Standardized template design is a useful tool to improve clinical documentation and reliable reporting of health care outcomes when constructed with clear objectives and with collaboration of key stakeholders. A standardized template should not only capture accurate diagnostic information, but also inform quality improvement (QI) measures and best practices.

Kang and colleagues showed that a correlation exists between organizational satisfaction and improved quality outcomes.¹ A new initiative should have a well-defined purpose reinforced by collaborative workgroups and engaged employees who understand their clinical care role with electronic health record (EHR) modifications.

Several studies have shown how the usefulness of templates achieve multipurpose goals, such as accurate documentation and improved care. Valluru and colleagues showed a significant increase in vaccination rates for patients with inflammatory bowel disease after implementing a standardized template.² By using a standardized template, Thaker and colleagues showed improved documentation regarding obesity and increased nutritional and physical activity counseling.³ Furthermore, Grogan and colleagues showed that templates are useful for house staff education on International Classification of Diseases (ICD) terminology and demonstrated improved documentation in the postintervention group.^4,5

This article discusses the US Department of Veterans Affairs (VA) North Florida/South Georgia Veterans Health System (NF/SGVHS) integrated informatics solutions within template design in the Veterans Health Administration (VHA) EHR system that was associated with an increase in its case severity index (CSI) through improved clinical documentation capture.

Methods

According to policy activities that constitute research at NF/SGVHS, institutional review board approval was not required as this work met the criteria for operational improvement activities exempt from ethics review.

NF/SGVHS includes 2 hospitals: Malcom Randall VA Medical Center (MRVAMC) in Gainesville, Florida, and Lake City VA Medical Center (LCVAMC) in Lake City, Florida. MRVAMC is a large, 1a, academic VA facility composed of rotating residents and fellows and includes multiple specialty care services. LCVAMC is a smaller, nonteaching facility.

Template Design Impact

CSI is a risk-adjusted formula developed by the Inpatient Evaluation Center within VHA. CSI is incorporated into the VHA quality metrics reporting system, Strategic Analytics for Improvement and Learning (SAIL). CSI risk-adjusts metrics such as length of stay and mortality before releasing SAIL reports. CSI is calculated separately for acute level of care (LOC) and for the intensive care unit (ICU). In fiscal year (FY) 2017, acute LOC preimplementation data for CSI at NF/SGVHS were 0.76 for MRVAMC and 0.81 for LCVAMC, which was significantly below the national VHA average of 0.96 (Table).

A below-average CSI conveys a less complicated case mix compared with most other VA facilities. Although smaller VA facilities may have a less complicated case mix, it is unusual for large, tertiary care 1a VA facilities to have a low CSI. This low CSI is usually due to inadequate documentation, which affects not only risk-adjusted quality metrics outcomes, but also potential reimbursement.⁶

An interdisciplinary team composed of attendings, residents, and a clinical document improvement specialist identified the below-average acute LOC CSI for MRVAMC and LCVAMC compared with that of the national VHA average. Further analysis by chart reviews showed inconsistencies with standardized documentation despite prior health care provider education on ICD terminology and specific groups of common comorbidities analyzed in administrative data reviews for risk-adjustment purposes, known as Elixhauser comorbidities.^5,7

A chart review showed lack of clarity regarding primary reason(s) for admission and chronic comorbidities within NF/SGVHS. Using Pareto chart analysis, the template team designed a standardized history and physical (H&P) medicine template based on NF/SGVHS common medicine admissions (Figure 1). A Pareto chart is a valuable QI tool that assists with identifying majority contributors to a problem(s) being analyzed when evaluating a large set of data points. Subsequently, this tool helps focus direction on QI efforts.⁸

In addition, data objects were created within the template that permitted the ability to retrieve information from the VHA EHR and insert specific data points of interest in the template; for example, body mass index to assess degree of obesity and estimated glomerular filtration rate to determine the stage of chronic kidney disease. This allowed users to easily reference data in one template in lieu of searching for data in multiple places in the EHR.⁹

Results

The standardized H&P medicine template was implemented at MRVAMC and LCVAMC in June 2018 (the final month of the third quarter of FY 2018). As clinical providers throughout NF/SGVHS used the standardized template, acute LOC postimplementation data for CSI significantly improved. Although the national VHA average slightly decreased from 0.96 in the first quarter of FY 2017 to 0.89, in the first quarter of FY 2019, MRVAMC acute LOC CSI improved from 0.76 to 0.97, and LCVAMC acute LOC CSI improved from 0.81 to 1.07 during the same period.

In addition, compliance also was monitored within MRVAMC and LCVAMC for about 1 year after standardized H&P medicine template implementation. Compliance was determined by how often the standardized H&P medicine template was used for inpatient medicine admissions to the acute care wards vs other H&P notes used (such as personalized templates).

Methodology for compliance analysis included acquisition of completed H&P medicine notes from June 18, 2018 to June 30, 2019, within the VHA Veterans Information Systems and Technology Architecture (VistA) clinical and business information system using the search strings: “H&P admission history and physical” and “history of present illness.”¹⁰

A review identified 10,845 completed medicine H&P notes. Nine hundred eighteen notes were excluded as their search function yielded a location not corresponding to MRVAMC or LCVAMC. Of the 9,927 notes remaining, 8,025 of these were completed medicine H&P notes at MRVAMC and 1,902 were completed medicine H&P notes at LCVAMC (Figure 2).

Discussion

Template design with clear objectives, strategic collaboration, and integrated informatics solutions has the potential to increase accuracy of documentation. As shown, the NF/SGVHS template design was associated with significant improvement in acute LOC CSI for both MRVAMC and LCVAMC due to more accurate documentation using the standardized H&P medicine template.

Numerous factors contributed to the success of this template design. First, a clear vision for application of the template was communicated with key stakeholders. In addition, the template design team was focused on specific goals rather than a one size fits all approach, which was crucial for sustainable execution. Although interdisciplinary teamwork has the potential to result in innovative practices, large multidisciplinary teams also may have difficulty establishing a shared vision that can result in barriers to achieving project goals.

Balancing standardization and customization was essential for user buy-in. As noted by Gardner and Pearce, inviting clinical providers to participate in template design and allowing for customization has the potential to increase acceptance and use of templates.¹¹ Although the original design for the standardized H&P medicine template started with the medicine service at NF/SGVHS, the design framework is applicable to numerous services where various clinical care elements can be customized.

Explaining the informatics tools built into the template allowed clinicians to see opportunities to improve clinical documentation and the impact it has on reporting health care outcomes. When improvement work involves integrating clinical care delivery and administrative expectations, it is essential that health care systems understand and strategically execute project initiatives at this critical juncture.

Finally, incorporation of a sustainability plan when process improvement strategies are implemented is vital. In addition to collaboration with the clinical providers during design and implementation of the standardized template, leadership buy-in was key. Compliance with standardized H&P medicine template use was monitored monthly and reviewed by the NF/SGVHS Chief of Staff.

As noted, LCVAMC postimplementation acute LOC CSI was higher than that of MRVAMC despite being a smaller facility. This might be due to the MRVAMC designation as a teaching institution. Medicine is the only inpatient service at LCVAMC staffed by hospitalists with limited specialists available for consultation, whereas MRVAMC is a tertiary care teaching facility with numerous inpatient services and subspecialties. As LCVAMC has more continuity, house staff rotating at MRVAMC require continued training/education on new templates and process changes.

Limitations

Although standardized template design was successful at NF/SGVHS, limitations should be noted. Our clinical documentation improvement (CDI) program also was expanded about the same time as the new templates were released. The expansion of the CDI program in addition to new template design likely had a synergistic effect on acute LOC CSI.

CSI is a complex, risk-adjusted model that includes numerous factors, including but not limited to diagnosis and comorbid conditions. Other factors include age, marital status, procedures, source of admission, specific laboratory values, medical or surgical diagnosis-related group, intensive care unit stays, and immunosuppressive status. CSI also includes operative and nonoperative components that average into an overall CSI. As the majority of CSI is composed of nonoperative constituents within NF/SGVHS, we do not believe this had any substantial impact on reporting of CSI improvements.

In addition, template entry into VHA EHR requires a location selection (such as a clinic name or ward name following an inpatient admission). Of the 10,845 completed H&P medicine notes identified in VistA, 918 notes were excluded from analysis as their search function yielded a location not corresponding to MRVAMC or LCVAMC. For the 918 notes excluded, we believe this was likely due to user error where locations not related to MRVAMC or LCVAMC were selected during standardized H&P medicine template entry.

Conclusions

After the NF/SGVHS implementation of a uniquely designed template embedded with informatics solutions within the VHA EHR, the CSI increased due to more accurate documentation.

Next steps include determining the impact of the NF/SGVHS template design on potential reimbursement and expanding template design into the outpatient setting where there are additional opportunities to improve clinical documentation and reliable reporting of health care outcomes.

Acknowledgments

The authors thank the following individuals for their experience and contribution: Beverley White is the Clinical Documentation Improvement Coordinator at North Florida/South Georgia Veterans Health System and provided expertise on documentation requirements. Russell Jacobitz and Susan Rozelle provided technical expertise on electronic health record system enhancements and implemented the template design. Jess Delaune, MD, and Robert Carroll, MD, provided additional physician input during template design. We also acknowledge the Inpatient Evaluation Center (IPEC) within the Veterans Health Administration (VHA). IPEC developed the case severity index, a risk-adjusted formula incorporated into the VHA quality metric reporting system, Strategic Analytics for Improvement and Learning (SAIL).

Standardized template design is a useful tool to improve clinical documentation and reliable reporting of health care outcomes when constructed with clear objectives and with collaboration of key stakeholders. A standardized template should not only capture accurate diagnostic information, but also inform quality improvement (QI) measures and best practices.

Kang and colleagues showed that a correlation exists between organizational satisfaction and improved quality outcomes.¹ A new initiative should have a well-defined purpose reinforced by collaborative workgroups and engaged employees who understand their clinical care role with electronic health record (EHR) modifications.

Several studies have shown how the usefulness of templates achieve multipurpose goals, such as accurate documentation and improved care. Valluru and colleagues showed a significant increase in vaccination rates for patients with inflammatory bowel disease after implementing a standardized template.² By using a standardized template, Thaker and colleagues showed improved documentation regarding obesity and increased nutritional and physical activity counseling.³ Furthermore, Grogan and colleagues showed that templates are useful for house staff education on International Classification of Diseases (ICD) terminology and demonstrated improved documentation in the postintervention group.^4,5

This article discusses the US Department of Veterans Affairs (VA) North Florida/South Georgia Veterans Health System (NF/SGVHS) integrated informatics solutions within template design in the Veterans Health Administration (VHA) EHR system that was associated with an increase in its case severity index (CSI) through improved clinical documentation capture.

Methods

According to policy activities that constitute research at NF/SGVHS, institutional review board approval was not required as this work met the criteria for operational improvement activities exempt from ethics review.

NF/SGVHS includes 2 hospitals: Malcom Randall VA Medical Center (MRVAMC) in Gainesville, Florida, and Lake City VA Medical Center (LCVAMC) in Lake City, Florida. MRVAMC is a large, 1a, academic VA facility composed of rotating residents and fellows and includes multiple specialty care services. LCVAMC is a smaller, nonteaching facility.

Template Design Impact

CSI is a risk-adjusted formula developed by the Inpatient Evaluation Center within VHA. CSI is incorporated into the VHA quality metrics reporting system, Strategic Analytics for Improvement and Learning (SAIL). CSI risk-adjusts metrics such as length of stay and mortality before releasing SAIL reports. CSI is calculated separately for acute level of care (LOC) and for the intensive care unit (ICU). In fiscal year (FY) 2017, acute LOC preimplementation data for CSI at NF/SGVHS were 0.76 for MRVAMC and 0.81 for LCVAMC, which was significantly below the national VHA average of 0.96 (Table).

A below-average CSI conveys a less complicated case mix compared with most other VA facilities. Although smaller VA facilities may have a less complicated case mix, it is unusual for large, tertiary care 1a VA facilities to have a low CSI. This low CSI is usually due to inadequate documentation, which affects not only risk-adjusted quality metrics outcomes, but also potential reimbursement.⁶

An interdisciplinary team composed of attendings, residents, and a clinical document improvement specialist identified the below-average acute LOC CSI for MRVAMC and LCVAMC compared with that of the national VHA average. Further analysis by chart reviews showed inconsistencies with standardized documentation despite prior health care provider education on ICD terminology and specific groups of common comorbidities analyzed in administrative data reviews for risk-adjustment purposes, known as Elixhauser comorbidities.^5,7

A chart review showed lack of clarity regarding primary reason(s) for admission and chronic comorbidities within NF/SGVHS. Using Pareto chart analysis, the template team designed a standardized history and physical (H&P) medicine template based on NF/SGVHS common medicine admissions (Figure 1). A Pareto chart is a valuable QI tool that assists with identifying majority contributors to a problem(s) being analyzed when evaluating a large set of data points. Subsequently, this tool helps focus direction on QI efforts.⁸

In addition, data objects were created within the template that permitted the ability to retrieve information from the VHA EHR and insert specific data points of interest in the template; for example, body mass index to assess degree of obesity and estimated glomerular filtration rate to determine the stage of chronic kidney disease. This allowed users to easily reference data in one template in lieu of searching for data in multiple places in the EHR.⁹

Results

The standardized H&P medicine template was implemented at MRVAMC and LCVAMC in June 2018 (the final month of the third quarter of FY 2018). As clinical providers throughout NF/SGVHS used the standardized template, acute LOC postimplementation data for CSI significantly improved. Although the national VHA average slightly decreased from 0.96 in the first quarter of FY 2017 to 0.89, in the first quarter of FY 2019, MRVAMC acute LOC CSI improved from 0.76 to 0.97, and LCVAMC acute LOC CSI improved from 0.81 to 1.07 during the same period.

In addition, compliance also was monitored within MRVAMC and LCVAMC for about 1 year after standardized H&P medicine template implementation. Compliance was determined by how often the standardized H&P medicine template was used for inpatient medicine admissions to the acute care wards vs other H&P notes used (such as personalized templates).

Methodology for compliance analysis included acquisition of completed H&P medicine notes from June 18, 2018 to June 30, 2019, within the VHA Veterans Information Systems and Technology Architecture (VistA) clinical and business information system using the search strings: “H&P admission history and physical” and “history of present illness.”¹⁰

A review identified 10,845 completed medicine H&P notes. Nine hundred eighteen notes were excluded as their search function yielded a location not corresponding to MRVAMC or LCVAMC. Of the 9,927 notes remaining, 8,025 of these were completed medicine H&P notes at MRVAMC and 1,902 were completed medicine H&P notes at LCVAMC (Figure 2).

Discussion

Template design with clear objectives, strategic collaboration, and integrated informatics solutions has the potential to increase accuracy of documentation. As shown, the NF/SGVHS template design was associated with significant improvement in acute LOC CSI for both MRVAMC and LCVAMC due to more accurate documentation using the standardized H&P medicine template.

Numerous factors contributed to the success of this template design. First, a clear vision for application of the template was communicated with key stakeholders. In addition, the template design team was focused on specific goals rather than a one size fits all approach, which was crucial for sustainable execution. Although interdisciplinary teamwork has the potential to result in innovative practices, large multidisciplinary teams also may have difficulty establishing a shared vision that can result in barriers to achieving project goals.

Balancing standardization and customization was essential for user buy-in. As noted by Gardner and Pearce, inviting clinical providers to participate in template design and allowing for customization has the potential to increase acceptance and use of templates.¹¹ Although the original design for the standardized H&P medicine template started with the medicine service at NF/SGVHS, the design framework is applicable to numerous services where various clinical care elements can be customized.

Explaining the informatics tools built into the template allowed clinicians to see opportunities to improve clinical documentation and the impact it has on reporting health care outcomes. When improvement work involves integrating clinical care delivery and administrative expectations, it is essential that health care systems understand and strategically execute project initiatives at this critical juncture.

Finally, incorporation of a sustainability plan when process improvement strategies are implemented is vital. In addition to collaboration with the clinical providers during design and implementation of the standardized template, leadership buy-in was key. Compliance with standardized H&P medicine template use was monitored monthly and reviewed by the NF/SGVHS Chief of Staff.

As noted, LCVAMC postimplementation acute LOC CSI was higher than that of MRVAMC despite being a smaller facility. This might be due to the MRVAMC designation as a teaching institution. Medicine is the only inpatient service at LCVAMC staffed by hospitalists with limited specialists available for consultation, whereas MRVAMC is a tertiary care teaching facility with numerous inpatient services and subspecialties. As LCVAMC has more continuity, house staff rotating at MRVAMC require continued training/education on new templates and process changes.

Limitations

Although standardized template design was successful at NF/SGVHS, limitations should be noted. Our clinical documentation improvement (CDI) program also was expanded about the same time as the new templates were released. The expansion of the CDI program in addition to new template design likely had a synergistic effect on acute LOC CSI.

CSI is a complex, risk-adjusted model that includes numerous factors, including but not limited to diagnosis and comorbid conditions. Other factors include age, marital status, procedures, source of admission, specific laboratory values, medical or surgical diagnosis-related group, intensive care unit stays, and immunosuppressive status. CSI also includes operative and nonoperative components that average into an overall CSI. As the majority of CSI is composed of nonoperative constituents within NF/SGVHS, we do not believe this had any substantial impact on reporting of CSI improvements.

In addition, template entry into VHA EHR requires a location selection (such as a clinic name or ward name following an inpatient admission). Of the 10,845 completed H&P medicine notes identified in VistA, 918 notes were excluded from analysis as their search function yielded a location not corresponding to MRVAMC or LCVAMC. For the 918 notes excluded, we believe this was likely due to user error where locations not related to MRVAMC or LCVAMC were selected during standardized H&P medicine template entry.

Conclusions

After the NF/SGVHS implementation of a uniquely designed template embedded with informatics solutions within the VHA EHR, the CSI increased due to more accurate documentation.

Next steps include determining the impact of the NF/SGVHS template design on potential reimbursement and expanding template design into the outpatient setting where there are additional opportunities to improve clinical documentation and reliable reporting of health care outcomes.

Acknowledgments

The authors thank the following individuals for their experience and contribution: Beverley White is the Clinical Documentation Improvement Coordinator at North Florida/South Georgia Veterans Health System and provided expertise on documentation requirements. Russell Jacobitz and Susan Rozelle provided technical expertise on electronic health record system enhancements and implemented the template design. Jess Delaune, MD, and Robert Carroll, MD, provided additional physician input during template design. We also acknowledge the Inpatient Evaluation Center (IPEC) within the Veterans Health Administration (VHA). IPEC developed the case severity index, a risk-adjusted formula incorporated into the VHA quality metric reporting system, Strategic Analytics for Improvement and Learning (SAIL).

Standardized template design is a useful tool to improve clinical documentation and reliable reporting of health care outcomes when constructed with clear objectives and with collaboration of key stakeholders. A standardized template should not only capture accurate diagnostic information, but also inform quality improvement (QI) measures and best practices.

Kang and colleagues showed that a correlation exists between organizational satisfaction and improved quality outcomes.¹ A new initiative should have a well-defined purpose reinforced by collaborative workgroups and engaged employees who understand their clinical care role with electronic health record (EHR) modifications.

Several studies have shown how the usefulness of templates achieve multipurpose goals, such as accurate documentation and improved care. Valluru and colleagues showed a significant increase in vaccination rates for patients with inflammatory bowel disease after implementing a standardized template.² By using a standardized template, Thaker and colleagues showed improved documentation regarding obesity and increased nutritional and physical activity counseling.³ Furthermore, Grogan and colleagues showed that templates are useful for house staff education on International Classification of Diseases (ICD) terminology and demonstrated improved documentation in the postintervention group.^4,5

This article discusses the US Department of Veterans Affairs (VA) North Florida/South Georgia Veterans Health System (NF/SGVHS) integrated informatics solutions within template design in the Veterans Health Administration (VHA) EHR system that was associated with an increase in its case severity index (CSI) through improved clinical documentation capture.

Methods

According to policy activities that constitute research at NF/SGVHS, institutional review board approval was not required as this work met the criteria for operational improvement activities exempt from ethics review.

NF/SGVHS includes 2 hospitals: Malcom Randall VA Medical Center (MRVAMC) in Gainesville, Florida, and Lake City VA Medical Center (LCVAMC) in Lake City, Florida. MRVAMC is a large, 1a, academic VA facility composed of rotating residents and fellows and includes multiple specialty care services. LCVAMC is a smaller, nonteaching facility.

Template Design Impact

CSI is a risk-adjusted formula developed by the Inpatient Evaluation Center within VHA. CSI is incorporated into the VHA quality metrics reporting system, Strategic Analytics for Improvement and Learning (SAIL). CSI risk-adjusts metrics such as length of stay and mortality before releasing SAIL reports. CSI is calculated separately for acute level of care (LOC) and for the intensive care unit (ICU). In fiscal year (FY) 2017, acute LOC preimplementation data for CSI at NF/SGVHS were 0.76 for MRVAMC and 0.81 for LCVAMC, which was significantly below the national VHA average of 0.96 (Table).

A below-average CSI conveys a less complicated case mix compared with most other VA facilities. Although smaller VA facilities may have a less complicated case mix, it is unusual for large, tertiary care 1a VA facilities to have a low CSI. This low CSI is usually due to inadequate documentation, which affects not only risk-adjusted quality metrics outcomes, but also potential reimbursement.⁶

An interdisciplinary team composed of attendings, residents, and a clinical document improvement specialist identified the below-average acute LOC CSI for MRVAMC and LCVAMC compared with that of the national VHA average. Further analysis by chart reviews showed inconsistencies with standardized documentation despite prior health care provider education on ICD terminology and specific groups of common comorbidities analyzed in administrative data reviews for risk-adjustment purposes, known as Elixhauser comorbidities.^5,7

A chart review showed lack of clarity regarding primary reason(s) for admission and chronic comorbidities within NF/SGVHS. Using Pareto chart analysis, the template team designed a standardized history and physical (H&P) medicine template based on NF/SGVHS common medicine admissions (Figure 1). A Pareto chart is a valuable QI tool that assists with identifying majority contributors to a problem(s) being analyzed when evaluating a large set of data points. Subsequently, this tool helps focus direction on QI efforts.⁸

In addition, data objects were created within the template that permitted the ability to retrieve information from the VHA EHR and insert specific data points of interest in the template; for example, body mass index to assess degree of obesity and estimated glomerular filtration rate to determine the stage of chronic kidney disease. This allowed users to easily reference data in one template in lieu of searching for data in multiple places in the EHR.⁹

Results

The standardized H&P medicine template was implemented at MRVAMC and LCVAMC in June 2018 (the final month of the third quarter of FY 2018). As clinical providers throughout NF/SGVHS used the standardized template, acute LOC postimplementation data for CSI significantly improved. Although the national VHA average slightly decreased from 0.96 in the first quarter of FY 2017 to 0.89, in the first quarter of FY 2019, MRVAMC acute LOC CSI improved from 0.76 to 0.97, and LCVAMC acute LOC CSI improved from 0.81 to 1.07 during the same period.

In addition, compliance also was monitored within MRVAMC and LCVAMC for about 1 year after standardized H&P medicine template implementation. Compliance was determined by how often the standardized H&P medicine template was used for inpatient medicine admissions to the acute care wards vs other H&P notes used (such as personalized templates).

Methodology for compliance analysis included acquisition of completed H&P medicine notes from June 18, 2018 to June 30, 2019, within the VHA Veterans Information Systems and Technology Architecture (VistA) clinical and business information system using the search strings: “H&P admission history and physical” and “history of present illness.”¹⁰

A review identified 10,845 completed medicine H&P notes. Nine hundred eighteen notes were excluded as their search function yielded a location not corresponding to MRVAMC or LCVAMC. Of the 9,927 notes remaining, 8,025 of these were completed medicine H&P notes at MRVAMC and 1,902 were completed medicine H&P notes at LCVAMC (Figure 2).

Discussion

Template design with clear objectives, strategic collaboration, and integrated informatics solutions has the potential to increase accuracy of documentation. As shown, the NF/SGVHS template design was associated with significant improvement in acute LOC CSI for both MRVAMC and LCVAMC due to more accurate documentation using the standardized H&P medicine template.

Numerous factors contributed to the success of this template design. First, a clear vision for application of the template was communicated with key stakeholders. In addition, the template design team was focused on specific goals rather than a one size fits all approach, which was crucial for sustainable execution. Although interdisciplinary teamwork has the potential to result in innovative practices, large multidisciplinary teams also may have difficulty establishing a shared vision that can result in barriers to achieving project goals.

Balancing standardization and customization was essential for user buy-in. As noted by Gardner and Pearce, inviting clinical providers to participate in template design and allowing for customization has the potential to increase acceptance and use of templates.¹¹ Although the original design for the standardized H&P medicine template started with the medicine service at NF/SGVHS, the design framework is applicable to numerous services where various clinical care elements can be customized.

Explaining the informatics tools built into the template allowed clinicians to see opportunities to improve clinical documentation and the impact it has on reporting health care outcomes. When improvement work involves integrating clinical care delivery and administrative expectations, it is essential that health care systems understand and strategically execute project initiatives at this critical juncture.

Finally, incorporation of a sustainability plan when process improvement strategies are implemented is vital. In addition to collaboration with the clinical providers during design and implementation of the standardized template, leadership buy-in was key. Compliance with standardized H&P medicine template use was monitored monthly and reviewed by the NF/SGVHS Chief of Staff.

As noted, LCVAMC postimplementation acute LOC CSI was higher than that of MRVAMC despite being a smaller facility. This might be due to the MRVAMC designation as a teaching institution. Medicine is the only inpatient service at LCVAMC staffed by hospitalists with limited specialists available for consultation, whereas MRVAMC is a tertiary care teaching facility with numerous inpatient services and subspecialties. As LCVAMC has more continuity, house staff rotating at MRVAMC require continued training/education on new templates and process changes.

Limitations

Although standardized template design was successful at NF/SGVHS, limitations should be noted. Our clinical documentation improvement (CDI) program also was expanded about the same time as the new templates were released. The expansion of the CDI program in addition to new template design likely had a synergistic effect on acute LOC CSI.

CSI is a complex, risk-adjusted model that includes numerous factors, including but not limited to diagnosis and comorbid conditions. Other factors include age, marital status, procedures, source of admission, specific laboratory values, medical or surgical diagnosis-related group, intensive care unit stays, and immunosuppressive status. CSI also includes operative and nonoperative components that average into an overall CSI. As the majority of CSI is composed of nonoperative constituents within NF/SGVHS, we do not believe this had any substantial impact on reporting of CSI improvements.

In addition, template entry into VHA EHR requires a location selection (such as a clinic name or ward name following an inpatient admission). Of the 10,845 completed H&P medicine notes identified in VistA, 918 notes were excluded from analysis as their search function yielded a location not corresponding to MRVAMC or LCVAMC. For the 918 notes excluded, we believe this was likely due to user error where locations not related to MRVAMC or LCVAMC were selected during standardized H&P medicine template entry.

Conclusions

After the NF/SGVHS implementation of a uniquely designed template embedded with informatics solutions within the VHA EHR, the CSI increased due to more accurate documentation.

Next steps include determining the impact of the NF/SGVHS template design on potential reimbursement and expanding template design into the outpatient setting where there are additional opportunities to improve clinical documentation and reliable reporting of health care outcomes.

Acknowledgments

The authors thank the following individuals for their experience and contribution: Beverley White is the Clinical Documentation Improvement Coordinator at North Florida/South Georgia Veterans Health System and provided expertise on documentation requirements. Russell Jacobitz and Susan Rozelle provided technical expertise on electronic health record system enhancements and implemented the template design. Jess Delaune, MD, and Robert Carroll, MD, provided additional physician input during template design. We also acknowledge the Inpatient Evaluation Center (IPEC) within the Veterans Health Administration (VHA). IPEC developed the case severity index, a risk-adjusted formula incorporated into the VHA quality metric reporting system, Strategic Analytics for Improvement and Learning (SAIL).

New data show that new CFTR modulator therapies for cystic fibrosis may be driving down hospitalizations in this patient population.

The triple combination therapy elexacaftor/tezacaftor/ivacaftor was associated with a near elimination of hospital stays in one hospital in Oregon, according to a new report. The hospital savings still weren’t nearly enough to pay for the cost of therapy, but the study underscores what many institutions have observed and adds a new layer to the view of quality of life improvements that the new therapy brings.

“After we started prescribing it, we noticed pretty quickly that hospitalizations appeared to be declining after patients started triple combination therapy, and we were hearing [similar reports] from other centers as well. We wanted to quantify this,” Eric C. Walter, MD, a pulmonologist at the Kaiser Permanente Cystic Fibrosis Clinic in Portland, Ore., said during a presentation of the results at the virtual North American Cystic Fibrosis Conference.

“We’re seeing that across the board in real practice, the number of cystic fibrosis patients that have to be hospitalized since starting this triple combination has gone down,” Robert Giusti, MD, said in an interview. “When they’ve had pulmonary exacerbations in the past, it was frequently because they failed outpatient antibiotics, but I think with triple combination therapy, if they do get sick, the likelihood is they will respond to oral antibiotics, so they may not need that prolonged IV course in the hospital.” Dr. Giusti is clinical professor of pediatrics at New York University and director of the Pediatric Cystic Fibrosis Center. He was not involved in the study.

The therapy gained Food and Drug Administration approval in 2019 for the treatment of individuals with CF who are aged 12 years and older, and who have at least one copy of the F508del mutation. Its cost is about $317,000 per year within the Kaiser Permanente system, according to Dr. Walter. His group compared hospitalization days for CF-related diagnoses from Jan. 1 through Aug. 31, 2020, before and after initiation of triple combination therapy.

Of 47 eligible patients, 32 initiated therapy during the study period; 38% had severe lung disease, defined by forced expiratory volume in 1 second (FEV₁₎ value less than 40%. In 2020, before initiation of therapy, there were an average of 27 hospital days per month, all among patients with severe lung disease.

Among the therapy group, there were no hospitalizations after initiation of therapy through Aug. 31. Dr. Walter noted that the first hospitalization of a patient on triple combination therapy didn’t occur until early October.

At an average daily cost of $6,700, the researchers calculated that triple combination therapy saved about $189,000 per month in this group of patients. Comparing numbers to previous years, in which some patients with FEV₁ greater than 40% were hospitalized, the researchers calculated that the therapy saved about $151,000 per month among individuals with severe lung disease: Patients with severe lung disease contributed about 80% to total hospital costs.

The drug itself for the whole group cost $845,000, dwarfing the $189,000 savings overall. But among patients with severe disease, hospitalization savings were about $151,000 per month, while the drug cost in this group was $316,800 per month.

Cost savings are important, but the improvement in quality of life for a patient – avoiding hospitalization, fewer impacts on work and education – should not be overlooked, according to Ryan Perkins, MD, a pediatric and adult pulmonary fellow at Boston Children’s Hospital and Brigham and Women’s Hospital, who moderated the session. “Some of these aren’t things people typically quantify and assign a price tag to,” Dr. Perkins said in an interview.

A big limitation of the work is that it was conducted during the COVID-19 pandemic, which may have reduced hospitalizations. “We did have patients that called in, told us they were sick, that they needed to be treated for an exacerbation but didn’t want to go to the hospital,” said Dr. Walter. To help adjust for this, Dr. Walter’s team plans to compare intravenous antibiotic exposure before and after triple combination therapy, reasoning that it could help clarify the pandemic’s impact on hospitalizations.

Dr. Walter, Dr. Giusti, and Dr. Perkins have no relevant financial disclosures.

SOURCE: Walter E et al. NACFC 2020. Abstract 795.

New data show that new CFTR modulator therapies for cystic fibrosis may be driving down hospitalizations in this patient population.

The triple combination therapy elexacaftor/tezacaftor/ivacaftor was associated with a near elimination of hospital stays in one hospital in Oregon, according to a new report. The hospital savings still weren’t nearly enough to pay for the cost of therapy, but the study underscores what many institutions have observed and adds a new layer to the view of quality of life improvements that the new therapy brings.

“After we started prescribing it, we noticed pretty quickly that hospitalizations appeared to be declining after patients started triple combination therapy, and we were hearing [similar reports] from other centers as well. We wanted to quantify this,” Eric C. Walter, MD, a pulmonologist at the Kaiser Permanente Cystic Fibrosis Clinic in Portland, Ore., said during a presentation of the results at the virtual North American Cystic Fibrosis Conference.

“We’re seeing that across the board in real practice, the number of cystic fibrosis patients that have to be hospitalized since starting this triple combination has gone down,” Robert Giusti, MD, said in an interview. “When they’ve had pulmonary exacerbations in the past, it was frequently because they failed outpatient antibiotics, but I think with triple combination therapy, if they do get sick, the likelihood is they will respond to oral antibiotics, so they may not need that prolonged IV course in the hospital.” Dr. Giusti is clinical professor of pediatrics at New York University and director of the Pediatric Cystic Fibrosis Center. He was not involved in the study.

The therapy gained Food and Drug Administration approval in 2019 for the treatment of individuals with CF who are aged 12 years and older, and who have at least one copy of the F508del mutation. Its cost is about $317,000 per year within the Kaiser Permanente system, according to Dr. Walter. His group compared hospitalization days for CF-related diagnoses from Jan. 1 through Aug. 31, 2020, before and after initiation of triple combination therapy.

Of 47 eligible patients, 32 initiated therapy during the study period; 38% had severe lung disease, defined by forced expiratory volume in 1 second (FEV₁₎ value less than 40%. In 2020, before initiation of therapy, there were an average of 27 hospital days per month, all among patients with severe lung disease.

Among the therapy group, there were no hospitalizations after initiation of therapy through Aug. 31. Dr. Walter noted that the first hospitalization of a patient on triple combination therapy didn’t occur until early October.

At an average daily cost of $6,700, the researchers calculated that triple combination therapy saved about $189,000 per month in this group of patients. Comparing numbers to previous years, in which some patients with FEV₁ greater than 40% were hospitalized, the researchers calculated that the therapy saved about $151,000 per month among individuals with severe lung disease: Patients with severe lung disease contributed about 80% to total hospital costs.

The drug itself for the whole group cost $845,000, dwarfing the $189,000 savings overall. But among patients with severe disease, hospitalization savings were about $151,000 per month, while the drug cost in this group was $316,800 per month.

Cost savings are important, but the improvement in quality of life for a patient – avoiding hospitalization, fewer impacts on work and education – should not be overlooked, according to Ryan Perkins, MD, a pediatric and adult pulmonary fellow at Boston Children’s Hospital and Brigham and Women’s Hospital, who moderated the session. “Some of these aren’t things people typically quantify and assign a price tag to,” Dr. Perkins said in an interview.

A big limitation of the work is that it was conducted during the COVID-19 pandemic, which may have reduced hospitalizations. “We did have patients that called in, told us they were sick, that they needed to be treated for an exacerbation but didn’t want to go to the hospital,” said Dr. Walter. To help adjust for this, Dr. Walter’s team plans to compare intravenous antibiotic exposure before and after triple combination therapy, reasoning that it could help clarify the pandemic’s impact on hospitalizations.

Dr. Walter, Dr. Giusti, and Dr. Perkins have no relevant financial disclosures.

SOURCE: Walter E et al. NACFC 2020. Abstract 795.

New data show that new CFTR modulator therapies for cystic fibrosis may be driving down hospitalizations in this patient population.

The triple combination therapy elexacaftor/tezacaftor/ivacaftor was associated with a near elimination of hospital stays in one hospital in Oregon, according to a new report. The hospital savings still weren’t nearly enough to pay for the cost of therapy, but the study underscores what many institutions have observed and adds a new layer to the view of quality of life improvements that the new therapy brings.

“After we started prescribing it, we noticed pretty quickly that hospitalizations appeared to be declining after patients started triple combination therapy, and we were hearing [similar reports] from other centers as well. We wanted to quantify this,” Eric C. Walter, MD, a pulmonologist at the Kaiser Permanente Cystic Fibrosis Clinic in Portland, Ore., said during a presentation of the results at the virtual North American Cystic Fibrosis Conference.

“We’re seeing that across the board in real practice, the number of cystic fibrosis patients that have to be hospitalized since starting this triple combination has gone down,” Robert Giusti, MD, said in an interview. “When they’ve had pulmonary exacerbations in the past, it was frequently because they failed outpatient antibiotics, but I think with triple combination therapy, if they do get sick, the likelihood is they will respond to oral antibiotics, so they may not need that prolonged IV course in the hospital.” Dr. Giusti is clinical professor of pediatrics at New York University and director of the Pediatric Cystic Fibrosis Center. He was not involved in the study.

The therapy gained Food and Drug Administration approval in 2019 for the treatment of individuals with CF who are aged 12 years and older, and who have at least one copy of the F508del mutation. Its cost is about $317,000 per year within the Kaiser Permanente system, according to Dr. Walter. His group compared hospitalization days for CF-related diagnoses from Jan. 1 through Aug. 31, 2020, before and after initiation of triple combination therapy.

Of 47 eligible patients, 32 initiated therapy during the study period; 38% had severe lung disease, defined by forced expiratory volume in 1 second (FEV₁₎ value less than 40%. In 2020, before initiation of therapy, there were an average of 27 hospital days per month, all among patients with severe lung disease.

Among the therapy group, there were no hospitalizations after initiation of therapy through Aug. 31. Dr. Walter noted that the first hospitalization of a patient on triple combination therapy didn’t occur until early October.

At an average daily cost of $6,700, the researchers calculated that triple combination therapy saved about $189,000 per month in this group of patients. Comparing numbers to previous years, in which some patients with FEV₁ greater than 40% were hospitalized, the researchers calculated that the therapy saved about $151,000 per month among individuals with severe lung disease: Patients with severe lung disease contributed about 80% to total hospital costs.

The drug itself for the whole group cost $845,000, dwarfing the $189,000 savings overall. But among patients with severe disease, hospitalization savings were about $151,000 per month, while the drug cost in this group was $316,800 per month.

Cost savings are important, but the improvement in quality of life for a patient – avoiding hospitalization, fewer impacts on work and education – should not be overlooked, according to Ryan Perkins, MD, a pediatric and adult pulmonary fellow at Boston Children’s Hospital and Brigham and Women’s Hospital, who moderated the session. “Some of these aren’t things people typically quantify and assign a price tag to,” Dr. Perkins said in an interview.

A big limitation of the work is that it was conducted during the COVID-19 pandemic, which may have reduced hospitalizations. “We did have patients that called in, told us they were sick, that they needed to be treated for an exacerbation but didn’t want to go to the hospital,” said Dr. Walter. To help adjust for this, Dr. Walter’s team plans to compare intravenous antibiotic exposure before and after triple combination therapy, reasoning that it could help clarify the pandemic’s impact on hospitalizations.

Dr. Walter, Dr. Giusti, and Dr. Perkins have no relevant financial disclosures.

SOURCE: Walter E et al. NACFC 2020. Abstract 795.

New data support genetic testing in breast cancer patients older than 65 years, according to researchers.

The prevalence of pathogenic variants in genes predisposing women to breast cancer was 3.18% among women with breast cancer and 1.48% among women without breast cancer in a case-control study of 26,707 women older than 65 years.

Variants in BRCA1/2, CHEK2, and PALB2 were significantly associated with increased breast cancer risk. The residual risk of breast cancer for women aged 66-85 years was 18.3% for BRCA1, 18.6% for BRCA2, 14.9% for CHEK2, and 15.8% for PALB2. In comparison, the residual risk of breast cancer for the general population was 6.8%, according to Surveillance, Epidemiology, and End Results data.

The investigators noted that women who develop breast cancer beyond 65 years of age – a large percentage of the breast cancer population – do not often qualify for genetic testing, but the frequency of pathogenic variants “is not negligible in this population” and significantly elevates remaining lifetime risk.

The data from this study “can be used to reevaluate cancer screening and additional risk management strategies for women over the age of 65,” investigator Nicholas Boddicker, PhD, of the Mayo Clinic in Rochester, Minn., and colleagues wrote in a poster presentation.

The researchers presented their findings at the American Society of Human Genetics Virtual Meeting 2020.
 

Results may inform guidelines

National guidelines generally recommend screening for genetic variants when women develop breast cancer early in life or if they have a family history of breast cancer, but there has been controversy about whether those screening recommendations should be expanded, Dr. Boddicker and colleagues noted. The team thinks data from their study should help inform the discussion.

“We had an idea that the prevalence of these mutations in this population was not going to be zero, but I am not sure we were thinking that it was going to be over 3%. We believe these data will assist with reassessing genetic testing guidelines,” Dr. Boddicker said in an interview.

He said expanding genetic screening to include older women would have clinical implications. Women found to have pathogenic variants could perhaps undergo MRI surveillance in addition to mammography. If they are especially high risk, prophylactic mastectomy could be considered. Also, newer treatments hinge on the presence of pathogenic variants, such as PARP inhibitors for HER2-negative metastatic breast cancer with BRCA mutations.
 

Current testing limits ‘ridiculous’

“This is an excellent study and shows that even women over 65 have significant risk of breast cancer if they have a pathogenic variant. The variant could absolutely affect their treatment,” said Peter Beitsch, MD, a breast cancer surgical oncologist at the Dallas Surgical Group.

Dr. Beitsch was the lead author of a study, published in the Journal of Clinical Oncology in 2019, that showed that nearly half of breast cancer patients with a clinically actionable pathogenic variant were missed by current testing guidelines.

“All patients with a diagnosis of breast cancer [should] undergo expanded panel testing,” Dr. Beitsch and colleagues concluded in the paper.

Dr. Beitsch said current limitations on genetic screening make “no common sense. It’s OK to genetically test a woman who is 64 years and 11 months, but not 1 month later? Obviously ridiculous,” he said when asked for comment on the new report.

“The bigger impact is on their relatives,” Dr. Beitsch added. “Identifying people (men and women) with the same pathogenic variant can potentially save lives from more intensive screening or even prevent a cancer by doing prophylactic mastectomies. Male relatives have increased incidence of cancers with pathogenic variants in many of these genes.”

Screening for those variants could “lead to earlier detection or prevention,” Dr. Beitsch said.

As Dr. Boddicker noted, however, there is the question of who would pay for expanded screening and how to counsel patients who, despite increased risk, may never develop cancer.
 

Study details and next steps

The study included 13,762 women with breast cancer who were older than 65 years and 12,945 age-matched controls without breast cancer. A multigene amplicon-based panel was used to identify 12 known pathogenic variants in breast cancer–predisposing genes.

The women were part of the CARRIERS consortium, which pools breast cancer patients from case-control studies. Overall, 82.6% of subjects were non-Hispanic White, 25.6% of breast cancer patients and 17.9% of control subjects had a positive family history, and the mean age was 72.8 years (range, 66-94.3 years).

Across the entire study population, 0.48% of subjects had variants in ATM, 0.18% in BRCA1, 0.49% in BRCA2, 0.67% in CHEK2, and 0.23% in PALB2.

After adjustment for age, race, and family history, pathogenic variants in BRCA1 increased the risk of cancer more than threefold (odds ratio, 3.37), with similar findings for BRCA2 (OR, 2.64), PALB2 (OR, 3.09), and CHEK2 (OR, 2.13). ATM variants were not associated with a significantly increased risk of breast cancer (OR, 1.38).

Dr. Boddicker said the researchers’ next steps are to incorporate polygenic risk scores into the analyses and further investigate the impact of race.

The study is funded by the National Institutes of Health. Dr. Boddicker and Dr. Beitsch didn’t have any disclosures.

[email protected]

SOURCE: Boddicker NJ et al. ASHG 2020, Abstract 2412.

New data support genetic testing in breast cancer patients older than 65 years, according to researchers.

The prevalence of pathogenic variants in genes predisposing women to breast cancer was 3.18% among women with breast cancer and 1.48% among women without breast cancer in a case-control study of 26,707 women older than 65 years.

Variants in BRCA1/2, CHEK2, and PALB2 were significantly associated with increased breast cancer risk. The residual risk of breast cancer for women aged 66-85 years was 18.3% for BRCA1, 18.6% for BRCA2, 14.9% for CHEK2, and 15.8% for PALB2. In comparison, the residual risk of breast cancer for the general population was 6.8%, according to Surveillance, Epidemiology, and End Results data.

The investigators noted that women who develop breast cancer beyond 65 years of age – a large percentage of the breast cancer population – do not often qualify for genetic testing, but the frequency of pathogenic variants “is not negligible in this population” and significantly elevates remaining lifetime risk.

The data from this study “can be used to reevaluate cancer screening and additional risk management strategies for women over the age of 65,” investigator Nicholas Boddicker, PhD, of the Mayo Clinic in Rochester, Minn., and colleagues wrote in a poster presentation.

The researchers presented their findings at the American Society of Human Genetics Virtual Meeting 2020.
 

Results may inform guidelines

National guidelines generally recommend screening for genetic variants when women develop breast cancer early in life or if they have a family history of breast cancer, but there has been controversy about whether those screening recommendations should be expanded, Dr. Boddicker and colleagues noted. The team thinks data from their study should help inform the discussion.

“We had an idea that the prevalence of these mutations in this population was not going to be zero, but I am not sure we were thinking that it was going to be over 3%. We believe these data will assist with reassessing genetic testing guidelines,” Dr. Boddicker said in an interview.

He said expanding genetic screening to include older women would have clinical implications. Women found to have pathogenic variants could perhaps undergo MRI surveillance in addition to mammography. If they are especially high risk, prophylactic mastectomy could be considered. Also, newer treatments hinge on the presence of pathogenic variants, such as PARP inhibitors for HER2-negative metastatic breast cancer with BRCA mutations.
 

Current testing limits ‘ridiculous’

“This is an excellent study and shows that even women over 65 have significant risk of breast cancer if they have a pathogenic variant. The variant could absolutely affect their treatment,” said Peter Beitsch, MD, a breast cancer surgical oncologist at the Dallas Surgical Group.

Dr. Beitsch was the lead author of a study, published in the Journal of Clinical Oncology in 2019, that showed that nearly half of breast cancer patients with a clinically actionable pathogenic variant were missed by current testing guidelines.

“All patients with a diagnosis of breast cancer [should] undergo expanded panel testing,” Dr. Beitsch and colleagues concluded in the paper.

Dr. Beitsch said current limitations on genetic screening make “no common sense. It’s OK to genetically test a woman who is 64 years and 11 months, but not 1 month later? Obviously ridiculous,” he said when asked for comment on the new report.

“The bigger impact is on their relatives,” Dr. Beitsch added. “Identifying people (men and women) with the same pathogenic variant can potentially save lives from more intensive screening or even prevent a cancer by doing prophylactic mastectomies. Male relatives have increased incidence of cancers with pathogenic variants in many of these genes.”

Screening for those variants could “lead to earlier detection or prevention,” Dr. Beitsch said.

As Dr. Boddicker noted, however, there is the question of who would pay for expanded screening and how to counsel patients who, despite increased risk, may never develop cancer.
 

Study details and next steps

The study included 13,762 women with breast cancer who were older than 65 years and 12,945 age-matched controls without breast cancer. A multigene amplicon-based panel was used to identify 12 known pathogenic variants in breast cancer–predisposing genes.

The women were part of the CARRIERS consortium, which pools breast cancer patients from case-control studies. Overall, 82.6% of subjects were non-Hispanic White, 25.6% of breast cancer patients and 17.9% of control subjects had a positive family history, and the mean age was 72.8 years (range, 66-94.3 years).

Across the entire study population, 0.48% of subjects had variants in ATM, 0.18% in BRCA1, 0.49% in BRCA2, 0.67% in CHEK2, and 0.23% in PALB2.

After adjustment for age, race, and family history, pathogenic variants in BRCA1 increased the risk of cancer more than threefold (odds ratio, 3.37), with similar findings for BRCA2 (OR, 2.64), PALB2 (OR, 3.09), and CHEK2 (OR, 2.13). ATM variants were not associated with a significantly increased risk of breast cancer (OR, 1.38).

Dr. Boddicker said the researchers’ next steps are to incorporate polygenic risk scores into the analyses and further investigate the impact of race.

The study is funded by the National Institutes of Health. Dr. Boddicker and Dr. Beitsch didn’t have any disclosures.

[email protected]

SOURCE: Boddicker NJ et al. ASHG 2020, Abstract 2412.

New data support genetic testing in breast cancer patients older than 65 years, according to researchers.

The prevalence of pathogenic variants in genes predisposing women to breast cancer was 3.18% among women with breast cancer and 1.48% among women without breast cancer in a case-control study of 26,707 women older than 65 years.

Variants in BRCA1/2, CHEK2, and PALB2 were significantly associated with increased breast cancer risk. The residual risk of breast cancer for women aged 66-85 years was 18.3% for BRCA1, 18.6% for BRCA2, 14.9% for CHEK2, and 15.8% for PALB2. In comparison, the residual risk of breast cancer for the general population was 6.8%, according to Surveillance, Epidemiology, and End Results data.

The investigators noted that women who develop breast cancer beyond 65 years of age – a large percentage of the breast cancer population – do not often qualify for genetic testing, but the frequency of pathogenic variants “is not negligible in this population” and significantly elevates remaining lifetime risk.

The data from this study “can be used to reevaluate cancer screening and additional risk management strategies for women over the age of 65,” investigator Nicholas Boddicker, PhD, of the Mayo Clinic in Rochester, Minn., and colleagues wrote in a poster presentation.

The researchers presented their findings at the American Society of Human Genetics Virtual Meeting 2020.
 

Results may inform guidelines

National guidelines generally recommend screening for genetic variants when women develop breast cancer early in life or if they have a family history of breast cancer, but there has been controversy about whether those screening recommendations should be expanded, Dr. Boddicker and colleagues noted. The team thinks data from their study should help inform the discussion.

“We had an idea that the prevalence of these mutations in this population was not going to be zero, but I am not sure we were thinking that it was going to be over 3%. We believe these data will assist with reassessing genetic testing guidelines,” Dr. Boddicker said in an interview.

He said expanding genetic screening to include older women would have clinical implications. Women found to have pathogenic variants could perhaps undergo MRI surveillance in addition to mammography. If they are especially high risk, prophylactic mastectomy could be considered. Also, newer treatments hinge on the presence of pathogenic variants, such as PARP inhibitors for HER2-negative metastatic breast cancer with BRCA mutations.
 

Current testing limits ‘ridiculous’

“This is an excellent study and shows that even women over 65 have significant risk of breast cancer if they have a pathogenic variant. The variant could absolutely affect their treatment,” said Peter Beitsch, MD, a breast cancer surgical oncologist at the Dallas Surgical Group.

Dr. Beitsch was the lead author of a study, published in the Journal of Clinical Oncology in 2019, that showed that nearly half of breast cancer patients with a clinically actionable pathogenic variant were missed by current testing guidelines.

“All patients with a diagnosis of breast cancer [should] undergo expanded panel testing,” Dr. Beitsch and colleagues concluded in the paper.

Dr. Beitsch said current limitations on genetic screening make “no common sense. It’s OK to genetically test a woman who is 64 years and 11 months, but not 1 month later? Obviously ridiculous,” he said when asked for comment on the new report.

“The bigger impact is on their relatives,” Dr. Beitsch added. “Identifying people (men and women) with the same pathogenic variant can potentially save lives from more intensive screening or even prevent a cancer by doing prophylactic mastectomies. Male relatives have increased incidence of cancers with pathogenic variants in many of these genes.”

Screening for those variants could “lead to earlier detection or prevention,” Dr. Beitsch said.

As Dr. Boddicker noted, however, there is the question of who would pay for expanded screening and how to counsel patients who, despite increased risk, may never develop cancer.
 

Study details and next steps

The study included 13,762 women with breast cancer who were older than 65 years and 12,945 age-matched controls without breast cancer. A multigene amplicon-based panel was used to identify 12 known pathogenic variants in breast cancer–predisposing genes.

The women were part of the CARRIERS consortium, which pools breast cancer patients from case-control studies. Overall, 82.6% of subjects were non-Hispanic White, 25.6% of breast cancer patients and 17.9% of control subjects had a positive family history, and the mean age was 72.8 years (range, 66-94.3 years).

Across the entire study population, 0.48% of subjects had variants in ATM, 0.18% in BRCA1, 0.49% in BRCA2, 0.67% in CHEK2, and 0.23% in PALB2.

After adjustment for age, race, and family history, pathogenic variants in BRCA1 increased the risk of cancer more than threefold (odds ratio, 3.37), with similar findings for BRCA2 (OR, 2.64), PALB2 (OR, 3.09), and CHEK2 (OR, 2.13). ATM variants were not associated with a significantly increased risk of breast cancer (OR, 1.38).

Dr. Boddicker said the researchers’ next steps are to incorporate polygenic risk scores into the analyses and further investigate the impact of race.

The study is funded by the National Institutes of Health. Dr. Boddicker and Dr. Beitsch didn’t have any disclosures.

[email protected]

SOURCE: Boddicker NJ et al. ASHG 2020, Abstract 2412.

Mention the word “botulinum toxin” and one’s mind is likely to go to the big business of cosmetic procedures. Among the 15.7 minimally invasive cosmetic procedures performed in 2017, botulinum toxin type A ­(BoNT-A) made up the largest share, with 7.23 million procedures.¹ However, botulinum toxin—which was first recognized for the ability to paralyze muscles through decreased release of acetylcholine—also has many pain-related and noncosmetic uses; some are approved by the US Food and Drug Administration (FDA) and others are off-label (see TABLE 1^2-31). This review provides an evidence-based look at these uses, from those that have good evidence to support them—including chronic migraine and overactive bladder—to those that have limited (or no) evidence to support them—such as chronic pelvic pain and cluster headache.

BoNT-A is 1 of 7 recognized serotypes derived from Clostridium botulinum.

But before we get into the evidence behind specific uses for botulinum toxin, let’s review the available options and the potential risks they pose.

Many options

Although botulinum toxin is produced by Clostridium botulinum, the synthetic process to produce pharmaceuticals is patented and branded. BoNT-A is 1 of 7 recognized serotypes derived from C botulinum; some examples of BoNT-A include onabotulinumtoxinA, abobotulinumtoxinA, and incobotulinumtoxinA. Clinically, the differences are minor, but they do allow for use of other brands if a patient becomes intolerant to the selected therapy. Treatment doses and costs for each brand vary.

Training. Primary care providers can obtain didactic training from pharmaceutical companies as well as skills training through workshops on botulinum toxin. Credentialed providers can perform some procedures in the primary care setting (TABLE 2).

Adverse effects also vary depending on the formulation and the sites injected. Patients generally tolerate the procedure well, with discomfort from injections and localized bleeding as the major complaints. However, systemic events such as anaphylaxis and antibody development can occur. Depending on the formulation injected, the molecule can migrate and cause weakness in adjacent muscles, leading to undesired effects. Compensatory muscles can become strained, resulting in pain. Serious complications such as pneumonia and death have occurred with injection of botulinum toxin in or around the neck.

A note about pain management. In addition to muscle relaxation, analgesic properties are among the identified benefits of BoNT-A injections.^32,33 BoNT-A suppresses the release of norepinephrine, substance P, and glutamate, which reduces pain sensitization.³² However, the extent of ongoing research involving BoNT-A uses in pain management exceeds the scope of this article. Some pain-related indications will be discussed, but the focus will be on other noncosmetic uses.

Headache disorders

Chronic migraine affects 1.3% to 2.2% of the population and is defined as headaches occurring ≥ 15 days (≥ 8 migrainous days) per month.² To qualify for BoNT-A treatment, patients must have tried 2 prophylactic medications that failed to provide relief, and their headaches must last at least 4 hours. Injections every 12 weeks with 5 U in each of 31 prescribed sites is effective, as shown in the PREEMPT 2 study² with external verification.³ The 24-week, double-blind, placebo-­controlled study showed that BoNT-A treatment reduced headache days by 9 days (P < .001) and migraine days by 8.7 days (P < .001)² and, at 108 weeks, injections reduced headache days by 10.7 days (P < .0001).^4,5

Continue to: Episodic migraine, tension headache, and cluster headaches

Episodic migraine, tension headache, and cluster headaches. There is no significant BoNT-A-related pain reduction in episodic migraine (n = 1838; 0.05 headaches/mo; 95% CI, –0.26 to –0.36) or tension headaches (n = 675; –1.43 headaches/mo; 95% CI, –3.13 to –0.27).^5,6 For cluster headaches, a single prospective study with low enrollment showed no consistent benefit,⁷ while a pilot study showed some improvement, with reduction of attacks by 50% in half of subjects.⁸

Patients generally tolerate the procedure well, with discomfort from injections and localized bleeding as the major complaints.

Occipital neuralgia and trigeminal neuralgia entail paroxysmal, brief, shock-like pain without associated deficits affecting the respective nerve distributions. Multiple prospective and double-blind placebo-­controlled studies with relatively low enrollment show consistent improvement in pain intensity, number of pain-free days, analgesic consumption, and headache frequency with BoNT-A added to nerve blocks.⁶

ENT disorders

Tinnitus by involuntary palatal tremor causes a discontinuous clicking noise. Palatal tremor can be treated with BoNT-A 15 U to tensor veli palatini and levator veli muscles to provide temporary relief for 2 to 6 months.⁹

Spasmodic dysphonia and voice tremor are the result of laryngeal hyperkinesis, and BoNT-A has been deemed the gold standard of treatment. BoNT-A is administered via bilateral injection of the thyroarytenoid muscles for patients with adductor-type spasmodic dysphonia and of the posterior cricoarytenoid muscles for those with the abductor type. A series of 1300 patients (predominantly with the adductor type) treated with BoNT-A showed a 100% improvement in symptoms for 6 to 15 weeks. Patients with abductor-type spasmodic dysphonia were found to have 89% improvement in Voice Related Quality of Life Index score.¹⁰

Secretory disorders

Primary axillary hyperhidrosis (PAH) is an idiopathic excessive production of sweat occurring for at least 6 months, typically with onset before age 25 years. PAH can cause significant psychosocial and physical impairment. Current treatments include topical aluminum chloride, systemic anticholinergics, and thoracic sympathectomy, which can provide temporary relief but are not well tolerated.

Continue to: BoNT-A treatment is efficacious...

Evaluation of BoNT-A as an adjunctive therapy in cerebral palsy has been extensive and conflicting.

BoNT-A treatment is efficacious, safe, and improves quality of life for PAH patients. A 52-week, multicenter, double-blind, randomized, placebo-controlled study showed significant reductions in symptom severity, decreased sweating at rest by gravimetric testing, and improvements in self-reported quality of life.¹¹ A 10-year retrospective study in patients ages 12 years and older showed a 75% to 100% improvement in hyperhidrosis, with a median treatment effect duration of 7 months.¹²

Sialorrhea, or hypersalivation, is typically associated with neurological conditions such as cerebral palsy, amyotrophic lateral sclerosis, Parkinson disease, and posttraumatic brain injuries. It typically is treated with anticholinergic drugs, surgery, and irradiation of salivary glands, which can have significant adverse effects and complications. In a randomized blinded study, BoNT-A injections in the parotid and submandibular glands resulted in a dramatic reduction of sialorrhea and were safe and well tolerated.¹³

Gastric disorders

Achalasia is a syndrome of aperistalsis and incomplete lower esophageal sphincter (LES) relaxation with a “bird beak” appearance on barium swallow. Patients who meet diagnostic criteria are treated with pneumatic dilation or myotomy; however, some patients demonstrate symptoms of achalasia but don’t meet the diagnostic criteria. In these patients, BoNT-A injection in the LES provides symptomatic relief. In a case series, LES BoNT-A injections 20 U were used as a decision tool in whether to proceed with definitive treatment.¹⁴

Gastroparesis is a disorder of impaired gastric motility without mechanical obstruction. Pyloric sphincter BoNT-A injections are useful in refractory patients. Multiple prospective, noncontrolled (4), retrospective (3), and randomized placebo-controlled (2), studies with limited enrollment showed benefit for 37.5% to 100% of patients receiving ­BoNT-A injections of 80 to 200 U.¹⁵

Musculoskeletal disorders

Cervical dystonia (CD) entails involuntary contractions of the neck and upper shoulder musculature, causing abnormal neck, shoulder, and head posturing. BoNT-A is first-line treatment for CD.⁵ BoNT-A is more efficacious than trihexyphenidyl based on multiple large, high-quality studies.¹⁶

Continue to: Chronic low back pain

Chronic low back pain (CLBP) is defined as back pain persisting ≥ 12 weeks. More than 80% of adults have had at least 1 episode of back pain in their lifetime. A 14-month open-label, pilot study evaluating the short- and long-term effects of paraspinal muscle ­BoNT-A injections for refractory CLBP showed reduced pain intensity, reduced number of pain days, and functional improvements.¹⁷

Myofascial pain syndrome (MPS) consists of myofascial trigger points (palpable, tender nodules that produce pain) with multiple pathophysiological etiologies that include dysfunctional acetylcholine activity, which releases nociceptive neurotransmitters. Studies have yielded inconsistent effects of BoNT-A on MPS.¹⁸

Spastic disorders

Cerebral palsy (CP) involves altered muscle tone, posture, and movement secondary to central motor dysfunction with spasticity. Evaluation of BoNT-A as an adjunctive therapy in CP has been extensive and conflicting. A prospective cohort study evaluating gastrocsoleus BoNT-A injections along with gait analysis in 37 children with CP showed no significant improvements.³⁰ In 60 children with CP who received BoNT-A injections, there was improvement in muscle tone and range of motion, while gait improved in patients up to (but not after) age 7 years.¹⁹ A multicenter Dutch study of 65 children compared BoNT-A injections in addition to a comprehensive rehabilitation program vs rehabilitation alone, with no difference identified.²⁰

Neonatal brachial plexus palsy (NBPP) is damage to the brachial plexus as a result of trauma during the perinatal period. It is typically self-resolving but can cause residual functional impairment. Surgery is recommended for serious injuries or if functional recovery is not achieved within 9 months. Off-label use of BoNT-A has been shown to be effective in relieving muscle contractures and imbalance, but data are limited and there have only been small studies performed.²¹ A retrospective cohort study of 59 patients with NBPP who received BoNT-A injections showed improved range of motion and function of the affected extremity. Moreover, surgical intervention was deferred, modified, or averted in patients who were under consideration for more invasive treatment.²¹

Post-stroke spasticity can be temporarily relieved with the use of BoNT-A injections. Several studies have examined the effect of BoNT-A coupled with rehabilitation programs vs injections alone in the treatment of post-stroke spasticity. Devier et al found that improvements in spasticity scores did not differ between groups; however, implementing rehabilitation after BoNT-A injections was associated with improved function compared to injection alone.³¹ A 2018 randomized, double-blind, placebo-controlled trial demonstrated improvements in both treatment groups: those who received ­BoNT-A plus targeted rehab regimen and those who received saline injection plus rehab.²² In this case, it appears BoNT-A acts as more of an adjunct to physical therapy in the treatment of post-stroke spasticity.⁵

Continue to: Hemifacial spasm

Hemifacial spasm is an involuntary, brief, irregular unilateral (sometimes bilateral) spasm of the face in the distribution of the facial nerve. Injections with BoNT-A have been deemed effective by the American Academy of Neurology.²³ A 16-year retrospective study examined the efficacy and adverse effects of BoNT-A in the treatment of hemifacial spasm in 113 patients with a mean age of 63.1 years; it demonstrated high efficacy and mild temporary adverse effects.²⁴ The duration of improvement averaged 16 weeks; pretarsal injections had better results than preseptal injections; and there were no differences between the commercial brands.

Blepharospasm is a focal dystonia marked by excessive blinking and involuntary eye closures due to overexcitability of orbicularis oculi and periocular muscles, and BoNT-A is the treatment of choice.^5,25 A retrospective review of 19 patients with blepharospasm who were treated with BoNT-A for more than 5 years found that BoNT-A is a stable and effective treatment with an adverse event rate of 4%. Additionally, there were no differences found in clinical efficacy between the 4 BoNT-A brands on the market.²⁵

It appears BoNT-A acts as more of an adjunct to physical therapy in the treatment of post-stroke spasticity.

Laryngeal tics can cause significant psychosocial distress for patients. This condition is characterized by involuntary, recurrent rhythmic sounds that are often preceded by premonitory urges that are relieved by the behavior. An open-label, uncontrolled, confirmatory study with 30 subjects showed that bilateral vocal cord BoNT-A injections resulted in 93% improvement in vocal tics.²⁶ A subsequent study highlighted case histories of 2 patients with laryngeal tics who received thyroarytenoid muscle BoNT-A injections and had marked reduction in symptoms and premonitory sensations.²⁷ Although these small studies have suggested possible effectiveness of BoNT-A for laryngeal tics, there is no high-quality evidence.

Urologic disorders

Overactive, idiopathic overactive, or neurogenic bladder causes increased urinary frequency, urgency, and nocturia without infectious etiology; they can be a result of neurologic dysregulation, detrusor overactivity, or idiopathic causes. Intravesical BoNT-A injection of 100 to 300 U has been found effective for symptoms refractory to anticholinergic and lifestyle therapy, with increased cystometric capacity (229.1 to 427 mL, P < .00001), decreased maximum detrusor pressure (60.7 to 26.1 cm H2O, P < .00001), and resolution of urgency in 87% of patients (P < .001).²⁸

Interstitial cystitis, also known as painful bladder syndrome, is characterized by reduced bladder emptying, urethral pressure, and residual urine pressure, with symptoms of increased urinary frequency without infection. Intravesicular BoNT-A injections have not consistently been effective in treatment of this condition.²⁸

Continue to: Dysfunctional voiding, urethral sphincter overactivity, and Fowler syndrome

Dysfunctional voiding, urethral sphincter overactivity, and Fowler syndrome involve urethral sphincter spasticity with difficulty passing urine and possibly retention. Urethral sphincter injections of 100 U ­BoNT-A improved flow rates and decreased residual volume. A randomized, double-blinded, ­placebo-controlled study showed a significantly improved International Prostate Symptom Score (IPSS), quality of life index, maximum flow rate, voided volume, and decreased detrusor voiding pressure at 1 month.²⁹

Intravesicular BoNT-A injections have not consistently been effective in the treatment of interstitial cystitis.

Benign prostatic hypertrophy (BPH) is a very common condition leading to outlet obstruction. The mainstays of treatment are 5-α-reductase inhibitors, α-adrenergic blockers, and surgical removal. Intraprostatic BoNT-A injections of 100 to 200 U were initially promising, and subsequent randomized, double-blind, placebo-controlled studies demonstrated patients with moderate-to-severe symptoms (IPSS ≥ 19) had improved IPSS, maximum flow rate, and post-void residual volume compared to placebo.²⁹

Gynecologic disorders

Vaginismus is the involuntary, recurrent, or persistent contraction of the perineal muscles surrounding the outer third of the vagina; it is classified by 4 progressively more severe degrees of intensity. Levator ani, bulbospongiosus, bulbocavernosus, pubococcygeus, and/or puborectalis muscle BoNT-A injections have shown benefits in decreasing resistance to vaginal exams (95.8%) and the ability to achieve satisfactory sexual intercourse after first injection (75%-100%). Effects were transient for up to 15.4% of patients requiring repeat injections.²⁸

Vulvodynia is vulvar pain and orgasmic difficulties and has been treated with bulbospongiosus muscle BoNT-A injections in retrospective studies. A single randomized, double-blinded, placebo-controlled study showed significantly improved pain scores after 1 to 2 injection series.²⁸

Chronic pelvic pain is a syndrome of somatic functional or regional pain, which can be caused by the spasm of the pelvic musculature with or without trigger points. Patients with pain refractory to treatment have been treated with levator ani injections. A retrospective cohort study found 79.3% of patients experienced pain relief and 20.7% reported improved symptoms. In a double-blind, randomized, placebo-controlled trial, pelvic floor muscles were injected with 80 U BoNT or saline, and symptoms were evaluated along with vaginal manometry. BoNT was associated with a reduction in some pain but not as much as placebo, while vaginal pressures decreased more with BoNT than with placebo.²⁸

CORRESPONDENCE
Blake Busey, DO, FAAFP, Texas Tech University of Health Sciences El Paso–Transmountain, 2000B Transmountain Road, Suite B400, El Paso, TX 79911; [email protected]

Mention the word “botulinum toxin” and one’s mind is likely to go to the big business of cosmetic procedures. Among the 15.7 minimally invasive cosmetic procedures performed in 2017, botulinum toxin type A ­(BoNT-A) made up the largest share, with 7.23 million procedures.¹ However, botulinum toxin—which was first recognized for the ability to paralyze muscles through decreased release of acetylcholine—also has many pain-related and noncosmetic uses; some are approved by the US Food and Drug Administration (FDA) and others are off-label (see TABLE 1^2-31). This review provides an evidence-based look at these uses, from those that have good evidence to support them—including chronic migraine and overactive bladder—to those that have limited (or no) evidence to support them—such as chronic pelvic pain and cluster headache.

BoNT-A is 1 of 7 recognized serotypes derived from Clostridium botulinum.

But before we get into the evidence behind specific uses for botulinum toxin, let’s review the available options and the potential risks they pose.

Many options

Although botulinum toxin is produced by Clostridium botulinum, the synthetic process to produce pharmaceuticals is patented and branded. BoNT-A is 1 of 7 recognized serotypes derived from C botulinum; some examples of BoNT-A include onabotulinumtoxinA, abobotulinumtoxinA, and incobotulinumtoxinA. Clinically, the differences are minor, but they do allow for use of other brands if a patient becomes intolerant to the selected therapy. Treatment doses and costs for each brand vary.

Training. Primary care providers can obtain didactic training from pharmaceutical companies as well as skills training through workshops on botulinum toxin. Credentialed providers can perform some procedures in the primary care setting (TABLE 2).

Adverse effects also vary depending on the formulation and the sites injected. Patients generally tolerate the procedure well, with discomfort from injections and localized bleeding as the major complaints. However, systemic events such as anaphylaxis and antibody development can occur. Depending on the formulation injected, the molecule can migrate and cause weakness in adjacent muscles, leading to undesired effects. Compensatory muscles can become strained, resulting in pain. Serious complications such as pneumonia and death have occurred with injection of botulinum toxin in or around the neck.

A note about pain management. In addition to muscle relaxation, analgesic properties are among the identified benefits of BoNT-A injections.^32,33 BoNT-A suppresses the release of norepinephrine, substance P, and glutamate, which reduces pain sensitization.³² However, the extent of ongoing research involving BoNT-A uses in pain management exceeds the scope of this article. Some pain-related indications will be discussed, but the focus will be on other noncosmetic uses.

Headache disorders

Chronic migraine affects 1.3% to 2.2% of the population and is defined as headaches occurring ≥ 15 days (≥ 8 migrainous days) per month.² To qualify for BoNT-A treatment, patients must have tried 2 prophylactic medications that failed to provide relief, and their headaches must last at least 4 hours. Injections every 12 weeks with 5 U in each of 31 prescribed sites is effective, as shown in the PREEMPT 2 study² with external verification.³ The 24-week, double-blind, placebo-­controlled study showed that BoNT-A treatment reduced headache days by 9 days (P < .001) and migraine days by 8.7 days (P < .001)² and, at 108 weeks, injections reduced headache days by 10.7 days (P < .0001).^4,5

Continue to: Episodic migraine, tension headache, and cluster headaches

Episodic migraine, tension headache, and cluster headaches. There is no significant BoNT-A-related pain reduction in episodic migraine (n = 1838; 0.05 headaches/mo; 95% CI, –0.26 to –0.36) or tension headaches (n = 675; –1.43 headaches/mo; 95% CI, –3.13 to –0.27).^5,6 For cluster headaches, a single prospective study with low enrollment showed no consistent benefit,⁷ while a pilot study showed some improvement, with reduction of attacks by 50% in half of subjects.⁸

Patients generally tolerate the procedure well, with discomfort from injections and localized bleeding as the major complaints.

Occipital neuralgia and trigeminal neuralgia entail paroxysmal, brief, shock-like pain without associated deficits affecting the respective nerve distributions. Multiple prospective and double-blind placebo-­controlled studies with relatively low enrollment show consistent improvement in pain intensity, number of pain-free days, analgesic consumption, and headache frequency with BoNT-A added to nerve blocks.⁶

ENT disorders

Tinnitus by involuntary palatal tremor causes a discontinuous clicking noise. Palatal tremor can be treated with BoNT-A 15 U to tensor veli palatini and levator veli muscles to provide temporary relief for 2 to 6 months.⁹

Spasmodic dysphonia and voice tremor are the result of laryngeal hyperkinesis, and BoNT-A has been deemed the gold standard of treatment. BoNT-A is administered via bilateral injection of the thyroarytenoid muscles for patients with adductor-type spasmodic dysphonia and of the posterior cricoarytenoid muscles for those with the abductor type. A series of 1300 patients (predominantly with the adductor type) treated with BoNT-A showed a 100% improvement in symptoms for 6 to 15 weeks. Patients with abductor-type spasmodic dysphonia were found to have 89% improvement in Voice Related Quality of Life Index score.¹⁰

Secretory disorders

Primary axillary hyperhidrosis (PAH) is an idiopathic excessive production of sweat occurring for at least 6 months, typically with onset before age 25 years. PAH can cause significant psychosocial and physical impairment. Current treatments include topical aluminum chloride, systemic anticholinergics, and thoracic sympathectomy, which can provide temporary relief but are not well tolerated.

Continue to: BoNT-A treatment is efficacious...

Evaluation of BoNT-A as an adjunctive therapy in cerebral palsy has been extensive and conflicting.

BoNT-A treatment is efficacious, safe, and improves quality of life for PAH patients. A 52-week, multicenter, double-blind, randomized, placebo-controlled study showed significant reductions in symptom severity, decreased sweating at rest by gravimetric testing, and improvements in self-reported quality of life.¹¹ A 10-year retrospective study in patients ages 12 years and older showed a 75% to 100% improvement in hyperhidrosis, with a median treatment effect duration of 7 months.¹²

Sialorrhea, or hypersalivation, is typically associated with neurological conditions such as cerebral palsy, amyotrophic lateral sclerosis, Parkinson disease, and posttraumatic brain injuries. It typically is treated with anticholinergic drugs, surgery, and irradiation of salivary glands, which can have significant adverse effects and complications. In a randomized blinded study, BoNT-A injections in the parotid and submandibular glands resulted in a dramatic reduction of sialorrhea and were safe and well tolerated.¹³

Gastric disorders

Achalasia is a syndrome of aperistalsis and incomplete lower esophageal sphincter (LES) relaxation with a “bird beak” appearance on barium swallow. Patients who meet diagnostic criteria are treated with pneumatic dilation or myotomy; however, some patients demonstrate symptoms of achalasia but don’t meet the diagnostic criteria. In these patients, BoNT-A injection in the LES provides symptomatic relief. In a case series, LES BoNT-A injections 20 U were used as a decision tool in whether to proceed with definitive treatment.¹⁴

Gastroparesis is a disorder of impaired gastric motility without mechanical obstruction. Pyloric sphincter BoNT-A injections are useful in refractory patients. Multiple prospective, noncontrolled (4), retrospective (3), and randomized placebo-controlled (2), studies with limited enrollment showed benefit for 37.5% to 100% of patients receiving ­BoNT-A injections of 80 to 200 U.¹⁵

Musculoskeletal disorders

Cervical dystonia (CD) entails involuntary contractions of the neck and upper shoulder musculature, causing abnormal neck, shoulder, and head posturing. BoNT-A is first-line treatment for CD.⁵ BoNT-A is more efficacious than trihexyphenidyl based on multiple large, high-quality studies.¹⁶

Continue to: Chronic low back pain

Chronic low back pain (CLBP) is defined as back pain persisting ≥ 12 weeks. More than 80% of adults have had at least 1 episode of back pain in their lifetime. A 14-month open-label, pilot study evaluating the short- and long-term effects of paraspinal muscle ­BoNT-A injections for refractory CLBP showed reduced pain intensity, reduced number of pain days, and functional improvements.¹⁷

Myofascial pain syndrome (MPS) consists of myofascial trigger points (palpable, tender nodules that produce pain) with multiple pathophysiological etiologies that include dysfunctional acetylcholine activity, which releases nociceptive neurotransmitters. Studies have yielded inconsistent effects of BoNT-A on MPS.¹⁸

Spastic disorders

Cerebral palsy (CP) involves altered muscle tone, posture, and movement secondary to central motor dysfunction with spasticity. Evaluation of BoNT-A as an adjunctive therapy in CP has been extensive and conflicting. A prospective cohort study evaluating gastrocsoleus BoNT-A injections along with gait analysis in 37 children with CP showed no significant improvements.³⁰ In 60 children with CP who received BoNT-A injections, there was improvement in muscle tone and range of motion, while gait improved in patients up to (but not after) age 7 years.¹⁹ A multicenter Dutch study of 65 children compared BoNT-A injections in addition to a comprehensive rehabilitation program vs rehabilitation alone, with no difference identified.²⁰

Neonatal brachial plexus palsy (NBPP) is damage to the brachial plexus as a result of trauma during the perinatal period. It is typically self-resolving but can cause residual functional impairment. Surgery is recommended for serious injuries or if functional recovery is not achieved within 9 months. Off-label use of BoNT-A has been shown to be effective in relieving muscle contractures and imbalance, but data are limited and there have only been small studies performed.²¹ A retrospective cohort study of 59 patients with NBPP who received BoNT-A injections showed improved range of motion and function of the affected extremity. Moreover, surgical intervention was deferred, modified, or averted in patients who were under consideration for more invasive treatment.²¹

Post-stroke spasticity can be temporarily relieved with the use of BoNT-A injections. Several studies have examined the effect of BoNT-A coupled with rehabilitation programs vs injections alone in the treatment of post-stroke spasticity. Devier et al found that improvements in spasticity scores did not differ between groups; however, implementing rehabilitation after BoNT-A injections was associated with improved function compared to injection alone.³¹ A 2018 randomized, double-blind, placebo-controlled trial demonstrated improvements in both treatment groups: those who received ­BoNT-A plus targeted rehab regimen and those who received saline injection plus rehab.²² In this case, it appears BoNT-A acts as more of an adjunct to physical therapy in the treatment of post-stroke spasticity.⁵

Continue to: Hemifacial spasm

Hemifacial spasm is an involuntary, brief, irregular unilateral (sometimes bilateral) spasm of the face in the distribution of the facial nerve. Injections with BoNT-A have been deemed effective by the American Academy of Neurology.²³ A 16-year retrospective study examined the efficacy and adverse effects of BoNT-A in the treatment of hemifacial spasm in 113 patients with a mean age of 63.1 years; it demonstrated high efficacy and mild temporary adverse effects.²⁴ The duration of improvement averaged 16 weeks; pretarsal injections had better results than preseptal injections; and there were no differences between the commercial brands.

Blepharospasm is a focal dystonia marked by excessive blinking and involuntary eye closures due to overexcitability of orbicularis oculi and periocular muscles, and BoNT-A is the treatment of choice.^5,25 A retrospective review of 19 patients with blepharospasm who were treated with BoNT-A for more than 5 years found that BoNT-A is a stable and effective treatment with an adverse event rate of 4%. Additionally, there were no differences found in clinical efficacy between the 4 BoNT-A brands on the market.²⁵

It appears BoNT-A acts as more of an adjunct to physical therapy in the treatment of post-stroke spasticity.

Laryngeal tics can cause significant psychosocial distress for patients. This condition is characterized by involuntary, recurrent rhythmic sounds that are often preceded by premonitory urges that are relieved by the behavior. An open-label, uncontrolled, confirmatory study with 30 subjects showed that bilateral vocal cord BoNT-A injections resulted in 93% improvement in vocal tics.²⁶ A subsequent study highlighted case histories of 2 patients with laryngeal tics who received thyroarytenoid muscle BoNT-A injections and had marked reduction in symptoms and premonitory sensations.²⁷ Although these small studies have suggested possible effectiveness of BoNT-A for laryngeal tics, there is no high-quality evidence.

Urologic disorders

Overactive, idiopathic overactive, or neurogenic bladder causes increased urinary frequency, urgency, and nocturia without infectious etiology; they can be a result of neurologic dysregulation, detrusor overactivity, or idiopathic causes. Intravesical BoNT-A injection of 100 to 300 U has been found effective for symptoms refractory to anticholinergic and lifestyle therapy, with increased cystometric capacity (229.1 to 427 mL, P < .00001), decreased maximum detrusor pressure (60.7 to 26.1 cm H2O, P < .00001), and resolution of urgency in 87% of patients (P < .001).²⁸

Interstitial cystitis, also known as painful bladder syndrome, is characterized by reduced bladder emptying, urethral pressure, and residual urine pressure, with symptoms of increased urinary frequency without infection. Intravesicular BoNT-A injections have not consistently been effective in treatment of this condition.²⁸

Continue to: Dysfunctional voiding, urethral sphincter overactivity, and Fowler syndrome

Dysfunctional voiding, urethral sphincter overactivity, and Fowler syndrome involve urethral sphincter spasticity with difficulty passing urine and possibly retention. Urethral sphincter injections of 100 U ­BoNT-A improved flow rates and decreased residual volume. A randomized, double-blinded, ­placebo-controlled study showed a significantly improved International Prostate Symptom Score (IPSS), quality of life index, maximum flow rate, voided volume, and decreased detrusor voiding pressure at 1 month.²⁹

Intravesicular BoNT-A injections have not consistently been effective in the treatment of interstitial cystitis.

Benign prostatic hypertrophy (BPH) is a very common condition leading to outlet obstruction. The mainstays of treatment are 5-α-reductase inhibitors, α-adrenergic blockers, and surgical removal. Intraprostatic BoNT-A injections of 100 to 200 U were initially promising, and subsequent randomized, double-blind, placebo-controlled studies demonstrated patients with moderate-to-severe symptoms (IPSS ≥ 19) had improved IPSS, maximum flow rate, and post-void residual volume compared to placebo.²⁹

Gynecologic disorders

Vaginismus is the involuntary, recurrent, or persistent contraction of the perineal muscles surrounding the outer third of the vagina; it is classified by 4 progressively more severe degrees of intensity. Levator ani, bulbospongiosus, bulbocavernosus, pubococcygeus, and/or puborectalis muscle BoNT-A injections have shown benefits in decreasing resistance to vaginal exams (95.8%) and the ability to achieve satisfactory sexual intercourse after first injection (75%-100%). Effects were transient for up to 15.4% of patients requiring repeat injections.²⁸

Vulvodynia is vulvar pain and orgasmic difficulties and has been treated with bulbospongiosus muscle BoNT-A injections in retrospective studies. A single randomized, double-blinded, placebo-controlled study showed significantly improved pain scores after 1 to 2 injection series.²⁸

Chronic pelvic pain is a syndrome of somatic functional or regional pain, which can be caused by the spasm of the pelvic musculature with or without trigger points. Patients with pain refractory to treatment have been treated with levator ani injections. A retrospective cohort study found 79.3% of patients experienced pain relief and 20.7% reported improved symptoms. In a double-blind, randomized, placebo-controlled trial, pelvic floor muscles were injected with 80 U BoNT or saline, and symptoms were evaluated along with vaginal manometry. BoNT was associated with a reduction in some pain but not as much as placebo, while vaginal pressures decreased more with BoNT than with placebo.²⁸

CORRESPONDENCE
Blake Busey, DO, FAAFP, Texas Tech University of Health Sciences El Paso–Transmountain, 2000B Transmountain Road, Suite B400, El Paso, TX 79911; [email protected]

Mention the word “botulinum toxin” and one’s mind is likely to go to the big business of cosmetic procedures. Among the 15.7 minimally invasive cosmetic procedures performed in 2017, botulinum toxin type A ­(BoNT-A) made up the largest share, with 7.23 million procedures.¹ However, botulinum toxin—which was first recognized for the ability to paralyze muscles through decreased release of acetylcholine—also has many pain-related and noncosmetic uses; some are approved by the US Food and Drug Administration (FDA) and others are off-label (see TABLE 1^2-31). This review provides an evidence-based look at these uses, from those that have good evidence to support them—including chronic migraine and overactive bladder—to those that have limited (or no) evidence to support them—such as chronic pelvic pain and cluster headache.

BoNT-A is 1 of 7 recognized serotypes derived from Clostridium botulinum.

But before we get into the evidence behind specific uses for botulinum toxin, let’s review the available options and the potential risks they pose.

Many options

Although botulinum toxin is produced by Clostridium botulinum, the synthetic process to produce pharmaceuticals is patented and branded. BoNT-A is 1 of 7 recognized serotypes derived from C botulinum; some examples of BoNT-A include onabotulinumtoxinA, abobotulinumtoxinA, and incobotulinumtoxinA. Clinically, the differences are minor, but they do allow for use of other brands if a patient becomes intolerant to the selected therapy. Treatment doses and costs for each brand vary.

Training. Primary care providers can obtain didactic training from pharmaceutical companies as well as skills training through workshops on botulinum toxin. Credentialed providers can perform some procedures in the primary care setting (TABLE 2).

Adverse effects also vary depending on the formulation and the sites injected. Patients generally tolerate the procedure well, with discomfort from injections and localized bleeding as the major complaints. However, systemic events such as anaphylaxis and antibody development can occur. Depending on the formulation injected, the molecule can migrate and cause weakness in adjacent muscles, leading to undesired effects. Compensatory muscles can become strained, resulting in pain. Serious complications such as pneumonia and death have occurred with injection of botulinum toxin in or around the neck.

A note about pain management. In addition to muscle relaxation, analgesic properties are among the identified benefits of BoNT-A injections.^32,33 BoNT-A suppresses the release of norepinephrine, substance P, and glutamate, which reduces pain sensitization.³² However, the extent of ongoing research involving BoNT-A uses in pain management exceeds the scope of this article. Some pain-related indications will be discussed, but the focus will be on other noncosmetic uses.

Headache disorders

Chronic migraine affects 1.3% to 2.2% of the population and is defined as headaches occurring ≥ 15 days (≥ 8 migrainous days) per month.² To qualify for BoNT-A treatment, patients must have tried 2 prophylactic medications that failed to provide relief, and their headaches must last at least 4 hours. Injections every 12 weeks with 5 U in each of 31 prescribed sites is effective, as shown in the PREEMPT 2 study² with external verification.³ The 24-week, double-blind, placebo-­controlled study showed that BoNT-A treatment reduced headache days by 9 days (P < .001) and migraine days by 8.7 days (P < .001)² and, at 108 weeks, injections reduced headache days by 10.7 days (P < .0001).^4,5

Continue to: Episodic migraine, tension headache, and cluster headaches

Episodic migraine, tension headache, and cluster headaches. There is no significant BoNT-A-related pain reduction in episodic migraine (n = 1838; 0.05 headaches/mo; 95% CI, –0.26 to –0.36) or tension headaches (n = 675; –1.43 headaches/mo; 95% CI, –3.13 to –0.27).^5,6 For cluster headaches, a single prospective study with low enrollment showed no consistent benefit,⁷ while a pilot study showed some improvement, with reduction of attacks by 50% in half of subjects.⁸

Patients generally tolerate the procedure well, with discomfort from injections and localized bleeding as the major complaints.

Occipital neuralgia and trigeminal neuralgia entail paroxysmal, brief, shock-like pain without associated deficits affecting the respective nerve distributions. Multiple prospective and double-blind placebo-­controlled studies with relatively low enrollment show consistent improvement in pain intensity, number of pain-free days, analgesic consumption, and headache frequency with BoNT-A added to nerve blocks.⁶

ENT disorders

Tinnitus by involuntary palatal tremor causes a discontinuous clicking noise. Palatal tremor can be treated with BoNT-A 15 U to tensor veli palatini and levator veli muscles to provide temporary relief for 2 to 6 months.⁹

Spasmodic dysphonia and voice tremor are the result of laryngeal hyperkinesis, and BoNT-A has been deemed the gold standard of treatment. BoNT-A is administered via bilateral injection of the thyroarytenoid muscles for patients with adductor-type spasmodic dysphonia and of the posterior cricoarytenoid muscles for those with the abductor type. A series of 1300 patients (predominantly with the adductor type) treated with BoNT-A showed a 100% improvement in symptoms for 6 to 15 weeks. Patients with abductor-type spasmodic dysphonia were found to have 89% improvement in Voice Related Quality of Life Index score.¹⁰

Secretory disorders

Primary axillary hyperhidrosis (PAH) is an idiopathic excessive production of sweat occurring for at least 6 months, typically with onset before age 25 years. PAH can cause significant psychosocial and physical impairment. Current treatments include topical aluminum chloride, systemic anticholinergics, and thoracic sympathectomy, which can provide temporary relief but are not well tolerated.

Continue to: BoNT-A treatment is efficacious...

Evaluation of BoNT-A as an adjunctive therapy in cerebral palsy has been extensive and conflicting.

BoNT-A treatment is efficacious, safe, and improves quality of life for PAH patients. A 52-week, multicenter, double-blind, randomized, placebo-controlled study showed significant reductions in symptom severity, decreased sweating at rest by gravimetric testing, and improvements in self-reported quality of life.¹¹ A 10-year retrospective study in patients ages 12 years and older showed a 75% to 100% improvement in hyperhidrosis, with a median treatment effect duration of 7 months.¹²

Sialorrhea, or hypersalivation, is typically associated with neurological conditions such as cerebral palsy, amyotrophic lateral sclerosis, Parkinson disease, and posttraumatic brain injuries. It typically is treated with anticholinergic drugs, surgery, and irradiation of salivary glands, which can have significant adverse effects and complications. In a randomized blinded study, BoNT-A injections in the parotid and submandibular glands resulted in a dramatic reduction of sialorrhea and were safe and well tolerated.¹³

Gastric disorders

Achalasia is a syndrome of aperistalsis and incomplete lower esophageal sphincter (LES) relaxation with a “bird beak” appearance on barium swallow. Patients who meet diagnostic criteria are treated with pneumatic dilation or myotomy; however, some patients demonstrate symptoms of achalasia but don’t meet the diagnostic criteria. In these patients, BoNT-A injection in the LES provides symptomatic relief. In a case series, LES BoNT-A injections 20 U were used as a decision tool in whether to proceed with definitive treatment.¹⁴

Gastroparesis is a disorder of impaired gastric motility without mechanical obstruction. Pyloric sphincter BoNT-A injections are useful in refractory patients. Multiple prospective, noncontrolled (4), retrospective (3), and randomized placebo-controlled (2), studies with limited enrollment showed benefit for 37.5% to 100% of patients receiving ­BoNT-A injections of 80 to 200 U.¹⁵

Musculoskeletal disorders

Cervical dystonia (CD) entails involuntary contractions of the neck and upper shoulder musculature, causing abnormal neck, shoulder, and head posturing. BoNT-A is first-line treatment for CD.⁵ BoNT-A is more efficacious than trihexyphenidyl based on multiple large, high-quality studies.¹⁶

Continue to: Chronic low back pain

Chronic low back pain (CLBP) is defined as back pain persisting ≥ 12 weeks. More than 80% of adults have had at least 1 episode of back pain in their lifetime. A 14-month open-label, pilot study evaluating the short- and long-term effects of paraspinal muscle ­BoNT-A injections for refractory CLBP showed reduced pain intensity, reduced number of pain days, and functional improvements.¹⁷

Myofascial pain syndrome (MPS) consists of myofascial trigger points (palpable, tender nodules that produce pain) with multiple pathophysiological etiologies that include dysfunctional acetylcholine activity, which releases nociceptive neurotransmitters. Studies have yielded inconsistent effects of BoNT-A on MPS.¹⁸

Spastic disorders

Cerebral palsy (CP) involves altered muscle tone, posture, and movement secondary to central motor dysfunction with spasticity. Evaluation of BoNT-A as an adjunctive therapy in CP has been extensive and conflicting. A prospective cohort study evaluating gastrocsoleus BoNT-A injections along with gait analysis in 37 children with CP showed no significant improvements.³⁰ In 60 children with CP who received BoNT-A injections, there was improvement in muscle tone and range of motion, while gait improved in patients up to (but not after) age 7 years.¹⁹ A multicenter Dutch study of 65 children compared BoNT-A injections in addition to a comprehensive rehabilitation program vs rehabilitation alone, with no difference identified.²⁰

Neonatal brachial plexus palsy (NBPP) is damage to the brachial plexus as a result of trauma during the perinatal period. It is typically self-resolving but can cause residual functional impairment. Surgery is recommended for serious injuries or if functional recovery is not achieved within 9 months. Off-label use of BoNT-A has been shown to be effective in relieving muscle contractures and imbalance, but data are limited and there have only been small studies performed.²¹ A retrospective cohort study of 59 patients with NBPP who received BoNT-A injections showed improved range of motion and function of the affected extremity. Moreover, surgical intervention was deferred, modified, or averted in patients who were under consideration for more invasive treatment.²¹

Post-stroke spasticity can be temporarily relieved with the use of BoNT-A injections. Several studies have examined the effect of BoNT-A coupled with rehabilitation programs vs injections alone in the treatment of post-stroke spasticity. Devier et al found that improvements in spasticity scores did not differ between groups; however, implementing rehabilitation after BoNT-A injections was associated with improved function compared to injection alone.³¹ A 2018 randomized, double-blind, placebo-controlled trial demonstrated improvements in both treatment groups: those who received ­BoNT-A plus targeted rehab regimen and those who received saline injection plus rehab.²² In this case, it appears BoNT-A acts as more of an adjunct to physical therapy in the treatment of post-stroke spasticity.⁵

Continue to: Hemifacial spasm

Hemifacial spasm is an involuntary, brief, irregular unilateral (sometimes bilateral) spasm of the face in the distribution of the facial nerve. Injections with BoNT-A have been deemed effective by the American Academy of Neurology.²³ A 16-year retrospective study examined the efficacy and adverse effects of BoNT-A in the treatment of hemifacial spasm in 113 patients with a mean age of 63.1 years; it demonstrated high efficacy and mild temporary adverse effects.²⁴ The duration of improvement averaged 16 weeks; pretarsal injections had better results than preseptal injections; and there were no differences between the commercial brands.

Blepharospasm is a focal dystonia marked by excessive blinking and involuntary eye closures due to overexcitability of orbicularis oculi and periocular muscles, and BoNT-A is the treatment of choice.^5,25 A retrospective review of 19 patients with blepharospasm who were treated with BoNT-A for more than 5 years found that BoNT-A is a stable and effective treatment with an adverse event rate of 4%. Additionally, there were no differences found in clinical efficacy between the 4 BoNT-A brands on the market.²⁵

It appears BoNT-A acts as more of an adjunct to physical therapy in the treatment of post-stroke spasticity.

Laryngeal tics can cause significant psychosocial distress for patients. This condition is characterized by involuntary, recurrent rhythmic sounds that are often preceded by premonitory urges that are relieved by the behavior. An open-label, uncontrolled, confirmatory study with 30 subjects showed that bilateral vocal cord BoNT-A injections resulted in 93% improvement in vocal tics.²⁶ A subsequent study highlighted case histories of 2 patients with laryngeal tics who received thyroarytenoid muscle BoNT-A injections and had marked reduction in symptoms and premonitory sensations.²⁷ Although these small studies have suggested possible effectiveness of BoNT-A for laryngeal tics, there is no high-quality evidence.

Urologic disorders

Overactive, idiopathic overactive, or neurogenic bladder causes increased urinary frequency, urgency, and nocturia without infectious etiology; they can be a result of neurologic dysregulation, detrusor overactivity, or idiopathic causes. Intravesical BoNT-A injection of 100 to 300 U has been found effective for symptoms refractory to anticholinergic and lifestyle therapy, with increased cystometric capacity (229.1 to 427 mL, P < .00001), decreased maximum detrusor pressure (60.7 to 26.1 cm H2O, P < .00001), and resolution of urgency in 87% of patients (P < .001).²⁸

Interstitial cystitis, also known as painful bladder syndrome, is characterized by reduced bladder emptying, urethral pressure, and residual urine pressure, with symptoms of increased urinary frequency without infection. Intravesicular BoNT-A injections have not consistently been effective in treatment of this condition.²⁸

Continue to: Dysfunctional voiding, urethral sphincter overactivity, and Fowler syndrome

Dysfunctional voiding, urethral sphincter overactivity, and Fowler syndrome involve urethral sphincter spasticity with difficulty passing urine and possibly retention. Urethral sphincter injections of 100 U ­BoNT-A improved flow rates and decreased residual volume. A randomized, double-blinded, ­placebo-controlled study showed a significantly improved International Prostate Symptom Score (IPSS), quality of life index, maximum flow rate, voided volume, and decreased detrusor voiding pressure at 1 month.²⁹

Intravesicular BoNT-A injections have not consistently been effective in the treatment of interstitial cystitis.

Benign prostatic hypertrophy (BPH) is a very common condition leading to outlet obstruction. The mainstays of treatment are 5-α-reductase inhibitors, α-adrenergic blockers, and surgical removal. Intraprostatic BoNT-A injections of 100 to 200 U were initially promising, and subsequent randomized, double-blind, placebo-controlled studies demonstrated patients with moderate-to-severe symptoms (IPSS ≥ 19) had improved IPSS, maximum flow rate, and post-void residual volume compared to placebo.²⁹

Gynecologic disorders

Vaginismus is the involuntary, recurrent, or persistent contraction of the perineal muscles surrounding the outer third of the vagina; it is classified by 4 progressively more severe degrees of intensity. Levator ani, bulbospongiosus, bulbocavernosus, pubococcygeus, and/or puborectalis muscle BoNT-A injections have shown benefits in decreasing resistance to vaginal exams (95.8%) and the ability to achieve satisfactory sexual intercourse after first injection (75%-100%). Effects were transient for up to 15.4% of patients requiring repeat injections.²⁸

Vulvodynia is vulvar pain and orgasmic difficulties and has been treated with bulbospongiosus muscle BoNT-A injections in retrospective studies. A single randomized, double-blinded, placebo-controlled study showed significantly improved pain scores after 1 to 2 injection series.²⁸

Chronic pelvic pain is a syndrome of somatic functional or regional pain, which can be caused by the spasm of the pelvic musculature with or without trigger points. Patients with pain refractory to treatment have been treated with levator ani injections. A retrospective cohort study found 79.3% of patients experienced pain relief and 20.7% reported improved symptoms. In a double-blind, randomized, placebo-controlled trial, pelvic floor muscles were injected with 80 U BoNT or saline, and symptoms were evaluated along with vaginal manometry. BoNT was associated with a reduction in some pain but not as much as placebo, while vaginal pressures decreased more with BoNT than with placebo.²⁸

CORRESPONDENCE
Blake Busey, DO, FAAFP, Texas Tech University of Health Sciences El Paso–Transmountain, 2000B Transmountain Road, Suite B400, El Paso, TX 79911; [email protected]

A new equation for estimating glomerular filtration rate (eGFR), a measure of kidney function, shows improved accuracy and precision, compared with commonly used equations.

The European Kidney Function Consortium (EKFC) equation surpasses existing equations by “resulting in generally lower bias across the spectrum of age and kidney function,” its developers wrote in an article published online Nov. 9 in Annals of Internal Medicine.

“The new EKFC equation may have helpful properties and perform better in estimating GFR, compared with the current KDIGO [Kidney Disease: Improving Global Outcomes]-recommended equations,” they added.

The primary KDIGO-recommended equation in its most recent guideline was the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation, designed for adults, and a companion equation, the CKiD, covers children and adolescents.

“Key in our [new] equation is the adjustment for differences in serum creatinine generation between children and adults, or between men and women,” lead author Hans Pottel, PhD, KU Leuven (Belgium), said in an interview.

In an accompanying editorial, Andrew M. Levey, MD, and associates wrote: “We agree that a single eGFR equation that can be used in children and adults and performs well in the transition from adolescence to young adulthood is a worthy goal.”

“But the claim of equivalent or superior performance, compared with the CKD-EPI equation is not conclusive,” claimed Dr. Levey, who led the research team that developed the CKD-EPI equation, and coauthors.

Dr. Levey is professor of medicine at Tufts University, Boston.
 

What’s new is Q

Dr. Pottel and codevelopers devised what they call Q values: age- and sex-dependent median creatinine levels in normal individuals.

Q values act to “normalize or rescale creatinine before entering it into the equation, because we know that creatinine generation is different” based on factors that include age, sex, and muscle mass.

The EKFC equation extends the CKD-EPI equation and first eGFR equation by using Q values and applying across age ranges, like the full-age spectrum (FAS) equation, first reported in 2016 by a team led by Dr. Pottel.

“Although the FAS equation was designed to overcome the challenge in measuring GFR in patients transitioning from adolescence to adult nephrology care, it also underestimates GFR at low serum creatinine values and in patients with chronic kidney disease,” wrote Dr. Pottel and coauthors.

Hence, their intent to tweak the FAS equation to overcome this limitation and create the EKFC equation.

“The new equation combines the strengths of the CKD-EPI and FAS equations,” they woite.

However, “we acknowledge that lack of precision is still a major problem with all eGFR equations,” including the new EKFC, they added.
 

Editorialists dispute better performance of EKFC over CKD-EPI

In their editorial, Dr. Levey and coauthors noted the EKFC equations and other adapted equations in development “represent a conceptual advance over the FAS equations,” but they dispute the claims of better performance, compared with the CKD-EPI.

“We compared the performance of the EKFC and CKD-EPI equations in a different, large external validation population of Black and non-Black adults,” the external population used to validate the CKD-EPI equation, the editorialists reported.

The upshot was “our results did not confirm the author’s conclusions” about the EKFC equation.

In response, Dr. Pottel highlighted that the EKFC equation is currently not designed for use in Black patients.

“With its derivation and validation now reported in the new article, the EKFC equation is fully validated and ready for routine use in Whites,” he said. “We plan to evaluate and possibly fine tune our equation for its application in other ethnicities.”

Regarding the inferior performance, compared with the CKD-EPI equation in the non-Black population tested by the editorialists, Dr. Pottel cited “calibration issues for serum creatinine” that some experts have found in the datasets compiled by developers of the CKI-EPI equation that could limit the utility of these data.
 

Still room for improvement; app hopefully coming next year

Dr. Pottel and coauthors developed and validated the EKFC equation with data from 19,629 patients drawn from 13 cohorts. This included 11,251 patients from seven cohorts for development and internal validation, and 8378 from six cohorts for external validation. The EKFC effort received endorsement from the European Renal Association–European Dialysis and Transplant Association.

However, “We acknowledge that there is still room for improvement,” Dr. Pottel said.

Although the new report presents the EKFC equations (actually two slightly different equations depending on whether a patient’s serum creatinine is higher or lower than the relevant Q value), most potential users will likely find the equations easier to work with once they’re in an app form that allows someone to simply plug in age, sex, and serum creatinine level. That app currently doesn’t exist but is coming soon, promised Dr. Pottel.

“I hope to have an electronic tool by the beginning of 2021,” he said. “I have to find a programmer who can do this for me.”

The EKFC project has received no commercial funding. Dr. Pottel reported no relevant financial relationships. Dr. Levey has reported receiving research funding from AstraZeneca.

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

A new equation for estimating glomerular filtration rate (eGFR), a measure of kidney function, shows improved accuracy and precision, compared with commonly used equations.

The European Kidney Function Consortium (EKFC) equation surpasses existing equations by “resulting in generally lower bias across the spectrum of age and kidney function,” its developers wrote in an article published online Nov. 9 in Annals of Internal Medicine.

“The new EKFC equation may have helpful properties and perform better in estimating GFR, compared with the current KDIGO [Kidney Disease: Improving Global Outcomes]-recommended equations,” they added.

The primary KDIGO-recommended equation in its most recent guideline was the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation, designed for adults, and a companion equation, the CKiD, covers children and adolescents.

“Key in our [new] equation is the adjustment for differences in serum creatinine generation between children and adults, or between men and women,” lead author Hans Pottel, PhD, KU Leuven (Belgium), said in an interview.

In an accompanying editorial, Andrew M. Levey, MD, and associates wrote: “We agree that a single eGFR equation that can be used in children and adults and performs well in the transition from adolescence to young adulthood is a worthy goal.”

“But the claim of equivalent or superior performance, compared with the CKD-EPI equation is not conclusive,” claimed Dr. Levey, who led the research team that developed the CKD-EPI equation, and coauthors.

Dr. Levey is professor of medicine at Tufts University, Boston.
 

What’s new is Q

Dr. Pottel and codevelopers devised what they call Q values: age- and sex-dependent median creatinine levels in normal individuals.

Q values act to “normalize or rescale creatinine before entering it into the equation, because we know that creatinine generation is different” based on factors that include age, sex, and muscle mass.

The EKFC equation extends the CKD-EPI equation and first eGFR equation by using Q values and applying across age ranges, like the full-age spectrum (FAS) equation, first reported in 2016 by a team led by Dr. Pottel.

“Although the FAS equation was designed to overcome the challenge in measuring GFR in patients transitioning from adolescence to adult nephrology care, it also underestimates GFR at low serum creatinine values and in patients with chronic kidney disease,” wrote Dr. Pottel and coauthors.

Hence, their intent to tweak the FAS equation to overcome this limitation and create the EKFC equation.

“The new equation combines the strengths of the CKD-EPI and FAS equations,” they woite.

However, “we acknowledge that lack of precision is still a major problem with all eGFR equations,” including the new EKFC, they added.
 

Editorialists dispute better performance of EKFC over CKD-EPI

In their editorial, Dr. Levey and coauthors noted the EKFC equations and other adapted equations in development “represent a conceptual advance over the FAS equations,” but they dispute the claims of better performance, compared with the CKD-EPI.

“We compared the performance of the EKFC and CKD-EPI equations in a different, large external validation population of Black and non-Black adults,” the external population used to validate the CKD-EPI equation, the editorialists reported.

The upshot was “our results did not confirm the author’s conclusions” about the EKFC equation.

In response, Dr. Pottel highlighted that the EKFC equation is currently not designed for use in Black patients.

“With its derivation and validation now reported in the new article, the EKFC equation is fully validated and ready for routine use in Whites,” he said. “We plan to evaluate and possibly fine tune our equation for its application in other ethnicities.”

Regarding the inferior performance, compared with the CKD-EPI equation in the non-Black population tested by the editorialists, Dr. Pottel cited “calibration issues for serum creatinine” that some experts have found in the datasets compiled by developers of the CKI-EPI equation that could limit the utility of these data.
 

Still room for improvement; app hopefully coming next year

Dr. Pottel and coauthors developed and validated the EKFC equation with data from 19,629 patients drawn from 13 cohorts. This included 11,251 patients from seven cohorts for development and internal validation, and 8378 from six cohorts for external validation. The EKFC effort received endorsement from the European Renal Association–European Dialysis and Transplant Association.

However, “We acknowledge that there is still room for improvement,” Dr. Pottel said.

Although the new report presents the EKFC equations (actually two slightly different equations depending on whether a patient’s serum creatinine is higher or lower than the relevant Q value), most potential users will likely find the equations easier to work with once they’re in an app form that allows someone to simply plug in age, sex, and serum creatinine level. That app currently doesn’t exist but is coming soon, promised Dr. Pottel.

“I hope to have an electronic tool by the beginning of 2021,” he said. “I have to find a programmer who can do this for me.”

The EKFC project has received no commercial funding. Dr. Pottel reported no relevant financial relationships. Dr. Levey has reported receiving research funding from AstraZeneca.

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

A new equation for estimating glomerular filtration rate (eGFR), a measure of kidney function, shows improved accuracy and precision, compared with commonly used equations.

The European Kidney Function Consortium (EKFC) equation surpasses existing equations by “resulting in generally lower bias across the spectrum of age and kidney function,” its developers wrote in an article published online Nov. 9 in Annals of Internal Medicine.

“The new EKFC equation may have helpful properties and perform better in estimating GFR, compared with the current KDIGO [Kidney Disease: Improving Global Outcomes]-recommended equations,” they added.

The primary KDIGO-recommended equation in its most recent guideline was the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation, designed for adults, and a companion equation, the CKiD, covers children and adolescents.

“Key in our [new] equation is the adjustment for differences in serum creatinine generation between children and adults, or between men and women,” lead author Hans Pottel, PhD, KU Leuven (Belgium), said in an interview.

In an accompanying editorial, Andrew M. Levey, MD, and associates wrote: “We agree that a single eGFR equation that can be used in children and adults and performs well in the transition from adolescence to young adulthood is a worthy goal.”

“But the claim of equivalent or superior performance, compared with the CKD-EPI equation is not conclusive,” claimed Dr. Levey, who led the research team that developed the CKD-EPI equation, and coauthors.

Dr. Levey is professor of medicine at Tufts University, Boston.
 

What’s new is Q

Dr. Pottel and codevelopers devised what they call Q values: age- and sex-dependent median creatinine levels in normal individuals.

Q values act to “normalize or rescale creatinine before entering it into the equation, because we know that creatinine generation is different” based on factors that include age, sex, and muscle mass.

The EKFC equation extends the CKD-EPI equation and first eGFR equation by using Q values and applying across age ranges, like the full-age spectrum (FAS) equation, first reported in 2016 by a team led by Dr. Pottel.

“Although the FAS equation was designed to overcome the challenge in measuring GFR in patients transitioning from adolescence to adult nephrology care, it also underestimates GFR at low serum creatinine values and in patients with chronic kidney disease,” wrote Dr. Pottel and coauthors.

Hence, their intent to tweak the FAS equation to overcome this limitation and create the EKFC equation.

“The new equation combines the strengths of the CKD-EPI and FAS equations,” they woite.

However, “we acknowledge that lack of precision is still a major problem with all eGFR equations,” including the new EKFC, they added.
 

Editorialists dispute better performance of EKFC over CKD-EPI

In their editorial, Dr. Levey and coauthors noted the EKFC equations and other adapted equations in development “represent a conceptual advance over the FAS equations,” but they dispute the claims of better performance, compared with the CKD-EPI.

“We compared the performance of the EKFC and CKD-EPI equations in a different, large external validation population of Black and non-Black adults,” the external population used to validate the CKD-EPI equation, the editorialists reported.

The upshot was “our results did not confirm the author’s conclusions” about the EKFC equation.

In response, Dr. Pottel highlighted that the EKFC equation is currently not designed for use in Black patients.

“With its derivation and validation now reported in the new article, the EKFC equation is fully validated and ready for routine use in Whites,” he said. “We plan to evaluate and possibly fine tune our equation for its application in other ethnicities.”

Regarding the inferior performance, compared with the CKD-EPI equation in the non-Black population tested by the editorialists, Dr. Pottel cited “calibration issues for serum creatinine” that some experts have found in the datasets compiled by developers of the CKI-EPI equation that could limit the utility of these data.
 

Still room for improvement; app hopefully coming next year

Dr. Pottel and coauthors developed and validated the EKFC equation with data from 19,629 patients drawn from 13 cohorts. This included 11,251 patients from seven cohorts for development and internal validation, and 8378 from six cohorts for external validation. The EKFC effort received endorsement from the European Renal Association–European Dialysis and Transplant Association.

However, “We acknowledge that there is still room for improvement,” Dr. Pottel said.

Although the new report presents the EKFC equations (actually two slightly different equations depending on whether a patient’s serum creatinine is higher or lower than the relevant Q value), most potential users will likely find the equations easier to work with once they’re in an app form that allows someone to simply plug in age, sex, and serum creatinine level. That app currently doesn’t exist but is coming soon, promised Dr. Pottel.

“I hope to have an electronic tool by the beginning of 2021,” he said. “I have to find a programmer who can do this for me.”

The EKFC project has received no commercial funding. Dr. Pottel reported no relevant financial relationships. Dr. Levey has reported receiving research funding from AstraZeneca.

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

A 53-year-old woman was referred for surveillance colonoscopy. She is a current smoker with a history of chronic kidney disease, chronic obstructive pulmonary disease, atrial fibrillation, and two diminutive hyperplastic polyps found on average-risk screening colonoscopy 3 years previously. Her prep at the time was excellent and she was advised to return in 10 years for follow-up. She has taken the day off work, arranged for a driver, is prepped, and is on your schedule for a colonoscopy for a “history of polyps.” Is this an appropriate referral and how should you handle it?

Most of us have had questionable referrals on our endoscopy schedules. While judgments can vary among providers about when a patient should undergo a procedure or what intervention is most needed, some direct-access referrals for endoscopy are considered inappropriate by most standards. In examining referrals for colonoscopy, studies have shown that as many as 23% of screening colonoscopies among Medicare beneficiaries and 14.2% of Veterans Affairs patients in a large colorectal cancer screening study are inappropriate.^1,2 A prospective multicenter study found 29% of colonoscopies to be inappropriate, and surveillance studies were confirmed as the most frequent source of inappropriate procedures.^3,4 Endoscopies are performed so frequently, effectively, and safely that they can be readily scheduled by gastroenterologists and nongastroenterologists alike. Open access has facilitated and expedited needed procedures, providing benefit to patient and provider and freeing clinic visit time for more complex consults. But while endoscopy is very safe, it is not without risk or cost. What should be the response when a patient in the endoscopy unit appears to be inappropriately referred?

The first step is to determine what is inappropriate. There are several situations when a procedure might be considered inappropriate, particularly when we try to apply ethical principles.

1. The performance of the procedure is contrary to society guidelines. The American Gastroenterological Association, American Society for Gastrointestinal Endoscopy, and American College of Gastroenterology publish clinical guidelines. These documents are drafted after rigorous research and literature review, and the strength of the recommendations is confirmed by incorporation of GRADE (Grading of Recommendations Assessment, Development, and Evaluation) methodology. Such guidelines allow gastroenterologists across the country to practice confidently in a manner consistent with the current available data and the standards of care for the GI community. A patient who is referred for a procedure for an indication that does not adhere to – or contradicts – guidelines, may be at risk for substandard care and possibly at risk for harm. It is the physician’s ethical responsibility to provide the most “good” and the least harm for patients, consistent with the ethical principle of beneficence.

Guidelines, however, are not mandates, and an argument may be made that in order to provide the best care, alternatives may be offered to a patient. Some circumstances require clinical judgments based on unique patient characteristics and the need for individualized care. As a rule, however, the goal of guidelines is to assist doctors in providing the best care.

2. The procedure is not the correct test for the clinical question. While endoscopy can address many clinical queries, endoscopy is not always the right procedure for a specific medical question. A patient referred for an esophagogastroduodenoscopy (EGD) to rule out gastroparesis is being subjected to the wrong test to answer the clinical question. Some information may be obtained from an EGD (e.g., retained food may suggest dysmotility or the patient could have gastric outlet obstruction) but this is not the recommended initial management step. Is it reasonable to proceed with a test that cannot answer the question asked? Continuing with the endoscopy would not enhance beneficence and might be a futile service for the patient. Is this doing the best for the patient?

Dr. Fisher is professor of clinical medicine and director of small-bowel imaging, division of gastroenterology, University of Pennsylvania, Philadelphia.

References

1. Sheffield KM et al. JAMA Intern Med. 2013 Apr 8;173(7):542-50.

2. Powell AA et al. J Gen Intern Med. 2015 Jun;30(6):732-41.

3. Petruzziello L et al. J Clin Gastroenterol. 2012;46(7):590-4.

4. Kapila N et al. Dig Dis Sci. 2019;64(10):2798-805.

A 53-year-old woman was referred for surveillance colonoscopy. She is a current smoker with a history of chronic kidney disease, chronic obstructive pulmonary disease, atrial fibrillation, and two diminutive hyperplastic polyps found on average-risk screening colonoscopy 3 years previously. Her prep at the time was excellent and she was advised to return in 10 years for follow-up. She has taken the day off work, arranged for a driver, is prepped, and is on your schedule for a colonoscopy for a “history of polyps.” Is this an appropriate referral and how should you handle it?

Most of us have had questionable referrals on our endoscopy schedules. While judgments can vary among providers about when a patient should undergo a procedure or what intervention is most needed, some direct-access referrals for endoscopy are considered inappropriate by most standards. In examining referrals for colonoscopy, studies have shown that as many as 23% of screening colonoscopies among Medicare beneficiaries and 14.2% of Veterans Affairs patients in a large colorectal cancer screening study are inappropriate.^1,2 A prospective multicenter study found 29% of colonoscopies to be inappropriate, and surveillance studies were confirmed as the most frequent source of inappropriate procedures.^3,4 Endoscopies are performed so frequently, effectively, and safely that they can be readily scheduled by gastroenterologists and nongastroenterologists alike. Open access has facilitated and expedited needed procedures, providing benefit to patient and provider and freeing clinic visit time for more complex consults. But while endoscopy is very safe, it is not without risk or cost. What should be the response when a patient in the endoscopy unit appears to be inappropriately referred?

The first step is to determine what is inappropriate. There are several situations when a procedure might be considered inappropriate, particularly when we try to apply ethical principles.

1. The performance of the procedure is contrary to society guidelines. The American Gastroenterological Association, American Society for Gastrointestinal Endoscopy, and American College of Gastroenterology publish clinical guidelines. These documents are drafted after rigorous research and literature review, and the strength of the recommendations is confirmed by incorporation of GRADE (Grading of Recommendations Assessment, Development, and Evaluation) methodology. Such guidelines allow gastroenterologists across the country to practice confidently in a manner consistent with the current available data and the standards of care for the GI community. A patient who is referred for a procedure for an indication that does not adhere to – or contradicts – guidelines, may be at risk for substandard care and possibly at risk for harm. It is the physician’s ethical responsibility to provide the most “good” and the least harm for patients, consistent with the ethical principle of beneficence.

Guidelines, however, are not mandates, and an argument may be made that in order to provide the best care, alternatives may be offered to a patient. Some circumstances require clinical judgments based on unique patient characteristics and the need for individualized care. As a rule, however, the goal of guidelines is to assist doctors in providing the best care.

2. The procedure is not the correct test for the clinical question. While endoscopy can address many clinical queries, endoscopy is not always the right procedure for a specific medical question. A patient referred for an esophagogastroduodenoscopy (EGD) to rule out gastroparesis is being subjected to the wrong test to answer the clinical question. Some information may be obtained from an EGD (e.g., retained food may suggest dysmotility or the patient could have gastric outlet obstruction) but this is not the recommended initial management step. Is it reasonable to proceed with a test that cannot answer the question asked? Continuing with the endoscopy would not enhance beneficence and might be a futile service for the patient. Is this doing the best for the patient?

Dr. Fisher is professor of clinical medicine and director of small-bowel imaging, division of gastroenterology, University of Pennsylvania, Philadelphia.

References

1. Sheffield KM et al. JAMA Intern Med. 2013 Apr 8;173(7):542-50.

2. Powell AA et al. J Gen Intern Med. 2015 Jun;30(6):732-41.

3. Petruzziello L et al. J Clin Gastroenterol. 2012;46(7):590-4.

4. Kapila N et al. Dig Dis Sci. 2019;64(10):2798-805.

A 53-year-old woman was referred for surveillance colonoscopy. She is a current smoker with a history of chronic kidney disease, chronic obstructive pulmonary disease, atrial fibrillation, and two diminutive hyperplastic polyps found on average-risk screening colonoscopy 3 years previously. Her prep at the time was excellent and she was advised to return in 10 years for follow-up. She has taken the day off work, arranged for a driver, is prepped, and is on your schedule for a colonoscopy for a “history of polyps.” Is this an appropriate referral and how should you handle it?

Most of us have had questionable referrals on our endoscopy schedules. While judgments can vary among providers about when a patient should undergo a procedure or what intervention is most needed, some direct-access referrals for endoscopy are considered inappropriate by most standards. In examining referrals for colonoscopy, studies have shown that as many as 23% of screening colonoscopies among Medicare beneficiaries and 14.2% of Veterans Affairs patients in a large colorectal cancer screening study are inappropriate.^1,2 A prospective multicenter study found 29% of colonoscopies to be inappropriate, and surveillance studies were confirmed as the most frequent source of inappropriate procedures.^3,4 Endoscopies are performed so frequently, effectively, and safely that they can be readily scheduled by gastroenterologists and nongastroenterologists alike. Open access has facilitated and expedited needed procedures, providing benefit to patient and provider and freeing clinic visit time for more complex consults. But while endoscopy is very safe, it is not without risk or cost. What should be the response when a patient in the endoscopy unit appears to be inappropriately referred?

The first step is to determine what is inappropriate. There are several situations when a procedure might be considered inappropriate, particularly when we try to apply ethical principles.

1. The performance of the procedure is contrary to society guidelines. The American Gastroenterological Association, American Society for Gastrointestinal Endoscopy, and American College of Gastroenterology publish clinical guidelines. These documents are drafted after rigorous research and literature review, and the strength of the recommendations is confirmed by incorporation of GRADE (Grading of Recommendations Assessment, Development, and Evaluation) methodology. Such guidelines allow gastroenterologists across the country to practice confidently in a manner consistent with the current available data and the standards of care for the GI community. A patient who is referred for a procedure for an indication that does not adhere to – or contradicts – guidelines, may be at risk for substandard care and possibly at risk for harm. It is the physician’s ethical responsibility to provide the most “good” and the least harm for patients, consistent with the ethical principle of beneficence.

Guidelines, however, are not mandates, and an argument may be made that in order to provide the best care, alternatives may be offered to a patient. Some circumstances require clinical judgments based on unique patient characteristics and the need for individualized care. As a rule, however, the goal of guidelines is to assist doctors in providing the best care.

2. The procedure is not the correct test for the clinical question. While endoscopy can address many clinical queries, endoscopy is not always the right procedure for a specific medical question. A patient referred for an esophagogastroduodenoscopy (EGD) to rule out gastroparesis is being subjected to the wrong test to answer the clinical question. Some information may be obtained from an EGD (e.g., retained food may suggest dysmotility or the patient could have gastric outlet obstruction) but this is not the recommended initial management step. Is it reasonable to proceed with a test that cannot answer the question asked? Continuing with the endoscopy would not enhance beneficence and might be a futile service for the patient. Is this doing the best for the patient?

Dr. Fisher is professor of clinical medicine and director of small-bowel imaging, division of gastroenterology, University of Pennsylvania, Philadelphia.

References

1. Sheffield KM et al. JAMA Intern Med. 2013 Apr 8;173(7):542-50.

2. Powell AA et al. J Gen Intern Med. 2015 Jun;30(6):732-41.

3. Petruzziello L et al. J Clin Gastroenterol. 2012;46(7):590-4.

4. Kapila N et al. Dig Dis Sci. 2019;64(10):2798-805.

The Food and Drug Administration has cleared for marketing a smartphone app that can detect and interrupt nightmares in adults with posttraumatic stress disorder (PTSD).

The NightWare app, from Minneapolis-based NightWare Inc., runs on the Apple Watch and Apple iPhone.

During sleep, Apple Watch sensors monitor heart rate and body movement. These data are used to create a unique sleep profile using a proprietary algorithm.

When the NightWare app detects that a patient is experiencing a nightmare based on changes in heart rate and movement, it provides slight vibrations through the Apple Watch to arouse the patient and interrupt the nightmare, without fully awakening the patient, the company notes.

NightWare is available by prescription only and is intended for use in adults aged 22 years and older with PTSD.

“Sleep is an essential part of a person’s daily routine. However, certain adults who have a nightmare disorder or who experience nightmares from PTSD are not able to get the rest they need,” Carlos Peña, PhD, director, Office of Neurological and Physical Medicine Devices, Center for Devices and Radiological Health at the FDA, said in a news release.

This authorization “offers a new, low-risk treatment option that uses digital technology in an effort to provide temporary relief from sleep disturbance related to nightmares,” said Dr. Peña.

NightWare was tested in a 30-day randomized, sham-controlled trial of 70 patients. Patients in the sham group wore the device, but no vibrations were provided.

Both the sham and active groups showed improvement in sleep on standard sleep scales, with the active group showing greater improvement than sham. “The evidence demonstrated the probable benefits outweighed the probable risks,” the FDA said in a statement.

NightWare is not a standalone therapy for PTSD and should be used in conjunction with prescribed medications for PTSD and other recommended therapies for PTSD-associated nightmares and nightmare disorder, the agency said.

NightWare was granted breakthrough device designation for the treatment of nightmares in patients with PTSD. The device reviewed through the de novo premarket pathway, a regulatory pathway for some low- to moderate-risk devices of a new type.

Along with this marketing authorization, the FDA is establishing “special controls” designed to provide a “reasonable assurance of safety and effectiveness for tests of this type,” the agency said.

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

The Food and Drug Administration has cleared for marketing a smartphone app that can detect and interrupt nightmares in adults with posttraumatic stress disorder (PTSD).

The NightWare app, from Minneapolis-based NightWare Inc., runs on the Apple Watch and Apple iPhone.

During sleep, Apple Watch sensors monitor heart rate and body movement. These data are used to create a unique sleep profile using a proprietary algorithm.

When the NightWare app detects that a patient is experiencing a nightmare based on changes in heart rate and movement, it provides slight vibrations through the Apple Watch to arouse the patient and interrupt the nightmare, without fully awakening the patient, the company notes.

NightWare is available by prescription only and is intended for use in adults aged 22 years and older with PTSD.

“Sleep is an essential part of a person’s daily routine. However, certain adults who have a nightmare disorder or who experience nightmares from PTSD are not able to get the rest they need,” Carlos Peña, PhD, director, Office of Neurological and Physical Medicine Devices, Center for Devices and Radiological Health at the FDA, said in a news release.

This authorization “offers a new, low-risk treatment option that uses digital technology in an effort to provide temporary relief from sleep disturbance related to nightmares,” said Dr. Peña.

NightWare was tested in a 30-day randomized, sham-controlled trial of 70 patients. Patients in the sham group wore the device, but no vibrations were provided.

Both the sham and active groups showed improvement in sleep on standard sleep scales, with the active group showing greater improvement than sham. “The evidence demonstrated the probable benefits outweighed the probable risks,” the FDA said in a statement.

NightWare is not a standalone therapy for PTSD and should be used in conjunction with prescribed medications for PTSD and other recommended therapies for PTSD-associated nightmares and nightmare disorder, the agency said.

NightWare was granted breakthrough device designation for the treatment of nightmares in patients with PTSD. The device reviewed through the de novo premarket pathway, a regulatory pathway for some low- to moderate-risk devices of a new type.

Along with this marketing authorization, the FDA is establishing “special controls” designed to provide a “reasonable assurance of safety and effectiveness for tests of this type,” the agency said.

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

The Food and Drug Administration has cleared for marketing a smartphone app that can detect and interrupt nightmares in adults with posttraumatic stress disorder (PTSD).

The NightWare app, from Minneapolis-based NightWare Inc., runs on the Apple Watch and Apple iPhone.

During sleep, Apple Watch sensors monitor heart rate and body movement. These data are used to create a unique sleep profile using a proprietary algorithm.

When the NightWare app detects that a patient is experiencing a nightmare based on changes in heart rate and movement, it provides slight vibrations through the Apple Watch to arouse the patient and interrupt the nightmare, without fully awakening the patient, the company notes.

NightWare is available by prescription only and is intended for use in adults aged 22 years and older with PTSD.

“Sleep is an essential part of a person’s daily routine. However, certain adults who have a nightmare disorder or who experience nightmares from PTSD are not able to get the rest they need,” Carlos Peña, PhD, director, Office of Neurological and Physical Medicine Devices, Center for Devices and Radiological Health at the FDA, said in a news release.

This authorization “offers a new, low-risk treatment option that uses digital technology in an effort to provide temporary relief from sleep disturbance related to nightmares,” said Dr. Peña.

NightWare was tested in a 30-day randomized, sham-controlled trial of 70 patients. Patients in the sham group wore the device, but no vibrations were provided.

Both the sham and active groups showed improvement in sleep on standard sleep scales, with the active group showing greater improvement than sham. “The evidence demonstrated the probable benefits outweighed the probable risks,” the FDA said in a statement.

NightWare is not a standalone therapy for PTSD and should be used in conjunction with prescribed medications for PTSD and other recommended therapies for PTSD-associated nightmares and nightmare disorder, the agency said.

NightWare was granted breakthrough device designation for the treatment of nightmares in patients with PTSD. The device reviewed through the de novo premarket pathway, a regulatory pathway for some low- to moderate-risk devices of a new type.

Along with this marketing authorization, the FDA is establishing “special controls” designed to provide a “reasonable assurance of safety and effectiveness for tests of this type,” the agency said.

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

Eleven operational taxonomic units (OTUs) of fecal bacteria were less abundant in children with celiac disease than in healthy children, according to the findings of a study published in Gastroenterology.

chameleonseye/Thinkstock

This microbial signature correctly identified approximately four out of five cases of celiac disease, regardless of whether children were newly diagnosed or had already modified their diet, reported Konstantina Zafeiropoulou and Ben Nichols, PhD, of the Glasgow Royal Infirmary. “It is not clear whether the microbes identified [in this study] contribute to the pathogenesis of celiac disease or are the result of it. Future research should explore the role of the disease-specific species identified here,” the researchers wrote in Gastroenterology.

Celiac disease is multifactorial. While up to 40% of people are genetically predisposed, only a small proportion develop it, suggesting that environmental factors are key to pathogenesis. Recent studies have linked celiac disease with alterations in the gut microbiome, but it is unclear whether dysbiosis is pathogenic or a secondary effect of disease processes such as nutrient malabsorption, or whether dysbiosis is present at disease onset or results from a gluten-free diet.

For the study, the researchers performed gas chromatography and 16S ribosomal RNA sequencing of fecal samples from 141 children, including 20 with newly biopsy-confirmed, previously untreated celiac disease, 45 who were previously diagnosed and on a gluten-free diet, 19 unaffected siblings, and 57 healthy children who were not on regular medications and had no history of chronic gastrointestinal symptoms. A single fecal sample was tested for all but the previously untreated children, who were tested at baseline and then after 6 and 12 months on a gluten-free diet.

Children with new-onset celiac disease showed no evidence of dysbiosis, while a gluten-free diet explained up to 2.8% of variation in microbiota between patients and controls. Microbial alpha diversity, a measure of species-level diversity, was generally similar among groups, but between 3% and 5% of all taxa differed. Irrespective of treatment, the decreased abundance of the 11 OTUs was diagnostic for celiac disease with an error rate of 21.5% (P < .001 vs. random classification). Notably, most of these 11 discrepant OTUs were associated with nutrient or food group intake and with biomarkers of gluten ingestion, the researchers said. Gas chromatography showed that, after patients started a gluten-free diet, fecal levels of butyrate and ammonia decreased.

“Even though we identified differences in the abundance of a few species between patients with untreated celiac disease and healthy controls, the profound microbial dysbiosis noted in Crohn’s disease was not observed, at least using crude diversity indices,” the investigators commented. “Although several alterations in the intestinal microbiota of children with established celiac disease appear to be effects of a gluten-free diet, there are specific bacteria that are distinct biomarkers of celiac disease.”

Future research might involve performing in vitro tests of “candidate” bacteria, coculturing these bacteria with human immune cells, and studying whether dietary interventions alter the relative abundance of these bacteria in the gut microbiome, the researchers said.

Nutricia Research Foundation, the Biotechnology and Biological Sciences Research Council, and The Catherine McEwan Foundation provided funding. Three coinvestigators disclosed ties to Nutricia, 4D Pharma, AbbVie, Celltrion, Janssen, Takeda, and several other pharmaceutical companies. One coinvestigator reported chairing the working group for ISLI Europe. The remaining investigators reported having no conflicts of interest.

SOURCE: Zafeiropoulou K et al. Gastroenterology. 2020 Aug 10;S0016-5085(20)35023-X. doi: 10.1053/j.gastro.2020.08.007.

Eleven operational taxonomic units (OTUs) of fecal bacteria were less abundant in children with celiac disease than in healthy children, according to the findings of a study published in Gastroenterology.

chameleonseye/Thinkstock

This microbial signature correctly identified approximately four out of five cases of celiac disease, regardless of whether children were newly diagnosed or had already modified their diet, reported Konstantina Zafeiropoulou and Ben Nichols, PhD, of the Glasgow Royal Infirmary. “It is not clear whether the microbes identified [in this study] contribute to the pathogenesis of celiac disease or are the result of it. Future research should explore the role of the disease-specific species identified here,” the researchers wrote in Gastroenterology.

Celiac disease is multifactorial. While up to 40% of people are genetically predisposed, only a small proportion develop it, suggesting that environmental factors are key to pathogenesis. Recent studies have linked celiac disease with alterations in the gut microbiome, but it is unclear whether dysbiosis is pathogenic or a secondary effect of disease processes such as nutrient malabsorption, or whether dysbiosis is present at disease onset or results from a gluten-free diet.

For the study, the researchers performed gas chromatography and 16S ribosomal RNA sequencing of fecal samples from 141 children, including 20 with newly biopsy-confirmed, previously untreated celiac disease, 45 who were previously diagnosed and on a gluten-free diet, 19 unaffected siblings, and 57 healthy children who were not on regular medications and had no history of chronic gastrointestinal symptoms. A single fecal sample was tested for all but the previously untreated children, who were tested at baseline and then after 6 and 12 months on a gluten-free diet.

Children with new-onset celiac disease showed no evidence of dysbiosis, while a gluten-free diet explained up to 2.8% of variation in microbiota between patients and controls. Microbial alpha diversity, a measure of species-level diversity, was generally similar among groups, but between 3% and 5% of all taxa differed. Irrespective of treatment, the decreased abundance of the 11 OTUs was diagnostic for celiac disease with an error rate of 21.5% (P < .001 vs. random classification). Notably, most of these 11 discrepant OTUs were associated with nutrient or food group intake and with biomarkers of gluten ingestion, the researchers said. Gas chromatography showed that, after patients started a gluten-free diet, fecal levels of butyrate and ammonia decreased.

“Even though we identified differences in the abundance of a few species between patients with untreated celiac disease and healthy controls, the profound microbial dysbiosis noted in Crohn’s disease was not observed, at least using crude diversity indices,” the investigators commented. “Although several alterations in the intestinal microbiota of children with established celiac disease appear to be effects of a gluten-free diet, there are specific bacteria that are distinct biomarkers of celiac disease.”

Future research might involve performing in vitro tests of “candidate” bacteria, coculturing these bacteria with human immune cells, and studying whether dietary interventions alter the relative abundance of these bacteria in the gut microbiome, the researchers said.

Nutricia Research Foundation, the Biotechnology and Biological Sciences Research Council, and The Catherine McEwan Foundation provided funding. Three coinvestigators disclosed ties to Nutricia, 4D Pharma, AbbVie, Celltrion, Janssen, Takeda, and several other pharmaceutical companies. One coinvestigator reported chairing the working group for ISLI Europe. The remaining investigators reported having no conflicts of interest.

SOURCE: Zafeiropoulou K et al. Gastroenterology. 2020 Aug 10;S0016-5085(20)35023-X. doi: 10.1053/j.gastro.2020.08.007.

Eleven operational taxonomic units (OTUs) of fecal bacteria were less abundant in children with celiac disease than in healthy children, according to the findings of a study published in Gastroenterology.

chameleonseye/Thinkstock

This microbial signature correctly identified approximately four out of five cases of celiac disease, regardless of whether children were newly diagnosed or had already modified their diet, reported Konstantina Zafeiropoulou and Ben Nichols, PhD, of the Glasgow Royal Infirmary. “It is not clear whether the microbes identified [in this study] contribute to the pathogenesis of celiac disease or are the result of it. Future research should explore the role of the disease-specific species identified here,” the researchers wrote in Gastroenterology.

Celiac disease is multifactorial. While up to 40% of people are genetically predisposed, only a small proportion develop it, suggesting that environmental factors are key to pathogenesis. Recent studies have linked celiac disease with alterations in the gut microbiome, but it is unclear whether dysbiosis is pathogenic or a secondary effect of disease processes such as nutrient malabsorption, or whether dysbiosis is present at disease onset or results from a gluten-free diet.

For the study, the researchers performed gas chromatography and 16S ribosomal RNA sequencing of fecal samples from 141 children, including 20 with newly biopsy-confirmed, previously untreated celiac disease, 45 who were previously diagnosed and on a gluten-free diet, 19 unaffected siblings, and 57 healthy children who were not on regular medications and had no history of chronic gastrointestinal symptoms. A single fecal sample was tested for all but the previously untreated children, who were tested at baseline and then after 6 and 12 months on a gluten-free diet.

Children with new-onset celiac disease showed no evidence of dysbiosis, while a gluten-free diet explained up to 2.8% of variation in microbiota between patients and controls. Microbial alpha diversity, a measure of species-level diversity, was generally similar among groups, but between 3% and 5% of all taxa differed. Irrespective of treatment, the decreased abundance of the 11 OTUs was diagnostic for celiac disease with an error rate of 21.5% (P < .001 vs. random classification). Notably, most of these 11 discrepant OTUs were associated with nutrient or food group intake and with biomarkers of gluten ingestion, the researchers said. Gas chromatography showed that, after patients started a gluten-free diet, fecal levels of butyrate and ammonia decreased.

“Even though we identified differences in the abundance of a few species between patients with untreated celiac disease and healthy controls, the profound microbial dysbiosis noted in Crohn’s disease was not observed, at least using crude diversity indices,” the investigators commented. “Although several alterations in the intestinal microbiota of children with established celiac disease appear to be effects of a gluten-free diet, there are specific bacteria that are distinct biomarkers of celiac disease.”

Future research might involve performing in vitro tests of “candidate” bacteria, coculturing these bacteria with human immune cells, and studying whether dietary interventions alter the relative abundance of these bacteria in the gut microbiome, the researchers said.

Nutricia Research Foundation, the Biotechnology and Biological Sciences Research Council, and The Catherine McEwan Foundation provided funding. Three coinvestigators disclosed ties to Nutricia, 4D Pharma, AbbVie, Celltrion, Janssen, Takeda, and several other pharmaceutical companies. One coinvestigator reported chairing the working group for ISLI Europe. The remaining investigators reported having no conflicts of interest.

SOURCE: Zafeiropoulou K et al. Gastroenterology. 2020 Aug 10;S0016-5085(20)35023-X. doi: 10.1053/j.gastro.2020.08.007.

A coauthor of the Great Barrington Declaration says that he and colleagues have never argued against using mitigation strategies to keep COVID-19 from spreading, and that critics have mischaracterized the document as a “let it rip” strategy.

Jay Bhattacharya, MD, PhD, a professor and public health policy expert in infectious diseases at Stanford University in California, spoke on a JAMA Livestream debate on November 6. Marc Lipsitch, MD, an epidemiology professor at the Harvard T.H. Chan School of Public Health in Boston, Massachusetts, represented the 6900 signatories of the John Snow Memorandum, a rebuttal to the Great Barrington document.

The Great Barrington approach of “Focused Protection” advocates isolation and protection of people who are most vulnerable to COVID-19 while avoiding what they characterize as lockdowns. “The most compassionate approach that balances the risks and benefits of reaching herd immunity, is to allow those who are at minimal risk of death to live their lives normally to build up immunity to the virus through natural infection, while better protecting those who are at highest risk,” the document reads.

The Infectious Diseases Society of America (IDSA) and its HIV Medicine Association denounced the declaration, as reported by Medscape Medical News, and the World Health Organization (WHO) Director General Tedros Adhanom Ghebreyesus called the proposal “unethical.” But the idea has gained some traction at the White House, where Coronavirus Task Force Member and Stanford professor Scott Atlas, MD, has been advising President Donald J. Trump.

On the JAMA debate, Bhattacharya said, “I think all of the mitigation measures are really important,” listing social distancing, hand washing, and masks when distancing is not possible as chief among those strategies for the less vulnerable. “I don’t want to create infections intentionally, but I want us to allow people to go back to their lives as best they can, understanding of the risks they are taking when they do it,” he said, claiming that 99.95% of the population will survive infection.

“The harmful lockdowns are worse for many, many people,” Bhattacharya said.

“I think Jay is moving towards a middle ground which is not really what the Great Barrington Declaration seems to promote,” countered Lipsitch. The declaration does not say use masks or social distance, he said. “It just says we need to go back to a normal life.” 

Bhattacharya’s statements to JAMA mean that “maybe we are approaching some common ground,” Lipsitch said.
 

Definition of a lockdown

Both men were asked to give their definition of a “lockdown.” To Lipsitch, it means people are not allowed out except for essential services and that most businesses are closed, with exceptions for those deemed essential.

Bhattacharya, however, said he views that as a quarantine. Lockdowns “are what we’re currently doing,” he said. Schools, churches, businesses, and arts and culture organizations are shuttered, and “almost every aspect of society is restricted in some way,” Bhattacharya said.

He blamed these lockdowns for most of the excess deaths over and above the COVID-19 deaths and said they had failed to control the pandemic.

Lipsitch said that “it feels to me that Jay is describing as lockdown everything that causes harm, even when it’s not locked down.” He noted that the country was truly closed down for 2 months or so in the spring.

“All of these harms I agree are real,” said Lipsitch. “But they are because the normal life of our society is being interfered with by viral transmission and by people’s inability to live their normal lives.”

Closures and lockdowns are essential to delaying cases and deaths, said Lipsitch. “A case today is worse than a case tomorrow and a lot worse than a case 6 months from now,” he said, noting that a vaccine or improved therapeutics could evolve.

“Delay is not nothing,” Lipsitch added. “It’s actually the goal as I see it, and as the John Snow memo says, we want to keep the virus under control in such a way as that the vulnerable people are not at risk.”

He predicted that cases will continue to grow exponentially because the nation is “not even close to herd immunity.” And, if intensive care units fill up, “there will be a responsive lockdown,” he said, adding that he did not endorse that as a general matter or favor it as a default position.

Bhattacharya claimed that Sweden has tallied only 1800 excess deaths since the pandemic began. “That’s lockdown harm avoided,” he said, advocating a similar strategy for the United States. But, infections have been on the rise in Sweden, and the nation has a higher COVID-19 death rate — with 6000 deaths — than other Nordic countries.

“If we keep this policy of lockdown we will have the same kind of outcomes we’ve already had — high excess deaths and sort of indifferent control of COVID,” Bhattacharya said.

“We’re still going to have misery and death going forward until we reach a point where there’s sufficient immunity either though a vaccine or through natural infection,” he said.

This article first appeared on Medscape.com.

A coauthor of the Great Barrington Declaration says that he and colleagues have never argued against using mitigation strategies to keep COVID-19 from spreading, and that critics have mischaracterized the document as a “let it rip” strategy.

Jay Bhattacharya, MD, PhD, a professor and public health policy expert in infectious diseases at Stanford University in California, spoke on a JAMA Livestream debate on November 6. Marc Lipsitch, MD, an epidemiology professor at the Harvard T.H. Chan School of Public Health in Boston, Massachusetts, represented the 6900 signatories of the John Snow Memorandum, a rebuttal to the Great Barrington document.

The Great Barrington approach of “Focused Protection” advocates isolation and protection of people who are most vulnerable to COVID-19 while avoiding what they characterize as lockdowns. “The most compassionate approach that balances the risks and benefits of reaching herd immunity, is to allow those who are at minimal risk of death to live their lives normally to build up immunity to the virus through natural infection, while better protecting those who are at highest risk,” the document reads.

The Infectious Diseases Society of America (IDSA) and its HIV Medicine Association denounced the declaration, as reported by Medscape Medical News, and the World Health Organization (WHO) Director General Tedros Adhanom Ghebreyesus called the proposal “unethical.” But the idea has gained some traction at the White House, where Coronavirus Task Force Member and Stanford professor Scott Atlas, MD, has been advising President Donald J. Trump.

On the JAMA debate, Bhattacharya said, “I think all of the mitigation measures are really important,” listing social distancing, hand washing, and masks when distancing is not possible as chief among those strategies for the less vulnerable. “I don’t want to create infections intentionally, but I want us to allow people to go back to their lives as best they can, understanding of the risks they are taking when they do it,” he said, claiming that 99.95% of the population will survive infection.

“The harmful lockdowns are worse for many, many people,” Bhattacharya said.

“I think Jay is moving towards a middle ground which is not really what the Great Barrington Declaration seems to promote,” countered Lipsitch. The declaration does not say use masks or social distance, he said. “It just says we need to go back to a normal life.” 

Bhattacharya’s statements to JAMA mean that “maybe we are approaching some common ground,” Lipsitch said.
 

Definition of a lockdown

Both men were asked to give their definition of a “lockdown.” To Lipsitch, it means people are not allowed out except for essential services and that most businesses are closed, with exceptions for those deemed essential.

Bhattacharya, however, said he views that as a quarantine. Lockdowns “are what we’re currently doing,” he said. Schools, churches, businesses, and arts and culture organizations are shuttered, and “almost every aspect of society is restricted in some way,” Bhattacharya said.

He blamed these lockdowns for most of the excess deaths over and above the COVID-19 deaths and said they had failed to control the pandemic.

Lipsitch said that “it feels to me that Jay is describing as lockdown everything that causes harm, even when it’s not locked down.” He noted that the country was truly closed down for 2 months or so in the spring.

“All of these harms I agree are real,” said Lipsitch. “But they are because the normal life of our society is being interfered with by viral transmission and by people’s inability to live their normal lives.”

Closures and lockdowns are essential to delaying cases and deaths, said Lipsitch. “A case today is worse than a case tomorrow and a lot worse than a case 6 months from now,” he said, noting that a vaccine or improved therapeutics could evolve.

“Delay is not nothing,” Lipsitch added. “It’s actually the goal as I see it, and as the John Snow memo says, we want to keep the virus under control in such a way as that the vulnerable people are not at risk.”

He predicted that cases will continue to grow exponentially because the nation is “not even close to herd immunity.” And, if intensive care units fill up, “there will be a responsive lockdown,” he said, adding that he did not endorse that as a general matter or favor it as a default position.

Bhattacharya claimed that Sweden has tallied only 1800 excess deaths since the pandemic began. “That’s lockdown harm avoided,” he said, advocating a similar strategy for the United States. But, infections have been on the rise in Sweden, and the nation has a higher COVID-19 death rate — with 6000 deaths — than other Nordic countries.

“If we keep this policy of lockdown we will have the same kind of outcomes we’ve already had — high excess deaths and sort of indifferent control of COVID,” Bhattacharya said.

“We’re still going to have misery and death going forward until we reach a point where there’s sufficient immunity either though a vaccine or through natural infection,” he said.

This article first appeared on Medscape.com.

A coauthor of the Great Barrington Declaration says that he and colleagues have never argued against using mitigation strategies to keep COVID-19 from spreading, and that critics have mischaracterized the document as a “let it rip” strategy.

Jay Bhattacharya, MD, PhD, a professor and public health policy expert in infectious diseases at Stanford University in California, spoke on a JAMA Livestream debate on November 6. Marc Lipsitch, MD, an epidemiology professor at the Harvard T.H. Chan School of Public Health in Boston, Massachusetts, represented the 6900 signatories of the John Snow Memorandum, a rebuttal to the Great Barrington document.

The Great Barrington approach of “Focused Protection” advocates isolation and protection of people who are most vulnerable to COVID-19 while avoiding what they characterize as lockdowns. “The most compassionate approach that balances the risks and benefits of reaching herd immunity, is to allow those who are at minimal risk of death to live their lives normally to build up immunity to the virus through natural infection, while better protecting those who are at highest risk,” the document reads.

The Infectious Diseases Society of America (IDSA) and its HIV Medicine Association denounced the declaration, as reported by Medscape Medical News, and the World Health Organization (WHO) Director General Tedros Adhanom Ghebreyesus called the proposal “unethical.” But the idea has gained some traction at the White House, where Coronavirus Task Force Member and Stanford professor Scott Atlas, MD, has been advising President Donald J. Trump.

On the JAMA debate, Bhattacharya said, “I think all of the mitigation measures are really important,” listing social distancing, hand washing, and masks when distancing is not possible as chief among those strategies for the less vulnerable. “I don’t want to create infections intentionally, but I want us to allow people to go back to their lives as best they can, understanding of the risks they are taking when they do it,” he said, claiming that 99.95% of the population will survive infection.

“The harmful lockdowns are worse for many, many people,” Bhattacharya said.

“I think Jay is moving towards a middle ground which is not really what the Great Barrington Declaration seems to promote,” countered Lipsitch. The declaration does not say use masks or social distance, he said. “It just says we need to go back to a normal life.” 

Bhattacharya’s statements to JAMA mean that “maybe we are approaching some common ground,” Lipsitch said.
 

Definition of a lockdown

Both men were asked to give their definition of a “lockdown.” To Lipsitch, it means people are not allowed out except for essential services and that most businesses are closed, with exceptions for those deemed essential.

Bhattacharya, however, said he views that as a quarantine. Lockdowns “are what we’re currently doing,” he said. Schools, churches, businesses, and arts and culture organizations are shuttered, and “almost every aspect of society is restricted in some way,” Bhattacharya said.

He blamed these lockdowns for most of the excess deaths over and above the COVID-19 deaths and said they had failed to control the pandemic.

Lipsitch said that “it feels to me that Jay is describing as lockdown everything that causes harm, even when it’s not locked down.” He noted that the country was truly closed down for 2 months or so in the spring.

“All of these harms I agree are real,” said Lipsitch. “But they are because the normal life of our society is being interfered with by viral transmission and by people’s inability to live their normal lives.”

Closures and lockdowns are essential to delaying cases and deaths, said Lipsitch. “A case today is worse than a case tomorrow and a lot worse than a case 6 months from now,” he said, noting that a vaccine or improved therapeutics could evolve.

“Delay is not nothing,” Lipsitch added. “It’s actually the goal as I see it, and as the John Snow memo says, we want to keep the virus under control in such a way as that the vulnerable people are not at risk.”

He predicted that cases will continue to grow exponentially because the nation is “not even close to herd immunity.” And, if intensive care units fill up, “there will be a responsive lockdown,” he said, adding that he did not endorse that as a general matter or favor it as a default position.

Bhattacharya claimed that Sweden has tallied only 1800 excess deaths since the pandemic began. “That’s lockdown harm avoided,” he said, advocating a similar strategy for the United States. But, infections have been on the rise in Sweden, and the nation has a higher COVID-19 death rate — with 6000 deaths — than other Nordic countries.

“If we keep this policy of lockdown we will have the same kind of outcomes we’ve already had — high excess deaths and sort of indifferent control of COVID,” Bhattacharya said.

“We’re still going to have misery and death going forward until we reach a point where there’s sufficient immunity either though a vaccine or through natural infection,” he said.

This article first appeared on Medscape.com.

Stroke ranks second behind heart disease as the leading cause of mortality worldwide, accounting for 1 of every 19 deaths,¹ and remains a serious cause of morbidity. Best practices in stroke diagnosis and management can seem elusive to front-line clinicians, for 2 reasons: the rate of proliferation and nuance in stroke medicine and the fact that the typical scope of primary care practice exists apart from much of the diagnostic tools and management schema provided in stroke centers.² In this article, we describe and update the diagnosis of stroke and review imaging modalities, their nuances, and their application in practice.

Diagnosis of acute stroke

Acute stroke is diagnosed upon observation of new neurologic deficits and congruent neuroimaging. Some updated definitions favor a silent form of cerebral ischemia manifested by imaging pathology only; this form is not discussed in this article. Although there are several characteristically distinct stroke syndromes, there is no way to clinically distinguish ischemic pathology from hemorrhagic pathology.

Some common symptoms that should prompt evaluation for stroke are part of the American Stroke Association FAST mnemonic designed to promote public health awareness^3-5:

• face drooping
• arm weakness
• speech difficulty
• time to call 911.

There are several characteristically distinct stroke syndromes, but no way to differentiate ischemic and hemorrhagic pathologies clinically.

Other commonly reported stroke symptoms include unilateral weakness or numbness, confusion, word-finding difficulty, visual problems, difficulty ambulating, dizziness, loss of balance or coordination, and thunderclap headache. A stroke should also be considered in the presence of any new focal neurologic deficit.^3,4

Stroke patients should be triaged by emergency medical services using a stroke screening scale, such as BE-FAST⁵ (a modification of FAST that adds balance and eye assessments); the Los Angeles Prehospital Stroke Screen (LAPSS)^6,7; the Rapid Arterial oCclusion Evaluation (RACE)⁸; and the Cincinnati Prehospital Stroke Severity Scale (CP-SSS)^9,10 (see “Stroke screening scales for early identification and triage"). Studies have not found that any single prehospital stroke scale is superior to the others for reliably predicting large-vessel occlusion; therefore, prehospital assessment is typically based on practice patterns in a given locale.¹¹ A patient (or family member or caregiver) who seeks your care for stroke symptoms should be told to call 911 and get emergency transport to a health care facility that can capably administer intravenous (IV) thrombolysis.^a

First responders should elicit “last-known-normal” time; this critical information can aid in diagnosis and drive therapeutic options, especially if patients are unaccompanied at time of transport to a higher echelon of care. A point-of-care blood glucose test should be performed by emergency medical staff, with dextrose administered for a level < 45 mg/dL. Establishing IV access for fluids, medications, and contrast can be considered if it does not delay transport. A 12-lead electrocardiogram can also be considered, again, as long as it does not delay transport to a facility capable of providing definitive therapy. Notification by emergency services staff before arrival and transport of the patient to such a facility is the essential element of prehospital care, and should be prioritized above ancillary testing beyond the stroke assessment.¹⁴

Guidelines recommend use of the National Institutes of Health Stroke Scale ­(NIHSS; www.stroke.nih.gov/resources/scale.htm) for clinical evaluation upon arrival at the ED.¹⁵ Although no scale has been identified that can reliably predict large-vessel occlusion amenable to endovascular therapy (EVT), no other score has been found to outperform the NIHSS in achieving meaningful patient outcomes.¹⁶ Furthermore, NIHSS has been validated to track clinical changes in response to therapy, is widely utilized, and is free.

Continue to: A criticism of the NIHSS...

A criticism of the NIHSS is its bias toward left-hemispheric ischemic pathology.¹⁷ NIHSS includes 11 questions on a scale of 0 to 42; typically, a score < 4 is associated with a higher chance of a positive clinical outcome.¹⁸ There is no minimum or maximum NIHSS score that precludes treatment with thrombolysis or EVT.

Other commonly used scores in acute stroke include disability assessments. The modified Rankin scale, which is used most often, features a score of 0 (symptom-free) to 6 (death). A modified Rankin scale score of 0 or 1 is considered an indication of a favorable outcome after stroke.¹⁹ Note that these functional scores are not always part of an acute assessment but can be done early in the clinical course to gauge the response to treatment, and are collected for stroke-center certification.

Imaging modalities

Imaging is recommended within 20 minutes of arrival in the ED in a stroke patient who might be a candidate for thrombolysis or thrombectomy.³ There, imaging modalities commonly performed are noncontrast-enhanced head computed tomography (NCHCT); computed tomography (CT) angiography, with or without perfusion; and diffusion-weighted magnetic resonance imaging (MRI).^20,21 In addition, more highly specialized imaging modalities are available for the evaluation of the stroke patient in specific, often limited, circumstances. All these modalities are described below and compared in the TABLE,^20,21 using the ACR Appropriateness Criteria (of the American College of Radiology),²¹ which are guidelines for appropriate imaging of stroke, based on a clinical complaint. Separate recommendations and appraisals are offered by the most recent American Heart Association/American Stroke Association (AHA/ASA) guideline.³

NCHCT. This study should be performed within 20 minutes after arrival at the ED because it provides rapid assessment of intracerebral hemorrhage, can effectively corroborate the diagnosis of some stroke mimickers, and identifies some candidates for EVT or thrombolysis^3,21,22 (typically, the decision to proceed with EVT is based on adjunct imaging studies discussed in a bit). Evaluation for intracerebral hemorrhage is required prior to administering thrombolysis. Ischemic changes can be seen with variable specificity and sensitivity on NCHCT, depending on how much time has passed since the original insult. In all historical trials, CT was the only imaging modality used in the diagnosis of acute ischemic stroke (AIS) that suggested benefit from IV thrombolysis.^23-25

Acute, subacute, and chronic changes can be seen on NCHCT, although the modality has limited sensitivity for identifying AIS (ie, approximately 75% within 6 hours after the original insult):

• Acute findings on NCHCT include intracellular edema, which causes loss of the gray matter–white matter interface and effacement of the cortical sulci. This occurs as a result of increased cellular uptake of water in response to ischemia and cell death, resulting in a decreased density of tissue (hypoattenuation) in affected areas.
• Subacute changes appear in the 2- to 5-day window, including vasogenic edema with greater mass effect, hypoattenuation, and well-defined margins.^3,20,21
• Chronic vascular findings on NCHCT include loss of brain tissue and hypoattenuation.

Continue to: NCHCT is typically performed...

NCHCT is typically performed in advance of other adjunct imaging modalities.^3,20,21 Baseline NCHCT can be performed on patients with advanced kidney disease and those who have an indwelling metallic device.

CT angiography is performed with timed contrast, providing a 3-dimensional representation of the cerebral vasculature; the entire intracranial and extracranial vasculature, including the aortic arch, can be mapped in approximately 60 seconds. CT angiography is sensitive in identifying areas of stenosis > 50% and identifies clinically significant areas of stenosis up to approximately 90% of the time.²⁶ For this reason, it is particularly helpful in identifying candidates for an interventional strategy beyond pharmacotherapeutic thrombolysis. In addition, CT angiography can visualize aneurysmal dilation and dissection, and help with the planning of interventions—specifically, the confident administration of thrombolysis or more specific planning for target lesions and EVT.

Commonly used scoring systems in acute stroke include disability assessments— not always part of the acute assessment but undertaken early in the clinical course to gauge response to treatment.

It also can help identify a host of vascular phenomena, such as arteriovenous malformations, Moyamoya disease (progressive arterial blockage within the basal ganglia and compensatory microvascularization), and some vasculopathies.^20,27 In intracranial hemorrhage, CT with angiography can help evaluate for structural malformations and identify patients at risk of hematoma expansion.²²

CT perfusion. Many stroke centers will perform a CT perfusion study,²⁸ which encompasses as many as 3 different CT sequences:

• NCHCT
• vertex-to-arch angiography with contrast bolus
• administration of contrast and capture of a dynamic sequence through 1 or 2 slabs of tissue, allowing for the generation of maps of cerebral blood flow (CBF), mean transit time (MTT), and cerebral blood volume (CBV) of the entire cerebral vasculature.

The interplay of these 3 sequences drives characterization of lesions (ie, CBF = CBV/MTT). An infarct is characterized by low CBF, low CBV, and elevated MTT. In penumbral tissue, MTT is elevated but CBF is slightly decreased and CBV is normal or increased. Using CT perfusion, areas throughout the ischemic penumbra can be surveyed for favorable interventional characteristics.^20,29

Continue to: A CT perfusion study adds...

A CT perfusion study adds at least 60 seconds to NCHCT. This modality can be useful in planning interventions and for stratifying appropriateness of reperfusion strategies in strokes of unknown duration.^3,30 CT perfusion can be performed on any multidetector CT scan but (1) requires specialized software and expertise to interpret and (2) subjects the patient to a significant radiation dose, which, if incorrectly administered, can be considerably higher than intended.^20,26,27

Diffusion-weighted MRI. This is the most sensitive study for demonstrating early ischemic changes; however, limitations include lack of availability, contraindication in patients with metallic indwelling implants, and duration of the study—although, at some stroke centers, diffusion-weighted MRI can be performed in ≤ 10 minutes.

MRI and NCHCT have comparable sensitivity in detecting intracranial hemorrhage. MRI is likely more sensitive in identifying areas of microhemorrhage: In diffusion-weighted MRI, the sensitivity of stroke detection increases to > 95%.³¹ The modality relies on the comparable movement of water through damaged vs normal neuronal tissue. Diffusion-weighted MRI does not require administration of concomitant contrast, which can be a benefit in patients who are allergic to gadolinium-based contrast agents or have advanced kidney disease that precludes the use of contrast. It typically does not result in adequate characterization of extracranial vasculature.

Other MRI modalities. These MRI extensions include magnetic resonance (MR) perfusion and MR angiography. Whereas diffusion-weighted MRI (discussed above) offers the most rapid and sensitive evaluation for ischemia, fluid-attenuated inversion recovery (FLAIR) imaging has been utilized as a comparator to isolated diffusion-weighted MRI to help determine stroke duration. FLAIR signal positivity typically occurs 6 to 24 hours after the initial insult but is negative in stroke that occurred < 3 hours earlier.³²

MRI is limited, in terms of availability and increased study duration, especially when it comes to timely administration of thrombolysis. A benefit of this modality is less radiation and, as noted, superior sensitivity for ischemia. Diffusion-weighted MRI combined with MR perfusion analysis can help isolate areas of the ischemic penumbra. MR perfusion is performed for a similar reason as CT perfusion, although logistical execution across those modalities is significantly different. Considerations for choosing MR perfusion or CT perfusion should be made on an individual basis and based on available local resources and accepted local practice patterns.²⁶

Continue to: In the subacute setting...

Knowledge of historic details of the event, the patient (eg, known atrial fibrillation), and findings on imaging can facilitate communication between the primary care physician and inpatient teams.

In the subacute setting, MR perfusion and MR angiography of the head and the neck are often performed to identify stenosis, dissection, and more subtle mimickers of cerebrovascular accident not ascertained on initial CT evaluation. These studies are typically performed well outside the window for thrombolysis or intervention.²⁶ No guidelines specifically direct or recommend this practice pattern. The superior sensitivity and cerebral blood flow mapping of MR perfusion and MR angiography might be useful for validating a suspected diagnosis of ischemic stroke and providing phenotypic information about AIS events.

Transcranial Doppler imaging relies on bony windows to assess intracranial vascular flow, velocity, direction, and reactivity. This information can be utilized to diagnose stenosis or occlusion. This modality is principally used to evaluate for stenosis in the anterior circulation (sensitivity, 70%-90%; specificity, 90%-95%).²⁰ Evaluation of the basilar, vertebral, and internal carotid arteries is less accurate (sensitivity, 55%-80%).²⁰ Transcranial Doppler imaging is also used to assess for cerebral vasospasm after subarachnoid hemorrhage, monitor sickle cell disease patients’ overall risk for ischemic stroke, and augment thrombolysis. It is limited by the availability of an expert technician, and therefore is typically reserved for unstable patients or those who cannot receive contrast.²⁰

Carotid duplex ultrasonography. A dynamic study such as duplex ultrasonography can be strongly considered for flow imaging of the extracranial carotids to evaluate for stenosis. Indications for carotid stenting or endarterectomy include 50% to 79% occlusion of the carotid artery on the same side as a recent transient ischemic attack or AIS. Carotid stenosis > 80% warrants consideration for intervention independent of a recent cerebrovascular accident. Interventions are typically performed 2 to 14 days after stroke.³³ Although this study is of limited utility in the hyperacute setting, it is recommended within 24 hours after nondisabling stroke in the carotid territory, when (1) the patient is otherwise a candidate for a surgical or procedural intervention to address the stenosis and (2) none of the aforementioned studies that focus on neck vasculature have been performed.

Conventional (digital subtraction) ­angiography is the gold standard for mapping cerebrovascular disease because it is dynamic and highly accurate. It is, however, typically limited by the number of required personnel, its invasive nature, and the requirement for IV contrast. This study is performed during intra-arterial intervention techniques, including stent retrieval and intra-arterial thrombolysis.²⁶

Impact of imaging on treatment

Imaging helps determine the cause and some characteristics of stroke, both of which can help determine therapy. Strokes can be broadly subcategorized as hemorrhagic or ischemic; recent studies suggest that 87% are ischemic.³⁴ Knowledge of the historic details of the event, the patient (eg, known atrial fibrillation, anticoagulant use, history of falls), and findings on imaging can contribute to determine the cause of AIS, and can facilitate communication and consultation between the primary care physician and inpatient teams.³⁵

Continue to: Best practices for stroke treatment...

Best practices for stroke treatment are based on the cause of the event.³ To identify the likely cause, the aforementioned characteristics are incorporated into one of the scoring systems, which seek to clarify either the cause or the phenotypic appearance of the AIS, which helps direct further testing and treatment. (The ASCOD³⁶ and TOAST³⁷ classification schemes are commonly used phenotypic and causative classifications, respectively.) Several (not all) of the broad phenotypic imaging patterns, with myriad clinical manifestations, are reviewed below. They include:

• Embolic stroke, which, classically, involves end circulation and therefore has cortical involvement. Typically, these originate from the heart or large extracranial arteries, and higher rates of atrial fibrillation and hypercoagulable states are implicated.
• Thrombotic stroke, which, typically, is from large vessels or small vessels, and occurs as a result of atherosclerosis. These strokes are more common at the origins or bifurcations of vessels. Symptoms of thrombotic stroke classically wax and wane slightly more frequently. Lacunar strokes are typically from thrombotic causes, although there are rare episodes of an embolic source contributing to a lacunar stroke syndrome.³⁸

There is evidence for using MRI discrepancies between diffusion-weighted and FLAIR imaging to time AIS findings in so-called wake-up strokes.³⁹ The rationale is that strokes < 4.5 hours old can be identified because they would have abnormal diffusion imaging components but normal findings with FLAIR. When these criteria were utilized in considering whether to treat with thrombolysis, there was a statistically significant improvement in 90-day modified Rankin scale (odds ratio = 1.61; 95% confidence interval, 1.09-2.36), but also an increased probability of death and intracerebral hemorrhage.³⁹

This trial showed that thrombectomy could be performed as long as 16 hours after the patient was last well-appearing and still result in an improved outcome.

A recent multicenter, randomized, open-label trial, with blinded outcomes assessment, showcased the efficacy of thrombectomy as an adjunct when ischemic brain territory was identified without frank infarction, as ascertained by CT perfusion within the anterior circulation. This trial showed that thrombectomy could be performed as long as 16 hours after the patient was last well-appearing and still result in an improved outcome with favorable imaging characteristics (on the modified Rankin scale, an ordinal score of 4 with medical therapy and an ordinal score of 3 with EVT [odds ratio = 2.77; 95% confidence interval, 1.63-4.70]).²⁹ A 2018 multicenter, prospective, randomized trial with blinded assessment of endpoints extended this idea, demonstrating that, when there was mismatch of the clinical deficit (ie, high NIHSS score) and infarct volume (measured on diffusion-weighted MRI or CT perfusion), thrombectomy as late as 24 hours after the patient was last known to be well was beneficial for lesions in the anterior circulation—specifically, the intracranial internal carotid artery or the proximal middle cerebral artery.⁴⁰

^a Whether local emergency departments (EDs) should be bypassed in favor of a specialized stroke center is the subject of debate. The 2019 American Heart Association/American Stroke Association guidelines note the AHA’s Mission: Lifeline Stroke EMS algorithm, which bypasses the nearest ED in feared cases of large-vessel occlusion if travel to a comprehensive stroke center can be accomplished within 30 minutes of arrival at the scene. This is based on expert consensus.^3,12,13

CORRESPONDENCE
Brian Ford, MD, 4301 Jones Bridge Road, Bethesda, MD; [email protected].

Stroke ranks second behind heart disease as the leading cause of mortality worldwide, accounting for 1 of every 19 deaths,¹ and remains a serious cause of morbidity. Best practices in stroke diagnosis and management can seem elusive to front-line clinicians, for 2 reasons: the rate of proliferation and nuance in stroke medicine and the fact that the typical scope of primary care practice exists apart from much of the diagnostic tools and management schema provided in stroke centers.² In this article, we describe and update the diagnosis of stroke and review imaging modalities, their nuances, and their application in practice.

Diagnosis of acute stroke

Acute stroke is diagnosed upon observation of new neurologic deficits and congruent neuroimaging. Some updated definitions favor a silent form of cerebral ischemia manifested by imaging pathology only; this form is not discussed in this article. Although there are several characteristically distinct stroke syndromes, there is no way to clinically distinguish ischemic pathology from hemorrhagic pathology.

Some common symptoms that should prompt evaluation for stroke are part of the American Stroke Association FAST mnemonic designed to promote public health awareness^3-5:

• face drooping
• arm weakness
• speech difficulty
• time to call 911.

There are several characteristically distinct stroke syndromes, but no way to differentiate ischemic and hemorrhagic pathologies clinically.

Other commonly reported stroke symptoms include unilateral weakness or numbness, confusion, word-finding difficulty, visual problems, difficulty ambulating, dizziness, loss of balance or coordination, and thunderclap headache. A stroke should also be considered in the presence of any new focal neurologic deficit.^3,4

Stroke patients should be triaged by emergency medical services using a stroke screening scale, such as BE-FAST⁵ (a modification of FAST that adds balance and eye assessments); the Los Angeles Prehospital Stroke Screen (LAPSS)^6,7; the Rapid Arterial oCclusion Evaluation (RACE)⁸; and the Cincinnati Prehospital Stroke Severity Scale (CP-SSS)^9,10 (see “Stroke screening scales for early identification and triage"). Studies have not found that any single prehospital stroke scale is superior to the others for reliably predicting large-vessel occlusion; therefore, prehospital assessment is typically based on practice patterns in a given locale.¹¹ A patient (or family member or caregiver) who seeks your care for stroke symptoms should be told to call 911 and get emergency transport to a health care facility that can capably administer intravenous (IV) thrombolysis.^a

First responders should elicit “last-known-normal” time; this critical information can aid in diagnosis and drive therapeutic options, especially if patients are unaccompanied at time of transport to a higher echelon of care. A point-of-care blood glucose test should be performed by emergency medical staff, with dextrose administered for a level < 45 mg/dL. Establishing IV access for fluids, medications, and contrast can be considered if it does not delay transport. A 12-lead electrocardiogram can also be considered, again, as long as it does not delay transport to a facility capable of providing definitive therapy. Notification by emergency services staff before arrival and transport of the patient to such a facility is the essential element of prehospital care, and should be prioritized above ancillary testing beyond the stroke assessment.¹⁴

Guidelines recommend use of the National Institutes of Health Stroke Scale ­(NIHSS; www.stroke.nih.gov/resources/scale.htm) for clinical evaluation upon arrival at the ED.¹⁵ Although no scale has been identified that can reliably predict large-vessel occlusion amenable to endovascular therapy (EVT), no other score has been found to outperform the NIHSS in achieving meaningful patient outcomes.¹⁶ Furthermore, NIHSS has been validated to track clinical changes in response to therapy, is widely utilized, and is free.

Continue to: A criticism of the NIHSS...

A criticism of the NIHSS is its bias toward left-hemispheric ischemic pathology.¹⁷ NIHSS includes 11 questions on a scale of 0 to 42; typically, a score < 4 is associated with a higher chance of a positive clinical outcome.¹⁸ There is no minimum or maximum NIHSS score that precludes treatment with thrombolysis or EVT.

Other commonly used scores in acute stroke include disability assessments. The modified Rankin scale, which is used most often, features a score of 0 (symptom-free) to 6 (death). A modified Rankin scale score of 0 or 1 is considered an indication of a favorable outcome after stroke.¹⁹ Note that these functional scores are not always part of an acute assessment but can be done early in the clinical course to gauge the response to treatment, and are collected for stroke-center certification.

Imaging modalities

Imaging is recommended within 20 minutes of arrival in the ED in a stroke patient who might be a candidate for thrombolysis or thrombectomy.³ There, imaging modalities commonly performed are noncontrast-enhanced head computed tomography (NCHCT); computed tomography (CT) angiography, with or without perfusion; and diffusion-weighted magnetic resonance imaging (MRI).^20,21 In addition, more highly specialized imaging modalities are available for the evaluation of the stroke patient in specific, often limited, circumstances. All these modalities are described below and compared in the TABLE,^20,21 using the ACR Appropriateness Criteria (of the American College of Radiology),²¹ which are guidelines for appropriate imaging of stroke, based on a clinical complaint. Separate recommendations and appraisals are offered by the most recent American Heart Association/American Stroke Association (AHA/ASA) guideline.³

NCHCT. This study should be performed within 20 minutes after arrival at the ED because it provides rapid assessment of intracerebral hemorrhage, can effectively corroborate the diagnosis of some stroke mimickers, and identifies some candidates for EVT or thrombolysis^3,21,22 (typically, the decision to proceed with EVT is based on adjunct imaging studies discussed in a bit). Evaluation for intracerebral hemorrhage is required prior to administering thrombolysis. Ischemic changes can be seen with variable specificity and sensitivity on NCHCT, depending on how much time has passed since the original insult. In all historical trials, CT was the only imaging modality used in the diagnosis of acute ischemic stroke (AIS) that suggested benefit from IV thrombolysis.^23-25

Acute, subacute, and chronic changes can be seen on NCHCT, although the modality has limited sensitivity for identifying AIS (ie, approximately 75% within 6 hours after the original insult):

• Acute findings on NCHCT include intracellular edema, which causes loss of the gray matter–white matter interface and effacement of the cortical sulci. This occurs as a result of increased cellular uptake of water in response to ischemia and cell death, resulting in a decreased density of tissue (hypoattenuation) in affected areas.
• Subacute changes appear in the 2- to 5-day window, including vasogenic edema with greater mass effect, hypoattenuation, and well-defined margins.^3,20,21
• Chronic vascular findings on NCHCT include loss of brain tissue and hypoattenuation.

Continue to: NCHCT is typically performed...

NCHCT is typically performed in advance of other adjunct imaging modalities.^3,20,21 Baseline NCHCT can be performed on patients with advanced kidney disease and those who have an indwelling metallic device.

CT angiography is performed with timed contrast, providing a 3-dimensional representation of the cerebral vasculature; the entire intracranial and extracranial vasculature, including the aortic arch, can be mapped in approximately 60 seconds. CT angiography is sensitive in identifying areas of stenosis > 50% and identifies clinically significant areas of stenosis up to approximately 90% of the time.²⁶ For this reason, it is particularly helpful in identifying candidates for an interventional strategy beyond pharmacotherapeutic thrombolysis. In addition, CT angiography can visualize aneurysmal dilation and dissection, and help with the planning of interventions—specifically, the confident administration of thrombolysis or more specific planning for target lesions and EVT.

Commonly used scoring systems in acute stroke include disability assessments— not always part of the acute assessment but undertaken early in the clinical course to gauge response to treatment.

It also can help identify a host of vascular phenomena, such as arteriovenous malformations, Moyamoya disease (progressive arterial blockage within the basal ganglia and compensatory microvascularization), and some vasculopathies.^20,27 In intracranial hemorrhage, CT with angiography can help evaluate for structural malformations and identify patients at risk of hematoma expansion.²²

CT perfusion. Many stroke centers will perform a CT perfusion study,²⁸ which encompasses as many as 3 different CT sequences:

• NCHCT
• vertex-to-arch angiography with contrast bolus
• administration of contrast and capture of a dynamic sequence through 1 or 2 slabs of tissue, allowing for the generation of maps of cerebral blood flow (CBF), mean transit time (MTT), and cerebral blood volume (CBV) of the entire cerebral vasculature.

The interplay of these 3 sequences drives characterization of lesions (ie, CBF = CBV/MTT). An infarct is characterized by low CBF, low CBV, and elevated MTT. In penumbral tissue, MTT is elevated but CBF is slightly decreased and CBV is normal or increased. Using CT perfusion, areas throughout the ischemic penumbra can be surveyed for favorable interventional characteristics.^20,29

Continue to: A CT perfusion study adds...

A CT perfusion study adds at least 60 seconds to NCHCT. This modality can be useful in planning interventions and for stratifying appropriateness of reperfusion strategies in strokes of unknown duration.^3,30 CT perfusion can be performed on any multidetector CT scan but (1) requires specialized software and expertise to interpret and (2) subjects the patient to a significant radiation dose, which, if incorrectly administered, can be considerably higher than intended.^20,26,27

Diffusion-weighted MRI. This is the most sensitive study for demonstrating early ischemic changes; however, limitations include lack of availability, contraindication in patients with metallic indwelling implants, and duration of the study—although, at some stroke centers, diffusion-weighted MRI can be performed in ≤ 10 minutes.

MRI and NCHCT have comparable sensitivity in detecting intracranial hemorrhage. MRI is likely more sensitive in identifying areas of microhemorrhage: In diffusion-weighted MRI, the sensitivity of stroke detection increases to > 95%.³¹ The modality relies on the comparable movement of water through damaged vs normal neuronal tissue. Diffusion-weighted MRI does not require administration of concomitant contrast, which can be a benefit in patients who are allergic to gadolinium-based contrast agents or have advanced kidney disease that precludes the use of contrast. It typically does not result in adequate characterization of extracranial vasculature.

Other MRI modalities. These MRI extensions include magnetic resonance (MR) perfusion and MR angiography. Whereas diffusion-weighted MRI (discussed above) offers the most rapid and sensitive evaluation for ischemia, fluid-attenuated inversion recovery (FLAIR) imaging has been utilized as a comparator to isolated diffusion-weighted MRI to help determine stroke duration. FLAIR signal positivity typically occurs 6 to 24 hours after the initial insult but is negative in stroke that occurred < 3 hours earlier.³²

MRI is limited, in terms of availability and increased study duration, especially when it comes to timely administration of thrombolysis. A benefit of this modality is less radiation and, as noted, superior sensitivity for ischemia. Diffusion-weighted MRI combined with MR perfusion analysis can help isolate areas of the ischemic penumbra. MR perfusion is performed for a similar reason as CT perfusion, although logistical execution across those modalities is significantly different. Considerations for choosing MR perfusion or CT perfusion should be made on an individual basis and based on available local resources and accepted local practice patterns.²⁶

Continue to: In the subacute setting...

Knowledge of historic details of the event, the patient (eg, known atrial fibrillation), and findings on imaging can facilitate communication between the primary care physician and inpatient teams.

In the subacute setting, MR perfusion and MR angiography of the head and the neck are often performed to identify stenosis, dissection, and more subtle mimickers of cerebrovascular accident not ascertained on initial CT evaluation. These studies are typically performed well outside the window for thrombolysis or intervention.²⁶ No guidelines specifically direct or recommend this practice pattern. The superior sensitivity and cerebral blood flow mapping of MR perfusion and MR angiography might be useful for validating a suspected diagnosis of ischemic stroke and providing phenotypic information about AIS events.

Transcranial Doppler imaging relies on bony windows to assess intracranial vascular flow, velocity, direction, and reactivity. This information can be utilized to diagnose stenosis or occlusion. This modality is principally used to evaluate for stenosis in the anterior circulation (sensitivity, 70%-90%; specificity, 90%-95%).²⁰ Evaluation of the basilar, vertebral, and internal carotid arteries is less accurate (sensitivity, 55%-80%).²⁰ Transcranial Doppler imaging is also used to assess for cerebral vasospasm after subarachnoid hemorrhage, monitor sickle cell disease patients’ overall risk for ischemic stroke, and augment thrombolysis. It is limited by the availability of an expert technician, and therefore is typically reserved for unstable patients or those who cannot receive contrast.²⁰

Carotid duplex ultrasonography. A dynamic study such as duplex ultrasonography can be strongly considered for flow imaging of the extracranial carotids to evaluate for stenosis. Indications for carotid stenting or endarterectomy include 50% to 79% occlusion of the carotid artery on the same side as a recent transient ischemic attack or AIS. Carotid stenosis > 80% warrants consideration for intervention independent of a recent cerebrovascular accident. Interventions are typically performed 2 to 14 days after stroke.³³ Although this study is of limited utility in the hyperacute setting, it is recommended within 24 hours after nondisabling stroke in the carotid territory, when (1) the patient is otherwise a candidate for a surgical or procedural intervention to address the stenosis and (2) none of the aforementioned studies that focus on neck vasculature have been performed.

Conventional (digital subtraction) ­angiography is the gold standard for mapping cerebrovascular disease because it is dynamic and highly accurate. It is, however, typically limited by the number of required personnel, its invasive nature, and the requirement for IV contrast. This study is performed during intra-arterial intervention techniques, including stent retrieval and intra-arterial thrombolysis.²⁶

Impact of imaging on treatment

Imaging helps determine the cause and some characteristics of stroke, both of which can help determine therapy. Strokes can be broadly subcategorized as hemorrhagic or ischemic; recent studies suggest that 87% are ischemic.³⁴ Knowledge of the historic details of the event, the patient (eg, known atrial fibrillation, anticoagulant use, history of falls), and findings on imaging can contribute to determine the cause of AIS, and can facilitate communication and consultation between the primary care physician and inpatient teams.³⁵

Continue to: Best practices for stroke treatment...

Best practices for stroke treatment are based on the cause of the event.³ To identify the likely cause, the aforementioned characteristics are incorporated into one of the scoring systems, which seek to clarify either the cause or the phenotypic appearance of the AIS, which helps direct further testing and treatment. (The ASCOD³⁶ and TOAST³⁷ classification schemes are commonly used phenotypic and causative classifications, respectively.) Several (not all) of the broad phenotypic imaging patterns, with myriad clinical manifestations, are reviewed below. They include:

• Embolic stroke, which, classically, involves end circulation and therefore has cortical involvement. Typically, these originate from the heart or large extracranial arteries, and higher rates of atrial fibrillation and hypercoagulable states are implicated.
• Thrombotic stroke, which, typically, is from large vessels or small vessels, and occurs as a result of atherosclerosis. These strokes are more common at the origins or bifurcations of vessels. Symptoms of thrombotic stroke classically wax and wane slightly more frequently. Lacunar strokes are typically from thrombotic causes, although there are rare episodes of an embolic source contributing to a lacunar stroke syndrome.³⁸

There is evidence for using MRI discrepancies between diffusion-weighted and FLAIR imaging to time AIS findings in so-called wake-up strokes.³⁹ The rationale is that strokes < 4.5 hours old can be identified because they would have abnormal diffusion imaging components but normal findings with FLAIR. When these criteria were utilized in considering whether to treat with thrombolysis, there was a statistically significant improvement in 90-day modified Rankin scale (odds ratio = 1.61; 95% confidence interval, 1.09-2.36), but also an increased probability of death and intracerebral hemorrhage.³⁹

This trial showed that thrombectomy could be performed as long as 16 hours after the patient was last well-appearing and still result in an improved outcome.

A recent multicenter, randomized, open-label trial, with blinded outcomes assessment, showcased the efficacy of thrombectomy as an adjunct when ischemic brain territory was identified without frank infarction, as ascertained by CT perfusion within the anterior circulation. This trial showed that thrombectomy could be performed as long as 16 hours after the patient was last well-appearing and still result in an improved outcome with favorable imaging characteristics (on the modified Rankin scale, an ordinal score of 4 with medical therapy and an ordinal score of 3 with EVT [odds ratio = 2.77; 95% confidence interval, 1.63-4.70]).²⁹ A 2018 multicenter, prospective, randomized trial with blinded assessment of endpoints extended this idea, demonstrating that, when there was mismatch of the clinical deficit (ie, high NIHSS score) and infarct volume (measured on diffusion-weighted MRI or CT perfusion), thrombectomy as late as 24 hours after the patient was last known to be well was beneficial for lesions in the anterior circulation—specifically, the intracranial internal carotid artery or the proximal middle cerebral artery.⁴⁰

^a Whether local emergency departments (EDs) should be bypassed in favor of a specialized stroke center is the subject of debate. The 2019 American Heart Association/American Stroke Association guidelines note the AHA’s Mission: Lifeline Stroke EMS algorithm, which bypasses the nearest ED in feared cases of large-vessel occlusion if travel to a comprehensive stroke center can be accomplished within 30 minutes of arrival at the scene. This is based on expert consensus.^3,12,13

CORRESPONDENCE
Brian Ford, MD, 4301 Jones Bridge Road, Bethesda, MD; [email protected].

Stroke ranks second behind heart disease as the leading cause of mortality worldwide, accounting for 1 of every 19 deaths,¹ and remains a serious cause of morbidity. Best practices in stroke diagnosis and management can seem elusive to front-line clinicians, for 2 reasons: the rate of proliferation and nuance in stroke medicine and the fact that the typical scope of primary care practice exists apart from much of the diagnostic tools and management schema provided in stroke centers.² In this article, we describe and update the diagnosis of stroke and review imaging modalities, their nuances, and their application in practice.

Diagnosis of acute stroke

Acute stroke is diagnosed upon observation of new neurologic deficits and congruent neuroimaging. Some updated definitions favor a silent form of cerebral ischemia manifested by imaging pathology only; this form is not discussed in this article. Although there are several characteristically distinct stroke syndromes, there is no way to clinically distinguish ischemic pathology from hemorrhagic pathology.

Some common symptoms that should prompt evaluation for stroke are part of the American Stroke Association FAST mnemonic designed to promote public health awareness^3-5:

• face drooping
• arm weakness
• speech difficulty
• time to call 911.

There are several characteristically distinct stroke syndromes, but no way to differentiate ischemic and hemorrhagic pathologies clinically.

Other commonly reported stroke symptoms include unilateral weakness or numbness, confusion, word-finding difficulty, visual problems, difficulty ambulating, dizziness, loss of balance or coordination, and thunderclap headache. A stroke should also be considered in the presence of any new focal neurologic deficit.^3,4

Stroke patients should be triaged by emergency medical services using a stroke screening scale, such as BE-FAST⁵ (a modification of FAST that adds balance and eye assessments); the Los Angeles Prehospital Stroke Screen (LAPSS)^6,7; the Rapid Arterial oCclusion Evaluation (RACE)⁸; and the Cincinnati Prehospital Stroke Severity Scale (CP-SSS)^9,10 (see “Stroke screening scales for early identification and triage"). Studies have not found that any single prehospital stroke scale is superior to the others for reliably predicting large-vessel occlusion; therefore, prehospital assessment is typically based on practice patterns in a given locale.¹¹ A patient (or family member or caregiver) who seeks your care for stroke symptoms should be told to call 911 and get emergency transport to a health care facility that can capably administer intravenous (IV) thrombolysis.^a

First responders should elicit “last-known-normal” time; this critical information can aid in diagnosis and drive therapeutic options, especially if patients are unaccompanied at time of transport to a higher echelon of care. A point-of-care blood glucose test should be performed by emergency medical staff, with dextrose administered for a level < 45 mg/dL. Establishing IV access for fluids, medications, and contrast can be considered if it does not delay transport. A 12-lead electrocardiogram can also be considered, again, as long as it does not delay transport to a facility capable of providing definitive therapy. Notification by emergency services staff before arrival and transport of the patient to such a facility is the essential element of prehospital care, and should be prioritized above ancillary testing beyond the stroke assessment.¹⁴

Guidelines recommend use of the National Institutes of Health Stroke Scale ­(NIHSS; www.stroke.nih.gov/resources/scale.htm) for clinical evaluation upon arrival at the ED.¹⁵ Although no scale has been identified that can reliably predict large-vessel occlusion amenable to endovascular therapy (EVT), no other score has been found to outperform the NIHSS in achieving meaningful patient outcomes.¹⁶ Furthermore, NIHSS has been validated to track clinical changes in response to therapy, is widely utilized, and is free.

Continue to: A criticism of the NIHSS...

A criticism of the NIHSS is its bias toward left-hemispheric ischemic pathology.¹⁷ NIHSS includes 11 questions on a scale of 0 to 42; typically, a score < 4 is associated with a higher chance of a positive clinical outcome.¹⁸ There is no minimum or maximum NIHSS score that precludes treatment with thrombolysis or EVT.

Other commonly used scores in acute stroke include disability assessments. The modified Rankin scale, which is used most often, features a score of 0 (symptom-free) to 6 (death). A modified Rankin scale score of 0 or 1 is considered an indication of a favorable outcome after stroke.¹⁹ Note that these functional scores are not always part of an acute assessment but can be done early in the clinical course to gauge the response to treatment, and are collected for stroke-center certification.

Imaging modalities

Imaging is recommended within 20 minutes of arrival in the ED in a stroke patient who might be a candidate for thrombolysis or thrombectomy.³ There, imaging modalities commonly performed are noncontrast-enhanced head computed tomography (NCHCT); computed tomography (CT) angiography, with or without perfusion; and diffusion-weighted magnetic resonance imaging (MRI).^20,21 In addition, more highly specialized imaging modalities are available for the evaluation of the stroke patient in specific, often limited, circumstances. All these modalities are described below and compared in the TABLE,^20,21 using the ACR Appropriateness Criteria (of the American College of Radiology),²¹ which are guidelines for appropriate imaging of stroke, based on a clinical complaint. Separate recommendations and appraisals are offered by the most recent American Heart Association/American Stroke Association (AHA/ASA) guideline.³

NCHCT. This study should be performed within 20 minutes after arrival at the ED because it provides rapid assessment of intracerebral hemorrhage, can effectively corroborate the diagnosis of some stroke mimickers, and identifies some candidates for EVT or thrombolysis^3,21,22 (typically, the decision to proceed with EVT is based on adjunct imaging studies discussed in a bit). Evaluation for intracerebral hemorrhage is required prior to administering thrombolysis. Ischemic changes can be seen with variable specificity and sensitivity on NCHCT, depending on how much time has passed since the original insult. In all historical trials, CT was the only imaging modality used in the diagnosis of acute ischemic stroke (AIS) that suggested benefit from IV thrombolysis.^23-25

Acute, subacute, and chronic changes can be seen on NCHCT, although the modality has limited sensitivity for identifying AIS (ie, approximately 75% within 6 hours after the original insult):

• Acute findings on NCHCT include intracellular edema, which causes loss of the gray matter–white matter interface and effacement of the cortical sulci. This occurs as a result of increased cellular uptake of water in response to ischemia and cell death, resulting in a decreased density of tissue (hypoattenuation) in affected areas.
• Subacute changes appear in the 2- to 5-day window, including vasogenic edema with greater mass effect, hypoattenuation, and well-defined margins.^3,20,21
• Chronic vascular findings on NCHCT include loss of brain tissue and hypoattenuation.

Continue to: NCHCT is typically performed...

NCHCT is typically performed in advance of other adjunct imaging modalities.^3,20,21 Baseline NCHCT can be performed on patients with advanced kidney disease and those who have an indwelling metallic device.

CT angiography is performed with timed contrast, providing a 3-dimensional representation of the cerebral vasculature; the entire intracranial and extracranial vasculature, including the aortic arch, can be mapped in approximately 60 seconds. CT angiography is sensitive in identifying areas of stenosis > 50% and identifies clinically significant areas of stenosis up to approximately 90% of the time.²⁶ For this reason, it is particularly helpful in identifying candidates for an interventional strategy beyond pharmacotherapeutic thrombolysis. In addition, CT angiography can visualize aneurysmal dilation and dissection, and help with the planning of interventions—specifically, the confident administration of thrombolysis or more specific planning for target lesions and EVT.

Commonly used scoring systems in acute stroke include disability assessments— not always part of the acute assessment but undertaken early in the clinical course to gauge response to treatment.

It also can help identify a host of vascular phenomena, such as arteriovenous malformations, Moyamoya disease (progressive arterial blockage within the basal ganglia and compensatory microvascularization), and some vasculopathies.^20,27 In intracranial hemorrhage, CT with angiography can help evaluate for structural malformations and identify patients at risk of hematoma expansion.²²

CT perfusion. Many stroke centers will perform a CT perfusion study,²⁸ which encompasses as many as 3 different CT sequences:

• NCHCT
• vertex-to-arch angiography with contrast bolus
• administration of contrast and capture of a dynamic sequence through 1 or 2 slabs of tissue, allowing for the generation of maps of cerebral blood flow (CBF), mean transit time (MTT), and cerebral blood volume (CBV) of the entire cerebral vasculature.

The interplay of these 3 sequences drives characterization of lesions (ie, CBF = CBV/MTT). An infarct is characterized by low CBF, low CBV, and elevated MTT. In penumbral tissue, MTT is elevated but CBF is slightly decreased and CBV is normal or increased. Using CT perfusion, areas throughout the ischemic penumbra can be surveyed for favorable interventional characteristics.^20,29

Continue to: A CT perfusion study adds...

A CT perfusion study adds at least 60 seconds to NCHCT. This modality can be useful in planning interventions and for stratifying appropriateness of reperfusion strategies in strokes of unknown duration.^3,30 CT perfusion can be performed on any multidetector CT scan but (1) requires specialized software and expertise to interpret and (2) subjects the patient to a significant radiation dose, which, if incorrectly administered, can be considerably higher than intended.^20,26,27

Diffusion-weighted MRI. This is the most sensitive study for demonstrating early ischemic changes; however, limitations include lack of availability, contraindication in patients with metallic indwelling implants, and duration of the study—although, at some stroke centers, diffusion-weighted MRI can be performed in ≤ 10 minutes.

MRI and NCHCT have comparable sensitivity in detecting intracranial hemorrhage. MRI is likely more sensitive in identifying areas of microhemorrhage: In diffusion-weighted MRI, the sensitivity of stroke detection increases to > 95%.³¹ The modality relies on the comparable movement of water through damaged vs normal neuronal tissue. Diffusion-weighted MRI does not require administration of concomitant contrast, which can be a benefit in patients who are allergic to gadolinium-based contrast agents or have advanced kidney disease that precludes the use of contrast. It typically does not result in adequate characterization of extracranial vasculature.

Other MRI modalities. These MRI extensions include magnetic resonance (MR) perfusion and MR angiography. Whereas diffusion-weighted MRI (discussed above) offers the most rapid and sensitive evaluation for ischemia, fluid-attenuated inversion recovery (FLAIR) imaging has been utilized as a comparator to isolated diffusion-weighted MRI to help determine stroke duration. FLAIR signal positivity typically occurs 6 to 24 hours after the initial insult but is negative in stroke that occurred < 3 hours earlier.³²

MRI is limited, in terms of availability and increased study duration, especially when it comes to timely administration of thrombolysis. A benefit of this modality is less radiation and, as noted, superior sensitivity for ischemia. Diffusion-weighted MRI combined with MR perfusion analysis can help isolate areas of the ischemic penumbra. MR perfusion is performed for a similar reason as CT perfusion, although logistical execution across those modalities is significantly different. Considerations for choosing MR perfusion or CT perfusion should be made on an individual basis and based on available local resources and accepted local practice patterns.²⁶

Continue to: In the subacute setting...

Knowledge of historic details of the event, the patient (eg, known atrial fibrillation), and findings on imaging can facilitate communication between the primary care physician and inpatient teams.

In the subacute setting, MR perfusion and MR angiography of the head and the neck are often performed to identify stenosis, dissection, and more subtle mimickers of cerebrovascular accident not ascertained on initial CT evaluation. These studies are typically performed well outside the window for thrombolysis or intervention.²⁶ No guidelines specifically direct or recommend this practice pattern. The superior sensitivity and cerebral blood flow mapping of MR perfusion and MR angiography might be useful for validating a suspected diagnosis of ischemic stroke and providing phenotypic information about AIS events.

Transcranial Doppler imaging relies on bony windows to assess intracranial vascular flow, velocity, direction, and reactivity. This information can be utilized to diagnose stenosis or occlusion. This modality is principally used to evaluate for stenosis in the anterior circulation (sensitivity, 70%-90%; specificity, 90%-95%).²⁰ Evaluation of the basilar, vertebral, and internal carotid arteries is less accurate (sensitivity, 55%-80%).²⁰ Transcranial Doppler imaging is also used to assess for cerebral vasospasm after subarachnoid hemorrhage, monitor sickle cell disease patients’ overall risk for ischemic stroke, and augment thrombolysis. It is limited by the availability of an expert technician, and therefore is typically reserved for unstable patients or those who cannot receive contrast.²⁰

Carotid duplex ultrasonography. A dynamic study such as duplex ultrasonography can be strongly considered for flow imaging of the extracranial carotids to evaluate for stenosis. Indications for carotid stenting or endarterectomy include 50% to 79% occlusion of the carotid artery on the same side as a recent transient ischemic attack or AIS. Carotid stenosis > 80% warrants consideration for intervention independent of a recent cerebrovascular accident. Interventions are typically performed 2 to 14 days after stroke.³³ Although this study is of limited utility in the hyperacute setting, it is recommended within 24 hours after nondisabling stroke in the carotid territory, when (1) the patient is otherwise a candidate for a surgical or procedural intervention to address the stenosis and (2) none of the aforementioned studies that focus on neck vasculature have been performed.

Conventional (digital subtraction) ­angiography is the gold standard for mapping cerebrovascular disease because it is dynamic and highly accurate. It is, however, typically limited by the number of required personnel, its invasive nature, and the requirement for IV contrast. This study is performed during intra-arterial intervention techniques, including stent retrieval and intra-arterial thrombolysis.²⁶

Impact of imaging on treatment

Imaging helps determine the cause and some characteristics of stroke, both of which can help determine therapy. Strokes can be broadly subcategorized as hemorrhagic or ischemic; recent studies suggest that 87% are ischemic.³⁴ Knowledge of the historic details of the event, the patient (eg, known atrial fibrillation, anticoagulant use, history of falls), and findings on imaging can contribute to determine the cause of AIS, and can facilitate communication and consultation between the primary care physician and inpatient teams.³⁵

Continue to: Best practices for stroke treatment...

Best practices for stroke treatment are based on the cause of the event.³ To identify the likely cause, the aforementioned characteristics are incorporated into one of the scoring systems, which seek to clarify either the cause or the phenotypic appearance of the AIS, which helps direct further testing and treatment. (The ASCOD³⁶ and TOAST³⁷ classification schemes are commonly used phenotypic and causative classifications, respectively.) Several (not all) of the broad phenotypic imaging patterns, with myriad clinical manifestations, are reviewed below. They include:

• Embolic stroke, which, classically, involves end circulation and therefore has cortical involvement. Typically, these originate from the heart or large extracranial arteries, and higher rates of atrial fibrillation and hypercoagulable states are implicated.
• Thrombotic stroke, which, typically, is from large vessels or small vessels, and occurs as a result of atherosclerosis. These strokes are more common at the origins or bifurcations of vessels. Symptoms of thrombotic stroke classically wax and wane slightly more frequently. Lacunar strokes are typically from thrombotic causes, although there are rare episodes of an embolic source contributing to a lacunar stroke syndrome.³⁸

There is evidence for using MRI discrepancies between diffusion-weighted and FLAIR imaging to time AIS findings in so-called wake-up strokes.³⁹ The rationale is that strokes < 4.5 hours old can be identified because they would have abnormal diffusion imaging components but normal findings with FLAIR. When these criteria were utilized in considering whether to treat with thrombolysis, there was a statistically significant improvement in 90-day modified Rankin scale (odds ratio = 1.61; 95% confidence interval, 1.09-2.36), but also an increased probability of death and intracerebral hemorrhage.³⁹

This trial showed that thrombectomy could be performed as long as 16 hours after the patient was last well-appearing and still result in an improved outcome.

A recent multicenter, randomized, open-label trial, with blinded outcomes assessment, showcased the efficacy of thrombectomy as an adjunct when ischemic brain territory was identified without frank infarction, as ascertained by CT perfusion within the anterior circulation. This trial showed that thrombectomy could be performed as long as 16 hours after the patient was last well-appearing and still result in an improved outcome with favorable imaging characteristics (on the modified Rankin scale, an ordinal score of 4 with medical therapy and an ordinal score of 3 with EVT [odds ratio = 2.77; 95% confidence interval, 1.63-4.70]).²⁹ A 2018 multicenter, prospective, randomized trial with blinded assessment of endpoints extended this idea, demonstrating that, when there was mismatch of the clinical deficit (ie, high NIHSS score) and infarct volume (measured on diffusion-weighted MRI or CT perfusion), thrombectomy as late as 24 hours after the patient was last known to be well was beneficial for lesions in the anterior circulation—specifically, the intracranial internal carotid artery or the proximal middle cerebral artery.⁴⁰

^a Whether local emergency departments (EDs) should be bypassed in favor of a specialized stroke center is the subject of debate. The 2019 American Heart Association/American Stroke Association guidelines note the AHA’s Mission: Lifeline Stroke EMS algorithm, which bypasses the nearest ED in feared cases of large-vessel occlusion if travel to a comprehensive stroke center can be accomplished within 30 minutes of arrival at the scene. This is based on expert consensus.^3,12,13

CORRESPONDENCE
Brian Ford, MD, 4301 Jones Bridge Road, Bethesda, MD; [email protected].