The Food and Drug Administration has expanded the indication for linaclotide (Linzess) to children as young as age 6 years with functional constipation, making it the first approved treatment for pediatric functional constipation.

The recommended dosage in pediatric patients is 72 mcg orally once daily.

Functional constipation is common in children and adolescents. Symptoms include infrequent bowel movements with hard stools that can be difficult or painful to pass.

Olivier Le Moal/Getty Images

There is no known underlying organic cause and there are typically multiple contributing factors, the FDA noted in a statement announcing the approval.

The efficacy of linaclotide in children with functional constipation was demonstrated in a 12-week double-blind, placebo-controlled, randomized, multicenter clinical trial (Trial 7; NCT04026113) and supported by efficacy data from trials in adults with chronic idiopathic constipation, the FDA said.

The FDA first approved linaclotide in 2012 for the treatment of chronic idiopathic constipation and irritable bowel syndrome with constipation (IBS-C) in adults.
 

Study details

To be eligible for the pediatric clinical trial, patients had to have experienced fewer than three spontaneous bowel movements (SBMs) per week.

They also had to experience one or more of the following at least once weekly, for at least 2 months prior to the trial screening visit:

• History of stool withholding or excessive voluntary stool retention.
• History of painful or hard bowel movements.
• History of large diameter stools that may obstruct the toilet.
• Presence of a large fecal mass in the rectum.
• At least one episode of fecal incontinence per week.

The primary efficacy endpoint was a 12-week change from baseline in SBM frequency rate. Children on linaclotide experienced greater improvement in the average number of SBMs per week than peers given placebo.

SBM frequency improved during the first week and was maintained throughout the remainder of the 12-week treatment period, the FDA said.

The most common adverse reaction is diarrhea. If severe diarrhea occurs, linaclotide should be discontinued and rehydration started.

The product’s boxed warning states that linaclotide is contraindicated in children younger than 2 years. In neonatal mice, linaclotide caused deaths due to dehydration.

Patients with known or suspected mechanical gastrointestinal obstruction should not take linaclotide.

Full prescribing information is available online.

The application for linaclotide in children received priority review.

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

The Food and Drug Administration has expanded the indication for linaclotide (Linzess) to children as young as age 6 years with functional constipation, making it the first approved treatment for pediatric functional constipation.

The recommended dosage in pediatric patients is 72 mcg orally once daily.

Functional constipation is common in children and adolescents. Symptoms include infrequent bowel movements with hard stools that can be difficult or painful to pass.

Olivier Le Moal/Getty Images

There is no known underlying organic cause and there are typically multiple contributing factors, the FDA noted in a statement announcing the approval.

The efficacy of linaclotide in children with functional constipation was demonstrated in a 12-week double-blind, placebo-controlled, randomized, multicenter clinical trial (Trial 7; NCT04026113) and supported by efficacy data from trials in adults with chronic idiopathic constipation, the FDA said.

The FDA first approved linaclotide in 2012 for the treatment of chronic idiopathic constipation and irritable bowel syndrome with constipation (IBS-C) in adults.
 

Study details

To be eligible for the pediatric clinical trial, patients had to have experienced fewer than three spontaneous bowel movements (SBMs) per week.

They also had to experience one or more of the following at least once weekly, for at least 2 months prior to the trial screening visit:

• History of stool withholding or excessive voluntary stool retention.
• History of painful or hard bowel movements.
• History of large diameter stools that may obstruct the toilet.
• Presence of a large fecal mass in the rectum.
• At least one episode of fecal incontinence per week.

The primary efficacy endpoint was a 12-week change from baseline in SBM frequency rate. Children on linaclotide experienced greater improvement in the average number of SBMs per week than peers given placebo.

SBM frequency improved during the first week and was maintained throughout the remainder of the 12-week treatment period, the FDA said.

The most common adverse reaction is diarrhea. If severe diarrhea occurs, linaclotide should be discontinued and rehydration started.

The product’s boxed warning states that linaclotide is contraindicated in children younger than 2 years. In neonatal mice, linaclotide caused deaths due to dehydration.

Patients with known or suspected mechanical gastrointestinal obstruction should not take linaclotide.

Full prescribing information is available online.

The application for linaclotide in children received priority review.

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

The Food and Drug Administration has expanded the indication for linaclotide (Linzess) to children as young as age 6 years with functional constipation, making it the first approved treatment for pediatric functional constipation.

The recommended dosage in pediatric patients is 72 mcg orally once daily.

Functional constipation is common in children and adolescents. Symptoms include infrequent bowel movements with hard stools that can be difficult or painful to pass.

Olivier Le Moal/Getty Images

There is no known underlying organic cause and there are typically multiple contributing factors, the FDA noted in a statement announcing the approval.

The efficacy of linaclotide in children with functional constipation was demonstrated in a 12-week double-blind, placebo-controlled, randomized, multicenter clinical trial (Trial 7; NCT04026113) and supported by efficacy data from trials in adults with chronic idiopathic constipation, the FDA said.

The FDA first approved linaclotide in 2012 for the treatment of chronic idiopathic constipation and irritable bowel syndrome with constipation (IBS-C) in adults.
 

Study details

To be eligible for the pediatric clinical trial, patients had to have experienced fewer than three spontaneous bowel movements (SBMs) per week.

They also had to experience one or more of the following at least once weekly, for at least 2 months prior to the trial screening visit:

• History of stool withholding or excessive voluntary stool retention.
• History of painful or hard bowel movements.
• History of large diameter stools that may obstruct the toilet.
• Presence of a large fecal mass in the rectum.
• At least one episode of fecal incontinence per week.

The primary efficacy endpoint was a 12-week change from baseline in SBM frequency rate. Children on linaclotide experienced greater improvement in the average number of SBMs per week than peers given placebo.

SBM frequency improved during the first week and was maintained throughout the remainder of the 12-week treatment period, the FDA said.

The most common adverse reaction is diarrhea. If severe diarrhea occurs, linaclotide should be discontinued and rehydration started.

The product’s boxed warning states that linaclotide is contraindicated in children younger than 2 years. In neonatal mice, linaclotide caused deaths due to dehydration.

Patients with known or suspected mechanical gastrointestinal obstruction should not take linaclotide.

Full prescribing information is available online.

The application for linaclotide in children received priority review.

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

DENVER – Taking ozanimod for relapsing multiple sclerosis (MS) at the same time as taking antidepressants that increase serotonin levels does not appear to increase the risk for hypertension or any other adverse events related to serotonin toxicity, according to research presented at the annual meeting of the Consortium of Multiple Sclerosis Centers.

“Depression and anxiety are prevalent comorbidities occurring in up to 54% of patients with multiple sclerosis, and selective serotonin reuptake inhibitors (SSRIs)/serotonin-norepinephrine reuptake inhibitors (SNRIs) are first-line treatments for depression and anxiety disorders,” Robert T. Naismith, MD, of Washington University in St. Louis, and his colleagues reported.

“Coadministration of ozanimod with drugs that increase serotonin could hypothetically lead to serotonin accumulation,” which can increase the likelihood of hypertension. U.S. prescribing information recommends that patients taking both ozanimod and medications that increase norepinephrine or serotonin be monitored for hypertension, an adverse reaction reported in 3.9% of patients receiving ozanimod in the phase 3 trials for relapsing MS.
 

Clarifying the risk

“It’s important to be aware of potential drug interactions and risks from MS disease modifying therapies,” Lauren Gluck, MD, an assistant professor and director of the division of multiple sclerosis at Montefiore Medical Center/Albert Einstein College of Medicine, New York, said in an interview. Dr. Gluck was not involved in this study but described some of the history that revealed the value of this type of research. For example, the first sphingosine-1-phosphate receptor (S1PR) modulator approved for MS, fingolimod (Gilenya), has a risk of cardiac conduction dysfunction with QTc prolongation, so people taking fingolimod with other medications that prolong QTc, such as SSRIs, need additional monitoring.

“Ozanimod is a newer, more selective S1PR modulator that initially raised concerns about interaction with serotonin-increasing drugs based on in vitro studies,” Dr. Gluck said. “This could mean that people on ozanimod and other serotonin-increasing medicine could be at risk for dangerous events like serotonin syndrome. However, in vitro studies do not always translate to how something affects the human body, so it is not clear how much risk truly exists.”
 

Examining open-label extension trial data

The researchers therefore evaluated the safety of taking ozanimod and SSRIs or SNRIs in a subset of patients with relapsing MS who participated in the DAYBREAK open-label extension trial. The phase 3 parent trials compared 30 mcg once weekly of intramuscular interferon beta-1a with 0.92 mg of once-daily oral ozanimod and 0.46 mg of once-daily oral ozanimod. In the DAYBREAK open-label extension, 2,256 participants underwent a dose escalation over one week until all reached 0.92 mg of ozanimod, where they remained for an average of just under 5 years of follow-up. Nearly all the participants (99.4%) were White, and two-thirds (66.5%) were female.

The researchers searched the study data for terms related to serotonin toxicity and compared the rates of adverse events related with those terms and the rates of hypertension in the 274 participants who were and the 2,032 participant who were not taking antidepressants at the same time as ozanimod.

They found that 13.9% of patients taking SSRIs or SNRIs experienced at least one treatment-emergent adverse event related to their search criteria, compared with 17.7% of patients not taking SSRIs or SNRIs. Similarly, 9.2% of trial participants not taking SSRIs or SNRIs had hypertension, compared with 4.7% of participants who were taking antidepressants. The authors further noted that “similar trends were observed when 6 weeks after the end date of concomitant SSRIs/SNRI use were included in the ‘on SSRI/SNRI’ analysis period.”

When the researchers searched specifically for three terms directly related to serotonin toxicity – “serotonin syndrome,” “neuroleptic malignant syndrome,” and “hyperthermia malignant” – they did not find any patients who had treatment-emergent adverse events related to those terms.

“SSRIs/SNRIs were freely allowed as concomitant medications in the DAYBREAK open-label extension, and among the patients from SUNBEAM or RADIANCE who were followed for up to 6 years, there have been no reported safety concerns during the concurrent administration of serotonergic antidepressants and ozanimod in patients with relapsing MS as of the data cutoff,” concluded the authors, though they also noted that the overall rate of SSRI and SNRI use was low in the extension trial.
 

A reassuring finding for clinicians and patients alike

“It is reassuring, if not unexpected, that there were no clinically significant rates of symptoms associated with excess serotonin in patients on ozanimod and SSRI/SNRIs,” Dr. Gluck commented. “These findings are important for both clinicians and patients – they can help [both] feel comfortable considering ozanimod if SSRI/SNRIs are already being used. There is also freedom to use SSRI/SNRIs for symptom management in patients already on ozanimod.”

The research was funded by Bristol Myers Squibb. Dr. Naismith reported consulting for Abata Therapeutics, Banner Life Sciences, BeiGene, Biogen, Bristol Myers Squibb, Celltrion, Genentech, Genzyme, GW Therapeutics, Janssen, Horizon Therapeutics, Lundbeck, NervGen, and TG Therapeutics. Six other authors reported disclosures for various pharmaceutical companies, and six other authors are employees and/or shareholders of Bristol Myers Squibb. Dr. Gluck has served on advisory boards with Genentech and EMD Serono.
 

DENVER – Taking ozanimod for relapsing multiple sclerosis (MS) at the same time as taking antidepressants that increase serotonin levels does not appear to increase the risk for hypertension or any other adverse events related to serotonin toxicity, according to research presented at the annual meeting of the Consortium of Multiple Sclerosis Centers.

“Depression and anxiety are prevalent comorbidities occurring in up to 54% of patients with multiple sclerosis, and selective serotonin reuptake inhibitors (SSRIs)/serotonin-norepinephrine reuptake inhibitors (SNRIs) are first-line treatments for depression and anxiety disorders,” Robert T. Naismith, MD, of Washington University in St. Louis, and his colleagues reported.

“Coadministration of ozanimod with drugs that increase serotonin could hypothetically lead to serotonin accumulation,” which can increase the likelihood of hypertension. U.S. prescribing information recommends that patients taking both ozanimod and medications that increase norepinephrine or serotonin be monitored for hypertension, an adverse reaction reported in 3.9% of patients receiving ozanimod in the phase 3 trials for relapsing MS.
 

Clarifying the risk

“It’s important to be aware of potential drug interactions and risks from MS disease modifying therapies,” Lauren Gluck, MD, an assistant professor and director of the division of multiple sclerosis at Montefiore Medical Center/Albert Einstein College of Medicine, New York, said in an interview. Dr. Gluck was not involved in this study but described some of the history that revealed the value of this type of research. For example, the first sphingosine-1-phosphate receptor (S1PR) modulator approved for MS, fingolimod (Gilenya), has a risk of cardiac conduction dysfunction with QTc prolongation, so people taking fingolimod with other medications that prolong QTc, such as SSRIs, need additional monitoring.

“Ozanimod is a newer, more selective S1PR modulator that initially raised concerns about interaction with serotonin-increasing drugs based on in vitro studies,” Dr. Gluck said. “This could mean that people on ozanimod and other serotonin-increasing medicine could be at risk for dangerous events like serotonin syndrome. However, in vitro studies do not always translate to how something affects the human body, so it is not clear how much risk truly exists.”
 

Examining open-label extension trial data

The researchers therefore evaluated the safety of taking ozanimod and SSRIs or SNRIs in a subset of patients with relapsing MS who participated in the DAYBREAK open-label extension trial. The phase 3 parent trials compared 30 mcg once weekly of intramuscular interferon beta-1a with 0.92 mg of once-daily oral ozanimod and 0.46 mg of once-daily oral ozanimod. In the DAYBREAK open-label extension, 2,256 participants underwent a dose escalation over one week until all reached 0.92 mg of ozanimod, where they remained for an average of just under 5 years of follow-up. Nearly all the participants (99.4%) were White, and two-thirds (66.5%) were female.

The researchers searched the study data for terms related to serotonin toxicity and compared the rates of adverse events related with those terms and the rates of hypertension in the 274 participants who were and the 2,032 participant who were not taking antidepressants at the same time as ozanimod.

They found that 13.9% of patients taking SSRIs or SNRIs experienced at least one treatment-emergent adverse event related to their search criteria, compared with 17.7% of patients not taking SSRIs or SNRIs. Similarly, 9.2% of trial participants not taking SSRIs or SNRIs had hypertension, compared with 4.7% of participants who were taking antidepressants. The authors further noted that “similar trends were observed when 6 weeks after the end date of concomitant SSRIs/SNRI use were included in the ‘on SSRI/SNRI’ analysis period.”

When the researchers searched specifically for three terms directly related to serotonin toxicity – “serotonin syndrome,” “neuroleptic malignant syndrome,” and “hyperthermia malignant” – they did not find any patients who had treatment-emergent adverse events related to those terms.

“SSRIs/SNRIs were freely allowed as concomitant medications in the DAYBREAK open-label extension, and among the patients from SUNBEAM or RADIANCE who were followed for up to 6 years, there have been no reported safety concerns during the concurrent administration of serotonergic antidepressants and ozanimod in patients with relapsing MS as of the data cutoff,” concluded the authors, though they also noted that the overall rate of SSRI and SNRI use was low in the extension trial.
 

A reassuring finding for clinicians and patients alike

“It is reassuring, if not unexpected, that there were no clinically significant rates of symptoms associated with excess serotonin in patients on ozanimod and SSRI/SNRIs,” Dr. Gluck commented. “These findings are important for both clinicians and patients – they can help [both] feel comfortable considering ozanimod if SSRI/SNRIs are already being used. There is also freedom to use SSRI/SNRIs for symptom management in patients already on ozanimod.”

The research was funded by Bristol Myers Squibb. Dr. Naismith reported consulting for Abata Therapeutics, Banner Life Sciences, BeiGene, Biogen, Bristol Myers Squibb, Celltrion, Genentech, Genzyme, GW Therapeutics, Janssen, Horizon Therapeutics, Lundbeck, NervGen, and TG Therapeutics. Six other authors reported disclosures for various pharmaceutical companies, and six other authors are employees and/or shareholders of Bristol Myers Squibb. Dr. Gluck has served on advisory boards with Genentech and EMD Serono.
 

DENVER – Taking ozanimod for relapsing multiple sclerosis (MS) at the same time as taking antidepressants that increase serotonin levels does not appear to increase the risk for hypertension or any other adverse events related to serotonin toxicity, according to research presented at the annual meeting of the Consortium of Multiple Sclerosis Centers.

“Depression and anxiety are prevalent comorbidities occurring in up to 54% of patients with multiple sclerosis, and selective serotonin reuptake inhibitors (SSRIs)/serotonin-norepinephrine reuptake inhibitors (SNRIs) are first-line treatments for depression and anxiety disorders,” Robert T. Naismith, MD, of Washington University in St. Louis, and his colleagues reported.

“Coadministration of ozanimod with drugs that increase serotonin could hypothetically lead to serotonin accumulation,” which can increase the likelihood of hypertension. U.S. prescribing information recommends that patients taking both ozanimod and medications that increase norepinephrine or serotonin be monitored for hypertension, an adverse reaction reported in 3.9% of patients receiving ozanimod in the phase 3 trials for relapsing MS.
 

Clarifying the risk

“It’s important to be aware of potential drug interactions and risks from MS disease modifying therapies,” Lauren Gluck, MD, an assistant professor and director of the division of multiple sclerosis at Montefiore Medical Center/Albert Einstein College of Medicine, New York, said in an interview. Dr. Gluck was not involved in this study but described some of the history that revealed the value of this type of research. For example, the first sphingosine-1-phosphate receptor (S1PR) modulator approved for MS, fingolimod (Gilenya), has a risk of cardiac conduction dysfunction with QTc prolongation, so people taking fingolimod with other medications that prolong QTc, such as SSRIs, need additional monitoring.

“Ozanimod is a newer, more selective S1PR modulator that initially raised concerns about interaction with serotonin-increasing drugs based on in vitro studies,” Dr. Gluck said. “This could mean that people on ozanimod and other serotonin-increasing medicine could be at risk for dangerous events like serotonin syndrome. However, in vitro studies do not always translate to how something affects the human body, so it is not clear how much risk truly exists.”
 

Examining open-label extension trial data

The researchers therefore evaluated the safety of taking ozanimod and SSRIs or SNRIs in a subset of patients with relapsing MS who participated in the DAYBREAK open-label extension trial. The phase 3 parent trials compared 30 mcg once weekly of intramuscular interferon beta-1a with 0.92 mg of once-daily oral ozanimod and 0.46 mg of once-daily oral ozanimod. In the DAYBREAK open-label extension, 2,256 participants underwent a dose escalation over one week until all reached 0.92 mg of ozanimod, where they remained for an average of just under 5 years of follow-up. Nearly all the participants (99.4%) were White, and two-thirds (66.5%) were female.

The researchers searched the study data for terms related to serotonin toxicity and compared the rates of adverse events related with those terms and the rates of hypertension in the 274 participants who were and the 2,032 participant who were not taking antidepressants at the same time as ozanimod.

They found that 13.9% of patients taking SSRIs or SNRIs experienced at least one treatment-emergent adverse event related to their search criteria, compared with 17.7% of patients not taking SSRIs or SNRIs. Similarly, 9.2% of trial participants not taking SSRIs or SNRIs had hypertension, compared with 4.7% of participants who were taking antidepressants. The authors further noted that “similar trends were observed when 6 weeks after the end date of concomitant SSRIs/SNRI use were included in the ‘on SSRI/SNRI’ analysis period.”

When the researchers searched specifically for three terms directly related to serotonin toxicity – “serotonin syndrome,” “neuroleptic malignant syndrome,” and “hyperthermia malignant” – they did not find any patients who had treatment-emergent adverse events related to those terms.

“SSRIs/SNRIs were freely allowed as concomitant medications in the DAYBREAK open-label extension, and among the patients from SUNBEAM or RADIANCE who were followed for up to 6 years, there have been no reported safety concerns during the concurrent administration of serotonergic antidepressants and ozanimod in patients with relapsing MS as of the data cutoff,” concluded the authors, though they also noted that the overall rate of SSRI and SNRI use was low in the extension trial.
 

A reassuring finding for clinicians and patients alike

“It is reassuring, if not unexpected, that there were no clinically significant rates of symptoms associated with excess serotonin in patients on ozanimod and SSRI/SNRIs,” Dr. Gluck commented. “These findings are important for both clinicians and patients – they can help [both] feel comfortable considering ozanimod if SSRI/SNRIs are already being used. There is also freedom to use SSRI/SNRIs for symptom management in patients already on ozanimod.”

The research was funded by Bristol Myers Squibb. Dr. Naismith reported consulting for Abata Therapeutics, Banner Life Sciences, BeiGene, Biogen, Bristol Myers Squibb, Celltrion, Genentech, Genzyme, GW Therapeutics, Janssen, Horizon Therapeutics, Lundbeck, NervGen, and TG Therapeutics. Six other authors reported disclosures for various pharmaceutical companies, and six other authors are employees and/or shareholders of Bristol Myers Squibb. Dr. Gluck has served on advisory boards with Genentech and EMD Serono.
 

This little fellow greets you at my office. He’s been there for 25 years.

Dr. Block

I don’t know where he came from originally. When I started out he was up front with the physician I subleased from and when he retired he passed him on to me (thanks, Fran!).

From the beginning he’s been the first thing I see when I arrive each morning. Because of my suprachiasmatic nucleus kicking me out of bed between 4 and 5 each morning, I’m always the first one in the office and so I update him. At this point he’s as much a part of my morning ritual as coffee and tea. I juggle the cubes to change the day (12 times a year I change the month) and once this is done I don’t think of him again until the next morning.

Over time this whimsical character and the calendar blocks he holds have taken on a bigger significance, quietly counting out the days of my career and life. When I started setting him each morning I didn’t have kids. Now I have three, all grown. Patients, years, drug reps, and even a pandemic have all been marked by the clicking of his cubes when I change them each morning.

Now two-thirds of the way through my career, he’s taken on a different meaning. He’s counting down the days until I walk away and leave neurology in the hands of another generation. I don’t have a date for doing that, nor a plan to do so anytime soon, but sooner or later I’ll be changing his cubes for the last office day of my life as a neurologist.

What will happen to him then? Seems like a strange question to ask about an inanimate object, but after this much time I’ve gotten attached to the little guy. He’s come to symbolize more than just the date – he’s the passage of time. Maybe he’ll stay on a shelf at home, giving me something to do each morning of my retirement. Maybe one of my kids will want him.

Inevitably, he’ll probably end up at a charity store, awaiting a new owner. When that happens I hope he gives them something to pause, smile, and think about each day, like he did with me, as we travel around the sun together.

Dr. Block has a solo neurology practice in Scottsdale, Ariz.

This little fellow greets you at my office. He’s been there for 25 years.

Dr. Block

I don’t know where he came from originally. When I started out he was up front with the physician I subleased from and when he retired he passed him on to me (thanks, Fran!).

From the beginning he’s been the first thing I see when I arrive each morning. Because of my suprachiasmatic nucleus kicking me out of bed between 4 and 5 each morning, I’m always the first one in the office and so I update him. At this point he’s as much a part of my morning ritual as coffee and tea. I juggle the cubes to change the day (12 times a year I change the month) and once this is done I don’t think of him again until the next morning.

Over time this whimsical character and the calendar blocks he holds have taken on a bigger significance, quietly counting out the days of my career and life. When I started setting him each morning I didn’t have kids. Now I have three, all grown. Patients, years, drug reps, and even a pandemic have all been marked by the clicking of his cubes when I change them each morning.

Now two-thirds of the way through my career, he’s taken on a different meaning. He’s counting down the days until I walk away and leave neurology in the hands of another generation. I don’t have a date for doing that, nor a plan to do so anytime soon, but sooner or later I’ll be changing his cubes for the last office day of my life as a neurologist.

What will happen to him then? Seems like a strange question to ask about an inanimate object, but after this much time I’ve gotten attached to the little guy. He’s come to symbolize more than just the date – he’s the passage of time. Maybe he’ll stay on a shelf at home, giving me something to do each morning of my retirement. Maybe one of my kids will want him.

Inevitably, he’ll probably end up at a charity store, awaiting a new owner. When that happens I hope he gives them something to pause, smile, and think about each day, like he did with me, as we travel around the sun together.

Dr. Block has a solo neurology practice in Scottsdale, Ariz.

This little fellow greets you at my office. He’s been there for 25 years.

Dr. Block

I don’t know where he came from originally. When I started out he was up front with the physician I subleased from and when he retired he passed him on to me (thanks, Fran!).

From the beginning he’s been the first thing I see when I arrive each morning. Because of my suprachiasmatic nucleus kicking me out of bed between 4 and 5 each morning, I’m always the first one in the office and so I update him. At this point he’s as much a part of my morning ritual as coffee and tea. I juggle the cubes to change the day (12 times a year I change the month) and once this is done I don’t think of him again until the next morning.

Over time this whimsical character and the calendar blocks he holds have taken on a bigger significance, quietly counting out the days of my career and life. When I started setting him each morning I didn’t have kids. Now I have three, all grown. Patients, years, drug reps, and even a pandemic have all been marked by the clicking of his cubes when I change them each morning.

Now two-thirds of the way through my career, he’s taken on a different meaning. He’s counting down the days until I walk away and leave neurology in the hands of another generation. I don’t have a date for doing that, nor a plan to do so anytime soon, but sooner or later I’ll be changing his cubes for the last office day of my life as a neurologist.

What will happen to him then? Seems like a strange question to ask about an inanimate object, but after this much time I’ve gotten attached to the little guy. He’s come to symbolize more than just the date – he’s the passage of time. Maybe he’ll stay on a shelf at home, giving me something to do each morning of my retirement. Maybe one of my kids will want him.

Inevitably, he’ll probably end up at a charity store, awaiting a new owner. When that happens I hope he gives them something to pause, smile, and think about each day, like he did with me, as we travel around the sun together.

Dr. Block has a solo neurology practice in Scottsdale, Ariz.

THE CASE

A 55-year-old woman was evaluated in a family medicine clinic for clear, right-side nasal drainage. She stated that the drainage began 5 months earlier after 2 hospitalizations for severe anxiety leading to emesis and hypokalemia. She reported 3 different COVID-19 nasal swab tests performed on the right nare. Chart review showed 2 negative COVID-19 tests, 6 days apart. Since the hospitalizations, the patient had been given antihistamines for rhinorrhea at an urgent care visit. Despite this treatment, the patient reported a constant drip from the right nare with a salty taste. She also reported experiencing occasional headaches but denied nausea/vomiting. 

The patient’s history included uncontrolled hypertension, treatment-resistant anxiety and depression, obstructive sleep apnea, chronic sinus disease (observed on computed tomography [CT] scans), and type 2 diabetes. She was on amlodipine 10 mg/d for hypertension and was not taking any medication for diabetes.

On examination, the patient’s vital signs were within normal limits except for an elevated blood pressure of 158/88 mm Hg. The patient had persistent clear rhinorrhea fluid draining from the right nostril that was exacerbated when she looked down. Right nasal erythema was present. 

THE DIAGNOSIS 

The patient’s negative COVID-19 tests, lack of improvement on antihistamines, and description of the nasal fluid as salty tasting prompted us to suspect a cerebrospinal fluid (CSF) leak. The clinical work-up included a halo (“double-ring”) sign test, a β-2 transferrin test, and a sinus x-ray.

The halo sign test was negative for CSF fluid. Sinus/skull x-ray did not show a cribriform or other fracture. However, a sample of the nasal fluid collected in a sterile container was positive for β-2 transferrin, the gold-standard laboratory test to confirm a CSF leak.

The patient was sent for a maxillofacial CT scan without contrast. Results showed a 3-mm defect over the right ethmoid roof associated with a 10 × 16–mm low-attenuation structure in the right ethmoid labyrinth, suspicious for encephalocele. This defect, in the setting of the patient’s history of chronic sinus disease, furthered our suspicion of a CSF leak secondary to COVID-19 testing. Radiology confirmed the diagnosis.

DISCUSSION

CSF rhinorrhea is CSF leakage through the nasal cavity due to abnormal communication between the arachnoid membrane and nasal mucosa.¹ The most commonly reported risk factors for this include female sex, middle age (fourth to fifth decade), obesity (body mass index > 40), intracranial hypertension, and obstructive sleep apnea.^1,2

Continue to: Clear, unilateral rhinorrhea...

Clear, unilateral rhinorrhea drainage that increases at times of relatively increased intracranial pressure and has a metallic or salty taste is suspicious for CSF rhinorrhea.³ It can occur following skull‐base trauma (eg, cribriform plate, temporal bone), endoscopic sinus surgery, or neurosurgical procedures, or have a spontaneous etiology.^3,4

Modalities to confirm CSF rhinorrhea include radionuclide cisternography and testing of fluid for the halo sign, glucose, and the CSF-specific proteins β‐2 transferrin and β-trace protein.^3,4 High‐resolution CT is the imaging method most commonly used for localizing a CSF leak.⁴

Treatment is provided in the hospital

Patients with CSF rhinorrhea typically require inpatient management with bed rest, head-of-bed elevation, and frequent neurologic evaluation, as persistent CSF rhinorrhea increases the risk for meningitis, thus necessitating surgical intervention.^3,5 Some cases resolve with bed rest alone. Endonasal endoscopic repair of CSF leaks has become the standard of care because of its high success rate and lower morbidity profile.⁴ 

The preferred treatment method for encephalocele is surgical removal after diagnosis is confirmed with CT or magnetic resonance imaging.⁶

Our patient underwent surgery to remove the encephalocele. The surgeons reported no evidence of fracture. 

Endonasal endoscopic repair of CSF leaks has become the standard of care because of its high success rate and lower morbidity profile.

The final cause of her CSF leak is still uncertain. The surgeons felt confident it was due to ethmoidal encephalocele, a form of neural tube defect in which brain tissue herniates through structural weaknesses of the skull.^6-8 While more common in infants, encephalocele can manifest in adulthood due to traumatic or iatrogenic causes.^7,8

There is a previous report of encephalocele with CSF leak after COVID-19 testing.⁹ This case report suggests the possibility of a nasal swab causing trauma to a patient’s pre‐existing encephalocele—a probability in our patient’s case. It is unlikely, however, that the nasal swab itself violated the bony skull base.

THE TAKEAWAY

This case exemplifies how unexplained local symptoms, a high index of suspicion, and adequate work-up can lead to a rare diagnosis. Diagnostic strategies employed for cases of CSF rhinorrhea vary widely due to limited evidence-based guidance.⁴ Unilateral rhinorrhea with clear fluid that increases at times of increased intracranial pressure, such as bending over, should prompt suspicion for CSF rhinorrhea. With millions of people getting nasal swabs daily during the COVID-19 pandemic, it is even more important to keep CSF leak in our differential diagnosis.

CORRESPONDENCE
Eliana Lizeth Garcia, MD, BS, BA, University of New Mexico Health Sciences Center, 1209 University Boulevard NE, Albuquerque, NM 87131-5001; [email protected]

THE CASE

A 55-year-old woman was evaluated in a family medicine clinic for clear, right-side nasal drainage. She stated that the drainage began 5 months earlier after 2 hospitalizations for severe anxiety leading to emesis and hypokalemia. She reported 3 different COVID-19 nasal swab tests performed on the right nare. Chart review showed 2 negative COVID-19 tests, 6 days apart. Since the hospitalizations, the patient had been given antihistamines for rhinorrhea at an urgent care visit. Despite this treatment, the patient reported a constant drip from the right nare with a salty taste. She also reported experiencing occasional headaches but denied nausea/vomiting. 

The patient’s history included uncontrolled hypertension, treatment-resistant anxiety and depression, obstructive sleep apnea, chronic sinus disease (observed on computed tomography [CT] scans), and type 2 diabetes. She was on amlodipine 10 mg/d for hypertension and was not taking any medication for diabetes.

On examination, the patient’s vital signs were within normal limits except for an elevated blood pressure of 158/88 mm Hg. The patient had persistent clear rhinorrhea fluid draining from the right nostril that was exacerbated when she looked down. Right nasal erythema was present. 

THE DIAGNOSIS 

The patient’s negative COVID-19 tests, lack of improvement on antihistamines, and description of the nasal fluid as salty tasting prompted us to suspect a cerebrospinal fluid (CSF) leak. The clinical work-up included a halo (“double-ring”) sign test, a β-2 transferrin test, and a sinus x-ray.

The halo sign test was negative for CSF fluid. Sinus/skull x-ray did not show a cribriform or other fracture. However, a sample of the nasal fluid collected in a sterile container was positive for β-2 transferrin, the gold-standard laboratory test to confirm a CSF leak.

The patient was sent for a maxillofacial CT scan without contrast. Results showed a 3-mm defect over the right ethmoid roof associated with a 10 × 16–mm low-attenuation structure in the right ethmoid labyrinth, suspicious for encephalocele. This defect, in the setting of the patient’s history of chronic sinus disease, furthered our suspicion of a CSF leak secondary to COVID-19 testing. Radiology confirmed the diagnosis.

DISCUSSION

CSF rhinorrhea is CSF leakage through the nasal cavity due to abnormal communication between the arachnoid membrane and nasal mucosa.¹ The most commonly reported risk factors for this include female sex, middle age (fourth to fifth decade), obesity (body mass index > 40), intracranial hypertension, and obstructive sleep apnea.^1,2

Continue to: Clear, unilateral rhinorrhea...

Clear, unilateral rhinorrhea drainage that increases at times of relatively increased intracranial pressure and has a metallic or salty taste is suspicious for CSF rhinorrhea.³ It can occur following skull‐base trauma (eg, cribriform plate, temporal bone), endoscopic sinus surgery, or neurosurgical procedures, or have a spontaneous etiology.^3,4

Modalities to confirm CSF rhinorrhea include radionuclide cisternography and testing of fluid for the halo sign, glucose, and the CSF-specific proteins β‐2 transferrin and β-trace protein.^3,4 High‐resolution CT is the imaging method most commonly used for localizing a CSF leak.⁴

Treatment is provided in the hospital

Patients with CSF rhinorrhea typically require inpatient management with bed rest, head-of-bed elevation, and frequent neurologic evaluation, as persistent CSF rhinorrhea increases the risk for meningitis, thus necessitating surgical intervention.^3,5 Some cases resolve with bed rest alone. Endonasal endoscopic repair of CSF leaks has become the standard of care because of its high success rate and lower morbidity profile.⁴ 

The preferred treatment method for encephalocele is surgical removal after diagnosis is confirmed with CT or magnetic resonance imaging.⁶

Our patient underwent surgery to remove the encephalocele. The surgeons reported no evidence of fracture. 

Endonasal endoscopic repair of CSF leaks has become the standard of care because of its high success rate and lower morbidity profile.

The final cause of her CSF leak is still uncertain. The surgeons felt confident it was due to ethmoidal encephalocele, a form of neural tube defect in which brain tissue herniates through structural weaknesses of the skull.^6-8 While more common in infants, encephalocele can manifest in adulthood due to traumatic or iatrogenic causes.^7,8

There is a previous report of encephalocele with CSF leak after COVID-19 testing.⁹ This case report suggests the possibility of a nasal swab causing trauma to a patient’s pre‐existing encephalocele—a probability in our patient’s case. It is unlikely, however, that the nasal swab itself violated the bony skull base.

THE TAKEAWAY

This case exemplifies how unexplained local symptoms, a high index of suspicion, and adequate work-up can lead to a rare diagnosis. Diagnostic strategies employed for cases of CSF rhinorrhea vary widely due to limited evidence-based guidance.⁴ Unilateral rhinorrhea with clear fluid that increases at times of increased intracranial pressure, such as bending over, should prompt suspicion for CSF rhinorrhea. With millions of people getting nasal swabs daily during the COVID-19 pandemic, it is even more important to keep CSF leak in our differential diagnosis.

CORRESPONDENCE
Eliana Lizeth Garcia, MD, BS, BA, University of New Mexico Health Sciences Center, 1209 University Boulevard NE, Albuquerque, NM 87131-5001; [email protected]

THE CASE

A 55-year-old woman was evaluated in a family medicine clinic for clear, right-side nasal drainage. She stated that the drainage began 5 months earlier after 2 hospitalizations for severe anxiety leading to emesis and hypokalemia. She reported 3 different COVID-19 nasal swab tests performed on the right nare. Chart review showed 2 negative COVID-19 tests, 6 days apart. Since the hospitalizations, the patient had been given antihistamines for rhinorrhea at an urgent care visit. Despite this treatment, the patient reported a constant drip from the right nare with a salty taste. She also reported experiencing occasional headaches but denied nausea/vomiting. 

The patient’s history included uncontrolled hypertension, treatment-resistant anxiety and depression, obstructive sleep apnea, chronic sinus disease (observed on computed tomography [CT] scans), and type 2 diabetes. She was on amlodipine 10 mg/d for hypertension and was not taking any medication for diabetes.

On examination, the patient’s vital signs were within normal limits except for an elevated blood pressure of 158/88 mm Hg. The patient had persistent clear rhinorrhea fluid draining from the right nostril that was exacerbated when she looked down. Right nasal erythema was present. 

THE DIAGNOSIS 

The patient’s negative COVID-19 tests, lack of improvement on antihistamines, and description of the nasal fluid as salty tasting prompted us to suspect a cerebrospinal fluid (CSF) leak. The clinical work-up included a halo (“double-ring”) sign test, a β-2 transferrin test, and a sinus x-ray.

The halo sign test was negative for CSF fluid. Sinus/skull x-ray did not show a cribriform or other fracture. However, a sample of the nasal fluid collected in a sterile container was positive for β-2 transferrin, the gold-standard laboratory test to confirm a CSF leak.

The patient was sent for a maxillofacial CT scan without contrast. Results showed a 3-mm defect over the right ethmoid roof associated with a 10 × 16–mm low-attenuation structure in the right ethmoid labyrinth, suspicious for encephalocele. This defect, in the setting of the patient’s history of chronic sinus disease, furthered our suspicion of a CSF leak secondary to COVID-19 testing. Radiology confirmed the diagnosis.

DISCUSSION

CSF rhinorrhea is CSF leakage through the nasal cavity due to abnormal communication between the arachnoid membrane and nasal mucosa.¹ The most commonly reported risk factors for this include female sex, middle age (fourth to fifth decade), obesity (body mass index > 40), intracranial hypertension, and obstructive sleep apnea.^1,2

Continue to: Clear, unilateral rhinorrhea...

Clear, unilateral rhinorrhea drainage that increases at times of relatively increased intracranial pressure and has a metallic or salty taste is suspicious for CSF rhinorrhea.³ It can occur following skull‐base trauma (eg, cribriform plate, temporal bone), endoscopic sinus surgery, or neurosurgical procedures, or have a spontaneous etiology.^3,4

Modalities to confirm CSF rhinorrhea include radionuclide cisternography and testing of fluid for the halo sign, glucose, and the CSF-specific proteins β‐2 transferrin and β-trace protein.^3,4 High‐resolution CT is the imaging method most commonly used for localizing a CSF leak.⁴

Treatment is provided in the hospital

Patients with CSF rhinorrhea typically require inpatient management with bed rest, head-of-bed elevation, and frequent neurologic evaluation, as persistent CSF rhinorrhea increases the risk for meningitis, thus necessitating surgical intervention.^3,5 Some cases resolve with bed rest alone. Endonasal endoscopic repair of CSF leaks has become the standard of care because of its high success rate and lower morbidity profile.⁴ 

The preferred treatment method for encephalocele is surgical removal after diagnosis is confirmed with CT or magnetic resonance imaging.⁶

Our patient underwent surgery to remove the encephalocele. The surgeons reported no evidence of fracture. 

Endonasal endoscopic repair of CSF leaks has become the standard of care because of its high success rate and lower morbidity profile.

The final cause of her CSF leak is still uncertain. The surgeons felt confident it was due to ethmoidal encephalocele, a form of neural tube defect in which brain tissue herniates through structural weaknesses of the skull.^6-8 While more common in infants, encephalocele can manifest in adulthood due to traumatic or iatrogenic causes.^7,8

There is a previous report of encephalocele with CSF leak after COVID-19 testing.⁹ This case report suggests the possibility of a nasal swab causing trauma to a patient’s pre‐existing encephalocele—a probability in our patient’s case. It is unlikely, however, that the nasal swab itself violated the bony skull base.

THE TAKEAWAY

This case exemplifies how unexplained local symptoms, a high index of suspicion, and adequate work-up can lead to a rare diagnosis. Diagnostic strategies employed for cases of CSF rhinorrhea vary widely due to limited evidence-based guidance.⁴ Unilateral rhinorrhea with clear fluid that increases at times of increased intracranial pressure, such as bending over, should prompt suspicion for CSF rhinorrhea. With millions of people getting nasal swabs daily during the COVID-19 pandemic, it is even more important to keep CSF leak in our differential diagnosis.

CORRESPONDENCE
Eliana Lizeth Garcia, MD, BS, BA, University of New Mexico Health Sciences Center, 1209 University Boulevard NE, Albuquerque, NM 87131-5001; [email protected]

Evidence summary

Adding ezetimibe reduces nonfatal events but does not improve mortality

A 2018 Cochrane meta-analysis included 10 RCTs (N = 21,919 patients) that evaluated the efficacy and safety of ezetimibe plus a statin (dual therapy) vs a statin alone or plus placebo (monotherapy) for the secondary prevention of CVD. Mean age of patients ranged from 55 to 84 years. Almost all of the patients (> 99%) included in the analyses had existing ASCVD. The dose of ezetimibe was 10 mg; statins used included atorvastatin 10 to 80 mg, pitavastatin 2 to 4 mg, rosuva­statin 10 mg, and simvastatin 20 to 80 mg.¹

The primary outcomes were MACE and all-cause mortality. MACE is defined as a composite of CVD, nonfatal myocardial infarction (MI), nonfatal stroke, hospitalization for unstable angina, or coronary revascularization procedures. The TABLE¹ provides a detailed breakdown of each of the outcomes.

The dual-therapy group compared to the monotherapy group had a lower risk for MACE (26.6% vs 28.3%; 1.7% absolute risk reduction; 6% relative risk reduction; NNT = 59) and little or no difference in the reduction of all-cause mortality. For secondary outcomes, the dual-therapy group had a lower risk for nonfatal MI, nonfatal stroke, and coronary revascularization. There was no difference in cardiovascular mortality or adverse events between the 2 groups. The quality of evidence was high for all-cause mortality and moderate for cardiovascular mortality, MACE, MI, and stroke.¹

The 2015 IMPROVE-IT study, the largest included in the Cochrane review, was a double-blind RCT (N = 18,144) conducted at 1147 sites in 39 countries comparing simva­statin 40 mg/d plus ezetimibe 10 mg/d (dual therapy) vs simvastatin 40 mg/d plus placebo (monotherapy). Patients were at least 50 years old (average age, 64 years) and had been hospitalized for acute coronary syndrome (ACS) within the previous 10 days; 76% were male and 84% were White. The average low-density lipoprotein (LDL) concentration at baseline was 94 mg/dL in both groups.²

The primary endpoint was a composite of cardiovascular death, a major coronary event (nonfatal MI, unstable angina requiring hospitalization, coronary revascularization at least 30 days after randomization), or nonfatal stroke, with a median follow-up of 6 years. The simvastatin plus ezetimibe group compared to the simvastatin-only group had a lower risk for the primary end point (HR = 0.94; 95% CI, 0.89-0.99; NNT = 50), but no differences in cardiovascular or all-cause mortality. Since the study only recruited patients with recent ACS, results are only applicable to that specific population.²

The 2022 RACING study was a multicenter, open-label, randomized, noninferiority trial that evaluated the combination of ezetimibe 10 mg and a moderate-intensity statin (rosuvastatin 10 mg) compared to a high-intensity statin alone (rosuvastatin 20 mg) in adults (N = 3780) with ASCVD. Included patients were ages 19 to 80 years (mean, 64 years) and had a baseline LDL concentration of 80 mg/dL (standard deviation, 64-100 mg/dL) with known ASCVD (defined by prior MI, ACS, history of coronary or other arterial revascularization, ischemic stroke, or peripheral artery disease); 75% were male.³

The primary outcome was a composite of cardiovascular death, major cardiovascular events, or nonfatal stroke. At 3 years, an intention-to-treat analysis found no significant difference between the combination and monotherapy groups (9% vs 9.9%; absolute difference, –0.78%; 95% CI, –2.39% to 0.83%). Dose reduction or discontinuation of the study drug(s) due to intolerance was lower in the combination group than in the monotherapy group (4.8% vs 8.2%; P < 0.0001). The study may be limited by the fact that it was nonblinded and all participants were South Korean, which limits generalizability.³

Recommendations from others

A 2022 evidence-based clinical practice guideline published in BMJ recommends adding ezetimibe to a statin to decrease all-cause mortality, cardiovascular mortality, nonfatal stroke, and nonfatal MI in patients with known CVD, regardless of their LDL concentration (weak recommendation based on a systematic review and network meta-analysis).⁴

In 2019, the American Heart Association and the American College of Cardiology recommended ezetimibe for patients with clinical ASCVD who are on maximally tolerated statin therapy and have an LDL concentration of 70 mg/dL or higher (Class 2b recommendation [meaning it can be considered] based on a meta-analysis of moderate-­quality RCTs).⁵

Editor’s takeaway

The data on this important and well-studied question have inched closer to firm and clear answers. First, adding ezetimibe to a lower-intensity statin when a higher-intensity statin is not tolerated is an effective treatment. Second, adding ezetimibe to a statin improves nonfatal ASCVD outcomes but not fatal ones. What has not yet been made clear, because a noninferiority trial does not answer this question, is whether the highest intensity statin plus ezetimibe is superior to that high-intensity statin alone, regardless of LDL concentration.

Evidence summary

Adding ezetimibe reduces nonfatal events but does not improve mortality

A 2018 Cochrane meta-analysis included 10 RCTs (N = 21,919 patients) that evaluated the efficacy and safety of ezetimibe plus a statin (dual therapy) vs a statin alone or plus placebo (monotherapy) for the secondary prevention of CVD. Mean age of patients ranged from 55 to 84 years. Almost all of the patients (> 99%) included in the analyses had existing ASCVD. The dose of ezetimibe was 10 mg; statins used included atorvastatin 10 to 80 mg, pitavastatin 2 to 4 mg, rosuva­statin 10 mg, and simvastatin 20 to 80 mg.¹

The primary outcomes were MACE and all-cause mortality. MACE is defined as a composite of CVD, nonfatal myocardial infarction (MI), nonfatal stroke, hospitalization for unstable angina, or coronary revascularization procedures. The TABLE¹ provides a detailed breakdown of each of the outcomes.

The dual-therapy group compared to the monotherapy group had a lower risk for MACE (26.6% vs 28.3%; 1.7% absolute risk reduction; 6% relative risk reduction; NNT = 59) and little or no difference in the reduction of all-cause mortality. For secondary outcomes, the dual-therapy group had a lower risk for nonfatal MI, nonfatal stroke, and coronary revascularization. There was no difference in cardiovascular mortality or adverse events between the 2 groups. The quality of evidence was high for all-cause mortality and moderate for cardiovascular mortality, MACE, MI, and stroke.¹

The 2015 IMPROVE-IT study, the largest included in the Cochrane review, was a double-blind RCT (N = 18,144) conducted at 1147 sites in 39 countries comparing simva­statin 40 mg/d plus ezetimibe 10 mg/d (dual therapy) vs simvastatin 40 mg/d plus placebo (monotherapy). Patients were at least 50 years old (average age, 64 years) and had been hospitalized for acute coronary syndrome (ACS) within the previous 10 days; 76% were male and 84% were White. The average low-density lipoprotein (LDL) concentration at baseline was 94 mg/dL in both groups.²

The primary endpoint was a composite of cardiovascular death, a major coronary event (nonfatal MI, unstable angina requiring hospitalization, coronary revascularization at least 30 days after randomization), or nonfatal stroke, with a median follow-up of 6 years. The simvastatin plus ezetimibe group compared to the simvastatin-only group had a lower risk for the primary end point (HR = 0.94; 95% CI, 0.89-0.99; NNT = 50), but no differences in cardiovascular or all-cause mortality. Since the study only recruited patients with recent ACS, results are only applicable to that specific population.²

The 2022 RACING study was a multicenter, open-label, randomized, noninferiority trial that evaluated the combination of ezetimibe 10 mg and a moderate-intensity statin (rosuvastatin 10 mg) compared to a high-intensity statin alone (rosuvastatin 20 mg) in adults (N = 3780) with ASCVD. Included patients were ages 19 to 80 years (mean, 64 years) and had a baseline LDL concentration of 80 mg/dL (standard deviation, 64-100 mg/dL) with known ASCVD (defined by prior MI, ACS, history of coronary or other arterial revascularization, ischemic stroke, or peripheral artery disease); 75% were male.³

The primary outcome was a composite of cardiovascular death, major cardiovascular events, or nonfatal stroke. At 3 years, an intention-to-treat analysis found no significant difference between the combination and monotherapy groups (9% vs 9.9%; absolute difference, –0.78%; 95% CI, –2.39% to 0.83%). Dose reduction or discontinuation of the study drug(s) due to intolerance was lower in the combination group than in the monotherapy group (4.8% vs 8.2%; P < 0.0001). The study may be limited by the fact that it was nonblinded and all participants were South Korean, which limits generalizability.³

Recommendations from others

A 2022 evidence-based clinical practice guideline published in BMJ recommends adding ezetimibe to a statin to decrease all-cause mortality, cardiovascular mortality, nonfatal stroke, and nonfatal MI in patients with known CVD, regardless of their LDL concentration (weak recommendation based on a systematic review and network meta-analysis).⁴

In 2019, the American Heart Association and the American College of Cardiology recommended ezetimibe for patients with clinical ASCVD who are on maximally tolerated statin therapy and have an LDL concentration of 70 mg/dL or higher (Class 2b recommendation [meaning it can be considered] based on a meta-analysis of moderate-­quality RCTs).⁵

Editor’s takeaway

The data on this important and well-studied question have inched closer to firm and clear answers. First, adding ezetimibe to a lower-intensity statin when a higher-intensity statin is not tolerated is an effective treatment. Second, adding ezetimibe to a statin improves nonfatal ASCVD outcomes but not fatal ones. What has not yet been made clear, because a noninferiority trial does not answer this question, is whether the highest intensity statin plus ezetimibe is superior to that high-intensity statin alone, regardless of LDL concentration.

Evidence summary

Adding ezetimibe reduces nonfatal events but does not improve mortality

A 2018 Cochrane meta-analysis included 10 RCTs (N = 21,919 patients) that evaluated the efficacy and safety of ezetimibe plus a statin (dual therapy) vs a statin alone or plus placebo (monotherapy) for the secondary prevention of CVD. Mean age of patients ranged from 55 to 84 years. Almost all of the patients (> 99%) included in the analyses had existing ASCVD. The dose of ezetimibe was 10 mg; statins used included atorvastatin 10 to 80 mg, pitavastatin 2 to 4 mg, rosuva­statin 10 mg, and simvastatin 20 to 80 mg.¹

The primary outcomes were MACE and all-cause mortality. MACE is defined as a composite of CVD, nonfatal myocardial infarction (MI), nonfatal stroke, hospitalization for unstable angina, or coronary revascularization procedures. The TABLE¹ provides a detailed breakdown of each of the outcomes.

The dual-therapy group compared to the monotherapy group had a lower risk for MACE (26.6% vs 28.3%; 1.7% absolute risk reduction; 6% relative risk reduction; NNT = 59) and little or no difference in the reduction of all-cause mortality. For secondary outcomes, the dual-therapy group had a lower risk for nonfatal MI, nonfatal stroke, and coronary revascularization. There was no difference in cardiovascular mortality or adverse events between the 2 groups. The quality of evidence was high for all-cause mortality and moderate for cardiovascular mortality, MACE, MI, and stroke.¹

The 2015 IMPROVE-IT study, the largest included in the Cochrane review, was a double-blind RCT (N = 18,144) conducted at 1147 sites in 39 countries comparing simva­statin 40 mg/d plus ezetimibe 10 mg/d (dual therapy) vs simvastatin 40 mg/d plus placebo (monotherapy). Patients were at least 50 years old (average age, 64 years) and had been hospitalized for acute coronary syndrome (ACS) within the previous 10 days; 76% were male and 84% were White. The average low-density lipoprotein (LDL) concentration at baseline was 94 mg/dL in both groups.²

The primary endpoint was a composite of cardiovascular death, a major coronary event (nonfatal MI, unstable angina requiring hospitalization, coronary revascularization at least 30 days after randomization), or nonfatal stroke, with a median follow-up of 6 years. The simvastatin plus ezetimibe group compared to the simvastatin-only group had a lower risk for the primary end point (HR = 0.94; 95% CI, 0.89-0.99; NNT = 50), but no differences in cardiovascular or all-cause mortality. Since the study only recruited patients with recent ACS, results are only applicable to that specific population.²

The 2022 RACING study was a multicenter, open-label, randomized, noninferiority trial that evaluated the combination of ezetimibe 10 mg and a moderate-intensity statin (rosuvastatin 10 mg) compared to a high-intensity statin alone (rosuvastatin 20 mg) in adults (N = 3780) with ASCVD. Included patients were ages 19 to 80 years (mean, 64 years) and had a baseline LDL concentration of 80 mg/dL (standard deviation, 64-100 mg/dL) with known ASCVD (defined by prior MI, ACS, history of coronary or other arterial revascularization, ischemic stroke, or peripheral artery disease); 75% were male.³

The primary outcome was a composite of cardiovascular death, major cardiovascular events, or nonfatal stroke. At 3 years, an intention-to-treat analysis found no significant difference between the combination and monotherapy groups (9% vs 9.9%; absolute difference, –0.78%; 95% CI, –2.39% to 0.83%). Dose reduction or discontinuation of the study drug(s) due to intolerance was lower in the combination group than in the monotherapy group (4.8% vs 8.2%; P < 0.0001). The study may be limited by the fact that it was nonblinded and all participants were South Korean, which limits generalizability.³

Recommendations from others

A 2022 evidence-based clinical practice guideline published in BMJ recommends adding ezetimibe to a statin to decrease all-cause mortality, cardiovascular mortality, nonfatal stroke, and nonfatal MI in patients with known CVD, regardless of their LDL concentration (weak recommendation based on a systematic review and network meta-analysis).⁴

In 2019, the American Heart Association and the American College of Cardiology recommended ezetimibe for patients with clinical ASCVD who are on maximally tolerated statin therapy and have an LDL concentration of 70 mg/dL or higher (Class 2b recommendation [meaning it can be considered] based on a meta-analysis of moderate-­quality RCTs).⁵

Editor’s takeaway

The data on this important and well-studied question have inched closer to firm and clear answers. First, adding ezetimibe to a lower-intensity statin when a higher-intensity statin is not tolerated is an effective treatment. Second, adding ezetimibe to a statin improves nonfatal ASCVD outcomes but not fatal ones. What has not yet been made clear, because a noninferiority trial does not answer this question, is whether the highest intensity statin plus ezetimibe is superior to that high-intensity statin alone, regardless of LDL concentration.

This is the exciting time of year when we graduate new classes of medical students and residents. Med school graduation brings mixed emotions; the new doctors and I both know residency will bring growth and challenges. Residency graduation is a wistful passage as well. It is so rewarding to welcome the newly board-certified family physicians to family medicine, but we miss them even as we orient a new class.

Every year, a few months (or even a few years) after graduation, I hear from a former resident, sometimes several. They ask to talk and, although it can be hard for them to explain exactly the ennui and disillusionment they’re feeling, their concerns boil down to: Is this all there is?

If what you’re doing isn’t working for you, look for opportunities (big or small) that make it better.

They are not burnt out, exactly, but they were hoping for more from their careers in family medicine.¹ They find their hopes and expectations are not fulfilled by seeing patients in the office 8 hours per day, 4.5 days per week. Even those who report rewarding relationships with patients express less overall enthusiasm for jobs they were excited to start just months or years earlier.

Some of the difficulties I hear the graduates report are expected growing pains. It is a transition to go from supervised practice with attending backup to a setting where you are on your own, typically with a 4-fold increase in volume compared with residency. But the monotony is real for family physicians in full-time outpatient practice.

Research suggests an expanded scope of practice—including hospital medicine, obstetrics, and procedures—is associated with physician well-being.^2,3 A broad scope of practice can bring stress, but it also brings meaning, and that meaning is protective to our well-being. However, a robust scope of practice is not always supported by medical groups or hospital systems, who prefer a more compartmentalized, widgetized physician.⁴ It would be easier for their algorithms if family physicians picked a lane and stayed in it. Alas, the broader our scope of practice, the healthier our population, the more equitable our care,^5,6 and the happier our physicians.

The disconnect and hopelessness experienced by family physicians is more concerning. Many of my graduates report feeling disconnected from their patients, because they begin to feel disillusioned by the demands and requests that practice and patients place on them. The paperwork, “permission slips,” and requests for tests and studies not only feel overwhelming and exhausting but also create distance between physicians and patients.⁷ We want to help our patients, so we do the forms and order the tests. As the quantity of forms, slips, and requests adds up, we begin to feel resentful at what the forms take away: time with our patients, perhaps, or time with our families. We get angry at the forms and the “asks,” and then begin to get angry at the patients simply for having needs. Administrative burden is a hassle, but it is also insidiously destructive.⁸

Family physicians confront hopelessness when, day after day, we diagnose problems that no physician is likely to fix in a single office visit: chronic stress, family dysfunction, violence, unemployment, poverty, racism, loneliness, and the hopelessness of the patients themselves. This is not to say that we ignore these concerns or their impact on health. It is because we see and feel them, and deeply understand their consequences for our patients, that we grow frustrated with the lack of solutions.^9,10

Thankfully, we have strong teams working at the policy level to improve the primary care and public health infrastructure so that we can maintain some hope that it will be better in the future. Sometimes when I counsel a former resident, they decide to join those teams so that they can work on the solutions. Others decide to expand their scope of practice. Others seek out virtual scribes to streamline charting and regain time. Some build better boundaries with their EHR inboxes.

The key is figuring out what we can do and making peace with our limits. When disillusionment hits, what we can do includes seeking connection and social contact and remembering that we are not trapped in our situation, even if we are practicing in a less-than-functional health care system. There are many ways to “be” a family physician—if what you’re doing isn’t working for you, look for opportunities (big or small) that make it better. We can all reach out to coaches, therapists, colleagues, and friends for support to remain steadfast in our purpose as family physicians. This support and the power of change means that from residency to the latter parts of our careers, we will continue to bring the tremendous good of family medicine to the communities we serve.

This is the exciting time of year when we graduate new classes of medical students and residents. Med school graduation brings mixed emotions; the new doctors and I both know residency will bring growth and challenges. Residency graduation is a wistful passage as well. It is so rewarding to welcome the newly board-certified family physicians to family medicine, but we miss them even as we orient a new class.

Every year, a few months (or even a few years) after graduation, I hear from a former resident, sometimes several. They ask to talk and, although it can be hard for them to explain exactly the ennui and disillusionment they’re feeling, their concerns boil down to: Is this all there is?

If what you’re doing isn’t working for you, look for opportunities (big or small) that make it better.

They are not burnt out, exactly, but they were hoping for more from their careers in family medicine.¹ They find their hopes and expectations are not fulfilled by seeing patients in the office 8 hours per day, 4.5 days per week. Even those who report rewarding relationships with patients express less overall enthusiasm for jobs they were excited to start just months or years earlier.

Some of the difficulties I hear the graduates report are expected growing pains. It is a transition to go from supervised practice with attending backup to a setting where you are on your own, typically with a 4-fold increase in volume compared with residency. But the monotony is real for family physicians in full-time outpatient practice.

Research suggests an expanded scope of practice—including hospital medicine, obstetrics, and procedures—is associated with physician well-being.^2,3 A broad scope of practice can bring stress, but it also brings meaning, and that meaning is protective to our well-being. However, a robust scope of practice is not always supported by medical groups or hospital systems, who prefer a more compartmentalized, widgetized physician.⁴ It would be easier for their algorithms if family physicians picked a lane and stayed in it. Alas, the broader our scope of practice, the healthier our population, the more equitable our care,^5,6 and the happier our physicians.

The disconnect and hopelessness experienced by family physicians is more concerning. Many of my graduates report feeling disconnected from their patients, because they begin to feel disillusioned by the demands and requests that practice and patients place on them. The paperwork, “permission slips,” and requests for tests and studies not only feel overwhelming and exhausting but also create distance between physicians and patients.⁷ We want to help our patients, so we do the forms and order the tests. As the quantity of forms, slips, and requests adds up, we begin to feel resentful at what the forms take away: time with our patients, perhaps, or time with our families. We get angry at the forms and the “asks,” and then begin to get angry at the patients simply for having needs. Administrative burden is a hassle, but it is also insidiously destructive.⁸

Family physicians confront hopelessness when, day after day, we diagnose problems that no physician is likely to fix in a single office visit: chronic stress, family dysfunction, violence, unemployment, poverty, racism, loneliness, and the hopelessness of the patients themselves. This is not to say that we ignore these concerns or their impact on health. It is because we see and feel them, and deeply understand their consequences for our patients, that we grow frustrated with the lack of solutions.^9,10

Thankfully, we have strong teams working at the policy level to improve the primary care and public health infrastructure so that we can maintain some hope that it will be better in the future. Sometimes when I counsel a former resident, they decide to join those teams so that they can work on the solutions. Others decide to expand their scope of practice. Others seek out virtual scribes to streamline charting and regain time. Some build better boundaries with their EHR inboxes.

The key is figuring out what we can do and making peace with our limits. When disillusionment hits, what we can do includes seeking connection and social contact and remembering that we are not trapped in our situation, even if we are practicing in a less-than-functional health care system. There are many ways to “be” a family physician—if what you’re doing isn’t working for you, look for opportunities (big or small) that make it better. We can all reach out to coaches, therapists, colleagues, and friends for support to remain steadfast in our purpose as family physicians. This support and the power of change means that from residency to the latter parts of our careers, we will continue to bring the tremendous good of family medicine to the communities we serve.

This is the exciting time of year when we graduate new classes of medical students and residents. Med school graduation brings mixed emotions; the new doctors and I both know residency will bring growth and challenges. Residency graduation is a wistful passage as well. It is so rewarding to welcome the newly board-certified family physicians to family medicine, but we miss them even as we orient a new class.

Every year, a few months (or even a few years) after graduation, I hear from a former resident, sometimes several. They ask to talk and, although it can be hard for them to explain exactly the ennui and disillusionment they’re feeling, their concerns boil down to: Is this all there is?

If what you’re doing isn’t working for you, look for opportunities (big or small) that make it better.

They are not burnt out, exactly, but they were hoping for more from their careers in family medicine.¹ They find their hopes and expectations are not fulfilled by seeing patients in the office 8 hours per day, 4.5 days per week. Even those who report rewarding relationships with patients express less overall enthusiasm for jobs they were excited to start just months or years earlier.

Some of the difficulties I hear the graduates report are expected growing pains. It is a transition to go from supervised practice with attending backup to a setting where you are on your own, typically with a 4-fold increase in volume compared with residency. But the monotony is real for family physicians in full-time outpatient practice.

Research suggests an expanded scope of practice—including hospital medicine, obstetrics, and procedures—is associated with physician well-being.^2,3 A broad scope of practice can bring stress, but it also brings meaning, and that meaning is protective to our well-being. However, a robust scope of practice is not always supported by medical groups or hospital systems, who prefer a more compartmentalized, widgetized physician.⁴ It would be easier for their algorithms if family physicians picked a lane and stayed in it. Alas, the broader our scope of practice, the healthier our population, the more equitable our care,^5,6 and the happier our physicians.

The disconnect and hopelessness experienced by family physicians is more concerning. Many of my graduates report feeling disconnected from their patients, because they begin to feel disillusioned by the demands and requests that practice and patients place on them. The paperwork, “permission slips,” and requests for tests and studies not only feel overwhelming and exhausting but also create distance between physicians and patients.⁷ We want to help our patients, so we do the forms and order the tests. As the quantity of forms, slips, and requests adds up, we begin to feel resentful at what the forms take away: time with our patients, perhaps, or time with our families. We get angry at the forms and the “asks,” and then begin to get angry at the patients simply for having needs. Administrative burden is a hassle, but it is also insidiously destructive.⁸

Family physicians confront hopelessness when, day after day, we diagnose problems that no physician is likely to fix in a single office visit: chronic stress, family dysfunction, violence, unemployment, poverty, racism, loneliness, and the hopelessness of the patients themselves. This is not to say that we ignore these concerns or their impact on health. It is because we see and feel them, and deeply understand their consequences for our patients, that we grow frustrated with the lack of solutions.^9,10

Thankfully, we have strong teams working at the policy level to improve the primary care and public health infrastructure so that we can maintain some hope that it will be better in the future. Sometimes when I counsel a former resident, they decide to join those teams so that they can work on the solutions. Others decide to expand their scope of practice. Others seek out virtual scribes to streamline charting and regain time. Some build better boundaries with their EHR inboxes.

The key is figuring out what we can do and making peace with our limits. When disillusionment hits, what we can do includes seeking connection and social contact and remembering that we are not trapped in our situation, even if we are practicing in a less-than-functional health care system. There are many ways to “be” a family physician—if what you’re doing isn’t working for you, look for opportunities (big or small) that make it better. We can all reach out to coaches, therapists, colleagues, and friends for support to remain steadfast in our purpose as family physicians. This support and the power of change means that from residency to the latter parts of our careers, we will continue to bring the tremendous good of family medicine to the communities we serve.

A 30-YEAR-OLD MAN presented for evaluation of a solitary, flesh-colored, pedunculated mass on his right inner gluteal area (FIGURE) that had gradually enlarged over the previous 18 months. The lesion had manifested 4 years prior as a small papule that was stable for many years. It began to grow steadily after the patient compressed the papule forcefully. Activities of daily living, such as sitting, were now uncomfortable, so he sought treatment. He denied pain, pruritis, and bleeding and reported no history of trauma or surgery in the area of the mass.

On physical examination, the mass measured 3.5 × 4.5 cm with a 1.2-cm base. It was smooth, soft, nontender, and compressible—but nonfluctuant. There were no signs of ulceration or bleeding. No regional lymphadenopathy was noted. An excisional biopsy was performed.

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

The biopsy confirmed a diagnosis of ­fibrolipoma—a rare variant of lipoma composed of a mixture of adipocytes and thick bands of fibrous connective tissues.¹ Etiology for fibrolipomas is unknown. Blunt trauma rupture of the fibrous septa that prevent fat migration may result in a proliferation of adipose tissue and thereby enlargement of fibrolipomas and other lipoma variants.² In this case, the patient’s compression of the original papule likely served as the trauma that led to its enlargement. Malignant change has not been reported with fibrolipomas.

What you’ll see—and on whom. ­Fibrolipomas typically are flesh-colored, ­pedunculated, compressible, and relatively asymp­tomatic.³ They have been reported on the face, neck, back, and pubic areas, among other locations. Size is variable; they can be as small as 1 cm in diameter and as large as 10 cm in diameter.⁴ However, fibrolipomas can grow to be “giant” if they exceed 10 cm (or 1000 g).²

The patient’s compression of the original papule likely served as the trauma that led to its enlargement.

Men and women are affected equally by fibrolipomas. Prevalence does not differ by race or ethnicity.

The differential include sother lipomas and skin tags

The differential for a mass such as this one includes lipomas, acrochordons (also known as skin tags), and fibrokeratomas.

Lipomas are the most common benign soft-tissue tumors and are composed of adipocytes.⁵ The fibrolipoma is just one variant of ­lipoma; others include the myxolipoma, myolipoma, spindle cell lipoma, angiolipoma, osteolipoma, and chondrolipoma.² Lipomas typically are subcutaneous and located over the scalp, neck, and upper trunk area but can occur anywhere on the body. They are mobile and typically well circumscribed. Lipomas have a broad base with well-demarcated swelling; fibrolipomas are usually pedunculated.

Continue to: Acrochordons ("skin tags")

Acrochordons (“skin tags”) usually contain a peduncle but may be sessile. They range from 1 mm to 1 cm in diameter and typically are located in skin folds, especially in the neck, axillae, and inguinal areas.⁶ Obesity, older age (> 50 years), and diabetes have been associated with occurrence.⁷ Acrochordons generally are smaller than fibrolipomas and often occur in multiples.

Fibrokeratomas typically are benign, solitary, fibrous tissue tumors that are found on fingers and seldom are pedunculated. They are flesh-colored and conical or nodular, with a hyperkeratotic collar. Fibrokeratomas are smaller and thicker than fibromas, as well as firm in consistency. They are acquired tumors that have been shown to be related to repetitive trauma.⁶

Treatment involves surgical excision

The preferred treatment for fibrolipoma is complete surgical excision, although cryotherapy is another option for lesions < 1 cm.⁴ Without surgical excision, the mass will continue to grow, albeit slowly.

This patient’s mass was excised successfully in its entirety; there were no complications. Follow-up is usually unnecessary.

A 30-YEAR-OLD MAN presented for evaluation of a solitary, flesh-colored, pedunculated mass on his right inner gluteal area (FIGURE) that had gradually enlarged over the previous 18 months. The lesion had manifested 4 years prior as a small papule that was stable for many years. It began to grow steadily after the patient compressed the papule forcefully. Activities of daily living, such as sitting, were now uncomfortable, so he sought treatment. He denied pain, pruritis, and bleeding and reported no history of trauma or surgery in the area of the mass.

On physical examination, the mass measured 3.5 × 4.5 cm with a 1.2-cm base. It was smooth, soft, nontender, and compressible—but nonfluctuant. There were no signs of ulceration or bleeding. No regional lymphadenopathy was noted. An excisional biopsy was performed.

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

The biopsy confirmed a diagnosis of ­fibrolipoma—a rare variant of lipoma composed of a mixture of adipocytes and thick bands of fibrous connective tissues.¹ Etiology for fibrolipomas is unknown. Blunt trauma rupture of the fibrous septa that prevent fat migration may result in a proliferation of adipose tissue and thereby enlargement of fibrolipomas and other lipoma variants.² In this case, the patient’s compression of the original papule likely served as the trauma that led to its enlargement. Malignant change has not been reported with fibrolipomas.

What you’ll see—and on whom. ­Fibrolipomas typically are flesh-colored, ­pedunculated, compressible, and relatively asymp­tomatic.³ They have been reported on the face, neck, back, and pubic areas, among other locations. Size is variable; they can be as small as 1 cm in diameter and as large as 10 cm in diameter.⁴ However, fibrolipomas can grow to be “giant” if they exceed 10 cm (or 1000 g).²

The patient’s compression of the original papule likely served as the trauma that led to its enlargement.

Men and women are affected equally by fibrolipomas. Prevalence does not differ by race or ethnicity.

The differential include sother lipomas and skin tags

The differential for a mass such as this one includes lipomas, acrochordons (also known as skin tags), and fibrokeratomas.

Lipomas are the most common benign soft-tissue tumors and are composed of adipocytes.⁵ The fibrolipoma is just one variant of ­lipoma; others include the myxolipoma, myolipoma, spindle cell lipoma, angiolipoma, osteolipoma, and chondrolipoma.² Lipomas typically are subcutaneous and located over the scalp, neck, and upper trunk area but can occur anywhere on the body. They are mobile and typically well circumscribed. Lipomas have a broad base with well-demarcated swelling; fibrolipomas are usually pedunculated.

Continue to: Acrochordons ("skin tags")

Acrochordons (“skin tags”) usually contain a peduncle but may be sessile. They range from 1 mm to 1 cm in diameter and typically are located in skin folds, especially in the neck, axillae, and inguinal areas.⁶ Obesity, older age (> 50 years), and diabetes have been associated with occurrence.⁷ Acrochordons generally are smaller than fibrolipomas and often occur in multiples.

Fibrokeratomas typically are benign, solitary, fibrous tissue tumors that are found on fingers and seldom are pedunculated. They are flesh-colored and conical or nodular, with a hyperkeratotic collar. Fibrokeratomas are smaller and thicker than fibromas, as well as firm in consistency. They are acquired tumors that have been shown to be related to repetitive trauma.⁶

Treatment involves surgical excision

The preferred treatment for fibrolipoma is complete surgical excision, although cryotherapy is another option for lesions < 1 cm.⁴ Without surgical excision, the mass will continue to grow, albeit slowly.

This patient’s mass was excised successfully in its entirety; there were no complications. Follow-up is usually unnecessary.

A 30-YEAR-OLD MAN presented for evaluation of a solitary, flesh-colored, pedunculated mass on his right inner gluteal area (FIGURE) that had gradually enlarged over the previous 18 months. The lesion had manifested 4 years prior as a small papule that was stable for many years. It began to grow steadily after the patient compressed the papule forcefully. Activities of daily living, such as sitting, were now uncomfortable, so he sought treatment. He denied pain, pruritis, and bleeding and reported no history of trauma or surgery in the area of the mass.

On physical examination, the mass measured 3.5 × 4.5 cm with a 1.2-cm base. It was smooth, soft, nontender, and compressible—but nonfluctuant. There were no signs of ulceration or bleeding. No regional lymphadenopathy was noted. An excisional biopsy was performed.

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

The biopsy confirmed a diagnosis of ­fibrolipoma—a rare variant of lipoma composed of a mixture of adipocytes and thick bands of fibrous connective tissues.¹ Etiology for fibrolipomas is unknown. Blunt trauma rupture of the fibrous septa that prevent fat migration may result in a proliferation of adipose tissue and thereby enlargement of fibrolipomas and other lipoma variants.² In this case, the patient’s compression of the original papule likely served as the trauma that led to its enlargement. Malignant change has not been reported with fibrolipomas.

What you’ll see—and on whom. ­Fibrolipomas typically are flesh-colored, ­pedunculated, compressible, and relatively asymp­tomatic.³ They have been reported on the face, neck, back, and pubic areas, among other locations. Size is variable; they can be as small as 1 cm in diameter and as large as 10 cm in diameter.⁴ However, fibrolipomas can grow to be “giant” if they exceed 10 cm (or 1000 g).²

The patient’s compression of the original papule likely served as the trauma that led to its enlargement.

Men and women are affected equally by fibrolipomas. Prevalence does not differ by race or ethnicity.

The differential include sother lipomas and skin tags

The differential for a mass such as this one includes lipomas, acrochordons (also known as skin tags), and fibrokeratomas.

Lipomas are the most common benign soft-tissue tumors and are composed of adipocytes.⁵ The fibrolipoma is just one variant of ­lipoma; others include the myxolipoma, myolipoma, spindle cell lipoma, angiolipoma, osteolipoma, and chondrolipoma.² Lipomas typically are subcutaneous and located over the scalp, neck, and upper trunk area but can occur anywhere on the body. They are mobile and typically well circumscribed. Lipomas have a broad base with well-demarcated swelling; fibrolipomas are usually pedunculated.

Continue to: Acrochordons ("skin tags")

Acrochordons (“skin tags”) usually contain a peduncle but may be sessile. They range from 1 mm to 1 cm in diameter and typically are located in skin folds, especially in the neck, axillae, and inguinal areas.⁶ Obesity, older age (> 50 years), and diabetes have been associated with occurrence.⁷ Acrochordons generally are smaller than fibrolipomas and often occur in multiples.

Fibrokeratomas typically are benign, solitary, fibrous tissue tumors that are found on fingers and seldom are pedunculated. They are flesh-colored and conical or nodular, with a hyperkeratotic collar. Fibrokeratomas are smaller and thicker than fibromas, as well as firm in consistency. They are acquired tumors that have been shown to be related to repetitive trauma.⁶

Treatment involves surgical excision

The preferred treatment for fibrolipoma is complete surgical excision, although cryotherapy is another option for lesions < 1 cm.⁴ Without surgical excision, the mass will continue to grow, albeit slowly.

This patient’s mass was excised successfully in its entirety; there were no complications. Follow-up is usually unnecessary.

THE CASE

A 64-year-old woman sought care after having hot flashes, facial flushing, excessive sweating, palpitations, and daily headaches for 1 month. She had a history of hypertension that was well controlled with hydrochlorothiazide 25 mg/d but over the previous month, it had become more difficult to control. Her blood pressure remained elevated to 150/100 mm Hg despite the addition of lisinopril 40 mg/d and amlodipine 10 mg/d, indicating resistant hypertension. She had no family history of hypertension, diabetes, or obesity or any other pertinent medical or surgical history. Physical examination was negative for weight gain, stretch marks, or muscle weakness.

Laboratory tests revealed a normal serum aldosterone-renin ratio, renal function, and thyroid function; however, she had elevated levels of normetanephrine (2429 pg/mL; normal range, 0-145 pg/mL) and metanephrine (143 pg/mL; normal range, 0-62 pg/mL). Computed tomography (CT) revealed an 8.6-cm complex, hemorrhagic, necrotic left adrenal mass with attenuation of 33.1 Hounsfield units (HU) (FIGURE 1). Magnetic resonance imaging (MRI) demonstrated a T2 hyperintense left adrenal mass. An evaluation for Cushing syndrome was negative, and positron emission tomography (PET)/CT with gallium-68 dotatate was ordered. It showed intense radiotracer uptake in the left adrenal gland, with a maximum standardized uptake value of 70.1 (FIGURE 2).

THE DIAGNOSIS

After appropriate preparation with alpha blockade (phenoxybenzamine 20 mg twice daily for 7 days) and fluid resuscitation (normal saline run over 12 hours preoperatively), the patient underwent successful open surgical resection of the adrenal mass, during which her blood pressure was controlled with a nitroprusside infusion and boluses of esmolol and labetalol. Pathology results showed cells in a nested pattern with round to oval nuclei in a vascular background. There was no necrosis, increased mitotic figures, capsular invasion, or increased cellularity. Chromogranin immunohistochemical staining was positive. Given her resistant hypertension, clinical symptoms, and pathology results, the patient was given a diagnosis of pheochromocytoma.

DISCUSSION

Resistant hypertension is defined as blood pressure that is elevated above goal despite the use of 3 maximally titrated antihypertensive agents from different classes or that is well controlled with at least 4 antihypertensive medications.¹ The prevalence of resistant hypertension is 12% to 18% in adults being treated for hypertension.¹ Patients with resistant hypertension have a higher risk for cardiovascular events and death, are more likely to have a secondary cause of hypertension, and may benefit from special diagnostic testing or treatment approaches to control their blood pressure.¹

There are many causes of resistant hypertension; primary aldosteronism is the most common cause (prevalence as high as 20%).² Given the increased risk for cardiovascular/cerebrovascular disease, all patients with resistant hypertension should be screened for this condition.² Other causes of resistant hypertension include renal parenchymal disease, renal artery stenosis, coarctation of the aorta, thyroid dysfunction, Cushing syndrome, paraganglioma, and as seen in our case, pheochromocytoma. Although pheochromocytoma is a rare cause of resistant hypertension (0.01%-4%),¹ it is associated with high rates of morbidity and mortality if left untreated and may be inherited, making it an essential diagnosis to consider in all patients with resistant hypertension.^1,3

Common symptoms of pheochromocytoma are hypertension (paroxysmal or sustained), headaches, palpitations, pallor, and piloerection (or cold sweats).¹ Patients with pheochromocytoma typically exhibit metanephrine levels that are more than 4 times the upper limit of normal.⁴ Therefore, measurement of plasma free metanephrines or urinary fractionated metanephrines is recommended.⁵ Elevated metanephrine levels also are caused by obesity, obstructive sleep apnea, and certain medications and should be ruled out.⁵

All pheochromocytomas are potentially malignant. Despite the existence of pathologic scoring systems^6,7 and radiographic features that suggest malignancy,^8,9 no single risk-stratification tool is recommended in the current literature.¹⁰ Ultimately, the only way to confirm malignancy is to see metastases where chromaffin tissue is not normally found on imaging.¹⁰

Continue to: Pathologic features to look for...

Pathologic features to look for include capsular/periadrenal adipose invasion, increased cellularity, necrosis, tumor cell ­spindling, increased/atypical mitotic figures, and nuclear pleomorphism. Radiographic features include larger size (≥ 4-6 cm),¹¹ an irregular shape, necrosis, calcifications, attenuation of 10 HU or higher on noncontrast CT, absolute washout of 60% or lower, and relative washout of 40% or lower.^8,12 On MRI, malignant lesions appear hypointense on T1-weighted imaging and hyperintense on T2-weighted imaging.⁹ Fluorodeoxyglucose avidity on PET scan also is indicative of malignancy.^8,9

Treatment for pheochromocytoma is surgical resection. An experienced surgical team and proper preoperative preparation are necessary because the induction of anesthesia, endotracheal intubation, and tumor manipulation can lead to a release of catecholamines, potentially resulting in an intraoperative hypertensive crisis, cardiac arrhythmias, and multiorgan failure.

Metastatic lesions can occur decades after resection, making long-term follow-up critical.

Proper preoperative preparation includes taking an alpha-adrenergic blocker, such as phenoxybenzamine, prazosin, terazosin, or doxazosin, for at least 7 days to normalize the patient’s blood pressure. Patients should be counseled that they may experience nasal congestion, orthostasis, and fatigue while taking these medications. Volume expansion with intravenous fluids also should be performed and a high-salt diet considered. Beta-adrenergic blockade can be initiated once appropriate alpha-adrenergic blockade is achieved to control the patient’s heart rate; beta-blockers should never be started first because of the risk for severe hypertension. Careful hemodynamic monitoring is vital intraoperatively and postoperatively.^5,13 Because metastatic lesions can occur decades after resection, long-term follow-up is critical.^5,10

Following tumor resection, our patient’s blood pressure was supported with intravenous fluids and phenylephrine. She was able to discontinue all her antihypertensive medications postoperatively, and her plasma free and urinary fractionated metanephrine levels returned to within normal limits 8 weeks after surgery. Five years after surgery, she continues to have no signs of recurrence, as evidenced by annual negative plasma free metanephrines testing and abdominal/­pelvic CT.

THE TAKEAWAY

This case highlights the importance of recognizing resistant hypertension and a potential secondary cause of this disease—pheochromocytoma. Although rare, pheochromocytomas confer increased risk for cardiovascular disease and death. Thus, swift recognition and proper preparation for surgical resection are necessary. Malignant lesions can be diagnosed only upon discovery of metastatic disease and can recur for decades after surgical resection, making diligent long-term follow-up imperative.

CORRESPONDENCE
Nicole O. Vietor, MD, Division of Endocrinology, Walter Reed National Military Medical Center, 8901 Wisconsin Avenue, Bethesda, MD 20889; [email protected]

THE CASE

A 64-year-old woman sought care after having hot flashes, facial flushing, excessive sweating, palpitations, and daily headaches for 1 month. She had a history of hypertension that was well controlled with hydrochlorothiazide 25 mg/d but over the previous month, it had become more difficult to control. Her blood pressure remained elevated to 150/100 mm Hg despite the addition of lisinopril 40 mg/d and amlodipine 10 mg/d, indicating resistant hypertension. She had no family history of hypertension, diabetes, or obesity or any other pertinent medical or surgical history. Physical examination was negative for weight gain, stretch marks, or muscle weakness.

Laboratory tests revealed a normal serum aldosterone-renin ratio, renal function, and thyroid function; however, she had elevated levels of normetanephrine (2429 pg/mL; normal range, 0-145 pg/mL) and metanephrine (143 pg/mL; normal range, 0-62 pg/mL). Computed tomography (CT) revealed an 8.6-cm complex, hemorrhagic, necrotic left adrenal mass with attenuation of 33.1 Hounsfield units (HU) (FIGURE 1). Magnetic resonance imaging (MRI) demonstrated a T2 hyperintense left adrenal mass. An evaluation for Cushing syndrome was negative, and positron emission tomography (PET)/CT with gallium-68 dotatate was ordered. It showed intense radiotracer uptake in the left adrenal gland, with a maximum standardized uptake value of 70.1 (FIGURE 2).

THE DIAGNOSIS

After appropriate preparation with alpha blockade (phenoxybenzamine 20 mg twice daily for 7 days) and fluid resuscitation (normal saline run over 12 hours preoperatively), the patient underwent successful open surgical resection of the adrenal mass, during which her blood pressure was controlled with a nitroprusside infusion and boluses of esmolol and labetalol. Pathology results showed cells in a nested pattern with round to oval nuclei in a vascular background. There was no necrosis, increased mitotic figures, capsular invasion, or increased cellularity. Chromogranin immunohistochemical staining was positive. Given her resistant hypertension, clinical symptoms, and pathology results, the patient was given a diagnosis of pheochromocytoma.

DISCUSSION

Resistant hypertension is defined as blood pressure that is elevated above goal despite the use of 3 maximally titrated antihypertensive agents from different classes or that is well controlled with at least 4 antihypertensive medications.¹ The prevalence of resistant hypertension is 12% to 18% in adults being treated for hypertension.¹ Patients with resistant hypertension have a higher risk for cardiovascular events and death, are more likely to have a secondary cause of hypertension, and may benefit from special diagnostic testing or treatment approaches to control their blood pressure.¹

There are many causes of resistant hypertension; primary aldosteronism is the most common cause (prevalence as high as 20%).² Given the increased risk for cardiovascular/cerebrovascular disease, all patients with resistant hypertension should be screened for this condition.² Other causes of resistant hypertension include renal parenchymal disease, renal artery stenosis, coarctation of the aorta, thyroid dysfunction, Cushing syndrome, paraganglioma, and as seen in our case, pheochromocytoma. Although pheochromocytoma is a rare cause of resistant hypertension (0.01%-4%),¹ it is associated with high rates of morbidity and mortality if left untreated and may be inherited, making it an essential diagnosis to consider in all patients with resistant hypertension.^1,3

Common symptoms of pheochromocytoma are hypertension (paroxysmal or sustained), headaches, palpitations, pallor, and piloerection (or cold sweats).¹ Patients with pheochromocytoma typically exhibit metanephrine levels that are more than 4 times the upper limit of normal.⁴ Therefore, measurement of plasma free metanephrines or urinary fractionated metanephrines is recommended.⁵ Elevated metanephrine levels also are caused by obesity, obstructive sleep apnea, and certain medications and should be ruled out.⁵

All pheochromocytomas are potentially malignant. Despite the existence of pathologic scoring systems^6,7 and radiographic features that suggest malignancy,^8,9 no single risk-stratification tool is recommended in the current literature.¹⁰ Ultimately, the only way to confirm malignancy is to see metastases where chromaffin tissue is not normally found on imaging.¹⁰

Continue to: Pathologic features to look for...

Pathologic features to look for include capsular/periadrenal adipose invasion, increased cellularity, necrosis, tumor cell ­spindling, increased/atypical mitotic figures, and nuclear pleomorphism. Radiographic features include larger size (≥ 4-6 cm),¹¹ an irregular shape, necrosis, calcifications, attenuation of 10 HU or higher on noncontrast CT, absolute washout of 60% or lower, and relative washout of 40% or lower.^8,12 On MRI, malignant lesions appear hypointense on T1-weighted imaging and hyperintense on T2-weighted imaging.⁹ Fluorodeoxyglucose avidity on PET scan also is indicative of malignancy.^8,9

Treatment for pheochromocytoma is surgical resection. An experienced surgical team and proper preoperative preparation are necessary because the induction of anesthesia, endotracheal intubation, and tumor manipulation can lead to a release of catecholamines, potentially resulting in an intraoperative hypertensive crisis, cardiac arrhythmias, and multiorgan failure.

Metastatic lesions can occur decades after resection, making long-term follow-up critical.

Proper preoperative preparation includes taking an alpha-adrenergic blocker, such as phenoxybenzamine, prazosin, terazosin, or doxazosin, for at least 7 days to normalize the patient’s blood pressure. Patients should be counseled that they may experience nasal congestion, orthostasis, and fatigue while taking these medications. Volume expansion with intravenous fluids also should be performed and a high-salt diet considered. Beta-adrenergic blockade can be initiated once appropriate alpha-adrenergic blockade is achieved to control the patient’s heart rate; beta-blockers should never be started first because of the risk for severe hypertension. Careful hemodynamic monitoring is vital intraoperatively and postoperatively.^5,13 Because metastatic lesions can occur decades after resection, long-term follow-up is critical.^5,10

Following tumor resection, our patient’s blood pressure was supported with intravenous fluids and phenylephrine. She was able to discontinue all her antihypertensive medications postoperatively, and her plasma free and urinary fractionated metanephrine levels returned to within normal limits 8 weeks after surgery. Five years after surgery, she continues to have no signs of recurrence, as evidenced by annual negative plasma free metanephrines testing and abdominal/­pelvic CT.

THE TAKEAWAY

This case highlights the importance of recognizing resistant hypertension and a potential secondary cause of this disease—pheochromocytoma. Although rare, pheochromocytomas confer increased risk for cardiovascular disease and death. Thus, swift recognition and proper preparation for surgical resection are necessary. Malignant lesions can be diagnosed only upon discovery of metastatic disease and can recur for decades after surgical resection, making diligent long-term follow-up imperative.

CORRESPONDENCE
Nicole O. Vietor, MD, Division of Endocrinology, Walter Reed National Military Medical Center, 8901 Wisconsin Avenue, Bethesda, MD 20889; [email protected]

THE CASE

A 64-year-old woman sought care after having hot flashes, facial flushing, excessive sweating, palpitations, and daily headaches for 1 month. She had a history of hypertension that was well controlled with hydrochlorothiazide 25 mg/d but over the previous month, it had become more difficult to control. Her blood pressure remained elevated to 150/100 mm Hg despite the addition of lisinopril 40 mg/d and amlodipine 10 mg/d, indicating resistant hypertension. She had no family history of hypertension, diabetes, or obesity or any other pertinent medical or surgical history. Physical examination was negative for weight gain, stretch marks, or muscle weakness.

Laboratory tests revealed a normal serum aldosterone-renin ratio, renal function, and thyroid function; however, she had elevated levels of normetanephrine (2429 pg/mL; normal range, 0-145 pg/mL) and metanephrine (143 pg/mL; normal range, 0-62 pg/mL). Computed tomography (CT) revealed an 8.6-cm complex, hemorrhagic, necrotic left adrenal mass with attenuation of 33.1 Hounsfield units (HU) (FIGURE 1). Magnetic resonance imaging (MRI) demonstrated a T2 hyperintense left adrenal mass. An evaluation for Cushing syndrome was negative, and positron emission tomography (PET)/CT with gallium-68 dotatate was ordered. It showed intense radiotracer uptake in the left adrenal gland, with a maximum standardized uptake value of 70.1 (FIGURE 2).

THE DIAGNOSIS

After appropriate preparation with alpha blockade (phenoxybenzamine 20 mg twice daily for 7 days) and fluid resuscitation (normal saline run over 12 hours preoperatively), the patient underwent successful open surgical resection of the adrenal mass, during which her blood pressure was controlled with a nitroprusside infusion and boluses of esmolol and labetalol. Pathology results showed cells in a nested pattern with round to oval nuclei in a vascular background. There was no necrosis, increased mitotic figures, capsular invasion, or increased cellularity. Chromogranin immunohistochemical staining was positive. Given her resistant hypertension, clinical symptoms, and pathology results, the patient was given a diagnosis of pheochromocytoma.

DISCUSSION

Resistant hypertension is defined as blood pressure that is elevated above goal despite the use of 3 maximally titrated antihypertensive agents from different classes or that is well controlled with at least 4 antihypertensive medications.¹ The prevalence of resistant hypertension is 12% to 18% in adults being treated for hypertension.¹ Patients with resistant hypertension have a higher risk for cardiovascular events and death, are more likely to have a secondary cause of hypertension, and may benefit from special diagnostic testing or treatment approaches to control their blood pressure.¹

There are many causes of resistant hypertension; primary aldosteronism is the most common cause (prevalence as high as 20%).² Given the increased risk for cardiovascular/cerebrovascular disease, all patients with resistant hypertension should be screened for this condition.² Other causes of resistant hypertension include renal parenchymal disease, renal artery stenosis, coarctation of the aorta, thyroid dysfunction, Cushing syndrome, paraganglioma, and as seen in our case, pheochromocytoma. Although pheochromocytoma is a rare cause of resistant hypertension (0.01%-4%),¹ it is associated with high rates of morbidity and mortality if left untreated and may be inherited, making it an essential diagnosis to consider in all patients with resistant hypertension.^1,3

Common symptoms of pheochromocytoma are hypertension (paroxysmal or sustained), headaches, palpitations, pallor, and piloerection (or cold sweats).¹ Patients with pheochromocytoma typically exhibit metanephrine levels that are more than 4 times the upper limit of normal.⁴ Therefore, measurement of plasma free metanephrines or urinary fractionated metanephrines is recommended.⁵ Elevated metanephrine levels also are caused by obesity, obstructive sleep apnea, and certain medications and should be ruled out.⁵

All pheochromocytomas are potentially malignant. Despite the existence of pathologic scoring systems^6,7 and radiographic features that suggest malignancy,^8,9 no single risk-stratification tool is recommended in the current literature.¹⁰ Ultimately, the only way to confirm malignancy is to see metastases where chromaffin tissue is not normally found on imaging.¹⁰

Continue to: Pathologic features to look for...

Pathologic features to look for include capsular/periadrenal adipose invasion, increased cellularity, necrosis, tumor cell ­spindling, increased/atypical mitotic figures, and nuclear pleomorphism. Radiographic features include larger size (≥ 4-6 cm),¹¹ an irregular shape, necrosis, calcifications, attenuation of 10 HU or higher on noncontrast CT, absolute washout of 60% or lower, and relative washout of 40% or lower.^8,12 On MRI, malignant lesions appear hypointense on T1-weighted imaging and hyperintense on T2-weighted imaging.⁹ Fluorodeoxyglucose avidity on PET scan also is indicative of malignancy.^8,9

Treatment for pheochromocytoma is surgical resection. An experienced surgical team and proper preoperative preparation are necessary because the induction of anesthesia, endotracheal intubation, and tumor manipulation can lead to a release of catecholamines, potentially resulting in an intraoperative hypertensive crisis, cardiac arrhythmias, and multiorgan failure.

Metastatic lesions can occur decades after resection, making long-term follow-up critical.

Proper preoperative preparation includes taking an alpha-adrenergic blocker, such as phenoxybenzamine, prazosin, terazosin, or doxazosin, for at least 7 days to normalize the patient’s blood pressure. Patients should be counseled that they may experience nasal congestion, orthostasis, and fatigue while taking these medications. Volume expansion with intravenous fluids also should be performed and a high-salt diet considered. Beta-adrenergic blockade can be initiated once appropriate alpha-adrenergic blockade is achieved to control the patient’s heart rate; beta-blockers should never be started first because of the risk for severe hypertension. Careful hemodynamic monitoring is vital intraoperatively and postoperatively.^5,13 Because metastatic lesions can occur decades after resection, long-term follow-up is critical.^5,10

Following tumor resection, our patient’s blood pressure was supported with intravenous fluids and phenylephrine. She was able to discontinue all her antihypertensive medications postoperatively, and her plasma free and urinary fractionated metanephrine levels returned to within normal limits 8 weeks after surgery. Five years after surgery, she continues to have no signs of recurrence, as evidenced by annual negative plasma free metanephrines testing and abdominal/­pelvic CT.

THE TAKEAWAY

This case highlights the importance of recognizing resistant hypertension and a potential secondary cause of this disease—pheochromocytoma. Although rare, pheochromocytomas confer increased risk for cardiovascular disease and death. Thus, swift recognition and proper preparation for surgical resection are necessary. Malignant lesions can be diagnosed only upon discovery of metastatic disease and can recur for decades after surgical resection, making diligent long-term follow-up imperative.

CORRESPONDENCE
Nicole O. Vietor, MD, Division of Endocrinology, Walter Reed National Military Medical Center, 8901 Wisconsin Avenue, Bethesda, MD 20889; [email protected]

ILLUSTRATIVE CASE

An otherwise healthy 45-year-old man sustained an acute right-side Achilles tendon rupture while playing tennis. He has not taken quinolones recently, has no history of previous Achilles tendon rupture, and prior to this injury had no difficulty walking. He presents initially to his primary care physician and wants advice: Does he need surgery?

Acute Achilles tendon rupture manifests as acute-onset pain and impaired plantar flexion.² Older, active, male patients are at increased risk. There is disagreement among treating physicians regarding best practices for managing this common and debilitating injury. Prior clinical trials comparing operative to nonoperative management, as well as those comparing different surgical techniques, were limited by small sample sizes.^3-5

A 2019 systematic review and meta-­analysis that relied heavily on observational data suggested that nonoperative management carries greater risk for rerupture but lower risk for complications than surgical treatment, without differences in patient-reported functional outcomes.⁵ This 2022 RCT adds certainty to comparisons of surgical and nonoperative treatment.

STUDY SUMMARY

Equivalent outcomes but higher rates of rerupture for nonoperative patients

Norwegian investigators conducted a prospective, single-blind RCT at 4 treating facilities among patients ages 18 to 60 years with unilateral acute Achilles tendon rupture. A total of 554 patients were randomized in a 1:1:1 ratio to 1 of 3 groups: nonoperative treatment, open-repair surgery, or minimally invasive surgery. Ultimately, 526 patients who completed the intervention and at least 1 follow-up survey were included in the final analysis, which exceeded the number needed according to the pre-study 80% power calculation. Seventy-four percent of the patients were male, and the average age at time of injury was 40 years. Nearly all patients were classified as healthy or having only mild or well-controlled chronic illnesses.

Before randomization, patients completed the 10-item Achilles tendon Total Rupture Score (ATRS) questionnaire to gauge their pre-injury baseline function. ATRS is scored 0 to 100, with lower scores indicating more limitation in function; a clinically important difference is 8 to 10 points. There were no statistically significant differences in pre-injury baseline ATRS (92.7, 93.9, and 94.2 for the nonoperative, open-repair, and minimally invasive groups, respectively) or other patient characteristics among the 3 groups.

For all participants, application of a below-the-knee equinus cast with plantar flexion was performed within 72 hours after the injury. Patients in the surgical arms had surgery within 8 days, followed by application of a new cast. For all study groups, the cast was maintained for a total of 2 weeks, followed by 6 weeks of weight-bearing in an ankle-foot orthosis with heel wedges that were gradually reduced in number. All patients were treated with identical serial immobilization and physical therapy programs for 36 weeks.

The primary study outcome was change from baseline ATRS at 12 months after injury. Secondary outcomes included ATRS at 3 and 6 months and domain-specific quality-of-life scores (from the 36-Item Short Form Health Survey; SF-36) at 6 and 12 months. Patients also underwent physical testing of their Achilles tendon function at 6 and 12 months, during which they wore knee-high socks in order to blind the evaluators. Reruptures were recorded as secondary outcomes as well.

Continue to: There were no significant...

There were no significant differences between groups in the primary outcome. The mean changes in ATRS were −2.6 points (95% CI, −6.5 to 2.0) for nonoperative treatment compared with minimally invasive surgery, and 1.0 point (95% CI, −5.2 to 3.1) for nonoperative treatment compared with open repair.

All groups had similar secondary self-reported ATRS at 3 and 6 months and SF-36 scores at 6 and 12 months. Blinded physical test results also were similar between groups at 6 and 12 months.

Tendon rerupture within 12 months was more common in the nonoperative arm than in the 2 surgical arms (6.2% vs 0.6% in both operative groups; 5.6% difference; 95% CI for difference, 1.9-10.2 for open repair and 1.8-10.2 for minimally invasive surgery). Risk for nerve injury was higher in both the minimally invasive surgery group (5.2%) and the open-repair surgery group (2.8%) compared with the nonoperative group (0.6%; no P value given for comparison).

WHAT’S NEW

Largest RCT to date showed ­effectiveness of nonoperative Tx

This study is the largest well-powered and rigorously conducted RCT to show that nonoperative management of acute Achilles tendon rupture offers equivalent patient-reported outcomes at 12 months after injury. Nonoperative management was associated with a lower risk for nerve injury but higher risk for tendon rerupture.

Patients wishing to minimize the risk for rerupture may still prefer to have surgery after acute Achilles tendon rupture.

These findings support previous studies on the topic. As previously mentioned, a 2019 systematic review and meta-analysis of 10 RCTs (N = 944) and 19 observational studies (N = 14,918) examined operative compared with nonoperative treatment of acute Achilles tendon rupture and found a lower rerupture rate in the operative group but a higher complication rate.⁵ An underpowered 2010 RCT (N = 97) of operative vs nonoperative treatment of acute Achilles tendon rupture found no statistical difference in ATRS.³ Another underpowered RCT conducted in 2013 (N = 100) compared surgical treatment, accelerated rehabilitation, and nonsurgical treatment in acute Achilles tendon rupture and found no statistical difference in ATRS.⁴

CAVEATS

Study results may not apply to some patient groups

These findings may not apply to patients older than 60 years, who were excluded from this RCT, or patients with debilitation or significant chronic disease. Patients with prior Achilles rupture also were excluded.

The study population in Norway, which is more physically active than nearby countries, may not be generalizable worldwide.⁶ Patients wishing to minimize the risk for rerupture may still prefer to have surgery after acute Achilles tendon rupture.

CHALLENGES TO IMPLEMENTATION

Potentially limited options for patients

Most patients with acute Achilles tendon rupture are evaluated by orthopedic surgeons, who may or may not offer nonoperative management. Availability of practitioners to provide serial casting, appropriate heel wedges, and rehabilitation may vary regionally. All patients in this study were evaluated within 72 hours of injury; these findings may not be applicable for patients at a longer time since injury.

ILLUSTRATIVE CASE

An otherwise healthy 45-year-old man sustained an acute right-side Achilles tendon rupture while playing tennis. He has not taken quinolones recently, has no history of previous Achilles tendon rupture, and prior to this injury had no difficulty walking. He presents initially to his primary care physician and wants advice: Does he need surgery?

Acute Achilles tendon rupture manifests as acute-onset pain and impaired plantar flexion.² Older, active, male patients are at increased risk. There is disagreement among treating physicians regarding best practices for managing this common and debilitating injury. Prior clinical trials comparing operative to nonoperative management, as well as those comparing different surgical techniques, were limited by small sample sizes.^3-5

A 2019 systematic review and meta-­analysis that relied heavily on observational data suggested that nonoperative management carries greater risk for rerupture but lower risk for complications than surgical treatment, without differences in patient-reported functional outcomes.⁵ This 2022 RCT adds certainty to comparisons of surgical and nonoperative treatment.

STUDY SUMMARY

Equivalent outcomes but higher rates of rerupture for nonoperative patients

Norwegian investigators conducted a prospective, single-blind RCT at 4 treating facilities among patients ages 18 to 60 years with unilateral acute Achilles tendon rupture. A total of 554 patients were randomized in a 1:1:1 ratio to 1 of 3 groups: nonoperative treatment, open-repair surgery, or minimally invasive surgery. Ultimately, 526 patients who completed the intervention and at least 1 follow-up survey were included in the final analysis, which exceeded the number needed according to the pre-study 80% power calculation. Seventy-four percent of the patients were male, and the average age at time of injury was 40 years. Nearly all patients were classified as healthy or having only mild or well-controlled chronic illnesses.

Before randomization, patients completed the 10-item Achilles tendon Total Rupture Score (ATRS) questionnaire to gauge their pre-injury baseline function. ATRS is scored 0 to 100, with lower scores indicating more limitation in function; a clinically important difference is 8 to 10 points. There were no statistically significant differences in pre-injury baseline ATRS (92.7, 93.9, and 94.2 for the nonoperative, open-repair, and minimally invasive groups, respectively) or other patient characteristics among the 3 groups.

For all participants, application of a below-the-knee equinus cast with plantar flexion was performed within 72 hours after the injury. Patients in the surgical arms had surgery within 8 days, followed by application of a new cast. For all study groups, the cast was maintained for a total of 2 weeks, followed by 6 weeks of weight-bearing in an ankle-foot orthosis with heel wedges that were gradually reduced in number. All patients were treated with identical serial immobilization and physical therapy programs for 36 weeks.

The primary study outcome was change from baseline ATRS at 12 months after injury. Secondary outcomes included ATRS at 3 and 6 months and domain-specific quality-of-life scores (from the 36-Item Short Form Health Survey; SF-36) at 6 and 12 months. Patients also underwent physical testing of their Achilles tendon function at 6 and 12 months, during which they wore knee-high socks in order to blind the evaluators. Reruptures were recorded as secondary outcomes as well.

Continue to: There were no significant...

There were no significant differences between groups in the primary outcome. The mean changes in ATRS were −2.6 points (95% CI, −6.5 to 2.0) for nonoperative treatment compared with minimally invasive surgery, and 1.0 point (95% CI, −5.2 to 3.1) for nonoperative treatment compared with open repair.

All groups had similar secondary self-reported ATRS at 3 and 6 months and SF-36 scores at 6 and 12 months. Blinded physical test results also were similar between groups at 6 and 12 months.

Tendon rerupture within 12 months was more common in the nonoperative arm than in the 2 surgical arms (6.2% vs 0.6% in both operative groups; 5.6% difference; 95% CI for difference, 1.9-10.2 for open repair and 1.8-10.2 for minimally invasive surgery). Risk for nerve injury was higher in both the minimally invasive surgery group (5.2%) and the open-repair surgery group (2.8%) compared with the nonoperative group (0.6%; no P value given for comparison).

WHAT’S NEW

Largest RCT to date showed ­effectiveness of nonoperative Tx

This study is the largest well-powered and rigorously conducted RCT to show that nonoperative management of acute Achilles tendon rupture offers equivalent patient-reported outcomes at 12 months after injury. Nonoperative management was associated with a lower risk for nerve injury but higher risk for tendon rerupture.

Patients wishing to minimize the risk for rerupture may still prefer to have surgery after acute Achilles tendon rupture.

These findings support previous studies on the topic. As previously mentioned, a 2019 systematic review and meta-analysis of 10 RCTs (N = 944) and 19 observational studies (N = 14,918) examined operative compared with nonoperative treatment of acute Achilles tendon rupture and found a lower rerupture rate in the operative group but a higher complication rate.⁵ An underpowered 2010 RCT (N = 97) of operative vs nonoperative treatment of acute Achilles tendon rupture found no statistical difference in ATRS.³ Another underpowered RCT conducted in 2013 (N = 100) compared surgical treatment, accelerated rehabilitation, and nonsurgical treatment in acute Achilles tendon rupture and found no statistical difference in ATRS.⁴

CAVEATS

Study results may not apply to some patient groups

These findings may not apply to patients older than 60 years, who were excluded from this RCT, or patients with debilitation or significant chronic disease. Patients with prior Achilles rupture also were excluded.

The study population in Norway, which is more physically active than nearby countries, may not be generalizable worldwide.⁶ Patients wishing to minimize the risk for rerupture may still prefer to have surgery after acute Achilles tendon rupture.

CHALLENGES TO IMPLEMENTATION

Potentially limited options for patients

Most patients with acute Achilles tendon rupture are evaluated by orthopedic surgeons, who may or may not offer nonoperative management. Availability of practitioners to provide serial casting, appropriate heel wedges, and rehabilitation may vary regionally. All patients in this study were evaluated within 72 hours of injury; these findings may not be applicable for patients at a longer time since injury.

ILLUSTRATIVE CASE

An otherwise healthy 45-year-old man sustained an acute right-side Achilles tendon rupture while playing tennis. He has not taken quinolones recently, has no history of previous Achilles tendon rupture, and prior to this injury had no difficulty walking. He presents initially to his primary care physician and wants advice: Does he need surgery?

Acute Achilles tendon rupture manifests as acute-onset pain and impaired plantar flexion.² Older, active, male patients are at increased risk. There is disagreement among treating physicians regarding best practices for managing this common and debilitating injury. Prior clinical trials comparing operative to nonoperative management, as well as those comparing different surgical techniques, were limited by small sample sizes.^3-5

A 2019 systematic review and meta-­analysis that relied heavily on observational data suggested that nonoperative management carries greater risk for rerupture but lower risk for complications than surgical treatment, without differences in patient-reported functional outcomes.⁵ This 2022 RCT adds certainty to comparisons of surgical and nonoperative treatment.

STUDY SUMMARY

Equivalent outcomes but higher rates of rerupture for nonoperative patients

Norwegian investigators conducted a prospective, single-blind RCT at 4 treating facilities among patients ages 18 to 60 years with unilateral acute Achilles tendon rupture. A total of 554 patients were randomized in a 1:1:1 ratio to 1 of 3 groups: nonoperative treatment, open-repair surgery, or minimally invasive surgery. Ultimately, 526 patients who completed the intervention and at least 1 follow-up survey were included in the final analysis, which exceeded the number needed according to the pre-study 80% power calculation. Seventy-four percent of the patients were male, and the average age at time of injury was 40 years. Nearly all patients were classified as healthy or having only mild or well-controlled chronic illnesses.

Before randomization, patients completed the 10-item Achilles tendon Total Rupture Score (ATRS) questionnaire to gauge their pre-injury baseline function. ATRS is scored 0 to 100, with lower scores indicating more limitation in function; a clinically important difference is 8 to 10 points. There were no statistically significant differences in pre-injury baseline ATRS (92.7, 93.9, and 94.2 for the nonoperative, open-repair, and minimally invasive groups, respectively) or other patient characteristics among the 3 groups.

For all participants, application of a below-the-knee equinus cast with plantar flexion was performed within 72 hours after the injury. Patients in the surgical arms had surgery within 8 days, followed by application of a new cast. For all study groups, the cast was maintained for a total of 2 weeks, followed by 6 weeks of weight-bearing in an ankle-foot orthosis with heel wedges that were gradually reduced in number. All patients were treated with identical serial immobilization and physical therapy programs for 36 weeks.

The primary study outcome was change from baseline ATRS at 12 months after injury. Secondary outcomes included ATRS at 3 and 6 months and domain-specific quality-of-life scores (from the 36-Item Short Form Health Survey; SF-36) at 6 and 12 months. Patients also underwent physical testing of their Achilles tendon function at 6 and 12 months, during which they wore knee-high socks in order to blind the evaluators. Reruptures were recorded as secondary outcomes as well.

Continue to: There were no significant...

There were no significant differences between groups in the primary outcome. The mean changes in ATRS were −2.6 points (95% CI, −6.5 to 2.0) for nonoperative treatment compared with minimally invasive surgery, and 1.0 point (95% CI, −5.2 to 3.1) for nonoperative treatment compared with open repair.

All groups had similar secondary self-reported ATRS at 3 and 6 months and SF-36 scores at 6 and 12 months. Blinded physical test results also were similar between groups at 6 and 12 months.

Tendon rerupture within 12 months was more common in the nonoperative arm than in the 2 surgical arms (6.2% vs 0.6% in both operative groups; 5.6% difference; 95% CI for difference, 1.9-10.2 for open repair and 1.8-10.2 for minimally invasive surgery). Risk for nerve injury was higher in both the minimally invasive surgery group (5.2%) and the open-repair surgery group (2.8%) compared with the nonoperative group (0.6%; no P value given for comparison).

WHAT’S NEW

Largest RCT to date showed ­effectiveness of nonoperative Tx

This study is the largest well-powered and rigorously conducted RCT to show that nonoperative management of acute Achilles tendon rupture offers equivalent patient-reported outcomes at 12 months after injury. Nonoperative management was associated with a lower risk for nerve injury but higher risk for tendon rerupture.

Patients wishing to minimize the risk for rerupture may still prefer to have surgery after acute Achilles tendon rupture.

These findings support previous studies on the topic. As previously mentioned, a 2019 systematic review and meta-analysis of 10 RCTs (N = 944) and 19 observational studies (N = 14,918) examined operative compared with nonoperative treatment of acute Achilles tendon rupture and found a lower rerupture rate in the operative group but a higher complication rate.⁵ An underpowered 2010 RCT (N = 97) of operative vs nonoperative treatment of acute Achilles tendon rupture found no statistical difference in ATRS.³ Another underpowered RCT conducted in 2013 (N = 100) compared surgical treatment, accelerated rehabilitation, and nonsurgical treatment in acute Achilles tendon rupture and found no statistical difference in ATRS.⁴

CAVEATS

Study results may not apply to some patient groups

These findings may not apply to patients older than 60 years, who were excluded from this RCT, or patients with debilitation or significant chronic disease. Patients with prior Achilles rupture also were excluded.

The study population in Norway, which is more physically active than nearby countries, may not be generalizable worldwide.⁶ Patients wishing to minimize the risk for rerupture may still prefer to have surgery after acute Achilles tendon rupture.

CHALLENGES TO IMPLEMENTATION

Potentially limited options for patients

Most patients with acute Achilles tendon rupture are evaluated by orthopedic surgeons, who may or may not offer nonoperative management. Availability of practitioners to provide serial casting, appropriate heel wedges, and rehabilitation may vary regionally. All patients in this study were evaluated within 72 hours of injury; these findings may not be applicable for patients at a longer time since injury.

THE CASE

Sam C* is a 68-year-old man who presented to his family physician in a rural health clinic due to concerns about weight loss. Since his visit 8 months prior, Mr. C unintentionally had lost 20 pounds. Upon questioning, Mr. C also reported feeling irritable and having difficulty with sleep and concentration.

A review of systems did not indicate the presence of infection or other medical conditions. In the 6 years since becoming a patient to the practice, he had reported no chronic health concerns, was taking no medications, and had only been to the clinic for his annual check-up appointments. He completed a Patient Health Questionnaire (PHQ-9) and scored 18, indicating moderately severe depression.

Mr. C had established care with his physician when he moved to the area from out of state so that he could be closer to his parents, who were in their mid-80s at the time. Mr. C’s physician also had been the family physician for his parents for the previous 20 years. Three years prior to Mr. C’s presentation for weight loss, his mother had received a diagnosis of acute leukemia; she died a year later.

Over the past year, Mr. C had needed to take a more active role in the care of his father, who was now in his early 90s. Mr. C’s father, who was previously in excellent health, had begun to develop significant health problems, including degenerative arthritis and progressive vascular dementia. He also had ataxia, leading to poor mobility, and a neurogenic bladder requiring self-catheterization, which required Mr. C’s assistance. Mr. C lived next door to his father and provided frequent assistance with activities of daily living. However, his father, who always had been the dominant figure in the family, was determined to maintain his independence and not relinquish control to others.

The strain of caregiving activities, along with managing his father’s inflexibility, was causing increasing distress for Mr. C. As he told his family physician, “I just don’t know what to do.”

● How would you proceed with this patient?

* The patient’s name has been changed to protect his identity.

It is estimated that more than 11 million Americans provided more than 18 billion hours in unpaid support for individuals with dementia in 2022, averaging 30 hours of care per caregiver per week.¹ As individuals with dementia progressively decline, they require increased assistance with activities of daily living (ADLs, such as bathing and dressing) and instrumental activities of daily living (IADLs, such as paying bills and using transportation). Most of this assistance comes from informal caregiving provided by family members and friends.

Caregiver burden can be defined as “the strain or load borne by a person who cares for a chronically ill, disabled, or elderly family member.”² Caregiver stress has been found to be higher for dementia caregiving than other types of caregiving.³ In particular, caring for someone with greater behavioral and psychological symptoms of dementia (BPSDs) has been associated with higher caregiver burden.^4-7

Beyond the subjective burden of care­giving, there are other potential negative ­consequences for dementia caregivers (see ­TABLE 1^8-14 and TABLE 2^15,16). In addition, caregiver distress is related to a number of care recipient outcomes, including earlier institutionalization, more hospitalizations, more BPSDs, poorer quality of life, and greater likelihood of experiencing elder abuse.¹⁷

Assessment, reassessment are key to meeting needs

Numerous factors can foster caregiver well-­being, including feelings of accomplishment and contribution, a strengthening of the relationship with the care recipient, and feeling supported by friends, family, and formal care systems.^18,19 Family physicians can play an important role by assessing and supporting patients with dementia and their caregivers. Ideally, the individual with dementia and the caregiver will be assessed both together and separately.

Caregiver distress is related to care recipient outcomes, such as earlier institutionalization, more hospitalizations, and poorer quality of life.

A thorough assessment includes gathering information about the context and quality of the caregiving relationship; caregiver perception of the care recipient’s health and functional status; caregiver values and preferences; caregiver well-being (including mental health assessment); caregiver skills, abilities, and knowledge about caregiving; and positive and negative consequences of caregiving.²⁰ Caregiver needs—including informational, care support, emotional, physical, and social needs—also should be assessed.

Continue to: Tools are available...

Tools are available to facilitate caregiver assessment. For example, the Zarit Burden Interview is a 22-item self-report measure that can be given to the caregiver²¹; shorter versions (4 and 12 items) are also available.²² Another resource available for caregiver assessment guidance is a toolkit developed by the Family Caregiver Alliance.²⁰

Continually assess for changing needs

As the condition of the individual with dementia progresses, it will be important to reassess the caregiver, as stressors and needs will change over the course of the caregiving relationship. Support should be adapted ­accordingly.

In the early stage of dementia, caregivers may need information on disease progression and dementia care planning, ways to navigate the health care system, financial planning, and useful resources. Caregivers also may need emotional support to help them adapt to the role of caregiver, deal with denial, and manage their stress.^23,24

With dementia progression, caregivers may need support related to increased decision-making responsibility, managing challenging behaviors, assisting with ADLs and IADLs, and identifying opportunities to meet personal social and well-being needs. They also may need support to accept the changes they are seeing in the individual with dementia and the shifts they are experiencing in their relationship with him or her.^23,25

In late-stage dementia, caregiver needs tend to shift to determining the need for long-term care placement vs staying at home, end-of-life planning, loneliness, and anticipatory grief.^23,26 Support with managing changing and accumulating stress typically remains a primary need throughout the progression of dementia.²⁷

Continue to: Specific populations have distinct needs

Specific populations have distinct needs. Some caregivers, including members of the LGBTQ+ community and different racial and ethnic groups, as well as caregivers of people with younger-onset dementia, may have additional support needs.²⁸

More than 11 million Americans provided more than 18 billion hours in unpaid support for individuals with dementia in 2022, averaging 30 hours of care per caregiver per week.

For example, African American and ­Latino caregivers tend to have caregiving relationships of longer duration, requiring more time-­intensive care, but use fewer formal support services than White caregivers.²⁹ Caregivers from non-White racial and ethnic groups also are more likely to experience discrimination when interacting with health care services on behalf of care recipients.³⁰

Having an awareness of potential specialized needs may help to prevent or address potential care disparities, and cultural humility may help to improve caregiver experiences with primary care physicians.

Resources to support caregivers

Family physicians are well situated to provide informational and emotional support for both patients with dementia and their informal care providers.³¹ Given the variability of caregiver concerns, multicomponent interventions addressing informational, self-care, social support, and financial needs often are needed.³¹ Supportive counseling and psychoeducation can help dementia caregivers with stress management, self-care, coping, and skills training—supporting the development of self-efficacy.^32,33

Outside resources. Although significant caregiver support can be provided directly by the physician, caregivers should be connected with outside resources, including support groups, counselors, psychotherapists, financial and legal support, and formal care services.³⁴

Continue to: Psychosocial and complementary interventions

Psychosocial and complementary interventions. Various psychosocial interventions (eg, psychoeducation, cognitive behavioral therapy, support groups) have been found to be beneficial in alleviating caregiver symptoms of depression, anxiety, and stress and improving well-being, perceived burden, and quality of life. However, systematic reviews have found variability in the degree of helpfulness of these interventions.^35,36

Some caregivers and care recipients may benefit from complementary and integrative medicine referrals. Mind–body therapies such as mindfulness, yoga, and Tai Chi have shown some beneficial effects.³⁷

Online resources. Caregivers also can be directed to online resources from organizations such as the Alzheimer’s Association (www.alz.org), the National Institutes of Health (www.alzheimers.gov), and the Family Caregiver Alliance (www.caregiver.org).

In rural settings, such as the one in which this case took place, online resources may decrease some barriers to supporting caregivers.³⁸ Internet-based interventions also have been found to have some benefit for dementia caregivers.^31,39

However, some rural locations continue to have limited reliable Internet services.⁴⁰ In affected areas, a strong relationship with a primary care physician may be even more important to the well-being of caregivers, since other support services may be less accessible.⁴¹

Continue to: Impacts of the pandemic

Impacts of the pandemic. Although our case took place prior to the COVID-19 pandemic, it is important to acknowledge ways the pandemic has impacted informal dementia caregiving.

Caregiver stress, depression, and anxiety increased during the pandemic, and the need for greater home confinement and social ­distancing amplified the negative impact of social isolation, including loneliness, on ­caregivers.^42,43 Caregivers often needed to increase their caregiving responsibilities and had more difficulty with care coordination due to limited access to in-person resources.⁴³ The pandemic led to increased reliance on technology and telehealth in the support of dementia caregivers.⁴³

THE CASE

The physician prescribed mirtazapine for Mr. C, titrating the dose as needed to address depressive symptoms and promote weight gain. The physician connected Mr. C’s father with home health services, including physical therapy for fall risk reduction. Mr. C also hired part-time support to provide additional assistance with ADLs and IADLs, allowing Mr. C to have time to attend to his own needs. Though provided with information about a local caregiver support group, Mr. C chose not to attend. The physician also assisted the family with advanced directives.

African American and Latino caregivers tend to have caregiving relationships of longer duration, requiring more time-intensive care, but they tend to use fewer formal support services than White caregivers.

A particular challenge that occurred during care for the family was addressing Mr. C’s father’s driving capacity, considering his strong need for independence. To address this concern, a family meeting was held with Mr. C, his father, and his siblings from out of town. Although Mr. C’s father was not willing to relinquish his driver’s license during that meeting, he agreed to complete a functional driving assessment.

The physician continued to meet with Mr. C and his father together, as well as with Mr. C individually, to provide supportive counseling as needed. As the father’s dementia progressed and it became more difficult to complete office appointments, the physician transitioned to home visits to provide care until the father’s death.

After the death of Mr. C’s father, the physician continued to serve as Mr. C’s primary care provider.

Keeping the “family”in family medicine

Through longitudinal assessment, needs identification, and provision of relevant information, emotional support, and resources, family physicians can provide care that can improve the quality of life and well-being and help alleviate burden experienced by dementia caregivers. Family physicians also are positioned to provide treatments that can address the negative physical and psychological health outcomes associated with informal dementia caregiving. By building relationships with multiple family members across generations, family physicians can understand the context of caregiving dynamics and work together with individuals with dementia and their caregivers throughout disease progression, providing consistent support to the family unit.

CORRESPONDENCE
Kathleen M. Young, PhD, MPH, Novant Health Family Medicine Wilmington, 2523 Delaney Avenue, Wilmington, NC 28403; [email protected]

THE CASE

Sam C* is a 68-year-old man who presented to his family physician in a rural health clinic due to concerns about weight loss. Since his visit 8 months prior, Mr. C unintentionally had lost 20 pounds. Upon questioning, Mr. C also reported feeling irritable and having difficulty with sleep and concentration.

A review of systems did not indicate the presence of infection or other medical conditions. In the 6 years since becoming a patient to the practice, he had reported no chronic health concerns, was taking no medications, and had only been to the clinic for his annual check-up appointments. He completed a Patient Health Questionnaire (PHQ-9) and scored 18, indicating moderately severe depression.

Mr. C had established care with his physician when he moved to the area from out of state so that he could be closer to his parents, who were in their mid-80s at the time. Mr. C’s physician also had been the family physician for his parents for the previous 20 years. Three years prior to Mr. C’s presentation for weight loss, his mother had received a diagnosis of acute leukemia; she died a year later.

Over the past year, Mr. C had needed to take a more active role in the care of his father, who was now in his early 90s. Mr. C’s father, who was previously in excellent health, had begun to develop significant health problems, including degenerative arthritis and progressive vascular dementia. He also had ataxia, leading to poor mobility, and a neurogenic bladder requiring self-catheterization, which required Mr. C’s assistance. Mr. C lived next door to his father and provided frequent assistance with activities of daily living. However, his father, who always had been the dominant figure in the family, was determined to maintain his independence and not relinquish control to others.

The strain of caregiving activities, along with managing his father’s inflexibility, was causing increasing distress for Mr. C. As he told his family physician, “I just don’t know what to do.”

● How would you proceed with this patient?

* The patient’s name has been changed to protect his identity.

It is estimated that more than 11 million Americans provided more than 18 billion hours in unpaid support for individuals with dementia in 2022, averaging 30 hours of care per caregiver per week.¹ As individuals with dementia progressively decline, they require increased assistance with activities of daily living (ADLs, such as bathing and dressing) and instrumental activities of daily living (IADLs, such as paying bills and using transportation). Most of this assistance comes from informal caregiving provided by family members and friends.

Caregiver burden can be defined as “the strain or load borne by a person who cares for a chronically ill, disabled, or elderly family member.”² Caregiver stress has been found to be higher for dementia caregiving than other types of caregiving.³ In particular, caring for someone with greater behavioral and psychological symptoms of dementia (BPSDs) has been associated with higher caregiver burden.^4-7

Beyond the subjective burden of care­giving, there are other potential negative ­consequences for dementia caregivers (see ­TABLE 1^8-14 and TABLE 2^15,16). In addition, caregiver distress is related to a number of care recipient outcomes, including earlier institutionalization, more hospitalizations, more BPSDs, poorer quality of life, and greater likelihood of experiencing elder abuse.¹⁷

Assessment, reassessment are key to meeting needs

Numerous factors can foster caregiver well-­being, including feelings of accomplishment and contribution, a strengthening of the relationship with the care recipient, and feeling supported by friends, family, and formal care systems.^18,19 Family physicians can play an important role by assessing and supporting patients with dementia and their caregivers. Ideally, the individual with dementia and the caregiver will be assessed both together and separately.

Caregiver distress is related to care recipient outcomes, such as earlier institutionalization, more hospitalizations, and poorer quality of life.

A thorough assessment includes gathering information about the context and quality of the caregiving relationship; caregiver perception of the care recipient’s health and functional status; caregiver values and preferences; caregiver well-being (including mental health assessment); caregiver skills, abilities, and knowledge about caregiving; and positive and negative consequences of caregiving.²⁰ Caregiver needs—including informational, care support, emotional, physical, and social needs—also should be assessed.

Continue to: Tools are available...

Tools are available to facilitate caregiver assessment. For example, the Zarit Burden Interview is a 22-item self-report measure that can be given to the caregiver²¹; shorter versions (4 and 12 items) are also available.²² Another resource available for caregiver assessment guidance is a toolkit developed by the Family Caregiver Alliance.²⁰

Continually assess for changing needs

As the condition of the individual with dementia progresses, it will be important to reassess the caregiver, as stressors and needs will change over the course of the caregiving relationship. Support should be adapted ­accordingly.

In the early stage of dementia, caregivers may need information on disease progression and dementia care planning, ways to navigate the health care system, financial planning, and useful resources. Caregivers also may need emotional support to help them adapt to the role of caregiver, deal with denial, and manage their stress.^23,24

With dementia progression, caregivers may need support related to increased decision-making responsibility, managing challenging behaviors, assisting with ADLs and IADLs, and identifying opportunities to meet personal social and well-being needs. They also may need support to accept the changes they are seeing in the individual with dementia and the shifts they are experiencing in their relationship with him or her.^23,25

In late-stage dementia, caregiver needs tend to shift to determining the need for long-term care placement vs staying at home, end-of-life planning, loneliness, and anticipatory grief.^23,26 Support with managing changing and accumulating stress typically remains a primary need throughout the progression of dementia.²⁷

Continue to: Specific populations have distinct needs

Specific populations have distinct needs. Some caregivers, including members of the LGBTQ+ community and different racial and ethnic groups, as well as caregivers of people with younger-onset dementia, may have additional support needs.²⁸

More than 11 million Americans provided more than 18 billion hours in unpaid support for individuals with dementia in 2022, averaging 30 hours of care per caregiver per week.

For example, African American and ­Latino caregivers tend to have caregiving relationships of longer duration, requiring more time-­intensive care, but use fewer formal support services than White caregivers.²⁹ Caregivers from non-White racial and ethnic groups also are more likely to experience discrimination when interacting with health care services on behalf of care recipients.³⁰

Having an awareness of potential specialized needs may help to prevent or address potential care disparities, and cultural humility may help to improve caregiver experiences with primary care physicians.

Resources to support caregivers

Family physicians are well situated to provide informational and emotional support for both patients with dementia and their informal care providers.³¹ Given the variability of caregiver concerns, multicomponent interventions addressing informational, self-care, social support, and financial needs often are needed.³¹ Supportive counseling and psychoeducation can help dementia caregivers with stress management, self-care, coping, and skills training—supporting the development of self-efficacy.^32,33

Outside resources. Although significant caregiver support can be provided directly by the physician, caregivers should be connected with outside resources, including support groups, counselors, psychotherapists, financial and legal support, and formal care services.³⁴

Continue to: Psychosocial and complementary interventions

Psychosocial and complementary interventions. Various psychosocial interventions (eg, psychoeducation, cognitive behavioral therapy, support groups) have been found to be beneficial in alleviating caregiver symptoms of depression, anxiety, and stress and improving well-being, perceived burden, and quality of life. However, systematic reviews have found variability in the degree of helpfulness of these interventions.^35,36

Some caregivers and care recipients may benefit from complementary and integrative medicine referrals. Mind–body therapies such as mindfulness, yoga, and Tai Chi have shown some beneficial effects.³⁷

Online resources. Caregivers also can be directed to online resources from organizations such as the Alzheimer’s Association (www.alz.org), the National Institutes of Health (www.alzheimers.gov), and the Family Caregiver Alliance (www.caregiver.org).

In rural settings, such as the one in which this case took place, online resources may decrease some barriers to supporting caregivers.³⁸ Internet-based interventions also have been found to have some benefit for dementia caregivers.^31,39

However, some rural locations continue to have limited reliable Internet services.⁴⁰ In affected areas, a strong relationship with a primary care physician may be even more important to the well-being of caregivers, since other support services may be less accessible.⁴¹

Continue to: Impacts of the pandemic

Impacts of the pandemic. Although our case took place prior to the COVID-19 pandemic, it is important to acknowledge ways the pandemic has impacted informal dementia caregiving.

Caregiver stress, depression, and anxiety increased during the pandemic, and the need for greater home confinement and social ­distancing amplified the negative impact of social isolation, including loneliness, on ­caregivers.^42,43 Caregivers often needed to increase their caregiving responsibilities and had more difficulty with care coordination due to limited access to in-person resources.⁴³ The pandemic led to increased reliance on technology and telehealth in the support of dementia caregivers.⁴³

THE CASE

The physician prescribed mirtazapine for Mr. C, titrating the dose as needed to address depressive symptoms and promote weight gain. The physician connected Mr. C’s father with home health services, including physical therapy for fall risk reduction. Mr. C also hired part-time support to provide additional assistance with ADLs and IADLs, allowing Mr. C to have time to attend to his own needs. Though provided with information about a local caregiver support group, Mr. C chose not to attend. The physician also assisted the family with advanced directives.

African American and Latino caregivers tend to have caregiving relationships of longer duration, requiring more time-intensive care, but they tend to use fewer formal support services than White caregivers.

A particular challenge that occurred during care for the family was addressing Mr. C’s father’s driving capacity, considering his strong need for independence. To address this concern, a family meeting was held with Mr. C, his father, and his siblings from out of town. Although Mr. C’s father was not willing to relinquish his driver’s license during that meeting, he agreed to complete a functional driving assessment.

The physician continued to meet with Mr. C and his father together, as well as with Mr. C individually, to provide supportive counseling as needed. As the father’s dementia progressed and it became more difficult to complete office appointments, the physician transitioned to home visits to provide care until the father’s death.

After the death of Mr. C’s father, the physician continued to serve as Mr. C’s primary care provider.

Keeping the “family”in family medicine

Through longitudinal assessment, needs identification, and provision of relevant information, emotional support, and resources, family physicians can provide care that can improve the quality of life and well-being and help alleviate burden experienced by dementia caregivers. Family physicians also are positioned to provide treatments that can address the negative physical and psychological health outcomes associated with informal dementia caregiving. By building relationships with multiple family members across generations, family physicians can understand the context of caregiving dynamics and work together with individuals with dementia and their caregivers throughout disease progression, providing consistent support to the family unit.

CORRESPONDENCE
Kathleen M. Young, PhD, MPH, Novant Health Family Medicine Wilmington, 2523 Delaney Avenue, Wilmington, NC 28403; [email protected]

THE CASE

Sam C* is a 68-year-old man who presented to his family physician in a rural health clinic due to concerns about weight loss. Since his visit 8 months prior, Mr. C unintentionally had lost 20 pounds. Upon questioning, Mr. C also reported feeling irritable and having difficulty with sleep and concentration.

A review of systems did not indicate the presence of infection or other medical conditions. In the 6 years since becoming a patient to the practice, he had reported no chronic health concerns, was taking no medications, and had only been to the clinic for his annual check-up appointments. He completed a Patient Health Questionnaire (PHQ-9) and scored 18, indicating moderately severe depression.

Mr. C had established care with his physician when he moved to the area from out of state so that he could be closer to his parents, who were in their mid-80s at the time. Mr. C’s physician also had been the family physician for his parents for the previous 20 years. Three years prior to Mr. C’s presentation for weight loss, his mother had received a diagnosis of acute leukemia; she died a year later.

Over the past year, Mr. C had needed to take a more active role in the care of his father, who was now in his early 90s. Mr. C’s father, who was previously in excellent health, had begun to develop significant health problems, including degenerative arthritis and progressive vascular dementia. He also had ataxia, leading to poor mobility, and a neurogenic bladder requiring self-catheterization, which required Mr. C’s assistance. Mr. C lived next door to his father and provided frequent assistance with activities of daily living. However, his father, who always had been the dominant figure in the family, was determined to maintain his independence and not relinquish control to others.

The strain of caregiving activities, along with managing his father’s inflexibility, was causing increasing distress for Mr. C. As he told his family physician, “I just don’t know what to do.”

● How would you proceed with this patient?

* The patient’s name has been changed to protect his identity.

It is estimated that more than 11 million Americans provided more than 18 billion hours in unpaid support for individuals with dementia in 2022, averaging 30 hours of care per caregiver per week.¹ As individuals with dementia progressively decline, they require increased assistance with activities of daily living (ADLs, such as bathing and dressing) and instrumental activities of daily living (IADLs, such as paying bills and using transportation). Most of this assistance comes from informal caregiving provided by family members and friends.

Caregiver burden can be defined as “the strain or load borne by a person who cares for a chronically ill, disabled, or elderly family member.”² Caregiver stress has been found to be higher for dementia caregiving than other types of caregiving.³ In particular, caring for someone with greater behavioral and psychological symptoms of dementia (BPSDs) has been associated with higher caregiver burden.^4-7

Beyond the subjective burden of care­giving, there are other potential negative ­consequences for dementia caregivers (see ­TABLE 1^8-14 and TABLE 2^15,16). In addition, caregiver distress is related to a number of care recipient outcomes, including earlier institutionalization, more hospitalizations, more BPSDs, poorer quality of life, and greater likelihood of experiencing elder abuse.¹⁷

Assessment, reassessment are key to meeting needs

Numerous factors can foster caregiver well-­being, including feelings of accomplishment and contribution, a strengthening of the relationship with the care recipient, and feeling supported by friends, family, and formal care systems.^18,19 Family physicians can play an important role by assessing and supporting patients with dementia and their caregivers. Ideally, the individual with dementia and the caregiver will be assessed both together and separately.

Caregiver distress is related to care recipient outcomes, such as earlier institutionalization, more hospitalizations, and poorer quality of life.

A thorough assessment includes gathering information about the context and quality of the caregiving relationship; caregiver perception of the care recipient’s health and functional status; caregiver values and preferences; caregiver well-being (including mental health assessment); caregiver skills, abilities, and knowledge about caregiving; and positive and negative consequences of caregiving.²⁰ Caregiver needs—including informational, care support, emotional, physical, and social needs—also should be assessed.

Continue to: Tools are available...

Tools are available to facilitate caregiver assessment. For example, the Zarit Burden Interview is a 22-item self-report measure that can be given to the caregiver²¹; shorter versions (4 and 12 items) are also available.²² Another resource available for caregiver assessment guidance is a toolkit developed by the Family Caregiver Alliance.²⁰

Continually assess for changing needs

As the condition of the individual with dementia progresses, it will be important to reassess the caregiver, as stressors and needs will change over the course of the caregiving relationship. Support should be adapted ­accordingly.

In the early stage of dementia, caregivers may need information on disease progression and dementia care planning, ways to navigate the health care system, financial planning, and useful resources. Caregivers also may need emotional support to help them adapt to the role of caregiver, deal with denial, and manage their stress.^23,24

With dementia progression, caregivers may need support related to increased decision-making responsibility, managing challenging behaviors, assisting with ADLs and IADLs, and identifying opportunities to meet personal social and well-being needs. They also may need support to accept the changes they are seeing in the individual with dementia and the shifts they are experiencing in their relationship with him or her.^23,25

In late-stage dementia, caregiver needs tend to shift to determining the need for long-term care placement vs staying at home, end-of-life planning, loneliness, and anticipatory grief.^23,26 Support with managing changing and accumulating stress typically remains a primary need throughout the progression of dementia.²⁷

Continue to: Specific populations have distinct needs

Specific populations have distinct needs. Some caregivers, including members of the LGBTQ+ community and different racial and ethnic groups, as well as caregivers of people with younger-onset dementia, may have additional support needs.²⁸

More than 11 million Americans provided more than 18 billion hours in unpaid support for individuals with dementia in 2022, averaging 30 hours of care per caregiver per week.

For example, African American and ­Latino caregivers tend to have caregiving relationships of longer duration, requiring more time-­intensive care, but use fewer formal support services than White caregivers.²⁹ Caregivers from non-White racial and ethnic groups also are more likely to experience discrimination when interacting with health care services on behalf of care recipients.³⁰

Having an awareness of potential specialized needs may help to prevent or address potential care disparities, and cultural humility may help to improve caregiver experiences with primary care physicians.

Resources to support caregivers

Family physicians are well situated to provide informational and emotional support for both patients with dementia and their informal care providers.³¹ Given the variability of caregiver concerns, multicomponent interventions addressing informational, self-care, social support, and financial needs often are needed.³¹ Supportive counseling and psychoeducation can help dementia caregivers with stress management, self-care, coping, and skills training—supporting the development of self-efficacy.^32,33

Outside resources. Although significant caregiver support can be provided directly by the physician, caregivers should be connected with outside resources, including support groups, counselors, psychotherapists, financial and legal support, and formal care services.³⁴

Continue to: Psychosocial and complementary interventions

Psychosocial and complementary interventions. Various psychosocial interventions (eg, psychoeducation, cognitive behavioral therapy, support groups) have been found to be beneficial in alleviating caregiver symptoms of depression, anxiety, and stress and improving well-being, perceived burden, and quality of life. However, systematic reviews have found variability in the degree of helpfulness of these interventions.^35,36

Some caregivers and care recipients may benefit from complementary and integrative medicine referrals. Mind–body therapies such as mindfulness, yoga, and Tai Chi have shown some beneficial effects.³⁷

Online resources. Caregivers also can be directed to online resources from organizations such as the Alzheimer’s Association (www.alz.org), the National Institutes of Health (www.alzheimers.gov), and the Family Caregiver Alliance (www.caregiver.org).

In rural settings, such as the one in which this case took place, online resources may decrease some barriers to supporting caregivers.³⁸ Internet-based interventions also have been found to have some benefit for dementia caregivers.^31,39

However, some rural locations continue to have limited reliable Internet services.⁴⁰ In affected areas, a strong relationship with a primary care physician may be even more important to the well-being of caregivers, since other support services may be less accessible.⁴¹

Continue to: Impacts of the pandemic

Impacts of the pandemic. Although our case took place prior to the COVID-19 pandemic, it is important to acknowledge ways the pandemic has impacted informal dementia caregiving.

Caregiver stress, depression, and anxiety increased during the pandemic, and the need for greater home confinement and social ­distancing amplified the negative impact of social isolation, including loneliness, on ­caregivers.^42,43 Caregivers often needed to increase their caregiving responsibilities and had more difficulty with care coordination due to limited access to in-person resources.⁴³ The pandemic led to increased reliance on technology and telehealth in the support of dementia caregivers.⁴³

THE CASE

The physician prescribed mirtazapine for Mr. C, titrating the dose as needed to address depressive symptoms and promote weight gain. The physician connected Mr. C’s father with home health services, including physical therapy for fall risk reduction. Mr. C also hired part-time support to provide additional assistance with ADLs and IADLs, allowing Mr. C to have time to attend to his own needs. Though provided with information about a local caregiver support group, Mr. C chose not to attend. The physician also assisted the family with advanced directives.

African American and Latino caregivers tend to have caregiving relationships of longer duration, requiring more time-intensive care, but they tend to use fewer formal support services than White caregivers.

A particular challenge that occurred during care for the family was addressing Mr. C’s father’s driving capacity, considering his strong need for independence. To address this concern, a family meeting was held with Mr. C, his father, and his siblings from out of town. Although Mr. C’s father was not willing to relinquish his driver’s license during that meeting, he agreed to complete a functional driving assessment.

The physician continued to meet with Mr. C and his father together, as well as with Mr. C individually, to provide supportive counseling as needed. As the father’s dementia progressed and it became more difficult to complete office appointments, the physician transitioned to home visits to provide care until the father’s death.

After the death of Mr. C’s father, the physician continued to serve as Mr. C’s primary care provider.

Keeping the “family”in family medicine

Through longitudinal assessment, needs identification, and provision of relevant information, emotional support, and resources, family physicians can provide care that can improve the quality of life and well-being and help alleviate burden experienced by dementia caregivers. Family physicians also are positioned to provide treatments that can address the negative physical and psychological health outcomes associated with informal dementia caregiving. By building relationships with multiple family members across generations, family physicians can understand the context of caregiving dynamics and work together with individuals with dementia and their caregivers throughout disease progression, providing consistent support to the family unit.

CORRESPONDENCE
Kathleen M. Young, PhD, MPH, Novant Health Family Medicine Wilmington, 2523 Delaney Avenue, Wilmington, NC 28403; [email protected]