The benefit of endovascular therapy in the treatment of stroke caused by an occlusion of the basilar artery has finally been confirmed in the ATTENTION randomized trial.

The study, conducted in China, showed that endovascular therapy for basilar artery occlusion is associated with higher rates of favorable and independent outcomes, as well as lower overall disability and lower mortality at 90 days, than best medical management alone.

The results were presented by Raul Nogueira, MD, professor of neurology at the University of Pittsburgh School of Medicine, at the European Stroke Organisation Conference (ESOC) 2022, where they were greeted with applause from the audience.

The number needed to treat was just four.

“There were no surprises with secondary endpoints; everything was highly statistically significant,” Dr. Nogueira said.

Specifically, there was a lower rate of overall disability in the shift analysis, with a common odds ratio of 2.8 favoring the intervention.  

Safety results showed an increased risk for symptomatic ICH in the endovascular group (5.3% vs. 0.0%) but, despite that, 90-day mortality was significantly lower in the endovascular group (36.7% vs. 55.3%).

Dr. Nogueira noted a limitation of the study was that it was conducted in China.

“This was a Chinese study and, as Asians are known to have higher rates of intracranial atherosclerotic disease, the overall degree of generalizability of our findings to Western countries needs to be considered,” he commented.

However, subgroup analysis showed no treatment effect modification based on the presence of intracranial atherosclerotic disease, he noted.

Also, the proportion of comorbidities in the ATTENTION trial was similar to that in the BASICS trial, with the same degree of diabetes and atrial fibrillation.

Dr. Nogueira concluded that, in contrast to previous randomized trials of endovascular treatment for basilar artery occlusion, the ATTENTION trial was able to reinforce consecutive enrollment, resulting in a fast recruitment while minimizing crossovers. 

Furthermore, he pointed out that the overall results are consistent with modern era observational studies, large registries, and meta-analysis.

Commenting on the study, Joanna Wardlaw, MD, professor of applied neuroimaging at the University of Edinburgh (Scotland), and chair of the ESOC Planning Group, said: “This is a very important result, since it provides confirmation beyond doubt the benefit of thrombectomy versus medical therapy for basilar artery occlusion stroke up to 12 hours after onset.”

Dr. Wardlaw added: “The trial was large enough to provide clear results and to enable subgroup analyses; no subgroup did not benefit from thrombectomy.”

In a discussion after the presentation, Urs Fischer, MD, chair of the department of neurology at the University Hospital Basel, Switzerland, said he was not surprised by the results of the ATTENTION trial.

“We have been doing thrombectomy in patients with basilar artery occlusion now for 20 years, although trials are extremely important to answer these questions, so now we have some clear evidence,” Dr. Fischer said. “Nevertheless, there are some caveats, as this is an Asian population, but this is a proof of concept, and it is going in the right direction.”

The ATTENTION trial was sponsored by the First Affiliated Hospital of University of Science and Technology of China.

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

The benefit of endovascular therapy in the treatment of stroke caused by an occlusion of the basilar artery has finally been confirmed in the ATTENTION randomized trial.

The study, conducted in China, showed that endovascular therapy for basilar artery occlusion is associated with higher rates of favorable and independent outcomes, as well as lower overall disability and lower mortality at 90 days, than best medical management alone.

The results were presented by Raul Nogueira, MD, professor of neurology at the University of Pittsburgh School of Medicine, at the European Stroke Organisation Conference (ESOC) 2022, where they were greeted with applause from the audience.

The number needed to treat was just four.

“There were no surprises with secondary endpoints; everything was highly statistically significant,” Dr. Nogueira said.

Specifically, there was a lower rate of overall disability in the shift analysis, with a common odds ratio of 2.8 favoring the intervention.  

Safety results showed an increased risk for symptomatic ICH in the endovascular group (5.3% vs. 0.0%) but, despite that, 90-day mortality was significantly lower in the endovascular group (36.7% vs. 55.3%).

Dr. Nogueira noted a limitation of the study was that it was conducted in China.

“This was a Chinese study and, as Asians are known to have higher rates of intracranial atherosclerotic disease, the overall degree of generalizability of our findings to Western countries needs to be considered,” he commented.

However, subgroup analysis showed no treatment effect modification based on the presence of intracranial atherosclerotic disease, he noted.

Also, the proportion of comorbidities in the ATTENTION trial was similar to that in the BASICS trial, with the same degree of diabetes and atrial fibrillation.

Dr. Nogueira concluded that, in contrast to previous randomized trials of endovascular treatment for basilar artery occlusion, the ATTENTION trial was able to reinforce consecutive enrollment, resulting in a fast recruitment while minimizing crossovers. 

Furthermore, he pointed out that the overall results are consistent with modern era observational studies, large registries, and meta-analysis.

Commenting on the study, Joanna Wardlaw, MD, professor of applied neuroimaging at the University of Edinburgh (Scotland), and chair of the ESOC Planning Group, said: “This is a very important result, since it provides confirmation beyond doubt the benefit of thrombectomy versus medical therapy for basilar artery occlusion stroke up to 12 hours after onset.”

Dr. Wardlaw added: “The trial was large enough to provide clear results and to enable subgroup analyses; no subgroup did not benefit from thrombectomy.”

In a discussion after the presentation, Urs Fischer, MD, chair of the department of neurology at the University Hospital Basel, Switzerland, said he was not surprised by the results of the ATTENTION trial.

“We have been doing thrombectomy in patients with basilar artery occlusion now for 20 years, although trials are extremely important to answer these questions, so now we have some clear evidence,” Dr. Fischer said. “Nevertheless, there are some caveats, as this is an Asian population, but this is a proof of concept, and it is going in the right direction.”

The ATTENTION trial was sponsored by the First Affiliated Hospital of University of Science and Technology of China.

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

The benefit of endovascular therapy in the treatment of stroke caused by an occlusion of the basilar artery has finally been confirmed in the ATTENTION randomized trial.

The study, conducted in China, showed that endovascular therapy for basilar artery occlusion is associated with higher rates of favorable and independent outcomes, as well as lower overall disability and lower mortality at 90 days, than best medical management alone.

The results were presented by Raul Nogueira, MD, professor of neurology at the University of Pittsburgh School of Medicine, at the European Stroke Organisation Conference (ESOC) 2022, where they were greeted with applause from the audience.

The number needed to treat was just four.

“There were no surprises with secondary endpoints; everything was highly statistically significant,” Dr. Nogueira said.

Specifically, there was a lower rate of overall disability in the shift analysis, with a common odds ratio of 2.8 favoring the intervention.  

Safety results showed an increased risk for symptomatic ICH in the endovascular group (5.3% vs. 0.0%) but, despite that, 90-day mortality was significantly lower in the endovascular group (36.7% vs. 55.3%).

Dr. Nogueira noted a limitation of the study was that it was conducted in China.

“This was a Chinese study and, as Asians are known to have higher rates of intracranial atherosclerotic disease, the overall degree of generalizability of our findings to Western countries needs to be considered,” he commented.

However, subgroup analysis showed no treatment effect modification based on the presence of intracranial atherosclerotic disease, he noted.

Also, the proportion of comorbidities in the ATTENTION trial was similar to that in the BASICS trial, with the same degree of diabetes and atrial fibrillation.

Dr. Nogueira concluded that, in contrast to previous randomized trials of endovascular treatment for basilar artery occlusion, the ATTENTION trial was able to reinforce consecutive enrollment, resulting in a fast recruitment while minimizing crossovers. 

Furthermore, he pointed out that the overall results are consistent with modern era observational studies, large registries, and meta-analysis.

Commenting on the study, Joanna Wardlaw, MD, professor of applied neuroimaging at the University of Edinburgh (Scotland), and chair of the ESOC Planning Group, said: “This is a very important result, since it provides confirmation beyond doubt the benefit of thrombectomy versus medical therapy for basilar artery occlusion stroke up to 12 hours after onset.”

Dr. Wardlaw added: “The trial was large enough to provide clear results and to enable subgroup analyses; no subgroup did not benefit from thrombectomy.”

In a discussion after the presentation, Urs Fischer, MD, chair of the department of neurology at the University Hospital Basel, Switzerland, said he was not surprised by the results of the ATTENTION trial.

“We have been doing thrombectomy in patients with basilar artery occlusion now for 20 years, although trials are extremely important to answer these questions, so now we have some clear evidence,” Dr. Fischer said. “Nevertheless, there are some caveats, as this is an Asian population, but this is a proof of concept, and it is going in the right direction.”

The ATTENTION trial was sponsored by the First Affiliated Hospital of University of Science and Technology of China.

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

This spring, global health advisories have been issued regarding an alarming – and as-yet unexplained – uptick of hepatitis in children. Currently, over 200 cases have been reported worldwide, a relatively small amount that nonetheless belies a considerable toll, including several deaths and the need for liver transplantation in a number of patients. The long-term implications are not yet known. Global health officials are working hard to determine a cause, with many focusing on the underlying cases of adenovirus that several patients have presented with.

To understand more, this news organization reached out to frequent contributor William F. Balistreri, MD, a specialist in pediatric gastroenterology and hepatology at Cincinnati Children’s Hospital Medical Center, where to date they have treated at least six cases of hepatitis in otherwise healthy young children, with one requiring a liver transplant. Dr. Balistreri discussed how the outbreak has developed to date, his advice to hepatologists and pediatricians, and where we stand now in this fast-evolving crisis.
 

Tracing the outbreak in the United States

How has this outbreak played out thus far in the United States, and what have we learned from that?

Sporadic reports of cases in multiple states are appearing. On April 21, 2022, a health alert was issued by the Centers for Disease Control and Prevention, recommending testing for adenovirus in children with acute hepatitis of an unknown etiology.

Baker and colleagues recently described five children with severe hepatitis and adenovirus viremia who were admitted to a children’s hospital in Birmingham, Ala., between October and November 2021. In collaboration with local and state officials, the CDC reviewed clinical records in order to identify patients with hepatitis and concomitant adenovirus infection, confirmed by polymerase chain reaction (PCR).

By February 2022, a total of nine children were identified. There was no epidemiologic linkage among these nine patients; all were well and immunocompetent. The prodromal features were somewhat similar: upper respiratory infection, vomiting, diarrhea, and jaundice. All children had markedly elevated aminotransferase levels and variably elevated total bilirubin levels. Extensive workup for other causes of acute liver injury (for example, other viruses, toxins/drugs, metabolic and autoimmune diseases) was unrevealing.

Specifically, none had documented SARS-CoV-2 infection. However, in all nine children, adenovirus was detected in whole blood samples. In the six children who underwent liver biopsy, there was nonspecific hepatitis, without inclusions or immunohistochemical detection of viral agents, including adenovirus. In three patients, the liver injury progressed, and despite the administration of antiviral agents, two underwent liver transplantation.

Baker and colleagues also suggested that measurement of adenovirus titers in whole blood (rather than plasma) may be more sensitive.

The CDC has recommended monitoring and surveillance in order to more fully understand the nature of the illness.
 

European and global cases

What has been the experience with this in Europe and elsewhere globally?

In mid-to-late 2021, several cases of acute hepatitis of unknown nature in children were identified in Europe. Public health officials in the United Kingdom investigated the high number of cases seen in children from England, Scotland, and Wales. They noted approximately 60 cases in England, mostly in children aged 2-5 years.

Marsh and colleagues reported a cluster of cases of severe hepatitis of unknown origin in Scotland affecting children aged 3-5 years. In Scotland, admitted cases were routinely tested for SARS-CoV-2. Of the 13 cases, five had a recent positive test. They discussed the possibility of increased severity of disease following infection with Omicron BA.2 (the dominant SARS-CoV-2 virus circulating in Scotland at that time) or infection by an uncharacterized SARS-CoV-2 variant. None of the children had been vaccinated for SARS-CoV-2.

On April 15, 2022, the World Health Organization Disease Outbreak News published a report of acute hepatitis of unknown etiology occurring in Great Britain and Northern Ireland. By April 21, 2022, 169 cases of acute hepatitis of unknown origin in children younger than 16 years had been reported from 11 countries in the WHO European region and 1 country in the WHO region of the Americas. Approximately 10% required a liver transplantation and at least one death was reported.

What has been established about the possible connection to the SARS-CoV-2 virus, particularly as it relates to coinfection with adenovirus?

In that WHO report of 169 cases, adenovirus was detected in 74 and SARS-CoV-2 in 20. Of note, 19 cases had a SARS-CoV-2 and adenovirus coinfection.

The report’s authors emphasized that, “while adenovirus is a possible hypothesis, investigations are ongoing for the causative agent.” The authors questioned whether this represents a continuing increase in cases of hepatitis or reflects an increased awareness.

The stated priority of the WHO is to determine the cause and to further refine control and prevention actions.

Given the worldwide nature of this outbreak, have connections between any of the cases been made yet?

Not to my knowledge.
 

What clinicians need to know

What makes this outbreak of hepatitis cases particularly concerning to the health care community, in comparison to other childhood diseases that occur globally? Is it because the cause is unknown or is it for other reasons?

It may be a collective heightened concern following the emergence of COVID.

Whether it represents a new form of acute hepatitis, a continuing increase in cases of hepatitis, or an increased awareness because of the well-publicized alerts remains to be determined. We certainly saw “viral-induced hepatitis” in the past.

Young patients may first be brought to pediatricians. What, if anything, should pediatricians be on the lookout for? Do they need a heightened index of suspicion or are the cases too rare at this point?

An awareness of the “outbreak” may allow the clinician to extend the typical workup of a child presenting with an undefined, presumably viral illness.

In the cases reported, the prodromal and/or presenting symptoms were respiratory and gastrointestinal in nature. They include nausea, vomiting, diarrhea, and abdominal pain.

Specifically, if jaundice and/or scleral icterus is noted, then hepatitis should be suspected.

Should pediatricians consider early referral to a pediatric gastroenterologist or hepatologist?

Yes, because there is the potential for finding a treatable cause (for example, autoimmune hepatitis or a specific metabolic disease) in a patient presenting in this fashion.

In addition, the potential for progression to acute liver failure (with coagulopathy and encephalopathy), albeit rare, exists.

What do hepatologists need to be doing when presented with suspected cases?

The typical clinical picture holds and the workup is standard. The one new key, given the recent data, is to test for adenovirus, using whole blood versus plasma, as the former may be more sensitive.

In addition, it is prudent to check for SARS-CoV-2 by PCR.

What are the major questions that remain and that you’d like to see elucidated going forward?

There are many. Is this a new disease? A new variant of adenovirus? A synergy or susceptibility related to SARS-CoV-2? Is it related to a variant of SARS-CoV-2? Is it triggering an adverse immune response? Are there other epigenetic factors involved? And finally, is this an increase, or is it related to a collective heightened concern following the pandemic?

Dr. Balistreri is the Dorothy M.M. Kersten Professor of Pediatrics, director emeritus of the Pediatric Liver Care Center, medical director emeritus of liver transplantation, and professor at the University of Cincinnati; he is also with the department of pediatrics at Cincinnati Children’s Hospital Medical Center.

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

This spring, global health advisories have been issued regarding an alarming – and as-yet unexplained – uptick of hepatitis in children. Currently, over 200 cases have been reported worldwide, a relatively small amount that nonetheless belies a considerable toll, including several deaths and the need for liver transplantation in a number of patients. The long-term implications are not yet known. Global health officials are working hard to determine a cause, with many focusing on the underlying cases of adenovirus that several patients have presented with.

To understand more, this news organization reached out to frequent contributor William F. Balistreri, MD, a specialist in pediatric gastroenterology and hepatology at Cincinnati Children’s Hospital Medical Center, where to date they have treated at least six cases of hepatitis in otherwise healthy young children, with one requiring a liver transplant. Dr. Balistreri discussed how the outbreak has developed to date, his advice to hepatologists and pediatricians, and where we stand now in this fast-evolving crisis.
 

Tracing the outbreak in the United States

How has this outbreak played out thus far in the United States, and what have we learned from that?

Sporadic reports of cases in multiple states are appearing. On April 21, 2022, a health alert was issued by the Centers for Disease Control and Prevention, recommending testing for adenovirus in children with acute hepatitis of an unknown etiology.

Baker and colleagues recently described five children with severe hepatitis and adenovirus viremia who were admitted to a children’s hospital in Birmingham, Ala., between October and November 2021. In collaboration with local and state officials, the CDC reviewed clinical records in order to identify patients with hepatitis and concomitant adenovirus infection, confirmed by polymerase chain reaction (PCR).

By February 2022, a total of nine children were identified. There was no epidemiologic linkage among these nine patients; all were well and immunocompetent. The prodromal features were somewhat similar: upper respiratory infection, vomiting, diarrhea, and jaundice. All children had markedly elevated aminotransferase levels and variably elevated total bilirubin levels. Extensive workup for other causes of acute liver injury (for example, other viruses, toxins/drugs, metabolic and autoimmune diseases) was unrevealing.

Specifically, none had documented SARS-CoV-2 infection. However, in all nine children, adenovirus was detected in whole blood samples. In the six children who underwent liver biopsy, there was nonspecific hepatitis, without inclusions or immunohistochemical detection of viral agents, including adenovirus. In three patients, the liver injury progressed, and despite the administration of antiviral agents, two underwent liver transplantation.

Baker and colleagues also suggested that measurement of adenovirus titers in whole blood (rather than plasma) may be more sensitive.

The CDC has recommended monitoring and surveillance in order to more fully understand the nature of the illness.
 

European and global cases

What has been the experience with this in Europe and elsewhere globally?

In mid-to-late 2021, several cases of acute hepatitis of unknown nature in children were identified in Europe. Public health officials in the United Kingdom investigated the high number of cases seen in children from England, Scotland, and Wales. They noted approximately 60 cases in England, mostly in children aged 2-5 years.

Marsh and colleagues reported a cluster of cases of severe hepatitis of unknown origin in Scotland affecting children aged 3-5 years. In Scotland, admitted cases were routinely tested for SARS-CoV-2. Of the 13 cases, five had a recent positive test. They discussed the possibility of increased severity of disease following infection with Omicron BA.2 (the dominant SARS-CoV-2 virus circulating in Scotland at that time) or infection by an uncharacterized SARS-CoV-2 variant. None of the children had been vaccinated for SARS-CoV-2.

On April 15, 2022, the World Health Organization Disease Outbreak News published a report of acute hepatitis of unknown etiology occurring in Great Britain and Northern Ireland. By April 21, 2022, 169 cases of acute hepatitis of unknown origin in children younger than 16 years had been reported from 11 countries in the WHO European region and 1 country in the WHO region of the Americas. Approximately 10% required a liver transplantation and at least one death was reported.

What has been established about the possible connection to the SARS-CoV-2 virus, particularly as it relates to coinfection with adenovirus?

In that WHO report of 169 cases, adenovirus was detected in 74 and SARS-CoV-2 in 20. Of note, 19 cases had a SARS-CoV-2 and adenovirus coinfection.

The report’s authors emphasized that, “while adenovirus is a possible hypothesis, investigations are ongoing for the causative agent.” The authors questioned whether this represents a continuing increase in cases of hepatitis or reflects an increased awareness.

The stated priority of the WHO is to determine the cause and to further refine control and prevention actions.

Given the worldwide nature of this outbreak, have connections between any of the cases been made yet?

Not to my knowledge.
 

What clinicians need to know

What makes this outbreak of hepatitis cases particularly concerning to the health care community, in comparison to other childhood diseases that occur globally? Is it because the cause is unknown or is it for other reasons?

It may be a collective heightened concern following the emergence of COVID.

Whether it represents a new form of acute hepatitis, a continuing increase in cases of hepatitis, or an increased awareness because of the well-publicized alerts remains to be determined. We certainly saw “viral-induced hepatitis” in the past.

Young patients may first be brought to pediatricians. What, if anything, should pediatricians be on the lookout for? Do they need a heightened index of suspicion or are the cases too rare at this point?

An awareness of the “outbreak” may allow the clinician to extend the typical workup of a child presenting with an undefined, presumably viral illness.

In the cases reported, the prodromal and/or presenting symptoms were respiratory and gastrointestinal in nature. They include nausea, vomiting, diarrhea, and abdominal pain.

Specifically, if jaundice and/or scleral icterus is noted, then hepatitis should be suspected.

Should pediatricians consider early referral to a pediatric gastroenterologist or hepatologist?

Yes, because there is the potential for finding a treatable cause (for example, autoimmune hepatitis or a specific metabolic disease) in a patient presenting in this fashion.

In addition, the potential for progression to acute liver failure (with coagulopathy and encephalopathy), albeit rare, exists.

What do hepatologists need to be doing when presented with suspected cases?

The typical clinical picture holds and the workup is standard. The one new key, given the recent data, is to test for adenovirus, using whole blood versus plasma, as the former may be more sensitive.

In addition, it is prudent to check for SARS-CoV-2 by PCR.

What are the major questions that remain and that you’d like to see elucidated going forward?

There are many. Is this a new disease? A new variant of adenovirus? A synergy or susceptibility related to SARS-CoV-2? Is it related to a variant of SARS-CoV-2? Is it triggering an adverse immune response? Are there other epigenetic factors involved? And finally, is this an increase, or is it related to a collective heightened concern following the pandemic?

Dr. Balistreri is the Dorothy M.M. Kersten Professor of Pediatrics, director emeritus of the Pediatric Liver Care Center, medical director emeritus of liver transplantation, and professor at the University of Cincinnati; he is also with the department of pediatrics at Cincinnati Children’s Hospital Medical Center.

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

This spring, global health advisories have been issued regarding an alarming – and as-yet unexplained – uptick of hepatitis in children. Currently, over 200 cases have been reported worldwide, a relatively small amount that nonetheless belies a considerable toll, including several deaths and the need for liver transplantation in a number of patients. The long-term implications are not yet known. Global health officials are working hard to determine a cause, with many focusing on the underlying cases of adenovirus that several patients have presented with.

To understand more, this news organization reached out to frequent contributor William F. Balistreri, MD, a specialist in pediatric gastroenterology and hepatology at Cincinnati Children’s Hospital Medical Center, where to date they have treated at least six cases of hepatitis in otherwise healthy young children, with one requiring a liver transplant. Dr. Balistreri discussed how the outbreak has developed to date, his advice to hepatologists and pediatricians, and where we stand now in this fast-evolving crisis.
 

Tracing the outbreak in the United States

How has this outbreak played out thus far in the United States, and what have we learned from that?

Sporadic reports of cases in multiple states are appearing. On April 21, 2022, a health alert was issued by the Centers for Disease Control and Prevention, recommending testing for adenovirus in children with acute hepatitis of an unknown etiology.

Baker and colleagues recently described five children with severe hepatitis and adenovirus viremia who were admitted to a children’s hospital in Birmingham, Ala., between October and November 2021. In collaboration with local and state officials, the CDC reviewed clinical records in order to identify patients with hepatitis and concomitant adenovirus infection, confirmed by polymerase chain reaction (PCR).

By February 2022, a total of nine children were identified. There was no epidemiologic linkage among these nine patients; all were well and immunocompetent. The prodromal features were somewhat similar: upper respiratory infection, vomiting, diarrhea, and jaundice. All children had markedly elevated aminotransferase levels and variably elevated total bilirubin levels. Extensive workup for other causes of acute liver injury (for example, other viruses, toxins/drugs, metabolic and autoimmune diseases) was unrevealing.

Specifically, none had documented SARS-CoV-2 infection. However, in all nine children, adenovirus was detected in whole blood samples. In the six children who underwent liver biopsy, there was nonspecific hepatitis, without inclusions or immunohistochemical detection of viral agents, including adenovirus. In three patients, the liver injury progressed, and despite the administration of antiviral agents, two underwent liver transplantation.

Baker and colleagues also suggested that measurement of adenovirus titers in whole blood (rather than plasma) may be more sensitive.

The CDC has recommended monitoring and surveillance in order to more fully understand the nature of the illness.
 

European and global cases

What has been the experience with this in Europe and elsewhere globally?

In mid-to-late 2021, several cases of acute hepatitis of unknown nature in children were identified in Europe. Public health officials in the United Kingdom investigated the high number of cases seen in children from England, Scotland, and Wales. They noted approximately 60 cases in England, mostly in children aged 2-5 years.

Marsh and colleagues reported a cluster of cases of severe hepatitis of unknown origin in Scotland affecting children aged 3-5 years. In Scotland, admitted cases were routinely tested for SARS-CoV-2. Of the 13 cases, five had a recent positive test. They discussed the possibility of increased severity of disease following infection with Omicron BA.2 (the dominant SARS-CoV-2 virus circulating in Scotland at that time) or infection by an uncharacterized SARS-CoV-2 variant. None of the children had been vaccinated for SARS-CoV-2.

On April 15, 2022, the World Health Organization Disease Outbreak News published a report of acute hepatitis of unknown etiology occurring in Great Britain and Northern Ireland. By April 21, 2022, 169 cases of acute hepatitis of unknown origin in children younger than 16 years had been reported from 11 countries in the WHO European region and 1 country in the WHO region of the Americas. Approximately 10% required a liver transplantation and at least one death was reported.

What has been established about the possible connection to the SARS-CoV-2 virus, particularly as it relates to coinfection with adenovirus?

In that WHO report of 169 cases, adenovirus was detected in 74 and SARS-CoV-2 in 20. Of note, 19 cases had a SARS-CoV-2 and adenovirus coinfection.

The report’s authors emphasized that, “while adenovirus is a possible hypothesis, investigations are ongoing for the causative agent.” The authors questioned whether this represents a continuing increase in cases of hepatitis or reflects an increased awareness.

The stated priority of the WHO is to determine the cause and to further refine control and prevention actions.

Given the worldwide nature of this outbreak, have connections between any of the cases been made yet?

Not to my knowledge.
 

What clinicians need to know

What makes this outbreak of hepatitis cases particularly concerning to the health care community, in comparison to other childhood diseases that occur globally? Is it because the cause is unknown or is it for other reasons?

It may be a collective heightened concern following the emergence of COVID.

Whether it represents a new form of acute hepatitis, a continuing increase in cases of hepatitis, or an increased awareness because of the well-publicized alerts remains to be determined. We certainly saw “viral-induced hepatitis” in the past.

Young patients may first be brought to pediatricians. What, if anything, should pediatricians be on the lookout for? Do they need a heightened index of suspicion or are the cases too rare at this point?

An awareness of the “outbreak” may allow the clinician to extend the typical workup of a child presenting with an undefined, presumably viral illness.

In the cases reported, the prodromal and/or presenting symptoms were respiratory and gastrointestinal in nature. They include nausea, vomiting, diarrhea, and abdominal pain.

Specifically, if jaundice and/or scleral icterus is noted, then hepatitis should be suspected.

Should pediatricians consider early referral to a pediatric gastroenterologist or hepatologist?

Yes, because there is the potential for finding a treatable cause (for example, autoimmune hepatitis or a specific metabolic disease) in a patient presenting in this fashion.

In addition, the potential for progression to acute liver failure (with coagulopathy and encephalopathy), albeit rare, exists.

What do hepatologists need to be doing when presented with suspected cases?

The typical clinical picture holds and the workup is standard. The one new key, given the recent data, is to test for adenovirus, using whole blood versus plasma, as the former may be more sensitive.

In addition, it is prudent to check for SARS-CoV-2 by PCR.

What are the major questions that remain and that you’d like to see elucidated going forward?

There are many. Is this a new disease? A new variant of adenovirus? A synergy or susceptibility related to SARS-CoV-2? Is it related to a variant of SARS-CoV-2? Is it triggering an adverse immune response? Are there other epigenetic factors involved? And finally, is this an increase, or is it related to a collective heightened concern following the pandemic?

Dr. Balistreri is the Dorothy M.M. Kersten Professor of Pediatrics, director emeritus of the Pediatric Liver Care Center, medical director emeritus of liver transplantation, and professor at the University of Cincinnati; he is also with the department of pediatrics at Cincinnati Children’s Hospital Medical Center.

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

A new study finds clinicians are shifting away from the U.S. Food and Drug Administration–approved combination of warfarin and aspirin after left atrial appendage occlusion (LAAO) with the Watchman device and that adverse events, particularly bleeding, are lower when aspirin is dropped.

Of 31,994 patients successfully implanted with the Watchman 2.5 device in the 3 years after its March 2015 approval, only 1 in 10 received the full postprocedure protocol studied in pivotal trials and codified into the FDA-device approval.

The protocol consisted of aspirin (81-325 mg) indefinitely and warfarin for 45 days. Following transesophageal echocardiography, patients were then maintained on warfarin and aspirin if there was a peridevice leak greater than 5 mm or switched to clopidogrel 75 mg for 6 months if a peridevice leak was ruled out or was 5 mm or less.

Based on the results, drawn from the National Cardiovascular Data Registry (NCDR) LAAO Registry, the most common discharge medications were warfarin and aspirin in 36.9% of patients, followed by a direct oral anticoagulant (DOAC) and aspirin (20.8%), warfarin alone (13.5%), DOAC only (12.3%), and dual antiplatelet therapy (DAPT) with aspirin and a P2Y12 inhibitor (5%).

“There’s a little bit of practice leading the science in this space,” lead author James V. Freeman, MD, MPH, Yale School of Medicine, New Haven, Conn., told this news organization.

Patients who couldn’t tolerate long-term anticoagulation were excluded from the pivotal trials but are now the patients in whom the device is most often used, because of the Centers for Medicare & Medicaid reimbursement mandate for a relative or absolute contraindication to long-term anticoagulation, he noted.

Not surprisingly, 70% of patients in the registry had history of clinically relevant bleeding, the mean CHA2DS2-VASc score was 4.6, and mean HAS-BLED score was 3. At an average age of 76, they were also older, by years, than those in the clinical trials.

Secular trends at the time also saw the ascendancy of the DOACs relative to warfarin, observed Dr. Freeman. “So I think it’s pretty reasonable for physicians to be considering DOACs rather than warfarin in this context.”
 

Aspirin takes another hit

Results, published May 2 in the Journal of the American College of Cardiology, showed that any adverse event occurred at 45 days in 5.7% of patients discharged on warfarin and aspirin, 4% on warfarin alone, 5.2% on DOAC and aspirin, 3.8% on DOAC only, and 5.5% on DAPT.

Rates of any major adverse event were 4.4%, 3.3%, 4.3%, 3.1%, and 4.2% respectively, and for major bleeding were 3%, 1.8%, 2.8%, 1.7%, and 2.2% respectively. Although patients were similar across treatment groups, those treated with DAPT were slightly older and had more comorbidities, Dr. Freeman said.

In Cox frailty regression, the adjusted risk of any adverse event at 45 days was significantly lower when patients were discharged on warfarin alone (hazard ratio, 0.692; 95% confidence interval, 0.56-0.84) and a DOAC alone (HR, 0.731; 95% CI, 0.57-0.93), compared with warfarin and aspirin. There were no differences among the other groups.

The risk of any major adverse event was also significantly lower with warfarin alone (HR, 0.658; 95% CI, 0.53-0.80) and DOAC alone (HR, 0.767; 95% CI, 0.59-0.98).

At 6 months, rates of any adverse event (HR, 0.814; 95% CI, 0.72-0.93) and any major adverse event (HR, 0.840; 95% CI, 0.73-0.95) were significantly lower only in patients treated with warfarin alone.

“I think if there’s a take-home [message] here, it’s that for a lot of patients there’s good data now to suggest getting rid of the aspirin is a very reasonable thing to do,” Dr. Freeman said.

Further studies are needed in the space, but the results are consistent with those from transcatheter aortic valve replacement studies showing discharge on warfarin or DOAC anticoagulation alone reduces major adverse events without increasing thrombotic events, he said.

“I do think if there’s a strong indication for aspirin – someone has terrible coronary disease – there may be a role for using it,” Dr. Freeman said. But for a lot of these patients, anticoagulation alone without aspirin “may present a big opportunity to mitigate morbidity associated with this procedure.”

Dr. Freeman said he doesn’t expect the findings would be dramatically different with the second-generation Watchman FLX device but noted that randomized data will be forthcoming, as Boston Scientific changed the CHAMPION-AF trial protocol to include DOAC alone without aspirin.

Commenting for this news organization, Domenico Della Rocca, MD, Texas Cardiac Arrhythmia Institute at St. David’s Medical Center, Austin, said the study is a useful overview of post-LAAO therapies in a large population – but not surprising.

“Practice has changed over the years. More and more we are adopting and trusting the DOACs,” he said. “And, we are realizing that dual antiplatelet therapy is so aggressive and antiplatelet therapy alone maybe is not the best choice based on data on activation of coagulation.”

Commenting further, he said “I think it’s too early to suggest being too keen to completely drop aspirin,” noting that 20%-25% of patients have clopidogrel resistance and that the combination of two antiplatelets may be too aggressive a strategy for others.

Dr. Della Rocca and colleagues recently reported favorable long-term results with half-dose DOAC therapy after Watchman implantation and said the team is launching a randomized trial in more than 500 LAAO patients in the United States and Europe later this year. The trial will be comparing a DOAC-based strategy with low-dose apixaban long-term versus clopidogrel and aspirin initially and then switching to 100 mg aspirin long-term.

“We hope that in the next 2-3 years we will have some better answers, but at this point I would say that clopidogrel is kind of an obsolete strategy for appendage closure,” Dr. Della Rocca said.

In an accompanying editorial, David R. Holmes Jr., MD, Mayo Clinic, Rochester, Minn., says “the cornucopia of these specific strategies can be expected to change as practices evolve, as instructions for use broaden and, hopefully, with the results of well-done, scientifically performed trials. This current LAAO Registry report, however, serves as a useful benchmark.”

He cautioned that this is an observational cohort study and that unmeasured imbalances still may affect the ability to identify an unbiased treatment signal. The use of DAPT was also infrequent during the study and “conclusions based on this information are soft.”

The study was funded by the American College of Cardiology National Cardiovascular Data Registry (NCDR), and the National Heart, Lung, and Blood Institute (NHLBI) grants. Dr. Freeman has received salary support from the ACC NCDR and the NHLBI and has received consulting/advisory board fees from Boston Scientific, Medtronic, Janssen Pharmaceuticals, and Biosense Webster.

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

A new study finds clinicians are shifting away from the U.S. Food and Drug Administration–approved combination of warfarin and aspirin after left atrial appendage occlusion (LAAO) with the Watchman device and that adverse events, particularly bleeding, are lower when aspirin is dropped.

Of 31,994 patients successfully implanted with the Watchman 2.5 device in the 3 years after its March 2015 approval, only 1 in 10 received the full postprocedure protocol studied in pivotal trials and codified into the FDA-device approval.

The protocol consisted of aspirin (81-325 mg) indefinitely and warfarin for 45 days. Following transesophageal echocardiography, patients were then maintained on warfarin and aspirin if there was a peridevice leak greater than 5 mm or switched to clopidogrel 75 mg for 6 months if a peridevice leak was ruled out or was 5 mm or less.

Based on the results, drawn from the National Cardiovascular Data Registry (NCDR) LAAO Registry, the most common discharge medications were warfarin and aspirin in 36.9% of patients, followed by a direct oral anticoagulant (DOAC) and aspirin (20.8%), warfarin alone (13.5%), DOAC only (12.3%), and dual antiplatelet therapy (DAPT) with aspirin and a P2Y12 inhibitor (5%).

“There’s a little bit of practice leading the science in this space,” lead author James V. Freeman, MD, MPH, Yale School of Medicine, New Haven, Conn., told this news organization.

Patients who couldn’t tolerate long-term anticoagulation were excluded from the pivotal trials but are now the patients in whom the device is most often used, because of the Centers for Medicare & Medicaid reimbursement mandate for a relative or absolute contraindication to long-term anticoagulation, he noted.

Not surprisingly, 70% of patients in the registry had history of clinically relevant bleeding, the mean CHA2DS2-VASc score was 4.6, and mean HAS-BLED score was 3. At an average age of 76, they were also older, by years, than those in the clinical trials.

Secular trends at the time also saw the ascendancy of the DOACs relative to warfarin, observed Dr. Freeman. “So I think it’s pretty reasonable for physicians to be considering DOACs rather than warfarin in this context.”
 

Aspirin takes another hit

Results, published May 2 in the Journal of the American College of Cardiology, showed that any adverse event occurred at 45 days in 5.7% of patients discharged on warfarin and aspirin, 4% on warfarin alone, 5.2% on DOAC and aspirin, 3.8% on DOAC only, and 5.5% on DAPT.

Rates of any major adverse event were 4.4%, 3.3%, 4.3%, 3.1%, and 4.2% respectively, and for major bleeding were 3%, 1.8%, 2.8%, 1.7%, and 2.2% respectively. Although patients were similar across treatment groups, those treated with DAPT were slightly older and had more comorbidities, Dr. Freeman said.

In Cox frailty regression, the adjusted risk of any adverse event at 45 days was significantly lower when patients were discharged on warfarin alone (hazard ratio, 0.692; 95% confidence interval, 0.56-0.84) and a DOAC alone (HR, 0.731; 95% CI, 0.57-0.93), compared with warfarin and aspirin. There were no differences among the other groups.

The risk of any major adverse event was also significantly lower with warfarin alone (HR, 0.658; 95% CI, 0.53-0.80) and DOAC alone (HR, 0.767; 95% CI, 0.59-0.98).

At 6 months, rates of any adverse event (HR, 0.814; 95% CI, 0.72-0.93) and any major adverse event (HR, 0.840; 95% CI, 0.73-0.95) were significantly lower only in patients treated with warfarin alone.

“I think if there’s a take-home [message] here, it’s that for a lot of patients there’s good data now to suggest getting rid of the aspirin is a very reasonable thing to do,” Dr. Freeman said.

Further studies are needed in the space, but the results are consistent with those from transcatheter aortic valve replacement studies showing discharge on warfarin or DOAC anticoagulation alone reduces major adverse events without increasing thrombotic events, he said.

“I do think if there’s a strong indication for aspirin – someone has terrible coronary disease – there may be a role for using it,” Dr. Freeman said. But for a lot of these patients, anticoagulation alone without aspirin “may present a big opportunity to mitigate morbidity associated with this procedure.”

Dr. Freeman said he doesn’t expect the findings would be dramatically different with the second-generation Watchman FLX device but noted that randomized data will be forthcoming, as Boston Scientific changed the CHAMPION-AF trial protocol to include DOAC alone without aspirin.

Commenting for this news organization, Domenico Della Rocca, MD, Texas Cardiac Arrhythmia Institute at St. David’s Medical Center, Austin, said the study is a useful overview of post-LAAO therapies in a large population – but not surprising.

“Practice has changed over the years. More and more we are adopting and trusting the DOACs,” he said. “And, we are realizing that dual antiplatelet therapy is so aggressive and antiplatelet therapy alone maybe is not the best choice based on data on activation of coagulation.”

Commenting further, he said “I think it’s too early to suggest being too keen to completely drop aspirin,” noting that 20%-25% of patients have clopidogrel resistance and that the combination of two antiplatelets may be too aggressive a strategy for others.

Dr. Della Rocca and colleagues recently reported favorable long-term results with half-dose DOAC therapy after Watchman implantation and said the team is launching a randomized trial in more than 500 LAAO patients in the United States and Europe later this year. The trial will be comparing a DOAC-based strategy with low-dose apixaban long-term versus clopidogrel and aspirin initially and then switching to 100 mg aspirin long-term.

“We hope that in the next 2-3 years we will have some better answers, but at this point I would say that clopidogrel is kind of an obsolete strategy for appendage closure,” Dr. Della Rocca said.

In an accompanying editorial, David R. Holmes Jr., MD, Mayo Clinic, Rochester, Minn., says “the cornucopia of these specific strategies can be expected to change as practices evolve, as instructions for use broaden and, hopefully, with the results of well-done, scientifically performed trials. This current LAAO Registry report, however, serves as a useful benchmark.”

He cautioned that this is an observational cohort study and that unmeasured imbalances still may affect the ability to identify an unbiased treatment signal. The use of DAPT was also infrequent during the study and “conclusions based on this information are soft.”

The study was funded by the American College of Cardiology National Cardiovascular Data Registry (NCDR), and the National Heart, Lung, and Blood Institute (NHLBI) grants. Dr. Freeman has received salary support from the ACC NCDR and the NHLBI and has received consulting/advisory board fees from Boston Scientific, Medtronic, Janssen Pharmaceuticals, and Biosense Webster.

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

A new study finds clinicians are shifting away from the U.S. Food and Drug Administration–approved combination of warfarin and aspirin after left atrial appendage occlusion (LAAO) with the Watchman device and that adverse events, particularly bleeding, are lower when aspirin is dropped.

Of 31,994 patients successfully implanted with the Watchman 2.5 device in the 3 years after its March 2015 approval, only 1 in 10 received the full postprocedure protocol studied in pivotal trials and codified into the FDA-device approval.

The protocol consisted of aspirin (81-325 mg) indefinitely and warfarin for 45 days. Following transesophageal echocardiography, patients were then maintained on warfarin and aspirin if there was a peridevice leak greater than 5 mm or switched to clopidogrel 75 mg for 6 months if a peridevice leak was ruled out or was 5 mm or less.

Based on the results, drawn from the National Cardiovascular Data Registry (NCDR) LAAO Registry, the most common discharge medications were warfarin and aspirin in 36.9% of patients, followed by a direct oral anticoagulant (DOAC) and aspirin (20.8%), warfarin alone (13.5%), DOAC only (12.3%), and dual antiplatelet therapy (DAPT) with aspirin and a P2Y12 inhibitor (5%).

“There’s a little bit of practice leading the science in this space,” lead author James V. Freeman, MD, MPH, Yale School of Medicine, New Haven, Conn., told this news organization.

Patients who couldn’t tolerate long-term anticoagulation were excluded from the pivotal trials but are now the patients in whom the device is most often used, because of the Centers for Medicare & Medicaid reimbursement mandate for a relative or absolute contraindication to long-term anticoagulation, he noted.

Not surprisingly, 70% of patients in the registry had history of clinically relevant bleeding, the mean CHA2DS2-VASc score was 4.6, and mean HAS-BLED score was 3. At an average age of 76, they were also older, by years, than those in the clinical trials.

Secular trends at the time also saw the ascendancy of the DOACs relative to warfarin, observed Dr. Freeman. “So I think it’s pretty reasonable for physicians to be considering DOACs rather than warfarin in this context.”
 

Aspirin takes another hit

Results, published May 2 in the Journal of the American College of Cardiology, showed that any adverse event occurred at 45 days in 5.7% of patients discharged on warfarin and aspirin, 4% on warfarin alone, 5.2% on DOAC and aspirin, 3.8% on DOAC only, and 5.5% on DAPT.

Rates of any major adverse event were 4.4%, 3.3%, 4.3%, 3.1%, and 4.2% respectively, and for major bleeding were 3%, 1.8%, 2.8%, 1.7%, and 2.2% respectively. Although patients were similar across treatment groups, those treated with DAPT were slightly older and had more comorbidities, Dr. Freeman said.

In Cox frailty regression, the adjusted risk of any adverse event at 45 days was significantly lower when patients were discharged on warfarin alone (hazard ratio, 0.692; 95% confidence interval, 0.56-0.84) and a DOAC alone (HR, 0.731; 95% CI, 0.57-0.93), compared with warfarin and aspirin. There were no differences among the other groups.

The risk of any major adverse event was also significantly lower with warfarin alone (HR, 0.658; 95% CI, 0.53-0.80) and DOAC alone (HR, 0.767; 95% CI, 0.59-0.98).

At 6 months, rates of any adverse event (HR, 0.814; 95% CI, 0.72-0.93) and any major adverse event (HR, 0.840; 95% CI, 0.73-0.95) were significantly lower only in patients treated with warfarin alone.

“I think if there’s a take-home [message] here, it’s that for a lot of patients there’s good data now to suggest getting rid of the aspirin is a very reasonable thing to do,” Dr. Freeman said.

Further studies are needed in the space, but the results are consistent with those from transcatheter aortic valve replacement studies showing discharge on warfarin or DOAC anticoagulation alone reduces major adverse events without increasing thrombotic events, he said.

“I do think if there’s a strong indication for aspirin – someone has terrible coronary disease – there may be a role for using it,” Dr. Freeman said. But for a lot of these patients, anticoagulation alone without aspirin “may present a big opportunity to mitigate morbidity associated with this procedure.”

Dr. Freeman said he doesn’t expect the findings would be dramatically different with the second-generation Watchman FLX device but noted that randomized data will be forthcoming, as Boston Scientific changed the CHAMPION-AF trial protocol to include DOAC alone without aspirin.

Commenting for this news organization, Domenico Della Rocca, MD, Texas Cardiac Arrhythmia Institute at St. David’s Medical Center, Austin, said the study is a useful overview of post-LAAO therapies in a large population – but not surprising.

“Practice has changed over the years. More and more we are adopting and trusting the DOACs,” he said. “And, we are realizing that dual antiplatelet therapy is so aggressive and antiplatelet therapy alone maybe is not the best choice based on data on activation of coagulation.”

Commenting further, he said “I think it’s too early to suggest being too keen to completely drop aspirin,” noting that 20%-25% of patients have clopidogrel resistance and that the combination of two antiplatelets may be too aggressive a strategy for others.

Dr. Della Rocca and colleagues recently reported favorable long-term results with half-dose DOAC therapy after Watchman implantation and said the team is launching a randomized trial in more than 500 LAAO patients in the United States and Europe later this year. The trial will be comparing a DOAC-based strategy with low-dose apixaban long-term versus clopidogrel and aspirin initially and then switching to 100 mg aspirin long-term.

“We hope that in the next 2-3 years we will have some better answers, but at this point I would say that clopidogrel is kind of an obsolete strategy for appendage closure,” Dr. Della Rocca said.

In an accompanying editorial, David R. Holmes Jr., MD, Mayo Clinic, Rochester, Minn., says “the cornucopia of these specific strategies can be expected to change as practices evolve, as instructions for use broaden and, hopefully, with the results of well-done, scientifically performed trials. This current LAAO Registry report, however, serves as a useful benchmark.”

He cautioned that this is an observational cohort study and that unmeasured imbalances still may affect the ability to identify an unbiased treatment signal. The use of DAPT was also infrequent during the study and “conclusions based on this information are soft.”

The study was funded by the American College of Cardiology National Cardiovascular Data Registry (NCDR), and the National Heart, Lung, and Blood Institute (NHLBI) grants. Dr. Freeman has received salary support from the ACC NCDR and the NHLBI and has received consulting/advisory board fees from Boston Scientific, Medtronic, Janssen Pharmaceuticals, and Biosense Webster.

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

With an abundance of targeted therapies transforming the treatment landscape for chronic lymphocytic leukemia (CLL), picking the optimal drug or drug sequence for the right situation can be a challenge, but emerging data is helping guide clinicians facing the “agony of choice,” a new review reports.

“Targeted therapies have outnumbered chemoimmunotherapy-based treatment approaches, demonstrating superior efficacy and tolerability profiles across nearly all CLL patient subgroups in the frontline and relapsed disease treatment setting,” author Jan-Paul Bohn, MD, PhD, of the department of internal medicine V, hematology and oncology, at Medical University of Innsbruck (Austria), reported in the review published in Memo, the Magazine of European Medical Oncology.

The options leave clinicians “spoilt for choice when selecting optimal therapy,” he said.

The three major drug classes to emerge – inhibitors of Bruton tyrosine kinase (BTK), antiapoptotic protein B-cell lymphoma 2 (BCL2) and phosphoinositide 3’-kinase (PI3K) – all appear similar in efficacy and tolerability.

Particularly in high-risk patients, the drugs have been so effective that the less desirable previous standard of “chemoimmunotherapy has widely faded into the background in the Western hemisphere,” Dr. Bohn wrote.

However, with caveats of the newer drugs including acquired resistances and potential toxicities, challenges have shifted to determining how to best juggle and/or combine the agents.
 

Frontline therapy

In terms of frontline options for CLL therapy, the BTK inhibitors, along with the BCL2 inhibitor venetoclax have been key in negating the need for chemotherapy, with some of the latest data showing superiority of venetoclax in combination with obinutuzumab (GVe) over chemotherapy even in the higher-risk subset of patients with mutated IGHV status and without TP53 disruption.

Hence, “chemoimmunotherapy may now even be questioned in the remaining subset of CLL patients with mutated IGHV status and without TP53 disruption,” Dr. Bohn reported.

That being said, the criteria for treatment choices in the frontline setting among the newer drug classes can often come down to the key issues of patients’ comorbidities and treatment preferences.

For example, in terms of patients who have higher risk because of tumor lysis syndrome (TLS), or issues including declining renal function, continuous BTK inhibitor treatment may be the preferred choice over the combination of venetoclax plus obinutuzumab (GVe), Dr. Bohn noted.

Conversely, for patients with cardiac comorbidities or a higher risk of bleeding, the GVe combination may be preferred over ibrutinib, with recent findings showing ibrutinib to be associated with as much as an 18-times higher risk of sudden unexplained death or cardiac death in young and fit patients who had preexisting arterial hypertension and/or a history of cardiac disorders requiring therapy.

For those with cardiac comorbidities, the more selective second-generation BTK inhibitor acalabrutinib is a potentially favorable alternative, as the drug is “at least similarly effective and more favorable in terms of tolerability, compared with ibrutinib, particularly as far as cardiac and bleeding side effects are considered,” Dr. Bohn said.

And in higher-risk cases involving TP53 dysfunction, a BTK inhibitor may be superior to GVe for frontline treatment, Dr. Bohn noted, with data showing progression-free survival in patients with and without deletion 17p to be significantly reduced with GVe versus the BTK inhibitor ibrutinib.
 

Relapsed and refractory disease

With similarly high efficacy observed with the new drug classes among relapsed and/or refractory patients, chemoimmunotherapy has likewise “become obsolete in nearly all patients naive to novel agents at relapse who typically present with genetically high-risk disease,” Dr. Bohn noted.

He wrote that most of the recommendations for frontline therapy hold true in the relapsed and refractory patients, with comorbidities and personal preferences again key drivers of treatment choices.

While data is currently limited regarding benefits of venetoclax-based regimens over BTK inhibitors in relapsed/refractory patients, there is “growing evidence suggesting similar clinical outcomes achievable with these agents in either order,” Dr. Bohn wrote.

Further recommendations regarding relapsed or refractory patients include:

• Among patients who do experience disease progression while on continuous treatment with BTK inhibitors, venetoclax-based regimes seem most effective. However, with relapse after venetoclax-based regimes, some growing evidence supports retreatment with the drug “depending on depth and duration of response achieved after first venetoclax exposure,” Dr. Bohn noted.
• For patients with deletion 17p, venetoclax shows promising efficacy during relapse when given as monotherapy until disease progression or occurrence of unacceptable toxicity.
• And for patients with TP53 abnormalities, the considerations are the same as for frontline therapy, with venetoclax showing promising efficacy when given in monotherapy until disease progression or occurrence of unacceptable toxicity.

Of note, PI3K inhibitors are generally not used in CLL patients naive to BTK and BCL2 inhibitors because of the higher risk of immune-mediated toxicities and infectious complications associated with the currently approved PI3K inhibitors idelalisib and duvelisib, he reported.

Nevertheless, “PI3K inhibitors remain a valuable therapeutic addition in patients refractory or intolerant to BTK inhibitors and venetoclax-based regimens,” Dr. Bohn said.
 

Newer agents, fixed duration

Commenting on the review, hematologist Seema A. Bhat, MD, an assistant professor with the Ohio State University Comprehensive Cancer Center, Columbus, said that the advances with targeted therapies in CLL are paying off with improved survival.

“With these recent advances in the treatment of CLL, especially the availability of targeted therapies, there has been an improvement in survival of patients with CLL, as the CLL-related death rate steadily reduced by approximately 3% per year between 2006 and 2015,” she said in an interview.

She added that even-newer agents in development, including the reversibly binding BTK inhibitor–like pirtobrutinib and nemtabrutinib, when approved, will further add to the treatment choices for patients.

Meanwhile, a key area of focus is the combination of BTK inhibitors and BCL2 inhibitors, specifically for a fixed duration of time to obtain a deeper response and hence possibility a time-limited therapy, she noted. “We are also excited about the possibility of having more fixed-duration treatments available for our patients, which will make their treatment journey less troublesome, both physically as well as financially.”

Dr. Bohn reported receiving personal fees from AbbVie, AstraZeneca and Janssen for advisory board participation. Dr. Bhat has served on advisory board for AstraZeneca and received honorarium from them.

With an abundance of targeted therapies transforming the treatment landscape for chronic lymphocytic leukemia (CLL), picking the optimal drug or drug sequence for the right situation can be a challenge, but emerging data is helping guide clinicians facing the “agony of choice,” a new review reports.

“Targeted therapies have outnumbered chemoimmunotherapy-based treatment approaches, demonstrating superior efficacy and tolerability profiles across nearly all CLL patient subgroups in the frontline and relapsed disease treatment setting,” author Jan-Paul Bohn, MD, PhD, of the department of internal medicine V, hematology and oncology, at Medical University of Innsbruck (Austria), reported in the review published in Memo, the Magazine of European Medical Oncology.

The options leave clinicians “spoilt for choice when selecting optimal therapy,” he said.

The three major drug classes to emerge – inhibitors of Bruton tyrosine kinase (BTK), antiapoptotic protein B-cell lymphoma 2 (BCL2) and phosphoinositide 3’-kinase (PI3K) – all appear similar in efficacy and tolerability.

Particularly in high-risk patients, the drugs have been so effective that the less desirable previous standard of “chemoimmunotherapy has widely faded into the background in the Western hemisphere,” Dr. Bohn wrote.

However, with caveats of the newer drugs including acquired resistances and potential toxicities, challenges have shifted to determining how to best juggle and/or combine the agents.
 

Frontline therapy

In terms of frontline options for CLL therapy, the BTK inhibitors, along with the BCL2 inhibitor venetoclax have been key in negating the need for chemotherapy, with some of the latest data showing superiority of venetoclax in combination with obinutuzumab (GVe) over chemotherapy even in the higher-risk subset of patients with mutated IGHV status and without TP53 disruption.

Hence, “chemoimmunotherapy may now even be questioned in the remaining subset of CLL patients with mutated IGHV status and without TP53 disruption,” Dr. Bohn reported.

That being said, the criteria for treatment choices in the frontline setting among the newer drug classes can often come down to the key issues of patients’ comorbidities and treatment preferences.

For example, in terms of patients who have higher risk because of tumor lysis syndrome (TLS), or issues including declining renal function, continuous BTK inhibitor treatment may be the preferred choice over the combination of venetoclax plus obinutuzumab (GVe), Dr. Bohn noted.

Conversely, for patients with cardiac comorbidities or a higher risk of bleeding, the GVe combination may be preferred over ibrutinib, with recent findings showing ibrutinib to be associated with as much as an 18-times higher risk of sudden unexplained death or cardiac death in young and fit patients who had preexisting arterial hypertension and/or a history of cardiac disorders requiring therapy.

For those with cardiac comorbidities, the more selective second-generation BTK inhibitor acalabrutinib is a potentially favorable alternative, as the drug is “at least similarly effective and more favorable in terms of tolerability, compared with ibrutinib, particularly as far as cardiac and bleeding side effects are considered,” Dr. Bohn said.

And in higher-risk cases involving TP53 dysfunction, a BTK inhibitor may be superior to GVe for frontline treatment, Dr. Bohn noted, with data showing progression-free survival in patients with and without deletion 17p to be significantly reduced with GVe versus the BTK inhibitor ibrutinib.
 

Relapsed and refractory disease

With similarly high efficacy observed with the new drug classes among relapsed and/or refractory patients, chemoimmunotherapy has likewise “become obsolete in nearly all patients naive to novel agents at relapse who typically present with genetically high-risk disease,” Dr. Bohn noted.

He wrote that most of the recommendations for frontline therapy hold true in the relapsed and refractory patients, with comorbidities and personal preferences again key drivers of treatment choices.

While data is currently limited regarding benefits of venetoclax-based regimens over BTK inhibitors in relapsed/refractory patients, there is “growing evidence suggesting similar clinical outcomes achievable with these agents in either order,” Dr. Bohn wrote.

Further recommendations regarding relapsed or refractory patients include:

• Among patients who do experience disease progression while on continuous treatment with BTK inhibitors, venetoclax-based regimes seem most effective. However, with relapse after venetoclax-based regimes, some growing evidence supports retreatment with the drug “depending on depth and duration of response achieved after first venetoclax exposure,” Dr. Bohn noted.
• For patients with deletion 17p, venetoclax shows promising efficacy during relapse when given as monotherapy until disease progression or occurrence of unacceptable toxicity.
• And for patients with TP53 abnormalities, the considerations are the same as for frontline therapy, with venetoclax showing promising efficacy when given in monotherapy until disease progression or occurrence of unacceptable toxicity.

Of note, PI3K inhibitors are generally not used in CLL patients naive to BTK and BCL2 inhibitors because of the higher risk of immune-mediated toxicities and infectious complications associated with the currently approved PI3K inhibitors idelalisib and duvelisib, he reported.

Nevertheless, “PI3K inhibitors remain a valuable therapeutic addition in patients refractory or intolerant to BTK inhibitors and venetoclax-based regimens,” Dr. Bohn said.
 

Newer agents, fixed duration

Commenting on the review, hematologist Seema A. Bhat, MD, an assistant professor with the Ohio State University Comprehensive Cancer Center, Columbus, said that the advances with targeted therapies in CLL are paying off with improved survival.

“With these recent advances in the treatment of CLL, especially the availability of targeted therapies, there has been an improvement in survival of patients with CLL, as the CLL-related death rate steadily reduced by approximately 3% per year between 2006 and 2015,” she said in an interview.

She added that even-newer agents in development, including the reversibly binding BTK inhibitor–like pirtobrutinib and nemtabrutinib, when approved, will further add to the treatment choices for patients.

Meanwhile, a key area of focus is the combination of BTK inhibitors and BCL2 inhibitors, specifically for a fixed duration of time to obtain a deeper response and hence possibility a time-limited therapy, she noted. “We are also excited about the possibility of having more fixed-duration treatments available for our patients, which will make their treatment journey less troublesome, both physically as well as financially.”

Dr. Bohn reported receiving personal fees from AbbVie, AstraZeneca and Janssen for advisory board participation. Dr. Bhat has served on advisory board for AstraZeneca and received honorarium from them.

With an abundance of targeted therapies transforming the treatment landscape for chronic lymphocytic leukemia (CLL), picking the optimal drug or drug sequence for the right situation can be a challenge, but emerging data is helping guide clinicians facing the “agony of choice,” a new review reports.

“Targeted therapies have outnumbered chemoimmunotherapy-based treatment approaches, demonstrating superior efficacy and tolerability profiles across nearly all CLL patient subgroups in the frontline and relapsed disease treatment setting,” author Jan-Paul Bohn, MD, PhD, of the department of internal medicine V, hematology and oncology, at Medical University of Innsbruck (Austria), reported in the review published in Memo, the Magazine of European Medical Oncology.

The options leave clinicians “spoilt for choice when selecting optimal therapy,” he said.

The three major drug classes to emerge – inhibitors of Bruton tyrosine kinase (BTK), antiapoptotic protein B-cell lymphoma 2 (BCL2) and phosphoinositide 3’-kinase (PI3K) – all appear similar in efficacy and tolerability.

Particularly in high-risk patients, the drugs have been so effective that the less desirable previous standard of “chemoimmunotherapy has widely faded into the background in the Western hemisphere,” Dr. Bohn wrote.

However, with caveats of the newer drugs including acquired resistances and potential toxicities, challenges have shifted to determining how to best juggle and/or combine the agents.
 

Frontline therapy

In terms of frontline options for CLL therapy, the BTK inhibitors, along with the BCL2 inhibitor venetoclax have been key in negating the need for chemotherapy, with some of the latest data showing superiority of venetoclax in combination with obinutuzumab (GVe) over chemotherapy even in the higher-risk subset of patients with mutated IGHV status and without TP53 disruption.

Hence, “chemoimmunotherapy may now even be questioned in the remaining subset of CLL patients with mutated IGHV status and without TP53 disruption,” Dr. Bohn reported.

That being said, the criteria for treatment choices in the frontline setting among the newer drug classes can often come down to the key issues of patients’ comorbidities and treatment preferences.

For example, in terms of patients who have higher risk because of tumor lysis syndrome (TLS), or issues including declining renal function, continuous BTK inhibitor treatment may be the preferred choice over the combination of venetoclax plus obinutuzumab (GVe), Dr. Bohn noted.

Conversely, for patients with cardiac comorbidities or a higher risk of bleeding, the GVe combination may be preferred over ibrutinib, with recent findings showing ibrutinib to be associated with as much as an 18-times higher risk of sudden unexplained death or cardiac death in young and fit patients who had preexisting arterial hypertension and/or a history of cardiac disorders requiring therapy.

For those with cardiac comorbidities, the more selective second-generation BTK inhibitor acalabrutinib is a potentially favorable alternative, as the drug is “at least similarly effective and more favorable in terms of tolerability, compared with ibrutinib, particularly as far as cardiac and bleeding side effects are considered,” Dr. Bohn said.

And in higher-risk cases involving TP53 dysfunction, a BTK inhibitor may be superior to GVe for frontline treatment, Dr. Bohn noted, with data showing progression-free survival in patients with and without deletion 17p to be significantly reduced with GVe versus the BTK inhibitor ibrutinib.
 

Relapsed and refractory disease

With similarly high efficacy observed with the new drug classes among relapsed and/or refractory patients, chemoimmunotherapy has likewise “become obsolete in nearly all patients naive to novel agents at relapse who typically present with genetically high-risk disease,” Dr. Bohn noted.

He wrote that most of the recommendations for frontline therapy hold true in the relapsed and refractory patients, with comorbidities and personal preferences again key drivers of treatment choices.

While data is currently limited regarding benefits of venetoclax-based regimens over BTK inhibitors in relapsed/refractory patients, there is “growing evidence suggesting similar clinical outcomes achievable with these agents in either order,” Dr. Bohn wrote.

Further recommendations regarding relapsed or refractory patients include:

• Among patients who do experience disease progression while on continuous treatment with BTK inhibitors, venetoclax-based regimes seem most effective. However, with relapse after venetoclax-based regimes, some growing evidence supports retreatment with the drug “depending on depth and duration of response achieved after first venetoclax exposure,” Dr. Bohn noted.
• For patients with deletion 17p, venetoclax shows promising efficacy during relapse when given as monotherapy until disease progression or occurrence of unacceptable toxicity.
• And for patients with TP53 abnormalities, the considerations are the same as for frontline therapy, with venetoclax showing promising efficacy when given in monotherapy until disease progression or occurrence of unacceptable toxicity.

Of note, PI3K inhibitors are generally not used in CLL patients naive to BTK and BCL2 inhibitors because of the higher risk of immune-mediated toxicities and infectious complications associated with the currently approved PI3K inhibitors idelalisib and duvelisib, he reported.

Nevertheless, “PI3K inhibitors remain a valuable therapeutic addition in patients refractory or intolerant to BTK inhibitors and venetoclax-based regimens,” Dr. Bohn said.
 

Newer agents, fixed duration

Commenting on the review, hematologist Seema A. Bhat, MD, an assistant professor with the Ohio State University Comprehensive Cancer Center, Columbus, said that the advances with targeted therapies in CLL are paying off with improved survival.

“With these recent advances in the treatment of CLL, especially the availability of targeted therapies, there has been an improvement in survival of patients with CLL, as the CLL-related death rate steadily reduced by approximately 3% per year between 2006 and 2015,” she said in an interview.

She added that even-newer agents in development, including the reversibly binding BTK inhibitor–like pirtobrutinib and nemtabrutinib, when approved, will further add to the treatment choices for patients.

Meanwhile, a key area of focus is the combination of BTK inhibitors and BCL2 inhibitors, specifically for a fixed duration of time to obtain a deeper response and hence possibility a time-limited therapy, she noted. “We are also excited about the possibility of having more fixed-duration treatments available for our patients, which will make their treatment journey less troublesome, both physically as well as financially.”

Dr. Bohn reported receiving personal fees from AbbVie, AstraZeneca and Janssen for advisory board participation. Dr. Bhat has served on advisory board for AstraZeneca and received honorarium from them.

Physician assistants (PAs) entered dermatology at a higher rate than all other specialties combined from 2013 to 2018, based on national certification data.

Dermatology added PAs at a mean rate of 11.6% annually over that 6-year period, compared with a mean of 7.8% for all other specialties (P <.001), as the National Commission on Certification of Physician Assistants (NCCPA) tallied 2,324 working in dermatology and 64,490 in all other specialties in 2013 and 3,938/94,616, respectively, in 2018, Justin D. Arnold, MD, of the University of California, Irvine, and associates reported in JAMA Dermatology.

“There is, however, a lack of racial and ethnic diversity within the dermatology PA workforce,” they noted. A detailed comparison using the 2018 data showed that only 1.6% of dermatology PAs identified as Black, compared with 3.7% of those in all other specialties (P <.001), although “similar rates of Hispanic ethnicity were observed” in dermatology PAs (6.0%) and PAs in other fields (6.5%), the investigators added.

That was not the case for women in the profession, as 82% of PAs in dermatology were female in 2018, compared with 67% in the other specialties. Dermatology PAs also were significantly more likely to work in office-based practices than their nondermatology peers (93% vs. 37%, P < .001) and to reside in metropolitan areas (95% vs. 92%, P < .001), Dr. Arnold and associates said in the research letter.

The dermatology PAs also were more likely to work part time (30 or fewer hours per week) than those outside dermatology, 19.1% vs. 12.9% (P < .001). Despite that, the dermatology PAs reported seeing more patients per week (a mean of 119) than those in all of the other specialties (a mean of 71), the investigators said.

The total number of certified PAs was over 131,000 in 2018, but about 25% had not selected a principal specialty in their PA Professional Profiles and were not included in the study, they explained.

“Although this study did not assess the reasons for the substantial increase of dermatology PAs, numerous factors, such as a potential physician shortage or the expansion of private equity–owned practices, may contribute to the accelerating use of PAs within the field,” they wrote.

Physician assistants (PAs) entered dermatology at a higher rate than all other specialties combined from 2013 to 2018, based on national certification data.

Dermatology added PAs at a mean rate of 11.6% annually over that 6-year period, compared with a mean of 7.8% for all other specialties (P <.001), as the National Commission on Certification of Physician Assistants (NCCPA) tallied 2,324 working in dermatology and 64,490 in all other specialties in 2013 and 3,938/94,616, respectively, in 2018, Justin D. Arnold, MD, of the University of California, Irvine, and associates reported in JAMA Dermatology.

“There is, however, a lack of racial and ethnic diversity within the dermatology PA workforce,” they noted. A detailed comparison using the 2018 data showed that only 1.6% of dermatology PAs identified as Black, compared with 3.7% of those in all other specialties (P <.001), although “similar rates of Hispanic ethnicity were observed” in dermatology PAs (6.0%) and PAs in other fields (6.5%), the investigators added.

That was not the case for women in the profession, as 82% of PAs in dermatology were female in 2018, compared with 67% in the other specialties. Dermatology PAs also were significantly more likely to work in office-based practices than their nondermatology peers (93% vs. 37%, P < .001) and to reside in metropolitan areas (95% vs. 92%, P < .001), Dr. Arnold and associates said in the research letter.

The dermatology PAs also were more likely to work part time (30 or fewer hours per week) than those outside dermatology, 19.1% vs. 12.9% (P < .001). Despite that, the dermatology PAs reported seeing more patients per week (a mean of 119) than those in all of the other specialties (a mean of 71), the investigators said.

The total number of certified PAs was over 131,000 in 2018, but about 25% had not selected a principal specialty in their PA Professional Profiles and were not included in the study, they explained.

“Although this study did not assess the reasons for the substantial increase of dermatology PAs, numerous factors, such as a potential physician shortage or the expansion of private equity–owned practices, may contribute to the accelerating use of PAs within the field,” they wrote.

Physician assistants (PAs) entered dermatology at a higher rate than all other specialties combined from 2013 to 2018, based on national certification data.

Dermatology added PAs at a mean rate of 11.6% annually over that 6-year period, compared with a mean of 7.8% for all other specialties (P <.001), as the National Commission on Certification of Physician Assistants (NCCPA) tallied 2,324 working in dermatology and 64,490 in all other specialties in 2013 and 3,938/94,616, respectively, in 2018, Justin D. Arnold, MD, of the University of California, Irvine, and associates reported in JAMA Dermatology.

“There is, however, a lack of racial and ethnic diversity within the dermatology PA workforce,” they noted. A detailed comparison using the 2018 data showed that only 1.6% of dermatology PAs identified as Black, compared with 3.7% of those in all other specialties (P <.001), although “similar rates of Hispanic ethnicity were observed” in dermatology PAs (6.0%) and PAs in other fields (6.5%), the investigators added.

That was not the case for women in the profession, as 82% of PAs in dermatology were female in 2018, compared with 67% in the other specialties. Dermatology PAs also were significantly more likely to work in office-based practices than their nondermatology peers (93% vs. 37%, P < .001) and to reside in metropolitan areas (95% vs. 92%, P < .001), Dr. Arnold and associates said in the research letter.

The dermatology PAs also were more likely to work part time (30 or fewer hours per week) than those outside dermatology, 19.1% vs. 12.9% (P < .001). Despite that, the dermatology PAs reported seeing more patients per week (a mean of 119) than those in all of the other specialties (a mean of 71), the investigators said.

The total number of certified PAs was over 131,000 in 2018, but about 25% had not selected a principal specialty in their PA Professional Profiles and were not included in the study, they explained.

“Although this study did not assess the reasons for the substantial increase of dermatology PAs, numerous factors, such as a potential physician shortage or the expansion of private equity–owned practices, may contribute to the accelerating use of PAs within the field,” they wrote.

THE CASE

A 43-year-old Black male presented to his primary care physician with an 8-month history of progressive fatigue, weakness, and unintentional weight loss. The patient’s history also included antiphospholipid antibody syndrome (APS) with prior deep venous thrombosis/­pulmonary embolism for which he was taking warfarin.

At the time of presentation, he reported profound dyspnea on exertion, lightheadedness, dry mouth, low back pain, and worsening nocturia. The remainder of the review of systems was negative. He denied tobacco, alcohol, or illicit drug use or recent travel. His personal and family histories were negative for cancer.

Laboratory data collected during the outpatient visit were notable for a white blood cell count of 2300/mcL (reference range, 4000-11,000/mcL); hemoglobin, 8.6 g/dL (13.5-17.5 g/dL); and platelets, 44,000/mcL (150,000-400,000/mcL). Proteinuria was indicated by a measurement > 500 mg/dL on urine dipstick.

The patient was admitted to the hospital for further work-up of new pancytopenia. His vital signs on admission were notable for tachycardia and a weight of 237 lbs, decreased from 283 lbs 8 months prior. His physical exam revealed dry mucous membranes, bruising of fingertips, and marked lower extremity weakness with preserved sensation. No lymphadenopathy was noted on the admission physical exam.

THE DIAGNOSIS

Inpatient laboratory studies showed elevated inflammatory markers and a positive Coombs test with low haptoglobin. There was no evidence of bacterial or viral infection. Computed tomography of the chest, abdomen, and pelvis revealed axillary, subpectoral, and pelvic lymphadenopathy (see FIGURE). A work-up for multiple myeloma was negative, and a bone marrow biopsy was nondiagnostic.

Autoimmune laboratory data included a positive antiphospholipid antibody (ANA) test (1:10,240, diffuse; reference < 1:160), an elevated dsDNA antibody level (800 IU/mL; reference range, 0-99 IU/mL), low complement levels, and antibody titers consistent with the patient’s known APS. Based on these findings, the patient was given a diagnosis of systemic lupus erythematosus (SLE).

DISCUSSION

Lymphadenopathy, revealed by exam or by imaging, in combination with systemic symptoms such as weight loss and fatigue, elicits an extensive differential diagnosis. In the absence of recent exposures, travel, or risk factors for infectious causes, our patient’s work-up was appropriately narrowed to noninfectious etiologies of pancytopenia and lymphadenopathy. At the top of this differential are malignancies—in particular, multiple myeloma and lymphoma—and rheumatologic processes, such as sarcoidosis, connective tissue disease, and SLE.^1,2 Ultimately, the combination of autoimmune markers with the pancytopenia and a negative work-up for malignancy confirmed a diagnosis of SLE.

Continue to: SLE classification and generalized lymphadenopathy

SLE classification and generalized lymphadenopathy. SLE is a multisystem inflammatory process with a wide spectrum of clinical presentations. The American College of Rheumatology (ACR) has established validated criteria to aid in the diagnosis of SLE,³ which were most recently updated in 2012 to improve clinical utility. For a diagnosis to be made, at least 1 clinical and 1 immunologic criterion must be present or a renal biopsy must show lupus nephritis.³

Notably, lymphadenopathy is not included in this validated model, despite its occurrence in 25% to 50% of patients with SLE.^1,3,4 With this in mind, SLE should be considered in the work-up of generalized lymphadenopathy.

ANA and SLE. Although it is estimated that 30% to 40% of patients with SLE test positive for ANA,⁵ the presence of ANA also is not part of the diagnostic criteria for SLE. Interestingly, the co-occurrence of the 2 has clinical implications for patients. In particular, patients with SLE and a positive ANA have higher prevalence of thrombosis, valvular disease, thrombocytopenia, and hemolytic anemia, among other complications.⁵ Although our patient’s presentation of thrombocytopenia and hemolysis clouded the initial work-up, such a combination is consistent with co-presentation of SLE and APS.

Differences in sex, age, and race. SLE is more common in women than in men, with a prevalence ratio of 7:1.⁶ It is estimated that 65% of patients with SLE experience disease onset between the ages of 16 and 55 years.⁷

The median age of diagnosis also differs based on sex and race: According to Rus et al,⁸ the typical age ranges are 37 to 50 years for White women; 50 to 59 for White men; 15 to 44 for Black women; and 45 to 64 for Black men. These estimates of incidence stratified by race, sex, and age can be helpful when evaluating patients with confusing clinical presentations. Our patient’s age was consistent with the median for his sex and race.

Continue to: Our patient

Our patient was started on oral prednisone 60 mg/d with plans for a prolonged taper over 6 months under the close supervision of Rheumatology. His weakness and polyuria began to improve within a month, and lupus-­related symptoms resolved within 3 months. His cytopenia also significantly improved, with the exception of refractory thrombocytopenia.

THE TAKEAWAY

SLE is a common diagnosis with multiple presentations. Although lymphadenopathy is not part of the clinical criteria for the diagnosis of SLE, multiple case studies have highlighted its prevalence among affected patients.^1,2,4,9-17 APS and antiphospholipid antibodies are also absent in the diagnostic criteria despite being highly associated with SLE. Thus, co-­presentation (as well as age and sex) can be helpful with both disease stratification and risk assessment once a diagnosis is made.

CORRESPONDENCE
Isabella Buzzo Bellon Brout, MD, 409 West Broadway, Boston, MA 02127; [email protected]

THE CASE

A 43-year-old Black male presented to his primary care physician with an 8-month history of progressive fatigue, weakness, and unintentional weight loss. The patient’s history also included antiphospholipid antibody syndrome (APS) with prior deep venous thrombosis/­pulmonary embolism for which he was taking warfarin.

At the time of presentation, he reported profound dyspnea on exertion, lightheadedness, dry mouth, low back pain, and worsening nocturia. The remainder of the review of systems was negative. He denied tobacco, alcohol, or illicit drug use or recent travel. His personal and family histories were negative for cancer.

Laboratory data collected during the outpatient visit were notable for a white blood cell count of 2300/mcL (reference range, 4000-11,000/mcL); hemoglobin, 8.6 g/dL (13.5-17.5 g/dL); and platelets, 44,000/mcL (150,000-400,000/mcL). Proteinuria was indicated by a measurement > 500 mg/dL on urine dipstick.

The patient was admitted to the hospital for further work-up of new pancytopenia. His vital signs on admission were notable for tachycardia and a weight of 237 lbs, decreased from 283 lbs 8 months prior. His physical exam revealed dry mucous membranes, bruising of fingertips, and marked lower extremity weakness with preserved sensation. No lymphadenopathy was noted on the admission physical exam.

THE DIAGNOSIS

Inpatient laboratory studies showed elevated inflammatory markers and a positive Coombs test with low haptoglobin. There was no evidence of bacterial or viral infection. Computed tomography of the chest, abdomen, and pelvis revealed axillary, subpectoral, and pelvic lymphadenopathy (see FIGURE). A work-up for multiple myeloma was negative, and a bone marrow biopsy was nondiagnostic.

Autoimmune laboratory data included a positive antiphospholipid antibody (ANA) test (1:10,240, diffuse; reference < 1:160), an elevated dsDNA antibody level (800 IU/mL; reference range, 0-99 IU/mL), low complement levels, and antibody titers consistent with the patient’s known APS. Based on these findings, the patient was given a diagnosis of systemic lupus erythematosus (SLE).

DISCUSSION

Lymphadenopathy, revealed by exam or by imaging, in combination with systemic symptoms such as weight loss and fatigue, elicits an extensive differential diagnosis. In the absence of recent exposures, travel, or risk factors for infectious causes, our patient’s work-up was appropriately narrowed to noninfectious etiologies of pancytopenia and lymphadenopathy. At the top of this differential are malignancies—in particular, multiple myeloma and lymphoma—and rheumatologic processes, such as sarcoidosis, connective tissue disease, and SLE.^1,2 Ultimately, the combination of autoimmune markers with the pancytopenia and a negative work-up for malignancy confirmed a diagnosis of SLE.

Continue to: SLE classification and generalized lymphadenopathy

SLE classification and generalized lymphadenopathy. SLE is a multisystem inflammatory process with a wide spectrum of clinical presentations. The American College of Rheumatology (ACR) has established validated criteria to aid in the diagnosis of SLE,³ which were most recently updated in 2012 to improve clinical utility. For a diagnosis to be made, at least 1 clinical and 1 immunologic criterion must be present or a renal biopsy must show lupus nephritis.³

Notably, lymphadenopathy is not included in this validated model, despite its occurrence in 25% to 50% of patients with SLE.^1,3,4 With this in mind, SLE should be considered in the work-up of generalized lymphadenopathy.

ANA and SLE. Although it is estimated that 30% to 40% of patients with SLE test positive for ANA,⁵ the presence of ANA also is not part of the diagnostic criteria for SLE. Interestingly, the co-occurrence of the 2 has clinical implications for patients. In particular, patients with SLE and a positive ANA have higher prevalence of thrombosis, valvular disease, thrombocytopenia, and hemolytic anemia, among other complications.⁵ Although our patient’s presentation of thrombocytopenia and hemolysis clouded the initial work-up, such a combination is consistent with co-presentation of SLE and APS.

Differences in sex, age, and race. SLE is more common in women than in men, with a prevalence ratio of 7:1.⁶ It is estimated that 65% of patients with SLE experience disease onset between the ages of 16 and 55 years.⁷

The median age of diagnosis also differs based on sex and race: According to Rus et al,⁸ the typical age ranges are 37 to 50 years for White women; 50 to 59 for White men; 15 to 44 for Black women; and 45 to 64 for Black men. These estimates of incidence stratified by race, sex, and age can be helpful when evaluating patients with confusing clinical presentations. Our patient’s age was consistent with the median for his sex and race.

Continue to: Our patient

Our patient was started on oral prednisone 60 mg/d with plans for a prolonged taper over 6 months under the close supervision of Rheumatology. His weakness and polyuria began to improve within a month, and lupus-­related symptoms resolved within 3 months. His cytopenia also significantly improved, with the exception of refractory thrombocytopenia.

THE TAKEAWAY

SLE is a common diagnosis with multiple presentations. Although lymphadenopathy is not part of the clinical criteria for the diagnosis of SLE, multiple case studies have highlighted its prevalence among affected patients.^1,2,4,9-17 APS and antiphospholipid antibodies are also absent in the diagnostic criteria despite being highly associated with SLE. Thus, co-­presentation (as well as age and sex) can be helpful with both disease stratification and risk assessment once a diagnosis is made.

CORRESPONDENCE
Isabella Buzzo Bellon Brout, MD, 409 West Broadway, Boston, MA 02127; [email protected]

THE CASE

A 43-year-old Black male presented to his primary care physician with an 8-month history of progressive fatigue, weakness, and unintentional weight loss. The patient’s history also included antiphospholipid antibody syndrome (APS) with prior deep venous thrombosis/­pulmonary embolism for which he was taking warfarin.

At the time of presentation, he reported profound dyspnea on exertion, lightheadedness, dry mouth, low back pain, and worsening nocturia. The remainder of the review of systems was negative. He denied tobacco, alcohol, or illicit drug use or recent travel. His personal and family histories were negative for cancer.

Laboratory data collected during the outpatient visit were notable for a white blood cell count of 2300/mcL (reference range, 4000-11,000/mcL); hemoglobin, 8.6 g/dL (13.5-17.5 g/dL); and platelets, 44,000/mcL (150,000-400,000/mcL). Proteinuria was indicated by a measurement > 500 mg/dL on urine dipstick.

The patient was admitted to the hospital for further work-up of new pancytopenia. His vital signs on admission were notable for tachycardia and a weight of 237 lbs, decreased from 283 lbs 8 months prior. His physical exam revealed dry mucous membranes, bruising of fingertips, and marked lower extremity weakness with preserved sensation. No lymphadenopathy was noted on the admission physical exam.

THE DIAGNOSIS

Inpatient laboratory studies showed elevated inflammatory markers and a positive Coombs test with low haptoglobin. There was no evidence of bacterial or viral infection. Computed tomography of the chest, abdomen, and pelvis revealed axillary, subpectoral, and pelvic lymphadenopathy (see FIGURE). A work-up for multiple myeloma was negative, and a bone marrow biopsy was nondiagnostic.

Autoimmune laboratory data included a positive antiphospholipid antibody (ANA) test (1:10,240, diffuse; reference < 1:160), an elevated dsDNA antibody level (800 IU/mL; reference range, 0-99 IU/mL), low complement levels, and antibody titers consistent with the patient’s known APS. Based on these findings, the patient was given a diagnosis of systemic lupus erythematosus (SLE).

DISCUSSION

Lymphadenopathy, revealed by exam or by imaging, in combination with systemic symptoms such as weight loss and fatigue, elicits an extensive differential diagnosis. In the absence of recent exposures, travel, or risk factors for infectious causes, our patient’s work-up was appropriately narrowed to noninfectious etiologies of pancytopenia and lymphadenopathy. At the top of this differential are malignancies—in particular, multiple myeloma and lymphoma—and rheumatologic processes, such as sarcoidosis, connective tissue disease, and SLE.^1,2 Ultimately, the combination of autoimmune markers with the pancytopenia and a negative work-up for malignancy confirmed a diagnosis of SLE.

Continue to: SLE classification and generalized lymphadenopathy

SLE classification and generalized lymphadenopathy. SLE is a multisystem inflammatory process with a wide spectrum of clinical presentations. The American College of Rheumatology (ACR) has established validated criteria to aid in the diagnosis of SLE,³ which were most recently updated in 2012 to improve clinical utility. For a diagnosis to be made, at least 1 clinical and 1 immunologic criterion must be present or a renal biopsy must show lupus nephritis.³

Notably, lymphadenopathy is not included in this validated model, despite its occurrence in 25% to 50% of patients with SLE.^1,3,4 With this in mind, SLE should be considered in the work-up of generalized lymphadenopathy.

ANA and SLE. Although it is estimated that 30% to 40% of patients with SLE test positive for ANA,⁵ the presence of ANA also is not part of the diagnostic criteria for SLE. Interestingly, the co-occurrence of the 2 has clinical implications for patients. In particular, patients with SLE and a positive ANA have higher prevalence of thrombosis, valvular disease, thrombocytopenia, and hemolytic anemia, among other complications.⁵ Although our patient’s presentation of thrombocytopenia and hemolysis clouded the initial work-up, such a combination is consistent with co-presentation of SLE and APS.

Differences in sex, age, and race. SLE is more common in women than in men, with a prevalence ratio of 7:1.⁶ It is estimated that 65% of patients with SLE experience disease onset between the ages of 16 and 55 years.⁷

The median age of diagnosis also differs based on sex and race: According to Rus et al,⁸ the typical age ranges are 37 to 50 years for White women; 50 to 59 for White men; 15 to 44 for Black women; and 45 to 64 for Black men. These estimates of incidence stratified by race, sex, and age can be helpful when evaluating patients with confusing clinical presentations. Our patient’s age was consistent with the median for his sex and race.

Continue to: Our patient

Our patient was started on oral prednisone 60 mg/d with plans for a prolonged taper over 6 months under the close supervision of Rheumatology. His weakness and polyuria began to improve within a month, and lupus-­related symptoms resolved within 3 months. His cytopenia also significantly improved, with the exception of refractory thrombocytopenia.

THE TAKEAWAY

SLE is a common diagnosis with multiple presentations. Although lymphadenopathy is not part of the clinical criteria for the diagnosis of SLE, multiple case studies have highlighted its prevalence among affected patients.^1,2,4,9-17 APS and antiphospholipid antibodies are also absent in the diagnostic criteria despite being highly associated with SLE. Thus, co-­presentation (as well as age and sex) can be helpful with both disease stratification and risk assessment once a diagnosis is made.

CORRESPONDENCE
Isabella Buzzo Bellon Brout, MD, 409 West Broadway, Boston, MA 02127; [email protected]

An 83-year-old woman, with an otherwise noncontributory past medical history, presented with chronic right knee pain. Over the prior 4 years, she had undergone evaluation by an outside physician and received several corticosteroid and hyaluronic acid intra-­articular injections, without symptom resolution. She described the pain as a 4/10 at rest and as “severe” when climbing stairs and exercising. The pain was localized to her lower back and right groin and extended to her right knee. She also said that she found it difficult to put on her socks. An outside orthopedic surgeon recommended right total knee arthroplasty, prompting her to seek a second opinion.

Examination of her right knee was unrevealing. However, during the hip examination, there was a pronounced loss of range of motion and concordant pain reproduction with the FABER (combined flexion, abduction, external rotation) and FADIR (combined flexion, adduction, and internal rotation) maneuvers.

The patient’s extensive clinical and diagnostic history, combined with benign knee examination and imaging (FIGURE 1), ruled out isolated knee pathology.

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

The patient’s history and physical exam prompted us to suspect right hip osteoarthritis (OA) with referred pain to the right knee. This suspicion was confirmed with hip radiographs (FIGURE 2), which revealed significant OA of the right hip, as evidenced by marked joint space narrowing, subchondral sclerosis, and osteophytes. There was also superior migration of the right femoral head relative to the acetabulum. Additionally, there was loss of sphericity of the right femoral head, suggesting avascular necrosis with collapse.

Hip and knee OA are among the most common causes of disability worldwide. Knee and hip pain are estimated to affect up to 27% and 15% of the general population, respectively.^1,2 Referred knee pain secondary to hip pathology, also known as atypical knee pain, has been cited at highly variable rates, ranging from 2% to 27%.³

Eighty-six percent of patients with atypical knee pain experience a delay in diagnosis of more than 1 year.⁴ Half of these patients require the use of a wheelchair or walker for community navigation.⁴ These findings highlight the impact that a delay in diagnosis can have on the day-to-day quality of life for these patients. Also, delayed or missed diagnoses may have contributed to the doubling in the rate of knee replacement surgery from 2000 to 2010 and the reports that up to one-third of knee replacement surgeries did not meet appropriate criteria to be performed.^5,6

Convergence confusion

Referred pain is likely explained by the convergence of nociceptive and non-nociceptive nerve fibers.⁷ Both of these fiber types conduct action potentials that terminate at second order neurons. Occasionally, nociceptive nerve fibers from different parts of the body (ie, knee and hip) terminate at the same second order fiber. At this point of convergence, higher brain centers lose their ability to discriminate the anatomic location of origin. This results in the perception of pain in a different location, where there is no intrinsic pathology.

Patients with hip OA report that the most common locations of pain are the groin, anterior thigh, buttock, anterior knee, and greater trochanter.³ One small study revealed that 85% of patients with referred pain who underwent total hip arthroplasty (THA) reported complete resolution of pain symptoms within 4 days of the procedure.³

Continue to: A comprehensive exam can reveal a different origin of pain

A comprehensive exam can reveal a different origin of pain

As with any musculoskeletal complaint, history and physical examination should include a focus on the joints proximal and distal to the purported joint of concern. When the hip is in consideration, historical inquiry should focus on degree and timeline of pain, stiffness, and traumatic history. Our patient reported difficulty donning socks, an excellent screening question to evaluate loss of range of motion in the hip. On physical examination, the FABER and FADIR maneuvers are quite specific to hip OA. A comprehensive list of history and physical examination findings can be found in the TABLE.

The differential includes a broad range of musculoskeletal diagnoses

The differential diagnosis for knee pain includes knee OA, spinopelvic pathology, infection, and rheumatologic disease.

Knee OA can be confirmed with knee radiographs, but one must also assess the joint above and below, as with all musculoskeletal complaints.

Spinopelvic pathology may be established with radiographs and a thorough nervous system exam.

Infection, such as septic arthritis or gout, can be diagnosed through radiographs, physical exam, and lab tests to evaluate white blood cell count, erythrocyte sedimentation rate, and C-reactive protein levels. High clinical suspicion may warrant a joint aspiration.

Continue to: Rheumatologic disease

Rheumatologic disease can be evaluated with a comprehensive physical exam, as well as lab work.

Management includes both surgical and nonsurgical options

Hip OA can be managed much like OA in other areas of the body. The Osteoarthritis Research Society International guidelines provide direction and insight concerning outpatient nonsurgical management.⁸ Weight loss and land-based, low-impact exercise programs are excellent first-line options. Second-line therapies include symptomatic management with systemic nonsteroidal anti-inflammatory drugs (NSAIDs) in patients without contraindications. (Topical NSAIDs, while useful in the treatment of knee OA, are not as effective for hip OA due to thickness of soft tissue in this area of the body.)

Patients who do not achieve symptomatic relief with these first- and second-line therapies may benefit from other nonoperative measures, such as intra-articular corticosteroid injections. If pain persists, patients may need a referral to an orthopedic surgeon to discuss surgical candidacy.

Following the x-ray, our patient received a fluoroscopic guided intra-­articular hip joint anesthetic and corticosteroid injection. Her pain level went from a reported6/10 prior to the procedure to complete pain relief after it.

However, at her follow-up visit 4 weeks later, the patient reported return of functionally limiting pain. The orthopedic surgeon talked to the patient about the potential risks and benefits of THA. She elected to proceed with a right THA.

Six weeks after the surgery, the patient presented for follow-up with minimal hip pain and complete resolution of her knee pain (FIGURE 3). Functionally, she found it much easier to stand straight, and she was able to climb the stairs in her house independently.

An 83-year-old woman, with an otherwise noncontributory past medical history, presented with chronic right knee pain. Over the prior 4 years, she had undergone evaluation by an outside physician and received several corticosteroid and hyaluronic acid intra-­articular injections, without symptom resolution. She described the pain as a 4/10 at rest and as “severe” when climbing stairs and exercising. The pain was localized to her lower back and right groin and extended to her right knee. She also said that she found it difficult to put on her socks. An outside orthopedic surgeon recommended right total knee arthroplasty, prompting her to seek a second opinion.

Examination of her right knee was unrevealing. However, during the hip examination, there was a pronounced loss of range of motion and concordant pain reproduction with the FABER (combined flexion, abduction, external rotation) and FADIR (combined flexion, adduction, and internal rotation) maneuvers.

The patient’s extensive clinical and diagnostic history, combined with benign knee examination and imaging (FIGURE 1), ruled out isolated knee pathology.

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

The patient’s history and physical exam prompted us to suspect right hip osteoarthritis (OA) with referred pain to the right knee. This suspicion was confirmed with hip radiographs (FIGURE 2), which revealed significant OA of the right hip, as evidenced by marked joint space narrowing, subchondral sclerosis, and osteophytes. There was also superior migration of the right femoral head relative to the acetabulum. Additionally, there was loss of sphericity of the right femoral head, suggesting avascular necrosis with collapse.

Hip and knee OA are among the most common causes of disability worldwide. Knee and hip pain are estimated to affect up to 27% and 15% of the general population, respectively.^1,2 Referred knee pain secondary to hip pathology, also known as atypical knee pain, has been cited at highly variable rates, ranging from 2% to 27%.³

Eighty-six percent of patients with atypical knee pain experience a delay in diagnosis of more than 1 year.⁴ Half of these patients require the use of a wheelchair or walker for community navigation.⁴ These findings highlight the impact that a delay in diagnosis can have on the day-to-day quality of life for these patients. Also, delayed or missed diagnoses may have contributed to the doubling in the rate of knee replacement surgery from 2000 to 2010 and the reports that up to one-third of knee replacement surgeries did not meet appropriate criteria to be performed.^5,6

Convergence confusion

Referred pain is likely explained by the convergence of nociceptive and non-nociceptive nerve fibers.⁷ Both of these fiber types conduct action potentials that terminate at second order neurons. Occasionally, nociceptive nerve fibers from different parts of the body (ie, knee and hip) terminate at the same second order fiber. At this point of convergence, higher brain centers lose their ability to discriminate the anatomic location of origin. This results in the perception of pain in a different location, where there is no intrinsic pathology.

Patients with hip OA report that the most common locations of pain are the groin, anterior thigh, buttock, anterior knee, and greater trochanter.³ One small study revealed that 85% of patients with referred pain who underwent total hip arthroplasty (THA) reported complete resolution of pain symptoms within 4 days of the procedure.³

Continue to: A comprehensive exam can reveal a different origin of pain

A comprehensive exam can reveal a different origin of pain

As with any musculoskeletal complaint, history and physical examination should include a focus on the joints proximal and distal to the purported joint of concern. When the hip is in consideration, historical inquiry should focus on degree and timeline of pain, stiffness, and traumatic history. Our patient reported difficulty donning socks, an excellent screening question to evaluate loss of range of motion in the hip. On physical examination, the FABER and FADIR maneuvers are quite specific to hip OA. A comprehensive list of history and physical examination findings can be found in the TABLE.

The differential includes a broad range of musculoskeletal diagnoses

The differential diagnosis for knee pain includes knee OA, spinopelvic pathology, infection, and rheumatologic disease.

Knee OA can be confirmed with knee radiographs, but one must also assess the joint above and below, as with all musculoskeletal complaints.

Spinopelvic pathology may be established with radiographs and a thorough nervous system exam.

Infection, such as septic arthritis or gout, can be diagnosed through radiographs, physical exam, and lab tests to evaluate white blood cell count, erythrocyte sedimentation rate, and C-reactive protein levels. High clinical suspicion may warrant a joint aspiration.

Continue to: Rheumatologic disease

Rheumatologic disease can be evaluated with a comprehensive physical exam, as well as lab work.

Management includes both surgical and nonsurgical options

Hip OA can be managed much like OA in other areas of the body. The Osteoarthritis Research Society International guidelines provide direction and insight concerning outpatient nonsurgical management.⁸ Weight loss and land-based, low-impact exercise programs are excellent first-line options. Second-line therapies include symptomatic management with systemic nonsteroidal anti-inflammatory drugs (NSAIDs) in patients without contraindications. (Topical NSAIDs, while useful in the treatment of knee OA, are not as effective for hip OA due to thickness of soft tissue in this area of the body.)

Patients who do not achieve symptomatic relief with these first- and second-line therapies may benefit from other nonoperative measures, such as intra-articular corticosteroid injections. If pain persists, patients may need a referral to an orthopedic surgeon to discuss surgical candidacy.

Following the x-ray, our patient received a fluoroscopic guided intra-­articular hip joint anesthetic and corticosteroid injection. Her pain level went from a reported6/10 prior to the procedure to complete pain relief after it.

However, at her follow-up visit 4 weeks later, the patient reported return of functionally limiting pain. The orthopedic surgeon talked to the patient about the potential risks and benefits of THA. She elected to proceed with a right THA.

Six weeks after the surgery, the patient presented for follow-up with minimal hip pain and complete resolution of her knee pain (FIGURE 3). Functionally, she found it much easier to stand straight, and she was able to climb the stairs in her house independently.

An 83-year-old woman, with an otherwise noncontributory past medical history, presented with chronic right knee pain. Over the prior 4 years, she had undergone evaluation by an outside physician and received several corticosteroid and hyaluronic acid intra-­articular injections, without symptom resolution. She described the pain as a 4/10 at rest and as “severe” when climbing stairs and exercising. The pain was localized to her lower back and right groin and extended to her right knee. She also said that she found it difficult to put on her socks. An outside orthopedic surgeon recommended right total knee arthroplasty, prompting her to seek a second opinion.

Examination of her right knee was unrevealing. However, during the hip examination, there was a pronounced loss of range of motion and concordant pain reproduction with the FABER (combined flexion, abduction, external rotation) and FADIR (combined flexion, adduction, and internal rotation) maneuvers.

The patient’s extensive clinical and diagnostic history, combined with benign knee examination and imaging (FIGURE 1), ruled out isolated knee pathology.

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

The patient’s history and physical exam prompted us to suspect right hip osteoarthritis (OA) with referred pain to the right knee. This suspicion was confirmed with hip radiographs (FIGURE 2), which revealed significant OA of the right hip, as evidenced by marked joint space narrowing, subchondral sclerosis, and osteophytes. There was also superior migration of the right femoral head relative to the acetabulum. Additionally, there was loss of sphericity of the right femoral head, suggesting avascular necrosis with collapse.

Hip and knee OA are among the most common causes of disability worldwide. Knee and hip pain are estimated to affect up to 27% and 15% of the general population, respectively.^1,2 Referred knee pain secondary to hip pathology, also known as atypical knee pain, has been cited at highly variable rates, ranging from 2% to 27%.³

Eighty-six percent of patients with atypical knee pain experience a delay in diagnosis of more than 1 year.⁴ Half of these patients require the use of a wheelchair or walker for community navigation.⁴ These findings highlight the impact that a delay in diagnosis can have on the day-to-day quality of life for these patients. Also, delayed or missed diagnoses may have contributed to the doubling in the rate of knee replacement surgery from 2000 to 2010 and the reports that up to one-third of knee replacement surgeries did not meet appropriate criteria to be performed.^5,6

Convergence confusion

Referred pain is likely explained by the convergence of nociceptive and non-nociceptive nerve fibers.⁷ Both of these fiber types conduct action potentials that terminate at second order neurons. Occasionally, nociceptive nerve fibers from different parts of the body (ie, knee and hip) terminate at the same second order fiber. At this point of convergence, higher brain centers lose their ability to discriminate the anatomic location of origin. This results in the perception of pain in a different location, where there is no intrinsic pathology.

Patients with hip OA report that the most common locations of pain are the groin, anterior thigh, buttock, anterior knee, and greater trochanter.³ One small study revealed that 85% of patients with referred pain who underwent total hip arthroplasty (THA) reported complete resolution of pain symptoms within 4 days of the procedure.³

Continue to: A comprehensive exam can reveal a different origin of pain

A comprehensive exam can reveal a different origin of pain

As with any musculoskeletal complaint, history and physical examination should include a focus on the joints proximal and distal to the purported joint of concern. When the hip is in consideration, historical inquiry should focus on degree and timeline of pain, stiffness, and traumatic history. Our patient reported difficulty donning socks, an excellent screening question to evaluate loss of range of motion in the hip. On physical examination, the FABER and FADIR maneuvers are quite specific to hip OA. A comprehensive list of history and physical examination findings can be found in the TABLE.

The differential includes a broad range of musculoskeletal diagnoses

The differential diagnosis for knee pain includes knee OA, spinopelvic pathology, infection, and rheumatologic disease.

Knee OA can be confirmed with knee radiographs, but one must also assess the joint above and below, as with all musculoskeletal complaints.

Spinopelvic pathology may be established with radiographs and a thorough nervous system exam.

Infection, such as septic arthritis or gout, can be diagnosed through radiographs, physical exam, and lab tests to evaluate white blood cell count, erythrocyte sedimentation rate, and C-reactive protein levels. High clinical suspicion may warrant a joint aspiration.

Continue to: Rheumatologic disease

Rheumatologic disease can be evaluated with a comprehensive physical exam, as well as lab work.

Management includes both surgical and nonsurgical options

Hip OA can be managed much like OA in other areas of the body. The Osteoarthritis Research Society International guidelines provide direction and insight concerning outpatient nonsurgical management.⁸ Weight loss and land-based, low-impact exercise programs are excellent first-line options. Second-line therapies include symptomatic management with systemic nonsteroidal anti-inflammatory drugs (NSAIDs) in patients without contraindications. (Topical NSAIDs, while useful in the treatment of knee OA, are not as effective for hip OA due to thickness of soft tissue in this area of the body.)

Patients who do not achieve symptomatic relief with these first- and second-line therapies may benefit from other nonoperative measures, such as intra-articular corticosteroid injections. If pain persists, patients may need a referral to an orthopedic surgeon to discuss surgical candidacy.

Following the x-ray, our patient received a fluoroscopic guided intra-­articular hip joint anesthetic and corticosteroid injection. Her pain level went from a reported6/10 prior to the procedure to complete pain relief after it.

However, at her follow-up visit 4 weeks later, the patient reported return of functionally limiting pain. The orthopedic surgeon talked to the patient about the potential risks and benefits of THA. She elected to proceed with a right THA.

Six weeks after the surgery, the patient presented for follow-up with minimal hip pain and complete resolution of her knee pain (FIGURE 3). Functionally, she found it much easier to stand straight, and she was able to climb the stairs in her house independently.

ILLUSTRATIVE CASE

A 23-year-old man with no significant past medical history presents to an urgent care center after a fall on his right arm while playing football. He reports a pain level of 6 using the visual analog scale (VAS). Physical exam reveals minor erythema and edema of his forearm with pain to palpation. Range of motion, strength, and sensation are intact. No lacerations are present. His vital signs are normal. No fracture is found on imaging. The physician decides that treatment with a topical analgesic is reasonable for this uncomplicated contusion of the right forearm. Is there a role for topical capsaicin in the treatment of this patient’s pain?

Topical nonsteroidal anti-­inflammatory drugs (NSAIDs) are effective for the treatment of acute non–low back pain musculoskeletal injuries.² They are generally well tolerated and just as effective as oral NSAIDS or acetaminophen for localized injuries. Their ubiquitous availability, affordability, and low adverse effect profile make them an attractive first-line treatment option for acute musculoskeletal pain.

Capsaicin, a topical agent derived from a genus of red peppers, has been used for the treatment of neuropathic and chronic pain via its interactions with substance P, transient receptor potential vanilloid subtype 1 (TRPV1), and nociceptive nerve fibers.^3,4 It has demonstrated effectiveness in the management of diabetic neuropathy, knee osteoarthritis, and postherpetic neuralgia, as well as various causes of pruritus.^5,6

Although many studies have compared oral and topical NSAIDs, opiates, and acetaminophen, few studies have directly compared topical NSAIDs and capsaicin. This study compared the topical NSAID piroxicam with topical capsaicin.

STUDY SUMMARY

Topical capsaicin demonstrated superior pain reduction

This prospective, double-blind RCT compared the efficacy of topical capsaicin vs topical piroxicam for the treatment of acute pain following upper extremity blunt trauma. Patients (ages ≥ 18 years) who presented to a Turkish emergency department within 2 hours of upper extremity injury were randomized to receive either 0.05% capsaicin gel (n = 69) or 0.5% piroxicam gel (n = 67). Patients reported level 5 or higher pain on the VAS. Those with fractures, dislocations, skin disruption, or other trauma were excluded. Age, gender, pain duration, and mechanism of injury did not differ significantly between study groups.¹

Blinding was ensured by placing the gels in opaque containers containing 30 mg of either capsaicin or piroxicam and dyeing the medicine with red and yellow food coloring. A thin layer of medication was applied to an area no larger than 5 × 5 cm on the upper extremity and rubbed for 1 minute. Patients were observed in the emergency department for 2 hours and discharged with instructions to apply the medication 3 times daily for 72 hours.

Topical capsaicin is an effective alternative to a topical NSAID in reducing pain associated with acute upper extremity injuries.

The investigators measured pain using VAS scores at 1 hour, 2 hours, 24 hours, and 72 hours after treatment. Topical capsaicin was superior to topical piroxicam at achieving both primary outcomes: a VAS score of ≤ 4 (85.5% vs 50.7%; number needed to treat [NNT] = 2.9; P < .001) and a > 50% reduction in VAS score (87% vs 62.7%; NNT = 4.1; P < .01) at the end of treatment.¹ (These outcomes were based on earlier determinations of the minimal clinically important difference.^7,8)

Additionally, capsaicin was more effective than piroxicam at each time interval. This difference was most pronounced at 72 hours, with a mean difference of delta VAS scores of 1.53 (95% CI, 0.85-2.221) and a mean percentage of the reduction in VAS scores of 19.7% (95% CI, 12.4%-27.2%) (P < .001).¹

Reported adverse effects, such as burning, itching, and rash, were mild and infrequent and showed no significant difference between the treatment groups.

WHAT’S NEW

First study comparing topical capsaicin and a topical NSAID in acute trauma

Although both capsaicin and topical piroxicam have proven efficacy for the treatment of pain, this RCT is the first study to directly compare these agents in the setting of acute upper extremity blunt trauma. Capsaicin is currently more commonly prescribed as a treatment for chronic neuropathic pain.^4,9 In this study, capsaicin demonstrated superior results in pain reduction at each assessed time interval and at the primary end point of 72 hours.

CAVEATS

Limited generalizability to lower extremity and truncal trauma

This RCT included a relatively small sample size (136 patients). Researchers evaluated only blunt upper extremity injuries; as such, the generalizability of the effectiveness of topical capsaicin in blunt lower extremity and truncal trauma is limited, especially over larger surface areas.

CHALLENGES TO IMPLEMENTATION

No major challenges found

There are no major challenges to implementing this inexpensive treatment.

ILLUSTRATIVE CASE

A 23-year-old man with no significant past medical history presents to an urgent care center after a fall on his right arm while playing football. He reports a pain level of 6 using the visual analog scale (VAS). Physical exam reveals minor erythema and edema of his forearm with pain to palpation. Range of motion, strength, and sensation are intact. No lacerations are present. His vital signs are normal. No fracture is found on imaging. The physician decides that treatment with a topical analgesic is reasonable for this uncomplicated contusion of the right forearm. Is there a role for topical capsaicin in the treatment of this patient’s pain?

Topical nonsteroidal anti-­inflammatory drugs (NSAIDs) are effective for the treatment of acute non–low back pain musculoskeletal injuries.² They are generally well tolerated and just as effective as oral NSAIDS or acetaminophen for localized injuries. Their ubiquitous availability, affordability, and low adverse effect profile make them an attractive first-line treatment option for acute musculoskeletal pain.

Capsaicin, a topical agent derived from a genus of red peppers, has been used for the treatment of neuropathic and chronic pain via its interactions with substance P, transient receptor potential vanilloid subtype 1 (TRPV1), and nociceptive nerve fibers.^3,4 It has demonstrated effectiveness in the management of diabetic neuropathy, knee osteoarthritis, and postherpetic neuralgia, as well as various causes of pruritus.^5,6

Although many studies have compared oral and topical NSAIDs, opiates, and acetaminophen, few studies have directly compared topical NSAIDs and capsaicin. This study compared the topical NSAID piroxicam with topical capsaicin.

STUDY SUMMARY

Topical capsaicin demonstrated superior pain reduction

This prospective, double-blind RCT compared the efficacy of topical capsaicin vs topical piroxicam for the treatment of acute pain following upper extremity blunt trauma. Patients (ages ≥ 18 years) who presented to a Turkish emergency department within 2 hours of upper extremity injury were randomized to receive either 0.05% capsaicin gel (n = 69) or 0.5% piroxicam gel (n = 67). Patients reported level 5 or higher pain on the VAS. Those with fractures, dislocations, skin disruption, or other trauma were excluded. Age, gender, pain duration, and mechanism of injury did not differ significantly between study groups.¹

Blinding was ensured by placing the gels in opaque containers containing 30 mg of either capsaicin or piroxicam and dyeing the medicine with red and yellow food coloring. A thin layer of medication was applied to an area no larger than 5 × 5 cm on the upper extremity and rubbed for 1 minute. Patients were observed in the emergency department for 2 hours and discharged with instructions to apply the medication 3 times daily for 72 hours.

Topical capsaicin is an effective alternative to a topical NSAID in reducing pain associated with acute upper extremity injuries.

The investigators measured pain using VAS scores at 1 hour, 2 hours, 24 hours, and 72 hours after treatment. Topical capsaicin was superior to topical piroxicam at achieving both primary outcomes: a VAS score of ≤ 4 (85.5% vs 50.7%; number needed to treat [NNT] = 2.9; P < .001) and a > 50% reduction in VAS score (87% vs 62.7%; NNT = 4.1; P < .01) at the end of treatment.¹ (These outcomes were based on earlier determinations of the minimal clinically important difference.^7,8)

Additionally, capsaicin was more effective than piroxicam at each time interval. This difference was most pronounced at 72 hours, with a mean difference of delta VAS scores of 1.53 (95% CI, 0.85-2.221) and a mean percentage of the reduction in VAS scores of 19.7% (95% CI, 12.4%-27.2%) (P < .001).¹

Reported adverse effects, such as burning, itching, and rash, were mild and infrequent and showed no significant difference between the treatment groups.

WHAT’S NEW

First study comparing topical capsaicin and a topical NSAID in acute trauma

Although both capsaicin and topical piroxicam have proven efficacy for the treatment of pain, this RCT is the first study to directly compare these agents in the setting of acute upper extremity blunt trauma. Capsaicin is currently more commonly prescribed as a treatment for chronic neuropathic pain.^4,9 In this study, capsaicin demonstrated superior results in pain reduction at each assessed time interval and at the primary end point of 72 hours.

CAVEATS

Limited generalizability to lower extremity and truncal trauma

This RCT included a relatively small sample size (136 patients). Researchers evaluated only blunt upper extremity injuries; as such, the generalizability of the effectiveness of topical capsaicin in blunt lower extremity and truncal trauma is limited, especially over larger surface areas.

CHALLENGES TO IMPLEMENTATION

No major challenges found

There are no major challenges to implementing this inexpensive treatment.

ILLUSTRATIVE CASE

A 23-year-old man with no significant past medical history presents to an urgent care center after a fall on his right arm while playing football. He reports a pain level of 6 using the visual analog scale (VAS). Physical exam reveals minor erythema and edema of his forearm with pain to palpation. Range of motion, strength, and sensation are intact. No lacerations are present. His vital signs are normal. No fracture is found on imaging. The physician decides that treatment with a topical analgesic is reasonable for this uncomplicated contusion of the right forearm. Is there a role for topical capsaicin in the treatment of this patient’s pain?

Topical nonsteroidal anti-­inflammatory drugs (NSAIDs) are effective for the treatment of acute non–low back pain musculoskeletal injuries.² They are generally well tolerated and just as effective as oral NSAIDS or acetaminophen for localized injuries. Their ubiquitous availability, affordability, and low adverse effect profile make them an attractive first-line treatment option for acute musculoskeletal pain.

Capsaicin, a topical agent derived from a genus of red peppers, has been used for the treatment of neuropathic and chronic pain via its interactions with substance P, transient receptor potential vanilloid subtype 1 (TRPV1), and nociceptive nerve fibers.^3,4 It has demonstrated effectiveness in the management of diabetic neuropathy, knee osteoarthritis, and postherpetic neuralgia, as well as various causes of pruritus.^5,6

Although many studies have compared oral and topical NSAIDs, opiates, and acetaminophen, few studies have directly compared topical NSAIDs and capsaicin. This study compared the topical NSAID piroxicam with topical capsaicin.

STUDY SUMMARY

Topical capsaicin demonstrated superior pain reduction

This prospective, double-blind RCT compared the efficacy of topical capsaicin vs topical piroxicam for the treatment of acute pain following upper extremity blunt trauma. Patients (ages ≥ 18 years) who presented to a Turkish emergency department within 2 hours of upper extremity injury were randomized to receive either 0.05% capsaicin gel (n = 69) or 0.5% piroxicam gel (n = 67). Patients reported level 5 or higher pain on the VAS. Those with fractures, dislocations, skin disruption, or other trauma were excluded. Age, gender, pain duration, and mechanism of injury did not differ significantly between study groups.¹

Blinding was ensured by placing the gels in opaque containers containing 30 mg of either capsaicin or piroxicam and dyeing the medicine with red and yellow food coloring. A thin layer of medication was applied to an area no larger than 5 × 5 cm on the upper extremity and rubbed for 1 minute. Patients were observed in the emergency department for 2 hours and discharged with instructions to apply the medication 3 times daily for 72 hours.

Topical capsaicin is an effective alternative to a topical NSAID in reducing pain associated with acute upper extremity injuries.

The investigators measured pain using VAS scores at 1 hour, 2 hours, 24 hours, and 72 hours after treatment. Topical capsaicin was superior to topical piroxicam at achieving both primary outcomes: a VAS score of ≤ 4 (85.5% vs 50.7%; number needed to treat [NNT] = 2.9; P < .001) and a > 50% reduction in VAS score (87% vs 62.7%; NNT = 4.1; P < .01) at the end of treatment.¹ (These outcomes were based on earlier determinations of the minimal clinically important difference.^7,8)

Additionally, capsaicin was more effective than piroxicam at each time interval. This difference was most pronounced at 72 hours, with a mean difference of delta VAS scores of 1.53 (95% CI, 0.85-2.221) and a mean percentage of the reduction in VAS scores of 19.7% (95% CI, 12.4%-27.2%) (P < .001).¹

Reported adverse effects, such as burning, itching, and rash, were mild and infrequent and showed no significant difference between the treatment groups.

WHAT’S NEW

First study comparing topical capsaicin and a topical NSAID in acute trauma

Although both capsaicin and topical piroxicam have proven efficacy for the treatment of pain, this RCT is the first study to directly compare these agents in the setting of acute upper extremity blunt trauma. Capsaicin is currently more commonly prescribed as a treatment for chronic neuropathic pain.^4,9 In this study, capsaicin demonstrated superior results in pain reduction at each assessed time interval and at the primary end point of 72 hours.

CAVEATS

Limited generalizability to lower extremity and truncal trauma

This RCT included a relatively small sample size (136 patients). Researchers evaluated only blunt upper extremity injuries; as such, the generalizability of the effectiveness of topical capsaicin in blunt lower extremity and truncal trauma is limited, especially over larger surface areas.

CHALLENGES TO IMPLEMENTATION

No major challenges found

There are no major challenges to implementing this inexpensive treatment.

As many as 240,000 people per year in the United States experience a transient ischemic attack (TIA),^1,2 which is now defined by the American Heart Association and American Stroke Association as a “transient episode of neurological dysfunction caused by focal brain, spinal cord, or retinal ischemia, without acute infarction.”³ An older definition of TIA was based on the duration of the event (ie, resolution of symptoms at 24 hours); in the updated (2009) definition, the diagnostic criterion is the extent of focal tissue damage.³ Using the 2009 definition might mean a decrease in the number of patients who have a diagnosis of a TIA and an increase in the number who are determined to have had a stroke because an infarction is found on initial imaging.

Guided by the 2009 revised definition of a TIA, we review here the work-up and treatment of TIA, emphasizing immediacy of management to (1) prevent further tissue damage and (2) decrease the risk of a second event.

Copyright Scott Bodell

CASE

Martin L, 69 years old, retired, a nonsmoker, and with a history of peripheral arterial disease and hypercholesterolemia, presents to the emergency department (ED) of a rural hospital complaining of slurred speech and left-side facial numbness. He had an episode of facial numbness that lasted 30 minutes, then resolved, each of the 2 previous evenings; he did not seek care at those times. Now, in the ED, Mr. L is normotensive.

The patient’s medication history includes a selective serotonin reuptake inhibitor and melatonin to improve sleep. He reports having discontinued a statin because he could not tolerate its adverse effects.

What immediate steps are recommended for Mr. L’s care?

Common event callsfor quick action

A TIA is the strongest predictor of subsequent stroke and stroke-related death; the highest period of risk of these devastating outcomes is immediately following a TIA.^1,2,4,5 It is essential, therefore, for the physician who sees a patient with a current complaint or recent history of suspected focal neurologic deficits to direct that patient to an ED for an accurate diagnosis and, as appropriate, early treatment for the best possible outcome.

A TIA is the strongest predictor of subsequent stroke and stroke-related death; the highest period of risk of these devastating outcomes is immediately following a TIA.

Imaging—preferably, diffusion-­weighted magnetic resonance imaging (DW-MRI), the gold standard for diagnosing stroke (see “Diagnosis includes ruling out mimics”)^2,3—should be performed as soon as the patient with a suspected TIA arrives in the ED. Imaging should not be held while waiting for a stroke to declare itself—ie, by allowing symptoms to persist for longer than 24 hours. ⁶

Continue to: Late presentation

Late presentation. Some patients present ≥ 48 hours after onset of early symptoms of a TIA; for them, the work-up is the same as for prompt presentation but can be completed in the outpatient clinic—as long as the patient is stable clinically and imaging is accessible there. DW-MRI should be completed within 48 hours after late presentation. In such cases, the patient should be cautioned regarding risks and any recurrence of symptoms.^7,8

Diagnosis includes ruling out mimics

All patients in whom a stroke is suspected should be evaluated on an emergency basis with brain imaging upon arrival at the hospital, before any therapy is initiated. As noted, DW-MRI is the preferred modality; noncontrast computed tomography (CT) or CT angiography can be used if MRI is unavailable.^2,3

Mimics. Stroke has many mimics; quickly eliminating them from the differential diagnosis is important so that appropriate therapy can be initiated. Mimics usually have a prolonged presentation of symptoms, whereas the presentation of a TIA is usually abrupt. The 3 more common diagnoses that mimic a TIA are migraine with aura, seizure, and syncope.^9,10 Symptoms that generally are not associated with a TIA are chest pain, generalized weakness, and confusion.¹¹ A complete history and physical exam provide the path to the imaging, laboratory, and cardiac testing that is needed to differentiate these diagnoses from a TIA.

A thorough history is best obtained from the patient and a witness, if available, and should include identification of any focal neurologic deficits and the duration and time to resolution of symptoms. Obtain a history of risk factors for ischemia—tobacco use, diabetes, obesity, dyslipidemia, hypertension, previous TIA or stroke, atrial fibrillation, and any coagulopathy. Ask questions about a family history of TIA, stroke, and coagulopathy.¹¹

A comprehensive physical exam, including vital signs, cardiac exam, a check for carotid bruits, and complete neurologic exam, should be performed. Most patients present with concerns for unilateral weakness and changes in speech, which are usually associated with infarction on DW-MRI.¹² The most common findings on physical exam include cranial nerve abnormalities, such as diplopia, hemianopia, monocular blindness, disconjugate gaze, facial drooping, lateral tongue movement, dysphagia, and vestibular dysfunction. Cerebellar abnormalities are also often noted, including past pointing, dystaxia, ataxia, nystagmus, and motor abnormalities (eg, spasticity, clonus, or unilateral weakness in the face or extremities).¹¹

Electrocardiography at the bedside can confirm atrial fibrillation or another arrhythmia quickly.

Essential laboratory testing includes measurement of blood glucose and serum electrolytes to determine if these particular imbalances are the cause of symptoms. The presence of a hypercoaguable state is determined by a complete blood count and coagulation studies.^3,13 Urine toxicology should also be obtained to rule out other causes of symptoms. A lipid profile is beneficial for making long-term treatment decisions.

Continue to: ABCD2 score

ABCD2 score. Patients who have had a TIA and present within 72 hours after symptoms have resolved should be hospitalized if they have an ABCD2 (Age, Blood pressure [BP], Clinical presentation, Diabetes mellitus [type 1 or 2], Duration of symptoms) prediction system score > 3.¹⁴ ABCD2 criteria can be used to help identify patients who are at higher risk of stroke or need further therapy (TABLE 1).^14,15

Send a patient with a current complaint or recent history of suspected focal neurologic deficits to an ED for accurate diagnosis of a possible TIA and, as appropriate, early treatment.

The ABCD2 score is also used to determine whether a patient needs dual antiplatelet therapy. Patients who score at the higher end of the ABCD2 system usually have an increased risk of stroke, longer hospitalization, and greater disability.

CASE

In the ED, Mr. L is immediately assessed and airlifted to a larger regional medical center, where MRI confirms a stroke.

Management

Initial management of a TIA is aimed at reducing the risk of recurrent TIA or stroke. Early medical and possibly surgical treatment are key for preventing stroke and improving outcomes. The first 48 hours after a TIA are the most critical because the incidence of recurrent TIA or stroke is highest during this period.^16-18

What is the accepted strategy for early treatment?

Initial treatment must include antiplatelet therapy, BP management, anticoagulation, statin therapy, and carotid endarterectomy as indicated.^2,19,20 Control of hypertension and anticoagulation decrease the risk of recurrent stroke by the largest margin²⁰; both are “A”-level Strength of Recommendation Taxonomy interventions.^2,3

Step 1: Antiplatelet therapy. After initial imaging is complete and if there are no contraindications, antiplatelet agents are recommended for patients who have had a noncardioembolic TIA. The American Heart Association and American Stroke Association recommend either aspirin, clopidogrel, dipyridamole + aspirin (available in a single capsule [Aggrenox]), or clopidogrel + aspirin as first-line therapy.^2,20 The choice of agent needs to be individualized, based on tolerability and adverse effects (TABLE 2^2,20,21).

A meta-analysis of antiplatelet therapy reviewed the optimum dosing of each medication.^21,22 Reduction of the risk of ischemic stroke with aspirin is 21% to 22% at the optimal dosing of 75 to 150 mg/d, which also reduces the risk of gastrointestinal bleeding.

Continue to: For a patient who has...

For a patient who has an ABCD2 score ≥ 4, has had a prior TIA, or has large-vessel disease, dual antiplatelet therapy is recommended for the first 21 days, with a subsequent return to monotherapy. Dual antiplatelet therapy of clopidogrel + aspirin increases the risk of adverse reactions and has not been shown to have greater long-term benefit^23-25 (TABLE 2^2,20,21).

Step 2: BP management. This is the next immediate step. As many as 80% of patients who present with a TIA have elevated BP upon admission. BP needs to be treated and carefully monitored during this early treatment phase. The recommendation is for a systolic BP < 185 mm Hg and a diastolic BP < 110 mm Hg.²⁴

Step 3: Anticoagulation. Treatment with warfarin or a direct oral anticoagulant (DOAC) is recommended for patients who have the potential for forming emboli—eg, in the setting of atrial fibrillation, ventricular thrombus, mechanical heart valve, or venous thromboembolism.

Step 4. High-intensity statin. A statin agent is recommended as part of immediate and long-term medical management, regardless of the low-density lipoprotein cholesterol (LDL-C) level, to reduce the risk of stroke.^2,24

Carotid artery management. Surgical intervention is not always considered a component of immediate medical management. However, guidelines recommend that carotid endarterectomy or stenting be considered in patients who have stenosis > 70%.²

CASE

Mr. L is admitted to the hospital and undergoes neurosurgical intervention. Medical management is instituted.

Long-term management and secondary prevention

The main risk factors for stroke can be divided into modifiable, vascular, and unmodifiable. Addressing both modifiable and vascular risks is important for secondary prevention.

Continue to: Modifiable and vascular risk factors

Modifiable risk factors for stroke include hypertension, diabetes, dyslipidemia, smoking, and physical activity; the most important of these, for preventing subsequent stroke after an initial TIA, is hypertension.²⁶

The 2 more significant vascular risk factors for stroke are carotid artery stenosis and atrial fibrillation.

Hypertension. Improving control of hypertension can improve secondary risk reduction for recurrent stroke. Control of both systolic and diastolic BP is important in this regard, with larger systolic BP reductions having a greater impact on decreasing the risk of recurrent stroke.²⁴ Evidence supports lowering BP to improve secondary risk reduction in people with and without diagnosed hypertension: The goal is to lower systolic BP by ≥ 10 mm Hg and diastolic BP by 5 mm Hg.²⁴ No particular class of antihypertensive is recommended in the first line, although preliminary evidence shows that a diuretic, with or without an angiotensin-converting enzyme inhibitor, might be more beneficial than other options.²⁴

Diabetes. The risk of cardiovascular disease, including stroke, is higher in people with diabetes. Evidence shows that various (but not all) agents in 2 pharmaceutical classes—glucagon-like peptide-1 (GLP-1) receptor agonists and the sodium glucose-2 cotransporter (SGLT2) inhibitors—reduce the risk of major cardiovascular events and improve secondary prevention of recurrent stroke:

• EMPA-REG OUTCOME (ClinicalTrials.gov Identifier: NCT01131676) was the first trial to show cardiovascular benefit from an SGLT2 inhibitor (empagliflozin); subsequent studies confirmed the cardiovascular benefits found in EMPA-REG OUTCOME.^27,28
• The ELIXA trial (ClinicalTrials.gov Identifier: NCT01147250) was the first to show cardiovascular benefit from a GLP-1 receptor agonist (lixisenatide); subsequent studies supported this finding.^29,30

Appropriate agents in these 2 classes should be considered as first-line or adjunctive in patients with both diabetes and known cardiovascular disease, as long as there are no contraindications.^27,28

Pioglitazone, a thiazolidinedione-class antidiabetic agent, was once considered a potential option to improve secondary prevention of stroke. However, the thiazolidinediones are generally no longer considered; instead, the SGLT2 inhibitors and GLP-1 receptor agonists are favored.³¹

Evidence demonstrates the effect of hyperglycemia on cardiovascular events; however, it is important to note that hypoglycemia can result in symptoms and focal changes that mimic a stroke. In addition, some evidence suggests that hypoglycemia can increase cardiovascular risk—thereby supporting the importance of strict control of diabetes and maintenance of euglycemia in reducing overall cardiovascular risk.³²

Continue to: Lipids

Lipids. The SPARCL trial (ClinicalTrials.gov Identifier: NCT00147602) was the first study to demonstrate the benefit of high-­intensity statin therapy—specifically, atorvastatin 80 mg/d—for secondary prevention for recurrent stroke.³³ The recommendation is to use high-intensity statin therapy to decrease the risk of recurrent stroke by reducing the level of LDL-C—by ≥ 50% or to < 70 mg/dL, for maximum risk reduction.^24,34

Common conditions that mimic a TIA are migraine with aura, seizure, and syncope; a TIA is generally not associated with chest pain, generalized weakness, or confusion.

The IMPROVE-IT trial (ClinicalTrials.gov Identifier: NCT00202878) demonstrated the benefit of adding ezetimibe, 10 mg/d, to a moderate-to-high-intensity statin (simvastatin, 40-80 mg/d) to reduce the risk of recurrent stroke.³⁵

Results of recent studies support the use of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors for regulating levels of LDL-C, as an additional option to consider—if needed to further reduce the LDL-C level or if statins are contraindicated in a particular patient.³⁴

Smoking cessation. Cigarette smoking is known to increase the risk of ischemic stroke; newer evidence shows that second-hand exposure to smoke also increases the risk of ischemic stroke.^36,37 Although these studies focused on primary prevention of ischemic stroke, the data can reasonably be applied to secondary prevention.³⁸ The recommendation for secondary prevention is to quit smoking and avoid secondhand smoke.²⁴

Alcohol. Evidence demonstrates that heavy alcohol consumption and alcoholism increase the risk of stroke; similar to what is known about smoking, most available data relate to primary prevention.³⁸ The recommendation for providing secondary stroke prevention is to stop or decrease alcohol intake.²⁴

Weight reduction. Obesity (body mass index > 30) increases the risk of ischemic stroke. However, there is, as yet, no evidence that weight loss diminishes the risk of subsequent stroke for secondary prevention.²⁴

Physical activity. Aerobic exercise and strength-training programs after a stroke improve cardiovascular health and mobility. There is no evidence that exercise leads to a reduction in the risk of subsequent stroke.²⁴

Continue to: Nutrition

Nutrition. No current randomized controlled trials are focused on the relationship between diet and recurrent stroke for purposes of prevention; however, evidence for both BP and lipid control incorporate dietary guidance. Recommendations include reducing intake of saturated fats and of sodium (the latter, to < 2.3 g/d) and increasing intake of fruits and vegetables, both of which are beneficial for controlling BP and lipid levels and promoting overall cardiovascular health.³⁸

Carotid artery stenosis. Several randomized controlled trials have demonstrated benefit from treating carotid stenosis (> 70% stenosis but not < 50%) with carotid endarterectomy to reduce the risk of recurrent stroke after TIA.² The ideal timing of carotid endarterectomy is still being studied; however, available evidence supports intervention within 2 to 6 weeks after TIA or stroke.²⁵ Studies are ongoing that compare carotid angioplasty and stenting against carotid endarterectomy. Medical therapy, with antiplatelet agents and statins, is recommended after carotid endarterectomy.²⁵

Atrial fibrillation increases the risk of recurrent stroke after a TIA, and is the most important indication for secondary stroke prevention with anticoagulation therapy:

• Warfarin. Several studies have shown that warfarin provides a 68% relative risk reduction and a 1.4% absolute risk reduction in the annual stroke rate.²⁴ To achieve this reduction in risk, the optimal international normalized ratio is 2.5 (range, 2-3).²⁴
• Aspirin provides a 13% relative risk reduction for recurrent stroke, although there is evidence that long-term anticoagulation provides more benefit than aspirin after a TIA.^39-41 Optimal dosing of aspirin ranges from 75-100 mg/d; greatest benefit is likely in the 12 weeks after stroke, when the risk of recurrent stroke is highest.^31,41,42
• DOACs have similar efficacy to warfarin but more rapid onset, lower risk of bleeding, fewer drug interactions, and no requirement for monitoring—often making them a more tolerable long-term choice. Options are rivaroxaban 20 mg/d, dabigatran 150 mg twice daily, apixaban 5 mg twice daily, and edoxaban 60 mg/d.³⁹

Initial treatment of a TIA must include antiplatelet therapy, BP management, anticoagulation, and statin therapy; carotid endarterectomy might also be indicated.

When to start anticoagulation and the choice of agent should be weighed against a risk of bleeding, which is highest after the initial stroke. Cost is also a consideration: DOACs are more expensive than warfarin.

CASE

Mr. L is discharged 3 days after carotid endarterectomy and free of residual deficits. He is started on dual antiplatelet therapy (aspirin + clopidogrel) for 21 days, to be followed by a return to monotherapy. He is restarted on a high-intensity statin. He is instructed to resume taking the selective serotonin reuptake inhibitor and melatonin for sleep, as needed. Last, he is told to schedule follow-up with his primary care physician in 7 to 10 days to begin post-stroke care.

Final thoughts

Primary care physicians are often the first point of contact for patients with current or remote TIA symptoms. Based on that ­provider–patient relationship, evidence supports several recommendations for diagnosing and treating a TIA and for reducing the risk of recurrent stroke after TIA. Addressing each of these areas, in this order, is imperative to reduce the risk of recurrent stroke and improve overall cardiovascular outcomes:

• Obtain an accurate diagnosis of a TIA, using DW-MRI or comparable brain imaging, to allow for prompt intervention.
• Initiate BP management promptly in the acute setting and establish optimal BP control over the long term.
• Begin appropriate antiplatelet therapy.
• When indicated (eg, atrial fibrillation), begin anticoagulation therapy with a DOAC or warfarin.
• Begin high-intensity statin therapy.
• Consider treating patients with diabetes using an SGLT2 inhibitor or GLP-1 receptor agonist.
• Encourage smoking cessation, prescribe quit-smoking medications, or refer a smoker for behavioral support.

Education. Last, it is important to educate patients—especially those who have risk factors for a TIA or stroke—about the presentation of events, so that they know to seek immediate medical attention.

CORRESPONDENCE
Kristen Rundell, MD, Department of Family and Community Medicine, University of Arizona College of Medicine, 655 North Alvernon Way, Suite 228, Tucson, AZ 85711; [email protected]

As many as 240,000 people per year in the United States experience a transient ischemic attack (TIA),^1,2 which is now defined by the American Heart Association and American Stroke Association as a “transient episode of neurological dysfunction caused by focal brain, spinal cord, or retinal ischemia, without acute infarction.”³ An older definition of TIA was based on the duration of the event (ie, resolution of symptoms at 24 hours); in the updated (2009) definition, the diagnostic criterion is the extent of focal tissue damage.³ Using the 2009 definition might mean a decrease in the number of patients who have a diagnosis of a TIA and an increase in the number who are determined to have had a stroke because an infarction is found on initial imaging.

Guided by the 2009 revised definition of a TIA, we review here the work-up and treatment of TIA, emphasizing immediacy of management to (1) prevent further tissue damage and (2) decrease the risk of a second event.

Copyright Scott Bodell

CASE

Martin L, 69 years old, retired, a nonsmoker, and with a history of peripheral arterial disease and hypercholesterolemia, presents to the emergency department (ED) of a rural hospital complaining of slurred speech and left-side facial numbness. He had an episode of facial numbness that lasted 30 minutes, then resolved, each of the 2 previous evenings; he did not seek care at those times. Now, in the ED, Mr. L is normotensive.

The patient’s medication history includes a selective serotonin reuptake inhibitor and melatonin to improve sleep. He reports having discontinued a statin because he could not tolerate its adverse effects.

What immediate steps are recommended for Mr. L’s care?

Common event callsfor quick action

A TIA is the strongest predictor of subsequent stroke and stroke-related death; the highest period of risk of these devastating outcomes is immediately following a TIA.^1,2,4,5 It is essential, therefore, for the physician who sees a patient with a current complaint or recent history of suspected focal neurologic deficits to direct that patient to an ED for an accurate diagnosis and, as appropriate, early treatment for the best possible outcome.

A TIA is the strongest predictor of subsequent stroke and stroke-related death; the highest period of risk of these devastating outcomes is immediately following a TIA.

Imaging—preferably, diffusion-­weighted magnetic resonance imaging (DW-MRI), the gold standard for diagnosing stroke (see “Diagnosis includes ruling out mimics”)^2,3—should be performed as soon as the patient with a suspected TIA arrives in the ED. Imaging should not be held while waiting for a stroke to declare itself—ie, by allowing symptoms to persist for longer than 24 hours. ⁶

Continue to: Late presentation

Late presentation. Some patients present ≥ 48 hours after onset of early symptoms of a TIA; for them, the work-up is the same as for prompt presentation but can be completed in the outpatient clinic—as long as the patient is stable clinically and imaging is accessible there. DW-MRI should be completed within 48 hours after late presentation. In such cases, the patient should be cautioned regarding risks and any recurrence of symptoms.^7,8

Diagnosis includes ruling out mimics

All patients in whom a stroke is suspected should be evaluated on an emergency basis with brain imaging upon arrival at the hospital, before any therapy is initiated. As noted, DW-MRI is the preferred modality; noncontrast computed tomography (CT) or CT angiography can be used if MRI is unavailable.^2,3

Mimics. Stroke has many mimics; quickly eliminating them from the differential diagnosis is important so that appropriate therapy can be initiated. Mimics usually have a prolonged presentation of symptoms, whereas the presentation of a TIA is usually abrupt. The 3 more common diagnoses that mimic a TIA are migraine with aura, seizure, and syncope.^9,10 Symptoms that generally are not associated with a TIA are chest pain, generalized weakness, and confusion.¹¹ A complete history and physical exam provide the path to the imaging, laboratory, and cardiac testing that is needed to differentiate these diagnoses from a TIA.

A thorough history is best obtained from the patient and a witness, if available, and should include identification of any focal neurologic deficits and the duration and time to resolution of symptoms. Obtain a history of risk factors for ischemia—tobacco use, diabetes, obesity, dyslipidemia, hypertension, previous TIA or stroke, atrial fibrillation, and any coagulopathy. Ask questions about a family history of TIA, stroke, and coagulopathy.¹¹

A comprehensive physical exam, including vital signs, cardiac exam, a check for carotid bruits, and complete neurologic exam, should be performed. Most patients present with concerns for unilateral weakness and changes in speech, which are usually associated with infarction on DW-MRI.¹² The most common findings on physical exam include cranial nerve abnormalities, such as diplopia, hemianopia, monocular blindness, disconjugate gaze, facial drooping, lateral tongue movement, dysphagia, and vestibular dysfunction. Cerebellar abnormalities are also often noted, including past pointing, dystaxia, ataxia, nystagmus, and motor abnormalities (eg, spasticity, clonus, or unilateral weakness in the face or extremities).¹¹

Electrocardiography at the bedside can confirm atrial fibrillation or another arrhythmia quickly.

Essential laboratory testing includes measurement of blood glucose and serum electrolytes to determine if these particular imbalances are the cause of symptoms. The presence of a hypercoaguable state is determined by a complete blood count and coagulation studies.^3,13 Urine toxicology should also be obtained to rule out other causes of symptoms. A lipid profile is beneficial for making long-term treatment decisions.

Continue to: ABCD2 score

ABCD2 score. Patients who have had a TIA and present within 72 hours after symptoms have resolved should be hospitalized if they have an ABCD2 (Age, Blood pressure [BP], Clinical presentation, Diabetes mellitus [type 1 or 2], Duration of symptoms) prediction system score > 3.¹⁴ ABCD2 criteria can be used to help identify patients who are at higher risk of stroke or need further therapy (TABLE 1).^14,15

Send a patient with a current complaint or recent history of suspected focal neurologic deficits to an ED for accurate diagnosis of a possible TIA and, as appropriate, early treatment.

The ABCD2 score is also used to determine whether a patient needs dual antiplatelet therapy. Patients who score at the higher end of the ABCD2 system usually have an increased risk of stroke, longer hospitalization, and greater disability.

CASE

In the ED, Mr. L is immediately assessed and airlifted to a larger regional medical center, where MRI confirms a stroke.

Management

Initial management of a TIA is aimed at reducing the risk of recurrent TIA or stroke. Early medical and possibly surgical treatment are key for preventing stroke and improving outcomes. The first 48 hours after a TIA are the most critical because the incidence of recurrent TIA or stroke is highest during this period.^16-18

What is the accepted strategy for early treatment?

Initial treatment must include antiplatelet therapy, BP management, anticoagulation, statin therapy, and carotid endarterectomy as indicated.^2,19,20 Control of hypertension and anticoagulation decrease the risk of recurrent stroke by the largest margin²⁰; both are “A”-level Strength of Recommendation Taxonomy interventions.^2,3

Step 1: Antiplatelet therapy. After initial imaging is complete and if there are no contraindications, antiplatelet agents are recommended for patients who have had a noncardioembolic TIA. The American Heart Association and American Stroke Association recommend either aspirin, clopidogrel, dipyridamole + aspirin (available in a single capsule [Aggrenox]), or clopidogrel + aspirin as first-line therapy.^2,20 The choice of agent needs to be individualized, based on tolerability and adverse effects (TABLE 2^2,20,21).

A meta-analysis of antiplatelet therapy reviewed the optimum dosing of each medication.^21,22 Reduction of the risk of ischemic stroke with aspirin is 21% to 22% at the optimal dosing of 75 to 150 mg/d, which also reduces the risk of gastrointestinal bleeding.

Continue to: For a patient who has...

For a patient who has an ABCD2 score ≥ 4, has had a prior TIA, or has large-vessel disease, dual antiplatelet therapy is recommended for the first 21 days, with a subsequent return to monotherapy. Dual antiplatelet therapy of clopidogrel + aspirin increases the risk of adverse reactions and has not been shown to have greater long-term benefit^23-25 (TABLE 2^2,20,21).

Step 2: BP management. This is the next immediate step. As many as 80% of patients who present with a TIA have elevated BP upon admission. BP needs to be treated and carefully monitored during this early treatment phase. The recommendation is for a systolic BP < 185 mm Hg and a diastolic BP < 110 mm Hg.²⁴

Step 3: Anticoagulation. Treatment with warfarin or a direct oral anticoagulant (DOAC) is recommended for patients who have the potential for forming emboli—eg, in the setting of atrial fibrillation, ventricular thrombus, mechanical heart valve, or venous thromboembolism.

Step 4. High-intensity statin. A statin agent is recommended as part of immediate and long-term medical management, regardless of the low-density lipoprotein cholesterol (LDL-C) level, to reduce the risk of stroke.^2,24

Carotid artery management. Surgical intervention is not always considered a component of immediate medical management. However, guidelines recommend that carotid endarterectomy or stenting be considered in patients who have stenosis > 70%.²

CASE

Mr. L is admitted to the hospital and undergoes neurosurgical intervention. Medical management is instituted.

Long-term management and secondary prevention

The main risk factors for stroke can be divided into modifiable, vascular, and unmodifiable. Addressing both modifiable and vascular risks is important for secondary prevention.

Continue to: Modifiable and vascular risk factors

Modifiable risk factors for stroke include hypertension, diabetes, dyslipidemia, smoking, and physical activity; the most important of these, for preventing subsequent stroke after an initial TIA, is hypertension.²⁶

The 2 more significant vascular risk factors for stroke are carotid artery stenosis and atrial fibrillation.

Hypertension. Improving control of hypertension can improve secondary risk reduction for recurrent stroke. Control of both systolic and diastolic BP is important in this regard, with larger systolic BP reductions having a greater impact on decreasing the risk of recurrent stroke.²⁴ Evidence supports lowering BP to improve secondary risk reduction in people with and without diagnosed hypertension: The goal is to lower systolic BP by ≥ 10 mm Hg and diastolic BP by 5 mm Hg.²⁴ No particular class of antihypertensive is recommended in the first line, although preliminary evidence shows that a diuretic, with or without an angiotensin-converting enzyme inhibitor, might be more beneficial than other options.²⁴

Diabetes. The risk of cardiovascular disease, including stroke, is higher in people with diabetes. Evidence shows that various (but not all) agents in 2 pharmaceutical classes—glucagon-like peptide-1 (GLP-1) receptor agonists and the sodium glucose-2 cotransporter (SGLT2) inhibitors—reduce the risk of major cardiovascular events and improve secondary prevention of recurrent stroke:

• EMPA-REG OUTCOME (ClinicalTrials.gov Identifier: NCT01131676) was the first trial to show cardiovascular benefit from an SGLT2 inhibitor (empagliflozin); subsequent studies confirmed the cardiovascular benefits found in EMPA-REG OUTCOME.^27,28
• The ELIXA trial (ClinicalTrials.gov Identifier: NCT01147250) was the first to show cardiovascular benefit from a GLP-1 receptor agonist (lixisenatide); subsequent studies supported this finding.^29,30

Appropriate agents in these 2 classes should be considered as first-line or adjunctive in patients with both diabetes and known cardiovascular disease, as long as there are no contraindications.^27,28

Pioglitazone, a thiazolidinedione-class antidiabetic agent, was once considered a potential option to improve secondary prevention of stroke. However, the thiazolidinediones are generally no longer considered; instead, the SGLT2 inhibitors and GLP-1 receptor agonists are favored.³¹

Evidence demonstrates the effect of hyperglycemia on cardiovascular events; however, it is important to note that hypoglycemia can result in symptoms and focal changes that mimic a stroke. In addition, some evidence suggests that hypoglycemia can increase cardiovascular risk—thereby supporting the importance of strict control of diabetes and maintenance of euglycemia in reducing overall cardiovascular risk.³²

Continue to: Lipids

Lipids. The SPARCL trial (ClinicalTrials.gov Identifier: NCT00147602) was the first study to demonstrate the benefit of high-­intensity statin therapy—specifically, atorvastatin 80 mg/d—for secondary prevention for recurrent stroke.³³ The recommendation is to use high-intensity statin therapy to decrease the risk of recurrent stroke by reducing the level of LDL-C—by ≥ 50% or to < 70 mg/dL, for maximum risk reduction.^24,34

Common conditions that mimic a TIA are migraine with aura, seizure, and syncope; a TIA is generally not associated with chest pain, generalized weakness, or confusion.

The IMPROVE-IT trial (ClinicalTrials.gov Identifier: NCT00202878) demonstrated the benefit of adding ezetimibe, 10 mg/d, to a moderate-to-high-intensity statin (simvastatin, 40-80 mg/d) to reduce the risk of recurrent stroke.³⁵

Results of recent studies support the use of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors for regulating levels of LDL-C, as an additional option to consider—if needed to further reduce the LDL-C level or if statins are contraindicated in a particular patient.³⁴

Smoking cessation. Cigarette smoking is known to increase the risk of ischemic stroke; newer evidence shows that second-hand exposure to smoke also increases the risk of ischemic stroke.^36,37 Although these studies focused on primary prevention of ischemic stroke, the data can reasonably be applied to secondary prevention.³⁸ The recommendation for secondary prevention is to quit smoking and avoid secondhand smoke.²⁴

Alcohol. Evidence demonstrates that heavy alcohol consumption and alcoholism increase the risk of stroke; similar to what is known about smoking, most available data relate to primary prevention.³⁸ The recommendation for providing secondary stroke prevention is to stop or decrease alcohol intake.²⁴

Weight reduction. Obesity (body mass index > 30) increases the risk of ischemic stroke. However, there is, as yet, no evidence that weight loss diminishes the risk of subsequent stroke for secondary prevention.²⁴

Physical activity. Aerobic exercise and strength-training programs after a stroke improve cardiovascular health and mobility. There is no evidence that exercise leads to a reduction in the risk of subsequent stroke.²⁴

Continue to: Nutrition

Nutrition. No current randomized controlled trials are focused on the relationship between diet and recurrent stroke for purposes of prevention; however, evidence for both BP and lipid control incorporate dietary guidance. Recommendations include reducing intake of saturated fats and of sodium (the latter, to < 2.3 g/d) and increasing intake of fruits and vegetables, both of which are beneficial for controlling BP and lipid levels and promoting overall cardiovascular health.³⁸

Carotid artery stenosis. Several randomized controlled trials have demonstrated benefit from treating carotid stenosis (> 70% stenosis but not < 50%) with carotid endarterectomy to reduce the risk of recurrent stroke after TIA.² The ideal timing of carotid endarterectomy is still being studied; however, available evidence supports intervention within 2 to 6 weeks after TIA or stroke.²⁵ Studies are ongoing that compare carotid angioplasty and stenting against carotid endarterectomy. Medical therapy, with antiplatelet agents and statins, is recommended after carotid endarterectomy.²⁵

Atrial fibrillation increases the risk of recurrent stroke after a TIA, and is the most important indication for secondary stroke prevention with anticoagulation therapy:

• Warfarin. Several studies have shown that warfarin provides a 68% relative risk reduction and a 1.4% absolute risk reduction in the annual stroke rate.²⁴ To achieve this reduction in risk, the optimal international normalized ratio is 2.5 (range, 2-3).²⁴
• Aspirin provides a 13% relative risk reduction for recurrent stroke, although there is evidence that long-term anticoagulation provides more benefit than aspirin after a TIA.^39-41 Optimal dosing of aspirin ranges from 75-100 mg/d; greatest benefit is likely in the 12 weeks after stroke, when the risk of recurrent stroke is highest.^31,41,42
• DOACs have similar efficacy to warfarin but more rapid onset, lower risk of bleeding, fewer drug interactions, and no requirement for monitoring—often making them a more tolerable long-term choice. Options are rivaroxaban 20 mg/d, dabigatran 150 mg twice daily, apixaban 5 mg twice daily, and edoxaban 60 mg/d.³⁹

Initial treatment of a TIA must include antiplatelet therapy, BP management, anticoagulation, and statin therapy; carotid endarterectomy might also be indicated.

When to start anticoagulation and the choice of agent should be weighed against a risk of bleeding, which is highest after the initial stroke. Cost is also a consideration: DOACs are more expensive than warfarin.

CASE

Mr. L is discharged 3 days after carotid endarterectomy and free of residual deficits. He is started on dual antiplatelet therapy (aspirin + clopidogrel) for 21 days, to be followed by a return to monotherapy. He is restarted on a high-intensity statin. He is instructed to resume taking the selective serotonin reuptake inhibitor and melatonin for sleep, as needed. Last, he is told to schedule follow-up with his primary care physician in 7 to 10 days to begin post-stroke care.

Final thoughts

Primary care physicians are often the first point of contact for patients with current or remote TIA symptoms. Based on that ­provider–patient relationship, evidence supports several recommendations for diagnosing and treating a TIA and for reducing the risk of recurrent stroke after TIA. Addressing each of these areas, in this order, is imperative to reduce the risk of recurrent stroke and improve overall cardiovascular outcomes:

• Obtain an accurate diagnosis of a TIA, using DW-MRI or comparable brain imaging, to allow for prompt intervention.
• Initiate BP management promptly in the acute setting and establish optimal BP control over the long term.
• Begin appropriate antiplatelet therapy.
• When indicated (eg, atrial fibrillation), begin anticoagulation therapy with a DOAC or warfarin.
• Begin high-intensity statin therapy.
• Consider treating patients with diabetes using an SGLT2 inhibitor or GLP-1 receptor agonist.
• Encourage smoking cessation, prescribe quit-smoking medications, or refer a smoker for behavioral support.

Education. Last, it is important to educate patients—especially those who have risk factors for a TIA or stroke—about the presentation of events, so that they know to seek immediate medical attention.

CORRESPONDENCE
Kristen Rundell, MD, Department of Family and Community Medicine, University of Arizona College of Medicine, 655 North Alvernon Way, Suite 228, Tucson, AZ 85711; [email protected]

As many as 240,000 people per year in the United States experience a transient ischemic attack (TIA),^1,2 which is now defined by the American Heart Association and American Stroke Association as a “transient episode of neurological dysfunction caused by focal brain, spinal cord, or retinal ischemia, without acute infarction.”³ An older definition of TIA was based on the duration of the event (ie, resolution of symptoms at 24 hours); in the updated (2009) definition, the diagnostic criterion is the extent of focal tissue damage.³ Using the 2009 definition might mean a decrease in the number of patients who have a diagnosis of a TIA and an increase in the number who are determined to have had a stroke because an infarction is found on initial imaging.

Guided by the 2009 revised definition of a TIA, we review here the work-up and treatment of TIA, emphasizing immediacy of management to (1) prevent further tissue damage and (2) decrease the risk of a second event.

Copyright Scott Bodell

CASE

Martin L, 69 years old, retired, a nonsmoker, and with a history of peripheral arterial disease and hypercholesterolemia, presents to the emergency department (ED) of a rural hospital complaining of slurred speech and left-side facial numbness. He had an episode of facial numbness that lasted 30 minutes, then resolved, each of the 2 previous evenings; he did not seek care at those times. Now, in the ED, Mr. L is normotensive.

The patient’s medication history includes a selective serotonin reuptake inhibitor and melatonin to improve sleep. He reports having discontinued a statin because he could not tolerate its adverse effects.

What immediate steps are recommended for Mr. L’s care?

Common event callsfor quick action

A TIA is the strongest predictor of subsequent stroke and stroke-related death; the highest period of risk of these devastating outcomes is immediately following a TIA.^1,2,4,5 It is essential, therefore, for the physician who sees a patient with a current complaint or recent history of suspected focal neurologic deficits to direct that patient to an ED for an accurate diagnosis and, as appropriate, early treatment for the best possible outcome.

A TIA is the strongest predictor of subsequent stroke and stroke-related death; the highest period of risk of these devastating outcomes is immediately following a TIA.

Imaging—preferably, diffusion-­weighted magnetic resonance imaging (DW-MRI), the gold standard for diagnosing stroke (see “Diagnosis includes ruling out mimics”)^2,3—should be performed as soon as the patient with a suspected TIA arrives in the ED. Imaging should not be held while waiting for a stroke to declare itself—ie, by allowing symptoms to persist for longer than 24 hours. ⁶

Continue to: Late presentation

Late presentation. Some patients present ≥ 48 hours after onset of early symptoms of a TIA; for them, the work-up is the same as for prompt presentation but can be completed in the outpatient clinic—as long as the patient is stable clinically and imaging is accessible there. DW-MRI should be completed within 48 hours after late presentation. In such cases, the patient should be cautioned regarding risks and any recurrence of symptoms.^7,8

Diagnosis includes ruling out mimics

All patients in whom a stroke is suspected should be evaluated on an emergency basis with brain imaging upon arrival at the hospital, before any therapy is initiated. As noted, DW-MRI is the preferred modality; noncontrast computed tomography (CT) or CT angiography can be used if MRI is unavailable.^2,3

Mimics. Stroke has many mimics; quickly eliminating them from the differential diagnosis is important so that appropriate therapy can be initiated. Mimics usually have a prolonged presentation of symptoms, whereas the presentation of a TIA is usually abrupt. The 3 more common diagnoses that mimic a TIA are migraine with aura, seizure, and syncope.^9,10 Symptoms that generally are not associated with a TIA are chest pain, generalized weakness, and confusion.¹¹ A complete history and physical exam provide the path to the imaging, laboratory, and cardiac testing that is needed to differentiate these diagnoses from a TIA.

A thorough history is best obtained from the patient and a witness, if available, and should include identification of any focal neurologic deficits and the duration and time to resolution of symptoms. Obtain a history of risk factors for ischemia—tobacco use, diabetes, obesity, dyslipidemia, hypertension, previous TIA or stroke, atrial fibrillation, and any coagulopathy. Ask questions about a family history of TIA, stroke, and coagulopathy.¹¹

A comprehensive physical exam, including vital signs, cardiac exam, a check for carotid bruits, and complete neurologic exam, should be performed. Most patients present with concerns for unilateral weakness and changes in speech, which are usually associated with infarction on DW-MRI.¹² The most common findings on physical exam include cranial nerve abnormalities, such as diplopia, hemianopia, monocular blindness, disconjugate gaze, facial drooping, lateral tongue movement, dysphagia, and vestibular dysfunction. Cerebellar abnormalities are also often noted, including past pointing, dystaxia, ataxia, nystagmus, and motor abnormalities (eg, spasticity, clonus, or unilateral weakness in the face or extremities).¹¹

Electrocardiography at the bedside can confirm atrial fibrillation or another arrhythmia quickly.

Essential laboratory testing includes measurement of blood glucose and serum electrolytes to determine if these particular imbalances are the cause of symptoms. The presence of a hypercoaguable state is determined by a complete blood count and coagulation studies.^3,13 Urine toxicology should also be obtained to rule out other causes of symptoms. A lipid profile is beneficial for making long-term treatment decisions.

Continue to: ABCD2 score

ABCD2 score. Patients who have had a TIA and present within 72 hours after symptoms have resolved should be hospitalized if they have an ABCD2 (Age, Blood pressure [BP], Clinical presentation, Diabetes mellitus [type 1 or 2], Duration of symptoms) prediction system score > 3.¹⁴ ABCD2 criteria can be used to help identify patients who are at higher risk of stroke or need further therapy (TABLE 1).^14,15

Send a patient with a current complaint or recent history of suspected focal neurologic deficits to an ED for accurate diagnosis of a possible TIA and, as appropriate, early treatment.

The ABCD2 score is also used to determine whether a patient needs dual antiplatelet therapy. Patients who score at the higher end of the ABCD2 system usually have an increased risk of stroke, longer hospitalization, and greater disability.

CASE

In the ED, Mr. L is immediately assessed and airlifted to a larger regional medical center, where MRI confirms a stroke.

Management

Initial management of a TIA is aimed at reducing the risk of recurrent TIA or stroke. Early medical and possibly surgical treatment are key for preventing stroke and improving outcomes. The first 48 hours after a TIA are the most critical because the incidence of recurrent TIA or stroke is highest during this period.^16-18

What is the accepted strategy for early treatment?

Initial treatment must include antiplatelet therapy, BP management, anticoagulation, statin therapy, and carotid endarterectomy as indicated.^2,19,20 Control of hypertension and anticoagulation decrease the risk of recurrent stroke by the largest margin²⁰; both are “A”-level Strength of Recommendation Taxonomy interventions.^2,3

Step 1: Antiplatelet therapy. After initial imaging is complete and if there are no contraindications, antiplatelet agents are recommended for patients who have had a noncardioembolic TIA. The American Heart Association and American Stroke Association recommend either aspirin, clopidogrel, dipyridamole + aspirin (available in a single capsule [Aggrenox]), or clopidogrel + aspirin as first-line therapy.^2,20 The choice of agent needs to be individualized, based on tolerability and adverse effects (TABLE 2^2,20,21).

A meta-analysis of antiplatelet therapy reviewed the optimum dosing of each medication.^21,22 Reduction of the risk of ischemic stroke with aspirin is 21% to 22% at the optimal dosing of 75 to 150 mg/d, which also reduces the risk of gastrointestinal bleeding.

Continue to: For a patient who has...

For a patient who has an ABCD2 score ≥ 4, has had a prior TIA, or has large-vessel disease, dual antiplatelet therapy is recommended for the first 21 days, with a subsequent return to monotherapy. Dual antiplatelet therapy of clopidogrel + aspirin increases the risk of adverse reactions and has not been shown to have greater long-term benefit^23-25 (TABLE 2^2,20,21).

Step 2: BP management. This is the next immediate step. As many as 80% of patients who present with a TIA have elevated BP upon admission. BP needs to be treated and carefully monitored during this early treatment phase. The recommendation is for a systolic BP < 185 mm Hg and a diastolic BP < 110 mm Hg.²⁴

Step 3: Anticoagulation. Treatment with warfarin or a direct oral anticoagulant (DOAC) is recommended for patients who have the potential for forming emboli—eg, in the setting of atrial fibrillation, ventricular thrombus, mechanical heart valve, or venous thromboembolism.

Step 4. High-intensity statin. A statin agent is recommended as part of immediate and long-term medical management, regardless of the low-density lipoprotein cholesterol (LDL-C) level, to reduce the risk of stroke.^2,24

Carotid artery management. Surgical intervention is not always considered a component of immediate medical management. However, guidelines recommend that carotid endarterectomy or stenting be considered in patients who have stenosis > 70%.²

CASE

Mr. L is admitted to the hospital and undergoes neurosurgical intervention. Medical management is instituted.

Long-term management and secondary prevention

The main risk factors for stroke can be divided into modifiable, vascular, and unmodifiable. Addressing both modifiable and vascular risks is important for secondary prevention.

Continue to: Modifiable and vascular risk factors

Modifiable risk factors for stroke include hypertension, diabetes, dyslipidemia, smoking, and physical activity; the most important of these, for preventing subsequent stroke after an initial TIA, is hypertension.²⁶

The 2 more significant vascular risk factors for stroke are carotid artery stenosis and atrial fibrillation.

Hypertension. Improving control of hypertension can improve secondary risk reduction for recurrent stroke. Control of both systolic and diastolic BP is important in this regard, with larger systolic BP reductions having a greater impact on decreasing the risk of recurrent stroke.²⁴ Evidence supports lowering BP to improve secondary risk reduction in people with and without diagnosed hypertension: The goal is to lower systolic BP by ≥ 10 mm Hg and diastolic BP by 5 mm Hg.²⁴ No particular class of antihypertensive is recommended in the first line, although preliminary evidence shows that a diuretic, with or without an angiotensin-converting enzyme inhibitor, might be more beneficial than other options.²⁴

Diabetes. The risk of cardiovascular disease, including stroke, is higher in people with diabetes. Evidence shows that various (but not all) agents in 2 pharmaceutical classes—glucagon-like peptide-1 (GLP-1) receptor agonists and the sodium glucose-2 cotransporter (SGLT2) inhibitors—reduce the risk of major cardiovascular events and improve secondary prevention of recurrent stroke:

• EMPA-REG OUTCOME (ClinicalTrials.gov Identifier: NCT01131676) was the first trial to show cardiovascular benefit from an SGLT2 inhibitor (empagliflozin); subsequent studies confirmed the cardiovascular benefits found in EMPA-REG OUTCOME.^27,28
• The ELIXA trial (ClinicalTrials.gov Identifier: NCT01147250) was the first to show cardiovascular benefit from a GLP-1 receptor agonist (lixisenatide); subsequent studies supported this finding.^29,30

Appropriate agents in these 2 classes should be considered as first-line or adjunctive in patients with both diabetes and known cardiovascular disease, as long as there are no contraindications.^27,28

Pioglitazone, a thiazolidinedione-class antidiabetic agent, was once considered a potential option to improve secondary prevention of stroke. However, the thiazolidinediones are generally no longer considered; instead, the SGLT2 inhibitors and GLP-1 receptor agonists are favored.³¹

Evidence demonstrates the effect of hyperglycemia on cardiovascular events; however, it is important to note that hypoglycemia can result in symptoms and focal changes that mimic a stroke. In addition, some evidence suggests that hypoglycemia can increase cardiovascular risk—thereby supporting the importance of strict control of diabetes and maintenance of euglycemia in reducing overall cardiovascular risk.³²

Continue to: Lipids

Lipids. The SPARCL trial (ClinicalTrials.gov Identifier: NCT00147602) was the first study to demonstrate the benefit of high-­intensity statin therapy—specifically, atorvastatin 80 mg/d—for secondary prevention for recurrent stroke.³³ The recommendation is to use high-intensity statin therapy to decrease the risk of recurrent stroke by reducing the level of LDL-C—by ≥ 50% or to < 70 mg/dL, for maximum risk reduction.^24,34

Common conditions that mimic a TIA are migraine with aura, seizure, and syncope; a TIA is generally not associated with chest pain, generalized weakness, or confusion.

The IMPROVE-IT trial (ClinicalTrials.gov Identifier: NCT00202878) demonstrated the benefit of adding ezetimibe, 10 mg/d, to a moderate-to-high-intensity statin (simvastatin, 40-80 mg/d) to reduce the risk of recurrent stroke.³⁵

Results of recent studies support the use of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors for regulating levels of LDL-C, as an additional option to consider—if needed to further reduce the LDL-C level or if statins are contraindicated in a particular patient.³⁴

Smoking cessation. Cigarette smoking is known to increase the risk of ischemic stroke; newer evidence shows that second-hand exposure to smoke also increases the risk of ischemic stroke.^36,37 Although these studies focused on primary prevention of ischemic stroke, the data can reasonably be applied to secondary prevention.³⁸ The recommendation for secondary prevention is to quit smoking and avoid secondhand smoke.²⁴

Alcohol. Evidence demonstrates that heavy alcohol consumption and alcoholism increase the risk of stroke; similar to what is known about smoking, most available data relate to primary prevention.³⁸ The recommendation for providing secondary stroke prevention is to stop or decrease alcohol intake.²⁴

Weight reduction. Obesity (body mass index > 30) increases the risk of ischemic stroke. However, there is, as yet, no evidence that weight loss diminishes the risk of subsequent stroke for secondary prevention.²⁴

Physical activity. Aerobic exercise and strength-training programs after a stroke improve cardiovascular health and mobility. There is no evidence that exercise leads to a reduction in the risk of subsequent stroke.²⁴

Continue to: Nutrition

Nutrition. No current randomized controlled trials are focused on the relationship between diet and recurrent stroke for purposes of prevention; however, evidence for both BP and lipid control incorporate dietary guidance. Recommendations include reducing intake of saturated fats and of sodium (the latter, to < 2.3 g/d) and increasing intake of fruits and vegetables, both of which are beneficial for controlling BP and lipid levels and promoting overall cardiovascular health.³⁸

Carotid artery stenosis. Several randomized controlled trials have demonstrated benefit from treating carotid stenosis (> 70% stenosis but not < 50%) with carotid endarterectomy to reduce the risk of recurrent stroke after TIA.² The ideal timing of carotid endarterectomy is still being studied; however, available evidence supports intervention within 2 to 6 weeks after TIA or stroke.²⁵ Studies are ongoing that compare carotid angioplasty and stenting against carotid endarterectomy. Medical therapy, with antiplatelet agents and statins, is recommended after carotid endarterectomy.²⁵

Atrial fibrillation increases the risk of recurrent stroke after a TIA, and is the most important indication for secondary stroke prevention with anticoagulation therapy:

• Warfarin. Several studies have shown that warfarin provides a 68% relative risk reduction and a 1.4% absolute risk reduction in the annual stroke rate.²⁴ To achieve this reduction in risk, the optimal international normalized ratio is 2.5 (range, 2-3).²⁴
• Aspirin provides a 13% relative risk reduction for recurrent stroke, although there is evidence that long-term anticoagulation provides more benefit than aspirin after a TIA.^39-41 Optimal dosing of aspirin ranges from 75-100 mg/d; greatest benefit is likely in the 12 weeks after stroke, when the risk of recurrent stroke is highest.^31,41,42
• DOACs have similar efficacy to warfarin but more rapid onset, lower risk of bleeding, fewer drug interactions, and no requirement for monitoring—often making them a more tolerable long-term choice. Options are rivaroxaban 20 mg/d, dabigatran 150 mg twice daily, apixaban 5 mg twice daily, and edoxaban 60 mg/d.³⁹

Initial treatment of a TIA must include antiplatelet therapy, BP management, anticoagulation, and statin therapy; carotid endarterectomy might also be indicated.

When to start anticoagulation and the choice of agent should be weighed against a risk of bleeding, which is highest after the initial stroke. Cost is also a consideration: DOACs are more expensive than warfarin.

CASE

Mr. L is discharged 3 days after carotid endarterectomy and free of residual deficits. He is started on dual antiplatelet therapy (aspirin + clopidogrel) for 21 days, to be followed by a return to monotherapy. He is restarted on a high-intensity statin. He is instructed to resume taking the selective serotonin reuptake inhibitor and melatonin for sleep, as needed. Last, he is told to schedule follow-up with his primary care physician in 7 to 10 days to begin post-stroke care.

Final thoughts

Primary care physicians are often the first point of contact for patients with current or remote TIA symptoms. Based on that ­provider–patient relationship, evidence supports several recommendations for diagnosing and treating a TIA and for reducing the risk of recurrent stroke after TIA. Addressing each of these areas, in this order, is imperative to reduce the risk of recurrent stroke and improve overall cardiovascular outcomes:

• Obtain an accurate diagnosis of a TIA, using DW-MRI or comparable brain imaging, to allow for prompt intervention.
• Initiate BP management promptly in the acute setting and establish optimal BP control over the long term.
• Begin appropriate antiplatelet therapy.
• When indicated (eg, atrial fibrillation), begin anticoagulation therapy with a DOAC or warfarin.
• Begin high-intensity statin therapy.
• Consider treating patients with diabetes using an SGLT2 inhibitor or GLP-1 receptor agonist.
• Encourage smoking cessation, prescribe quit-smoking medications, or refer a smoker for behavioral support.

Education. Last, it is important to educate patients—especially those who have risk factors for a TIA or stroke—about the presentation of events, so that they know to seek immediate medical attention.

CORRESPONDENCE
Kristen Rundell, MD, Department of Family and Community Medicine, University of Arizona College of Medicine, 655 North Alvernon Way, Suite 228, Tucson, AZ 85711; [email protected]

An at-home investigational device is a promising noninvasive therapeutic approach for anxiety disorders, results from an open-label pilot trial suggest.

The small study showed users of the Mechanical Affective Touch Therapy (MATT) had improved anxiety and depression symptoms, which corresponded to positive changes in alpha and theta oscillatory activity.

Butler Hospital

Robust safety profile

Therapeutic noninvasive peripheral nerve stimulation is under investigation for anxiety as well as pain and depression. Nerve activation is achieved by delivering electrical or mechanical energy, although most devices to date have used electrical stimulation.

Although electrical stimulation is considered low risk, mechanical stimulation that activates somatosensory pathways has an even more robust safety profile, the investigators note.

The MATT device targets C-tactile fibers (CT) specialized unmyelinated Group C peripheral nerve fibers that fire when stroked at velocities perceived as pleasurable or comforting.

To use the device, participants wear a headset with a small vibrating piece that sits on the mastoid bone behind each ear. These pieces deliver gentle vibrations that can be adjusted by patients.  

During development of the MATT stimulation, researchers noted that an isochronic 10 Hz wave, cycling 2 seconds on and 2 seconds off, induced a state of relaxation and increased occipital alpha oscillations in pilot study participants.

The current study was designed to confirm preliminary efficacy and feasibility signals. The sample included 22 patients (mean age 37.3 years, 72.7% female, 77.3% White). All study participants were diagnosed with an anxiety disorder and had at least moderately severe anxiety symptoms. Some also had symptoms of panic or depression.

Many participants were on medications that weren’t effective, and they wanted to find a nondrug method of relieving their symptoms, said Dr. Carpenter.
 

What’s the mechanism?

Participants learned how to administer the stimulation and adjust the intensity of vibrations to a level where it was consistently detectable but not uncomfortable. Then they received a MATT device to use at home at least twice daily for 20 minutes.

Patients kept daily diaries documenting device use, adverse effects, and technological problems. In-person assessments were held at 2 and 4 weeks.

Researchers collected resting EEG immediately before, and after, the second stimulation session and again following 4 weeks of MATT use.

At baseline and after 2 and 4 weeks, patients self-reported anxiety using the 7-item Generalized Anxiety Disorder (GAD-7) scale, depression with the Beck Depression Inventory (BDI), and stress using the Perceived Stress Scale (PSS). They also reported symptoms with the Depression, Anxiety, Stress Scale (DASS).

Researchers also investigated “interoceptive awareness” or being mindful of your body and internal feelings. For this, they had participants complete the 32-item Multidimensional Assessment of Interoceptive Awareness pre- and post treatment.

Interoceptive awareness “is a whole new area of interest in neuroscience and brain health,” said Dr. Carpenter. “The hypothesis was that one way this device might work is that vibrations would travel to the insular cortex, the part of the brain that involves mindfulness and self-awareness.”
 

Symptom reduction

In the completer sample of 17 participants, mean scores on anxiety and depression symptoms fell significantly from baseline to 4 weeks (all P < .01). For example, the GAD-7 mean score fell from 14.3 to 7.1 and the BDI mean score from 30.6 to 14.8.

The study also showed that mindfulness was enhanced. The MAIA total score increased from 83.1 to 93.5 (P = .014).

Device users had increased alpha and theta brainwave activity, findings that “go along with the concept of decreased anxiety,” said Dr. Carpenter. She noted a recent study of the same patient population showed the device enhanced functional brain connectivity.

This current study was too small to pick up signals showing the device was effective in any particular subpopulation, said Dr. Carpenter.

Unlike other stimulation interventions that require clinic visits, patients use the MATT in the comfort of their own home and at their own convenience.

However, there are still questions surrounding the use of the noninvasive device. For example, said Dr. Carpenter, it’s unclear if it would be more effective if combined with psychotherapy or whether patients can use it while sleeping and driving. A next step could be a sham-controlled trial, she said.

The study was supported by Affect Neuro, developer of MATT therapy, and the National Institute of General Medical Sciences. Dr. Carpenter reports receiving a consultancy fee from Affect Neuro.

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

An at-home investigational device is a promising noninvasive therapeutic approach for anxiety disorders, results from an open-label pilot trial suggest.

The small study showed users of the Mechanical Affective Touch Therapy (MATT) had improved anxiety and depression symptoms, which corresponded to positive changes in alpha and theta oscillatory activity.

Butler Hospital

Robust safety profile

Therapeutic noninvasive peripheral nerve stimulation is under investigation for anxiety as well as pain and depression. Nerve activation is achieved by delivering electrical or mechanical energy, although most devices to date have used electrical stimulation.

Although electrical stimulation is considered low risk, mechanical stimulation that activates somatosensory pathways has an even more robust safety profile, the investigators note.

The MATT device targets C-tactile fibers (CT) specialized unmyelinated Group C peripheral nerve fibers that fire when stroked at velocities perceived as pleasurable or comforting.

To use the device, participants wear a headset with a small vibrating piece that sits on the mastoid bone behind each ear. These pieces deliver gentle vibrations that can be adjusted by patients.  

During development of the MATT stimulation, researchers noted that an isochronic 10 Hz wave, cycling 2 seconds on and 2 seconds off, induced a state of relaxation and increased occipital alpha oscillations in pilot study participants.

The current study was designed to confirm preliminary efficacy and feasibility signals. The sample included 22 patients (mean age 37.3 years, 72.7% female, 77.3% White). All study participants were diagnosed with an anxiety disorder and had at least moderately severe anxiety symptoms. Some also had symptoms of panic or depression.

Many participants were on medications that weren’t effective, and they wanted to find a nondrug method of relieving their symptoms, said Dr. Carpenter.
 

What’s the mechanism?

Participants learned how to administer the stimulation and adjust the intensity of vibrations to a level where it was consistently detectable but not uncomfortable. Then they received a MATT device to use at home at least twice daily for 20 minutes.

Patients kept daily diaries documenting device use, adverse effects, and technological problems. In-person assessments were held at 2 and 4 weeks.

Researchers collected resting EEG immediately before, and after, the second stimulation session and again following 4 weeks of MATT use.

At baseline and after 2 and 4 weeks, patients self-reported anxiety using the 7-item Generalized Anxiety Disorder (GAD-7) scale, depression with the Beck Depression Inventory (BDI), and stress using the Perceived Stress Scale (PSS). They also reported symptoms with the Depression, Anxiety, Stress Scale (DASS).

Researchers also investigated “interoceptive awareness” or being mindful of your body and internal feelings. For this, they had participants complete the 32-item Multidimensional Assessment of Interoceptive Awareness pre- and post treatment.

Interoceptive awareness “is a whole new area of interest in neuroscience and brain health,” said Dr. Carpenter. “The hypothesis was that one way this device might work is that vibrations would travel to the insular cortex, the part of the brain that involves mindfulness and self-awareness.”
 

Symptom reduction

In the completer sample of 17 participants, mean scores on anxiety and depression symptoms fell significantly from baseline to 4 weeks (all P < .01). For example, the GAD-7 mean score fell from 14.3 to 7.1 and the BDI mean score from 30.6 to 14.8.

The study also showed that mindfulness was enhanced. The MAIA total score increased from 83.1 to 93.5 (P = .014).

Device users had increased alpha and theta brainwave activity, findings that “go along with the concept of decreased anxiety,” said Dr. Carpenter. She noted a recent study of the same patient population showed the device enhanced functional brain connectivity.

This current study was too small to pick up signals showing the device was effective in any particular subpopulation, said Dr. Carpenter.

Unlike other stimulation interventions that require clinic visits, patients use the MATT in the comfort of their own home and at their own convenience.

However, there are still questions surrounding the use of the noninvasive device. For example, said Dr. Carpenter, it’s unclear if it would be more effective if combined with psychotherapy or whether patients can use it while sleeping and driving. A next step could be a sham-controlled trial, she said.

The study was supported by Affect Neuro, developer of MATT therapy, and the National Institute of General Medical Sciences. Dr. Carpenter reports receiving a consultancy fee from Affect Neuro.

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

An at-home investigational device is a promising noninvasive therapeutic approach for anxiety disorders, results from an open-label pilot trial suggest.

The small study showed users of the Mechanical Affective Touch Therapy (MATT) had improved anxiety and depression symptoms, which corresponded to positive changes in alpha and theta oscillatory activity.

Butler Hospital

Robust safety profile

Therapeutic noninvasive peripheral nerve stimulation is under investigation for anxiety as well as pain and depression. Nerve activation is achieved by delivering electrical or mechanical energy, although most devices to date have used electrical stimulation.

Although electrical stimulation is considered low risk, mechanical stimulation that activates somatosensory pathways has an even more robust safety profile, the investigators note.

The MATT device targets C-tactile fibers (CT) specialized unmyelinated Group C peripheral nerve fibers that fire when stroked at velocities perceived as pleasurable or comforting.

To use the device, participants wear a headset with a small vibrating piece that sits on the mastoid bone behind each ear. These pieces deliver gentle vibrations that can be adjusted by patients.  

During development of the MATT stimulation, researchers noted that an isochronic 10 Hz wave, cycling 2 seconds on and 2 seconds off, induced a state of relaxation and increased occipital alpha oscillations in pilot study participants.

The current study was designed to confirm preliminary efficacy and feasibility signals. The sample included 22 patients (mean age 37.3 years, 72.7% female, 77.3% White). All study participants were diagnosed with an anxiety disorder and had at least moderately severe anxiety symptoms. Some also had symptoms of panic or depression.

Many participants were on medications that weren’t effective, and they wanted to find a nondrug method of relieving their symptoms, said Dr. Carpenter.
 

What’s the mechanism?

Participants learned how to administer the stimulation and adjust the intensity of vibrations to a level where it was consistently detectable but not uncomfortable. Then they received a MATT device to use at home at least twice daily for 20 minutes.

Patients kept daily diaries documenting device use, adverse effects, and technological problems. In-person assessments were held at 2 and 4 weeks.

Researchers collected resting EEG immediately before, and after, the second stimulation session and again following 4 weeks of MATT use.

At baseline and after 2 and 4 weeks, patients self-reported anxiety using the 7-item Generalized Anxiety Disorder (GAD-7) scale, depression with the Beck Depression Inventory (BDI), and stress using the Perceived Stress Scale (PSS). They also reported symptoms with the Depression, Anxiety, Stress Scale (DASS).

Researchers also investigated “interoceptive awareness” or being mindful of your body and internal feelings. For this, they had participants complete the 32-item Multidimensional Assessment of Interoceptive Awareness pre- and post treatment.

Interoceptive awareness “is a whole new area of interest in neuroscience and brain health,” said Dr. Carpenter. “The hypothesis was that one way this device might work is that vibrations would travel to the insular cortex, the part of the brain that involves mindfulness and self-awareness.”
 

Symptom reduction

In the completer sample of 17 participants, mean scores on anxiety and depression symptoms fell significantly from baseline to 4 weeks (all P < .01). For example, the GAD-7 mean score fell from 14.3 to 7.1 and the BDI mean score from 30.6 to 14.8.

The study also showed that mindfulness was enhanced. The MAIA total score increased from 83.1 to 93.5 (P = .014).

Device users had increased alpha and theta brainwave activity, findings that “go along with the concept of decreased anxiety,” said Dr. Carpenter. She noted a recent study of the same patient population showed the device enhanced functional brain connectivity.

This current study was too small to pick up signals showing the device was effective in any particular subpopulation, said Dr. Carpenter.

Unlike other stimulation interventions that require clinic visits, patients use the MATT in the comfort of their own home and at their own convenience.

However, there are still questions surrounding the use of the noninvasive device. For example, said Dr. Carpenter, it’s unclear if it would be more effective if combined with psychotherapy or whether patients can use it while sleeping and driving. A next step could be a sham-controlled trial, she said.

The study was supported by Affect Neuro, developer of MATT therapy, and the National Institute of General Medical Sciences. Dr. Carpenter reports receiving a consultancy fee from Affect Neuro.

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