A group of teenage 4-H members take part in a state agricultural fair, after which one of the boys comes sick. But luckily they have also attended the CDC’s Disease Detective Camp in Atlanta and use their newly acquired detective skills to find out why their friend got sick.

That is the story in “The Junior Disease Detectives: Operation Outbreak,” the new graphic novel the CDC has developed with the Department of Agriculture and 4-H.

Spoiler alert: it was the flu. The novel is designed to help young people understand the potential health risks of human influenza viruses that normally circulate in swine, known as variant flu infections.

Four new variant virus infections have been associated with attendance at agricultural fairs in 2 US states, the CDC reports. Most are connected to infected pigs or their environments in fair settings. While variant flu infections in people are rare, the CDC says, they can lead to hospitalization and death. In 2017, 67 variant virus infections were reported in the US; 6 resulted in hospitalization, including 2 ICU admissions.

The novel is intended for use in middle and high school science, technology, engineering, and mathematics (STEM) classrooms. It is the first of a planned series of educational activities being rolled out throughout the 2018-2019 school year.

The novel is available as a free mobile app, and can be downloaded at https://www.cdc.gov/flu/resource-center/freeresources/graphic-novel/index.html?CDC_AA_refVal=https%3A%2F%2Fwww.cdc.gov%2Fflu%2Fgraphicnovel%2Findex.html.

A group of teenage 4-H members take part in a state agricultural fair, after which one of the boys comes sick. But luckily they have also attended the CDC’s Disease Detective Camp in Atlanta and use their newly acquired detective skills to find out why their friend got sick.

That is the story in “The Junior Disease Detectives: Operation Outbreak,” the new graphic novel the CDC has developed with the Department of Agriculture and 4-H.

Spoiler alert: it was the flu. The novel is designed to help young people understand the potential health risks of human influenza viruses that normally circulate in swine, known as variant flu infections.

Four new variant virus infections have been associated with attendance at agricultural fairs in 2 US states, the CDC reports. Most are connected to infected pigs or their environments in fair settings. While variant flu infections in people are rare, the CDC says, they can lead to hospitalization and death. In 2017, 67 variant virus infections were reported in the US; 6 resulted in hospitalization, including 2 ICU admissions.

The novel is intended for use in middle and high school science, technology, engineering, and mathematics (STEM) classrooms. It is the first of a planned series of educational activities being rolled out throughout the 2018-2019 school year.

The novel is available as a free mobile app, and can be downloaded at https://www.cdc.gov/flu/resource-center/freeresources/graphic-novel/index.html?CDC_AA_refVal=https%3A%2F%2Fwww.cdc.gov%2Fflu%2Fgraphicnovel%2Findex.html.

A group of teenage 4-H members take part in a state agricultural fair, after which one of the boys comes sick. But luckily they have also attended the CDC’s Disease Detective Camp in Atlanta and use their newly acquired detective skills to find out why their friend got sick.

That is the story in “The Junior Disease Detectives: Operation Outbreak,” the new graphic novel the CDC has developed with the Department of Agriculture and 4-H.

Spoiler alert: it was the flu. The novel is designed to help young people understand the potential health risks of human influenza viruses that normally circulate in swine, known as variant flu infections.

Four new variant virus infections have been associated with attendance at agricultural fairs in 2 US states, the CDC reports. Most are connected to infected pigs or their environments in fair settings. While variant flu infections in people are rare, the CDC says, they can lead to hospitalization and death. In 2017, 67 variant virus infections were reported in the US; 6 resulted in hospitalization, including 2 ICU admissions.

The novel is intended for use in middle and high school science, technology, engineering, and mathematics (STEM) classrooms. It is the first of a planned series of educational activities being rolled out throughout the 2018-2019 school year.

The novel is available as a free mobile app, and can be downloaded at https://www.cdc.gov/flu/resource-center/freeresources/graphic-novel/index.html?CDC_AA_refVal=https%3A%2F%2Fwww.cdc.gov%2Fflu%2Fgraphicnovel%2Findex.html.

Gut bacteria

A randomized, controlled study of 25 patients has demonstrated that an autologous fecal microbiota transplant (auto-FMT) can restore beneficial gut bacteria depleted during allogeneic hematopoietic stem cell transplant (auto-HSCT), according to researchers.

Antibiotics given to prevent and treat bacterial infections during HSCT can also destroy patients’ beneficial intestinal bacteria, increasing their risk for infections and graft-versus-host disease.

The researchers reported that auto-FMT is a safe and effective way to help replenish the beneficial bacteria to near baseline levels within days.

Study patients receiving HSCT at Memorial Sloan Kettering Cancer Center (MSKCC) in New York provided fecal samples collected before transplant conditioning, which were frozen and stored before undergoing transplant.

Between 1 and 5 weeks, when physicians could confirm that patients’ stem cells had engrafted, they collected another fecal sample from patients and randomized the first 25 who lacked known beneficial bacteria to one of two groups.

Eleven control patients received standard of care without fecal transplant and 14 received auto-FMT by enema.

Researchers followed the subjects for 1 year after randomization, with fecal samples collected during this time.

Eleven of the 14 patients (79%) in the auto-FMT group recovered 75% or more of their initial good gut bacteria within days. This helped restore their digestive, immune, and other essential functions.

The beneficial microbial groups restored included Lachnospiraceae (family), Ruminococcaceae (family), and Bacteroidetes (phylum).

Patients in the standard care group took many weeks to replenish the beneficial bacteria destroyed during antibiotic treatment. Only 3 of 11 (27%) control patients had regained 75% or more of the microbiota in their initial fecal sample.

The investigators acknowledge a few study limitations, including that it was conducted at a single institution. Therefore, they say, the findings may not apply to patients undergoing allo-HSCT at other institutions.

In addition, auto-FMT patients may have been treated previously for cancer and depleted of some good bacteria as a result of prior antibiotic therapy.

Nevertheless, the investigators believe their study demonstrated the potential of auto-FMT as a clinical intervention, “thereby reversing the disruptive effects of broad-spectrum antibiotic treatment for patients undergoing allo-HSCT transplant,” they wrote.

Lead author Ying Taur, MD, MPH, of MSKCC, and colleagues published their paper in Science Translational Medicine.

The trial, supported in part by the National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health, is ongoing and continues to accrue patients (NCT02269150).

“This important study suggests that clinical intervention using auto-FMT can safely reverse the disruptive effects of broad-spectrum antibiotic treatment,” said Anthony S. Fauci, MD, director of NIAID.

“If validated in larger studies, this approach may prove to be a relatively simple way to quickly restore a person’s healthy microbiome following intensive antimicrobial therapy.” 

Gut bacteria

A randomized, controlled study of 25 patients has demonstrated that an autologous fecal microbiota transplant (auto-FMT) can restore beneficial gut bacteria depleted during allogeneic hematopoietic stem cell transplant (auto-HSCT), according to researchers.

Antibiotics given to prevent and treat bacterial infections during HSCT can also destroy patients’ beneficial intestinal bacteria, increasing their risk for infections and graft-versus-host disease.

The researchers reported that auto-FMT is a safe and effective way to help replenish the beneficial bacteria to near baseline levels within days.

Study patients receiving HSCT at Memorial Sloan Kettering Cancer Center (MSKCC) in New York provided fecal samples collected before transplant conditioning, which were frozen and stored before undergoing transplant.

Between 1 and 5 weeks, when physicians could confirm that patients’ stem cells had engrafted, they collected another fecal sample from patients and randomized the first 25 who lacked known beneficial bacteria to one of two groups.

Eleven control patients received standard of care without fecal transplant and 14 received auto-FMT by enema.

Researchers followed the subjects for 1 year after randomization, with fecal samples collected during this time.

Eleven of the 14 patients (79%) in the auto-FMT group recovered 75% or more of their initial good gut bacteria within days. This helped restore their digestive, immune, and other essential functions.

The beneficial microbial groups restored included Lachnospiraceae (family), Ruminococcaceae (family), and Bacteroidetes (phylum).

Patients in the standard care group took many weeks to replenish the beneficial bacteria destroyed during antibiotic treatment. Only 3 of 11 (27%) control patients had regained 75% or more of the microbiota in their initial fecal sample.

The investigators acknowledge a few study limitations, including that it was conducted at a single institution. Therefore, they say, the findings may not apply to patients undergoing allo-HSCT at other institutions.

In addition, auto-FMT patients may have been treated previously for cancer and depleted of some good bacteria as a result of prior antibiotic therapy.

Nevertheless, the investigators believe their study demonstrated the potential of auto-FMT as a clinical intervention, “thereby reversing the disruptive effects of broad-spectrum antibiotic treatment for patients undergoing allo-HSCT transplant,” they wrote.

Lead author Ying Taur, MD, MPH, of MSKCC, and colleagues published their paper in Science Translational Medicine.

The trial, supported in part by the National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health, is ongoing and continues to accrue patients (NCT02269150).

“This important study suggests that clinical intervention using auto-FMT can safely reverse the disruptive effects of broad-spectrum antibiotic treatment,” said Anthony S. Fauci, MD, director of NIAID.

“If validated in larger studies, this approach may prove to be a relatively simple way to quickly restore a person’s healthy microbiome following intensive antimicrobial therapy.” 

Gut bacteria

A randomized, controlled study of 25 patients has demonstrated that an autologous fecal microbiota transplant (auto-FMT) can restore beneficial gut bacteria depleted during allogeneic hematopoietic stem cell transplant (auto-HSCT), according to researchers.

Antibiotics given to prevent and treat bacterial infections during HSCT can also destroy patients’ beneficial intestinal bacteria, increasing their risk for infections and graft-versus-host disease.

The researchers reported that auto-FMT is a safe and effective way to help replenish the beneficial bacteria to near baseline levels within days.

Study patients receiving HSCT at Memorial Sloan Kettering Cancer Center (MSKCC) in New York provided fecal samples collected before transplant conditioning, which were frozen and stored before undergoing transplant.

Between 1 and 5 weeks, when physicians could confirm that patients’ stem cells had engrafted, they collected another fecal sample from patients and randomized the first 25 who lacked known beneficial bacteria to one of two groups.

Eleven control patients received standard of care without fecal transplant and 14 received auto-FMT by enema.

Researchers followed the subjects for 1 year after randomization, with fecal samples collected during this time.

Eleven of the 14 patients (79%) in the auto-FMT group recovered 75% or more of their initial good gut bacteria within days. This helped restore their digestive, immune, and other essential functions.

The beneficial microbial groups restored included Lachnospiraceae (family), Ruminococcaceae (family), and Bacteroidetes (phylum).

Patients in the standard care group took many weeks to replenish the beneficial bacteria destroyed during antibiotic treatment. Only 3 of 11 (27%) control patients had regained 75% or more of the microbiota in their initial fecal sample.

The investigators acknowledge a few study limitations, including that it was conducted at a single institution. Therefore, they say, the findings may not apply to patients undergoing allo-HSCT at other institutions.

In addition, auto-FMT patients may have been treated previously for cancer and depleted of some good bacteria as a result of prior antibiotic therapy.

Nevertheless, the investigators believe their study demonstrated the potential of auto-FMT as a clinical intervention, “thereby reversing the disruptive effects of broad-spectrum antibiotic treatment for patients undergoing allo-HSCT transplant,” they wrote.

Lead author Ying Taur, MD, MPH, of MSKCC, and colleagues published their paper in Science Translational Medicine.

The trial, supported in part by the National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health, is ongoing and continues to accrue patients (NCT02269150).

“This important study suggests that clinical intervention using auto-FMT can safely reverse the disruptive effects of broad-spectrum antibiotic treatment,” said Anthony S. Fauci, MD, director of NIAID.

“If validated in larger studies, this approach may prove to be a relatively simple way to quickly restore a person’s healthy microbiome following intensive antimicrobial therapy.” 

Photo from CDC.gov

The U.S. Food and Drug Administration (FDA) has granted Qualified Infectious Disease Product (QIDP) and fast track designations for rezafungin, an injection for the prevention of invasive fungal infections in adults undergoing allogeneic bone marrow transplantation.

Rezafungin is a novel antifungal echinocandin being developed by Cidara Therapeutics to treat candidemia and invasive candidiasis and for prophylaxis of invasive fungal infections due to Candida, Aspergillus, and Pneumocystis.

These pathogens typically affect patients with compromised immune systems, such as patients undergoing organ, bone marrow transplants, or chemotherapy.

Rezafungin is administered as a once-weekly, high-exposure therapy. According to Cidara, no one agent is approved to prevent infections caused by these pathogens. Current prophylaxis regimens often require multiple antifungal drugs, causing safety and tolerability issues.

The QIDP designation offers incentives for the development of new antifungal and antibacterial drugs, including fast track, priority review and, if approved by the FDA, eligibility for an additional five years of marketing exclusivity.

Fast track designation enables more frequent interactions with the FDA review team to expedite drug development.

For QIDP designation, a drug candidate must treat serious or life-threatening infections, particularly those caused by bacteria and fungi resistant to treatment or by resistant pathogens identified by the FDA.

Rezafungin acetate, formerly known as CD101 IV, met its primary safety and efficacy objectives in the phase 2 STRIVE trial, providing support for the company to initiate phase 3 trials.

The phase 2 trial compared rezafungin to caspofungin in patients with candidemia and/or invasive candidiasis.

Investigators enrolled 92 patients in the microbial intent-to-treat population.

Patients were randomized to one of two dose groups of rezafungin or to the caspofungin arm.

One hundred percent of patients with invasive candidiasis responded to the rezafungin 400 mg first-week dose followed by 200 mg once weekly up to four weeks, compared to 33% of patients who responded to daily caspofungin.

The company reported no concerning adverse event trends.

Cidara is initiating phase 3 pivotal trials of rezafungin in the treatment of candidemia and invasive candidiasis and the prophylaxis of invasive fungal infections. 

Photo from CDC.gov

The U.S. Food and Drug Administration (FDA) has granted Qualified Infectious Disease Product (QIDP) and fast track designations for rezafungin, an injection for the prevention of invasive fungal infections in adults undergoing allogeneic bone marrow transplantation.

Rezafungin is a novel antifungal echinocandin being developed by Cidara Therapeutics to treat candidemia and invasive candidiasis and for prophylaxis of invasive fungal infections due to Candida, Aspergillus, and Pneumocystis.

These pathogens typically affect patients with compromised immune systems, such as patients undergoing organ, bone marrow transplants, or chemotherapy.

Rezafungin is administered as a once-weekly, high-exposure therapy. According to Cidara, no one agent is approved to prevent infections caused by these pathogens. Current prophylaxis regimens often require multiple antifungal drugs, causing safety and tolerability issues.

The QIDP designation offers incentives for the development of new antifungal and antibacterial drugs, including fast track, priority review and, if approved by the FDA, eligibility for an additional five years of marketing exclusivity.

Fast track designation enables more frequent interactions with the FDA review team to expedite drug development.

For QIDP designation, a drug candidate must treat serious or life-threatening infections, particularly those caused by bacteria and fungi resistant to treatment or by resistant pathogens identified by the FDA.

Rezafungin acetate, formerly known as CD101 IV, met its primary safety and efficacy objectives in the phase 2 STRIVE trial, providing support for the company to initiate phase 3 trials.

The phase 2 trial compared rezafungin to caspofungin in patients with candidemia and/or invasive candidiasis.

Investigators enrolled 92 patients in the microbial intent-to-treat population.

Patients were randomized to one of two dose groups of rezafungin or to the caspofungin arm.

One hundred percent of patients with invasive candidiasis responded to the rezafungin 400 mg first-week dose followed by 200 mg once weekly up to four weeks, compared to 33% of patients who responded to daily caspofungin.

The company reported no concerning adverse event trends.

Cidara is initiating phase 3 pivotal trials of rezafungin in the treatment of candidemia and invasive candidiasis and the prophylaxis of invasive fungal infections. 

Photo from CDC.gov

The U.S. Food and Drug Administration (FDA) has granted Qualified Infectious Disease Product (QIDP) and fast track designations for rezafungin, an injection for the prevention of invasive fungal infections in adults undergoing allogeneic bone marrow transplantation.

Rezafungin is a novel antifungal echinocandin being developed by Cidara Therapeutics to treat candidemia and invasive candidiasis and for prophylaxis of invasive fungal infections due to Candida, Aspergillus, and Pneumocystis.

These pathogens typically affect patients with compromised immune systems, such as patients undergoing organ, bone marrow transplants, or chemotherapy.

Rezafungin is administered as a once-weekly, high-exposure therapy. According to Cidara, no one agent is approved to prevent infections caused by these pathogens. Current prophylaxis regimens often require multiple antifungal drugs, causing safety and tolerability issues.

The QIDP designation offers incentives for the development of new antifungal and antibacterial drugs, including fast track, priority review and, if approved by the FDA, eligibility for an additional five years of marketing exclusivity.

Fast track designation enables more frequent interactions with the FDA review team to expedite drug development.

For QIDP designation, a drug candidate must treat serious or life-threatening infections, particularly those caused by bacteria and fungi resistant to treatment or by resistant pathogens identified by the FDA.

Rezafungin acetate, formerly known as CD101 IV, met its primary safety and efficacy objectives in the phase 2 STRIVE trial, providing support for the company to initiate phase 3 trials.

The phase 2 trial compared rezafungin to caspofungin in patients with candidemia and/or invasive candidiasis.

Investigators enrolled 92 patients in the microbial intent-to-treat population.

Patients were randomized to one of two dose groups of rezafungin or to the caspofungin arm.

One hundred percent of patients with invasive candidiasis responded to the rezafungin 400 mg first-week dose followed by 200 mg once weekly up to four weeks, compared to 33% of patients who responded to daily caspofungin.

The company reported no concerning adverse event trends.

Cidara is initiating phase 3 pivotal trials of rezafungin in the treatment of candidemia and invasive candidiasis and the prophylaxis of invasive fungal infections. 

During my residency, I have taken advantage of several opportunities that helped me develop and become more confident as I assumed the role of Academic Chief Resident in my final year of residency. In this article, I describe some of these opportunities, including seeking extra supervision while providing psychotherapy, engaging in psychotherapy for oneself, becoming part of leadership, and participating in quality improvement (QI) projects.

Obtain extra supervision while providing psychotherapy. I feel it is important to become comfortable with different types of therapy during residency. There are various opportunities to receive additional education via 1- and 2-year courses. I attended the Prelude to the Institute of Psychoanalytic Education, a 1-year introductory lecture series, and joined New York Psychiatric State Institute for my fellowship, which included reading papers describing different psychotherapeutic techniques and case discussions by experts in the field, which solidified many core concepts and helped me develop stronger therapeutic relationships with my patients. Advanced training in a specific evidence-based psychotherapy modality, such as cognitive-behavioral therapy, dialectical behavior therapy, or interpersonal therapy, is also an option.

Consider seeking out psychotherapy. When I started providing therapy to my patients, I became aware of how important it is to invest in your own personal therapy to understand your mind. I researched the importance of personal therapy for psychiatric clinicians, and to my surprise there have been lengthy debates on both its positive and negative impacts. However, I have come to believe that personal therapy is an important part of training for mental health professionals because it helps us better understand ourselves, since it is impossible to take the therapist’s mind out of the session. Although personal psycho­therapy is not required, residency is an opportune time to pursue it.

Get involved and become part of leadership. I always believed that when united, we are stronger. It is a great privilege that as residents, we can become an integral part of advocacy and leadership in different organizations at both the state and national level. Here are 2 examples of how I got involved:

• The American Psychiatric Association (APA). When I attended the APA to present my posters for the first time, I wanted to become more actively involved. So I contacted my district branch representatives for guidance. I attended meetings and became involved in the Brooklyn District Branch as a resident representative. I was elected APA Area 2 Resident Fellow Member Deputy representative (a 2-year position). In this position, I represent residents and fellows from New York in the APA assembly. This has been a gratifying experience, and I have come to appreciate the proceedings of the Assembly and the amount of work that goes into creating Action Papers and Policy Statements.
• The Committee of Interns and Residents (CIR). Representation in CIR is extremely important in this political climate. The resident CIR Delegates are selected via elections. Delegates have an excellent opportunity to attend the Delegate Conference to learn how CIR operates and represent the department in CIR meetings. CIR is extremely supportive of resident involvement in QI projects and provides opportunities to chair a quality council for residents.

Participate in QI projects. Involvement in QI projects provided me with the opportunity to learn unique skills, including how to think creatively, design a study, and work with statisticians to extract and analyze data. The main focus of my research has been resident well-being and burnout.

These are a few of the wonderful opportunities I have been able to experience during my residency. I would love to hear from other residents about their similar experiences.

During my residency, I have taken advantage of several opportunities that helped me develop and become more confident as I assumed the role of Academic Chief Resident in my final year of residency. In this article, I describe some of these opportunities, including seeking extra supervision while providing psychotherapy, engaging in psychotherapy for oneself, becoming part of leadership, and participating in quality improvement (QI) projects.

Obtain extra supervision while providing psychotherapy. I feel it is important to become comfortable with different types of therapy during residency. There are various opportunities to receive additional education via 1- and 2-year courses. I attended the Prelude to the Institute of Psychoanalytic Education, a 1-year introductory lecture series, and joined New York Psychiatric State Institute for my fellowship, which included reading papers describing different psychotherapeutic techniques and case discussions by experts in the field, which solidified many core concepts and helped me develop stronger therapeutic relationships with my patients. Advanced training in a specific evidence-based psychotherapy modality, such as cognitive-behavioral therapy, dialectical behavior therapy, or interpersonal therapy, is also an option.

Consider seeking out psychotherapy. When I started providing therapy to my patients, I became aware of how important it is to invest in your own personal therapy to understand your mind. I researched the importance of personal therapy for psychiatric clinicians, and to my surprise there have been lengthy debates on both its positive and negative impacts. However, I have come to believe that personal therapy is an important part of training for mental health professionals because it helps us better understand ourselves, since it is impossible to take the therapist’s mind out of the session. Although personal psycho­therapy is not required, residency is an opportune time to pursue it.

Get involved and become part of leadership. I always believed that when united, we are stronger. It is a great privilege that as residents, we can become an integral part of advocacy and leadership in different organizations at both the state and national level. Here are 2 examples of how I got involved:

• The American Psychiatric Association (APA). When I attended the APA to present my posters for the first time, I wanted to become more actively involved. So I contacted my district branch representatives for guidance. I attended meetings and became involved in the Brooklyn District Branch as a resident representative. I was elected APA Area 2 Resident Fellow Member Deputy representative (a 2-year position). In this position, I represent residents and fellows from New York in the APA assembly. This has been a gratifying experience, and I have come to appreciate the proceedings of the Assembly and the amount of work that goes into creating Action Papers and Policy Statements.
• The Committee of Interns and Residents (CIR). Representation in CIR is extremely important in this political climate. The resident CIR Delegates are selected via elections. Delegates have an excellent opportunity to attend the Delegate Conference to learn how CIR operates and represent the department in CIR meetings. CIR is extremely supportive of resident involvement in QI projects and provides opportunities to chair a quality council for residents.

Participate in QI projects. Involvement in QI projects provided me with the opportunity to learn unique skills, including how to think creatively, design a study, and work with statisticians to extract and analyze data. The main focus of my research has been resident well-being and burnout.

These are a few of the wonderful opportunities I have been able to experience during my residency. I would love to hear from other residents about their similar experiences.

During my residency, I have taken advantage of several opportunities that helped me develop and become more confident as I assumed the role of Academic Chief Resident in my final year of residency. In this article, I describe some of these opportunities, including seeking extra supervision while providing psychotherapy, engaging in psychotherapy for oneself, becoming part of leadership, and participating in quality improvement (QI) projects.

Obtain extra supervision while providing psychotherapy. I feel it is important to become comfortable with different types of therapy during residency. There are various opportunities to receive additional education via 1- and 2-year courses. I attended the Prelude to the Institute of Psychoanalytic Education, a 1-year introductory lecture series, and joined New York Psychiatric State Institute for my fellowship, which included reading papers describing different psychotherapeutic techniques and case discussions by experts in the field, which solidified many core concepts and helped me develop stronger therapeutic relationships with my patients. Advanced training in a specific evidence-based psychotherapy modality, such as cognitive-behavioral therapy, dialectical behavior therapy, or interpersonal therapy, is also an option.

Consider seeking out psychotherapy. When I started providing therapy to my patients, I became aware of how important it is to invest in your own personal therapy to understand your mind. I researched the importance of personal therapy for psychiatric clinicians, and to my surprise there have been lengthy debates on both its positive and negative impacts. However, I have come to believe that personal therapy is an important part of training for mental health professionals because it helps us better understand ourselves, since it is impossible to take the therapist’s mind out of the session. Although personal psycho­therapy is not required, residency is an opportune time to pursue it.

Get involved and become part of leadership. I always believed that when united, we are stronger. It is a great privilege that as residents, we can become an integral part of advocacy and leadership in different organizations at both the state and national level. Here are 2 examples of how I got involved:

• The American Psychiatric Association (APA). When I attended the APA to present my posters for the first time, I wanted to become more actively involved. So I contacted my district branch representatives for guidance. I attended meetings and became involved in the Brooklyn District Branch as a resident representative. I was elected APA Area 2 Resident Fellow Member Deputy representative (a 2-year position). In this position, I represent residents and fellows from New York in the APA assembly. This has been a gratifying experience, and I have come to appreciate the proceedings of the Assembly and the amount of work that goes into creating Action Papers and Policy Statements.
• The Committee of Interns and Residents (CIR). Representation in CIR is extremely important in this political climate. The resident CIR Delegates are selected via elections. Delegates have an excellent opportunity to attend the Delegate Conference to learn how CIR operates and represent the department in CIR meetings. CIR is extremely supportive of resident involvement in QI projects and provides opportunities to chair a quality council for residents.

Participate in QI projects. Involvement in QI projects provided me with the opportunity to learn unique skills, including how to think creatively, design a study, and work with statisticians to extract and analyze data. The main focus of my research has been resident well-being and burnout.

These are a few of the wonderful opportunities I have been able to experience during my residency. I would love to hear from other residents about their similar experiences.

Epidiolex, a cannabis-derived product approved earlier this year by the Food and Drug Administration for the treatment of childhood seizure syndromes, has been reclassified by the Drug Enforcement Administration. This paves the way for the manufacturer to begin marketing Epidiolex, which is expected to be on the market within 6 weeks.

rozmarina/Thinkstock

GW Pharmaceuticals, in a Sept. 27 press release announcing the rescheduling of the company’s oral cannabidiol (CBD) solution, said that the Drug Enforcement Administration had transferred Epidiolex to schedule V, the lowest category of scheduled substances.

The final rescheduling order from the DEA is limited to drugs approved by the FDA that contain cannabis-derived CBD and no more than 0.1% tetrahydrocannabinols. In practice, this means that the rescheduling currently applies only to Epidiolex, since this is the only formulation of CBD that has received FDA approval.

“We are pleased that the DEA has placed Epidiolex in the lowest restriction schedule, because it will help ensure that patients with LGS [Lennox-Gastaut syndrome] and Dravet syndrome, two of the most debilitating forms of epilepsy, can access this important new treatment option through their physicians,” said GW Pharmaceutical’s chief executive officer Justin Gover in a statement from the company announcing the reclassification.

During the FDA advisory committee meeting for the approval of Epidiolex to treat LGS and Dravet syndromes, both the FDA and GW Pharmaceuticals assessed the abuse potential for CBD as very low, since it does not contain tetrahydrocannabinol, the primary psychoactive component of cannabis.

All other marijuana products are currently classified as schedule I drugs, along with such illegal substances as heroin and cocaine.

Epidiolex had received fast track and rare pediatric designations from the FDA for LGS and Dravet syndrome; the approval was based on three pivotal randomized, double-blind, placebo-controlled clinical trials. The drug met its primary endpoint of reduced seizure frequency in all trials when added to standard of care for patients with drug-resistant LGS and Dravet syndrome.

Safety evaluations assessed data from 1,756 patients, finding that the 20 deaths seen during the study period were not clearly linked to Epidiolex and not unexpected for children with severe seizure disorders.

In supplementary information accompanying the order, the DEA’s acting administrator, Uttam Dhillon, noted that the FDA’s approval of Epidiolex means that “it has a currently accepted medical use in treatment for purposes of the CSA [Controlled Substances Act]. Accordingly, Epidiolex no longer meets the criteria for placement in schedule I of the CSA.” Schedule I drugs, by definition, do not have a currently accepted medical use.

Schedule V drugs, according to the DEA’s website, are currently defined as “drugs with lower potential for abuse than schedule IV and consist of preparations containing limited quantities of certain narcotics.” Other schedule V drugs include cough medicine with less than 200 mg of codeine/100 mL, antidiarrheal medications, pregabalin (Lyrica), and the antiepileptics brivaracetam (Briviact) and lacosamide (Vimpat). “Schedule V drugs represents the least potential for abuse,” according to the website.

Epidiolex is indicated for adjunctive treatment of seizures in patients with LGS or Dravet syndrome aged 2 years and older. Initial dosing recommendations are to titrate to a dose of 10 mg/kg/day, with dose adjustments permissible up to 20 mg/kg/day depending on clinical response and tolerability. The manufacturer has also submitted a marketing agreement to the European Medicines Agency and has received orphan drug designation for Epidiolex in the treatment of another seizure disorder, tuberous sclerosis complex.

koakes@mdedge.com

Epidiolex, a cannabis-derived product approved earlier this year by the Food and Drug Administration for the treatment of childhood seizure syndromes, has been reclassified by the Drug Enforcement Administration. This paves the way for the manufacturer to begin marketing Epidiolex, which is expected to be on the market within 6 weeks.

rozmarina/Thinkstock

GW Pharmaceuticals, in a Sept. 27 press release announcing the rescheduling of the company’s oral cannabidiol (CBD) solution, said that the Drug Enforcement Administration had transferred Epidiolex to schedule V, the lowest category of scheduled substances.

The final rescheduling order from the DEA is limited to drugs approved by the FDA that contain cannabis-derived CBD and no more than 0.1% tetrahydrocannabinols. In practice, this means that the rescheduling currently applies only to Epidiolex, since this is the only formulation of CBD that has received FDA approval.

“We are pleased that the DEA has placed Epidiolex in the lowest restriction schedule, because it will help ensure that patients with LGS [Lennox-Gastaut syndrome] and Dravet syndrome, two of the most debilitating forms of epilepsy, can access this important new treatment option through their physicians,” said GW Pharmaceutical’s chief executive officer Justin Gover in a statement from the company announcing the reclassification.

During the FDA advisory committee meeting for the approval of Epidiolex to treat LGS and Dravet syndromes, both the FDA and GW Pharmaceuticals assessed the abuse potential for CBD as very low, since it does not contain tetrahydrocannabinol, the primary psychoactive component of cannabis.

All other marijuana products are currently classified as schedule I drugs, along with such illegal substances as heroin and cocaine.

Epidiolex had received fast track and rare pediatric designations from the FDA for LGS and Dravet syndrome; the approval was based on three pivotal randomized, double-blind, placebo-controlled clinical trials. The drug met its primary endpoint of reduced seizure frequency in all trials when added to standard of care for patients with drug-resistant LGS and Dravet syndrome.

Safety evaluations assessed data from 1,756 patients, finding that the 20 deaths seen during the study period were not clearly linked to Epidiolex and not unexpected for children with severe seizure disorders.

In supplementary information accompanying the order, the DEA’s acting administrator, Uttam Dhillon, noted that the FDA’s approval of Epidiolex means that “it has a currently accepted medical use in treatment for purposes of the CSA [Controlled Substances Act]. Accordingly, Epidiolex no longer meets the criteria for placement in schedule I of the CSA.” Schedule I drugs, by definition, do not have a currently accepted medical use.

Schedule V drugs, according to the DEA’s website, are currently defined as “drugs with lower potential for abuse than schedule IV and consist of preparations containing limited quantities of certain narcotics.” Other schedule V drugs include cough medicine with less than 200 mg of codeine/100 mL, antidiarrheal medications, pregabalin (Lyrica), and the antiepileptics brivaracetam (Briviact) and lacosamide (Vimpat). “Schedule V drugs represents the least potential for abuse,” according to the website.

Epidiolex is indicated for adjunctive treatment of seizures in patients with LGS or Dravet syndrome aged 2 years and older. Initial dosing recommendations are to titrate to a dose of 10 mg/kg/day, with dose adjustments permissible up to 20 mg/kg/day depending on clinical response and tolerability. The manufacturer has also submitted a marketing agreement to the European Medicines Agency and has received orphan drug designation for Epidiolex in the treatment of another seizure disorder, tuberous sclerosis complex.

koakes@mdedge.com

Epidiolex, a cannabis-derived product approved earlier this year by the Food and Drug Administration for the treatment of childhood seizure syndromes, has been reclassified by the Drug Enforcement Administration. This paves the way for the manufacturer to begin marketing Epidiolex, which is expected to be on the market within 6 weeks.

rozmarina/Thinkstock

GW Pharmaceuticals, in a Sept. 27 press release announcing the rescheduling of the company’s oral cannabidiol (CBD) solution, said that the Drug Enforcement Administration had transferred Epidiolex to schedule V, the lowest category of scheduled substances.

The final rescheduling order from the DEA is limited to drugs approved by the FDA that contain cannabis-derived CBD and no more than 0.1% tetrahydrocannabinols. In practice, this means that the rescheduling currently applies only to Epidiolex, since this is the only formulation of CBD that has received FDA approval.

“We are pleased that the DEA has placed Epidiolex in the lowest restriction schedule, because it will help ensure that patients with LGS [Lennox-Gastaut syndrome] and Dravet syndrome, two of the most debilitating forms of epilepsy, can access this important new treatment option through their physicians,” said GW Pharmaceutical’s chief executive officer Justin Gover in a statement from the company announcing the reclassification.

During the FDA advisory committee meeting for the approval of Epidiolex to treat LGS and Dravet syndromes, both the FDA and GW Pharmaceuticals assessed the abuse potential for CBD as very low, since it does not contain tetrahydrocannabinol, the primary psychoactive component of cannabis.

All other marijuana products are currently classified as schedule I drugs, along with such illegal substances as heroin and cocaine.

Epidiolex had received fast track and rare pediatric designations from the FDA for LGS and Dravet syndrome; the approval was based on three pivotal randomized, double-blind, placebo-controlled clinical trials. The drug met its primary endpoint of reduced seizure frequency in all trials when added to standard of care for patients with drug-resistant LGS and Dravet syndrome.

Safety evaluations assessed data from 1,756 patients, finding that the 20 deaths seen during the study period were not clearly linked to Epidiolex and not unexpected for children with severe seizure disorders.

In supplementary information accompanying the order, the DEA’s acting administrator, Uttam Dhillon, noted that the FDA’s approval of Epidiolex means that “it has a currently accepted medical use in treatment for purposes of the CSA [Controlled Substances Act]. Accordingly, Epidiolex no longer meets the criteria for placement in schedule I of the CSA.” Schedule I drugs, by definition, do not have a currently accepted medical use.

Schedule V drugs, according to the DEA’s website, are currently defined as “drugs with lower potential for abuse than schedule IV and consist of preparations containing limited quantities of certain narcotics.” Other schedule V drugs include cough medicine with less than 200 mg of codeine/100 mL, antidiarrheal medications, pregabalin (Lyrica), and the antiepileptics brivaracetam (Briviact) and lacosamide (Vimpat). “Schedule V drugs represents the least potential for abuse,” according to the website.

Epidiolex is indicated for adjunctive treatment of seizures in patients with LGS or Dravet syndrome aged 2 years and older. Initial dosing recommendations are to titrate to a dose of 10 mg/kg/day, with dose adjustments permissible up to 20 mg/kg/day depending on clinical response and tolerability. The manufacturer has also submitted a marketing agreement to the European Medicines Agency and has received orphan drug designation for Epidiolex in the treatment of another seizure disorder, tuberous sclerosis complex.

koakes@mdedge.com

Adverse events related to sulfasalazine played a role in the higher discontinuation rate observed for rheumatoid arthritis (RA) patients on triple therapy when compared with similar patients taking methotrexate and a tumor necrosis factor inhibitor in an observational cohort study of historical data during 2006-2012.

copyright kgtoh/Thinkstock

The findings shed some light on understanding if the noninferior efficacy of triple therapy (TT) with methotrexate (MTX), sulfasalazine (SSZ), and hydroxychloroquine (HCQ) in randomized trials versus combination MTX plus tumor necrosis factor inhibitor (MTX-TNFi) is matched by patients’ persistence and adherence to TT in real-world data.

“With the proven efficacy of these combination therapies, an understanding of the real-world observations outside of clinical trials should be investigated to determine if similar experiences are seen in clinical practice as in clinical trials,” first author Daniel P. Erhardt, MD, MPH, of the George E. Wahlen VA Medical Center, Salt Lake City, and his colleagues wrote in Arthritis Care & Research.

In the current study, the research team identified veterans with RA escalating treatment from MTX to MTX-TNFi (n = 2,125) or to triple therapy (n = 171) from Veterans Affairs (VA) clinical and administrative databases during 2006-2012.

Patients taking MTX-TNFi consistently had significantly higher levels of persistence than did TT patients regardless of the strictness of the definition used. The highest level of persistence as defined in the study – all medications (including MTX) filled without a 90-day or longer gap in treatment over the 12-month study period – was observed in 43.2% of the MTX-TNFi arm, compared with 17.6% in the TT arm. A more liberal definition of persistence that allowed discontinuation of any one disease-modifying antirheumatic drug (DMARD) in TT or MTX in the MTX-TNFi group – provided no new DMARDs were initiated – yielded a persistence rate of 50.3% for MTX-TNFi vs. 32.8% for the TT arm. The persistence rate for MTX-TNFi worsened somewhat to 42.9% when the same discontinuation was allowed and switching was permitted between drugs within the TNFi class for the MTX-TNFi combination group, but it stayed lower for the TT group at 33.9% when single DMARD discontinuation was allowed and switching between nonbiologic DMARDs was permitted (without a 90-day or longer gap prior to the switch).

Adherence as defined by 80% or more of days covered at 1 year was 25.3% in the MTX-TNFi arm, with individual adherence rates of 44.3% for MTX and 46% for TNFi. In comparison, adherence for TT overall was 10.5%, with adherence rates of 48.6% for MTX, 32.8% for HCQ, and 18.7% for SSZ.

TT group patients most commonly discontinued sulfasalazine (20.9%), followed by MTX (8.7%) and HCQ (7.8%), whereas in those treated with MTX-TNFi, many more stopped TNFi alone (53.9%) than MTX alone (19.1%). It also was more common to stop SSZ and HCQ together (37.4%) or all TT drugs (23.5%) than it was to stop MTX plus HCQ together (1.7%).

The most common reason for discontinuation in both groups was an adverse drug event (ADE), cited as the reason in 43.5% of TT patients and 35.7% of combination-therapy patients. Most SSZ discontinuations were reported as an ADE, most often because of concerns of GI toxicity or symptoms, the researchers said. GI toxicity or symptoms was cited as a reason for discontinuing for 18.3% of TT patients who discontinued, compared with only 1.7% of MTX-TNFi patients.

“Findings from our study indicate that ADE play a significant role in influencing drug discontinuation, and further efforts should focus on ways to mitigate ADE when initiating or escalating drug regimens for RA,” they concluded.

They noted that a large percentage of subjects who discontinued their combination therapy for RA were lost to follow-up from the VA system: 34.8% in the TT group and 32.2% in the MTX-TNFi group.

“Research should continue to focus on ascertaining methods to improve real-world treatment retention rates,” they advised.

“More research is also warranted to determine whether patient factors that influence medication adherence independently affect the likelihood of achieving clinical remission, regardless of which therapy is chosen for the treatment of their RA,” they added.

The research was supported by Specialty Care Center of Innovation in the Veterans Health Administration and by the Health Services Research and Development division of the Department of Veterans Affairs. Several of the authors reported receiving research funding and grants from several pharmaceutical companies.

SOURCE: Erhardt DP et al. Arthritis Care Res. 2018 Sep 17. doi: 10.1002/acr.23759

Adverse events related to sulfasalazine played a role in the higher discontinuation rate observed for rheumatoid arthritis (RA) patients on triple therapy when compared with similar patients taking methotrexate and a tumor necrosis factor inhibitor in an observational cohort study of historical data during 2006-2012.

copyright kgtoh/Thinkstock

The findings shed some light on understanding if the noninferior efficacy of triple therapy (TT) with methotrexate (MTX), sulfasalazine (SSZ), and hydroxychloroquine (HCQ) in randomized trials versus combination MTX plus tumor necrosis factor inhibitor (MTX-TNFi) is matched by patients’ persistence and adherence to TT in real-world data.

“With the proven efficacy of these combination therapies, an understanding of the real-world observations outside of clinical trials should be investigated to determine if similar experiences are seen in clinical practice as in clinical trials,” first author Daniel P. Erhardt, MD, MPH, of the George E. Wahlen VA Medical Center, Salt Lake City, and his colleagues wrote in Arthritis Care & Research.

In the current study, the research team identified veterans with RA escalating treatment from MTX to MTX-TNFi (n = 2,125) or to triple therapy (n = 171) from Veterans Affairs (VA) clinical and administrative databases during 2006-2012.

Patients taking MTX-TNFi consistently had significantly higher levels of persistence than did TT patients regardless of the strictness of the definition used. The highest level of persistence as defined in the study – all medications (including MTX) filled without a 90-day or longer gap in treatment over the 12-month study period – was observed in 43.2% of the MTX-TNFi arm, compared with 17.6% in the TT arm. A more liberal definition of persistence that allowed discontinuation of any one disease-modifying antirheumatic drug (DMARD) in TT or MTX in the MTX-TNFi group – provided no new DMARDs were initiated – yielded a persistence rate of 50.3% for MTX-TNFi vs. 32.8% for the TT arm. The persistence rate for MTX-TNFi worsened somewhat to 42.9% when the same discontinuation was allowed and switching was permitted between drugs within the TNFi class for the MTX-TNFi combination group, but it stayed lower for the TT group at 33.9% when single DMARD discontinuation was allowed and switching between nonbiologic DMARDs was permitted (without a 90-day or longer gap prior to the switch).

Adherence as defined by 80% or more of days covered at 1 year was 25.3% in the MTX-TNFi arm, with individual adherence rates of 44.3% for MTX and 46% for TNFi. In comparison, adherence for TT overall was 10.5%, with adherence rates of 48.6% for MTX, 32.8% for HCQ, and 18.7% for SSZ.

TT group patients most commonly discontinued sulfasalazine (20.9%), followed by MTX (8.7%) and HCQ (7.8%), whereas in those treated with MTX-TNFi, many more stopped TNFi alone (53.9%) than MTX alone (19.1%). It also was more common to stop SSZ and HCQ together (37.4%) or all TT drugs (23.5%) than it was to stop MTX plus HCQ together (1.7%).

The most common reason for discontinuation in both groups was an adverse drug event (ADE), cited as the reason in 43.5% of TT patients and 35.7% of combination-therapy patients. Most SSZ discontinuations were reported as an ADE, most often because of concerns of GI toxicity or symptoms, the researchers said. GI toxicity or symptoms was cited as a reason for discontinuing for 18.3% of TT patients who discontinued, compared with only 1.7% of MTX-TNFi patients.

“Findings from our study indicate that ADE play a significant role in influencing drug discontinuation, and further efforts should focus on ways to mitigate ADE when initiating or escalating drug regimens for RA,” they concluded.

They noted that a large percentage of subjects who discontinued their combination therapy for RA were lost to follow-up from the VA system: 34.8% in the TT group and 32.2% in the MTX-TNFi group.

“Research should continue to focus on ascertaining methods to improve real-world treatment retention rates,” they advised.

“More research is also warranted to determine whether patient factors that influence medication adherence independently affect the likelihood of achieving clinical remission, regardless of which therapy is chosen for the treatment of their RA,” they added.

The research was supported by Specialty Care Center of Innovation in the Veterans Health Administration and by the Health Services Research and Development division of the Department of Veterans Affairs. Several of the authors reported receiving research funding and grants from several pharmaceutical companies.

SOURCE: Erhardt DP et al. Arthritis Care Res. 2018 Sep 17. doi: 10.1002/acr.23759

Adverse events related to sulfasalazine played a role in the higher discontinuation rate observed for rheumatoid arthritis (RA) patients on triple therapy when compared with similar patients taking methotrexate and a tumor necrosis factor inhibitor in an observational cohort study of historical data during 2006-2012.

copyright kgtoh/Thinkstock

The findings shed some light on understanding if the noninferior efficacy of triple therapy (TT) with methotrexate (MTX), sulfasalazine (SSZ), and hydroxychloroquine (HCQ) in randomized trials versus combination MTX plus tumor necrosis factor inhibitor (MTX-TNFi) is matched by patients’ persistence and adherence to TT in real-world data.

“With the proven efficacy of these combination therapies, an understanding of the real-world observations outside of clinical trials should be investigated to determine if similar experiences are seen in clinical practice as in clinical trials,” first author Daniel P. Erhardt, MD, MPH, of the George E. Wahlen VA Medical Center, Salt Lake City, and his colleagues wrote in Arthritis Care & Research.

In the current study, the research team identified veterans with RA escalating treatment from MTX to MTX-TNFi (n = 2,125) or to triple therapy (n = 171) from Veterans Affairs (VA) clinical and administrative databases during 2006-2012.

Patients taking MTX-TNFi consistently had significantly higher levels of persistence than did TT patients regardless of the strictness of the definition used. The highest level of persistence as defined in the study – all medications (including MTX) filled without a 90-day or longer gap in treatment over the 12-month study period – was observed in 43.2% of the MTX-TNFi arm, compared with 17.6% in the TT arm. A more liberal definition of persistence that allowed discontinuation of any one disease-modifying antirheumatic drug (DMARD) in TT or MTX in the MTX-TNFi group – provided no new DMARDs were initiated – yielded a persistence rate of 50.3% for MTX-TNFi vs. 32.8% for the TT arm. The persistence rate for MTX-TNFi worsened somewhat to 42.9% when the same discontinuation was allowed and switching was permitted between drugs within the TNFi class for the MTX-TNFi combination group, but it stayed lower for the TT group at 33.9% when single DMARD discontinuation was allowed and switching between nonbiologic DMARDs was permitted (without a 90-day or longer gap prior to the switch).

Adherence as defined by 80% or more of days covered at 1 year was 25.3% in the MTX-TNFi arm, with individual adherence rates of 44.3% for MTX and 46% for TNFi. In comparison, adherence for TT overall was 10.5%, with adherence rates of 48.6% for MTX, 32.8% for HCQ, and 18.7% for SSZ.

TT group patients most commonly discontinued sulfasalazine (20.9%), followed by MTX (8.7%) and HCQ (7.8%), whereas in those treated with MTX-TNFi, many more stopped TNFi alone (53.9%) than MTX alone (19.1%). It also was more common to stop SSZ and HCQ together (37.4%) or all TT drugs (23.5%) than it was to stop MTX plus HCQ together (1.7%).

The most common reason for discontinuation in both groups was an adverse drug event (ADE), cited as the reason in 43.5% of TT patients and 35.7% of combination-therapy patients. Most SSZ discontinuations were reported as an ADE, most often because of concerns of GI toxicity or symptoms, the researchers said. GI toxicity or symptoms was cited as a reason for discontinuing for 18.3% of TT patients who discontinued, compared with only 1.7% of MTX-TNFi patients.

“Findings from our study indicate that ADE play a significant role in influencing drug discontinuation, and further efforts should focus on ways to mitigate ADE when initiating or escalating drug regimens for RA,” they concluded.

They noted that a large percentage of subjects who discontinued their combination therapy for RA were lost to follow-up from the VA system: 34.8% in the TT group and 32.2% in the MTX-TNFi group.

“Research should continue to focus on ascertaining methods to improve real-world treatment retention rates,” they advised.

“More research is also warranted to determine whether patient factors that influence medication adherence independently affect the likelihood of achieving clinical remission, regardless of which therapy is chosen for the treatment of their RA,” they added.

The research was supported by Specialty Care Center of Innovation in the Veterans Health Administration and by the Health Services Research and Development division of the Department of Veterans Affairs. Several of the authors reported receiving research funding and grants from several pharmaceutical companies.

SOURCE: Erhardt DP et al. Arthritis Care Res. 2018 Sep 17. doi: 10.1002/acr.23759

BALTIMORE—Patients with stroke and obstructive sleep apnea (OSA) are more likely than patients without these conditions to have atrial fibrillation, said Melissa Lipford, MD, a neurologist and sleep specialist at Mayo Clinic in Rochester, Minnesota. If physicians detect atrial fibrillation in this patient population, the finding may lead to more effective preventive stroke treatment, Dr. Lipford said at the 32nd Annual Meeting of the Associated Professional Sleep Societies.

“In patients who present with cryptogenic stroke, if they have a known history of moderate to severe OSA, perhaps these are candidates where we would give higher consideration to doing long-term monitoring to screen for occult arrhythmia. If we find it and put them on anticoagulation therapy, they will be at a 40% to 70% reduced risk of having a stroke, compared with only 20% if we maintain antiplatelet therapy.”

Physicians must confirm that a patient has atrial fibrillation before starting anticoagulation therapy, however, she said. “We cannot just start them on warfarin because of the risk of bleeding. If you have patients on aspirin therapy, their risk of a major bleed is probably only 0.5% per year. The risk is doubled with warfarin in the lowest-risk patients. But if you tack on age, hypertension, and other risk factors, that goes up to almost a 12% per year risk with warfarin,” she said. “In every patient you have to do a risk–benefit analysis…. If you document atrial fibrillation, that risk of having a stroke is so high that the risk of a stroke outweighs the risks of anticoagulation in most cases.”

Potential Mechanisms

Dr. Lipford described a 65-year-old man with cryptogenic stroke who was found to have severe OSA. Although 24-hour telemetry monitoring showed no evidence of arrhythmia, he could be a candidate for 30-day noninvasive ambulatory heart monitoring, Dr. Lipford said.

“Typically, in these patients, we put them on aspirin and generally control their risk factors,” she said. “Knowing that this patient has severe OSA … we might consider more strongly long-term cardiac monitoring to help screen for occult atrial arrhythmia.”

Atrial fibrillation affects as many as six million people in the United States, including 9% of patients over age 65. It increases a person’s risk of stroke fivefold, Dr. Lipford said.

“Unfortunately, atrial fibrillation is commonly undetected,” she said. Many patients do not have symptoms. Patients may have paroxysmal disease. Some patients only have episodes at night.

Cardiogenic embolism accounts for between 20% and 30% of ischemic strokes each year. Most of these strokes are due to atrial fibrillation, Dr. Lipford said. About 60% of these strokes are severely disabling, and 20% result in death.

Gami and colleagues examined the prevalence of OSA in patients with and without atrial fibrillation. Patients with atrial fibrillation were more likely to have OSA, compared with patients without atrial fibrillation (49% vs 32%). Mansukhani et al found that in patients with OSA and a history of stroke, about 50% had a history of atrial fibrillation or atrial flutter, compared with 10.8% of patients with OSA and no history of stroke.

Data from the Sleep Heart Health Study indicate that patients with severe OSA have an increased risk of atrial fibrillation, compared with patients without sleep-disordered breathing (4.8% vs 0.9%).

After procedures such as cardioversion, patients with untreated OSA are more likely reconvert to atrial fibrillation, Dr. Lipford said. Kanagala and colleagues found that 82% of patients with untreated OSA had recurrence of atrial fibrillation at 12 months after cardioversion, compared with 42% of patients with OSA who used continuous positive airway pressure (CPAP) therapy and 53% of controls with no history of OSA.

Various mechanisms could explain the relationship between OSA and atrial fibrillation. Apnea episodes are associated with surges in heart rate, which may trigger arrhythmia. Patients exert tremendous force to try to open occluded airways, which may lead to left atrial enlargement. Recurrent hypoxemia and hypercapnia irritate the myocardium, which also may trigger arrhythmia. In addition, untreated OSA may be associated with hypercoagulability, which heightens patients’ risk of cardioembolism.

A Single-Center Study

Researchers at Mayo Clinic compared strokes in patients with and without OSA. They examined data from patients who had their first ischemic stroke within one year after undergoing polysomnography. Among patients with OSA, 72% of strokes were of a cardioembolic mechanism. In the group without OSA, 33% were cardioembolic. “The frequency of cardioembolic stroke increased as OSA severity increased, and that relationship held after we adjusted for multiple vascular risk factors,” said Dr. Lipford. The relationship remained after accounting for history of atrial fibrillation or atrial flutter. The results suggest that there may be a high burden of undiagnosed atrial fibrillation in people with OSA, she said.

The advent of long-term cardiac monitoring has raised the question of who should receive monitoring to screen for occult atrial arrhythmia. “This is an expensive procedure that sometimes requires an invasive procedure,” said Dr. Lipford.

The American Heart Association/American Stroke Association guidelines in 2014 advised that 30-day monitoring is reasonable within six months of a cardioembolic stroke, but the statement does not guide neurologists as to which patients are the right candidates. Screening may be warranted in patients with OSA, Dr. Lipford said.

Studies have found that long-term monitoring detects atrial fibrillation. “The EMBRACE study used 30-day noninvasive monitoring and looked at patients who had cryptogenic stroke and in the first 24 hours of telemetry monitoring had no evidence of arrhythmia. Over that 30-day period, they picked up on atrial fibrillation in 16% of the patients studied. That compares to 3.2% of controls who underwent traditional medical follow up. The CRYSTAL AF study used an insertable cardiac monitor and looked at patients over one year. They picked up on atrial fibrillation in 12.4% of patients.” The percentage of patients with atrial fibrillation is “on the smaller side,” Dr. Lipford said. “But if we start those patients on anticoagulation therapy, they are getting a dramatically reduced risk of having a stroke, compared with maintaining them on the antiplatelet therapy.”

—Jake Remaly

Suggested Reading

Gami AS, Pressman G, Caples SM, et al. Association of atrial fibrillation and obstructive sleep apnea. Circulation. 2004;110(4):364-367.

Gladstone DJ, Spring M, Dorian P, et al. Atrial fibrillation in patients with cryptogenic stroke. N Engl J Med. 2014;370(26):2467-2477.

Kanagala R, Murali NS, Friedman PA, et al. Obstructive sleep apnea and the recurrence of atrial fibrillation. Circulation. 2003;107(20):2589-2594.

Lipford MC, Flemming KD, Calvin AD, et al. Associations between cardioembolic stroke and obstructive sleep apnea. Sleep. 2015;38(11):1699-1705.

Mansukhani MP, Calvin AD, Kolla BP, et al. The association between atrial fibrillation and stroke in patients with obstructive sleep apnea: a population-based case-control study. Sleep Med. 2013;14(3):243-246.

Mehra R, Benjamin EJ, Shahar E, et al. Association of nocturnal arrhythmias with sleep-disordered breathing: The Sleep Heart Health Study. Am J Respir Crit Care Med. 2006;173(8):910-916.

Sanna T, Diener HC, Passman RS, et al. Cryptogenic stroke and underlying atrial fibrillation. N Engl J Med. 2014;370(26):2478-2486.

BALTIMORE—Patients with stroke and obstructive sleep apnea (OSA) are more likely than patients without these conditions to have atrial fibrillation, said Melissa Lipford, MD, a neurologist and sleep specialist at Mayo Clinic in Rochester, Minnesota. If physicians detect atrial fibrillation in this patient population, the finding may lead to more effective preventive stroke treatment, Dr. Lipford said at the 32nd Annual Meeting of the Associated Professional Sleep Societies.

“In patients who present with cryptogenic stroke, if they have a known history of moderate to severe OSA, perhaps these are candidates where we would give higher consideration to doing long-term monitoring to screen for occult arrhythmia. If we find it and put them on anticoagulation therapy, they will be at a 40% to 70% reduced risk of having a stroke, compared with only 20% if we maintain antiplatelet therapy.”

Physicians must confirm that a patient has atrial fibrillation before starting anticoagulation therapy, however, she said. “We cannot just start them on warfarin because of the risk of bleeding. If you have patients on aspirin therapy, their risk of a major bleed is probably only 0.5% per year. The risk is doubled with warfarin in the lowest-risk patients. But if you tack on age, hypertension, and other risk factors, that goes up to almost a 12% per year risk with warfarin,” she said. “In every patient you have to do a risk–benefit analysis…. If you document atrial fibrillation, that risk of having a stroke is so high that the risk of a stroke outweighs the risks of anticoagulation in most cases.”

Potential Mechanisms

Dr. Lipford described a 65-year-old man with cryptogenic stroke who was found to have severe OSA. Although 24-hour telemetry monitoring showed no evidence of arrhythmia, he could be a candidate for 30-day noninvasive ambulatory heart monitoring, Dr. Lipford said.

“Typically, in these patients, we put them on aspirin and generally control their risk factors,” she said. “Knowing that this patient has severe OSA … we might consider more strongly long-term cardiac monitoring to help screen for occult atrial arrhythmia.”

Atrial fibrillation affects as many as six million people in the United States, including 9% of patients over age 65. It increases a person’s risk of stroke fivefold, Dr. Lipford said.

“Unfortunately, atrial fibrillation is commonly undetected,” she said. Many patients do not have symptoms. Patients may have paroxysmal disease. Some patients only have episodes at night.

Cardiogenic embolism accounts for between 20% and 30% of ischemic strokes each year. Most of these strokes are due to atrial fibrillation, Dr. Lipford said. About 60% of these strokes are severely disabling, and 20% result in death.

Gami and colleagues examined the prevalence of OSA in patients with and without atrial fibrillation. Patients with atrial fibrillation were more likely to have OSA, compared with patients without atrial fibrillation (49% vs 32%). Mansukhani et al found that in patients with OSA and a history of stroke, about 50% had a history of atrial fibrillation or atrial flutter, compared with 10.8% of patients with OSA and no history of stroke.

Data from the Sleep Heart Health Study indicate that patients with severe OSA have an increased risk of atrial fibrillation, compared with patients without sleep-disordered breathing (4.8% vs 0.9%).

After procedures such as cardioversion, patients with untreated OSA are more likely reconvert to atrial fibrillation, Dr. Lipford said. Kanagala and colleagues found that 82% of patients with untreated OSA had recurrence of atrial fibrillation at 12 months after cardioversion, compared with 42% of patients with OSA who used continuous positive airway pressure (CPAP) therapy and 53% of controls with no history of OSA.

Various mechanisms could explain the relationship between OSA and atrial fibrillation. Apnea episodes are associated with surges in heart rate, which may trigger arrhythmia. Patients exert tremendous force to try to open occluded airways, which may lead to left atrial enlargement. Recurrent hypoxemia and hypercapnia irritate the myocardium, which also may trigger arrhythmia. In addition, untreated OSA may be associated with hypercoagulability, which heightens patients’ risk of cardioembolism.

A Single-Center Study

Researchers at Mayo Clinic compared strokes in patients with and without OSA. They examined data from patients who had their first ischemic stroke within one year after undergoing polysomnography. Among patients with OSA, 72% of strokes were of a cardioembolic mechanism. In the group without OSA, 33% were cardioembolic. “The frequency of cardioembolic stroke increased as OSA severity increased, and that relationship held after we adjusted for multiple vascular risk factors,” said Dr. Lipford. The relationship remained after accounting for history of atrial fibrillation or atrial flutter. The results suggest that there may be a high burden of undiagnosed atrial fibrillation in people with OSA, she said.

The advent of long-term cardiac monitoring has raised the question of who should receive monitoring to screen for occult atrial arrhythmia. “This is an expensive procedure that sometimes requires an invasive procedure,” said Dr. Lipford.

The American Heart Association/American Stroke Association guidelines in 2014 advised that 30-day monitoring is reasonable within six months of a cardioembolic stroke, but the statement does not guide neurologists as to which patients are the right candidates. Screening may be warranted in patients with OSA, Dr. Lipford said.

Studies have found that long-term monitoring detects atrial fibrillation. “The EMBRACE study used 30-day noninvasive monitoring and looked at patients who had cryptogenic stroke and in the first 24 hours of telemetry monitoring had no evidence of arrhythmia. Over that 30-day period, they picked up on atrial fibrillation in 16% of the patients studied. That compares to 3.2% of controls who underwent traditional medical follow up. The CRYSTAL AF study used an insertable cardiac monitor and looked at patients over one year. They picked up on atrial fibrillation in 12.4% of patients.” The percentage of patients with atrial fibrillation is “on the smaller side,” Dr. Lipford said. “But if we start those patients on anticoagulation therapy, they are getting a dramatically reduced risk of having a stroke, compared with maintaining them on the antiplatelet therapy.”

—Jake Remaly

Suggested Reading

Gami AS, Pressman G, Caples SM, et al. Association of atrial fibrillation and obstructive sleep apnea. Circulation. 2004;110(4):364-367.

Gladstone DJ, Spring M, Dorian P, et al. Atrial fibrillation in patients with cryptogenic stroke. N Engl J Med. 2014;370(26):2467-2477.

Kanagala R, Murali NS, Friedman PA, et al. Obstructive sleep apnea and the recurrence of atrial fibrillation. Circulation. 2003;107(20):2589-2594.

Lipford MC, Flemming KD, Calvin AD, et al. Associations between cardioembolic stroke and obstructive sleep apnea. Sleep. 2015;38(11):1699-1705.

Mansukhani MP, Calvin AD, Kolla BP, et al. The association between atrial fibrillation and stroke in patients with obstructive sleep apnea: a population-based case-control study. Sleep Med. 2013;14(3):243-246.

Mehra R, Benjamin EJ, Shahar E, et al. Association of nocturnal arrhythmias with sleep-disordered breathing: The Sleep Heart Health Study. Am J Respir Crit Care Med. 2006;173(8):910-916.

Sanna T, Diener HC, Passman RS, et al. Cryptogenic stroke and underlying atrial fibrillation. N Engl J Med. 2014;370(26):2478-2486.

BALTIMORE—Patients with stroke and obstructive sleep apnea (OSA) are more likely than patients without these conditions to have atrial fibrillation, said Melissa Lipford, MD, a neurologist and sleep specialist at Mayo Clinic in Rochester, Minnesota. If physicians detect atrial fibrillation in this patient population, the finding may lead to more effective preventive stroke treatment, Dr. Lipford said at the 32nd Annual Meeting of the Associated Professional Sleep Societies.

“In patients who present with cryptogenic stroke, if they have a known history of moderate to severe OSA, perhaps these are candidates where we would give higher consideration to doing long-term monitoring to screen for occult arrhythmia. If we find it and put them on anticoagulation therapy, they will be at a 40% to 70% reduced risk of having a stroke, compared with only 20% if we maintain antiplatelet therapy.”

Physicians must confirm that a patient has atrial fibrillation before starting anticoagulation therapy, however, she said. “We cannot just start them on warfarin because of the risk of bleeding. If you have patients on aspirin therapy, their risk of a major bleed is probably only 0.5% per year. The risk is doubled with warfarin in the lowest-risk patients. But if you tack on age, hypertension, and other risk factors, that goes up to almost a 12% per year risk with warfarin,” she said. “In every patient you have to do a risk–benefit analysis…. If you document atrial fibrillation, that risk of having a stroke is so high that the risk of a stroke outweighs the risks of anticoagulation in most cases.”

Potential Mechanisms

Dr. Lipford described a 65-year-old man with cryptogenic stroke who was found to have severe OSA. Although 24-hour telemetry monitoring showed no evidence of arrhythmia, he could be a candidate for 30-day noninvasive ambulatory heart monitoring, Dr. Lipford said.

“Typically, in these patients, we put them on aspirin and generally control their risk factors,” she said. “Knowing that this patient has severe OSA … we might consider more strongly long-term cardiac monitoring to help screen for occult atrial arrhythmia.”

Atrial fibrillation affects as many as six million people in the United States, including 9% of patients over age 65. It increases a person’s risk of stroke fivefold, Dr. Lipford said.

“Unfortunately, atrial fibrillation is commonly undetected,” she said. Many patients do not have symptoms. Patients may have paroxysmal disease. Some patients only have episodes at night.

Cardiogenic embolism accounts for between 20% and 30% of ischemic strokes each year. Most of these strokes are due to atrial fibrillation, Dr. Lipford said. About 60% of these strokes are severely disabling, and 20% result in death.

Gami and colleagues examined the prevalence of OSA in patients with and without atrial fibrillation. Patients with atrial fibrillation were more likely to have OSA, compared with patients without atrial fibrillation (49% vs 32%). Mansukhani et al found that in patients with OSA and a history of stroke, about 50% had a history of atrial fibrillation or atrial flutter, compared with 10.8% of patients with OSA and no history of stroke.

Data from the Sleep Heart Health Study indicate that patients with severe OSA have an increased risk of atrial fibrillation, compared with patients without sleep-disordered breathing (4.8% vs 0.9%).

After procedures such as cardioversion, patients with untreated OSA are more likely reconvert to atrial fibrillation, Dr. Lipford said. Kanagala and colleagues found that 82% of patients with untreated OSA had recurrence of atrial fibrillation at 12 months after cardioversion, compared with 42% of patients with OSA who used continuous positive airway pressure (CPAP) therapy and 53% of controls with no history of OSA.

Various mechanisms could explain the relationship between OSA and atrial fibrillation. Apnea episodes are associated with surges in heart rate, which may trigger arrhythmia. Patients exert tremendous force to try to open occluded airways, which may lead to left atrial enlargement. Recurrent hypoxemia and hypercapnia irritate the myocardium, which also may trigger arrhythmia. In addition, untreated OSA may be associated with hypercoagulability, which heightens patients’ risk of cardioembolism.

A Single-Center Study

Researchers at Mayo Clinic compared strokes in patients with and without OSA. They examined data from patients who had their first ischemic stroke within one year after undergoing polysomnography. Among patients with OSA, 72% of strokes were of a cardioembolic mechanism. In the group without OSA, 33% were cardioembolic. “The frequency of cardioembolic stroke increased as OSA severity increased, and that relationship held after we adjusted for multiple vascular risk factors,” said Dr. Lipford. The relationship remained after accounting for history of atrial fibrillation or atrial flutter. The results suggest that there may be a high burden of undiagnosed atrial fibrillation in people with OSA, she said.

The advent of long-term cardiac monitoring has raised the question of who should receive monitoring to screen for occult atrial arrhythmia. “This is an expensive procedure that sometimes requires an invasive procedure,” said Dr. Lipford.

The American Heart Association/American Stroke Association guidelines in 2014 advised that 30-day monitoring is reasonable within six months of a cardioembolic stroke, but the statement does not guide neurologists as to which patients are the right candidates. Screening may be warranted in patients with OSA, Dr. Lipford said.

Studies have found that long-term monitoring detects atrial fibrillation. “The EMBRACE study used 30-day noninvasive monitoring and looked at patients who had cryptogenic stroke and in the first 24 hours of telemetry monitoring had no evidence of arrhythmia. Over that 30-day period, they picked up on atrial fibrillation in 16% of the patients studied. That compares to 3.2% of controls who underwent traditional medical follow up. The CRYSTAL AF study used an insertable cardiac monitor and looked at patients over one year. They picked up on atrial fibrillation in 12.4% of patients.” The percentage of patients with atrial fibrillation is “on the smaller side,” Dr. Lipford said. “But if we start those patients on anticoagulation therapy, they are getting a dramatically reduced risk of having a stroke, compared with maintaining them on the antiplatelet therapy.”

—Jake Remaly

Suggested Reading

Gami AS, Pressman G, Caples SM, et al. Association of atrial fibrillation and obstructive sleep apnea. Circulation. 2004;110(4):364-367.

Gladstone DJ, Spring M, Dorian P, et al. Atrial fibrillation in patients with cryptogenic stroke. N Engl J Med. 2014;370(26):2467-2477.

Kanagala R, Murali NS, Friedman PA, et al. Obstructive sleep apnea and the recurrence of atrial fibrillation. Circulation. 2003;107(20):2589-2594.

Lipford MC, Flemming KD, Calvin AD, et al. Associations between cardioembolic stroke and obstructive sleep apnea. Sleep. 2015;38(11):1699-1705.

Mansukhani MP, Calvin AD, Kolla BP, et al. The association between atrial fibrillation and stroke in patients with obstructive sleep apnea: a population-based case-control study. Sleep Med. 2013;14(3):243-246.

Mehra R, Benjamin EJ, Shahar E, et al. Association of nocturnal arrhythmias with sleep-disordered breathing: The Sleep Heart Health Study. Am J Respir Crit Care Med. 2006;173(8):910-916.

Sanna T, Diener HC, Passman RS, et al. Cryptogenic stroke and underlying atrial fibrillation. N Engl J Med. 2014;370(26):2478-2486.

HILTON HEAD, SC—Behavioral variant frontotemporal dementia (bvFTD), a clinically and pathologically heterogenous condition, can be difficult to distinguish from other forms of dementia or frontotemporal disease. “Although clinical symptoms vary based on which part of the brain is affected, there is a significant amount of overlap, with different pathologies causing the same type of syndrome,” said Richard Ryan Darby, MD, Assistant Professor of Neurology at Vanderbilt University Medical School in Nashville. “In a large proportion of patients, behavioral changes can lead to criminal behavior.” Future research examining brain lesion networks may shed light on this condition, said Dr. Darby at the 41st Annual Contemporary Clinical Neurology Symposium.

Clinical Features and Diagnosis

The incidence of bvFTD is equal to that of Alzheimer’s disease. However, patients with bvFTD tend to be younger: between the ages of 45 and 65. “Social and behavioral features predominate,” said Dr. Darby. “If a patient in this age range with no previous psychiatric history presents to you with a new psychiatric diagnosis such as schizophrenia or bipolar disease, this should raise your suspicion of bvFTD.” These psychiatric problems often cause considerable disruptions in patients’ lives. They often have problems at work and lose their source of income. “Patients often have no insight about their symptoms,” said Dr. Darby.

A differential diagnosis of bvFTD is possible in patients with three or more of the following six clinical features: socially inappropriate behavior (eg, eating from the trash or walking around naked at inappropriate times); lack of empathy; apathy; stereotyped or repetitive behavior (eg, saying things repeatedly, pacing); hyperorality (eg, eating uncontrollably, particularly sweet foods); and executive dysfunction, especially when memory is preserved.

“When you talk to caregivers, they often say, ‘This is not the person I married,’ or, ‘This is not my father. He seems like a different person,’” said Dr. Darby. An MRI or a PET scan showing changes in the frontotemporal lobes is a firm basis for a diagnosis of bvFTD, said Dr. Darby. Genetic testing for autosomal dominant mutation or pathology or an autopsy provides a definite diagnosis.

Pathology

Between 40% and 50% of patients with bvFTD have tau pathology, said Dr. Darby. This pathology includes the classic Pick body form of tau, tufted astrocytes (which are associated with clinical symptoms of progressive supranuclear palsy), and astrocytic plaques (which are associated with symptoms of corticobasal degeneration). Similarly, between 40% and 50% of patients with bvFTD have a TAR DNA-binding protein 43 (TDP-43) pathology. TDP-43 Type A pathology is associated with perirolandic seizures, Type B is associated with amyotrophic lateral sclerosis (ALS), and Type C is associated with semantic dementia. Between 5% and 10% of patients with bvFTD have fused-in sarcoma pathology, which is associated with ALS.

Mutations in C9orf72 occur in 13% to 50% of patients with bvFTD who have genetic mutations. ALS and parkinsonism are common clinical presentations in patients with this genetic mutation. MAPT and GRN mutations are present in 5% to 20% of cases, and each can present clinically as parkinsonism.

Treatment

SSRIs, antipsychotics, anticonvulsants, and stimulants have been used to treat apathy, disinhibition, compulsive behaviors, agitation, and inappropriate behavior in patients with bvFTD. “There are no FDA-approved treatments for bvFTD, and the evidence for [these agents] has been mostly reported in case studies and small clinical trials,” said Dr. Darby. Among the SSRIs, paroxetine improved repetitive behavior in open-label trials, but not in a randomized controlled trial. Sertraline and citalopram have been studied in open-label trials, and trazodone was examined in a randomized controlled crossover trial involving 26 patients.

The FDA issued a black box warning against the use of atypical antipsychotics in patients with dementia because they entail a risk of cardiac- and infection-related mortality. “For patients with bvFTD tau pathology in particular, there is a risk of extrapyramidal adverse effects,” said Dr. Darby. A series of case reports of risperidone and aripiprazole provided evidence of symptom improvement, as did an open label study of olanzapine. Quetiapine improved agitation in a case series but failed to show benefit in a double-blind crossover trial of eight patients with FTD.

Case series have shown evidence that antiepileptic drugs (eg, valproic acid, topiramate, and carbamazepine) have a stabilizing effect. “Stimulants are tried in some patients, but should be used with caution,” said Dr. Darby.

Criminality

Between 37% and 57% of patients with bvFTD engage in criminal behavior. “Approximately 10% to 15% of the time, a patient’s getting in trouble with the law is the reason for the initial presentation,” said Dr. Darby. The types of crimes described in case reports include pedophilia, public masturbation, hit and run, traffic violations, and theft.

“Murder and violent crimes occur but are rare. Crimes committed by patients with bvFTD are usually reactive,” said Dr. Darby. “When asked, they can tell you whether a specific act is right or wrong; however, they don’t show remorse for criminal behavior.” It is not clear whether executive dysfunction and the inability to reason, social perception and the inability to empathize, or differences in moral decision making are the reasons for changes in patients’ behavior, he said.

“One idea is that a network of brain regions, not just one part of the brain, is responsible for formulating the complex concept of morality.” In 2017, Dr. Darby and colleagues systematically mapped brain lesions with a documented temporal association with criminal behavior in 17 patients who were identified through a literature search. Criminal behavior included white collar crimes, and 12 of 17 patients had committed violent crimes. Fifteen cases had no history of criminal behavior before the lesion, and the behavior resolved following treatment of the lesion in two cases.

No single brain region had been damaged in all cases. Because lesion-induced symptoms can arise from sites connected to the lesion location, the investigators identified these sites in the cases. The network of these sites included regions involved in morality, value-based decision making, and theory of mind, but not regions involved in cognitive control or empathy. Darby and colleagues replicated these results in a separate cohort of 23 cases in which a temporal relationship between brain lesions and criminal behavior was plausible, but not definite.

Prior research suggests that the areas associated with criminal behavior in patients with brain lesions closely resemble the areas typically affected in patients with bvFTD. Prospective studies are needed to further elucidate these results, Dr. Darby concluded.

—Adriene Marshall

Suggested Reading

Darby RR, Horn A, Cushman F, Fox MD. Lesion network localization of criminal behavior. Proc Natl Acad Sci U S A. 2018;115(3):601-606.

Perry DC, Brown JA, Possin KL, et al. Clinicopathological correlations in behavioural variant frontotemporal dementia. Brain. 2017;140(12):3329-3345.

HILTON HEAD, SC—Behavioral variant frontotemporal dementia (bvFTD), a clinically and pathologically heterogenous condition, can be difficult to distinguish from other forms of dementia or frontotemporal disease. “Although clinical symptoms vary based on which part of the brain is affected, there is a significant amount of overlap, with different pathologies causing the same type of syndrome,” said Richard Ryan Darby, MD, Assistant Professor of Neurology at Vanderbilt University Medical School in Nashville. “In a large proportion of patients, behavioral changes can lead to criminal behavior.” Future research examining brain lesion networks may shed light on this condition, said Dr. Darby at the 41st Annual Contemporary Clinical Neurology Symposium.

Clinical Features and Diagnosis

The incidence of bvFTD is equal to that of Alzheimer’s disease. However, patients with bvFTD tend to be younger: between the ages of 45 and 65. “Social and behavioral features predominate,” said Dr. Darby. “If a patient in this age range with no previous psychiatric history presents to you with a new psychiatric diagnosis such as schizophrenia or bipolar disease, this should raise your suspicion of bvFTD.” These psychiatric problems often cause considerable disruptions in patients’ lives. They often have problems at work and lose their source of income. “Patients often have no insight about their symptoms,” said Dr. Darby.

A differential diagnosis of bvFTD is possible in patients with three or more of the following six clinical features: socially inappropriate behavior (eg, eating from the trash or walking around naked at inappropriate times); lack of empathy; apathy; stereotyped or repetitive behavior (eg, saying things repeatedly, pacing); hyperorality (eg, eating uncontrollably, particularly sweet foods); and executive dysfunction, especially when memory is preserved.

“When you talk to caregivers, they often say, ‘This is not the person I married,’ or, ‘This is not my father. He seems like a different person,’” said Dr. Darby. An MRI or a PET scan showing changes in the frontotemporal lobes is a firm basis for a diagnosis of bvFTD, said Dr. Darby. Genetic testing for autosomal dominant mutation or pathology or an autopsy provides a definite diagnosis.

Pathology

Between 40% and 50% of patients with bvFTD have tau pathology, said Dr. Darby. This pathology includes the classic Pick body form of tau, tufted astrocytes (which are associated with clinical symptoms of progressive supranuclear palsy), and astrocytic plaques (which are associated with symptoms of corticobasal degeneration). Similarly, between 40% and 50% of patients with bvFTD have a TAR DNA-binding protein 43 (TDP-43) pathology. TDP-43 Type A pathology is associated with perirolandic seizures, Type B is associated with amyotrophic lateral sclerosis (ALS), and Type C is associated with semantic dementia. Between 5% and 10% of patients with bvFTD have fused-in sarcoma pathology, which is associated with ALS.

Mutations in C9orf72 occur in 13% to 50% of patients with bvFTD who have genetic mutations. ALS and parkinsonism are common clinical presentations in patients with this genetic mutation. MAPT and GRN mutations are present in 5% to 20% of cases, and each can present clinically as parkinsonism.

Treatment

SSRIs, antipsychotics, anticonvulsants, and stimulants have been used to treat apathy, disinhibition, compulsive behaviors, agitation, and inappropriate behavior in patients with bvFTD. “There are no FDA-approved treatments for bvFTD, and the evidence for [these agents] has been mostly reported in case studies and small clinical trials,” said Dr. Darby. Among the SSRIs, paroxetine improved repetitive behavior in open-label trials, but not in a randomized controlled trial. Sertraline and citalopram have been studied in open-label trials, and trazodone was examined in a randomized controlled crossover trial involving 26 patients.

The FDA issued a black box warning against the use of atypical antipsychotics in patients with dementia because they entail a risk of cardiac- and infection-related mortality. “For patients with bvFTD tau pathology in particular, there is a risk of extrapyramidal adverse effects,” said Dr. Darby. A series of case reports of risperidone and aripiprazole provided evidence of symptom improvement, as did an open label study of olanzapine. Quetiapine improved agitation in a case series but failed to show benefit in a double-blind crossover trial of eight patients with FTD.

Case series have shown evidence that antiepileptic drugs (eg, valproic acid, topiramate, and carbamazepine) have a stabilizing effect. “Stimulants are tried in some patients, but should be used with caution,” said Dr. Darby.

Criminality

Between 37% and 57% of patients with bvFTD engage in criminal behavior. “Approximately 10% to 15% of the time, a patient’s getting in trouble with the law is the reason for the initial presentation,” said Dr. Darby. The types of crimes described in case reports include pedophilia, public masturbation, hit and run, traffic violations, and theft.

“Murder and violent crimes occur but are rare. Crimes committed by patients with bvFTD are usually reactive,” said Dr. Darby. “When asked, they can tell you whether a specific act is right or wrong; however, they don’t show remorse for criminal behavior.” It is not clear whether executive dysfunction and the inability to reason, social perception and the inability to empathize, or differences in moral decision making are the reasons for changes in patients’ behavior, he said.

“One idea is that a network of brain regions, not just one part of the brain, is responsible for formulating the complex concept of morality.” In 2017, Dr. Darby and colleagues systematically mapped brain lesions with a documented temporal association with criminal behavior in 17 patients who were identified through a literature search. Criminal behavior included white collar crimes, and 12 of 17 patients had committed violent crimes. Fifteen cases had no history of criminal behavior before the lesion, and the behavior resolved following treatment of the lesion in two cases.

No single brain region had been damaged in all cases. Because lesion-induced symptoms can arise from sites connected to the lesion location, the investigators identified these sites in the cases. The network of these sites included regions involved in morality, value-based decision making, and theory of mind, but not regions involved in cognitive control or empathy. Darby and colleagues replicated these results in a separate cohort of 23 cases in which a temporal relationship between brain lesions and criminal behavior was plausible, but not definite.

Prior research suggests that the areas associated with criminal behavior in patients with brain lesions closely resemble the areas typically affected in patients with bvFTD. Prospective studies are needed to further elucidate these results, Dr. Darby concluded.

—Adriene Marshall

Suggested Reading

Darby RR, Horn A, Cushman F, Fox MD. Lesion network localization of criminal behavior. Proc Natl Acad Sci U S A. 2018;115(3):601-606.

Perry DC, Brown JA, Possin KL, et al. Clinicopathological correlations in behavioural variant frontotemporal dementia. Brain. 2017;140(12):3329-3345.

HILTON HEAD, SC—Behavioral variant frontotemporal dementia (bvFTD), a clinically and pathologically heterogenous condition, can be difficult to distinguish from other forms of dementia or frontotemporal disease. “Although clinical symptoms vary based on which part of the brain is affected, there is a significant amount of overlap, with different pathologies causing the same type of syndrome,” said Richard Ryan Darby, MD, Assistant Professor of Neurology at Vanderbilt University Medical School in Nashville. “In a large proportion of patients, behavioral changes can lead to criminal behavior.” Future research examining brain lesion networks may shed light on this condition, said Dr. Darby at the 41st Annual Contemporary Clinical Neurology Symposium.

Clinical Features and Diagnosis

The incidence of bvFTD is equal to that of Alzheimer’s disease. However, patients with bvFTD tend to be younger: between the ages of 45 and 65. “Social and behavioral features predominate,” said Dr. Darby. “If a patient in this age range with no previous psychiatric history presents to you with a new psychiatric diagnosis such as schizophrenia or bipolar disease, this should raise your suspicion of bvFTD.” These psychiatric problems often cause considerable disruptions in patients’ lives. They often have problems at work and lose their source of income. “Patients often have no insight about their symptoms,” said Dr. Darby.

A differential diagnosis of bvFTD is possible in patients with three or more of the following six clinical features: socially inappropriate behavior (eg, eating from the trash or walking around naked at inappropriate times); lack of empathy; apathy; stereotyped or repetitive behavior (eg, saying things repeatedly, pacing); hyperorality (eg, eating uncontrollably, particularly sweet foods); and executive dysfunction, especially when memory is preserved.

“When you talk to caregivers, they often say, ‘This is not the person I married,’ or, ‘This is not my father. He seems like a different person,’” said Dr. Darby. An MRI or a PET scan showing changes in the frontotemporal lobes is a firm basis for a diagnosis of bvFTD, said Dr. Darby. Genetic testing for autosomal dominant mutation or pathology or an autopsy provides a definite diagnosis.

Pathology

Between 40% and 50% of patients with bvFTD have tau pathology, said Dr. Darby. This pathology includes the classic Pick body form of tau, tufted astrocytes (which are associated with clinical symptoms of progressive supranuclear palsy), and astrocytic plaques (which are associated with symptoms of corticobasal degeneration). Similarly, between 40% and 50% of patients with bvFTD have a TAR DNA-binding protein 43 (TDP-43) pathology. TDP-43 Type A pathology is associated with perirolandic seizures, Type B is associated with amyotrophic lateral sclerosis (ALS), and Type C is associated with semantic dementia. Between 5% and 10% of patients with bvFTD have fused-in sarcoma pathology, which is associated with ALS.

Mutations in C9orf72 occur in 13% to 50% of patients with bvFTD who have genetic mutations. ALS and parkinsonism are common clinical presentations in patients with this genetic mutation. MAPT and GRN mutations are present in 5% to 20% of cases, and each can present clinically as parkinsonism.

Treatment

SSRIs, antipsychotics, anticonvulsants, and stimulants have been used to treat apathy, disinhibition, compulsive behaviors, agitation, and inappropriate behavior in patients with bvFTD. “There are no FDA-approved treatments for bvFTD, and the evidence for [these agents] has been mostly reported in case studies and small clinical trials,” said Dr. Darby. Among the SSRIs, paroxetine improved repetitive behavior in open-label trials, but not in a randomized controlled trial. Sertraline and citalopram have been studied in open-label trials, and trazodone was examined in a randomized controlled crossover trial involving 26 patients.

The FDA issued a black box warning against the use of atypical antipsychotics in patients with dementia because they entail a risk of cardiac- and infection-related mortality. “For patients with bvFTD tau pathology in particular, there is a risk of extrapyramidal adverse effects,” said Dr. Darby. A series of case reports of risperidone and aripiprazole provided evidence of symptom improvement, as did an open label study of olanzapine. Quetiapine improved agitation in a case series but failed to show benefit in a double-blind crossover trial of eight patients with FTD.

Case series have shown evidence that antiepileptic drugs (eg, valproic acid, topiramate, and carbamazepine) have a stabilizing effect. “Stimulants are tried in some patients, but should be used with caution,” said Dr. Darby.

Criminality

Between 37% and 57% of patients with bvFTD engage in criminal behavior. “Approximately 10% to 15% of the time, a patient’s getting in trouble with the law is the reason for the initial presentation,” said Dr. Darby. The types of crimes described in case reports include pedophilia, public masturbation, hit and run, traffic violations, and theft.

“Murder and violent crimes occur but are rare. Crimes committed by patients with bvFTD are usually reactive,” said Dr. Darby. “When asked, they can tell you whether a specific act is right or wrong; however, they don’t show remorse for criminal behavior.” It is not clear whether executive dysfunction and the inability to reason, social perception and the inability to empathize, or differences in moral decision making are the reasons for changes in patients’ behavior, he said.

“One idea is that a network of brain regions, not just one part of the brain, is responsible for formulating the complex concept of morality.” In 2017, Dr. Darby and colleagues systematically mapped brain lesions with a documented temporal association with criminal behavior in 17 patients who were identified through a literature search. Criminal behavior included white collar crimes, and 12 of 17 patients had committed violent crimes. Fifteen cases had no history of criminal behavior before the lesion, and the behavior resolved following treatment of the lesion in two cases.

No single brain region had been damaged in all cases. Because lesion-induced symptoms can arise from sites connected to the lesion location, the investigators identified these sites in the cases. The network of these sites included regions involved in morality, value-based decision making, and theory of mind, but not regions involved in cognitive control or empathy. Darby and colleagues replicated these results in a separate cohort of 23 cases in which a temporal relationship between brain lesions and criminal behavior was plausible, but not definite.

Prior research suggests that the areas associated with criminal behavior in patients with brain lesions closely resemble the areas typically affected in patients with bvFTD. Prospective studies are needed to further elucidate these results, Dr. Darby concluded.

—Adriene Marshall

Suggested Reading

Darby RR, Horn A, Cushman F, Fox MD. Lesion network localization of criminal behavior. Proc Natl Acad Sci U S A. 2018;115(3):601-606.

Perry DC, Brown JA, Possin KL, et al. Clinicopathological correlations in behavioural variant frontotemporal dementia. Brain. 2017;140(12):3329-3345.

The CDC has developed a guideline for the diagnosis and management of mild traumatic brain injury (mTBI) in children. The guideline was published online ahead of print September 4 in JAMA Pediatrics. To support the “multifaceted approach” that the authors recommend for implementing the guideline, the CDC has created materials such as a screening tool, online training, fact sheets, patient discharge instructions, and symptom-based recovery tips.

The number of emergency department visits for mTBI has increased significantly during the past decade, said the authors, yet no evidence-based clinical guidelines had been drafted in the United States to guide the diagnosis, prognosis, and management of this condition. To fill this gap, the CDC established the Pediatric mTBI Guideline Workgroup, which drafted recommendations based on a systematic review of research published from January 1990 through July 2015.

Diagnosis

The first section of the guideline offers recommendations for diagnosis. Health care professionals should not routinely obtain head CT in children with suspected mTBI, say the authors. They should, however, use validated clinical decision rules to identify children with mTBI at low risk for intracranial injury in whom CT is not indicated, as well as children at higher risk for intracranial injury for whom CT may be warranted. The authors cite the Pediatric Emergency Care Applied Research Network (PECARN) decision rules as an example.

Furthermore, health care professionals should not routinely use brain MRI to evaluate suspected or diagnosed mTBI in children, according to the guideline. No study examining whether this imaging technique is appropriate met the workgroup’s inclusion criteria.

An age-appropriate, validated symptom rating scale should be one component of the diagnostic evaluation, say the authors. The Standardized Assessment of Concussion, however, “should not be exclusively used to diagnose mTBI in children aged 6 to 18,” they add. Finally, the guideline discourages the use of biomarkers (ie, serum markers) for diagnosis outside of a research setting.

Prognosis

The second section of the document provides guidance on developing a prognosis. Clinicians should advise patients and their families that most children with mTBI do not have significant difficulties that last for more than one to three months after injury, say the authors. They also should state that even though certain factors predict a child’s risk for prolonged symptoms, “each child’s recovery from mTBI is unique and will follow its own trajectory.”

Health care professionals should evaluate a child’s premorbid history as soon as possible to help determine the prognosis, say the authors. Children and families should be advised that factors such as history of mTBI, lower cognitive ability, and neurologic disorder can delay recovery from mTBI. Clinicians should screen for known risk factors for persistent symptoms and use a combination of tools (eg, validated symptom scales, cognitive testing, and balance testing) to assess recovery, according to the guideline.

Children with mTBI at high risk for persistent symptoms should be monitored closely. “For children with mTBI whose symptoms do not resolve as expected with standard care (ie, within four to six weeks), health care professionals should provide or refer for appropriate assessments and interventions,” say the authors.

Management and Treatment

The guideline’s section devoted to management and treatment begins with recommendations for returning to normal activities. Clinicians should recommend restricting physical and cognitive activity during the first several days after pediatric mTBI, according to the authors. After that point, doctors should advise patients and families “to resume a gradual schedule of activity that does not exacerbate symptoms, with close monitoring of symptom expression.” If the patient completes this step successfully, the clinician should offer an active rehabilitation program that progressively reintroduces noncontact aerobic activity that does not worsen symptoms. The number and severity of symptoms should be monitored closely throughout the patient’s recovery. A patient should resume full activity when his or her performance returns to its premorbid level, provided that he or she has no symptoms at rest or with increasing levels of exertion, according to the guideline.

“To assist children returning to school after mTBI, medical and school-based teams should counsel the student and family regarding the process of gradually increasing the duration and intensity of academic activities as tolerated, with the goal of increasing participation without significantly exacerbating symptoms,” say the authors. Return-to-school protocols should be adapted to the severity of the child’s postconcussion symptoms. School personnel should assess the need for additional educational support in students with prolonged symptoms that harm their academic performance, according to the guideline.

If a child with mTBI develops severe headache, especially if the headache is associated with other risk factors or has worsened after mTBI, emergency department professionals should observe him or her and consider obtaining a head CT to evaluate for intracranial injury, say the authors. Health care professionals should explain proper sleep hygiene to all patients with mTBI and their families to facilitate recovery.

If a child with mTBI has cognitive dysfunction, clinicians should attempt to determine its etiology within the context of other mTBI symptoms, say the authors. Treatment for cognitive dysfunction should reflect its presumed etiology, they conclude.

—Erik Greb

Suggested Reading

Lumba-Brown A, Yeates KO, Sarmiento K, et al. Centers for Disease Control and Prevention guideline on the diagnosis and management of mild traumatic brain injury among children. JAMA Pediatr. 2018 Sep 4 [Epub ahead of print].

Lumba-Brown A, Yeates KO, Sarmiento K, et al. Diagnosis and management of mild traumatic brain injury in children: a systematic review. JAMA Pediatr. 2018 Sep 4 [Epub ahead of print].

McCrea M, Manley G. State of the science on pediatric mild traumatic brain injury: progress toward clinical translation. JAMA Pediatr. 2018 Sep 4 [Epub ahead of print].

The CDC has developed a guideline for the diagnosis and management of mild traumatic brain injury (mTBI) in children. The guideline was published online ahead of print September 4 in JAMA Pediatrics. To support the “multifaceted approach” that the authors recommend for implementing the guideline, the CDC has created materials such as a screening tool, online training, fact sheets, patient discharge instructions, and symptom-based recovery tips.

The number of emergency department visits for mTBI has increased significantly during the past decade, said the authors, yet no evidence-based clinical guidelines had been drafted in the United States to guide the diagnosis, prognosis, and management of this condition. To fill this gap, the CDC established the Pediatric mTBI Guideline Workgroup, which drafted recommendations based on a systematic review of research published from January 1990 through July 2015.

Diagnosis

The first section of the guideline offers recommendations for diagnosis. Health care professionals should not routinely obtain head CT in children with suspected mTBI, say the authors. They should, however, use validated clinical decision rules to identify children with mTBI at low risk for intracranial injury in whom CT is not indicated, as well as children at higher risk for intracranial injury for whom CT may be warranted. The authors cite the Pediatric Emergency Care Applied Research Network (PECARN) decision rules as an example.

Furthermore, health care professionals should not routinely use brain MRI to evaluate suspected or diagnosed mTBI in children, according to the guideline. No study examining whether this imaging technique is appropriate met the workgroup’s inclusion criteria.

An age-appropriate, validated symptom rating scale should be one component of the diagnostic evaluation, say the authors. The Standardized Assessment of Concussion, however, “should not be exclusively used to diagnose mTBI in children aged 6 to 18,” they add. Finally, the guideline discourages the use of biomarkers (ie, serum markers) for diagnosis outside of a research setting.

Prognosis

The second section of the document provides guidance on developing a prognosis. Clinicians should advise patients and their families that most children with mTBI do not have significant difficulties that last for more than one to three months after injury, say the authors. They also should state that even though certain factors predict a child’s risk for prolonged symptoms, “each child’s recovery from mTBI is unique and will follow its own trajectory.”

Health care professionals should evaluate a child’s premorbid history as soon as possible to help determine the prognosis, say the authors. Children and families should be advised that factors such as history of mTBI, lower cognitive ability, and neurologic disorder can delay recovery from mTBI. Clinicians should screen for known risk factors for persistent symptoms and use a combination of tools (eg, validated symptom scales, cognitive testing, and balance testing) to assess recovery, according to the guideline.

Children with mTBI at high risk for persistent symptoms should be monitored closely. “For children with mTBI whose symptoms do not resolve as expected with standard care (ie, within four to six weeks), health care professionals should provide or refer for appropriate assessments and interventions,” say the authors.

Management and Treatment

The guideline’s section devoted to management and treatment begins with recommendations for returning to normal activities. Clinicians should recommend restricting physical and cognitive activity during the first several days after pediatric mTBI, according to the authors. After that point, doctors should advise patients and families “to resume a gradual schedule of activity that does not exacerbate symptoms, with close monitoring of symptom expression.” If the patient completes this step successfully, the clinician should offer an active rehabilitation program that progressively reintroduces noncontact aerobic activity that does not worsen symptoms. The number and severity of symptoms should be monitored closely throughout the patient’s recovery. A patient should resume full activity when his or her performance returns to its premorbid level, provided that he or she has no symptoms at rest or with increasing levels of exertion, according to the guideline.

“To assist children returning to school after mTBI, medical and school-based teams should counsel the student and family regarding the process of gradually increasing the duration and intensity of academic activities as tolerated, with the goal of increasing participation without significantly exacerbating symptoms,” say the authors. Return-to-school protocols should be adapted to the severity of the child’s postconcussion symptoms. School personnel should assess the need for additional educational support in students with prolonged symptoms that harm their academic performance, according to the guideline.

If a child with mTBI develops severe headache, especially if the headache is associated with other risk factors or has worsened after mTBI, emergency department professionals should observe him or her and consider obtaining a head CT to evaluate for intracranial injury, say the authors. Health care professionals should explain proper sleep hygiene to all patients with mTBI and their families to facilitate recovery.

If a child with mTBI has cognitive dysfunction, clinicians should attempt to determine its etiology within the context of other mTBI symptoms, say the authors. Treatment for cognitive dysfunction should reflect its presumed etiology, they conclude.

—Erik Greb

Suggested Reading

Lumba-Brown A, Yeates KO, Sarmiento K, et al. Centers for Disease Control and Prevention guideline on the diagnosis and management of mild traumatic brain injury among children. JAMA Pediatr. 2018 Sep 4 [Epub ahead of print].

Lumba-Brown A, Yeates KO, Sarmiento K, et al. Diagnosis and management of mild traumatic brain injury in children: a systematic review. JAMA Pediatr. 2018 Sep 4 [Epub ahead of print].

McCrea M, Manley G. State of the science on pediatric mild traumatic brain injury: progress toward clinical translation. JAMA Pediatr. 2018 Sep 4 [Epub ahead of print].

The CDC has developed a guideline for the diagnosis and management of mild traumatic brain injury (mTBI) in children. The guideline was published online ahead of print September 4 in JAMA Pediatrics. To support the “multifaceted approach” that the authors recommend for implementing the guideline, the CDC has created materials such as a screening tool, online training, fact sheets, patient discharge instructions, and symptom-based recovery tips.

The number of emergency department visits for mTBI has increased significantly during the past decade, said the authors, yet no evidence-based clinical guidelines had been drafted in the United States to guide the diagnosis, prognosis, and management of this condition. To fill this gap, the CDC established the Pediatric mTBI Guideline Workgroup, which drafted recommendations based on a systematic review of research published from January 1990 through July 2015.

Diagnosis

The first section of the guideline offers recommendations for diagnosis. Health care professionals should not routinely obtain head CT in children with suspected mTBI, say the authors. They should, however, use validated clinical decision rules to identify children with mTBI at low risk for intracranial injury in whom CT is not indicated, as well as children at higher risk for intracranial injury for whom CT may be warranted. The authors cite the Pediatric Emergency Care Applied Research Network (PECARN) decision rules as an example.

Furthermore, health care professionals should not routinely use brain MRI to evaluate suspected or diagnosed mTBI in children, according to the guideline. No study examining whether this imaging technique is appropriate met the workgroup’s inclusion criteria.

An age-appropriate, validated symptom rating scale should be one component of the diagnostic evaluation, say the authors. The Standardized Assessment of Concussion, however, “should not be exclusively used to diagnose mTBI in children aged 6 to 18,” they add. Finally, the guideline discourages the use of biomarkers (ie, serum markers) for diagnosis outside of a research setting.

Prognosis

The second section of the document provides guidance on developing a prognosis. Clinicians should advise patients and their families that most children with mTBI do not have significant difficulties that last for more than one to three months after injury, say the authors. They also should state that even though certain factors predict a child’s risk for prolonged symptoms, “each child’s recovery from mTBI is unique and will follow its own trajectory.”

Health care professionals should evaluate a child’s premorbid history as soon as possible to help determine the prognosis, say the authors. Children and families should be advised that factors such as history of mTBI, lower cognitive ability, and neurologic disorder can delay recovery from mTBI. Clinicians should screen for known risk factors for persistent symptoms and use a combination of tools (eg, validated symptom scales, cognitive testing, and balance testing) to assess recovery, according to the guideline.

Children with mTBI at high risk for persistent symptoms should be monitored closely. “For children with mTBI whose symptoms do not resolve as expected with standard care (ie, within four to six weeks), health care professionals should provide or refer for appropriate assessments and interventions,” say the authors.

Management and Treatment

The guideline’s section devoted to management and treatment begins with recommendations for returning to normal activities. Clinicians should recommend restricting physical and cognitive activity during the first several days after pediatric mTBI, according to the authors. After that point, doctors should advise patients and families “to resume a gradual schedule of activity that does not exacerbate symptoms, with close monitoring of symptom expression.” If the patient completes this step successfully, the clinician should offer an active rehabilitation program that progressively reintroduces noncontact aerobic activity that does not worsen symptoms. The number and severity of symptoms should be monitored closely throughout the patient’s recovery. A patient should resume full activity when his or her performance returns to its premorbid level, provided that he or she has no symptoms at rest or with increasing levels of exertion, according to the guideline.

“To assist children returning to school after mTBI, medical and school-based teams should counsel the student and family regarding the process of gradually increasing the duration and intensity of academic activities as tolerated, with the goal of increasing participation without significantly exacerbating symptoms,” say the authors. Return-to-school protocols should be adapted to the severity of the child’s postconcussion symptoms. School personnel should assess the need for additional educational support in students with prolonged symptoms that harm their academic performance, according to the guideline.

If a child with mTBI develops severe headache, especially if the headache is associated with other risk factors or has worsened after mTBI, emergency department professionals should observe him or her and consider obtaining a head CT to evaluate for intracranial injury, say the authors. Health care professionals should explain proper sleep hygiene to all patients with mTBI and their families to facilitate recovery.

If a child with mTBI has cognitive dysfunction, clinicians should attempt to determine its etiology within the context of other mTBI symptoms, say the authors. Treatment for cognitive dysfunction should reflect its presumed etiology, they conclude.

—Erik Greb

Suggested Reading

Lumba-Brown A, Yeates KO, Sarmiento K, et al. Centers for Disease Control and Prevention guideline on the diagnosis and management of mild traumatic brain injury among children. JAMA Pediatr. 2018 Sep 4 [Epub ahead of print].

Lumba-Brown A, Yeates KO, Sarmiento K, et al. Diagnosis and management of mild traumatic brain injury in children: a systematic review. JAMA Pediatr. 2018 Sep 4 [Epub ahead of print].

McCrea M, Manley G. State of the science on pediatric mild traumatic brain injury: progress toward clinical translation. JAMA Pediatr. 2018 Sep 4 [Epub ahead of print].

On September 24, 2018, the FDA announced that it awarded 12 new clinical trial research grants totaling more than $18 million over the next four years to enhance the development of medical products for patients with rare diseases. These new grants were awarded to principal investigators from academia and industry across the country.

“Developing a treatment for a rare disease can be especially challenging. Given the often small number of patients affected by certain very rare diseases, there can be limited markets for new treatments, and as a result fewer resources devoted to researching these opportunities,” said FDA Commissioner Scott Gottlieb, MD. “The FDA is committed to doing its part to facilitate continued progress toward more treatments, and even potential cures, for patients with rare diseases. New scientific advances offer more opportunities to develop these potential cures. With efficient regulation, proper incentives for product development, and the continued support of patients, providers, and researchers, we have more opportunities to pursue these advances than ever before. For 35 years, the FDA has provided much-needed financial support for clinical trials of potentially life-changing treatments for patients with rare diseases. This funding helps support early-stage development activities targeting rare diseases that do not have effective treatments. By providing seed capital, these FDA-administered grants enable researchers to prove out important concepts. The FDA grants also provide some important recognition to promising development programs that ultimately can help researchers attract additional funding.”

Alkeus Pharmaceuticals, Inc (Cambridge, Massachusetts), Leonide Saad, phase 2 study of ALK-001 for the treatment of Stargardt disease—$1.75 million over four years

Arizona State University–Tempe Campus (Tempe, Arizona), Keith Lindor, phase 2 study of oral vancomycin for the treatment of primary sclerosing cholangitis—$2 million over four years

Cedars-Sinai Medical Center (Los Angeles), Shlomo Melmed, phase 2 study of seliciclib for the treatment of Cushing disease—$2 million over four years

Columbia University (New York), Yvonne Saenger, phase 1 study of talimogene laherparepvec for the treatment for advanced pancreatic cancer—$750,000 over three years

Emory University (Atlanta), Eric Sorscher, phase 1/ 2 study of Ad/PNP fludarabine for the treatment of head and neck squamous cell carcinoma—$1.5 million over three years

Fibrocell Technologies, Inc (Exton, Pennsylvania), John Maslowski, phase 1/2 study of gene-modified ex-vivo autologous fibroblasts for the treatment of dystrophic epidermolysis bullosa—$1.5 million over four years

Johns Hopkins University (Baltimore), Amy Dezern, phase 1/2 study of CD8-reduced T cells for the treatment of myelodysplastic syndrome or acute myeloid leukemia—$750,000 over three years

Oncolmmune, Inc (Rockville, Maryland) Yang Liu, phase 2b study of CD24Fc for the prevention of graft versus host disease—$2 million over four years

Patagonia Pharmaceuticals, LLC (Woodcliff Lake, New Jersey), Zachary Rome, phase 2 study of PAT-001 (isotretinoin) for the treatment of congenital ichthyosis—$1.5 million over three years

The General Hospital Corporation (Boston), Stephanie Seminara, phase 2 study of kisspeptin for the treatment of dopamine agonist intolerant hyperprolactinemia—$1.4 million over four years

University of Minnesota (Minneapolis), Kyriakie Sarafoglou, phase 2a study of subcutaneous hydrocortisone infusion pump for the treatment of congenital adrenal hyperplasia—$1.4 million over three years

University of North Carolina at Chapel Hill (Chapel Hill, North Carolina), Matthew Laughon, phase 2 study of sildenafil for the prevention of bronchopulmonary dysplasia—$2 million over four years.

“Since its creation in 1983, the Orphan Products Grants Program has provided more than $400 million to fund more than 600 new clinical studies,” said Debra Lewis, OD, Acting Director of the FDA’s Office of Orphan Products Development. “We are encouraged to see so much interest in our grants program and are pleased to support research for a variety of rare diseases that have little, or no, treatment options for patients.”

One-third of the new awards aim to accelerate cancer research by enrolling patients with rare forms of cancer, including advanced pancreatic cancer, head and neck squamous cell carcinoma, myelodysplastic syndrome, and acute myeloid leukemia. Another 25% of the new awards fund studies evaluating drug products for rare endocrine disorders, including Cushing disease, dopamine agonist intolerant hyperprolactinemia, and congenital adrenal hyperplasia. Another study addresses an unmet need in primary sclerosing cholangitis, a rare, chronic, and potentially serious bile duct disease.

About 42% of the grants fund studies that enroll children and adolescents, targeting a variety of rare diseases in children such as Stargardt disease, a juvenile genetic eye disorder that causes progressive vision loss; dystrophic epidermolysis bullosa, a genetic condition that causes the skin to be fragile resulting in painful blisters; and bronchopulmonary dysplasia, a serious lung condition that affects infants.

To date, the program’s grants have supported research that led to the marketing approval of more than 60 orphan products. Among the recent product approvals which were supported by studies funded by this grants program are a marketing approval for a much-needed treatment of human immunodeficiency virus type 1 (HIV-1) infection in adults with multidrug resistant HIV-1 infection and another approval to reduce the acute complications of sickle cell disease in adult and pediatric patients.

The FDA is also currently supporting six natural history studies for rare diseases to further advance the mission of bringing new therapies to market.

On September 24, 2018, the FDA announced that it awarded 12 new clinical trial research grants totaling more than $18 million over the next four years to enhance the development of medical products for patients with rare diseases. These new grants were awarded to principal investigators from academia and industry across the country.

“Developing a treatment for a rare disease can be especially challenging. Given the often small number of patients affected by certain very rare diseases, there can be limited markets for new treatments, and as a result fewer resources devoted to researching these opportunities,” said FDA Commissioner Scott Gottlieb, MD. “The FDA is committed to doing its part to facilitate continued progress toward more treatments, and even potential cures, for patients with rare diseases. New scientific advances offer more opportunities to develop these potential cures. With efficient regulation, proper incentives for product development, and the continued support of patients, providers, and researchers, we have more opportunities to pursue these advances than ever before. For 35 years, the FDA has provided much-needed financial support for clinical trials of potentially life-changing treatments for patients with rare diseases. This funding helps support early-stage development activities targeting rare diseases that do not have effective treatments. By providing seed capital, these FDA-administered grants enable researchers to prove out important concepts. The FDA grants also provide some important recognition to promising development programs that ultimately can help researchers attract additional funding.”

Alkeus Pharmaceuticals, Inc (Cambridge, Massachusetts), Leonide Saad, phase 2 study of ALK-001 for the treatment of Stargardt disease—$1.75 million over four years

Arizona State University–Tempe Campus (Tempe, Arizona), Keith Lindor, phase 2 study of oral vancomycin for the treatment of primary sclerosing cholangitis—$2 million over four years

Cedars-Sinai Medical Center (Los Angeles), Shlomo Melmed, phase 2 study of seliciclib for the treatment of Cushing disease—$2 million over four years

Columbia University (New York), Yvonne Saenger, phase 1 study of talimogene laherparepvec for the treatment for advanced pancreatic cancer—$750,000 over three years

Emory University (Atlanta), Eric Sorscher, phase 1/ 2 study of Ad/PNP fludarabine for the treatment of head and neck squamous cell carcinoma—$1.5 million over three years

Fibrocell Technologies, Inc (Exton, Pennsylvania), John Maslowski, phase 1/2 study of gene-modified ex-vivo autologous fibroblasts for the treatment of dystrophic epidermolysis bullosa—$1.5 million over four years

Johns Hopkins University (Baltimore), Amy Dezern, phase 1/2 study of CD8-reduced T cells for the treatment of myelodysplastic syndrome or acute myeloid leukemia—$750,000 over three years

Oncolmmune, Inc (Rockville, Maryland) Yang Liu, phase 2b study of CD24Fc for the prevention of graft versus host disease—$2 million over four years

Patagonia Pharmaceuticals, LLC (Woodcliff Lake, New Jersey), Zachary Rome, phase 2 study of PAT-001 (isotretinoin) for the treatment of congenital ichthyosis—$1.5 million over three years

The General Hospital Corporation (Boston), Stephanie Seminara, phase 2 study of kisspeptin for the treatment of dopamine agonist intolerant hyperprolactinemia—$1.4 million over four years

University of Minnesota (Minneapolis), Kyriakie Sarafoglou, phase 2a study of subcutaneous hydrocortisone infusion pump for the treatment of congenital adrenal hyperplasia—$1.4 million over three years

University of North Carolina at Chapel Hill (Chapel Hill, North Carolina), Matthew Laughon, phase 2 study of sildenafil for the prevention of bronchopulmonary dysplasia—$2 million over four years.

“Since its creation in 1983, the Orphan Products Grants Program has provided more than $400 million to fund more than 600 new clinical studies,” said Debra Lewis, OD, Acting Director of the FDA’s Office of Orphan Products Development. “We are encouraged to see so much interest in our grants program and are pleased to support research for a variety of rare diseases that have little, or no, treatment options for patients.”

One-third of the new awards aim to accelerate cancer research by enrolling patients with rare forms of cancer, including advanced pancreatic cancer, head and neck squamous cell carcinoma, myelodysplastic syndrome, and acute myeloid leukemia. Another 25% of the new awards fund studies evaluating drug products for rare endocrine disorders, including Cushing disease, dopamine agonist intolerant hyperprolactinemia, and congenital adrenal hyperplasia. Another study addresses an unmet need in primary sclerosing cholangitis, a rare, chronic, and potentially serious bile duct disease.

About 42% of the grants fund studies that enroll children and adolescents, targeting a variety of rare diseases in children such as Stargardt disease, a juvenile genetic eye disorder that causes progressive vision loss; dystrophic epidermolysis bullosa, a genetic condition that causes the skin to be fragile resulting in painful blisters; and bronchopulmonary dysplasia, a serious lung condition that affects infants.

To date, the program’s grants have supported research that led to the marketing approval of more than 60 orphan products. Among the recent product approvals which were supported by studies funded by this grants program are a marketing approval for a much-needed treatment of human immunodeficiency virus type 1 (HIV-1) infection in adults with multidrug resistant HIV-1 infection and another approval to reduce the acute complications of sickle cell disease in adult and pediatric patients.

The FDA is also currently supporting six natural history studies for rare diseases to further advance the mission of bringing new therapies to market.

On September 24, 2018, the FDA announced that it awarded 12 new clinical trial research grants totaling more than $18 million over the next four years to enhance the development of medical products for patients with rare diseases. These new grants were awarded to principal investigators from academia and industry across the country.

“Developing a treatment for a rare disease can be especially challenging. Given the often small number of patients affected by certain very rare diseases, there can be limited markets for new treatments, and as a result fewer resources devoted to researching these opportunities,” said FDA Commissioner Scott Gottlieb, MD. “The FDA is committed to doing its part to facilitate continued progress toward more treatments, and even potential cures, for patients with rare diseases. New scientific advances offer more opportunities to develop these potential cures. With efficient regulation, proper incentives for product development, and the continued support of patients, providers, and researchers, we have more opportunities to pursue these advances than ever before. For 35 years, the FDA has provided much-needed financial support for clinical trials of potentially life-changing treatments for patients with rare diseases. This funding helps support early-stage development activities targeting rare diseases that do not have effective treatments. By providing seed capital, these FDA-administered grants enable researchers to prove out important concepts. The FDA grants also provide some important recognition to promising development programs that ultimately can help researchers attract additional funding.”

Alkeus Pharmaceuticals, Inc (Cambridge, Massachusetts), Leonide Saad, phase 2 study of ALK-001 for the treatment of Stargardt disease—$1.75 million over four years

Arizona State University–Tempe Campus (Tempe, Arizona), Keith Lindor, phase 2 study of oral vancomycin for the treatment of primary sclerosing cholangitis—$2 million over four years

Cedars-Sinai Medical Center (Los Angeles), Shlomo Melmed, phase 2 study of seliciclib for the treatment of Cushing disease—$2 million over four years

Columbia University (New York), Yvonne Saenger, phase 1 study of talimogene laherparepvec for the treatment for advanced pancreatic cancer—$750,000 over three years

Emory University (Atlanta), Eric Sorscher, phase 1/ 2 study of Ad/PNP fludarabine for the treatment of head and neck squamous cell carcinoma—$1.5 million over three years

Fibrocell Technologies, Inc (Exton, Pennsylvania), John Maslowski, phase 1/2 study of gene-modified ex-vivo autologous fibroblasts for the treatment of dystrophic epidermolysis bullosa—$1.5 million over four years

Johns Hopkins University (Baltimore), Amy Dezern, phase 1/2 study of CD8-reduced T cells for the treatment of myelodysplastic syndrome or acute myeloid leukemia—$750,000 over three years

Oncolmmune, Inc (Rockville, Maryland) Yang Liu, phase 2b study of CD24Fc for the prevention of graft versus host disease—$2 million over four years

Patagonia Pharmaceuticals, LLC (Woodcliff Lake, New Jersey), Zachary Rome, phase 2 study of PAT-001 (isotretinoin) for the treatment of congenital ichthyosis—$1.5 million over three years

The General Hospital Corporation (Boston), Stephanie Seminara, phase 2 study of kisspeptin for the treatment of dopamine agonist intolerant hyperprolactinemia—$1.4 million over four years

University of Minnesota (Minneapolis), Kyriakie Sarafoglou, phase 2a study of subcutaneous hydrocortisone infusion pump for the treatment of congenital adrenal hyperplasia—$1.4 million over three years

University of North Carolina at Chapel Hill (Chapel Hill, North Carolina), Matthew Laughon, phase 2 study of sildenafil for the prevention of bronchopulmonary dysplasia—$2 million over four years.

“Since its creation in 1983, the Orphan Products Grants Program has provided more than $400 million to fund more than 600 new clinical studies,” said Debra Lewis, OD, Acting Director of the FDA’s Office of Orphan Products Development. “We are encouraged to see so much interest in our grants program and are pleased to support research for a variety of rare diseases that have little, or no, treatment options for patients.”

One-third of the new awards aim to accelerate cancer research by enrolling patients with rare forms of cancer, including advanced pancreatic cancer, head and neck squamous cell carcinoma, myelodysplastic syndrome, and acute myeloid leukemia. Another 25% of the new awards fund studies evaluating drug products for rare endocrine disorders, including Cushing disease, dopamine agonist intolerant hyperprolactinemia, and congenital adrenal hyperplasia. Another study addresses an unmet need in primary sclerosing cholangitis, a rare, chronic, and potentially serious bile duct disease.

About 42% of the grants fund studies that enroll children and adolescents, targeting a variety of rare diseases in children such as Stargardt disease, a juvenile genetic eye disorder that causes progressive vision loss; dystrophic epidermolysis bullosa, a genetic condition that causes the skin to be fragile resulting in painful blisters; and bronchopulmonary dysplasia, a serious lung condition that affects infants.

To date, the program’s grants have supported research that led to the marketing approval of more than 60 orphan products. Among the recent product approvals which were supported by studies funded by this grants program are a marketing approval for a much-needed treatment of human immunodeficiency virus type 1 (HIV-1) infection in adults with multidrug resistant HIV-1 infection and another approval to reduce the acute complications of sickle cell disease in adult and pediatric patients.

The FDA is also currently supporting six natural history studies for rare diseases to further advance the mission of bringing new therapies to market.