prolonged over months to years.6
Changes in the skin and subcutaneous tissue occur in patients with Cushing syndrome. Hyperpigmentation is induced by increased secretion of adrenocorticotropic hormone, not cortisol, and occurs most often in patients with the ectopic adrenocorticotropic hormone syndrome. Hyperpigmentation may be generalized but is more intense in areas exposed to light (eg, face, neck, dorsal aspects of the hands) or to chronic mild trauma, friction, or pressure (eg, elbows, knees, spine, knuckles). Patchy pigmentation may occur on the inner surface of the lips and the buccal mucosa along the line of dental occlusion. Acanthosis nigricans also can be present in the axillae and around the neck.7
- Ferre EM, Rose SR, Rosenzweig SD, et al. Redefined clinical features and diagnostic criteria in autoimmune polyendocrinopathycandidiasis-ectodermal dystrophy. JCI Insight. 2016;1:E88782.
- Orlova EM, Sozaeva LS, Kareva MA, et al. Expanding the phenotypic and genotypic landscape of autoimmune polyendocrine syndrome type 1. J Clin Endocrinol Metab. 2017;102:3546-3556.
- Ahonen P, Myllärniemi S, Sipilä I, et al. Clinical variation of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) in a series of 68 patients. N Engl J Med. 1990;322:1829-1836.
- Utsunomiya J, Gocho H, Miyanaga T, et al. Peutz-Jeghers syndrome: its natural course and management. Johns Hopkins Med J. 1975;136:71-82.
- Nayak RS, Kotrashetti VS, Hosmani JV. Laugier-Hunziker syndrome. J Oral Maxillofac Pathol. 2012;16:245-250.
- Krause W. Drug-induced hyperpigmentation: a systematic review. J Dtsch Dermatol Ges. 2013;11:644-651.
- Newell-Price J, Trainer P, Besser M, et al. The diagnosis and differential diagnosis of Cushing’s syndrome and pseudo-Cushing’s states. Endocr Rev. 1998;19:647-672.
The Diagnosis: Addison Disease in the Context of Polyglandular Autoimmune Syndrome Type 2
The patient’s hormone levels as well as distinct clinical features led to a diagnosis of Addison disease in the context of polyglandular autoimmune syndrome type 2 (PAS-2). Approximately 50% of PAS-2 cases are familiar, and different modes of inheritance—autosomal recessive, autosomal dominant, and polygenic—have been reported. Women are affected up to 3 times more often than men.1,2 The age of onset ranges from infancy to late adulthood, with most cases occurring in early adulthood. Primary adrenal insufficiency (Addison disease) is the principal manifestation of PAS-2. It appears in approximately 50% of patients, occurring simultaneously with autoimmune thyroid disease or diabetes mellitus in 20% of patients and following them in 30% of patients.1,2 Autoimmune thyroid diseases such as chronic autoimmune thyroiditis and occasionally Graves disease as well as type 1 diabetes mellitus also are common. Polyglandular autoimmune syndrome type 2 with primary adrenal insufficiency and autoimmune thyroid disease was formerly referred to as Schmidt syndrome.3 It must be differentiated from polyglandular autoimmune syndrome type 1, a rare condition that also is referred to as autoimmune polyendocrinopathycandidiasis-ectodermal dystrophy syndrome.1,3 As with any other cause of adrenal insufficiency, the treatment involves hormone replacement therapy up to normal levels and then tapering according to stress levels (ie, surgery or infections that require a dose increase). Our patient was diagnosed according to hormone levels and clinical features and was started on 30 mg daily of hydrocortisone and 50 μg daily of levothyroxine. No improvement in her condition was noted after 6 months of treatment. The patient is still under yearly follow-up, and the mucous hyperpigmentation faded approximately 6 months after hormonal homeostasis was achieved.
Peutz-Jeghers syndrome is inherited in an autosomal-dominant fashion. It is characterized by multiple hamartomatous polyps in the gastrointestinal tract, mucocutaneous pigmentation, and an increased risk for gastrointestinal and nongastrointestinal cancer. Mucocutaneous pigmented macules most commonly occur on the lips and perioral region, buccal mucosa, and the palms and soles. However, mucocutaneous pigmentation usually occurs during the first 1 to 2 years of life, increases in size and number over the ensuing years, and usually fades after puberty.4
Laugier-Hunziker syndrome is an acquired benign disorder presenting in adults with lentigines on the lips and buccal mucosa. It frequently is accompaniedby longitudinal melanonychia, macular pigmentation of the genitals, and involvement of the palms and soles. The diagnosis of Laugier-Hunziker syndrome is one of exclusion and is made after ruling out other causes of oral and labial hyperpigmentation, including physiologic pigmentation seen in darker-skinned individuals as well as inherited diseases associated with lentiginosis, requiring complete physical examination, endoscopy, and colonscopy.5
A wide variety of drugs and chemicals can lead to diffuse cutaneous hyperpigmentation. Increased production of melanin and/or the deposition of drug complexes or metals in the dermis is responsible for the skin discoloration. Drugs that most often cause hyperpigmentation on mucosal surfaces are hydroxychloroquine, minocycline, nicotine, silver, and some chemotherapy agents. The hyperpigmentation usually resolves with discontinuation of the offending agent, but the course may be prolonged over months to years.6
Changes in the skin and subcutaneous tissue occur in patients with Cushing syndrome. Hyperpigmentation is induced by increased secretion of adrenocorticotropic hormone, not cortisol, and occurs most often in patients with the ectopic adrenocorticotropic hormone syndrome. Hyperpigmentation may be generalized but is more intense in areas exposed to light (eg, face, neck, dorsal aspects of the hands) or to chronic mild trauma, friction, or pressure (eg, elbows, knees, spine, knuckles). Patchy pigmentation may occur on the inner surface of the lips and the buccal mucosa along the line of dental occlusion. Acanthosis nigricans also can be present in the axillae and around the neck.7
The Diagnosis: Addison Disease in the Context of Polyglandular Autoimmune Syndrome Type 2
The patient’s hormone levels as well as distinct clinical features led to a diagnosis of Addison disease in the context of polyglandular autoimmune syndrome type 2 (PAS-2). Approximately 50% of PAS-2 cases are familiar, and different modes of inheritance—autosomal recessive, autosomal dominant, and polygenic—have been reported. Women are affected up to 3 times more often than men.1,2 The age of onset ranges from infancy to late adulthood, with most cases occurring in early adulthood. Primary adrenal insufficiency (Addison disease) is the principal manifestation of PAS-2. It appears in approximately 50% of patients, occurring simultaneously with autoimmune thyroid disease or diabetes mellitus in 20% of patients and following them in 30% of patients.1,2 Autoimmune thyroid diseases such as chronic autoimmune thyroiditis and occasionally Graves disease as well as type 1 diabetes mellitus also are common. Polyglandular autoimmune syndrome type 2 with primary adrenal insufficiency and autoimmune thyroid disease was formerly referred to as Schmidt syndrome.3 It must be differentiated from polyglandular autoimmune syndrome type 1, a rare condition that also is referred to as autoimmune polyendocrinopathycandidiasis-ectodermal dystrophy syndrome.1,3 As with any other cause of adrenal insufficiency, the treatment involves hormone replacement therapy up to normal levels and then tapering according to stress levels (ie, surgery or infections that require a dose increase). Our patient was diagnosed according to hormone levels and clinical features and was started on 30 mg daily of hydrocortisone and 50 μg daily of levothyroxine. No improvement in her condition was noted after 6 months of treatment. The patient is still under yearly follow-up, and the mucous hyperpigmentation faded approximately 6 months after hormonal homeostasis was achieved.
Peutz-Jeghers syndrome is inherited in an autosomal-dominant fashion. It is characterized by multiple hamartomatous polyps in the gastrointestinal tract, mucocutaneous pigmentation, and an increased risk for gastrointestinal and nongastrointestinal cancer. Mucocutaneous pigmented macules most commonly occur on the lips and perioral region, buccal mucosa, and the palms and soles. However, mucocutaneous pigmentation usually occurs during the first 1 to 2 years of life, increases in size and number over the ensuing years, and usually fades after puberty.4
Laugier-Hunziker syndrome is an acquired benign disorder presenting in adults with lentigines on the lips and buccal mucosa. It frequently is accompaniedby longitudinal melanonychia, macular pigmentation of the genitals, and involvement of the palms and soles. The diagnosis of Laugier-Hunziker syndrome is one of exclusion and is made after ruling out other causes of oral and labial hyperpigmentation, including physiologic pigmentation seen in darker-skinned individuals as well as inherited diseases associated with lentiginosis, requiring complete physical examination, endoscopy, and colonscopy.5
A wide variety of drugs and chemicals can lead to diffuse cutaneous hyperpigmentation. Increased production of melanin and/or the deposition of drug complexes or metals in the dermis is responsible for the skin discoloration. Drugs that most often cause hyperpigmentation on mucosal surfaces are hydroxychloroquine, minocycline, nicotine, silver, and some chemotherapy agents. The hyperpigmentation usually resolves with discontinuation of the offending agent, but the course may be prolonged over months to years.6
Changes in the skin and subcutaneous tissue occur in patients with Cushing syndrome. Hyperpigmentation is induced by increased secretion of adrenocorticotropic hormone, not cortisol, and occurs most often in patients with the ectopic adrenocorticotropic hormone syndrome. Hyperpigmentation may be generalized but is more intense in areas exposed to light (eg, face, neck, dorsal aspects of the hands) or to chronic mild trauma, friction, or pressure (eg, elbows, knees, spine, knuckles). Patchy pigmentation may occur on the inner surface of the lips and the buccal mucosa along the line of dental occlusion. Acanthosis nigricans also can be present in the axillae and around the neck.7
- Ferre EM, Rose SR, Rosenzweig SD, et al. Redefined clinical features and diagnostic criteria in autoimmune polyendocrinopathycandidiasis-ectodermal dystrophy. JCI Insight. 2016;1:E88782.
- Orlova EM, Sozaeva LS, Kareva MA, et al. Expanding the phenotypic and genotypic landscape of autoimmune polyendocrine syndrome type 1. J Clin Endocrinol Metab. 2017;102:3546-3556.
- Ahonen P, Myllärniemi S, Sipilä I, et al. Clinical variation of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) in a series of 68 patients. N Engl J Med. 1990;322:1829-1836.
- Utsunomiya J, Gocho H, Miyanaga T, et al. Peutz-Jeghers syndrome: its natural course and management. Johns Hopkins Med J. 1975;136:71-82.
- Nayak RS, Kotrashetti VS, Hosmani JV. Laugier-Hunziker syndrome. J Oral Maxillofac Pathol. 2012;16:245-250.
- Krause W. Drug-induced hyperpigmentation: a systematic review. J Dtsch Dermatol Ges. 2013;11:644-651.
- Newell-Price J, Trainer P, Besser M, et al. The diagnosis and differential diagnosis of Cushing’s syndrome and pseudo-Cushing’s states. Endocr Rev. 1998;19:647-672.
- Ferre EM, Rose SR, Rosenzweig SD, et al. Redefined clinical features and diagnostic criteria in autoimmune polyendocrinopathycandidiasis-ectodermal dystrophy. JCI Insight. 2016;1:E88782.
- Orlova EM, Sozaeva LS, Kareva MA, et al. Expanding the phenotypic and genotypic landscape of autoimmune polyendocrine syndrome type 1. J Clin Endocrinol Metab. 2017;102:3546-3556.
- Ahonen P, Myllärniemi S, Sipilä I, et al. Clinical variation of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) in a series of 68 patients. N Engl J Med. 1990;322:1829-1836.
- Utsunomiya J, Gocho H, Miyanaga T, et al. Peutz-Jeghers syndrome: its natural course and management. Johns Hopkins Med J. 1975;136:71-82.
- Nayak RS, Kotrashetti VS, Hosmani JV. Laugier-Hunziker syndrome. J Oral Maxillofac Pathol. 2012;16:245-250.
- Krause W. Drug-induced hyperpigmentation: a systematic review. J Dtsch Dermatol Ges. 2013;11:644-651.
- Newell-Price J, Trainer P, Besser M, et al. The diagnosis and differential diagnosis of Cushing’s syndrome and pseudo-Cushing’s states. Endocr Rev. 1998;19:647-672.
An otherwise healthy 17-year-old adolescent girl from Spain presented with hyperpigmentation on the tongue of several weeks’ duration. She denied licking graphite pencils or pens. Physical examination revealed pigmentation in the palmar creases and a slight generalized tan. The patient denied sun exposure. Neither melanonychia nor genital hyperpigmented lesions were noted. Blood tests showed overt hypothyroidism.
Smallpox Vaccination-Associated Myopericarditis
A renewed effort to vaccinate service members fighting the global war on terrorism has brought new diagnostic challenges. Vaccinations not generally given to the public are routinely given to service members when they deploy to various parts of the world. Examples include anthrax, yellow fever, Japanese encephalitis, rabies, polio, and smallpox. Every vaccination has potential for adverse effects (AEs), which can range from mild to severe life-threatening complications. These AEs often go unrecognized and untreated because physicians are not routinely screening for vaccination administration.
Background
Smallpox (Variola major) was successfully eradicated in 1977 due to worldwide vaccination efforts.1 However, the threat of bioterrorism has renewed mandatory smallpox vaccinations for high-risk individuals, such as active-duty military personnel.1,2 A notable increase in myopericarditis has been reported with the new generation of smallpox vaccination, ACAM2000.3 We present a case of a 27-year-old healthy male who presented with chest pain and diffuse ST segment elevations consistent with myopericarditis after vaccination with ACAM2000.
Case Presentation
A healthy 27-year-old soldier presented to the emergency department with sudden, new onset, sharp-stabbing, substernal chest pain, which was made worse with lying flat and better with leaning forward. Vital signs were unremarkable. He recently enlisted in the US Army and received the smallpox vaccination about 11 days before as part of a routine predeployment checklist. The patient reported he did not have any viral symptoms, such as fever, chills, nausea, vomiting, diarrhea, shortness of breath, sore throat, rhinorrhea, or sputum production. He also reported having no prior illness for the past 3 months, sick contacts at home or work, or recent travel outside the US. He reported no tobacco use, alcohol use, or illicit drug use. The patient’s family history was negative for significant cardiac disease.
A physical examination was unremarkable. The initial laboratory report showed no leukocytosis, anemia, thrombocytopenia, electrolytes derangement, abnormal kidney function, or abnormal liver function tests. Initial troponin was 0.25 ng/mL, erythrocyte sedimentation rate (ESR) was 40 mmol/h and C-reactive protein (CRP) was 120.2 mg/L suggestive of acute inflammation. A urine drug screen was negative. D-dimer was < 0.27. An electrocardiogram (ECG) showed diffuse ST segment elevation (Figure 1). An echocardiogram showed normal left ventricle size, and function with ejection fraction 55 to 60%, normal diastolic dysfunction, and trivial pericardial effusion. Magnetic resonance imaging (MRI) showed increased T2 signal intensity of the myocardium suggestive of myopericarditis (Figure 2). A computed tomography (CT) angiogram of the coronary arteries showed no significant stenosis.
The patient was treated with ibuprofen for 2 weeks and colchicine for 3 months, and his symptoms resolved. He followed up with an appointment in the cardiology clinic 1 month later, and his ESR, CRP, and troponin results were negative. A limited echocardiogram showed ejection fraction 60 to 65%, no regional wall motion abnormalities, normal diastolic function, and resolution of the pericardial effusion.
Discussion
Smallpox was a major worldwide cause of mortality; about 30% of those infected died because of smallpox.2,4,5 Due to a worldwide vaccination effort, the World Health Organization declared smallpox was eradicated in 1977.2,4,5 However, despite successful eradication, smallpox is considered a possible bioterrorism target, which prompted a resurgence of mandatory smallpox vaccinations for active-duty personnel.2,5
Dryvax, a freeze-dried calf lymph smallpox vaccine was used extensively from the 1940s to the 1980s but was replaced in 2008 by ACAM2000, a smallpox vaccine cultured in kidney epithelial cells from African green monkeys.3,5 Myopericarditis was rarely associated with the Dryvax, with only 5 cases reported from 1955 to 1986 after millions of doses of vaccines were administered; however, in 230,734 administered ACAM2000 doses, 18 cases of myopericarditis (incidence, 7.8 per 100,000) were reported during a surveillance study in 2002 and 2003.3,5
Myopericarditis presents with a wide variety of symptoms, such as chest pain, palpitations, chills, shortness of breath, and fever.6,7 Mainstay diagnostic criteria include ECG findings consistent with myopericarditis (such as diffuse ST segment elevations) and elevated cardiac biomarkers (elevated troponins).5-7 An echocardiogram can be helpful in diagnosis, as most cases will not have regional wall motion abnormalities (to distinguish against coronary artery disease).5-7 MRI with diffuse enhancement of the myocardium can be helpful in diagnosis.5,6 The gold standard for diagnosis is an endomyocardial biopsy, which carries a significant risk of complications and is not routinely performed to diagnose myopericarditis.5,6 US military smallpox vaccination data showed that the onset of vaccine-associated myopericarditis averaged (SD) 10.4 (3.6) days after vaccination.5
Vaccine-associated myopericarditis treatment is focused on decreasing inflammation.5,6 Nonsteroidal anti-inflammatory drugs are advised for about 2 weeks with cessation of intensive cardiac activities for between 4 and 6 weeks due to risks of congestive heart failure and fatal cardiac arrhythmias.5,6
Conclusions
Since the September 11 attacks, the US needs to be continually prepared for potential terrorism on American soil and abroad. The threat of bioterrorism has renewed efforts to vaccinate or revaccinate American service members deployed to high-risk regions. These vaccinations put them at risk for vaccination-induced complications that can range from mild fever to life-threatening complications.
1. Bruner DI, Butler BS. Smallpox vaccination-associated myopericarditis is more common with the newest smallpox vaccine. J Emerg Med. 2014;46(3):e85-e87. doi:10.1016/j.jemermed.2013.06.001
2. Halsell JS, Riddle JR, Atwood JE, et al. Myopericarditis following smallpox vaccination among vaccinia-naive US military personnel. JAMA. 2003;289(24):3283-3289. doi:10.1001/jama.289.24.3283
3. Nalca A, Zumbrun EE. ACAM2000: the new smallpox vaccine for United States Strategic National Stockpile. Drug Des Devel Ther. 2010;4:71-79. doi:10.2147/dddt.s3687
4. Wollenberg A, Engler R. Smallpox, vaccination and adverse reactions to smallpox vaccine. Curr Opin Allergy Clin Immunol. 2004;4(4):271-275. doi:10.1097/01.all.0000136758.66442.28
5. Cassimatis DC, Atwood JE, Engler RM, Linz PE, Grabenstein JD, Vernalis MN. Smallpox vaccination and myopericarditis: a clinical review. J Am Coll Cardiol. 2004;43(9):1503-1510. doi:10.1016/j.jacc.2003.11.053
6. Sharma U, Tak T. A report of 2 cases of myopericarditis after Vaccinia virus (smallpox) immunization. WMJ. 2011;110(6):291-294.
7. Sarkisian SA, Hand G, Rivera VM, Smith M, Miller JA. A case series of smallpox vaccination-associated myopericarditis: effects on safety and readiness of the active duty soldier. Mil Med. 2019;184(1-2):e280-e283. doi:10.1093/milmed/usy159
A renewed effort to vaccinate service members fighting the global war on terrorism has brought new diagnostic challenges. Vaccinations not generally given to the public are routinely given to service members when they deploy to various parts of the world. Examples include anthrax, yellow fever, Japanese encephalitis, rabies, polio, and smallpox. Every vaccination has potential for adverse effects (AEs), which can range from mild to severe life-threatening complications. These AEs often go unrecognized and untreated because physicians are not routinely screening for vaccination administration.
Background
Smallpox (Variola major) was successfully eradicated in 1977 due to worldwide vaccination efforts.1 However, the threat of bioterrorism has renewed mandatory smallpox vaccinations for high-risk individuals, such as active-duty military personnel.1,2 A notable increase in myopericarditis has been reported with the new generation of smallpox vaccination, ACAM2000.3 We present a case of a 27-year-old healthy male who presented with chest pain and diffuse ST segment elevations consistent with myopericarditis after vaccination with ACAM2000.
Case Presentation
A healthy 27-year-old soldier presented to the emergency department with sudden, new onset, sharp-stabbing, substernal chest pain, which was made worse with lying flat and better with leaning forward. Vital signs were unremarkable. He recently enlisted in the US Army and received the smallpox vaccination about 11 days before as part of a routine predeployment checklist. The patient reported he did not have any viral symptoms, such as fever, chills, nausea, vomiting, diarrhea, shortness of breath, sore throat, rhinorrhea, or sputum production. He also reported having no prior illness for the past 3 months, sick contacts at home or work, or recent travel outside the US. He reported no tobacco use, alcohol use, or illicit drug use. The patient’s family history was negative for significant cardiac disease.
A physical examination was unremarkable. The initial laboratory report showed no leukocytosis, anemia, thrombocytopenia, electrolytes derangement, abnormal kidney function, or abnormal liver function tests. Initial troponin was 0.25 ng/mL, erythrocyte sedimentation rate (ESR) was 40 mmol/h and C-reactive protein (CRP) was 120.2 mg/L suggestive of acute inflammation. A urine drug screen was negative. D-dimer was < 0.27. An electrocardiogram (ECG) showed diffuse ST segment elevation (Figure 1). An echocardiogram showed normal left ventricle size, and function with ejection fraction 55 to 60%, normal diastolic dysfunction, and trivial pericardial effusion. Magnetic resonance imaging (MRI) showed increased T2 signal intensity of the myocardium suggestive of myopericarditis (Figure 2). A computed tomography (CT) angiogram of the coronary arteries showed no significant stenosis.
The patient was treated with ibuprofen for 2 weeks and colchicine for 3 months, and his symptoms resolved. He followed up with an appointment in the cardiology clinic 1 month later, and his ESR, CRP, and troponin results were negative. A limited echocardiogram showed ejection fraction 60 to 65%, no regional wall motion abnormalities, normal diastolic function, and resolution of the pericardial effusion.
Discussion
Smallpox was a major worldwide cause of mortality; about 30% of those infected died because of smallpox.2,4,5 Due to a worldwide vaccination effort, the World Health Organization declared smallpox was eradicated in 1977.2,4,5 However, despite successful eradication, smallpox is considered a possible bioterrorism target, which prompted a resurgence of mandatory smallpox vaccinations for active-duty personnel.2,5
Dryvax, a freeze-dried calf lymph smallpox vaccine was used extensively from the 1940s to the 1980s but was replaced in 2008 by ACAM2000, a smallpox vaccine cultured in kidney epithelial cells from African green monkeys.3,5 Myopericarditis was rarely associated with the Dryvax, with only 5 cases reported from 1955 to 1986 after millions of doses of vaccines were administered; however, in 230,734 administered ACAM2000 doses, 18 cases of myopericarditis (incidence, 7.8 per 100,000) were reported during a surveillance study in 2002 and 2003.3,5
Myopericarditis presents with a wide variety of symptoms, such as chest pain, palpitations, chills, shortness of breath, and fever.6,7 Mainstay diagnostic criteria include ECG findings consistent with myopericarditis (such as diffuse ST segment elevations) and elevated cardiac biomarkers (elevated troponins).5-7 An echocardiogram can be helpful in diagnosis, as most cases will not have regional wall motion abnormalities (to distinguish against coronary artery disease).5-7 MRI with diffuse enhancement of the myocardium can be helpful in diagnosis.5,6 The gold standard for diagnosis is an endomyocardial biopsy, which carries a significant risk of complications and is not routinely performed to diagnose myopericarditis.5,6 US military smallpox vaccination data showed that the onset of vaccine-associated myopericarditis averaged (SD) 10.4 (3.6) days after vaccination.5
Vaccine-associated myopericarditis treatment is focused on decreasing inflammation.5,6 Nonsteroidal anti-inflammatory drugs are advised for about 2 weeks with cessation of intensive cardiac activities for between 4 and 6 weeks due to risks of congestive heart failure and fatal cardiac arrhythmias.5,6
Conclusions
Since the September 11 attacks, the US needs to be continually prepared for potential terrorism on American soil and abroad. The threat of bioterrorism has renewed efforts to vaccinate or revaccinate American service members deployed to high-risk regions. These vaccinations put them at risk for vaccination-induced complications that can range from mild fever to life-threatening complications.
A renewed effort to vaccinate service members fighting the global war on terrorism has brought new diagnostic challenges. Vaccinations not generally given to the public are routinely given to service members when they deploy to various parts of the world. Examples include anthrax, yellow fever, Japanese encephalitis, rabies, polio, and smallpox. Every vaccination has potential for adverse effects (AEs), which can range from mild to severe life-threatening complications. These AEs often go unrecognized and untreated because physicians are not routinely screening for vaccination administration.
Background
Smallpox (Variola major) was successfully eradicated in 1977 due to worldwide vaccination efforts.1 However, the threat of bioterrorism has renewed mandatory smallpox vaccinations for high-risk individuals, such as active-duty military personnel.1,2 A notable increase in myopericarditis has been reported with the new generation of smallpox vaccination, ACAM2000.3 We present a case of a 27-year-old healthy male who presented with chest pain and diffuse ST segment elevations consistent with myopericarditis after vaccination with ACAM2000.
Case Presentation
A healthy 27-year-old soldier presented to the emergency department with sudden, new onset, sharp-stabbing, substernal chest pain, which was made worse with lying flat and better with leaning forward. Vital signs were unremarkable. He recently enlisted in the US Army and received the smallpox vaccination about 11 days before as part of a routine predeployment checklist. The patient reported he did not have any viral symptoms, such as fever, chills, nausea, vomiting, diarrhea, shortness of breath, sore throat, rhinorrhea, or sputum production. He also reported having no prior illness for the past 3 months, sick contacts at home or work, or recent travel outside the US. He reported no tobacco use, alcohol use, or illicit drug use. The patient’s family history was negative for significant cardiac disease.
A physical examination was unremarkable. The initial laboratory report showed no leukocytosis, anemia, thrombocytopenia, electrolytes derangement, abnormal kidney function, or abnormal liver function tests. Initial troponin was 0.25 ng/mL, erythrocyte sedimentation rate (ESR) was 40 mmol/h and C-reactive protein (CRP) was 120.2 mg/L suggestive of acute inflammation. A urine drug screen was negative. D-dimer was < 0.27. An electrocardiogram (ECG) showed diffuse ST segment elevation (Figure 1). An echocardiogram showed normal left ventricle size, and function with ejection fraction 55 to 60%, normal diastolic dysfunction, and trivial pericardial effusion. Magnetic resonance imaging (MRI) showed increased T2 signal intensity of the myocardium suggestive of myopericarditis (Figure 2). A computed tomography (CT) angiogram of the coronary arteries showed no significant stenosis.
The patient was treated with ibuprofen for 2 weeks and colchicine for 3 months, and his symptoms resolved. He followed up with an appointment in the cardiology clinic 1 month later, and his ESR, CRP, and troponin results were negative. A limited echocardiogram showed ejection fraction 60 to 65%, no regional wall motion abnormalities, normal diastolic function, and resolution of the pericardial effusion.
Discussion
Smallpox was a major worldwide cause of mortality; about 30% of those infected died because of smallpox.2,4,5 Due to a worldwide vaccination effort, the World Health Organization declared smallpox was eradicated in 1977.2,4,5 However, despite successful eradication, smallpox is considered a possible bioterrorism target, which prompted a resurgence of mandatory smallpox vaccinations for active-duty personnel.2,5
Dryvax, a freeze-dried calf lymph smallpox vaccine was used extensively from the 1940s to the 1980s but was replaced in 2008 by ACAM2000, a smallpox vaccine cultured in kidney epithelial cells from African green monkeys.3,5 Myopericarditis was rarely associated with the Dryvax, with only 5 cases reported from 1955 to 1986 after millions of doses of vaccines were administered; however, in 230,734 administered ACAM2000 doses, 18 cases of myopericarditis (incidence, 7.8 per 100,000) were reported during a surveillance study in 2002 and 2003.3,5
Myopericarditis presents with a wide variety of symptoms, such as chest pain, palpitations, chills, shortness of breath, and fever.6,7 Mainstay diagnostic criteria include ECG findings consistent with myopericarditis (such as diffuse ST segment elevations) and elevated cardiac biomarkers (elevated troponins).5-7 An echocardiogram can be helpful in diagnosis, as most cases will not have regional wall motion abnormalities (to distinguish against coronary artery disease).5-7 MRI with diffuse enhancement of the myocardium can be helpful in diagnosis.5,6 The gold standard for diagnosis is an endomyocardial biopsy, which carries a significant risk of complications and is not routinely performed to diagnose myopericarditis.5,6 US military smallpox vaccination data showed that the onset of vaccine-associated myopericarditis averaged (SD) 10.4 (3.6) days after vaccination.5
Vaccine-associated myopericarditis treatment is focused on decreasing inflammation.5,6 Nonsteroidal anti-inflammatory drugs are advised for about 2 weeks with cessation of intensive cardiac activities for between 4 and 6 weeks due to risks of congestive heart failure and fatal cardiac arrhythmias.5,6
Conclusions
Since the September 11 attacks, the US needs to be continually prepared for potential terrorism on American soil and abroad. The threat of bioterrorism has renewed efforts to vaccinate or revaccinate American service members deployed to high-risk regions. These vaccinations put them at risk for vaccination-induced complications that can range from mild fever to life-threatening complications.
1. Bruner DI, Butler BS. Smallpox vaccination-associated myopericarditis is more common with the newest smallpox vaccine. J Emerg Med. 2014;46(3):e85-e87. doi:10.1016/j.jemermed.2013.06.001
2. Halsell JS, Riddle JR, Atwood JE, et al. Myopericarditis following smallpox vaccination among vaccinia-naive US military personnel. JAMA. 2003;289(24):3283-3289. doi:10.1001/jama.289.24.3283
3. Nalca A, Zumbrun EE. ACAM2000: the new smallpox vaccine for United States Strategic National Stockpile. Drug Des Devel Ther. 2010;4:71-79. doi:10.2147/dddt.s3687
4. Wollenberg A, Engler R. Smallpox, vaccination and adverse reactions to smallpox vaccine. Curr Opin Allergy Clin Immunol. 2004;4(4):271-275. doi:10.1097/01.all.0000136758.66442.28
5. Cassimatis DC, Atwood JE, Engler RM, Linz PE, Grabenstein JD, Vernalis MN. Smallpox vaccination and myopericarditis: a clinical review. J Am Coll Cardiol. 2004;43(9):1503-1510. doi:10.1016/j.jacc.2003.11.053
6. Sharma U, Tak T. A report of 2 cases of myopericarditis after Vaccinia virus (smallpox) immunization. WMJ. 2011;110(6):291-294.
7. Sarkisian SA, Hand G, Rivera VM, Smith M, Miller JA. A case series of smallpox vaccination-associated myopericarditis: effects on safety and readiness of the active duty soldier. Mil Med. 2019;184(1-2):e280-e283. doi:10.1093/milmed/usy159
1. Bruner DI, Butler BS. Smallpox vaccination-associated myopericarditis is more common with the newest smallpox vaccine. J Emerg Med. 2014;46(3):e85-e87. doi:10.1016/j.jemermed.2013.06.001
2. Halsell JS, Riddle JR, Atwood JE, et al. Myopericarditis following smallpox vaccination among vaccinia-naive US military personnel. JAMA. 2003;289(24):3283-3289. doi:10.1001/jama.289.24.3283
3. Nalca A, Zumbrun EE. ACAM2000: the new smallpox vaccine for United States Strategic National Stockpile. Drug Des Devel Ther. 2010;4:71-79. doi:10.2147/dddt.s3687
4. Wollenberg A, Engler R. Smallpox, vaccination and adverse reactions to smallpox vaccine. Curr Opin Allergy Clin Immunol. 2004;4(4):271-275. doi:10.1097/01.all.0000136758.66442.28
5. Cassimatis DC, Atwood JE, Engler RM, Linz PE, Grabenstein JD, Vernalis MN. Smallpox vaccination and myopericarditis: a clinical review. J Am Coll Cardiol. 2004;43(9):1503-1510. doi:10.1016/j.jacc.2003.11.053
6. Sharma U, Tak T. A report of 2 cases of myopericarditis after Vaccinia virus (smallpox) immunization. WMJ. 2011;110(6):291-294.
7. Sarkisian SA, Hand G, Rivera VM, Smith M, Miller JA. A case series of smallpox vaccination-associated myopericarditis: effects on safety and readiness of the active duty soldier. Mil Med. 2019;184(1-2):e280-e283. doi:10.1093/milmed/usy159
Mild TBI/Concussion Clinical Tools for Providers Used Within the Department of Defense and Defense Health Agency
Traumatic brain injury (TBI) is a major health concern that can cause significant disability as well as economic and social burden. The Centers for Disease Control and Prevention (CDC) reported a 58% increase in the number of TBI-related emergency department visits, hospitalizations, and deaths from 2006 to 2014.1 In the CDC report, falls and motor vehicle accidents accounted for 52.3% and 20.4%, respectively, of all civilian TBI-related hospitalizations. In 2014, 56,800 TBIs in the US resulted in death. A large proportion of severe TBI survivors continue to experience long-term physical, cognitive, and psychologic disorders and require extensive rehabilitation, which may disrupt relationships and prevent return to work.2 About 37% of people with mild TBI (mTBI) cases and 51% of severe cases were unable to return to previous jobs. A study examining psychosocial burden found that people with a history of TBI reported greater feelings of loneliness compared with individuals without TBI.3
Within the US military, the Defense and Veterans Brain Injury Center (DVBIC) indicates that > 417,503 service members (SMs) have been diagnosed with TBI since November 2000.4 Of these, 82.4% were classified as having a mTBI, or concussion (Tables 1 and 2). The nature of combat and military training to which SMs are routinely exposed may increase the risk for sustaining a TBI. Specifically, the increased use of improvised explosives devices by enemy combatants in the recent military conflicts (ie, Operation Enduring Freedom, Operation Iraqi Freedom and Operation New Dawn) resulted in TBI being recognized as the signature injury of these conflicts and brought attention to the prevalence of concussion within the US military.5,6 In the military, the effects of concussion can decrease individual and unit effectiveness, emphasizing the importance of prompt diagnosis and proper management.7
Typically, patients recover from concussion within a few weeks of injury; however, some individuals experience symptoms that persist for months or years. Studies found that early intervention after concussion may aid in expediting recovery, stressing the importance of identifying concussion as promptly as possible.8,9 Active treatment is centered on patient education and symptom management, in addition to a progressive return to activities, as tolerated. Patient education may help validate the symptoms of some patients, as well as help to reattribute the symptoms to benign causes, leading to better outcomes.10 Since TBI is such a relevant health concern within the DoD, it is paramount for practitioners to understand what resources are available in order to identify and initiate treatment expeditiously.
This article focuses on the clinical tools used in evaluating and treating concussion, and best practices treatment guidelines for health care providers (HCPs) who are required to evaluate and treat military populations. While these resources are used for military SMs, they can also be used in veteran and civilian populations. This article showcases 3 DoD clinical tools that assist HCPs in evaluating and treating patients with TBI: (1) the Military Acute Concussion Evaluation 2 (MACE 2); (2) the Progressive Return to Activity (PRA) Clinical Recommendation (CR); and (3) the Concussion Management Tool (CMT). Additional DoD clinical tools and resources are discussed, and resources and links for the practitioner are provided for easy access and reference.
Military Acute Concussion Evaluation 2
Early concussion identification and evaluation are important steps in the treatment process to ensure timely recovery and return to duty for SMs. As such, DVBIC assembled a working group of military and civilian brain injury experts to create an evidence-based clinical practice guideline for the assessment and management of concussion in a military operational setting that could be learned and effectively used by corpsmen and combat medics in the battlefield to screen for a possible concussion.7 This team created the first version of the MACE, a clinical tool that prompted a systematic assessment of concussion related symptoms, neurologic signs, and cognitive deficits. The cognitive assessment portion was based on the standardized assessment of concussion (SAC) that had been reported by McCrea and colleagues in 1998.11 Soon after its creation, field utilization of the MACE for screening of concussion was mandated by the Army through an All Army Action (ALARACT 178/2008) and for all of the Services through the DoD Instruction (DoDI) 6490.11 published in 2014.12
The MACE has been updated several times since the original version. Most recently, the MACE was revised in 2018 to include a vestibular oculomotor assessment section, and red flags that immediately alert the HCP to the need for immediate triage referral and treatment of the patient possibly at a higher echelon of care or with more emergent evaluation.13-15 Additionally, the neurologic examination was expanded to increase clarity and comprehensiveness, including speech and balance testing. Updates made to the tool were intended to provide a more thorough and informative evaluation of the SM with suspected concussion.
This latest version, MACE 2, is designed to be used by any HCP who is treating SMs with a suspected or potential TBI, not just corpsmen and combat medics in theater. The MACE 2 is a comprehensive evaluation within a set of portable pocket cards designed to assist end-users in the proper triage of potentially concussed individuals. The DoD has specified 4 events that require a MACE 2 evaluation: (1) SM was in a vehicle associated with a blast event, collision, or roll over; (2) SM was within 50 meters of a blast; (3) anyone who sustained a direct blow to the head; or (4) when command provides direction (eg, repeated exposures to the events above or in accordance with protocols).12 Sleep deprivation, medications, and pain may affect MACE 2 results, in addition to deployment related stress, chronic stress, high adrenaline sustained over time, and additional comorbidities. This tool is most effective when used as close to the time of injury as possible but also may be used later (after 24 hours of rest) to reevaluate symptoms. The MACE 2 Instructor Guide, a student workbook, HCP training, and Vestibular/Ocular-Motor Screening (VOMS) for Concussion instructions can be found on the DVBIC website (Table 3).
Description
The MACE 2 is a brief multimodal screening tool that assists medics, corpsman, and primary care managers (PCMs) in the assessment and identification of a potential concussion (Figure 1). Embedded in the MACE 2 is the Standardized Assessment of Concussion (SAC), a well-validated sports concussion tool, and the VOMS tool as portions of the 2-part cognitive examination. The entirety of the tool has 5 sections: (1) red flags; (2) acute concussion screening; (3) cognitive examination, part 1; (4) neurologic examination; and (5) cognitive examination, part 2. The end of the MACE 2 includes sections on the scoring, instructions for International Classification of Diseases, Tenth Revision, TBI coding, and next steps following completion of the MACE 2. The latest version of this screening tool impacts TBI care in several noteworthy ways. First, it broadens the scope of users by expanding use to all medically trained personnel, allowing any provider to treat SMs in the field. Second, it combines state-of-the-science advances from the research field and reflects feedback from end-users collected during the development. Last, the MACE 2 is updated as changes in the field occur, and is currently undergoing research to better identify end-user utility and usability.
Screening Tools
• Red Flags. The red flags section aids in identifying potentially serious underlying conditions in patients presenting with Glasgow Coma Scale (GCS) between 13 and 15. A positive red flag prompts the practitioner to stop administering the MACE 2 and immediately consult a higher level of care and consider urgent evacuation. While the red flags are completed first, and advancement to later sections of the MACE 2 is dependent upon the absence of red flags, the red flags should be monitored throughout the completion of the MACE 2. Upon completion of patient demographics and red flags, the remaining sections of the MACE 2 are dedicated to acute concussion screening.
• Acute Concussion Screening. The acute concussion screening portion consists of 4 sections: description of the incident; alteration of consciousness or memory; a “check all that apply” symptom inventory; and a patient history that includes concussions within the past 12 months, headache disorders, and/or behavioral health concerns. The final portion of the acute concussion screening section provides an algorithm to identify a positive or negative concussion screen. When a negative screen is identified, the user is prompted to prescribe a 24-hour rest period and follow up with the SM based on the guidance in the CMT. A positive screen warrants the user to continue administration of the MACE 2.
Neurologic and CognitiveExaminations
• Cognitive Exam Part 1. The initial cognitive examination is designed to assess orientation to time (eg, What is the day of the week, day of the month, the month, the year, and the timeof day?) as well as immediate recall of a short list of concrete words (5 words total, repeated for 3 trials). These tests are based on other neuropsychological measures designed to assess cognitive/mental status and short-term memory.
• The Neurological Exam. The neurological exam section of the MACE 2 includes brief neuropsychologic tests such as speech fluency and word finding. Other sections within the neurological exam assess the
following: grip strength, vestibular function/balance (eg, tandem gait and single leg stance), as well as motor function (eg, pronator drift), autonomic nervous system function (eg, pupil response), and vestibular function (eye-tracking).
• Cognitive Exam Part 2. After completion of the first cognitive examination and the neurologic examination, the second part of the cognitive examination is initiated. Part 2 includes measures of short-term and working memory (eg, digits-reverse tasks, listing the months in reverse order, and a delayed recall task of the short list of concrete words presented in the first part). The final assessment is the administration of the VOMS, a tool developed from the sports concussion field and designed to measure vestibular-ocular function.13 It is critical to note that the VOMS is contraindicated if there is concern of an unstable cervical spine or absence of a trained HCP. An examination summary provides guidance on test scoring and yields a positive or negative indication for concussive injury. A positive test refers users to guidelines listed in the Concussion Management Tool for recommendations. The final page provides coding instructions for entering the results into the patient’s electronic medical record for documentation and future reference.
Progressive Return To Activities Clinical Recommendation
The Progressive Return to Activities Clinical Recommendation (PRA CR) also was developed by DVBIC for the DoD to assist military HCPs in managing SMs with concussion by providing systematic and evidence-based guidance to both prevent extended rest and promote return to full duty as quickly and safely as clinically indicated. The general guidance is to monitor the SM at each of the 6 stages in the process and safely and gradually increase activity to the next stage as tolerated. Daily symptoms are measured using the Neurobehavioral Symptom Inventory (NSI), which SMs self-administer every morning at each stage within the process.
Prior to initiation of the progressive return to activity, SM education using the educational brochure is strongly encouraged, as previous evidence suggests that it is an effective intervention during the acute stages of injury.10,11 Return to activity follows a 6 stage process, from stage 1 (rest) through stage 6 (unrestricted activity) (Table 4). Referral to rehabilitation providers (RPs) or higher care is left to the discretion of the PCM when (1) recovery is not progressing as anticipated; (2) progression is not being made within a 7-day period; or (3) symptoms worsen with time. The guidance outlined in the PRA CR is consistent with current policies and medical literature, and undergoes reviews as updates in the field emerge. The PRA for PCM, PRA for RP, Clinical Support Tool for PCM, Clinical Support Tool for RP, Training Slides for PCM, Training Slides for RP, Educational Brochure for PCM, and Patient Educational Tool for RP can be found on the DVBIC website (dvbic.dcoe.mil).
Description
To improve the clinical utility, 2 separate PRA CRs were developed specifically for PCMs (Figure 2) and RPs (Figure 3). The PRA CR for PCMs provides the initial framework to monitor SMs during recovery and gradually increase physical, cognitive, and vestibular/balance activities as symptoms improve in order to return to preinjury activities. The PRA CR for RPs outlines the approach for treating SMs who meet 1 of the following criteria: recovery is not progressing as anticipated, there is no progression in 7 days, symptoms are worsening, the SM is symptomatic after exertional testing following stage 5, or referral made per PCM judgment. Following the mandatory 24-hour rest period after a diagnosis of a concussion, progression through the PRA algorithm is based on history of concussion within the past 12 months (ie, 1, 2, or ≥ 3 concussions) and symptomatology, with varying treatment pathways depending on the SM’s responses to history and symptomology.
Guidelines
• One Concussion within Past 12 Months. Following the mandatory 24-hour rest period, if the SM is asymptomatic, then exertional testing (eg, activities such as push-ups, sit-ups, running in place, step aerobics, stationary bike, treadmill and/or hand crank) is performed at 65 to 85% of target heart rate for 2 minutes and symptoms are reassessed. If still asymptomatic, the SM may return to preinjury activity; however, if exertional testing provokes symptoms > 1 (mild) on the NSI, the SM should return to stage 1 with an additional 24 hours of rest. A second exertional test can be performed after stage 1, and if symptoms are provoked, progression through the remaining stages 2 to 5 is encouraged. Symptoms are continually monitored throughout each stage to determine whether the SM is recovered sufficiently to proceed to the next stage.
• Two Concussion Within Past 12 Months. Following the mandatory 24-hour rest period, no exertional testing is performed, and SMs move directly into stage 1 and remain at stage 1 or stage 2 for 7 consecutive days with no symptoms > 1 on the NSI before advancing through the remaining stages. Some defining features are longer rest periods (eg, 5 additional days of rest at stage 2) and additional patient education, symptom management, and follow-up.
• Three or more Concussions Within Past 12 Months. Following the 24 hour mandatory rest period, in cases where ≥ 3 concussions have occurred within a 12 month period, the recommendation is to provide guidance for symptom management rest and refer the SM to a higher level of care.
Concussion Management Tool
Beyond the initial assessment and concussion evaluation and the promotion of SMs’ timely return to duty, the DoD developed a tool to help endpoint users manage concussion, to include those with more protracted symptoms (Figure 4). The CMT assists HCPs and the SMs they treat in the management of symptoms before and after they return to duty. Specifically, the CMT is designed to be given in combination with guidelines issued by the DoD in the PRA CR but extends management of concussion to include those symptoms experienced more long-term, or symptoms that are not solely addressed during the timeline of the PRA CR. Together, the MACE 2, PRA CR, and the CMT provide endpoint users with a set of tools to comprehensively evaluate, treat, and manage concussions in SMs.
Description
The CMT provides step-by-step guidance for the initial and comprehensive management of concussion, once a diagnosis is made using assessments in the MACE 2. All types of HCPs, particularly those with limited training, such as Navy Hospital Corpsman and Army Combat Medics, are the intended clinical audience for the CMT. This tool was revised in 2019 to better align with the MACE 2, PRA CR, and other DVBIC CRs, and replaces the 2012 Concussion Management Algorithm and the 2014 Army Concussion Management in Garrison Setting Algorithm. The first 2 sections of the CMT are action cards, which provide management guidelines for acute injuries up to 7 days following injury and for comprehensive management beyond 1 week. Guidelines within the CMT partially overlap with those in the PRA CR; however, the PRA is designed for a more acute timeline, whereas the CMT focuses on symptom management following a more protracted recovery. The CMT clinical tool, provider training, instructor guide, and student workbook all can be found on the DVBIC website (Table 3).
Discussion
It is important for HCPs to have the skills and clinically relevant tools to optimize accurate TBI assessment. Early and accurate assessment and effective symptom management allows SMs to receive timely treatment based on clinical recommendations, and prevent and/or minimize secondary injury and prolonged recovery. Several longitudinal studies emphasize the benefits of early diagnosis and systematic follow-up.16-18 Prompt diagnosis, patient education, and early initiation to treatment may help optimize triage to care, mitigate prolonged symptoms by educating the patient on what to expect, and target specific symptoms early.8,10 Beyond the health outcomes of an individual SM, TBI recovery impacts unit readiness and consequently force readiness. As such, health outcomes and medical readiness are a priority of the Defense Health Agency (DHA).
The DHA priorities are, in part, based on DoD policy guidance for the management of concussion in the deployed setting. According to DoD instruction, “Medically documented mTBI/concussion in service members shall be clinically evaluated, treated, and managed according to the most current DoD clinical practice guidance for the deployed environment found in the Defense and Veterans Brain Injury Center (DVBIC) guidance, ‘Medical Providers: Clinical Tools.’”12 In 2018, the Deputy Secretary of Defense issued a memorandum regarding the comprehensive strategy and action plan for warfighter brain health.12 Therein, the memorandum acknowledges the enduring responsibility of the DoD to promote and protect the health and well-being of members of the nation’s armed forces. Particular emphasis was placed on issuing a response to the effects caused by concussive impacts and exposure to blast waves. This response resulted in a commitment by the DoD to understanding, preventing, diagnosing, and treating TBI in all forms. Taken together, the message from the secretary of defense and instruction from the DoD is clear and makes imperative the use of DoD clinical tools to accomplish this commitment.
Conclusion
This article showcases 3 of the DoD’s TBI clinical tools (MACE 2, PRA CR, and CMT) that assist HCPs in identifying and treating concussion. Over time, these tools undergo revisions according to the state of the science, and are adapted to meet the needs of clinicians and the SMs they treat. Studies are currently ongoing to better understand the effectiveness of these tools as well as to assist clinicians in making return-to-duty and/or medical separation decisions. These tools assist clinicians throughout the recovery process; from initial assessment and treatment (acute phase), as well as with symptom management (acute and protracted symptoms).
Concussion is not a homogenous condition and the experiences of the SM, including events that may cause emotional distress, other injuries and/or other factors, may further complicate the injury. Accordingly, there is no single clinical tool that can conclusively determine return-to-duty status; rather, these tools can help characterize injury, validate, and treat symptoms, which have been suggested to improve outcomes. More research and data are needed confirm the effectiveness of these tools to improve outcomes.
It is beyond the scope of this article to provide a more in-depth discussion on TBI prevention or longer term effects/care. However, there are additional, personalized tools for specific symptoms, deficits, or dysfunctions following concussion. These tools include the Management of Headache Following mTBI for PCM CR, Management of Sleep Disturbances Following mTBI for PCM CR, Assessment and Management of Visual Dysfunction Associated with mTBI CR, and Assessment and Management of Dizziness Associated mTBI CR. These tools enable endpoint users to evaluate and treat SMs as well as know when to elevate to higher levels of care.
The DoD commitment toward treating TBI influenced the development of the clinical tools highlighted in this article. They are the result of collective efforts among military and civilian TBI subject matter experts, data from medical literature and state-of-the-science research, and feedback from endpoint users to create the most effective, evidence-based tools. These tools undergo continuous review and revision to ensure alignment with the most up-to-date science within the field, to meet the needs of SMs and to continue the commitment to DoD concussion care.
Acknowledgments
This work was prepared under Contract (HT0014-19-C-0004) General Dynamics Information Technology and (W81XWH-16-F-0330) Credence Management Solutions, and is defined as U.S. Government work under Title 17 U.S.C.§101. Per Title 17 U.S.C.§105, copyright protection is not available for any work of the U.S. Government. For more information, please contact [email protected].
1. Centers for Disease Control and Prevention. Surveillance report of traumatic brain injury-related emergency department visits, hospitalizations, and deaths. https://www.cdc.gov/traumaticbraininjury/pdf/TBI-Surveillance-Report-FINAL_508.pdf. Published 2014. Accessed August 18, 2020.
2. Stocchetti N, Zanier ER. Chronic impact of traumatic brain injury on outcome and quality of life: a narrative review. Crit Care. 2016;20(1):148. Published 2016 Jun 21. doi:10.1186/s13054-016-1318-1
3. Kumar RG, Ornstein KA, Bollens-Lund E, et al. Lifetime history of traumatic brain injury is associated with increased loneliness in adults: A US nationally representative study. Int J Geriatr Psychiatry. 2020;35(5):553-563. doi:10.1002/gps.5271
4. Defense and Veterans Brain Injury Center. Worldwide DoD numbers for traumatic brain injury. 2020; https://dvbic.dcoe.mil/sites/default/files/tbi-numbers/DVBIC_WorldwideTotal_2000-2019.pdf. Updated March 10, 2020. Accessed August 18, 2020.
5. Kennedy JE, Lu LH, Reid MW, Leal FO, Cooper DB. Correlates of depression in U.S. military service members with a history of mild traumatic brain injury. Mil Med. 2019;184(suppl 1):148-154. doi:10.1093/milmed/usy321
6. Marshall KR, Holland SL, Meyer KS, Martin EM, Wilmore M, Grimes JB. Mild traumatic brain injury screening, diagnosis, and treatment. Mil Med. 2012;177(suppl 8):67-75. doi:10.7205/milmed-d-12-00110
7. French L, McCrea M., Baggett M. The Military Acute Concussion Evaluation. J Spec Oper Med. 2008;8(1):68-77. https://www.jsomonline.org/Publications/2008168French.pdf. Accessed August 18, 2020.
8. Kontos AP, Jorgensen-Wagers K, Trbovich AM, et al. Association of time since injury to the first clinic visit with recovery following concussion. JAMA Neurol. 2020;77(4):435-440. doi:10.1001/jamaneurol.2019.4552
9. Ponsford J, Willmott C, Rothwell A, et al. Impact of early intervention on outcome following mild head injury in adults. J Neurol Neurosurg Psychiatry. 2002;73(3):330-332. doi:10.1136/jnnp.73.3.33010.
10. Mittenberg W, Canyock EM, Condit D, Patton C. Treatment of post-concussion syndrome following mild head injury. J Clin Exp Neuropsychol. 2001;23(6):829-836. doi:10.1076/jcen.23.6.829.1022
11. McCrea M, Kelly JP, Randolph C, et al. Standardized assessment of concussion (SAC): on-site mental status evaluation of the athlete. J Head Trauma Rehabil. 1998;13(2):27-35. doi:10.1097/00001199-199804000-00005
12. US Department of Defense. Department of Defense Instruction, Number 6490.11. Policy guidance for management of mild traumatic brain injury/concussion in the deployed setting. https://www.esd.whs.mil/Portals/54/Documents/DD/issuances/dodi/649011p.pdf. Updated November 26, 2019. Accessed August 18, 2020.
13. Mucha A, Collins MW, Elbin RJ, et al. A brief Vestibular/Ocular Motor Screening (VOMS) assessment to evaluate concussions: preliminary findings. Am J Sports Med. 2014;42(10):2479-2486. doi:10.1177/0363546514543775
14. Defense and Veterans Brain Injury Center. Military Acute Concussion Evaluation 2 (MACE 2). https://dvbic.dcoe.mil/material/military-acute-concussion-evaluation-2-mace-2. Updated August 18, 2020. Accessed August 18, 2020.
15. US Department of Defense, Defense Health Agency. Defense and Veterans Brain Injury Center releases new concussion screening tool. https://www.health.mil/News/Articles/2019/03/15/Defense-and-Veterans-Brain-Injury-Center-releases-new-concussion-screening-tool. Published March 15, 2019. Accessed August 18, 2020.
16. Schwab K, Terrio HP, Brenner LA, et al. Epidemiology and prognosis of mild traumatic brain injury in returning soldiers: a cohort study. Neurology. 2017;88(16):1571-1579. doi:10.1212/WNL.0000000000003839
17. Mac Donald CL, Johnson AM, Wierzechowski L, et al. Outcome trends after US military concussive traumatic brain injury. J Neurotrauma. 2017;34(14):2206-2219. doi:10.1089/neu.2016.4434
18. Andelic N, Howe EI, Hellstrøm T, et al. Disability and quality of life 20 years after traumatic brain injury. Brain Behav. 2018;8(7):e01018. doi:10.1002/brb3.1018
Traumatic brain injury (TBI) is a major health concern that can cause significant disability as well as economic and social burden. The Centers for Disease Control and Prevention (CDC) reported a 58% increase in the number of TBI-related emergency department visits, hospitalizations, and deaths from 2006 to 2014.1 In the CDC report, falls and motor vehicle accidents accounted for 52.3% and 20.4%, respectively, of all civilian TBI-related hospitalizations. In 2014, 56,800 TBIs in the US resulted in death. A large proportion of severe TBI survivors continue to experience long-term physical, cognitive, and psychologic disorders and require extensive rehabilitation, which may disrupt relationships and prevent return to work.2 About 37% of people with mild TBI (mTBI) cases and 51% of severe cases were unable to return to previous jobs. A study examining psychosocial burden found that people with a history of TBI reported greater feelings of loneliness compared with individuals without TBI.3
Within the US military, the Defense and Veterans Brain Injury Center (DVBIC) indicates that > 417,503 service members (SMs) have been diagnosed with TBI since November 2000.4 Of these, 82.4% were classified as having a mTBI, or concussion (Tables 1 and 2). The nature of combat and military training to which SMs are routinely exposed may increase the risk for sustaining a TBI. Specifically, the increased use of improvised explosives devices by enemy combatants in the recent military conflicts (ie, Operation Enduring Freedom, Operation Iraqi Freedom and Operation New Dawn) resulted in TBI being recognized as the signature injury of these conflicts and brought attention to the prevalence of concussion within the US military.5,6 In the military, the effects of concussion can decrease individual and unit effectiveness, emphasizing the importance of prompt diagnosis and proper management.7
Typically, patients recover from concussion within a few weeks of injury; however, some individuals experience symptoms that persist for months or years. Studies found that early intervention after concussion may aid in expediting recovery, stressing the importance of identifying concussion as promptly as possible.8,9 Active treatment is centered on patient education and symptom management, in addition to a progressive return to activities, as tolerated. Patient education may help validate the symptoms of some patients, as well as help to reattribute the symptoms to benign causes, leading to better outcomes.10 Since TBI is such a relevant health concern within the DoD, it is paramount for practitioners to understand what resources are available in order to identify and initiate treatment expeditiously.
This article focuses on the clinical tools used in evaluating and treating concussion, and best practices treatment guidelines for health care providers (HCPs) who are required to evaluate and treat military populations. While these resources are used for military SMs, they can also be used in veteran and civilian populations. This article showcases 3 DoD clinical tools that assist HCPs in evaluating and treating patients with TBI: (1) the Military Acute Concussion Evaluation 2 (MACE 2); (2) the Progressive Return to Activity (PRA) Clinical Recommendation (CR); and (3) the Concussion Management Tool (CMT). Additional DoD clinical tools and resources are discussed, and resources and links for the practitioner are provided for easy access and reference.
Military Acute Concussion Evaluation 2
Early concussion identification and evaluation are important steps in the treatment process to ensure timely recovery and return to duty for SMs. As such, DVBIC assembled a working group of military and civilian brain injury experts to create an evidence-based clinical practice guideline for the assessment and management of concussion in a military operational setting that could be learned and effectively used by corpsmen and combat medics in the battlefield to screen for a possible concussion.7 This team created the first version of the MACE, a clinical tool that prompted a systematic assessment of concussion related symptoms, neurologic signs, and cognitive deficits. The cognitive assessment portion was based on the standardized assessment of concussion (SAC) that had been reported by McCrea and colleagues in 1998.11 Soon after its creation, field utilization of the MACE for screening of concussion was mandated by the Army through an All Army Action (ALARACT 178/2008) and for all of the Services through the DoD Instruction (DoDI) 6490.11 published in 2014.12
The MACE has been updated several times since the original version. Most recently, the MACE was revised in 2018 to include a vestibular oculomotor assessment section, and red flags that immediately alert the HCP to the need for immediate triage referral and treatment of the patient possibly at a higher echelon of care or with more emergent evaluation.13-15 Additionally, the neurologic examination was expanded to increase clarity and comprehensiveness, including speech and balance testing. Updates made to the tool were intended to provide a more thorough and informative evaluation of the SM with suspected concussion.
This latest version, MACE 2, is designed to be used by any HCP who is treating SMs with a suspected or potential TBI, not just corpsmen and combat medics in theater. The MACE 2 is a comprehensive evaluation within a set of portable pocket cards designed to assist end-users in the proper triage of potentially concussed individuals. The DoD has specified 4 events that require a MACE 2 evaluation: (1) SM was in a vehicle associated with a blast event, collision, or roll over; (2) SM was within 50 meters of a blast; (3) anyone who sustained a direct blow to the head; or (4) when command provides direction (eg, repeated exposures to the events above or in accordance with protocols).12 Sleep deprivation, medications, and pain may affect MACE 2 results, in addition to deployment related stress, chronic stress, high adrenaline sustained over time, and additional comorbidities. This tool is most effective when used as close to the time of injury as possible but also may be used later (after 24 hours of rest) to reevaluate symptoms. The MACE 2 Instructor Guide, a student workbook, HCP training, and Vestibular/Ocular-Motor Screening (VOMS) for Concussion instructions can be found on the DVBIC website (Table 3).
Description
The MACE 2 is a brief multimodal screening tool that assists medics, corpsman, and primary care managers (PCMs) in the assessment and identification of a potential concussion (Figure 1). Embedded in the MACE 2 is the Standardized Assessment of Concussion (SAC), a well-validated sports concussion tool, and the VOMS tool as portions of the 2-part cognitive examination. The entirety of the tool has 5 sections: (1) red flags; (2) acute concussion screening; (3) cognitive examination, part 1; (4) neurologic examination; and (5) cognitive examination, part 2. The end of the MACE 2 includes sections on the scoring, instructions for International Classification of Diseases, Tenth Revision, TBI coding, and next steps following completion of the MACE 2. The latest version of this screening tool impacts TBI care in several noteworthy ways. First, it broadens the scope of users by expanding use to all medically trained personnel, allowing any provider to treat SMs in the field. Second, it combines state-of-the-science advances from the research field and reflects feedback from end-users collected during the development. Last, the MACE 2 is updated as changes in the field occur, and is currently undergoing research to better identify end-user utility and usability.
Screening Tools
• Red Flags. The red flags section aids in identifying potentially serious underlying conditions in patients presenting with Glasgow Coma Scale (GCS) between 13 and 15. A positive red flag prompts the practitioner to stop administering the MACE 2 and immediately consult a higher level of care and consider urgent evacuation. While the red flags are completed first, and advancement to later sections of the MACE 2 is dependent upon the absence of red flags, the red flags should be monitored throughout the completion of the MACE 2. Upon completion of patient demographics and red flags, the remaining sections of the MACE 2 are dedicated to acute concussion screening.
• Acute Concussion Screening. The acute concussion screening portion consists of 4 sections: description of the incident; alteration of consciousness or memory; a “check all that apply” symptom inventory; and a patient history that includes concussions within the past 12 months, headache disorders, and/or behavioral health concerns. The final portion of the acute concussion screening section provides an algorithm to identify a positive or negative concussion screen. When a negative screen is identified, the user is prompted to prescribe a 24-hour rest period and follow up with the SM based on the guidance in the CMT. A positive screen warrants the user to continue administration of the MACE 2.
Neurologic and CognitiveExaminations
• Cognitive Exam Part 1. The initial cognitive examination is designed to assess orientation to time (eg, What is the day of the week, day of the month, the month, the year, and the timeof day?) as well as immediate recall of a short list of concrete words (5 words total, repeated for 3 trials). These tests are based on other neuropsychological measures designed to assess cognitive/mental status and short-term memory.
• The Neurological Exam. The neurological exam section of the MACE 2 includes brief neuropsychologic tests such as speech fluency and word finding. Other sections within the neurological exam assess the
following: grip strength, vestibular function/balance (eg, tandem gait and single leg stance), as well as motor function (eg, pronator drift), autonomic nervous system function (eg, pupil response), and vestibular function (eye-tracking).
• Cognitive Exam Part 2. After completion of the first cognitive examination and the neurologic examination, the second part of the cognitive examination is initiated. Part 2 includes measures of short-term and working memory (eg, digits-reverse tasks, listing the months in reverse order, and a delayed recall task of the short list of concrete words presented in the first part). The final assessment is the administration of the VOMS, a tool developed from the sports concussion field and designed to measure vestibular-ocular function.13 It is critical to note that the VOMS is contraindicated if there is concern of an unstable cervical spine or absence of a trained HCP. An examination summary provides guidance on test scoring and yields a positive or negative indication for concussive injury. A positive test refers users to guidelines listed in the Concussion Management Tool for recommendations. The final page provides coding instructions for entering the results into the patient’s electronic medical record for documentation and future reference.
Progressive Return To Activities Clinical Recommendation
The Progressive Return to Activities Clinical Recommendation (PRA CR) also was developed by DVBIC for the DoD to assist military HCPs in managing SMs with concussion by providing systematic and evidence-based guidance to both prevent extended rest and promote return to full duty as quickly and safely as clinically indicated. The general guidance is to monitor the SM at each of the 6 stages in the process and safely and gradually increase activity to the next stage as tolerated. Daily symptoms are measured using the Neurobehavioral Symptom Inventory (NSI), which SMs self-administer every morning at each stage within the process.
Prior to initiation of the progressive return to activity, SM education using the educational brochure is strongly encouraged, as previous evidence suggests that it is an effective intervention during the acute stages of injury.10,11 Return to activity follows a 6 stage process, from stage 1 (rest) through stage 6 (unrestricted activity) (Table 4). Referral to rehabilitation providers (RPs) or higher care is left to the discretion of the PCM when (1) recovery is not progressing as anticipated; (2) progression is not being made within a 7-day period; or (3) symptoms worsen with time. The guidance outlined in the PRA CR is consistent with current policies and medical literature, and undergoes reviews as updates in the field emerge. The PRA for PCM, PRA for RP, Clinical Support Tool for PCM, Clinical Support Tool for RP, Training Slides for PCM, Training Slides for RP, Educational Brochure for PCM, and Patient Educational Tool for RP can be found on the DVBIC website (dvbic.dcoe.mil).
Description
To improve the clinical utility, 2 separate PRA CRs were developed specifically for PCMs (Figure 2) and RPs (Figure 3). The PRA CR for PCMs provides the initial framework to monitor SMs during recovery and gradually increase physical, cognitive, and vestibular/balance activities as symptoms improve in order to return to preinjury activities. The PRA CR for RPs outlines the approach for treating SMs who meet 1 of the following criteria: recovery is not progressing as anticipated, there is no progression in 7 days, symptoms are worsening, the SM is symptomatic after exertional testing following stage 5, or referral made per PCM judgment. Following the mandatory 24-hour rest period after a diagnosis of a concussion, progression through the PRA algorithm is based on history of concussion within the past 12 months (ie, 1, 2, or ≥ 3 concussions) and symptomatology, with varying treatment pathways depending on the SM’s responses to history and symptomology.
Guidelines
• One Concussion within Past 12 Months. Following the mandatory 24-hour rest period, if the SM is asymptomatic, then exertional testing (eg, activities such as push-ups, sit-ups, running in place, step aerobics, stationary bike, treadmill and/or hand crank) is performed at 65 to 85% of target heart rate for 2 minutes and symptoms are reassessed. If still asymptomatic, the SM may return to preinjury activity; however, if exertional testing provokes symptoms > 1 (mild) on the NSI, the SM should return to stage 1 with an additional 24 hours of rest. A second exertional test can be performed after stage 1, and if symptoms are provoked, progression through the remaining stages 2 to 5 is encouraged. Symptoms are continually monitored throughout each stage to determine whether the SM is recovered sufficiently to proceed to the next stage.
• Two Concussion Within Past 12 Months. Following the mandatory 24-hour rest period, no exertional testing is performed, and SMs move directly into stage 1 and remain at stage 1 or stage 2 for 7 consecutive days with no symptoms > 1 on the NSI before advancing through the remaining stages. Some defining features are longer rest periods (eg, 5 additional days of rest at stage 2) and additional patient education, symptom management, and follow-up.
• Three or more Concussions Within Past 12 Months. Following the 24 hour mandatory rest period, in cases where ≥ 3 concussions have occurred within a 12 month period, the recommendation is to provide guidance for symptom management rest and refer the SM to a higher level of care.
Concussion Management Tool
Beyond the initial assessment and concussion evaluation and the promotion of SMs’ timely return to duty, the DoD developed a tool to help endpoint users manage concussion, to include those with more protracted symptoms (Figure 4). The CMT assists HCPs and the SMs they treat in the management of symptoms before and after they return to duty. Specifically, the CMT is designed to be given in combination with guidelines issued by the DoD in the PRA CR but extends management of concussion to include those symptoms experienced more long-term, or symptoms that are not solely addressed during the timeline of the PRA CR. Together, the MACE 2, PRA CR, and the CMT provide endpoint users with a set of tools to comprehensively evaluate, treat, and manage concussions in SMs.
Description
The CMT provides step-by-step guidance for the initial and comprehensive management of concussion, once a diagnosis is made using assessments in the MACE 2. All types of HCPs, particularly those with limited training, such as Navy Hospital Corpsman and Army Combat Medics, are the intended clinical audience for the CMT. This tool was revised in 2019 to better align with the MACE 2, PRA CR, and other DVBIC CRs, and replaces the 2012 Concussion Management Algorithm and the 2014 Army Concussion Management in Garrison Setting Algorithm. The first 2 sections of the CMT are action cards, which provide management guidelines for acute injuries up to 7 days following injury and for comprehensive management beyond 1 week. Guidelines within the CMT partially overlap with those in the PRA CR; however, the PRA is designed for a more acute timeline, whereas the CMT focuses on symptom management following a more protracted recovery. The CMT clinical tool, provider training, instructor guide, and student workbook all can be found on the DVBIC website (Table 3).
Discussion
It is important for HCPs to have the skills and clinically relevant tools to optimize accurate TBI assessment. Early and accurate assessment and effective symptom management allows SMs to receive timely treatment based on clinical recommendations, and prevent and/or minimize secondary injury and prolonged recovery. Several longitudinal studies emphasize the benefits of early diagnosis and systematic follow-up.16-18 Prompt diagnosis, patient education, and early initiation to treatment may help optimize triage to care, mitigate prolonged symptoms by educating the patient on what to expect, and target specific symptoms early.8,10 Beyond the health outcomes of an individual SM, TBI recovery impacts unit readiness and consequently force readiness. As such, health outcomes and medical readiness are a priority of the Defense Health Agency (DHA).
The DHA priorities are, in part, based on DoD policy guidance for the management of concussion in the deployed setting. According to DoD instruction, “Medically documented mTBI/concussion in service members shall be clinically evaluated, treated, and managed according to the most current DoD clinical practice guidance for the deployed environment found in the Defense and Veterans Brain Injury Center (DVBIC) guidance, ‘Medical Providers: Clinical Tools.’”12 In 2018, the Deputy Secretary of Defense issued a memorandum regarding the comprehensive strategy and action plan for warfighter brain health.12 Therein, the memorandum acknowledges the enduring responsibility of the DoD to promote and protect the health and well-being of members of the nation’s armed forces. Particular emphasis was placed on issuing a response to the effects caused by concussive impacts and exposure to blast waves. This response resulted in a commitment by the DoD to understanding, preventing, diagnosing, and treating TBI in all forms. Taken together, the message from the secretary of defense and instruction from the DoD is clear and makes imperative the use of DoD clinical tools to accomplish this commitment.
Conclusion
This article showcases 3 of the DoD’s TBI clinical tools (MACE 2, PRA CR, and CMT) that assist HCPs in identifying and treating concussion. Over time, these tools undergo revisions according to the state of the science, and are adapted to meet the needs of clinicians and the SMs they treat. Studies are currently ongoing to better understand the effectiveness of these tools as well as to assist clinicians in making return-to-duty and/or medical separation decisions. These tools assist clinicians throughout the recovery process; from initial assessment and treatment (acute phase), as well as with symptom management (acute and protracted symptoms).
Concussion is not a homogenous condition and the experiences of the SM, including events that may cause emotional distress, other injuries and/or other factors, may further complicate the injury. Accordingly, there is no single clinical tool that can conclusively determine return-to-duty status; rather, these tools can help characterize injury, validate, and treat symptoms, which have been suggested to improve outcomes. More research and data are needed confirm the effectiveness of these tools to improve outcomes.
It is beyond the scope of this article to provide a more in-depth discussion on TBI prevention or longer term effects/care. However, there are additional, personalized tools for specific symptoms, deficits, or dysfunctions following concussion. These tools include the Management of Headache Following mTBI for PCM CR, Management of Sleep Disturbances Following mTBI for PCM CR, Assessment and Management of Visual Dysfunction Associated with mTBI CR, and Assessment and Management of Dizziness Associated mTBI CR. These tools enable endpoint users to evaluate and treat SMs as well as know when to elevate to higher levels of care.
The DoD commitment toward treating TBI influenced the development of the clinical tools highlighted in this article. They are the result of collective efforts among military and civilian TBI subject matter experts, data from medical literature and state-of-the-science research, and feedback from endpoint users to create the most effective, evidence-based tools. These tools undergo continuous review and revision to ensure alignment with the most up-to-date science within the field, to meet the needs of SMs and to continue the commitment to DoD concussion care.
Acknowledgments
This work was prepared under Contract (HT0014-19-C-0004) General Dynamics Information Technology and (W81XWH-16-F-0330) Credence Management Solutions, and is defined as U.S. Government work under Title 17 U.S.C.§101. Per Title 17 U.S.C.§105, copyright protection is not available for any work of the U.S. Government. For more information, please contact [email protected].
Traumatic brain injury (TBI) is a major health concern that can cause significant disability as well as economic and social burden. The Centers for Disease Control and Prevention (CDC) reported a 58% increase in the number of TBI-related emergency department visits, hospitalizations, and deaths from 2006 to 2014.1 In the CDC report, falls and motor vehicle accidents accounted for 52.3% and 20.4%, respectively, of all civilian TBI-related hospitalizations. In 2014, 56,800 TBIs in the US resulted in death. A large proportion of severe TBI survivors continue to experience long-term physical, cognitive, and psychologic disorders and require extensive rehabilitation, which may disrupt relationships and prevent return to work.2 About 37% of people with mild TBI (mTBI) cases and 51% of severe cases were unable to return to previous jobs. A study examining psychosocial burden found that people with a history of TBI reported greater feelings of loneliness compared with individuals without TBI.3
Within the US military, the Defense and Veterans Brain Injury Center (DVBIC) indicates that > 417,503 service members (SMs) have been diagnosed with TBI since November 2000.4 Of these, 82.4% were classified as having a mTBI, or concussion (Tables 1 and 2). The nature of combat and military training to which SMs are routinely exposed may increase the risk for sustaining a TBI. Specifically, the increased use of improvised explosives devices by enemy combatants in the recent military conflicts (ie, Operation Enduring Freedom, Operation Iraqi Freedom and Operation New Dawn) resulted in TBI being recognized as the signature injury of these conflicts and brought attention to the prevalence of concussion within the US military.5,6 In the military, the effects of concussion can decrease individual and unit effectiveness, emphasizing the importance of prompt diagnosis and proper management.7
Typically, patients recover from concussion within a few weeks of injury; however, some individuals experience symptoms that persist for months or years. Studies found that early intervention after concussion may aid in expediting recovery, stressing the importance of identifying concussion as promptly as possible.8,9 Active treatment is centered on patient education and symptom management, in addition to a progressive return to activities, as tolerated. Patient education may help validate the symptoms of some patients, as well as help to reattribute the symptoms to benign causes, leading to better outcomes.10 Since TBI is such a relevant health concern within the DoD, it is paramount for practitioners to understand what resources are available in order to identify and initiate treatment expeditiously.
This article focuses on the clinical tools used in evaluating and treating concussion, and best practices treatment guidelines for health care providers (HCPs) who are required to evaluate and treat military populations. While these resources are used for military SMs, they can also be used in veteran and civilian populations. This article showcases 3 DoD clinical tools that assist HCPs in evaluating and treating patients with TBI: (1) the Military Acute Concussion Evaluation 2 (MACE 2); (2) the Progressive Return to Activity (PRA) Clinical Recommendation (CR); and (3) the Concussion Management Tool (CMT). Additional DoD clinical tools and resources are discussed, and resources and links for the practitioner are provided for easy access and reference.
Military Acute Concussion Evaluation 2
Early concussion identification and evaluation are important steps in the treatment process to ensure timely recovery and return to duty for SMs. As such, DVBIC assembled a working group of military and civilian brain injury experts to create an evidence-based clinical practice guideline for the assessment and management of concussion in a military operational setting that could be learned and effectively used by corpsmen and combat medics in the battlefield to screen for a possible concussion.7 This team created the first version of the MACE, a clinical tool that prompted a systematic assessment of concussion related symptoms, neurologic signs, and cognitive deficits. The cognitive assessment portion was based on the standardized assessment of concussion (SAC) that had been reported by McCrea and colleagues in 1998.11 Soon after its creation, field utilization of the MACE for screening of concussion was mandated by the Army through an All Army Action (ALARACT 178/2008) and for all of the Services through the DoD Instruction (DoDI) 6490.11 published in 2014.12
The MACE has been updated several times since the original version. Most recently, the MACE was revised in 2018 to include a vestibular oculomotor assessment section, and red flags that immediately alert the HCP to the need for immediate triage referral and treatment of the patient possibly at a higher echelon of care or with more emergent evaluation.13-15 Additionally, the neurologic examination was expanded to increase clarity and comprehensiveness, including speech and balance testing. Updates made to the tool were intended to provide a more thorough and informative evaluation of the SM with suspected concussion.
This latest version, MACE 2, is designed to be used by any HCP who is treating SMs with a suspected or potential TBI, not just corpsmen and combat medics in theater. The MACE 2 is a comprehensive evaluation within a set of portable pocket cards designed to assist end-users in the proper triage of potentially concussed individuals. The DoD has specified 4 events that require a MACE 2 evaluation: (1) SM was in a vehicle associated with a blast event, collision, or roll over; (2) SM was within 50 meters of a blast; (3) anyone who sustained a direct blow to the head; or (4) when command provides direction (eg, repeated exposures to the events above or in accordance with protocols).12 Sleep deprivation, medications, and pain may affect MACE 2 results, in addition to deployment related stress, chronic stress, high adrenaline sustained over time, and additional comorbidities. This tool is most effective when used as close to the time of injury as possible but also may be used later (after 24 hours of rest) to reevaluate symptoms. The MACE 2 Instructor Guide, a student workbook, HCP training, and Vestibular/Ocular-Motor Screening (VOMS) for Concussion instructions can be found on the DVBIC website (Table 3).
Description
The MACE 2 is a brief multimodal screening tool that assists medics, corpsman, and primary care managers (PCMs) in the assessment and identification of a potential concussion (Figure 1). Embedded in the MACE 2 is the Standardized Assessment of Concussion (SAC), a well-validated sports concussion tool, and the VOMS tool as portions of the 2-part cognitive examination. The entirety of the tool has 5 sections: (1) red flags; (2) acute concussion screening; (3) cognitive examination, part 1; (4) neurologic examination; and (5) cognitive examination, part 2. The end of the MACE 2 includes sections on the scoring, instructions for International Classification of Diseases, Tenth Revision, TBI coding, and next steps following completion of the MACE 2. The latest version of this screening tool impacts TBI care in several noteworthy ways. First, it broadens the scope of users by expanding use to all medically trained personnel, allowing any provider to treat SMs in the field. Second, it combines state-of-the-science advances from the research field and reflects feedback from end-users collected during the development. Last, the MACE 2 is updated as changes in the field occur, and is currently undergoing research to better identify end-user utility and usability.
Screening Tools
• Red Flags. The red flags section aids in identifying potentially serious underlying conditions in patients presenting with Glasgow Coma Scale (GCS) between 13 and 15. A positive red flag prompts the practitioner to stop administering the MACE 2 and immediately consult a higher level of care and consider urgent evacuation. While the red flags are completed first, and advancement to later sections of the MACE 2 is dependent upon the absence of red flags, the red flags should be monitored throughout the completion of the MACE 2. Upon completion of patient demographics and red flags, the remaining sections of the MACE 2 are dedicated to acute concussion screening.
• Acute Concussion Screening. The acute concussion screening portion consists of 4 sections: description of the incident; alteration of consciousness or memory; a “check all that apply” symptom inventory; and a patient history that includes concussions within the past 12 months, headache disorders, and/or behavioral health concerns. The final portion of the acute concussion screening section provides an algorithm to identify a positive or negative concussion screen. When a negative screen is identified, the user is prompted to prescribe a 24-hour rest period and follow up with the SM based on the guidance in the CMT. A positive screen warrants the user to continue administration of the MACE 2.
Neurologic and CognitiveExaminations
• Cognitive Exam Part 1. The initial cognitive examination is designed to assess orientation to time (eg, What is the day of the week, day of the month, the month, the year, and the timeof day?) as well as immediate recall of a short list of concrete words (5 words total, repeated for 3 trials). These tests are based on other neuropsychological measures designed to assess cognitive/mental status and short-term memory.
• The Neurological Exam. The neurological exam section of the MACE 2 includes brief neuropsychologic tests such as speech fluency and word finding. Other sections within the neurological exam assess the
following: grip strength, vestibular function/balance (eg, tandem gait and single leg stance), as well as motor function (eg, pronator drift), autonomic nervous system function (eg, pupil response), and vestibular function (eye-tracking).
• Cognitive Exam Part 2. After completion of the first cognitive examination and the neurologic examination, the second part of the cognitive examination is initiated. Part 2 includes measures of short-term and working memory (eg, digits-reverse tasks, listing the months in reverse order, and a delayed recall task of the short list of concrete words presented in the first part). The final assessment is the administration of the VOMS, a tool developed from the sports concussion field and designed to measure vestibular-ocular function.13 It is critical to note that the VOMS is contraindicated if there is concern of an unstable cervical spine or absence of a trained HCP. An examination summary provides guidance on test scoring and yields a positive or negative indication for concussive injury. A positive test refers users to guidelines listed in the Concussion Management Tool for recommendations. The final page provides coding instructions for entering the results into the patient’s electronic medical record for documentation and future reference.
Progressive Return To Activities Clinical Recommendation
The Progressive Return to Activities Clinical Recommendation (PRA CR) also was developed by DVBIC for the DoD to assist military HCPs in managing SMs with concussion by providing systematic and evidence-based guidance to both prevent extended rest and promote return to full duty as quickly and safely as clinically indicated. The general guidance is to monitor the SM at each of the 6 stages in the process and safely and gradually increase activity to the next stage as tolerated. Daily symptoms are measured using the Neurobehavioral Symptom Inventory (NSI), which SMs self-administer every morning at each stage within the process.
Prior to initiation of the progressive return to activity, SM education using the educational brochure is strongly encouraged, as previous evidence suggests that it is an effective intervention during the acute stages of injury.10,11 Return to activity follows a 6 stage process, from stage 1 (rest) through stage 6 (unrestricted activity) (Table 4). Referral to rehabilitation providers (RPs) or higher care is left to the discretion of the PCM when (1) recovery is not progressing as anticipated; (2) progression is not being made within a 7-day period; or (3) symptoms worsen with time. The guidance outlined in the PRA CR is consistent with current policies and medical literature, and undergoes reviews as updates in the field emerge. The PRA for PCM, PRA for RP, Clinical Support Tool for PCM, Clinical Support Tool for RP, Training Slides for PCM, Training Slides for RP, Educational Brochure for PCM, and Patient Educational Tool for RP can be found on the DVBIC website (dvbic.dcoe.mil).
Description
To improve the clinical utility, 2 separate PRA CRs were developed specifically for PCMs (Figure 2) and RPs (Figure 3). The PRA CR for PCMs provides the initial framework to monitor SMs during recovery and gradually increase physical, cognitive, and vestibular/balance activities as symptoms improve in order to return to preinjury activities. The PRA CR for RPs outlines the approach for treating SMs who meet 1 of the following criteria: recovery is not progressing as anticipated, there is no progression in 7 days, symptoms are worsening, the SM is symptomatic after exertional testing following stage 5, or referral made per PCM judgment. Following the mandatory 24-hour rest period after a diagnosis of a concussion, progression through the PRA algorithm is based on history of concussion within the past 12 months (ie, 1, 2, or ≥ 3 concussions) and symptomatology, with varying treatment pathways depending on the SM’s responses to history and symptomology.
Guidelines
• One Concussion within Past 12 Months. Following the mandatory 24-hour rest period, if the SM is asymptomatic, then exertional testing (eg, activities such as push-ups, sit-ups, running in place, step aerobics, stationary bike, treadmill and/or hand crank) is performed at 65 to 85% of target heart rate for 2 minutes and symptoms are reassessed. If still asymptomatic, the SM may return to preinjury activity; however, if exertional testing provokes symptoms > 1 (mild) on the NSI, the SM should return to stage 1 with an additional 24 hours of rest. A second exertional test can be performed after stage 1, and if symptoms are provoked, progression through the remaining stages 2 to 5 is encouraged. Symptoms are continually monitored throughout each stage to determine whether the SM is recovered sufficiently to proceed to the next stage.
• Two Concussion Within Past 12 Months. Following the mandatory 24-hour rest period, no exertional testing is performed, and SMs move directly into stage 1 and remain at stage 1 or stage 2 for 7 consecutive days with no symptoms > 1 on the NSI before advancing through the remaining stages. Some defining features are longer rest periods (eg, 5 additional days of rest at stage 2) and additional patient education, symptom management, and follow-up.
• Three or more Concussions Within Past 12 Months. Following the 24 hour mandatory rest period, in cases where ≥ 3 concussions have occurred within a 12 month period, the recommendation is to provide guidance for symptom management rest and refer the SM to a higher level of care.
Concussion Management Tool
Beyond the initial assessment and concussion evaluation and the promotion of SMs’ timely return to duty, the DoD developed a tool to help endpoint users manage concussion, to include those with more protracted symptoms (Figure 4). The CMT assists HCPs and the SMs they treat in the management of symptoms before and after they return to duty. Specifically, the CMT is designed to be given in combination with guidelines issued by the DoD in the PRA CR but extends management of concussion to include those symptoms experienced more long-term, or symptoms that are not solely addressed during the timeline of the PRA CR. Together, the MACE 2, PRA CR, and the CMT provide endpoint users with a set of tools to comprehensively evaluate, treat, and manage concussions in SMs.
Description
The CMT provides step-by-step guidance for the initial and comprehensive management of concussion, once a diagnosis is made using assessments in the MACE 2. All types of HCPs, particularly those with limited training, such as Navy Hospital Corpsman and Army Combat Medics, are the intended clinical audience for the CMT. This tool was revised in 2019 to better align with the MACE 2, PRA CR, and other DVBIC CRs, and replaces the 2012 Concussion Management Algorithm and the 2014 Army Concussion Management in Garrison Setting Algorithm. The first 2 sections of the CMT are action cards, which provide management guidelines for acute injuries up to 7 days following injury and for comprehensive management beyond 1 week. Guidelines within the CMT partially overlap with those in the PRA CR; however, the PRA is designed for a more acute timeline, whereas the CMT focuses on symptom management following a more protracted recovery. The CMT clinical tool, provider training, instructor guide, and student workbook all can be found on the DVBIC website (Table 3).
Discussion
It is important for HCPs to have the skills and clinically relevant tools to optimize accurate TBI assessment. Early and accurate assessment and effective symptom management allows SMs to receive timely treatment based on clinical recommendations, and prevent and/or minimize secondary injury and prolonged recovery. Several longitudinal studies emphasize the benefits of early diagnosis and systematic follow-up.16-18 Prompt diagnosis, patient education, and early initiation to treatment may help optimize triage to care, mitigate prolonged symptoms by educating the patient on what to expect, and target specific symptoms early.8,10 Beyond the health outcomes of an individual SM, TBI recovery impacts unit readiness and consequently force readiness. As such, health outcomes and medical readiness are a priority of the Defense Health Agency (DHA).
The DHA priorities are, in part, based on DoD policy guidance for the management of concussion in the deployed setting. According to DoD instruction, “Medically documented mTBI/concussion in service members shall be clinically evaluated, treated, and managed according to the most current DoD clinical practice guidance for the deployed environment found in the Defense and Veterans Brain Injury Center (DVBIC) guidance, ‘Medical Providers: Clinical Tools.’”12 In 2018, the Deputy Secretary of Defense issued a memorandum regarding the comprehensive strategy and action plan for warfighter brain health.12 Therein, the memorandum acknowledges the enduring responsibility of the DoD to promote and protect the health and well-being of members of the nation’s armed forces. Particular emphasis was placed on issuing a response to the effects caused by concussive impacts and exposure to blast waves. This response resulted in a commitment by the DoD to understanding, preventing, diagnosing, and treating TBI in all forms. Taken together, the message from the secretary of defense and instruction from the DoD is clear and makes imperative the use of DoD clinical tools to accomplish this commitment.
Conclusion
This article showcases 3 of the DoD’s TBI clinical tools (MACE 2, PRA CR, and CMT) that assist HCPs in identifying and treating concussion. Over time, these tools undergo revisions according to the state of the science, and are adapted to meet the needs of clinicians and the SMs they treat. Studies are currently ongoing to better understand the effectiveness of these tools as well as to assist clinicians in making return-to-duty and/or medical separation decisions. These tools assist clinicians throughout the recovery process; from initial assessment and treatment (acute phase), as well as with symptom management (acute and protracted symptoms).
Concussion is not a homogenous condition and the experiences of the SM, including events that may cause emotional distress, other injuries and/or other factors, may further complicate the injury. Accordingly, there is no single clinical tool that can conclusively determine return-to-duty status; rather, these tools can help characterize injury, validate, and treat symptoms, which have been suggested to improve outcomes. More research and data are needed confirm the effectiveness of these tools to improve outcomes.
It is beyond the scope of this article to provide a more in-depth discussion on TBI prevention or longer term effects/care. However, there are additional, personalized tools for specific symptoms, deficits, or dysfunctions following concussion. These tools include the Management of Headache Following mTBI for PCM CR, Management of Sleep Disturbances Following mTBI for PCM CR, Assessment and Management of Visual Dysfunction Associated with mTBI CR, and Assessment and Management of Dizziness Associated mTBI CR. These tools enable endpoint users to evaluate and treat SMs as well as know when to elevate to higher levels of care.
The DoD commitment toward treating TBI influenced the development of the clinical tools highlighted in this article. They are the result of collective efforts among military and civilian TBI subject matter experts, data from medical literature and state-of-the-science research, and feedback from endpoint users to create the most effective, evidence-based tools. These tools undergo continuous review and revision to ensure alignment with the most up-to-date science within the field, to meet the needs of SMs and to continue the commitment to DoD concussion care.
Acknowledgments
This work was prepared under Contract (HT0014-19-C-0004) General Dynamics Information Technology and (W81XWH-16-F-0330) Credence Management Solutions, and is defined as U.S. Government work under Title 17 U.S.C.§101. Per Title 17 U.S.C.§105, copyright protection is not available for any work of the U.S. Government. For more information, please contact [email protected].
1. Centers for Disease Control and Prevention. Surveillance report of traumatic brain injury-related emergency department visits, hospitalizations, and deaths. https://www.cdc.gov/traumaticbraininjury/pdf/TBI-Surveillance-Report-FINAL_508.pdf. Published 2014. Accessed August 18, 2020.
2. Stocchetti N, Zanier ER. Chronic impact of traumatic brain injury on outcome and quality of life: a narrative review. Crit Care. 2016;20(1):148. Published 2016 Jun 21. doi:10.1186/s13054-016-1318-1
3. Kumar RG, Ornstein KA, Bollens-Lund E, et al. Lifetime history of traumatic brain injury is associated with increased loneliness in adults: A US nationally representative study. Int J Geriatr Psychiatry. 2020;35(5):553-563. doi:10.1002/gps.5271
4. Defense and Veterans Brain Injury Center. Worldwide DoD numbers for traumatic brain injury. 2020; https://dvbic.dcoe.mil/sites/default/files/tbi-numbers/DVBIC_WorldwideTotal_2000-2019.pdf. Updated March 10, 2020. Accessed August 18, 2020.
5. Kennedy JE, Lu LH, Reid MW, Leal FO, Cooper DB. Correlates of depression in U.S. military service members with a history of mild traumatic brain injury. Mil Med. 2019;184(suppl 1):148-154. doi:10.1093/milmed/usy321
6. Marshall KR, Holland SL, Meyer KS, Martin EM, Wilmore M, Grimes JB. Mild traumatic brain injury screening, diagnosis, and treatment. Mil Med. 2012;177(suppl 8):67-75. doi:10.7205/milmed-d-12-00110
7. French L, McCrea M., Baggett M. The Military Acute Concussion Evaluation. J Spec Oper Med. 2008;8(1):68-77. https://www.jsomonline.org/Publications/2008168French.pdf. Accessed August 18, 2020.
8. Kontos AP, Jorgensen-Wagers K, Trbovich AM, et al. Association of time since injury to the first clinic visit with recovery following concussion. JAMA Neurol. 2020;77(4):435-440. doi:10.1001/jamaneurol.2019.4552
9. Ponsford J, Willmott C, Rothwell A, et al. Impact of early intervention on outcome following mild head injury in adults. J Neurol Neurosurg Psychiatry. 2002;73(3):330-332. doi:10.1136/jnnp.73.3.33010.
10. Mittenberg W, Canyock EM, Condit D, Patton C. Treatment of post-concussion syndrome following mild head injury. J Clin Exp Neuropsychol. 2001;23(6):829-836. doi:10.1076/jcen.23.6.829.1022
11. McCrea M, Kelly JP, Randolph C, et al. Standardized assessment of concussion (SAC): on-site mental status evaluation of the athlete. J Head Trauma Rehabil. 1998;13(2):27-35. doi:10.1097/00001199-199804000-00005
12. US Department of Defense. Department of Defense Instruction, Number 6490.11. Policy guidance for management of mild traumatic brain injury/concussion in the deployed setting. https://www.esd.whs.mil/Portals/54/Documents/DD/issuances/dodi/649011p.pdf. Updated November 26, 2019. Accessed August 18, 2020.
13. Mucha A, Collins MW, Elbin RJ, et al. A brief Vestibular/Ocular Motor Screening (VOMS) assessment to evaluate concussions: preliminary findings. Am J Sports Med. 2014;42(10):2479-2486. doi:10.1177/0363546514543775
14. Defense and Veterans Brain Injury Center. Military Acute Concussion Evaluation 2 (MACE 2). https://dvbic.dcoe.mil/material/military-acute-concussion-evaluation-2-mace-2. Updated August 18, 2020. Accessed August 18, 2020.
15. US Department of Defense, Defense Health Agency. Defense and Veterans Brain Injury Center releases new concussion screening tool. https://www.health.mil/News/Articles/2019/03/15/Defense-and-Veterans-Brain-Injury-Center-releases-new-concussion-screening-tool. Published March 15, 2019. Accessed August 18, 2020.
16. Schwab K, Terrio HP, Brenner LA, et al. Epidemiology and prognosis of mild traumatic brain injury in returning soldiers: a cohort study. Neurology. 2017;88(16):1571-1579. doi:10.1212/WNL.0000000000003839
17. Mac Donald CL, Johnson AM, Wierzechowski L, et al. Outcome trends after US military concussive traumatic brain injury. J Neurotrauma. 2017;34(14):2206-2219. doi:10.1089/neu.2016.4434
18. Andelic N, Howe EI, Hellstrøm T, et al. Disability and quality of life 20 years after traumatic brain injury. Brain Behav. 2018;8(7):e01018. doi:10.1002/brb3.1018
1. Centers for Disease Control and Prevention. Surveillance report of traumatic brain injury-related emergency department visits, hospitalizations, and deaths. https://www.cdc.gov/traumaticbraininjury/pdf/TBI-Surveillance-Report-FINAL_508.pdf. Published 2014. Accessed August 18, 2020.
2. Stocchetti N, Zanier ER. Chronic impact of traumatic brain injury on outcome and quality of life: a narrative review. Crit Care. 2016;20(1):148. Published 2016 Jun 21. doi:10.1186/s13054-016-1318-1
3. Kumar RG, Ornstein KA, Bollens-Lund E, et al. Lifetime history of traumatic brain injury is associated with increased loneliness in adults: A US nationally representative study. Int J Geriatr Psychiatry. 2020;35(5):553-563. doi:10.1002/gps.5271
4. Defense and Veterans Brain Injury Center. Worldwide DoD numbers for traumatic brain injury. 2020; https://dvbic.dcoe.mil/sites/default/files/tbi-numbers/DVBIC_WorldwideTotal_2000-2019.pdf. Updated March 10, 2020. Accessed August 18, 2020.
5. Kennedy JE, Lu LH, Reid MW, Leal FO, Cooper DB. Correlates of depression in U.S. military service members with a history of mild traumatic brain injury. Mil Med. 2019;184(suppl 1):148-154. doi:10.1093/milmed/usy321
6. Marshall KR, Holland SL, Meyer KS, Martin EM, Wilmore M, Grimes JB. Mild traumatic brain injury screening, diagnosis, and treatment. Mil Med. 2012;177(suppl 8):67-75. doi:10.7205/milmed-d-12-00110
7. French L, McCrea M., Baggett M. The Military Acute Concussion Evaluation. J Spec Oper Med. 2008;8(1):68-77. https://www.jsomonline.org/Publications/2008168French.pdf. Accessed August 18, 2020.
8. Kontos AP, Jorgensen-Wagers K, Trbovich AM, et al. Association of time since injury to the first clinic visit with recovery following concussion. JAMA Neurol. 2020;77(4):435-440. doi:10.1001/jamaneurol.2019.4552
9. Ponsford J, Willmott C, Rothwell A, et al. Impact of early intervention on outcome following mild head injury in adults. J Neurol Neurosurg Psychiatry. 2002;73(3):330-332. doi:10.1136/jnnp.73.3.33010.
10. Mittenberg W, Canyock EM, Condit D, Patton C. Treatment of post-concussion syndrome following mild head injury. J Clin Exp Neuropsychol. 2001;23(6):829-836. doi:10.1076/jcen.23.6.829.1022
11. McCrea M, Kelly JP, Randolph C, et al. Standardized assessment of concussion (SAC): on-site mental status evaluation of the athlete. J Head Trauma Rehabil. 1998;13(2):27-35. doi:10.1097/00001199-199804000-00005
12. US Department of Defense. Department of Defense Instruction, Number 6490.11. Policy guidance for management of mild traumatic brain injury/concussion in the deployed setting. https://www.esd.whs.mil/Portals/54/Documents/DD/issuances/dodi/649011p.pdf. Updated November 26, 2019. Accessed August 18, 2020.
13. Mucha A, Collins MW, Elbin RJ, et al. A brief Vestibular/Ocular Motor Screening (VOMS) assessment to evaluate concussions: preliminary findings. Am J Sports Med. 2014;42(10):2479-2486. doi:10.1177/0363546514543775
14. Defense and Veterans Brain Injury Center. Military Acute Concussion Evaluation 2 (MACE 2). https://dvbic.dcoe.mil/material/military-acute-concussion-evaluation-2-mace-2. Updated August 18, 2020. Accessed August 18, 2020.
15. US Department of Defense, Defense Health Agency. Defense and Veterans Brain Injury Center releases new concussion screening tool. https://www.health.mil/News/Articles/2019/03/15/Defense-and-Veterans-Brain-Injury-Center-releases-new-concussion-screening-tool. Published March 15, 2019. Accessed August 18, 2020.
16. Schwab K, Terrio HP, Brenner LA, et al. Epidemiology and prognosis of mild traumatic brain injury in returning soldiers: a cohort study. Neurology. 2017;88(16):1571-1579. doi:10.1212/WNL.0000000000003839
17. Mac Donald CL, Johnson AM, Wierzechowski L, et al. Outcome trends after US military concussive traumatic brain injury. J Neurotrauma. 2017;34(14):2206-2219. doi:10.1089/neu.2016.4434
18. Andelic N, Howe EI, Hellstrøm T, et al. Disability and quality of life 20 years after traumatic brain injury. Brain Behav. 2018;8(7):e01018. doi:10.1002/brb3.1018
The Brain in COVID-19: No One Is Okay
Knowing that I am a psychiatrist, my friends and colleagues recently started to ask me, “Am I losing my mind?” The symptoms underlying these concerned queries are remarkably similar: inability to concentrate, becoming easily frustrated, forgetting things, not being as productive as usual, being overly tired despite doing less, and feeling unusually irritable, among other vague somatic symptoms. This condition is to be distinguished from COVID-19 in the brain, which is the protean serious neuropsychiatric manifestations of infection with the virus ranging from strokes and seizures to encephalopathy and psychosis especially in severe cases of infection.1
As federal health care professionals (HCPs), many of us are familiar with acute high stress medical situations, which the pandemic has expanded and intensified: In New York City during the surge, the US Department of Veterans Affairs (VA) intensive care physician pushing life-sustaining resources to their limits in a valiant effort to keep alive as many people as possible; the US Public Health Service HCP working miracles without adequate supplies or staff in underserved hard-hit areas of the country; or the US Department of Defense clinician deftly trying to contain outbreaks in contained spaces like ships.
Emerging data already show that HCPs and other first responders facing these repeated episodes of acute stress are experiencing increased depression and anxiety.2 Research from prior pandemics suggests that this is only the beginning of a wave of negative mental health complications in HCPs.3
In the acute form of stress, the hypothalamic pituitary axis (HPA axis) is an evolutionary engine that coordinates multiple organ systems from lungs to liver to ensure efficient escape from primeval dinosaurs or more modern threats like viruses. Fueling that engine is the hormonal cascade that ends in excessive secretion of cortisol.
Chronic stress affects the body and brain in a different way than does acute stress. The problem is that this sympathetic nervous system surge is meant to power a sprint to survival not the marathon of uncertainty that COVID-19 has become. As long as the body stays in acute stress mode, the brain cannot downshift to the parasympathetic system that would usually moderate and regulate our neurobiologic circuits and neuropsychological processes. Like any other engine in overdrive, the stress gear erodes the machinery of our body and brain. Hence, the symptoms of psychophysical wear and tear—allostatic load—that most of us are experiencing.4
The subject of this column is the lower level of prolonged chronic stress. The mild and amorphous pertubations that can be described as “the brain in COVID-19.” It is a syndrome that affects even those who have never been infected with the actual virus. Though not usually life-threatening or disabling, it is unnerving and distressing as the queries from my colleagues and friends show. Their reports and my observations have led me to opine that “no one is okay” due to months of living under the strain of a pandemic.
The degree and scope of chronic stress that a person experiences caused by COVID-19 has to be contextualized and individualized. Those who have lost jobs, who are working while children are going to school online, who are caring for relatives, or who are in fear of losing their home face tremendous stress and challenges.5 Yet even those like me, whose biggest worry is a dog barking through important teleconference meetings, still undergo a milder form of near constant stress.
Consider that all of us have become strangers in an even stranger land. Masks have become an object of political controversy. In states where masking is mandatory, you must be mask vigilant every time you go out. In many areas of the country stores have limited hours, access, and supplies and any trip away from the house risks infection. Conversely, for those in a high-risk population, it may have been months since they have left home at all, and many sick, older, and vulnerable persons are suffering from isolation, loneliness, and boredom. The minor distractions and innocent pleasures that relieve day-to-day stress are no longer safe or available options, like eating out, attending shows, or taking trips.
Most of us are waiting for news of an effective available vaccine, some with yearning and others with dread. For George Gershwin, summertime meant that “the livin’ is easy,” but the summer of 2020 has been anything but easy and that takes its toll on the mind. Without adequate positive stimulation, attention wanders and memory fails to encode details, making even routine tasks more difficult; without meaningful social contact, emotions become sharp and ragged often hurting others. Most important, without periods in which we can relax, there is psychic exhaustion.6
At this point you may be thinking, “So, now that you told us we are all under chronic stress, are you going to tell us whether we can do anything about it?” There are many fantastic websites (including the VA) where experts far more qualified than I am offer excellent advice on coping with the pandemic.7 What I can provide is 5 reflections on managing the stress that I have used and that others with whom I shared them have found helpful.
1. Set realistic expectations. We are in a different reality in which we may need to take on smaller tasks, pace our work and take more breaks and, most of all, give ourselves a break when we are not as functional as we were before the pandemic.
2. Get out in nature. Find a green space to walk or sit, spend time with companion animals, go for a hike or bicycle near water or mountains, or watch the birds in a forest. Nothing can help restore our perspective or calm frayed nerves like the socially distanced outdoors.
3. Reach out. Even though we cannot hug or even shake hands, we can still pick up the phone or mouse and check on someone who is down. All the great traditions of the world agree that the best way to lift our own spirits is to help others.
4. Be kind. This is among the most important responses. As the epigraph suggests, everyone is engaged in an often silent and secret struggle and deserves our compassion. This call for kindness should be extended to ourselves so that we can be patient and compassionate to others.
5. Have courage and hope. This may be the most important of all. Whether we are infected or are fearing/avoiding infection, COVID-19 makes us sick in body and brain. We must have faith that there is something—the mind, the spirit—beyond the purely physical that gives us courage to outlast COVID-19 and to have hope for a postpandemic future that though not the same as before may well be in some ways better
1. Troyer EA, Kohn JN, Hong S. Are we facing a crashing wave of neuropsychiatric sequelae of COVID-19? Neuropsychiatric symptoms and potential immunologic mechanisms. Brain Behav Immun . 2020;87:34-39. doi:10.1016/j.bbi.2020.04.027
2. Pappa S, Ntella V, Giannakas T, Giannakoulis VG, Papoutsi E, Katsaounou P. Prevalence of depression, anxiety, and insomnia among healthcare workers during the COVID-19pandemic: a systematic review and meta-analysis. Brain Behav Immun. 2020;88:901-907. doi:10.1016/j.bbi.2020.05.026
3. Salazar de Pablo G, Vaquerizo-Serrano J, Catalan A, et al. Impact of coronavirus syndromes on physical and mental health of health care workers: systematic review and meta-analysis. J Affect Disord. 2020;275:48-57. doi:10.1016/j.jad.2020.06.022.
4. Harkness K. Strange physical symptoms? Blame the chronic stress of life during the Covid-19 pandemic. https://the-conversation.com/strange-physical-symptoms-blame-the-chronic-stress-of-life-during-the-covid-19-pandemic-139096. Published June 11, 2020. Accessed August 29, 2020.
5. Centers for Disease Control and Prevention. Coronavirus Disease (COVID-19) 2019. Coping with stress. https://www.cdc.gov/coronavirus/2019-ncov/daily-life-coping/managing-stress-anxiety.html. Updated July 1, 2020. Accessed August 29, 2020.
6. Greenberg M. How the stress of the COVID-9 pandemic scrambles your brain. https://www.psychologytoday.com/us/blog/the-mindful-self-express/202006/how-the-stress-the-covid-19-pandemic-scrambles-your-brain. Published June 28, 2020. Accessed August 29, 2020.
7. US Department of Veterans Affairs, National Center for PTSD. Healthcare workers and responders. https://www.ptsd.va.gov/covid/list_healthcare_responders.asp. Updated August 12, 2020. Accessed August 29, 2020.
Knowing that I am a psychiatrist, my friends and colleagues recently started to ask me, “Am I losing my mind?” The symptoms underlying these concerned queries are remarkably similar: inability to concentrate, becoming easily frustrated, forgetting things, not being as productive as usual, being overly tired despite doing less, and feeling unusually irritable, among other vague somatic symptoms. This condition is to be distinguished from COVID-19 in the brain, which is the protean serious neuropsychiatric manifestations of infection with the virus ranging from strokes and seizures to encephalopathy and psychosis especially in severe cases of infection.1
As federal health care professionals (HCPs), many of us are familiar with acute high stress medical situations, which the pandemic has expanded and intensified: In New York City during the surge, the US Department of Veterans Affairs (VA) intensive care physician pushing life-sustaining resources to their limits in a valiant effort to keep alive as many people as possible; the US Public Health Service HCP working miracles without adequate supplies or staff in underserved hard-hit areas of the country; or the US Department of Defense clinician deftly trying to contain outbreaks in contained spaces like ships.
Emerging data already show that HCPs and other first responders facing these repeated episodes of acute stress are experiencing increased depression and anxiety.2 Research from prior pandemics suggests that this is only the beginning of a wave of negative mental health complications in HCPs.3
In the acute form of stress, the hypothalamic pituitary axis (HPA axis) is an evolutionary engine that coordinates multiple organ systems from lungs to liver to ensure efficient escape from primeval dinosaurs or more modern threats like viruses. Fueling that engine is the hormonal cascade that ends in excessive secretion of cortisol.
Chronic stress affects the body and brain in a different way than does acute stress. The problem is that this sympathetic nervous system surge is meant to power a sprint to survival not the marathon of uncertainty that COVID-19 has become. As long as the body stays in acute stress mode, the brain cannot downshift to the parasympathetic system that would usually moderate and regulate our neurobiologic circuits and neuropsychological processes. Like any other engine in overdrive, the stress gear erodes the machinery of our body and brain. Hence, the symptoms of psychophysical wear and tear—allostatic load—that most of us are experiencing.4
The subject of this column is the lower level of prolonged chronic stress. The mild and amorphous pertubations that can be described as “the brain in COVID-19.” It is a syndrome that affects even those who have never been infected with the actual virus. Though not usually life-threatening or disabling, it is unnerving and distressing as the queries from my colleagues and friends show. Their reports and my observations have led me to opine that “no one is okay” due to months of living under the strain of a pandemic.
The degree and scope of chronic stress that a person experiences caused by COVID-19 has to be contextualized and individualized. Those who have lost jobs, who are working while children are going to school online, who are caring for relatives, or who are in fear of losing their home face tremendous stress and challenges.5 Yet even those like me, whose biggest worry is a dog barking through important teleconference meetings, still undergo a milder form of near constant stress.
Consider that all of us have become strangers in an even stranger land. Masks have become an object of political controversy. In states where masking is mandatory, you must be mask vigilant every time you go out. In many areas of the country stores have limited hours, access, and supplies and any trip away from the house risks infection. Conversely, for those in a high-risk population, it may have been months since they have left home at all, and many sick, older, and vulnerable persons are suffering from isolation, loneliness, and boredom. The minor distractions and innocent pleasures that relieve day-to-day stress are no longer safe or available options, like eating out, attending shows, or taking trips.
Most of us are waiting for news of an effective available vaccine, some with yearning and others with dread. For George Gershwin, summertime meant that “the livin’ is easy,” but the summer of 2020 has been anything but easy and that takes its toll on the mind. Without adequate positive stimulation, attention wanders and memory fails to encode details, making even routine tasks more difficult; without meaningful social contact, emotions become sharp and ragged often hurting others. Most important, without periods in which we can relax, there is psychic exhaustion.6
At this point you may be thinking, “So, now that you told us we are all under chronic stress, are you going to tell us whether we can do anything about it?” There are many fantastic websites (including the VA) where experts far more qualified than I am offer excellent advice on coping with the pandemic.7 What I can provide is 5 reflections on managing the stress that I have used and that others with whom I shared them have found helpful.
1. Set realistic expectations. We are in a different reality in which we may need to take on smaller tasks, pace our work and take more breaks and, most of all, give ourselves a break when we are not as functional as we were before the pandemic.
2. Get out in nature. Find a green space to walk or sit, spend time with companion animals, go for a hike or bicycle near water or mountains, or watch the birds in a forest. Nothing can help restore our perspective or calm frayed nerves like the socially distanced outdoors.
3. Reach out. Even though we cannot hug or even shake hands, we can still pick up the phone or mouse and check on someone who is down. All the great traditions of the world agree that the best way to lift our own spirits is to help others.
4. Be kind. This is among the most important responses. As the epigraph suggests, everyone is engaged in an often silent and secret struggle and deserves our compassion. This call for kindness should be extended to ourselves so that we can be patient and compassionate to others.
5. Have courage and hope. This may be the most important of all. Whether we are infected or are fearing/avoiding infection, COVID-19 makes us sick in body and brain. We must have faith that there is something—the mind, the spirit—beyond the purely physical that gives us courage to outlast COVID-19 and to have hope for a postpandemic future that though not the same as before may well be in some ways better
Knowing that I am a psychiatrist, my friends and colleagues recently started to ask me, “Am I losing my mind?” The symptoms underlying these concerned queries are remarkably similar: inability to concentrate, becoming easily frustrated, forgetting things, not being as productive as usual, being overly tired despite doing less, and feeling unusually irritable, among other vague somatic symptoms. This condition is to be distinguished from COVID-19 in the brain, which is the protean serious neuropsychiatric manifestations of infection with the virus ranging from strokes and seizures to encephalopathy and psychosis especially in severe cases of infection.1
As federal health care professionals (HCPs), many of us are familiar with acute high stress medical situations, which the pandemic has expanded and intensified: In New York City during the surge, the US Department of Veterans Affairs (VA) intensive care physician pushing life-sustaining resources to their limits in a valiant effort to keep alive as many people as possible; the US Public Health Service HCP working miracles without adequate supplies or staff in underserved hard-hit areas of the country; or the US Department of Defense clinician deftly trying to contain outbreaks in contained spaces like ships.
Emerging data already show that HCPs and other first responders facing these repeated episodes of acute stress are experiencing increased depression and anxiety.2 Research from prior pandemics suggests that this is only the beginning of a wave of negative mental health complications in HCPs.3
In the acute form of stress, the hypothalamic pituitary axis (HPA axis) is an evolutionary engine that coordinates multiple organ systems from lungs to liver to ensure efficient escape from primeval dinosaurs or more modern threats like viruses. Fueling that engine is the hormonal cascade that ends in excessive secretion of cortisol.
Chronic stress affects the body and brain in a different way than does acute stress. The problem is that this sympathetic nervous system surge is meant to power a sprint to survival not the marathon of uncertainty that COVID-19 has become. As long as the body stays in acute stress mode, the brain cannot downshift to the parasympathetic system that would usually moderate and regulate our neurobiologic circuits and neuropsychological processes. Like any other engine in overdrive, the stress gear erodes the machinery of our body and brain. Hence, the symptoms of psychophysical wear and tear—allostatic load—that most of us are experiencing.4
The subject of this column is the lower level of prolonged chronic stress. The mild and amorphous pertubations that can be described as “the brain in COVID-19.” It is a syndrome that affects even those who have never been infected with the actual virus. Though not usually life-threatening or disabling, it is unnerving and distressing as the queries from my colleagues and friends show. Their reports and my observations have led me to opine that “no one is okay” due to months of living under the strain of a pandemic.
The degree and scope of chronic stress that a person experiences caused by COVID-19 has to be contextualized and individualized. Those who have lost jobs, who are working while children are going to school online, who are caring for relatives, or who are in fear of losing their home face tremendous stress and challenges.5 Yet even those like me, whose biggest worry is a dog barking through important teleconference meetings, still undergo a milder form of near constant stress.
Consider that all of us have become strangers in an even stranger land. Masks have become an object of political controversy. In states where masking is mandatory, you must be mask vigilant every time you go out. In many areas of the country stores have limited hours, access, and supplies and any trip away from the house risks infection. Conversely, for those in a high-risk population, it may have been months since they have left home at all, and many sick, older, and vulnerable persons are suffering from isolation, loneliness, and boredom. The minor distractions and innocent pleasures that relieve day-to-day stress are no longer safe or available options, like eating out, attending shows, or taking trips.
Most of us are waiting for news of an effective available vaccine, some with yearning and others with dread. For George Gershwin, summertime meant that “the livin’ is easy,” but the summer of 2020 has been anything but easy and that takes its toll on the mind. Without adequate positive stimulation, attention wanders and memory fails to encode details, making even routine tasks more difficult; without meaningful social contact, emotions become sharp and ragged often hurting others. Most important, without periods in which we can relax, there is psychic exhaustion.6
At this point you may be thinking, “So, now that you told us we are all under chronic stress, are you going to tell us whether we can do anything about it?” There are many fantastic websites (including the VA) where experts far more qualified than I am offer excellent advice on coping with the pandemic.7 What I can provide is 5 reflections on managing the stress that I have used and that others with whom I shared them have found helpful.
1. Set realistic expectations. We are in a different reality in which we may need to take on smaller tasks, pace our work and take more breaks and, most of all, give ourselves a break when we are not as functional as we were before the pandemic.
2. Get out in nature. Find a green space to walk or sit, spend time with companion animals, go for a hike or bicycle near water or mountains, or watch the birds in a forest. Nothing can help restore our perspective or calm frayed nerves like the socially distanced outdoors.
3. Reach out. Even though we cannot hug or even shake hands, we can still pick up the phone or mouse and check on someone who is down. All the great traditions of the world agree that the best way to lift our own spirits is to help others.
4. Be kind. This is among the most important responses. As the epigraph suggests, everyone is engaged in an often silent and secret struggle and deserves our compassion. This call for kindness should be extended to ourselves so that we can be patient and compassionate to others.
5. Have courage and hope. This may be the most important of all. Whether we are infected or are fearing/avoiding infection, COVID-19 makes us sick in body and brain. We must have faith that there is something—the mind, the spirit—beyond the purely physical that gives us courage to outlast COVID-19 and to have hope for a postpandemic future that though not the same as before may well be in some ways better
1. Troyer EA, Kohn JN, Hong S. Are we facing a crashing wave of neuropsychiatric sequelae of COVID-19? Neuropsychiatric symptoms and potential immunologic mechanisms. Brain Behav Immun . 2020;87:34-39. doi:10.1016/j.bbi.2020.04.027
2. Pappa S, Ntella V, Giannakas T, Giannakoulis VG, Papoutsi E, Katsaounou P. Prevalence of depression, anxiety, and insomnia among healthcare workers during the COVID-19pandemic: a systematic review and meta-analysis. Brain Behav Immun. 2020;88:901-907. doi:10.1016/j.bbi.2020.05.026
3. Salazar de Pablo G, Vaquerizo-Serrano J, Catalan A, et al. Impact of coronavirus syndromes on physical and mental health of health care workers: systematic review and meta-analysis. J Affect Disord. 2020;275:48-57. doi:10.1016/j.jad.2020.06.022.
4. Harkness K. Strange physical symptoms? Blame the chronic stress of life during the Covid-19 pandemic. https://the-conversation.com/strange-physical-symptoms-blame-the-chronic-stress-of-life-during-the-covid-19-pandemic-139096. Published June 11, 2020. Accessed August 29, 2020.
5. Centers for Disease Control and Prevention. Coronavirus Disease (COVID-19) 2019. Coping with stress. https://www.cdc.gov/coronavirus/2019-ncov/daily-life-coping/managing-stress-anxiety.html. Updated July 1, 2020. Accessed August 29, 2020.
6. Greenberg M. How the stress of the COVID-9 pandemic scrambles your brain. https://www.psychologytoday.com/us/blog/the-mindful-self-express/202006/how-the-stress-the-covid-19-pandemic-scrambles-your-brain. Published June 28, 2020. Accessed August 29, 2020.
7. US Department of Veterans Affairs, National Center for PTSD. Healthcare workers and responders. https://www.ptsd.va.gov/covid/list_healthcare_responders.asp. Updated August 12, 2020. Accessed August 29, 2020.
1. Troyer EA, Kohn JN, Hong S. Are we facing a crashing wave of neuropsychiatric sequelae of COVID-19? Neuropsychiatric symptoms and potential immunologic mechanisms. Brain Behav Immun . 2020;87:34-39. doi:10.1016/j.bbi.2020.04.027
2. Pappa S, Ntella V, Giannakas T, Giannakoulis VG, Papoutsi E, Katsaounou P. Prevalence of depression, anxiety, and insomnia among healthcare workers during the COVID-19pandemic: a systematic review and meta-analysis. Brain Behav Immun. 2020;88:901-907. doi:10.1016/j.bbi.2020.05.026
3. Salazar de Pablo G, Vaquerizo-Serrano J, Catalan A, et al. Impact of coronavirus syndromes on physical and mental health of health care workers: systematic review and meta-analysis. J Affect Disord. 2020;275:48-57. doi:10.1016/j.jad.2020.06.022.
4. Harkness K. Strange physical symptoms? Blame the chronic stress of life during the Covid-19 pandemic. https://the-conversation.com/strange-physical-symptoms-blame-the-chronic-stress-of-life-during-the-covid-19-pandemic-139096. Published June 11, 2020. Accessed August 29, 2020.
5. Centers for Disease Control and Prevention. Coronavirus Disease (COVID-19) 2019. Coping with stress. https://www.cdc.gov/coronavirus/2019-ncov/daily-life-coping/managing-stress-anxiety.html. Updated July 1, 2020. Accessed August 29, 2020.
6. Greenberg M. How the stress of the COVID-9 pandemic scrambles your brain. https://www.psychologytoday.com/us/blog/the-mindful-self-express/202006/how-the-stress-the-covid-19-pandemic-scrambles-your-brain. Published June 28, 2020. Accessed August 29, 2020.
7. US Department of Veterans Affairs, National Center for PTSD. Healthcare workers and responders. https://www.ptsd.va.gov/covid/list_healthcare_responders.asp. Updated August 12, 2020. Accessed August 29, 2020.
