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Group B strep: Short-course IV controls infant infection
Infants with bacteremia caused by group B streptococcus (GBS) who were treated with intravenous antimicrobial therapy for 8 days or less had similarly successful outcomes, compared with those treated longer, based on data from 775 infants.
Current guidelines recommend intravenous antibiotics for a prolonged period of 10 days for infants (defined as 7-90 days old) with uncomplicated, late-onset GBS bacteremia, “however, no studies have compared outcomes among infants who receive prolonged versus shortened durations of IV antibiotic therapy,” wrote Eric R. Coon, MD, of the University of Utah, Salt Lake City, and colleagues. In a retrospective study published in Pediatrics, the researchers compared recurrence rates in infants who received prolonged vs. shortened therapy.
The study population included 612 infants with uncomplicated late-onset GBS bacteremia aged 4 months and younger who received prolonged IV therapy and 163 who received shortened therapy (defined as 8 days or less). Demographics were not significantly different between the groups, although infants who received a shortened treatment were more likely to be older, were more often admitted in later years of the study, and more likely to have a concomitant urinary tract infection.
Overall, 17 infants experienced recurrence; 3 in the shortened therapy group (1.8%) and 14 in the prolonged therapy group (2.3%). The average time to recurrence was 25 days.
Of note, 27 infants in the shortened treatment group received oral antibiotics on the day of their hospital discharge, and none of them experienced GBS recurrence, which suggests that “Early transition to oral antibiotic therapy may be appropriate for carefully selected infants with GBS bacteremia,” the researchers wrote.
In the prolonged treatment group, recurrence rates were 4.0% and 1.5%, respectively, for infants discharged with and without a peripherally inserted central catheter (PICC), but complications from the catheter may have been misclassified as disease recurrence to cause the difference in rate, as the noncatheter patients had similar recurrence rates to the shortened treatment group, the researchers noted.
“We found striking variation in IV antibiotic treatment duration by hospital and whether patients received prolonged or shortened IV courses; rates of GBS disease recurrence and treatment failure were low,” the researchers said. The top three antibiotics prescribed were ampicillin plus a third-generation cephalosporin (37%), third-generation cephalosporin monotherapy (28%), and third-generation cephalosporin monotherapy plus vancomycin (7%).
The findings were limited by the observational design, potential for misclassification of outcomes, and a lack of data to address the total duration of antibiotic therapy, the researchers noted. However, the results suggest that shorter treatment can be an informed decision considered in appropriate patients.
“Beyond decreased health care costs, shortened IV antibiotic courses provide the advantage of a diminished burden for families, allowing for patients to leave the hospital sooner, making it easier to administer the antibiotic at home, and decreasing the likelihood that they would develop a treatment-related complication,” the researchers said. The researchers had no financial conflicts to disclose.
SOURCE: Coon E et al. Pediatrics. 2018 Oct 11. doi: 10.1542/peds.2018-0131.
The 2007 French study investigating oral amoxicillin for early-onset group B streptococcus is one of the few times in the past 3 decades where I changed my practice based on a single article. It was a large, conclusive study with 222 patients, so it doesn’t need a meta-analysis in the way American research often requires. The research showed that most of what I had been taught about oral amoxicillin was false. Amoxicillin is absorbed well even at doses above 50 mg/kg per day. It is absorbed reliably by neonates, even mildly sick ones. It crosses the blood-brain barrier adequately. The French researchers measured serum levels and proved all this using scientific principles as well as clinical trials.
I have used this oral protocol (10 days total after 2-3 days IV therapy) on two occasions to treat GBS sepsis when I had informed consent of the parents and buy-in from the primary care pediatrician. I waited for the Red Book to update its recommendations. That didn’t happen.
Meanwhile, I saw other babies kept for 10 days in the hospital for IV therapy, with resultant wasted costs and income loss for the parents. I’ve treated complications and readmissions due to PICC line issues. One baby at home got a syringe of gentamicin given IV push instead of a normal saline flush. Mistakes happen at home and in the hospital.
Since late-onset GBS can be acquired environmentally, there will always be recurrences. The issue isn’t the rate of recurrence. It is whether the more invasive intervention reduces that rate. Then balance any measured reduction against the adverse effects of the invasive intervention, like PICC line infections. This Bayesian decision making is hard for some risk-adverse humans to assimilate.
Dr. Coon and associates have confirmed, using Big Data, that prolonged IV therapy of late-onset GBS bacteremia does not generate a clinically significant benefit. It is certainly possible to sow doubt by asking for proof in a variety of subpopulations. But this new article is in the context of multiple articles over the past decade that have disproved the myth of the superiority of IV therapy. Given the known risks and costs of PICC lines and prolonged IV therapy, the default should be, absent a credible rationale to the contrary, that oral therapy at home is better.
Dr. Coon and associates show that, by 2015, 5 of 49 children’s hospitals were early adopters and had made the switch to mostly using short treatment courses. Fourteen of 49 hadn’t changed at all. Given this new analysis, what are you laggards waiting for?
Dr. Kevin Powell is a pediatric hospitalist and clinical ethics consultant living in St. Louis. He reported no relevant financial disclosures.
The 2007 French study investigating oral amoxicillin for early-onset group B streptococcus is one of the few times in the past 3 decades where I changed my practice based on a single article. It was a large, conclusive study with 222 patients, so it doesn’t need a meta-analysis in the way American research often requires. The research showed that most of what I had been taught about oral amoxicillin was false. Amoxicillin is absorbed well even at doses above 50 mg/kg per day. It is absorbed reliably by neonates, even mildly sick ones. It crosses the blood-brain barrier adequately. The French researchers measured serum levels and proved all this using scientific principles as well as clinical trials.
I have used this oral protocol (10 days total after 2-3 days IV therapy) on two occasions to treat GBS sepsis when I had informed consent of the parents and buy-in from the primary care pediatrician. I waited for the Red Book to update its recommendations. That didn’t happen.
Meanwhile, I saw other babies kept for 10 days in the hospital for IV therapy, with resultant wasted costs and income loss for the parents. I’ve treated complications and readmissions due to PICC line issues. One baby at home got a syringe of gentamicin given IV push instead of a normal saline flush. Mistakes happen at home and in the hospital.
Since late-onset GBS can be acquired environmentally, there will always be recurrences. The issue isn’t the rate of recurrence. It is whether the more invasive intervention reduces that rate. Then balance any measured reduction against the adverse effects of the invasive intervention, like PICC line infections. This Bayesian decision making is hard for some risk-adverse humans to assimilate.
Dr. Coon and associates have confirmed, using Big Data, that prolonged IV therapy of late-onset GBS bacteremia does not generate a clinically significant benefit. It is certainly possible to sow doubt by asking for proof in a variety of subpopulations. But this new article is in the context of multiple articles over the past decade that have disproved the myth of the superiority of IV therapy. Given the known risks and costs of PICC lines and prolonged IV therapy, the default should be, absent a credible rationale to the contrary, that oral therapy at home is better.
Dr. Coon and associates show that, by 2015, 5 of 49 children’s hospitals were early adopters and had made the switch to mostly using short treatment courses. Fourteen of 49 hadn’t changed at all. Given this new analysis, what are you laggards waiting for?
Dr. Kevin Powell is a pediatric hospitalist and clinical ethics consultant living in St. Louis. He reported no relevant financial disclosures.
The 2007 French study investigating oral amoxicillin for early-onset group B streptococcus is one of the few times in the past 3 decades where I changed my practice based on a single article. It was a large, conclusive study with 222 patients, so it doesn’t need a meta-analysis in the way American research often requires. The research showed that most of what I had been taught about oral amoxicillin was false. Amoxicillin is absorbed well even at doses above 50 mg/kg per day. It is absorbed reliably by neonates, even mildly sick ones. It crosses the blood-brain barrier adequately. The French researchers measured serum levels and proved all this using scientific principles as well as clinical trials.
I have used this oral protocol (10 days total after 2-3 days IV therapy) on two occasions to treat GBS sepsis when I had informed consent of the parents and buy-in from the primary care pediatrician. I waited for the Red Book to update its recommendations. That didn’t happen.
Meanwhile, I saw other babies kept for 10 days in the hospital for IV therapy, with resultant wasted costs and income loss for the parents. I’ve treated complications and readmissions due to PICC line issues. One baby at home got a syringe of gentamicin given IV push instead of a normal saline flush. Mistakes happen at home and in the hospital.
Since late-onset GBS can be acquired environmentally, there will always be recurrences. The issue isn’t the rate of recurrence. It is whether the more invasive intervention reduces that rate. Then balance any measured reduction against the adverse effects of the invasive intervention, like PICC line infections. This Bayesian decision making is hard for some risk-adverse humans to assimilate.
Dr. Coon and associates have confirmed, using Big Data, that prolonged IV therapy of late-onset GBS bacteremia does not generate a clinically significant benefit. It is certainly possible to sow doubt by asking for proof in a variety of subpopulations. But this new article is in the context of multiple articles over the past decade that have disproved the myth of the superiority of IV therapy. Given the known risks and costs of PICC lines and prolonged IV therapy, the default should be, absent a credible rationale to the contrary, that oral therapy at home is better.
Dr. Coon and associates show that, by 2015, 5 of 49 children’s hospitals were early adopters and had made the switch to mostly using short treatment courses. Fourteen of 49 hadn’t changed at all. Given this new analysis, what are you laggards waiting for?
Dr. Kevin Powell is a pediatric hospitalist and clinical ethics consultant living in St. Louis. He reported no relevant financial disclosures.
Infants with bacteremia caused by group B streptococcus (GBS) who were treated with intravenous antimicrobial therapy for 8 days or less had similarly successful outcomes, compared with those treated longer, based on data from 775 infants.
Current guidelines recommend intravenous antibiotics for a prolonged period of 10 days for infants (defined as 7-90 days old) with uncomplicated, late-onset GBS bacteremia, “however, no studies have compared outcomes among infants who receive prolonged versus shortened durations of IV antibiotic therapy,” wrote Eric R. Coon, MD, of the University of Utah, Salt Lake City, and colleagues. In a retrospective study published in Pediatrics, the researchers compared recurrence rates in infants who received prolonged vs. shortened therapy.
The study population included 612 infants with uncomplicated late-onset GBS bacteremia aged 4 months and younger who received prolonged IV therapy and 163 who received shortened therapy (defined as 8 days or less). Demographics were not significantly different between the groups, although infants who received a shortened treatment were more likely to be older, were more often admitted in later years of the study, and more likely to have a concomitant urinary tract infection.
Overall, 17 infants experienced recurrence; 3 in the shortened therapy group (1.8%) and 14 in the prolonged therapy group (2.3%). The average time to recurrence was 25 days.
Of note, 27 infants in the shortened treatment group received oral antibiotics on the day of their hospital discharge, and none of them experienced GBS recurrence, which suggests that “Early transition to oral antibiotic therapy may be appropriate for carefully selected infants with GBS bacteremia,” the researchers wrote.
In the prolonged treatment group, recurrence rates were 4.0% and 1.5%, respectively, for infants discharged with and without a peripherally inserted central catheter (PICC), but complications from the catheter may have been misclassified as disease recurrence to cause the difference in rate, as the noncatheter patients had similar recurrence rates to the shortened treatment group, the researchers noted.
“We found striking variation in IV antibiotic treatment duration by hospital and whether patients received prolonged or shortened IV courses; rates of GBS disease recurrence and treatment failure were low,” the researchers said. The top three antibiotics prescribed were ampicillin plus a third-generation cephalosporin (37%), third-generation cephalosporin monotherapy (28%), and third-generation cephalosporin monotherapy plus vancomycin (7%).
The findings were limited by the observational design, potential for misclassification of outcomes, and a lack of data to address the total duration of antibiotic therapy, the researchers noted. However, the results suggest that shorter treatment can be an informed decision considered in appropriate patients.
“Beyond decreased health care costs, shortened IV antibiotic courses provide the advantage of a diminished burden for families, allowing for patients to leave the hospital sooner, making it easier to administer the antibiotic at home, and decreasing the likelihood that they would develop a treatment-related complication,” the researchers said. The researchers had no financial conflicts to disclose.
SOURCE: Coon E et al. Pediatrics. 2018 Oct 11. doi: 10.1542/peds.2018-0131.
Infants with bacteremia caused by group B streptococcus (GBS) who were treated with intravenous antimicrobial therapy for 8 days or less had similarly successful outcomes, compared with those treated longer, based on data from 775 infants.
Current guidelines recommend intravenous antibiotics for a prolonged period of 10 days for infants (defined as 7-90 days old) with uncomplicated, late-onset GBS bacteremia, “however, no studies have compared outcomes among infants who receive prolonged versus shortened durations of IV antibiotic therapy,” wrote Eric R. Coon, MD, of the University of Utah, Salt Lake City, and colleagues. In a retrospective study published in Pediatrics, the researchers compared recurrence rates in infants who received prolonged vs. shortened therapy.
The study population included 612 infants with uncomplicated late-onset GBS bacteremia aged 4 months and younger who received prolonged IV therapy and 163 who received shortened therapy (defined as 8 days or less). Demographics were not significantly different between the groups, although infants who received a shortened treatment were more likely to be older, were more often admitted in later years of the study, and more likely to have a concomitant urinary tract infection.
Overall, 17 infants experienced recurrence; 3 in the shortened therapy group (1.8%) and 14 in the prolonged therapy group (2.3%). The average time to recurrence was 25 days.
Of note, 27 infants in the shortened treatment group received oral antibiotics on the day of their hospital discharge, and none of them experienced GBS recurrence, which suggests that “Early transition to oral antibiotic therapy may be appropriate for carefully selected infants with GBS bacteremia,” the researchers wrote.
In the prolonged treatment group, recurrence rates were 4.0% and 1.5%, respectively, for infants discharged with and without a peripherally inserted central catheter (PICC), but complications from the catheter may have been misclassified as disease recurrence to cause the difference in rate, as the noncatheter patients had similar recurrence rates to the shortened treatment group, the researchers noted.
“We found striking variation in IV antibiotic treatment duration by hospital and whether patients received prolonged or shortened IV courses; rates of GBS disease recurrence and treatment failure were low,” the researchers said. The top three antibiotics prescribed were ampicillin plus a third-generation cephalosporin (37%), third-generation cephalosporin monotherapy (28%), and third-generation cephalosporin monotherapy plus vancomycin (7%).
The findings were limited by the observational design, potential for misclassification of outcomes, and a lack of data to address the total duration of antibiotic therapy, the researchers noted. However, the results suggest that shorter treatment can be an informed decision considered in appropriate patients.
“Beyond decreased health care costs, shortened IV antibiotic courses provide the advantage of a diminished burden for families, allowing for patients to leave the hospital sooner, making it easier to administer the antibiotic at home, and decreasing the likelihood that they would develop a treatment-related complication,” the researchers said. The researchers had no financial conflicts to disclose.
SOURCE: Coon E et al. Pediatrics. 2018 Oct 11. doi: 10.1542/peds.2018-0131.
FROM PEDIATRICS
Key clinical point: Courses of IV antibiotics shorter than recommended for group B streptococcus bacteremia yield low rates of recurrence and treatment failure.
Major finding: Three children treated with a shorter IV duration had recurrence of group B strep, compared with 14 children in a longer treatment group (1.8% vs. 2.3%).
Study details: The data come from a multicenter retrospective cohort study of 775 infants aged 7 days to 4 months.
Disclosures: The researchers had no financial conflicts to disclose.
Source: Coon E et al. Pediatrics. 2018 Oct 11. doi: 10.1542/peds.2018-0345.
Nf-L levels predictive of brain atrophy, disability in progressive MS
BERLIN – Neurofilament light chain (Nf-L) levels are higher in the plasma of patients with secondary progressive multiple sclerosis (SPMS) than primary progressive multiple sclerosis (PPMS) irrespective of age, according to an analysis of blood samples from two large phase 3 trials.
“Our data suggest that Nf-L should be considered as an informative endpoint for phase 2 studies in SPMS,” said the presenting study author Ludwig Kappos, MD, at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.
Much of the research on using Nf-L as a biomarker in MS to date has looked at patients with relapsing-remitting MS and the researchers wanted to see if Nf-L might be a useful biomarker in progressive MS because drug development in this area needs long-term and large trials to show an effect of a drug on disability. Conventional magnetic resonance imaging measures show only a modest association with disease evolution in SPMS and PPMS, and, as Nf-L is specific to neuronal damage, it should reflect damage to the brain and spinal cord, Dr. Kappos explained.
The aim of the study was to compare Nf-L levels in the two progressive subtypes of MS – SPMS and PPMS – and to see if it had any predictive value in determining the degree of brain atrophy or disability. Other objectives were to measure the sensitivity for Nf-L to detect treatment effects, and to estimate how big a sample size would be needed in a phase 2 study if it was used as a primary endpoint.
Blood samples from 1,830 patients who had participated in one of two phase 3 studies of siponimod in SPMS (EXPAND) and fingolimod (Gilyena) in PPMS (INFORMS). Nf-L levels were measured retrospectively in plasma using the SIMOA Nf-L immunoassay and categorized as being low (less than 30 pg/mL), medium (30-60 pg/mL), or high (greater than 60 pg/mL). Brain volume change on MRI was calculated using the SIENA (Structural Image Evaluation, using Normalization, of Atrophy) method, and disability changes assessed were evaluated by the Expanded Disability Status Scale (EDSS) score
“One of the confounders of measuring Nf-L is age,” Dr. Kappos acknowledged, “but we see a difference between SPMS and PPMS that is robust along the spectrum of ages.” The geometric mean of Nf-L at baseline was 32.1 pg/mL in patients with SPMS (n = 1,452) and 22.0 pg/mL in those with PPMS (n = 378).
Multiple regression analysis showed that, in both SPMS and PPMS patients, higher Nf-L levels were associated with older age and higher disease activity (increased EDSS score, more gadolinium-enhancing (Gd+) lesions and higher T2 lesion load).
Greater brain loss was seen at both 12 and 24 months in patients with high versus low Nf-L levels at baseline in both the SPMS and PPMS groups. For example, comparing high versus low Nf-L in SPMS, the mean brain volume change from baseline was –0.8% vs. –0.2% (P less than .0001) at 12 months and –1.5% vs. –0.5% at 24 months (P less than .0001). Corresponding values for PPMS were –0.8% vs. –0.4% (P = .0044) and –1.9% vs. –0.8% (P less than .0001).
Nf-L levels of 30 pg/mL were associated with a 32% increased risk of disability progression in patients with SPMS (P = .0055) and a 49% increased risk of disability progression in patients with PPMS (P = .0268).
In both groups of progressive MS patients, Nf-L levels were reduced in response to treatment at both 12 and 24 months, which remained significant.
“So, what about sample size calculation for a 1-year, phase 2 study with Nf-L as a primary endpoint?” Dr. Kappos queried. Assuming a reduction in Nf-L of 20% with a test drug, such a study would be likely to need to include 188 patients, or 94 patients per single arm to have 80% statistical power. To see a 30% reduction in Nf-L, fewer total and single-arm numbers would be needed, at 74 and 37 participants, respectively.
The study was funded by Novartis Pharma AG, Basel, Switzerland. Dr. Kappos disclosed that his institution (University Hospital Basel) had received steering committee, advisory board, and consultancy fees in the last 3 years that had been used exclusively for research support at the department from Novartis and a number of other pharmaceutical manufacturers. The Research of the MS Centre in Basel has been supported by grants from Bayer, Biogen, Novartis, the Swiss MS Society, the Swiss National Research Foundation, the European Union, and Roche Research Foundations.
SOURCE: Kuhle J et al. ECTRIMS 2018. Mult Scler. 2018;24(Suppl 2):111, Abstract 286.
BERLIN – Neurofilament light chain (Nf-L) levels are higher in the plasma of patients with secondary progressive multiple sclerosis (SPMS) than primary progressive multiple sclerosis (PPMS) irrespective of age, according to an analysis of blood samples from two large phase 3 trials.
“Our data suggest that Nf-L should be considered as an informative endpoint for phase 2 studies in SPMS,” said the presenting study author Ludwig Kappos, MD, at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.
Much of the research on using Nf-L as a biomarker in MS to date has looked at patients with relapsing-remitting MS and the researchers wanted to see if Nf-L might be a useful biomarker in progressive MS because drug development in this area needs long-term and large trials to show an effect of a drug on disability. Conventional magnetic resonance imaging measures show only a modest association with disease evolution in SPMS and PPMS, and, as Nf-L is specific to neuronal damage, it should reflect damage to the brain and spinal cord, Dr. Kappos explained.
The aim of the study was to compare Nf-L levels in the two progressive subtypes of MS – SPMS and PPMS – and to see if it had any predictive value in determining the degree of brain atrophy or disability. Other objectives were to measure the sensitivity for Nf-L to detect treatment effects, and to estimate how big a sample size would be needed in a phase 2 study if it was used as a primary endpoint.
Blood samples from 1,830 patients who had participated in one of two phase 3 studies of siponimod in SPMS (EXPAND) and fingolimod (Gilyena) in PPMS (INFORMS). Nf-L levels were measured retrospectively in plasma using the SIMOA Nf-L immunoassay and categorized as being low (less than 30 pg/mL), medium (30-60 pg/mL), or high (greater than 60 pg/mL). Brain volume change on MRI was calculated using the SIENA (Structural Image Evaluation, using Normalization, of Atrophy) method, and disability changes assessed were evaluated by the Expanded Disability Status Scale (EDSS) score
“One of the confounders of measuring Nf-L is age,” Dr. Kappos acknowledged, “but we see a difference between SPMS and PPMS that is robust along the spectrum of ages.” The geometric mean of Nf-L at baseline was 32.1 pg/mL in patients with SPMS (n = 1,452) and 22.0 pg/mL in those with PPMS (n = 378).
Multiple regression analysis showed that, in both SPMS and PPMS patients, higher Nf-L levels were associated with older age and higher disease activity (increased EDSS score, more gadolinium-enhancing (Gd+) lesions and higher T2 lesion load).
Greater brain loss was seen at both 12 and 24 months in patients with high versus low Nf-L levels at baseline in both the SPMS and PPMS groups. For example, comparing high versus low Nf-L in SPMS, the mean brain volume change from baseline was –0.8% vs. –0.2% (P less than .0001) at 12 months and –1.5% vs. –0.5% at 24 months (P less than .0001). Corresponding values for PPMS were –0.8% vs. –0.4% (P = .0044) and –1.9% vs. –0.8% (P less than .0001).
Nf-L levels of 30 pg/mL were associated with a 32% increased risk of disability progression in patients with SPMS (P = .0055) and a 49% increased risk of disability progression in patients with PPMS (P = .0268).
In both groups of progressive MS patients, Nf-L levels were reduced in response to treatment at both 12 and 24 months, which remained significant.
“So, what about sample size calculation for a 1-year, phase 2 study with Nf-L as a primary endpoint?” Dr. Kappos queried. Assuming a reduction in Nf-L of 20% with a test drug, such a study would be likely to need to include 188 patients, or 94 patients per single arm to have 80% statistical power. To see a 30% reduction in Nf-L, fewer total and single-arm numbers would be needed, at 74 and 37 participants, respectively.
The study was funded by Novartis Pharma AG, Basel, Switzerland. Dr. Kappos disclosed that his institution (University Hospital Basel) had received steering committee, advisory board, and consultancy fees in the last 3 years that had been used exclusively for research support at the department from Novartis and a number of other pharmaceutical manufacturers. The Research of the MS Centre in Basel has been supported by grants from Bayer, Biogen, Novartis, the Swiss MS Society, the Swiss National Research Foundation, the European Union, and Roche Research Foundations.
SOURCE: Kuhle J et al. ECTRIMS 2018. Mult Scler. 2018;24(Suppl 2):111, Abstract 286.
BERLIN – Neurofilament light chain (Nf-L) levels are higher in the plasma of patients with secondary progressive multiple sclerosis (SPMS) than primary progressive multiple sclerosis (PPMS) irrespective of age, according to an analysis of blood samples from two large phase 3 trials.
“Our data suggest that Nf-L should be considered as an informative endpoint for phase 2 studies in SPMS,” said the presenting study author Ludwig Kappos, MD, at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.
Much of the research on using Nf-L as a biomarker in MS to date has looked at patients with relapsing-remitting MS and the researchers wanted to see if Nf-L might be a useful biomarker in progressive MS because drug development in this area needs long-term and large trials to show an effect of a drug on disability. Conventional magnetic resonance imaging measures show only a modest association with disease evolution in SPMS and PPMS, and, as Nf-L is specific to neuronal damage, it should reflect damage to the brain and spinal cord, Dr. Kappos explained.
The aim of the study was to compare Nf-L levels in the two progressive subtypes of MS – SPMS and PPMS – and to see if it had any predictive value in determining the degree of brain atrophy or disability. Other objectives were to measure the sensitivity for Nf-L to detect treatment effects, and to estimate how big a sample size would be needed in a phase 2 study if it was used as a primary endpoint.
Blood samples from 1,830 patients who had participated in one of two phase 3 studies of siponimod in SPMS (EXPAND) and fingolimod (Gilyena) in PPMS (INFORMS). Nf-L levels were measured retrospectively in plasma using the SIMOA Nf-L immunoassay and categorized as being low (less than 30 pg/mL), medium (30-60 pg/mL), or high (greater than 60 pg/mL). Brain volume change on MRI was calculated using the SIENA (Structural Image Evaluation, using Normalization, of Atrophy) method, and disability changes assessed were evaluated by the Expanded Disability Status Scale (EDSS) score
“One of the confounders of measuring Nf-L is age,” Dr. Kappos acknowledged, “but we see a difference between SPMS and PPMS that is robust along the spectrum of ages.” The geometric mean of Nf-L at baseline was 32.1 pg/mL in patients with SPMS (n = 1,452) and 22.0 pg/mL in those with PPMS (n = 378).
Multiple regression analysis showed that, in both SPMS and PPMS patients, higher Nf-L levels were associated with older age and higher disease activity (increased EDSS score, more gadolinium-enhancing (Gd+) lesions and higher T2 lesion load).
Greater brain loss was seen at both 12 and 24 months in patients with high versus low Nf-L levels at baseline in both the SPMS and PPMS groups. For example, comparing high versus low Nf-L in SPMS, the mean brain volume change from baseline was –0.8% vs. –0.2% (P less than .0001) at 12 months and –1.5% vs. –0.5% at 24 months (P less than .0001). Corresponding values for PPMS were –0.8% vs. –0.4% (P = .0044) and –1.9% vs. –0.8% (P less than .0001).
Nf-L levels of 30 pg/mL were associated with a 32% increased risk of disability progression in patients with SPMS (P = .0055) and a 49% increased risk of disability progression in patients with PPMS (P = .0268).
In both groups of progressive MS patients, Nf-L levels were reduced in response to treatment at both 12 and 24 months, which remained significant.
“So, what about sample size calculation for a 1-year, phase 2 study with Nf-L as a primary endpoint?” Dr. Kappos queried. Assuming a reduction in Nf-L of 20% with a test drug, such a study would be likely to need to include 188 patients, or 94 patients per single arm to have 80% statistical power. To see a 30% reduction in Nf-L, fewer total and single-arm numbers would be needed, at 74 and 37 participants, respectively.
The study was funded by Novartis Pharma AG, Basel, Switzerland. Dr. Kappos disclosed that his institution (University Hospital Basel) had received steering committee, advisory board, and consultancy fees in the last 3 years that had been used exclusively for research support at the department from Novartis and a number of other pharmaceutical manufacturers. The Research of the MS Centre in Basel has been supported by grants from Bayer, Biogen, Novartis, the Swiss MS Society, the Swiss National Research Foundation, the European Union, and Roche Research Foundations.
SOURCE: Kuhle J et al. ECTRIMS 2018. Mult Scler. 2018;24(Suppl 2):111, Abstract 286.
REPORTING FROM ECTRIMS 2018
Key clinical point: Neurofilament light chain level was predictive of changes in brain atrophy, disability and sensitive to treatment effect in secondary progressive multiple sclerosis.
Major finding: Comparing high versus low baseline Nf-L in SPMS, the mean brain volume change from baseline was –0.8% vs. –0.2% (P less than .0001) at 12 months. Elevated Nf-L was associated with a 32% increase risk of disability progression.
Study details: Include study type and number of subjects.
Disclosures: The study was funded by Novartis Pharma AG, Basel, Switzerland. Dr. Kappos disclosed that his institution (University Hospital Basel) had received steering committee, advisory board, and consultancy fees in the last 3 years that had been used exclusively for research support at the department from Novartis and many other pharmaceutical manufacturers.
Source: Kuhle J et al. ECTRIMS 2018. Mult Scler. 2018;24(Suppl 2):111, Abstract 286.
FDA approves test to determine blood compatibility
The U.S. Food and Drug Administration (FDA) has approved ID CORE XT, a molecular-based assay used to determine blood donor and recipient compatibility.
ID CORE XT is a qualitative, polymerase chain reaction-based and hybridization-based genotyping test.
It is used for the simultaneous identification of multiple alleles encoding human erythrocyte antigens in genomic DNA extracted from whole blood specimens collected in ethylenediaminetetraacetic acid.
The test genotypes 29 polymorphisms determining 37 human erythrocyte antigen phenotypes of 10 blood group systems—Rh, Kell, Kidd, Duffy, MNS, Diego, Dombrock, Colton, Cartwright, and Lutheran.
ID CORE XT is the second molecular assay approved by the FDA for use in transfusion medicine and the first to report genotypes as final results.
The approval of ID CORE XT was granted to Progenika Biopharma S.A., a Grifols company.
According to Progenika, ID CORE XT will benefit patients who require ongoing transfusions, such as individuals with hemoglobinopathies.
ID CORE XT can also be used for cancer patients who require more thorough blood typing, patients with warm autoimmune hemolytic anemia, and patients taking daratumumab.
“The approval of the ID CORE XT test can streamline blood compatibility testing and provides an additional alternative to testing blood with antisera,” said Peter Marks, MD, PhD, director of the FDA’s Center for Biologics Evaluation and Research.
In a study published in Blood Transfusion this year, typing results with ID CORE XT were similar to results obtained with serology and molecular methods.
Researchers said there was 100% agreement between the positive results predicted by ID CORE XT and results obtained via serology (100% sensitivity).
For negative results, there was one discrepancy for E antigen (99.9% agreement) and 33 discrepancies for Fyb antigen (95.5% agreement). However, additional testing suggested that serology produced 34 false-negatives.
Both positive and negative results with ID CORE XT were in full agreement with results obtained via molecular methods (100% sensitivity and specificity).
The U.S. Food and Drug Administration (FDA) has approved ID CORE XT, a molecular-based assay used to determine blood donor and recipient compatibility.
ID CORE XT is a qualitative, polymerase chain reaction-based and hybridization-based genotyping test.
It is used for the simultaneous identification of multiple alleles encoding human erythrocyte antigens in genomic DNA extracted from whole blood specimens collected in ethylenediaminetetraacetic acid.
The test genotypes 29 polymorphisms determining 37 human erythrocyte antigen phenotypes of 10 blood group systems—Rh, Kell, Kidd, Duffy, MNS, Diego, Dombrock, Colton, Cartwright, and Lutheran.
ID CORE XT is the second molecular assay approved by the FDA for use in transfusion medicine and the first to report genotypes as final results.
The approval of ID CORE XT was granted to Progenika Biopharma S.A., a Grifols company.
According to Progenika, ID CORE XT will benefit patients who require ongoing transfusions, such as individuals with hemoglobinopathies.
ID CORE XT can also be used for cancer patients who require more thorough blood typing, patients with warm autoimmune hemolytic anemia, and patients taking daratumumab.
“The approval of the ID CORE XT test can streamline blood compatibility testing and provides an additional alternative to testing blood with antisera,” said Peter Marks, MD, PhD, director of the FDA’s Center for Biologics Evaluation and Research.
In a study published in Blood Transfusion this year, typing results with ID CORE XT were similar to results obtained with serology and molecular methods.
Researchers said there was 100% agreement between the positive results predicted by ID CORE XT and results obtained via serology (100% sensitivity).
For negative results, there was one discrepancy for E antigen (99.9% agreement) and 33 discrepancies for Fyb antigen (95.5% agreement). However, additional testing suggested that serology produced 34 false-negatives.
Both positive and negative results with ID CORE XT were in full agreement with results obtained via molecular methods (100% sensitivity and specificity).
The U.S. Food and Drug Administration (FDA) has approved ID CORE XT, a molecular-based assay used to determine blood donor and recipient compatibility.
ID CORE XT is a qualitative, polymerase chain reaction-based and hybridization-based genotyping test.
It is used for the simultaneous identification of multiple alleles encoding human erythrocyte antigens in genomic DNA extracted from whole blood specimens collected in ethylenediaminetetraacetic acid.
The test genotypes 29 polymorphisms determining 37 human erythrocyte antigen phenotypes of 10 blood group systems—Rh, Kell, Kidd, Duffy, MNS, Diego, Dombrock, Colton, Cartwright, and Lutheran.
ID CORE XT is the second molecular assay approved by the FDA for use in transfusion medicine and the first to report genotypes as final results.
The approval of ID CORE XT was granted to Progenika Biopharma S.A., a Grifols company.
According to Progenika, ID CORE XT will benefit patients who require ongoing transfusions, such as individuals with hemoglobinopathies.
ID CORE XT can also be used for cancer patients who require more thorough blood typing, patients with warm autoimmune hemolytic anemia, and patients taking daratumumab.
“The approval of the ID CORE XT test can streamline blood compatibility testing and provides an additional alternative to testing blood with antisera,” said Peter Marks, MD, PhD, director of the FDA’s Center for Biologics Evaluation and Research.
In a study published in Blood Transfusion this year, typing results with ID CORE XT were similar to results obtained with serology and molecular methods.
Researchers said there was 100% agreement between the positive results predicted by ID CORE XT and results obtained via serology (100% sensitivity).
For negative results, there was one discrepancy for E antigen (99.9% agreement) and 33 discrepancies for Fyb antigen (95.5% agreement). However, additional testing suggested that serology produced 34 false-negatives.
Both positive and negative results with ID CORE XT were in full agreement with results obtained via molecular methods (100% sensitivity and specificity).
Use of Musculoskeletal Ultrasound and Regenerative Therapies in Soccer
ABSTRACT
Improvements in ultrasound technology have increased the popularity and use of ultrasound as a diagnostic and therapeutic modality for many soccer-related musculoskeletal (MSK) injuries. As a dynamic imaging modality, ultrasound offers increased accuracy and efficacy with minimally invasive procedures, such as guided injections, percutaneous tenotomy, and regenerative therapies, in the clinical setting. Emerging evidence indicates that regenerative therapies, such as platelet-rich-plasma (PRP), mesenchymal stem cells, and amniotic products, are a promising treatment for many MSK injuries and are gaining popularity among professional athletes. PRP is a safe treatment for a number of MSK conditions and has been included in the standard of care. However, conflicting evidence on return-to-play timeframes and efficacy in certain MSK conditions have led to inconsistent recommendations on indications for use, dose, and timing of treatment. Mesenchymal stem cell therapy, while promising, lacks high-level evidence of efficacy despite its increasing use among athletes. Currently, no data are available regarding the outcome of the use of amniotic products for the treatment of injuries in athletes. Furthermore, preparation of many regenerative therapies eclipses the concept of minimal manipulation and is subject to US Food and Drug Administration phase I to III trials. High-level research on regenerative medicine therapies should be continuously conducted to establish their clinical efficacy and safety data.
ULTRASOUND
Ultrasound (US) was first introduced for musculoskeletal (MSK) evaluation in 1957.1 Since then, US has gained increasing attention due to its ease of utilization in the clinical setting, repeatability, noninvasiveness, capability for contralateral comparison, lack of radiation exposure, and capability to provide real-time dynamic tissue assessment.1 Compared with magnetic resonance imaging or computed tomography, US presents limitations, including decreased resolution of certain tissues, limited field of view, limited penetration beyond osseous structures, incomplete evaluation of a joint or structure, and operator experience. However, advancements in technology, image resolution, and portability have improved the visualization of multiple anatomic structures and the accuracy of minimally invasive ultrasound-guided procedures at the point of care. The use of US for guided hip injections possibly decreases the cost relative to fluoroscopic guidance.2 Other studies have reported that US, as a result of its safety profile, has replaced fluoroscopy for certain procedures, such as barbotage of calcific tendinosis.3 US has been used for diagnostic purposes and guidance for therapeutic interventions, such as needle aspiration, diagnostic or therapeutic injection, needle tenotomy, tissue release, hydro-dissection, and biopsy.3 Given its expanding application, US has been increasingly used in the clinical setting, athletic training room, and sidelines of athletic events.
DIAGNOSTIC ULTRASOUND
An epidemiologic review of the National Collegiate Athletic Association (NCAA) men’s and women’s soccer injuries from 1988 to 2003 reported over 24,000 combined injuries. Over 70% of these injuries are MSK in nature and often affect the lower extremities.4,5 Ekstrand and colleagues6 also conducted an epidemiological review of muscle injuries among professional soccer players from 2001 to 2009. They found that 92% of all muscle injuries involved the lower extremities. The portability of US allows it to serve as an ideal modality for diagnostic evaluation of acute MSK injuries. Klauser and colleagues7 developed consensus based on the recommendations of the European Society of Musculoskeletal Radiology (ESSR) for the clinical indication of diagnostic ultrasound. A grading system was developed to describe the clinical utility of diagnostic US evaluation of MSK structures:
• Grade 0: Ultrasound is not indicated;
• Grade 1: Ultrasound is indicated if other imaging techniques are not appropriate;
• Grade 2: Ultrasound indication is equivalent to other imaging modalities;
• Grade 3: Ultrasound is the first-choice technique.
Henderson and colleagues8 conducted a review of 95 studies (12 systemic reviews and 83 diagnostic studies) that investigated the accuracy of diagnostic US imaging on soft tissue MSK injuries of the upper and lower extremities. They reported the sensitivity and specificity of the method for detection of over 40 hip, knee, ankle, and foot injuries and assigned corresponding grades based on diagnostic accuracy by using the same system developed by Klauser and colleagues.7,8 Common MSK injuries of the lower extremity and their corresponding ESSR grades are listed in the Table. This study demonstrated that diagnostic US is highly accurate for a number of soft tissue MSK injuries of the lower extremity and consistently matches the recommendation grades issued by Klauser and colleagues.7 In the hands of a skilled operator, US has become an increasingly popular and cost-effective modality for diagnosis and monitoring of acute muscle injuries and chronic tendinopathies among soccer athletes.
Table. Clinical Indication Grades for Diagnostic Ultrasound Evaluation of Common Lower Extremity Injuries7,8
Hip | Knee | Foot/Ankle |
Synovitis/Effusion: 3 | Quadricep tendinosis/tear: 3 | Anterior talofibular ligament injury: 3 |
Snapping hip (extra-articular): 3 | Patella tendinopathy: 3 | Calcaneofibular ligament injury: 3 |
Gluteal tendon tear: 3 | Pes anserine bursitis: 3 | Peroneal tendon tear/subluxation: 3 |
Meralgia paresthetica: 3 | Periarticular bursitis & ganglion: 3 | Posterior tibial tendinopathy: 3 |
Lateral femoral cutaneous nerve injury: 3 | Osgood-Schlatter & Sinding-Larsen: 3 | Plantaris tendon tear: 3 |
Femoral nerve injury: 3 | Synovitis/Effusion: 3 | Plantar fasciitis: 3 |
Sports hernia: 3 | Baker’s Cyst: 2-3 | Calcific tendonitis: 3 |
Morel-Lavallée lesions: 3 | MCL injury: 2 | Retrocalcaneal bursitis: 3 |
Muscle injury (high grade): 3 | IT band friction: 2 | Joint effusion: 3 |
Trochanteric bursitis: 2 | Medial patella plica syndrome: 2 | Ganglion cyst: 3 |
Proximal hamstring injury: 2 | Meniscal cyst: 2 | Retinacula pathology: 3 |
Sciatica: 1-2 | Common perineal neuropathy: 2 | Achilles tendinopathy: 2 |
Muscle injury (low grade): 1 | Distal hamstring tendon injury: 1-2 | Haglund disease: 2 |
Psoas tendon pathology: 1 | Intra-articular ganglion: 1 | Deltoid ligament injury: 2 |
Osteoarthritis: 0 | Hoffa’s fat pad syndrome: 1 | Plantar plate tear: 2 |
Labral tear: 0 | Loose bodies: 1 | Syndesmotic injury: 2 |
| LCL injury: 0-1 | Morton’s neuroma: 2 |
| Popliteal injury: 0-1 | Deltoid ligament injury: 1 |
| Plica syndrome: 0 | Spring ligament injury: 1 |
| Full/partial ACL tear: 0 | Anterolateral ankle impingement: 0 |
| PCL tear: 0 | Posterior talofibular ligament injury: 0 |
| Medial/lateral meniscus tear: 0 |
|
| Osteochondritis dissecans: 0 |
|
Abbreviations: ACL, anterior cruciate ligament; IT, iliotibial; LCL, lateral collateral ligament; MCL, medial collateral ligament; PCL, posterior cruciate ligament.
ULTRASOUND-GUIDED THERAPEUTIC PROCEDURES
The use of US at the point of care for needle guidance has led to its widespread application for therapeutic procedures, including injections and multiple regenerative therapies. Intra-articular US-guided injection and aspiration are common therapeutic interventions performed in the clinical setting. In a position statement of the American Medical Society for Sports Medicine, US-guided injections were found to be more accurate (SORT A evidence), effective (SORT B evidence), and cost effective (SORT B evidence) than landmark-guided injections.3 A recent meta-analysis conducted by Daniels and colleagues1 demonstrated the improved accuracy and efficacy of US-guided injections at the knee, ankle, and foot. Injections may serve a diagnostic purpose when anesthetics, such as lidocaine, are used in isolation, a therapeutic purpose, or both.
Continue to: Percutaneous tenotomy involve...
REGENERATIVE THERAPIES FOR MUSCULOSKELETAL CONDITIONS
PERCUTANEOUS TENOTOMY
Percutaneous tenotomy involves the introduction of a needle into damaged soft tissues, most often tendons (“needling”), in an effort to stimulate a healing response and resect the diseased tendon tissue. Although tenotomy was initially performed as an open or arthroscopic surgical technique, advances in US technology have led to improved sensitivity and specificity identifying areas of tendinous injury (hypervascularity, hypoechogenicity, and calcification); as such, the combination of these techniques has been used in the outpatient setting. New commercial models incorporate ultrasound guidance with needles or micro-resection probes for real-time débridement of damaged tissues. Percutaneous tenotomy has been described in the management of tendinopathy involving the rotator cuff, medial and lateral epicondyles, patellar and Achilles tendons, and plantar fascia.
Housner and colleagues9 evaluated the safety and short-term efficacy of US-guided needle tenotomy in 13 patients with chronic tendinosis of the patella, Achilles tendon, gluteus medius, iliotibial tract, hamstring, and rectus femoris. They reported no procedural complications and a significant decrease in pain scores at 4 and 12 weeks of follow-up.
Koh and colleagues10 conducted a prospective case series to evaluate the safety and efficacy of office-based, US-guided percutaneous tenotomy (using a commercial model) on 20 patients with chronic lateral epicondylitis. The authors reported no wound complications and significant improvement in pain scores at each follow-up period up to 1 year. Subsequent post-procedural US evaluation of injured tissues revealed evidence of healing (decreased tendon thickness, vascularity, and hypoechogenicity) in over half the cohort after 6 months compared with the baseline.11
Lee and colleagues12 evaluated the efficacy of US-guided needle tenotomy combined with platelet-rich plasma (PRP) injection on chronic recalcitrant gluteus medius tendinopathy. In this case series, 21 patients underwent PRP and “needling” through the hypoechoic regions of the injured tendon under direct US guidance. After a period of rest, all patients completed the structured rehabilitation protocol. After an average follow-up of 10 months, all patients displayed significant improvements in all outcome questionnaires and did not report any significant adverse events. The authors concluded that tenotomy combined with PRP is a safe and effective method for treatment for recalcitrant gluteus medius tendinopathy.
These studies indicate that US-guided percutaneous tenotomy, alone or in combination with regenerative therapies, such as PRP, is a safe and effective treatment option for various tendinopathies. However, while tenotomy appears safe with promising results and no reported major adverse events, the level of evidence remains low.
ORTHOBIOLOGICS
Orthobiologics are substances composed of biological materials that can be used to aid or even hasten the healing of bones, muscles, tendons, and ligaments. Orthobiologics may contain growth factors, which initiate or stimulate the body’s reparative process; matrix proteins, which serve as scaffolding for healing tissues; or stem cells, specifically adult stem cells, which are multipotent and can differentiate into several cell lines. Adult stem cells are categorized as hematopoietic, neural, epithelial, skin, and mesenchymal types. Mesenchymal stem cells (MSCs) are of particular interest in sports medicine applications because they secrete growth factors and cytokines with trophic, chemotactic, and immunosuppressive properties.13 MSCs are also multipotent and can differentiate into bones, muscles, cartilages, and tendons.14-17MSCs are readily isolated from many sources, including bone marrow, adipose tissues, synovial tissues, peripheral blood, skeletal muscles, umbilical cord blood, and placenta.13,14Several types of regenerative therapies used in orthopedic and sports medicine practice include PRP, stem cell therapy, and amniotic membrane/fluid preparations. While each therapy possesses the potential for promising results, the paucity of research and discrepancies among studies regarding the description of stem cell lines used limit the available evidence on the true clinical benefits of these regenerative therapies.
[HEAD 3] PLATELET-RICH PLASMA
PRP is an autologous product that has been used to stimulate biological factors and promote healing since the 1970s. Through the activation of platelets, PRP improves localized recruitment, proliferation, and differentiation of cells involved in tissue repair. Platelets, which are non-nucleated bodies located in peripheral blood, contain and release 3 groups of bioactive factors that enhance the healing process. Growth factors and cytokines released from alpha-granules play a role in cell proliferation, chemotaxis, cell differentiation, and angiogenesis. Bioactive factors, such as serotonin and histamine, released from dense granules, increase capillary permeability and improve cell recruitment and migration. Adhesion molecules also assist in cell migration and creation of an extracellular matrix, which acts as a scaffold for wound healing.18 Platelets are activated by mechanical trauma or contact with multiple activators, including Von Willebrand factor, collagen, thrombin, or calcium chloride. When activated, platelets release growth factors and cytokines, which create a pro-inflammatory environment that mediates the tissue repair process. After the procedure, the pro-inflammatory environment may result in patient discomfort, which can be managed with ice and acetaminophen. Use of nonsteroidal anti-inflammatory drugs may theoretically inhibit the inflammatory cascade induced by PRP, and they are avoided before and after the procedure, although evidence regarding necessary time frames is lacking.
Continue to: PRP consists of...
PRP consists of the fractionated liquid component of autologous whole blood, which contains increased concentrations of platelets and cytokines. Different methods and commercial preparations are available for collecting and preparing PRP. Variations in the amount of blood drawn, use of anticoagulants, presence or absence of an activating agent, number of centrifuge spins, and overall platelet and white blood cell concentrations lead to difficulty in evaluating and interpreting the available evidence regarding PRP therapy.
In vitro and animal studies demonstrated promising and safe results regarding the healing effect of PRP on injured soft tissues, such as tendons, ligaments, and muscles. In this regard, a number of studies have evaluated the effect of PRP on human MSK injuries. However, in addition to the above-mentioned variabilities in PRP, many of such studies lack standardization and randomization techniques and include a small number of patients only, thereby limiting the overall comparison and clinical application.
A landmark study conducted by Mishra and Pavelko19 concluded that PRP significantly reduced pain in patients with chronic elbow tendinosis. Similar findings were reported in high-level overhead athletes with ulnar collateral ligament insufficiency, which did not improve with conservative management.20 Fitzpatrick and colleagues21 found improvements in pain with the use of single PRP injection as treatment for chronic gluteal tendinopathy. PRP can effectively improve pain and recovery in chronic ligament and tendon injuries, such as lateral epicondylitis, patellar tendinopathy, and plantar fasciitis, when patients are unresponsive to traditional conservative management. The application of PRP to treat acute MSK injuries has produced mixed results. Hamid and colleagues22 conducted a level II randomized controlled trial to evaluate the effect of PRP combined with a rehabilitation program for treatment of grade 2 hamstring injuries on return-to-play compared with rehabilitation alone. Fourteen athletes were randomized into the study and control groups. Hamid and colleagues22 reported improved return-to-play in the study group compared with that in the control (26.7 and 42.5 days, respectively). This study also reported lower pain scores in the PRP group over time, but the difference was not statistically significant. Zanon and colleagues23 conducted a prospective study to evaluate return-to-play in professional soccer players with acute hamstring strains treated with PRP and a rehabilitation program. This study determined that athletes treated with PRP were “match fit,” meaning they would be available for match selection in an average of 36.8 days. However, Zanon and colleagues23 did not include a control group for comparison. Other studies reported that PRP treatment of acutely injured muscles and medial collateral ligaments of soccer and basketball players decreased their return-to-play interval.18 Reviews by Hamilton and colleagues24 and Pas and colleagues25 concluded that PRP treatment of acutely injured tissues with good blood supply (eg, hamstring muscles) did not improve pain or return-to-play compared with standardized rehabilitation protocols. Similarly, in a double-blinded placebo controlled trial, Reurink and colleagues26 evaluated return-to-play in 80 athletes with acute hamstring injuries treated with a rehabilitation program and either PRP or placebo. Reurink and colleagues26 found no difference in return-to-play (42 days for both groups), but the difference was not statistically significant. PRP has also been used intraoperatively and shows promising results in total knee arthroplasty, anterior cruciate ligament reconstruction, acute Achilles tendon repair, rotator cuff repair, and cartilage repair. However, many of these intraoperative studies are limited to animal models.
In 2009, the World Anti-Doping Agency (WADA) prohibited the use of PRP because it contains autologous growth factors and IGF-1, which could produce an anabolic effect. Recent studies have failed to demonstrate any athletic advantages of using PRP. WADA has since removed PRP from its prohibited list. PRP is also not prohibited by the US Anti-Doping Agency (USADA) and many major professional sporting leagues in the United States. However, care must be taken in reviewing the components of PRP because many commercially available products differ in PRP formulation. Since 2010, many team physicians have increasingly used PRP to treat a wide range of athletic injuries. A recent anonymous survey conducted by a team of physicians on PRP use in elite athletes revealed minimal complications but significant variability among physicians with regard to timing, belief in evidence, and formulation and dosing of PRP treatments. Many physicians did implicate athlete desire as the main indication for treatment.27
As an autologous treatment, PRP injection has no serious adverse effects beyond mild discomfort as a result of the procedure and pro-inflammatory state in the days following injection. Recent concerns regarding the potential of PRP treatment for heterotopic ossification have been reported, but published information is limited to case reports. PRP can improve pain and function in patients with chronic MSK injury. PRP appears to be a safe and effective alternative to surgery for patients with injury to poorly perfused tissue, which has not improved with conservative measures, such as rest, physical therapy, and anti-inflammatory medications. Care should be taken when treating athletes with PRP to establish regulations on doping by individual governing bodies.
Continue to: Use of stem...
STEM CELL THERAPY
Use of stem cell therapy is based on the properties of the proliferation and differentiation of multipoint MSC lines. These stem cells can theoretically regenerate injured tissues and influence repair through immunomodulation; paracrine activity through the release of bioactive agents, such as cytokines, trophic, and chemotactic molecules; and cell differentiation into various cell lineages.15,16,13,17 Orthopedic surgeons have used microfracture to recruit MSCs during cartilage repair procedures for over 20 years. This procedure draws multipotent MSCs to the injured site to induce chondrogenic proliferation and fibrocartilage repair.28
Adult MSCs provide a readily accessible autologous source of stem cells for regenerative therapies. MSCs can be isolated from a variety of tissues, including bone marrow, adipose tissues, synovia, human umbilical cord blood, and peripheral blood. The majority of stem cell therapies in the United States for sports medicine purposes are conducted using bone marrow aspirate concentrate (BMAC) and adipose tissues. The US Food and Drug Administration (FDA) allows the use of minimally manipulated autologous stem cells to be injected into the same patient on the same day. However, some studies reported that culturing stem cells or introducing products, such as collagenase to stem cells, can increase the stem cell concentration prior to injection. These processes constitute more than “minimal manipulation” and therefore would require drug trials prior to use in the United States.
Although MSCs can be readily obtained from a variety of tissue sources, the makeup of the cell concentrate differs. Bone marrow and adipose tissues are readily available sources of homogenous MSCs. Harvesting stem cells from adipose tissues provides a less invasive route of collection than from BMAC. Harvested BMAC and adipose tissues consist of heterogeneous cell populations that are composed of precursor and accessory cells, such as pericytes, endothelial cells, smooth muscle cells, fibroblasts, and macrophages in addition to MSCs.
Animal studies reported promising results when evaluating soft tissue lesions in small and large animal models.14,15 Although clinical and human evidence remains limited, the potential of MSCs for regenerative repair has led to a recent increase in the number of related clinical studies. Multiple systematic reviews have concluded that MSC therapy is safe for the treatment of osteoarthritis, cartilage lesions, and tendinopathies. Limited evidence is available regarding the safety of intramuscular use, and a theoretical concern arises on the development of heterotopic bone formation as a result of treatment.13,16 The efficacy of MSC therapy is difficult to determine due to the lack of standardization in stem cell populations, adjuvants (eg, PRP, hyaluronic acid, and scaffolding preparations), and delivery methods used.13,17
Similar to PRP, the increased use of MSC therapy among high-profile athletes has led to the promotion of these therapies as safe and effective despite limited evidence.29 Although MSC therapy is a promising and safe treatment option for patients with soft tissue injuries, the paucity in data and human studies limit its clinical use. Moreover, data of MSC efficacy is complicated because of the disparity between clinical studies regarding MSC collection method (many of which eclipse the “minimal manipulation” standard), description of isolated cell concentrates, dosage, method of delivery, use of adjuvants, and lack of randomization. Further studies using [standardized] methods are needed before establishing a true consensus on the safety and efficacy of MSC therapy.
AMNIOTIC MEMBRANE
The placenta is a source of MSCs, a collagen-rich extracellular matrix, and bioactive growth and regulatory factors. The capacity of the placenta to modulate biological activities and tissue formation is thought to provide a means of tissue repair and healing. The placenta consists of amniotic fluid, amniotic membrane (AM), chorionic membrane, and umbilical cord blood and tissues. Although MSCs have been isolated from each component of placental tissues, amniotic and chorionic membranes and umbilical cord tissues yield the highest concentration.
The majority of regenerative studies involving the placenta used AM alone or in combination with other placental tissues. AM is a metabolically active tissue that consists of an epithelial layer, a basement membrane, and a mesenchymal tissue layer. In addition to being a source of stem cells, AM synthesizes many growth factors, vasoactive peptides, and cytokines, which are capable of tissue regeneration. AM was initially used as a biological scaffold for the treatment of skin burns and wounds. Other intrinsic properties of AM include the provision of a matrix for cellular migration and proliferation, enhanced wound healing with reduced scar formation, antibacterial activity, and lastly, non-immunogenic and immunosuppressive properties. These inherent characteristics have spurred studies on the potential use of AM in sports medicine as a minimally invasive means to treat osteoarthritis and injuries of tendons, ligaments, muscles, fascia, and cartilages.
Continue to: Animal studies reported...
Animal studies reported positive results with the use of AM to treat osteoarthritis, cartilage defects, and tendon and ligament injuries. Few studies involving human participants also revealed favorable results with regard to the use of AM for the treatment of plantar fasciitis and osteoarthritis; however, these studies are industry-sponsored and employed small sample sizes. The unique mixture of a collagen-rich extracellular matrix, bioactive growth factors, and pluripotent stem cells may allow AM to become an effective treatment for MSK injuries. Although initial animal and human studies show promising results, variabilities regarding models (animal and human), pathologies, placental tissues, and methods of preparation, preservation, and delivery used limit the ability for comparison, analysis, and drawing of definitive conclusions. Thus far, no studies have evaluated the use of currently available AM products for the treatment of injuries sustained by soccer players.
Despite the current popularity of AM as regenerative therapy in academic research and potential use in clinical treatment in sports medicine, physicians should remain aware of the limited evidence available. Other barriers to research and use AM as a regenerative therapy include regulatory classifications based on the concept of “minimal manipulation” in biologic therapies. Minimally manipulated placental allografts are less regulated, less costly to study, and more easily commercialized. These products are not required to undergo FDA phase I to III trials prior to premarket approval. In 2000, the FDA position on all AM products falls into 2 categories. The first position states that AM that contains allogenic stem cells mixed with another drug that is micronized and/or cryopreserved is more than “minimally manipulated” and therefore categorized as “biologic” and would be subject to phase I to III trials. Dehydrated and decellularized AM, however, may meet the concept of minimal manipulation and is only approved by the FDA as a wound covering. Thus, any application of AM for the treatment of sports medicine pathology is not currently FDA-approved, considered off-label, not covered by insurance, and subject to out-of-pocket pay.30,31
CONCLUSION
With improvements in technology and portability, US has become an effective imaging modality for point-of-care evaluation, diagnosis, and continuous monitoring of many MSK injuries. Additionally, as a dynamic imaging modality, US allows for increased accuracy and efficacy when combined with minimally invasive procedures, such as diagnostic and therapeutic guided injections and percutaneous tenotomy, in the clinical setting; thereby decreasing the overall healthcare costs. PRP is proven to be a safe treatment for several MSK conditions, such as lateral epicondylitis, patellar tendonitis, and plantar fasciitis. Although PRP has been included in the standard of care in some areas, this technique may be predominantly athlete driven. Conflicting evidence with regard to return-to-play timeframes following PRP treatment for muscular injuries and poor evidence in conditions, such as Achilles tendonitis, have led to inconsistent indications for use, dose, and timing of treatment. Although early evidence of MSC therapy is promising, high-level evidence for MSC therapy is insufficient, despite its increased use among athletes. Thus far, no data are available regarding the outcomes of the use of amniotic products for the treatment of injuries among athletes. Furthermore, the preparation of amniotic products has many regulatory concerns. The authors advocate for continuous high-level research on regenerative medicine therapies to establish clinical efficacy and safety data.
1. Daniels E, Cole D, Jacobs B, Phillips S. Existing Evidence on ultrasound-guided injections in sports medicine. Orthop J Sports Med. 2018;6(2):2325967118756576. doi:10.1177/2325967118756576.
2. Henne M, Centurion A, Rosas S, Youmans H, Osbahr D. Trends in utilization of image-guided hip joint injections. Unpublished. 2018.
3. Finnoff JT, Hall MM, Adams E, et al. American Medical Society for Sports Medicine position statement: Interventional musculoskeletal ultrasound in sports medicine. Clin J Sport Med. 2015;25:6-22. doi:10.1097/JSM.0000000000000175.
4. Agel J, Evans TA, Dick R, Putukian M, Marshal S. Descriptive epidemiology of collegiate men’s soccer injuries: National Collegiate Athletic Association Injury Surveillance System, 1988-1989 through 2002-2003. J Athl Train. 2007;42(2):270-277.
5. Dick R, Putukian M, Agel J, Evans T, Marshall S. Descriptive epidemiology of collegiate women’s soccer injuries: National Collegiate Athletic Association Injury Surveillance System, 1988-1989 through 2002-2003. J Athl Train. 2007;42(2):278-285.
6. Ekstrand J, Hagglund M, Walden M. Epidemiology of muscle injuries in professional football (soccer). Am J Sports Med. 2011;39(6):1226-1232. doi:10.1177/0363546510395879.
7. Klauser A, Tagliafico A, Allen G, et al. Clinical indications for musculoskeletal ultrasound: A Delphi-based consensus paper of the European society of musculoskeletal radiology. Eur Radiol. 2012;22(5):1140-1148. doi:10.1007/s00330-011-2356-3.
8. Henderson R, Walker B, Young K. The accuracy of diagnostic ultrasound imaging for musculoskeletal soft tissue pathology of the extremities: a comprehensive review of the literature. Chiropr Man Therap. 2015;23(1):31. doi:10.1186/s12998-015-0076-5.
9. Housner JA, Jacobson JA, Misko R. Sonographically guided percutaneous needle tenotomy for the treatment of chronic tendinosis. J Ultrasound Med. 2009;28(9):1187-1192. doi:10.7863/jum.2009.28.9.1187.
10. Koh J, Mohan PC, Howe TS, et al. Fasciotomy and surgical tenotomy for recalcitrant lateral elbow tendinopathy: early clinical experience with a novel device for minimally invasive percutaneous microresection. Am J Sports Med. 2013;41(3):636-644. doi:10.1177/0363546512470625.
11. Seng C, Mohan PC, Koh J, et al. Ultrasonic percutaneous tenotomy for recalcitrant lateral elbow tendinopathy: sustainability and sonographic progression at 3 years. Am J Sports Med. 2015;44(2):504-510. doi:10.1177/0363546515612758.
12. Lee J, Harrison J, Boachie-Adjei K, Vargas E, Moley P. Platelet-rich plasma injections with needle tenotomy for gluteus medius tendinopathy: A registry study with prospective follow-up. Orthop J Sports Med. 2016;4(11):2325967116671692. doi:10.1177/2325967116671692.
13. Osborne H, Anderson L, Burt P, Young M, Gerrard D. Australasian College of Sports Physicians-Position statement: the place of mesenchymal stem/stromal cell therapies in sport and exercise medicine. Br J Sports Med. 2016;50:1237-1244. doi:10.1136/bjsports-2015-095711.
14. Anderson J, Little D, Toth A, et al. Stem cell therapies for knee cartilage repair. The current status of preclinical and clinical studies. Am J Sports Med. 2013;42(9)2253-2261. doi:10.1177/0363546513508744.
15. Lee S, Kwon B, Lee Kyoungbun, Son Y, Chung S. Therapeutic mechanisms of human adipose-derived mesenchymal stem cells in a rat tendon injury model. Am J Sports Med. 2017;45(6):1429-1439. doi:10.1177/0363546517689874.
16. McIntyre J, Jones I, Han B, Vangsness C. Intra-articular mesenchymal stem cell therapy for the human joint. A systematic review. Am J Sports Med. 2017;0363546517735844. doi:10.1177/0363546517735844.
17. Pas HIMFL, Moen M, Haisma J, Winters M. No evidence for the use of stem cell therapy for tendon disorders: a systematic review. Br J Sports Med. 2017;51:996-1002. doi:10.1136/bjsports-2016-096794.
18. Foster T, Puskas B, Mandelbaum B, Gerhardt M, Rodeo S. Platelet-rich plasma: from basic science to clinical applications. Am J Sports Med. 2009;37(11):2259-2272. doi:10.1177/0363546509349921.
19. Mishra A, Pavelko T. Treatment of chronic elbow tendinosis with buffered platelet-rich plasma. Am J Sports Med. 2006;34(11):1774-1778. doi:10.1177/0363546506288850.
20. Dines J, Williams P, ElAttrache N, et al. Platelet-rich plasma can be used to successfully treat elbow ulnar collateral ligament insufficiency in high-level throwers. Am J Orthop. 2016;45(4):296-300.
21. Fitzpatrick J, Bulsara M, O’Donnel J, McCrory P, Zheng M. The effectiveness of platelet-rich plasma injections in gluteal tendinopathy. A randomized, double-blind controlled trial comparing a single platelet-rich plasma injection with a single corticosteroid injection. Am J Sports Med. 2018;46(4)933-939. doi:10.1177/0363546517745525.
22. Hamid M, Ali M, Yusof A, George J, Lee L. Platelet-rich plasma injections for the treatment of hamstring injuries: A randomized controlled trial. Am J Sports Med. 2014;42(10):2410-2418. doi:10.1177/0363546514541540.
23. Zanon G, Combi F, Combi A, Perticarini L, Sammarchi L, Benazzo F. Platelet-rich plasma in the treatment of acute hamstring injuries in professional football players. Joints. 2016;4(1):17-23. doi:10.11138/jts/2016.4.1.017.
24. Hamilton B, Tol JL, Almusa E, et al. Platelet-rich plasma does not enhance return to play in hamstring injuries: a randomized controlled trial. Br J Sports Med. 2015;49:943-950. doi:10.1136/bjsports-2015-094603.
25. Pas HIMFL, Reurink G, Tol JL, Wier A, Winters M, Moen M. Efficacy of rehabilitation (lengthening) exercises, platelet-rich plasma injections, and other conservative interventions in acute hamstring injuries: an updated systematic review and meta-analysis. Br J Sports Med. 2015;49:1197-1205. doi:10.1136/bjsports-2015-094879.
26. Reurink G, Goudswaard G, Moen M, et al. Platelet-rich plasma injections in acute muscle injury. N Engl J Med. 2014;370:2546-2547. doi:10.1056/NEJMc1402340.
27. Kantrowitz D, Padaki A, Ahmad C, Lynch T. Defining platelet-rich plasma usage by team physicians in elite athletes. Orthop J Sports Med. 2018;6(4):2325967118767077. doi:10.1177/2325967118767077.
28. Mithoefer K, Peterson L, Zenobi-Wong M, Mandelbaum B. Cartilage issues in football-today’s problems and tomorrow’s solutions. Br J Sports Med. 2015;49(9):590-596. doi:1136/bjsports-2015-094772.
29. Matthews K, Cuchiara M. Regional regulatory insights: U.S. National Football League Athletes seeking unproven stem cell treatments. Stem Cells Dev. 2014;23(S1):60-64. doi:10.1089/scd.2014.0358.
30. McIntyre J, Jones I, Danilkovich A, Vangsness T. The placenta: applications in orthopaedic sports medicine. Am J Sports Med. 2018;46(1):234-247. doi:10.1177/0363546517697682.
31. Riboh J, Saltzman B, Yankee A, Cole BJ. Human amniotic membrane-derived products in sports medicine: Basic science, early results, and potential clinical applications. Am J Sports Med. 2015;44(9)2425-2434. doi:10.1177/0363546515612750.
ABSTRACT
Improvements in ultrasound technology have increased the popularity and use of ultrasound as a diagnostic and therapeutic modality for many soccer-related musculoskeletal (MSK) injuries. As a dynamic imaging modality, ultrasound offers increased accuracy and efficacy with minimally invasive procedures, such as guided injections, percutaneous tenotomy, and regenerative therapies, in the clinical setting. Emerging evidence indicates that regenerative therapies, such as platelet-rich-plasma (PRP), mesenchymal stem cells, and amniotic products, are a promising treatment for many MSK injuries and are gaining popularity among professional athletes. PRP is a safe treatment for a number of MSK conditions and has been included in the standard of care. However, conflicting evidence on return-to-play timeframes and efficacy in certain MSK conditions have led to inconsistent recommendations on indications for use, dose, and timing of treatment. Mesenchymal stem cell therapy, while promising, lacks high-level evidence of efficacy despite its increasing use among athletes. Currently, no data are available regarding the outcome of the use of amniotic products for the treatment of injuries in athletes. Furthermore, preparation of many regenerative therapies eclipses the concept of minimal manipulation and is subject to US Food and Drug Administration phase I to III trials. High-level research on regenerative medicine therapies should be continuously conducted to establish their clinical efficacy and safety data.
ULTRASOUND
Ultrasound (US) was first introduced for musculoskeletal (MSK) evaluation in 1957.1 Since then, US has gained increasing attention due to its ease of utilization in the clinical setting, repeatability, noninvasiveness, capability for contralateral comparison, lack of radiation exposure, and capability to provide real-time dynamic tissue assessment.1 Compared with magnetic resonance imaging or computed tomography, US presents limitations, including decreased resolution of certain tissues, limited field of view, limited penetration beyond osseous structures, incomplete evaluation of a joint or structure, and operator experience. However, advancements in technology, image resolution, and portability have improved the visualization of multiple anatomic structures and the accuracy of minimally invasive ultrasound-guided procedures at the point of care. The use of US for guided hip injections possibly decreases the cost relative to fluoroscopic guidance.2 Other studies have reported that US, as a result of its safety profile, has replaced fluoroscopy for certain procedures, such as barbotage of calcific tendinosis.3 US has been used for diagnostic purposes and guidance for therapeutic interventions, such as needle aspiration, diagnostic or therapeutic injection, needle tenotomy, tissue release, hydro-dissection, and biopsy.3 Given its expanding application, US has been increasingly used in the clinical setting, athletic training room, and sidelines of athletic events.
DIAGNOSTIC ULTRASOUND
An epidemiologic review of the National Collegiate Athletic Association (NCAA) men’s and women’s soccer injuries from 1988 to 2003 reported over 24,000 combined injuries. Over 70% of these injuries are MSK in nature and often affect the lower extremities.4,5 Ekstrand and colleagues6 also conducted an epidemiological review of muscle injuries among professional soccer players from 2001 to 2009. They found that 92% of all muscle injuries involved the lower extremities. The portability of US allows it to serve as an ideal modality for diagnostic evaluation of acute MSK injuries. Klauser and colleagues7 developed consensus based on the recommendations of the European Society of Musculoskeletal Radiology (ESSR) for the clinical indication of diagnostic ultrasound. A grading system was developed to describe the clinical utility of diagnostic US evaluation of MSK structures:
• Grade 0: Ultrasound is not indicated;
• Grade 1: Ultrasound is indicated if other imaging techniques are not appropriate;
• Grade 2: Ultrasound indication is equivalent to other imaging modalities;
• Grade 3: Ultrasound is the first-choice technique.
Henderson and colleagues8 conducted a review of 95 studies (12 systemic reviews and 83 diagnostic studies) that investigated the accuracy of diagnostic US imaging on soft tissue MSK injuries of the upper and lower extremities. They reported the sensitivity and specificity of the method for detection of over 40 hip, knee, ankle, and foot injuries and assigned corresponding grades based on diagnostic accuracy by using the same system developed by Klauser and colleagues.7,8 Common MSK injuries of the lower extremity and their corresponding ESSR grades are listed in the Table. This study demonstrated that diagnostic US is highly accurate for a number of soft tissue MSK injuries of the lower extremity and consistently matches the recommendation grades issued by Klauser and colleagues.7 In the hands of a skilled operator, US has become an increasingly popular and cost-effective modality for diagnosis and monitoring of acute muscle injuries and chronic tendinopathies among soccer athletes.
Table. Clinical Indication Grades for Diagnostic Ultrasound Evaluation of Common Lower Extremity Injuries7,8
Hip | Knee | Foot/Ankle |
Synovitis/Effusion: 3 | Quadricep tendinosis/tear: 3 | Anterior talofibular ligament injury: 3 |
Snapping hip (extra-articular): 3 | Patella tendinopathy: 3 | Calcaneofibular ligament injury: 3 |
Gluteal tendon tear: 3 | Pes anserine bursitis: 3 | Peroneal tendon tear/subluxation: 3 |
Meralgia paresthetica: 3 | Periarticular bursitis & ganglion: 3 | Posterior tibial tendinopathy: 3 |
Lateral femoral cutaneous nerve injury: 3 | Osgood-Schlatter & Sinding-Larsen: 3 | Plantaris tendon tear: 3 |
Femoral nerve injury: 3 | Synovitis/Effusion: 3 | Plantar fasciitis: 3 |
Sports hernia: 3 | Baker’s Cyst: 2-3 | Calcific tendonitis: 3 |
Morel-Lavallée lesions: 3 | MCL injury: 2 | Retrocalcaneal bursitis: 3 |
Muscle injury (high grade): 3 | IT band friction: 2 | Joint effusion: 3 |
Trochanteric bursitis: 2 | Medial patella plica syndrome: 2 | Ganglion cyst: 3 |
Proximal hamstring injury: 2 | Meniscal cyst: 2 | Retinacula pathology: 3 |
Sciatica: 1-2 | Common perineal neuropathy: 2 | Achilles tendinopathy: 2 |
Muscle injury (low grade): 1 | Distal hamstring tendon injury: 1-2 | Haglund disease: 2 |
Psoas tendon pathology: 1 | Intra-articular ganglion: 1 | Deltoid ligament injury: 2 |
Osteoarthritis: 0 | Hoffa’s fat pad syndrome: 1 | Plantar plate tear: 2 |
Labral tear: 0 | Loose bodies: 1 | Syndesmotic injury: 2 |
| LCL injury: 0-1 | Morton’s neuroma: 2 |
| Popliteal injury: 0-1 | Deltoid ligament injury: 1 |
| Plica syndrome: 0 | Spring ligament injury: 1 |
| Full/partial ACL tear: 0 | Anterolateral ankle impingement: 0 |
| PCL tear: 0 | Posterior talofibular ligament injury: 0 |
| Medial/lateral meniscus tear: 0 |
|
| Osteochondritis dissecans: 0 |
|
Abbreviations: ACL, anterior cruciate ligament; IT, iliotibial; LCL, lateral collateral ligament; MCL, medial collateral ligament; PCL, posterior cruciate ligament.
ULTRASOUND-GUIDED THERAPEUTIC PROCEDURES
The use of US at the point of care for needle guidance has led to its widespread application for therapeutic procedures, including injections and multiple regenerative therapies. Intra-articular US-guided injection and aspiration are common therapeutic interventions performed in the clinical setting. In a position statement of the American Medical Society for Sports Medicine, US-guided injections were found to be more accurate (SORT A evidence), effective (SORT B evidence), and cost effective (SORT B evidence) than landmark-guided injections.3 A recent meta-analysis conducted by Daniels and colleagues1 demonstrated the improved accuracy and efficacy of US-guided injections at the knee, ankle, and foot. Injections may serve a diagnostic purpose when anesthetics, such as lidocaine, are used in isolation, a therapeutic purpose, or both.
Continue to: Percutaneous tenotomy involve...
REGENERATIVE THERAPIES FOR MUSCULOSKELETAL CONDITIONS
PERCUTANEOUS TENOTOMY
Percutaneous tenotomy involves the introduction of a needle into damaged soft tissues, most often tendons (“needling”), in an effort to stimulate a healing response and resect the diseased tendon tissue. Although tenotomy was initially performed as an open or arthroscopic surgical technique, advances in US technology have led to improved sensitivity and specificity identifying areas of tendinous injury (hypervascularity, hypoechogenicity, and calcification); as such, the combination of these techniques has been used in the outpatient setting. New commercial models incorporate ultrasound guidance with needles or micro-resection probes for real-time débridement of damaged tissues. Percutaneous tenotomy has been described in the management of tendinopathy involving the rotator cuff, medial and lateral epicondyles, patellar and Achilles tendons, and plantar fascia.
Housner and colleagues9 evaluated the safety and short-term efficacy of US-guided needle tenotomy in 13 patients with chronic tendinosis of the patella, Achilles tendon, gluteus medius, iliotibial tract, hamstring, and rectus femoris. They reported no procedural complications and a significant decrease in pain scores at 4 and 12 weeks of follow-up.
Koh and colleagues10 conducted a prospective case series to evaluate the safety and efficacy of office-based, US-guided percutaneous tenotomy (using a commercial model) on 20 patients with chronic lateral epicondylitis. The authors reported no wound complications and significant improvement in pain scores at each follow-up period up to 1 year. Subsequent post-procedural US evaluation of injured tissues revealed evidence of healing (decreased tendon thickness, vascularity, and hypoechogenicity) in over half the cohort after 6 months compared with the baseline.11
Lee and colleagues12 evaluated the efficacy of US-guided needle tenotomy combined with platelet-rich plasma (PRP) injection on chronic recalcitrant gluteus medius tendinopathy. In this case series, 21 patients underwent PRP and “needling” through the hypoechoic regions of the injured tendon under direct US guidance. After a period of rest, all patients completed the structured rehabilitation protocol. After an average follow-up of 10 months, all patients displayed significant improvements in all outcome questionnaires and did not report any significant adverse events. The authors concluded that tenotomy combined with PRP is a safe and effective method for treatment for recalcitrant gluteus medius tendinopathy.
These studies indicate that US-guided percutaneous tenotomy, alone or in combination with regenerative therapies, such as PRP, is a safe and effective treatment option for various tendinopathies. However, while tenotomy appears safe with promising results and no reported major adverse events, the level of evidence remains low.
ORTHOBIOLOGICS
Orthobiologics are substances composed of biological materials that can be used to aid or even hasten the healing of bones, muscles, tendons, and ligaments. Orthobiologics may contain growth factors, which initiate or stimulate the body’s reparative process; matrix proteins, which serve as scaffolding for healing tissues; or stem cells, specifically adult stem cells, which are multipotent and can differentiate into several cell lines. Adult stem cells are categorized as hematopoietic, neural, epithelial, skin, and mesenchymal types. Mesenchymal stem cells (MSCs) are of particular interest in sports medicine applications because they secrete growth factors and cytokines with trophic, chemotactic, and immunosuppressive properties.13 MSCs are also multipotent and can differentiate into bones, muscles, cartilages, and tendons.14-17MSCs are readily isolated from many sources, including bone marrow, adipose tissues, synovial tissues, peripheral blood, skeletal muscles, umbilical cord blood, and placenta.13,14Several types of regenerative therapies used in orthopedic and sports medicine practice include PRP, stem cell therapy, and amniotic membrane/fluid preparations. While each therapy possesses the potential for promising results, the paucity of research and discrepancies among studies regarding the description of stem cell lines used limit the available evidence on the true clinical benefits of these regenerative therapies.
[HEAD 3] PLATELET-RICH PLASMA
PRP is an autologous product that has been used to stimulate biological factors and promote healing since the 1970s. Through the activation of platelets, PRP improves localized recruitment, proliferation, and differentiation of cells involved in tissue repair. Platelets, which are non-nucleated bodies located in peripheral blood, contain and release 3 groups of bioactive factors that enhance the healing process. Growth factors and cytokines released from alpha-granules play a role in cell proliferation, chemotaxis, cell differentiation, and angiogenesis. Bioactive factors, such as serotonin and histamine, released from dense granules, increase capillary permeability and improve cell recruitment and migration. Adhesion molecules also assist in cell migration and creation of an extracellular matrix, which acts as a scaffold for wound healing.18 Platelets are activated by mechanical trauma or contact with multiple activators, including Von Willebrand factor, collagen, thrombin, or calcium chloride. When activated, platelets release growth factors and cytokines, which create a pro-inflammatory environment that mediates the tissue repair process. After the procedure, the pro-inflammatory environment may result in patient discomfort, which can be managed with ice and acetaminophen. Use of nonsteroidal anti-inflammatory drugs may theoretically inhibit the inflammatory cascade induced by PRP, and they are avoided before and after the procedure, although evidence regarding necessary time frames is lacking.
Continue to: PRP consists of...
PRP consists of the fractionated liquid component of autologous whole blood, which contains increased concentrations of platelets and cytokines. Different methods and commercial preparations are available for collecting and preparing PRP. Variations in the amount of blood drawn, use of anticoagulants, presence or absence of an activating agent, number of centrifuge spins, and overall platelet and white blood cell concentrations lead to difficulty in evaluating and interpreting the available evidence regarding PRP therapy.
In vitro and animal studies demonstrated promising and safe results regarding the healing effect of PRP on injured soft tissues, such as tendons, ligaments, and muscles. In this regard, a number of studies have evaluated the effect of PRP on human MSK injuries. However, in addition to the above-mentioned variabilities in PRP, many of such studies lack standardization and randomization techniques and include a small number of patients only, thereby limiting the overall comparison and clinical application.
A landmark study conducted by Mishra and Pavelko19 concluded that PRP significantly reduced pain in patients with chronic elbow tendinosis. Similar findings were reported in high-level overhead athletes with ulnar collateral ligament insufficiency, which did not improve with conservative management.20 Fitzpatrick and colleagues21 found improvements in pain with the use of single PRP injection as treatment for chronic gluteal tendinopathy. PRP can effectively improve pain and recovery in chronic ligament and tendon injuries, such as lateral epicondylitis, patellar tendinopathy, and plantar fasciitis, when patients are unresponsive to traditional conservative management. The application of PRP to treat acute MSK injuries has produced mixed results. Hamid and colleagues22 conducted a level II randomized controlled trial to evaluate the effect of PRP combined with a rehabilitation program for treatment of grade 2 hamstring injuries on return-to-play compared with rehabilitation alone. Fourteen athletes were randomized into the study and control groups. Hamid and colleagues22 reported improved return-to-play in the study group compared with that in the control (26.7 and 42.5 days, respectively). This study also reported lower pain scores in the PRP group over time, but the difference was not statistically significant. Zanon and colleagues23 conducted a prospective study to evaluate return-to-play in professional soccer players with acute hamstring strains treated with PRP and a rehabilitation program. This study determined that athletes treated with PRP were “match fit,” meaning they would be available for match selection in an average of 36.8 days. However, Zanon and colleagues23 did not include a control group for comparison. Other studies reported that PRP treatment of acutely injured muscles and medial collateral ligaments of soccer and basketball players decreased their return-to-play interval.18 Reviews by Hamilton and colleagues24 and Pas and colleagues25 concluded that PRP treatment of acutely injured tissues with good blood supply (eg, hamstring muscles) did not improve pain or return-to-play compared with standardized rehabilitation protocols. Similarly, in a double-blinded placebo controlled trial, Reurink and colleagues26 evaluated return-to-play in 80 athletes with acute hamstring injuries treated with a rehabilitation program and either PRP or placebo. Reurink and colleagues26 found no difference in return-to-play (42 days for both groups), but the difference was not statistically significant. PRP has also been used intraoperatively and shows promising results in total knee arthroplasty, anterior cruciate ligament reconstruction, acute Achilles tendon repair, rotator cuff repair, and cartilage repair. However, many of these intraoperative studies are limited to animal models.
In 2009, the World Anti-Doping Agency (WADA) prohibited the use of PRP because it contains autologous growth factors and IGF-1, which could produce an anabolic effect. Recent studies have failed to demonstrate any athletic advantages of using PRP. WADA has since removed PRP from its prohibited list. PRP is also not prohibited by the US Anti-Doping Agency (USADA) and many major professional sporting leagues in the United States. However, care must be taken in reviewing the components of PRP because many commercially available products differ in PRP formulation. Since 2010, many team physicians have increasingly used PRP to treat a wide range of athletic injuries. A recent anonymous survey conducted by a team of physicians on PRP use in elite athletes revealed minimal complications but significant variability among physicians with regard to timing, belief in evidence, and formulation and dosing of PRP treatments. Many physicians did implicate athlete desire as the main indication for treatment.27
As an autologous treatment, PRP injection has no serious adverse effects beyond mild discomfort as a result of the procedure and pro-inflammatory state in the days following injection. Recent concerns regarding the potential of PRP treatment for heterotopic ossification have been reported, but published information is limited to case reports. PRP can improve pain and function in patients with chronic MSK injury. PRP appears to be a safe and effective alternative to surgery for patients with injury to poorly perfused tissue, which has not improved with conservative measures, such as rest, physical therapy, and anti-inflammatory medications. Care should be taken when treating athletes with PRP to establish regulations on doping by individual governing bodies.
Continue to: Use of stem...
STEM CELL THERAPY
Use of stem cell therapy is based on the properties of the proliferation and differentiation of multipoint MSC lines. These stem cells can theoretically regenerate injured tissues and influence repair through immunomodulation; paracrine activity through the release of bioactive agents, such as cytokines, trophic, and chemotactic molecules; and cell differentiation into various cell lineages.15,16,13,17 Orthopedic surgeons have used microfracture to recruit MSCs during cartilage repair procedures for over 20 years. This procedure draws multipotent MSCs to the injured site to induce chondrogenic proliferation and fibrocartilage repair.28
Adult MSCs provide a readily accessible autologous source of stem cells for regenerative therapies. MSCs can be isolated from a variety of tissues, including bone marrow, adipose tissues, synovia, human umbilical cord blood, and peripheral blood. The majority of stem cell therapies in the United States for sports medicine purposes are conducted using bone marrow aspirate concentrate (BMAC) and adipose tissues. The US Food and Drug Administration (FDA) allows the use of minimally manipulated autologous stem cells to be injected into the same patient on the same day. However, some studies reported that culturing stem cells or introducing products, such as collagenase to stem cells, can increase the stem cell concentration prior to injection. These processes constitute more than “minimal manipulation” and therefore would require drug trials prior to use in the United States.
Although MSCs can be readily obtained from a variety of tissue sources, the makeup of the cell concentrate differs. Bone marrow and adipose tissues are readily available sources of homogenous MSCs. Harvesting stem cells from adipose tissues provides a less invasive route of collection than from BMAC. Harvested BMAC and adipose tissues consist of heterogeneous cell populations that are composed of precursor and accessory cells, such as pericytes, endothelial cells, smooth muscle cells, fibroblasts, and macrophages in addition to MSCs.
Animal studies reported promising results when evaluating soft tissue lesions in small and large animal models.14,15 Although clinical and human evidence remains limited, the potential of MSCs for regenerative repair has led to a recent increase in the number of related clinical studies. Multiple systematic reviews have concluded that MSC therapy is safe for the treatment of osteoarthritis, cartilage lesions, and tendinopathies. Limited evidence is available regarding the safety of intramuscular use, and a theoretical concern arises on the development of heterotopic bone formation as a result of treatment.13,16 The efficacy of MSC therapy is difficult to determine due to the lack of standardization in stem cell populations, adjuvants (eg, PRP, hyaluronic acid, and scaffolding preparations), and delivery methods used.13,17
Similar to PRP, the increased use of MSC therapy among high-profile athletes has led to the promotion of these therapies as safe and effective despite limited evidence.29 Although MSC therapy is a promising and safe treatment option for patients with soft tissue injuries, the paucity in data and human studies limit its clinical use. Moreover, data of MSC efficacy is complicated because of the disparity between clinical studies regarding MSC collection method (many of which eclipse the “minimal manipulation” standard), description of isolated cell concentrates, dosage, method of delivery, use of adjuvants, and lack of randomization. Further studies using [standardized] methods are needed before establishing a true consensus on the safety and efficacy of MSC therapy.
AMNIOTIC MEMBRANE
The placenta is a source of MSCs, a collagen-rich extracellular matrix, and bioactive growth and regulatory factors. The capacity of the placenta to modulate biological activities and tissue formation is thought to provide a means of tissue repair and healing. The placenta consists of amniotic fluid, amniotic membrane (AM), chorionic membrane, and umbilical cord blood and tissues. Although MSCs have been isolated from each component of placental tissues, amniotic and chorionic membranes and umbilical cord tissues yield the highest concentration.
The majority of regenerative studies involving the placenta used AM alone or in combination with other placental tissues. AM is a metabolically active tissue that consists of an epithelial layer, a basement membrane, and a mesenchymal tissue layer. In addition to being a source of stem cells, AM synthesizes many growth factors, vasoactive peptides, and cytokines, which are capable of tissue regeneration. AM was initially used as a biological scaffold for the treatment of skin burns and wounds. Other intrinsic properties of AM include the provision of a matrix for cellular migration and proliferation, enhanced wound healing with reduced scar formation, antibacterial activity, and lastly, non-immunogenic and immunosuppressive properties. These inherent characteristics have spurred studies on the potential use of AM in sports medicine as a minimally invasive means to treat osteoarthritis and injuries of tendons, ligaments, muscles, fascia, and cartilages.
Continue to: Animal studies reported...
Animal studies reported positive results with the use of AM to treat osteoarthritis, cartilage defects, and tendon and ligament injuries. Few studies involving human participants also revealed favorable results with regard to the use of AM for the treatment of plantar fasciitis and osteoarthritis; however, these studies are industry-sponsored and employed small sample sizes. The unique mixture of a collagen-rich extracellular matrix, bioactive growth factors, and pluripotent stem cells may allow AM to become an effective treatment for MSK injuries. Although initial animal and human studies show promising results, variabilities regarding models (animal and human), pathologies, placental tissues, and methods of preparation, preservation, and delivery used limit the ability for comparison, analysis, and drawing of definitive conclusions. Thus far, no studies have evaluated the use of currently available AM products for the treatment of injuries sustained by soccer players.
Despite the current popularity of AM as regenerative therapy in academic research and potential use in clinical treatment in sports medicine, physicians should remain aware of the limited evidence available. Other barriers to research and use AM as a regenerative therapy include regulatory classifications based on the concept of “minimal manipulation” in biologic therapies. Minimally manipulated placental allografts are less regulated, less costly to study, and more easily commercialized. These products are not required to undergo FDA phase I to III trials prior to premarket approval. In 2000, the FDA position on all AM products falls into 2 categories. The first position states that AM that contains allogenic stem cells mixed with another drug that is micronized and/or cryopreserved is more than “minimally manipulated” and therefore categorized as “biologic” and would be subject to phase I to III trials. Dehydrated and decellularized AM, however, may meet the concept of minimal manipulation and is only approved by the FDA as a wound covering. Thus, any application of AM for the treatment of sports medicine pathology is not currently FDA-approved, considered off-label, not covered by insurance, and subject to out-of-pocket pay.30,31
CONCLUSION
With improvements in technology and portability, US has become an effective imaging modality for point-of-care evaluation, diagnosis, and continuous monitoring of many MSK injuries. Additionally, as a dynamic imaging modality, US allows for increased accuracy and efficacy when combined with minimally invasive procedures, such as diagnostic and therapeutic guided injections and percutaneous tenotomy, in the clinical setting; thereby decreasing the overall healthcare costs. PRP is proven to be a safe treatment for several MSK conditions, such as lateral epicondylitis, patellar tendonitis, and plantar fasciitis. Although PRP has been included in the standard of care in some areas, this technique may be predominantly athlete driven. Conflicting evidence with regard to return-to-play timeframes following PRP treatment for muscular injuries and poor evidence in conditions, such as Achilles tendonitis, have led to inconsistent indications for use, dose, and timing of treatment. Although early evidence of MSC therapy is promising, high-level evidence for MSC therapy is insufficient, despite its increased use among athletes. Thus far, no data are available regarding the outcomes of the use of amniotic products for the treatment of injuries among athletes. Furthermore, the preparation of amniotic products has many regulatory concerns. The authors advocate for continuous high-level research on regenerative medicine therapies to establish clinical efficacy and safety data.
ABSTRACT
Improvements in ultrasound technology have increased the popularity and use of ultrasound as a diagnostic and therapeutic modality for many soccer-related musculoskeletal (MSK) injuries. As a dynamic imaging modality, ultrasound offers increased accuracy and efficacy with minimally invasive procedures, such as guided injections, percutaneous tenotomy, and regenerative therapies, in the clinical setting. Emerging evidence indicates that regenerative therapies, such as platelet-rich-plasma (PRP), mesenchymal stem cells, and amniotic products, are a promising treatment for many MSK injuries and are gaining popularity among professional athletes. PRP is a safe treatment for a number of MSK conditions and has been included in the standard of care. However, conflicting evidence on return-to-play timeframes and efficacy in certain MSK conditions have led to inconsistent recommendations on indications for use, dose, and timing of treatment. Mesenchymal stem cell therapy, while promising, lacks high-level evidence of efficacy despite its increasing use among athletes. Currently, no data are available regarding the outcome of the use of amniotic products for the treatment of injuries in athletes. Furthermore, preparation of many regenerative therapies eclipses the concept of minimal manipulation and is subject to US Food and Drug Administration phase I to III trials. High-level research on regenerative medicine therapies should be continuously conducted to establish their clinical efficacy and safety data.
ULTRASOUND
Ultrasound (US) was first introduced for musculoskeletal (MSK) evaluation in 1957.1 Since then, US has gained increasing attention due to its ease of utilization in the clinical setting, repeatability, noninvasiveness, capability for contralateral comparison, lack of radiation exposure, and capability to provide real-time dynamic tissue assessment.1 Compared with magnetic resonance imaging or computed tomography, US presents limitations, including decreased resolution of certain tissues, limited field of view, limited penetration beyond osseous structures, incomplete evaluation of a joint or structure, and operator experience. However, advancements in technology, image resolution, and portability have improved the visualization of multiple anatomic structures and the accuracy of minimally invasive ultrasound-guided procedures at the point of care. The use of US for guided hip injections possibly decreases the cost relative to fluoroscopic guidance.2 Other studies have reported that US, as a result of its safety profile, has replaced fluoroscopy for certain procedures, such as barbotage of calcific tendinosis.3 US has been used for diagnostic purposes and guidance for therapeutic interventions, such as needle aspiration, diagnostic or therapeutic injection, needle tenotomy, tissue release, hydro-dissection, and biopsy.3 Given its expanding application, US has been increasingly used in the clinical setting, athletic training room, and sidelines of athletic events.
DIAGNOSTIC ULTRASOUND
An epidemiologic review of the National Collegiate Athletic Association (NCAA) men’s and women’s soccer injuries from 1988 to 2003 reported over 24,000 combined injuries. Over 70% of these injuries are MSK in nature and often affect the lower extremities.4,5 Ekstrand and colleagues6 also conducted an epidemiological review of muscle injuries among professional soccer players from 2001 to 2009. They found that 92% of all muscle injuries involved the lower extremities. The portability of US allows it to serve as an ideal modality for diagnostic evaluation of acute MSK injuries. Klauser and colleagues7 developed consensus based on the recommendations of the European Society of Musculoskeletal Radiology (ESSR) for the clinical indication of diagnostic ultrasound. A grading system was developed to describe the clinical utility of diagnostic US evaluation of MSK structures:
• Grade 0: Ultrasound is not indicated;
• Grade 1: Ultrasound is indicated if other imaging techniques are not appropriate;
• Grade 2: Ultrasound indication is equivalent to other imaging modalities;
• Grade 3: Ultrasound is the first-choice technique.
Henderson and colleagues8 conducted a review of 95 studies (12 systemic reviews and 83 diagnostic studies) that investigated the accuracy of diagnostic US imaging on soft tissue MSK injuries of the upper and lower extremities. They reported the sensitivity and specificity of the method for detection of over 40 hip, knee, ankle, and foot injuries and assigned corresponding grades based on diagnostic accuracy by using the same system developed by Klauser and colleagues.7,8 Common MSK injuries of the lower extremity and their corresponding ESSR grades are listed in the Table. This study demonstrated that diagnostic US is highly accurate for a number of soft tissue MSK injuries of the lower extremity and consistently matches the recommendation grades issued by Klauser and colleagues.7 In the hands of a skilled operator, US has become an increasingly popular and cost-effective modality for diagnosis and monitoring of acute muscle injuries and chronic tendinopathies among soccer athletes.
Table. Clinical Indication Grades for Diagnostic Ultrasound Evaluation of Common Lower Extremity Injuries7,8
Hip | Knee | Foot/Ankle |
Synovitis/Effusion: 3 | Quadricep tendinosis/tear: 3 | Anterior talofibular ligament injury: 3 |
Snapping hip (extra-articular): 3 | Patella tendinopathy: 3 | Calcaneofibular ligament injury: 3 |
Gluteal tendon tear: 3 | Pes anserine bursitis: 3 | Peroneal tendon tear/subluxation: 3 |
Meralgia paresthetica: 3 | Periarticular bursitis & ganglion: 3 | Posterior tibial tendinopathy: 3 |
Lateral femoral cutaneous nerve injury: 3 | Osgood-Schlatter & Sinding-Larsen: 3 | Plantaris tendon tear: 3 |
Femoral nerve injury: 3 | Synovitis/Effusion: 3 | Plantar fasciitis: 3 |
Sports hernia: 3 | Baker’s Cyst: 2-3 | Calcific tendonitis: 3 |
Morel-Lavallée lesions: 3 | MCL injury: 2 | Retrocalcaneal bursitis: 3 |
Muscle injury (high grade): 3 | IT band friction: 2 | Joint effusion: 3 |
Trochanteric bursitis: 2 | Medial patella plica syndrome: 2 | Ganglion cyst: 3 |
Proximal hamstring injury: 2 | Meniscal cyst: 2 | Retinacula pathology: 3 |
Sciatica: 1-2 | Common perineal neuropathy: 2 | Achilles tendinopathy: 2 |
Muscle injury (low grade): 1 | Distal hamstring tendon injury: 1-2 | Haglund disease: 2 |
Psoas tendon pathology: 1 | Intra-articular ganglion: 1 | Deltoid ligament injury: 2 |
Osteoarthritis: 0 | Hoffa’s fat pad syndrome: 1 | Plantar plate tear: 2 |
Labral tear: 0 | Loose bodies: 1 | Syndesmotic injury: 2 |
| LCL injury: 0-1 | Morton’s neuroma: 2 |
| Popliteal injury: 0-1 | Deltoid ligament injury: 1 |
| Plica syndrome: 0 | Spring ligament injury: 1 |
| Full/partial ACL tear: 0 | Anterolateral ankle impingement: 0 |
| PCL tear: 0 | Posterior talofibular ligament injury: 0 |
| Medial/lateral meniscus tear: 0 |
|
| Osteochondritis dissecans: 0 |
|
Abbreviations: ACL, anterior cruciate ligament; IT, iliotibial; LCL, lateral collateral ligament; MCL, medial collateral ligament; PCL, posterior cruciate ligament.
ULTRASOUND-GUIDED THERAPEUTIC PROCEDURES
The use of US at the point of care for needle guidance has led to its widespread application for therapeutic procedures, including injections and multiple regenerative therapies. Intra-articular US-guided injection and aspiration are common therapeutic interventions performed in the clinical setting. In a position statement of the American Medical Society for Sports Medicine, US-guided injections were found to be more accurate (SORT A evidence), effective (SORT B evidence), and cost effective (SORT B evidence) than landmark-guided injections.3 A recent meta-analysis conducted by Daniels and colleagues1 demonstrated the improved accuracy and efficacy of US-guided injections at the knee, ankle, and foot. Injections may serve a diagnostic purpose when anesthetics, such as lidocaine, are used in isolation, a therapeutic purpose, or both.
Continue to: Percutaneous tenotomy involve...
REGENERATIVE THERAPIES FOR MUSCULOSKELETAL CONDITIONS
PERCUTANEOUS TENOTOMY
Percutaneous tenotomy involves the introduction of a needle into damaged soft tissues, most often tendons (“needling”), in an effort to stimulate a healing response and resect the diseased tendon tissue. Although tenotomy was initially performed as an open or arthroscopic surgical technique, advances in US technology have led to improved sensitivity and specificity identifying areas of tendinous injury (hypervascularity, hypoechogenicity, and calcification); as such, the combination of these techniques has been used in the outpatient setting. New commercial models incorporate ultrasound guidance with needles or micro-resection probes for real-time débridement of damaged tissues. Percutaneous tenotomy has been described in the management of tendinopathy involving the rotator cuff, medial and lateral epicondyles, patellar and Achilles tendons, and plantar fascia.
Housner and colleagues9 evaluated the safety and short-term efficacy of US-guided needle tenotomy in 13 patients with chronic tendinosis of the patella, Achilles tendon, gluteus medius, iliotibial tract, hamstring, and rectus femoris. They reported no procedural complications and a significant decrease in pain scores at 4 and 12 weeks of follow-up.
Koh and colleagues10 conducted a prospective case series to evaluate the safety and efficacy of office-based, US-guided percutaneous tenotomy (using a commercial model) on 20 patients with chronic lateral epicondylitis. The authors reported no wound complications and significant improvement in pain scores at each follow-up period up to 1 year. Subsequent post-procedural US evaluation of injured tissues revealed evidence of healing (decreased tendon thickness, vascularity, and hypoechogenicity) in over half the cohort after 6 months compared with the baseline.11
Lee and colleagues12 evaluated the efficacy of US-guided needle tenotomy combined with platelet-rich plasma (PRP) injection on chronic recalcitrant gluteus medius tendinopathy. In this case series, 21 patients underwent PRP and “needling” through the hypoechoic regions of the injured tendon under direct US guidance. After a period of rest, all patients completed the structured rehabilitation protocol. After an average follow-up of 10 months, all patients displayed significant improvements in all outcome questionnaires and did not report any significant adverse events. The authors concluded that tenotomy combined with PRP is a safe and effective method for treatment for recalcitrant gluteus medius tendinopathy.
These studies indicate that US-guided percutaneous tenotomy, alone or in combination with regenerative therapies, such as PRP, is a safe and effective treatment option for various tendinopathies. However, while tenotomy appears safe with promising results and no reported major adverse events, the level of evidence remains low.
ORTHOBIOLOGICS
Orthobiologics are substances composed of biological materials that can be used to aid or even hasten the healing of bones, muscles, tendons, and ligaments. Orthobiologics may contain growth factors, which initiate or stimulate the body’s reparative process; matrix proteins, which serve as scaffolding for healing tissues; or stem cells, specifically adult stem cells, which are multipotent and can differentiate into several cell lines. Adult stem cells are categorized as hematopoietic, neural, epithelial, skin, and mesenchymal types. Mesenchymal stem cells (MSCs) are of particular interest in sports medicine applications because they secrete growth factors and cytokines with trophic, chemotactic, and immunosuppressive properties.13 MSCs are also multipotent and can differentiate into bones, muscles, cartilages, and tendons.14-17MSCs are readily isolated from many sources, including bone marrow, adipose tissues, synovial tissues, peripheral blood, skeletal muscles, umbilical cord blood, and placenta.13,14Several types of regenerative therapies used in orthopedic and sports medicine practice include PRP, stem cell therapy, and amniotic membrane/fluid preparations. While each therapy possesses the potential for promising results, the paucity of research and discrepancies among studies regarding the description of stem cell lines used limit the available evidence on the true clinical benefits of these regenerative therapies.
[HEAD 3] PLATELET-RICH PLASMA
PRP is an autologous product that has been used to stimulate biological factors and promote healing since the 1970s. Through the activation of platelets, PRP improves localized recruitment, proliferation, and differentiation of cells involved in tissue repair. Platelets, which are non-nucleated bodies located in peripheral blood, contain and release 3 groups of bioactive factors that enhance the healing process. Growth factors and cytokines released from alpha-granules play a role in cell proliferation, chemotaxis, cell differentiation, and angiogenesis. Bioactive factors, such as serotonin and histamine, released from dense granules, increase capillary permeability and improve cell recruitment and migration. Adhesion molecules also assist in cell migration and creation of an extracellular matrix, which acts as a scaffold for wound healing.18 Platelets are activated by mechanical trauma or contact with multiple activators, including Von Willebrand factor, collagen, thrombin, or calcium chloride. When activated, platelets release growth factors and cytokines, which create a pro-inflammatory environment that mediates the tissue repair process. After the procedure, the pro-inflammatory environment may result in patient discomfort, which can be managed with ice and acetaminophen. Use of nonsteroidal anti-inflammatory drugs may theoretically inhibit the inflammatory cascade induced by PRP, and they are avoided before and after the procedure, although evidence regarding necessary time frames is lacking.
Continue to: PRP consists of...
PRP consists of the fractionated liquid component of autologous whole blood, which contains increased concentrations of platelets and cytokines. Different methods and commercial preparations are available for collecting and preparing PRP. Variations in the amount of blood drawn, use of anticoagulants, presence or absence of an activating agent, number of centrifuge spins, and overall platelet and white blood cell concentrations lead to difficulty in evaluating and interpreting the available evidence regarding PRP therapy.
In vitro and animal studies demonstrated promising and safe results regarding the healing effect of PRP on injured soft tissues, such as tendons, ligaments, and muscles. In this regard, a number of studies have evaluated the effect of PRP on human MSK injuries. However, in addition to the above-mentioned variabilities in PRP, many of such studies lack standardization and randomization techniques and include a small number of patients only, thereby limiting the overall comparison and clinical application.
A landmark study conducted by Mishra and Pavelko19 concluded that PRP significantly reduced pain in patients with chronic elbow tendinosis. Similar findings were reported in high-level overhead athletes with ulnar collateral ligament insufficiency, which did not improve with conservative management.20 Fitzpatrick and colleagues21 found improvements in pain with the use of single PRP injection as treatment for chronic gluteal tendinopathy. PRP can effectively improve pain and recovery in chronic ligament and tendon injuries, such as lateral epicondylitis, patellar tendinopathy, and plantar fasciitis, when patients are unresponsive to traditional conservative management. The application of PRP to treat acute MSK injuries has produced mixed results. Hamid and colleagues22 conducted a level II randomized controlled trial to evaluate the effect of PRP combined with a rehabilitation program for treatment of grade 2 hamstring injuries on return-to-play compared with rehabilitation alone. Fourteen athletes were randomized into the study and control groups. Hamid and colleagues22 reported improved return-to-play in the study group compared with that in the control (26.7 and 42.5 days, respectively). This study also reported lower pain scores in the PRP group over time, but the difference was not statistically significant. Zanon and colleagues23 conducted a prospective study to evaluate return-to-play in professional soccer players with acute hamstring strains treated with PRP and a rehabilitation program. This study determined that athletes treated with PRP were “match fit,” meaning they would be available for match selection in an average of 36.8 days. However, Zanon and colleagues23 did not include a control group for comparison. Other studies reported that PRP treatment of acutely injured muscles and medial collateral ligaments of soccer and basketball players decreased their return-to-play interval.18 Reviews by Hamilton and colleagues24 and Pas and colleagues25 concluded that PRP treatment of acutely injured tissues with good blood supply (eg, hamstring muscles) did not improve pain or return-to-play compared with standardized rehabilitation protocols. Similarly, in a double-blinded placebo controlled trial, Reurink and colleagues26 evaluated return-to-play in 80 athletes with acute hamstring injuries treated with a rehabilitation program and either PRP or placebo. Reurink and colleagues26 found no difference in return-to-play (42 days for both groups), but the difference was not statistically significant. PRP has also been used intraoperatively and shows promising results in total knee arthroplasty, anterior cruciate ligament reconstruction, acute Achilles tendon repair, rotator cuff repair, and cartilage repair. However, many of these intraoperative studies are limited to animal models.
In 2009, the World Anti-Doping Agency (WADA) prohibited the use of PRP because it contains autologous growth factors and IGF-1, which could produce an anabolic effect. Recent studies have failed to demonstrate any athletic advantages of using PRP. WADA has since removed PRP from its prohibited list. PRP is also not prohibited by the US Anti-Doping Agency (USADA) and many major professional sporting leagues in the United States. However, care must be taken in reviewing the components of PRP because many commercially available products differ in PRP formulation. Since 2010, many team physicians have increasingly used PRP to treat a wide range of athletic injuries. A recent anonymous survey conducted by a team of physicians on PRP use in elite athletes revealed minimal complications but significant variability among physicians with regard to timing, belief in evidence, and formulation and dosing of PRP treatments. Many physicians did implicate athlete desire as the main indication for treatment.27
As an autologous treatment, PRP injection has no serious adverse effects beyond mild discomfort as a result of the procedure and pro-inflammatory state in the days following injection. Recent concerns regarding the potential of PRP treatment for heterotopic ossification have been reported, but published information is limited to case reports. PRP can improve pain and function in patients with chronic MSK injury. PRP appears to be a safe and effective alternative to surgery for patients with injury to poorly perfused tissue, which has not improved with conservative measures, such as rest, physical therapy, and anti-inflammatory medications. Care should be taken when treating athletes with PRP to establish regulations on doping by individual governing bodies.
Continue to: Use of stem...
STEM CELL THERAPY
Use of stem cell therapy is based on the properties of the proliferation and differentiation of multipoint MSC lines. These stem cells can theoretically regenerate injured tissues and influence repair through immunomodulation; paracrine activity through the release of bioactive agents, such as cytokines, trophic, and chemotactic molecules; and cell differentiation into various cell lineages.15,16,13,17 Orthopedic surgeons have used microfracture to recruit MSCs during cartilage repair procedures for over 20 years. This procedure draws multipotent MSCs to the injured site to induce chondrogenic proliferation and fibrocartilage repair.28
Adult MSCs provide a readily accessible autologous source of stem cells for regenerative therapies. MSCs can be isolated from a variety of tissues, including bone marrow, adipose tissues, synovia, human umbilical cord blood, and peripheral blood. The majority of stem cell therapies in the United States for sports medicine purposes are conducted using bone marrow aspirate concentrate (BMAC) and adipose tissues. The US Food and Drug Administration (FDA) allows the use of minimally manipulated autologous stem cells to be injected into the same patient on the same day. However, some studies reported that culturing stem cells or introducing products, such as collagenase to stem cells, can increase the stem cell concentration prior to injection. These processes constitute more than “minimal manipulation” and therefore would require drug trials prior to use in the United States.
Although MSCs can be readily obtained from a variety of tissue sources, the makeup of the cell concentrate differs. Bone marrow and adipose tissues are readily available sources of homogenous MSCs. Harvesting stem cells from adipose tissues provides a less invasive route of collection than from BMAC. Harvested BMAC and adipose tissues consist of heterogeneous cell populations that are composed of precursor and accessory cells, such as pericytes, endothelial cells, smooth muscle cells, fibroblasts, and macrophages in addition to MSCs.
Animal studies reported promising results when evaluating soft tissue lesions in small and large animal models.14,15 Although clinical and human evidence remains limited, the potential of MSCs for regenerative repair has led to a recent increase in the number of related clinical studies. Multiple systematic reviews have concluded that MSC therapy is safe for the treatment of osteoarthritis, cartilage lesions, and tendinopathies. Limited evidence is available regarding the safety of intramuscular use, and a theoretical concern arises on the development of heterotopic bone formation as a result of treatment.13,16 The efficacy of MSC therapy is difficult to determine due to the lack of standardization in stem cell populations, adjuvants (eg, PRP, hyaluronic acid, and scaffolding preparations), and delivery methods used.13,17
Similar to PRP, the increased use of MSC therapy among high-profile athletes has led to the promotion of these therapies as safe and effective despite limited evidence.29 Although MSC therapy is a promising and safe treatment option for patients with soft tissue injuries, the paucity in data and human studies limit its clinical use. Moreover, data of MSC efficacy is complicated because of the disparity between clinical studies regarding MSC collection method (many of which eclipse the “minimal manipulation” standard), description of isolated cell concentrates, dosage, method of delivery, use of adjuvants, and lack of randomization. Further studies using [standardized] methods are needed before establishing a true consensus on the safety and efficacy of MSC therapy.
AMNIOTIC MEMBRANE
The placenta is a source of MSCs, a collagen-rich extracellular matrix, and bioactive growth and regulatory factors. The capacity of the placenta to modulate biological activities and tissue formation is thought to provide a means of tissue repair and healing. The placenta consists of amniotic fluid, amniotic membrane (AM), chorionic membrane, and umbilical cord blood and tissues. Although MSCs have been isolated from each component of placental tissues, amniotic and chorionic membranes and umbilical cord tissues yield the highest concentration.
The majority of regenerative studies involving the placenta used AM alone or in combination with other placental tissues. AM is a metabolically active tissue that consists of an epithelial layer, a basement membrane, and a mesenchymal tissue layer. In addition to being a source of stem cells, AM synthesizes many growth factors, vasoactive peptides, and cytokines, which are capable of tissue regeneration. AM was initially used as a biological scaffold for the treatment of skin burns and wounds. Other intrinsic properties of AM include the provision of a matrix for cellular migration and proliferation, enhanced wound healing with reduced scar formation, antibacterial activity, and lastly, non-immunogenic and immunosuppressive properties. These inherent characteristics have spurred studies on the potential use of AM in sports medicine as a minimally invasive means to treat osteoarthritis and injuries of tendons, ligaments, muscles, fascia, and cartilages.
Continue to: Animal studies reported...
Animal studies reported positive results with the use of AM to treat osteoarthritis, cartilage defects, and tendon and ligament injuries. Few studies involving human participants also revealed favorable results with regard to the use of AM for the treatment of plantar fasciitis and osteoarthritis; however, these studies are industry-sponsored and employed small sample sizes. The unique mixture of a collagen-rich extracellular matrix, bioactive growth factors, and pluripotent stem cells may allow AM to become an effective treatment for MSK injuries. Although initial animal and human studies show promising results, variabilities regarding models (animal and human), pathologies, placental tissues, and methods of preparation, preservation, and delivery used limit the ability for comparison, analysis, and drawing of definitive conclusions. Thus far, no studies have evaluated the use of currently available AM products for the treatment of injuries sustained by soccer players.
Despite the current popularity of AM as regenerative therapy in academic research and potential use in clinical treatment in sports medicine, physicians should remain aware of the limited evidence available. Other barriers to research and use AM as a regenerative therapy include regulatory classifications based on the concept of “minimal manipulation” in biologic therapies. Minimally manipulated placental allografts are less regulated, less costly to study, and more easily commercialized. These products are not required to undergo FDA phase I to III trials prior to premarket approval. In 2000, the FDA position on all AM products falls into 2 categories. The first position states that AM that contains allogenic stem cells mixed with another drug that is micronized and/or cryopreserved is more than “minimally manipulated” and therefore categorized as “biologic” and would be subject to phase I to III trials. Dehydrated and decellularized AM, however, may meet the concept of minimal manipulation and is only approved by the FDA as a wound covering. Thus, any application of AM for the treatment of sports medicine pathology is not currently FDA-approved, considered off-label, not covered by insurance, and subject to out-of-pocket pay.30,31
CONCLUSION
With improvements in technology and portability, US has become an effective imaging modality for point-of-care evaluation, diagnosis, and continuous monitoring of many MSK injuries. Additionally, as a dynamic imaging modality, US allows for increased accuracy and efficacy when combined with minimally invasive procedures, such as diagnostic and therapeutic guided injections and percutaneous tenotomy, in the clinical setting; thereby decreasing the overall healthcare costs. PRP is proven to be a safe treatment for several MSK conditions, such as lateral epicondylitis, patellar tendonitis, and plantar fasciitis. Although PRP has been included in the standard of care in some areas, this technique may be predominantly athlete driven. Conflicting evidence with regard to return-to-play timeframes following PRP treatment for muscular injuries and poor evidence in conditions, such as Achilles tendonitis, have led to inconsistent indications for use, dose, and timing of treatment. Although early evidence of MSC therapy is promising, high-level evidence for MSC therapy is insufficient, despite its increased use among athletes. Thus far, no data are available regarding the outcomes of the use of amniotic products for the treatment of injuries among athletes. Furthermore, the preparation of amniotic products has many regulatory concerns. The authors advocate for continuous high-level research on regenerative medicine therapies to establish clinical efficacy and safety data.
1. Daniels E, Cole D, Jacobs B, Phillips S. Existing Evidence on ultrasound-guided injections in sports medicine. Orthop J Sports Med. 2018;6(2):2325967118756576. doi:10.1177/2325967118756576.
2. Henne M, Centurion A, Rosas S, Youmans H, Osbahr D. Trends in utilization of image-guided hip joint injections. Unpublished. 2018.
3. Finnoff JT, Hall MM, Adams E, et al. American Medical Society for Sports Medicine position statement: Interventional musculoskeletal ultrasound in sports medicine. Clin J Sport Med. 2015;25:6-22. doi:10.1097/JSM.0000000000000175.
4. Agel J, Evans TA, Dick R, Putukian M, Marshal S. Descriptive epidemiology of collegiate men’s soccer injuries: National Collegiate Athletic Association Injury Surveillance System, 1988-1989 through 2002-2003. J Athl Train. 2007;42(2):270-277.
5. Dick R, Putukian M, Agel J, Evans T, Marshall S. Descriptive epidemiology of collegiate women’s soccer injuries: National Collegiate Athletic Association Injury Surveillance System, 1988-1989 through 2002-2003. J Athl Train. 2007;42(2):278-285.
6. Ekstrand J, Hagglund M, Walden M. Epidemiology of muscle injuries in professional football (soccer). Am J Sports Med. 2011;39(6):1226-1232. doi:10.1177/0363546510395879.
7. Klauser A, Tagliafico A, Allen G, et al. Clinical indications for musculoskeletal ultrasound: A Delphi-based consensus paper of the European society of musculoskeletal radiology. Eur Radiol. 2012;22(5):1140-1148. doi:10.1007/s00330-011-2356-3.
8. Henderson R, Walker B, Young K. The accuracy of diagnostic ultrasound imaging for musculoskeletal soft tissue pathology of the extremities: a comprehensive review of the literature. Chiropr Man Therap. 2015;23(1):31. doi:10.1186/s12998-015-0076-5.
9. Housner JA, Jacobson JA, Misko R. Sonographically guided percutaneous needle tenotomy for the treatment of chronic tendinosis. J Ultrasound Med. 2009;28(9):1187-1192. doi:10.7863/jum.2009.28.9.1187.
10. Koh J, Mohan PC, Howe TS, et al. Fasciotomy and surgical tenotomy for recalcitrant lateral elbow tendinopathy: early clinical experience with a novel device for minimally invasive percutaneous microresection. Am J Sports Med. 2013;41(3):636-644. doi:10.1177/0363546512470625.
11. Seng C, Mohan PC, Koh J, et al. Ultrasonic percutaneous tenotomy for recalcitrant lateral elbow tendinopathy: sustainability and sonographic progression at 3 years. Am J Sports Med. 2015;44(2):504-510. doi:10.1177/0363546515612758.
12. Lee J, Harrison J, Boachie-Adjei K, Vargas E, Moley P. Platelet-rich plasma injections with needle tenotomy for gluteus medius tendinopathy: A registry study with prospective follow-up. Orthop J Sports Med. 2016;4(11):2325967116671692. doi:10.1177/2325967116671692.
13. Osborne H, Anderson L, Burt P, Young M, Gerrard D. Australasian College of Sports Physicians-Position statement: the place of mesenchymal stem/stromal cell therapies in sport and exercise medicine. Br J Sports Med. 2016;50:1237-1244. doi:10.1136/bjsports-2015-095711.
14. Anderson J, Little D, Toth A, et al. Stem cell therapies for knee cartilage repair. The current status of preclinical and clinical studies. Am J Sports Med. 2013;42(9)2253-2261. doi:10.1177/0363546513508744.
15. Lee S, Kwon B, Lee Kyoungbun, Son Y, Chung S. Therapeutic mechanisms of human adipose-derived mesenchymal stem cells in a rat tendon injury model. Am J Sports Med. 2017;45(6):1429-1439. doi:10.1177/0363546517689874.
16. McIntyre J, Jones I, Han B, Vangsness C. Intra-articular mesenchymal stem cell therapy for the human joint. A systematic review. Am J Sports Med. 2017;0363546517735844. doi:10.1177/0363546517735844.
17. Pas HIMFL, Moen M, Haisma J, Winters M. No evidence for the use of stem cell therapy for tendon disorders: a systematic review. Br J Sports Med. 2017;51:996-1002. doi:10.1136/bjsports-2016-096794.
18. Foster T, Puskas B, Mandelbaum B, Gerhardt M, Rodeo S. Platelet-rich plasma: from basic science to clinical applications. Am J Sports Med. 2009;37(11):2259-2272. doi:10.1177/0363546509349921.
19. Mishra A, Pavelko T. Treatment of chronic elbow tendinosis with buffered platelet-rich plasma. Am J Sports Med. 2006;34(11):1774-1778. doi:10.1177/0363546506288850.
20. Dines J, Williams P, ElAttrache N, et al. Platelet-rich plasma can be used to successfully treat elbow ulnar collateral ligament insufficiency in high-level throwers. Am J Orthop. 2016;45(4):296-300.
21. Fitzpatrick J, Bulsara M, O’Donnel J, McCrory P, Zheng M. The effectiveness of platelet-rich plasma injections in gluteal tendinopathy. A randomized, double-blind controlled trial comparing a single platelet-rich plasma injection with a single corticosteroid injection. Am J Sports Med. 2018;46(4)933-939. doi:10.1177/0363546517745525.
22. Hamid M, Ali M, Yusof A, George J, Lee L. Platelet-rich plasma injections for the treatment of hamstring injuries: A randomized controlled trial. Am J Sports Med. 2014;42(10):2410-2418. doi:10.1177/0363546514541540.
23. Zanon G, Combi F, Combi A, Perticarini L, Sammarchi L, Benazzo F. Platelet-rich plasma in the treatment of acute hamstring injuries in professional football players. Joints. 2016;4(1):17-23. doi:10.11138/jts/2016.4.1.017.
24. Hamilton B, Tol JL, Almusa E, et al. Platelet-rich plasma does not enhance return to play in hamstring injuries: a randomized controlled trial. Br J Sports Med. 2015;49:943-950. doi:10.1136/bjsports-2015-094603.
25. Pas HIMFL, Reurink G, Tol JL, Wier A, Winters M, Moen M. Efficacy of rehabilitation (lengthening) exercises, platelet-rich plasma injections, and other conservative interventions in acute hamstring injuries: an updated systematic review and meta-analysis. Br J Sports Med. 2015;49:1197-1205. doi:10.1136/bjsports-2015-094879.
26. Reurink G, Goudswaard G, Moen M, et al. Platelet-rich plasma injections in acute muscle injury. N Engl J Med. 2014;370:2546-2547. doi:10.1056/NEJMc1402340.
27. Kantrowitz D, Padaki A, Ahmad C, Lynch T. Defining platelet-rich plasma usage by team physicians in elite athletes. Orthop J Sports Med. 2018;6(4):2325967118767077. doi:10.1177/2325967118767077.
28. Mithoefer K, Peterson L, Zenobi-Wong M, Mandelbaum B. Cartilage issues in football-today’s problems and tomorrow’s solutions. Br J Sports Med. 2015;49(9):590-596. doi:1136/bjsports-2015-094772.
29. Matthews K, Cuchiara M. Regional regulatory insights: U.S. National Football League Athletes seeking unproven stem cell treatments. Stem Cells Dev. 2014;23(S1):60-64. doi:10.1089/scd.2014.0358.
30. McIntyre J, Jones I, Danilkovich A, Vangsness T. The placenta: applications in orthopaedic sports medicine. Am J Sports Med. 2018;46(1):234-247. doi:10.1177/0363546517697682.
31. Riboh J, Saltzman B, Yankee A, Cole BJ. Human amniotic membrane-derived products in sports medicine: Basic science, early results, and potential clinical applications. Am J Sports Med. 2015;44(9)2425-2434. doi:10.1177/0363546515612750.
1. Daniels E, Cole D, Jacobs B, Phillips S. Existing Evidence on ultrasound-guided injections in sports medicine. Orthop J Sports Med. 2018;6(2):2325967118756576. doi:10.1177/2325967118756576.
2. Henne M, Centurion A, Rosas S, Youmans H, Osbahr D. Trends in utilization of image-guided hip joint injections. Unpublished. 2018.
3. Finnoff JT, Hall MM, Adams E, et al. American Medical Society for Sports Medicine position statement: Interventional musculoskeletal ultrasound in sports medicine. Clin J Sport Med. 2015;25:6-22. doi:10.1097/JSM.0000000000000175.
4. Agel J, Evans TA, Dick R, Putukian M, Marshal S. Descriptive epidemiology of collegiate men’s soccer injuries: National Collegiate Athletic Association Injury Surveillance System, 1988-1989 through 2002-2003. J Athl Train. 2007;42(2):270-277.
5. Dick R, Putukian M, Agel J, Evans T, Marshall S. Descriptive epidemiology of collegiate women’s soccer injuries: National Collegiate Athletic Association Injury Surveillance System, 1988-1989 through 2002-2003. J Athl Train. 2007;42(2):278-285.
6. Ekstrand J, Hagglund M, Walden M. Epidemiology of muscle injuries in professional football (soccer). Am J Sports Med. 2011;39(6):1226-1232. doi:10.1177/0363546510395879.
7. Klauser A, Tagliafico A, Allen G, et al. Clinical indications for musculoskeletal ultrasound: A Delphi-based consensus paper of the European society of musculoskeletal radiology. Eur Radiol. 2012;22(5):1140-1148. doi:10.1007/s00330-011-2356-3.
8. Henderson R, Walker B, Young K. The accuracy of diagnostic ultrasound imaging for musculoskeletal soft tissue pathology of the extremities: a comprehensive review of the literature. Chiropr Man Therap. 2015;23(1):31. doi:10.1186/s12998-015-0076-5.
9. Housner JA, Jacobson JA, Misko R. Sonographically guided percutaneous needle tenotomy for the treatment of chronic tendinosis. J Ultrasound Med. 2009;28(9):1187-1192. doi:10.7863/jum.2009.28.9.1187.
10. Koh J, Mohan PC, Howe TS, et al. Fasciotomy and surgical tenotomy for recalcitrant lateral elbow tendinopathy: early clinical experience with a novel device for minimally invasive percutaneous microresection. Am J Sports Med. 2013;41(3):636-644. doi:10.1177/0363546512470625.
11. Seng C, Mohan PC, Koh J, et al. Ultrasonic percutaneous tenotomy for recalcitrant lateral elbow tendinopathy: sustainability and sonographic progression at 3 years. Am J Sports Med. 2015;44(2):504-510. doi:10.1177/0363546515612758.
12. Lee J, Harrison J, Boachie-Adjei K, Vargas E, Moley P. Platelet-rich plasma injections with needle tenotomy for gluteus medius tendinopathy: A registry study with prospective follow-up. Orthop J Sports Med. 2016;4(11):2325967116671692. doi:10.1177/2325967116671692.
13. Osborne H, Anderson L, Burt P, Young M, Gerrard D. Australasian College of Sports Physicians-Position statement: the place of mesenchymal stem/stromal cell therapies in sport and exercise medicine. Br J Sports Med. 2016;50:1237-1244. doi:10.1136/bjsports-2015-095711.
14. Anderson J, Little D, Toth A, et al. Stem cell therapies for knee cartilage repair. The current status of preclinical and clinical studies. Am J Sports Med. 2013;42(9)2253-2261. doi:10.1177/0363546513508744.
15. Lee S, Kwon B, Lee Kyoungbun, Son Y, Chung S. Therapeutic mechanisms of human adipose-derived mesenchymal stem cells in a rat tendon injury model. Am J Sports Med. 2017;45(6):1429-1439. doi:10.1177/0363546517689874.
16. McIntyre J, Jones I, Han B, Vangsness C. Intra-articular mesenchymal stem cell therapy for the human joint. A systematic review. Am J Sports Med. 2017;0363546517735844. doi:10.1177/0363546517735844.
17. Pas HIMFL, Moen M, Haisma J, Winters M. No evidence for the use of stem cell therapy for tendon disorders: a systematic review. Br J Sports Med. 2017;51:996-1002. doi:10.1136/bjsports-2016-096794.
18. Foster T, Puskas B, Mandelbaum B, Gerhardt M, Rodeo S. Platelet-rich plasma: from basic science to clinical applications. Am J Sports Med. 2009;37(11):2259-2272. doi:10.1177/0363546509349921.
19. Mishra A, Pavelko T. Treatment of chronic elbow tendinosis with buffered platelet-rich plasma. Am J Sports Med. 2006;34(11):1774-1778. doi:10.1177/0363546506288850.
20. Dines J, Williams P, ElAttrache N, et al. Platelet-rich plasma can be used to successfully treat elbow ulnar collateral ligament insufficiency in high-level throwers. Am J Orthop. 2016;45(4):296-300.
21. Fitzpatrick J, Bulsara M, O’Donnel J, McCrory P, Zheng M. The effectiveness of platelet-rich plasma injections in gluteal tendinopathy. A randomized, double-blind controlled trial comparing a single platelet-rich plasma injection with a single corticosteroid injection. Am J Sports Med. 2018;46(4)933-939. doi:10.1177/0363546517745525.
22. Hamid M, Ali M, Yusof A, George J, Lee L. Platelet-rich plasma injections for the treatment of hamstring injuries: A randomized controlled trial. Am J Sports Med. 2014;42(10):2410-2418. doi:10.1177/0363546514541540.
23. Zanon G, Combi F, Combi A, Perticarini L, Sammarchi L, Benazzo F. Platelet-rich plasma in the treatment of acute hamstring injuries in professional football players. Joints. 2016;4(1):17-23. doi:10.11138/jts/2016.4.1.017.
24. Hamilton B, Tol JL, Almusa E, et al. Platelet-rich plasma does not enhance return to play in hamstring injuries: a randomized controlled trial. Br J Sports Med. 2015;49:943-950. doi:10.1136/bjsports-2015-094603.
25. Pas HIMFL, Reurink G, Tol JL, Wier A, Winters M, Moen M. Efficacy of rehabilitation (lengthening) exercises, platelet-rich plasma injections, and other conservative interventions in acute hamstring injuries: an updated systematic review and meta-analysis. Br J Sports Med. 2015;49:1197-1205. doi:10.1136/bjsports-2015-094879.
26. Reurink G, Goudswaard G, Moen M, et al. Platelet-rich plasma injections in acute muscle injury. N Engl J Med. 2014;370:2546-2547. doi:10.1056/NEJMc1402340.
27. Kantrowitz D, Padaki A, Ahmad C, Lynch T. Defining platelet-rich plasma usage by team physicians in elite athletes. Orthop J Sports Med. 2018;6(4):2325967118767077. doi:10.1177/2325967118767077.
28. Mithoefer K, Peterson L, Zenobi-Wong M, Mandelbaum B. Cartilage issues in football-today’s problems and tomorrow’s solutions. Br J Sports Med. 2015;49(9):590-596. doi:1136/bjsports-2015-094772.
29. Matthews K, Cuchiara M. Regional regulatory insights: U.S. National Football League Athletes seeking unproven stem cell treatments. Stem Cells Dev. 2014;23(S1):60-64. doi:10.1089/scd.2014.0358.
30. McIntyre J, Jones I, Danilkovich A, Vangsness T. The placenta: applications in orthopaedic sports medicine. Am J Sports Med. 2018;46(1):234-247. doi:10.1177/0363546517697682.
31. Riboh J, Saltzman B, Yankee A, Cole BJ. Human amniotic membrane-derived products in sports medicine: Basic science, early results, and potential clinical applications. Am J Sports Med. 2015;44(9)2425-2434. doi:10.1177/0363546515612750.
TAKE-HOME POINTS
- Improvements in ultrasound technology have increased its use as a therapeutic and diagnostic modality.
- Ultrasound offers increased accuracy and efficacy with minimally invasive procedures.
- PRP is a safe and effective treatment for many musculoskeletal injuries, however return-to-play time frames limit its efficacy.
- While stem cell and amniotic products offer promising results, the paucity in data limits overall use.
- Care should be taken when discussing regenerative therapy as many products eclipse the concept of “minimal manipulation” and therefore require USFDA trials to establish safety data.
Early childhood developmental screening differs in the U.S., Scandinavia
Nearly every parent gets excited about their child’s first smile, steps, and words. Developmental and behavioral screening helps to better track young children’s progress in areas like communication, motor, cognitive, and social/emotional skills. Approximately one in four or five children are at risk for a developmental/behavioral delay, which might indicate an emerging developmental disability or mental health disorder.
Regular screenings raise awareness of children’s development, which makes it easier for parents to expect and celebrate milestones. They encourage parents and doctors to avoid the common pitfall of taking a “wait and see” approach. Regular screenings might even help doctors more easily diagnose co-occurring conditions like autism, sleep disorders, iron deficiencies, hearing impairment, metabolic disorders, genetic disorders, in utero drug/alcohol exposure, or child maltreatment.
High-quality interventions for children aged 0-5 years can decrease rates of special education, substance abuse, criminality/incarceration, suicidal attempts, and unemployment or welfare dependency. The trick is to swiftly identify and refer at-risk and delayed children to the most effective resources in a family-centered manner.
Our new study, which has been published online in Developmental Medicine and Child Neurology, investigated early childhood screening practices across the United States and Scandinavia (Denmark, Norway, and Sweden), which lie relatively far apart on the spectrum of preventive care models (2018 Sep 23. doi: 10.1111/dmcn.14044).
Just like many other developed areas of the world, the United States and Scandinavia are increasingly using two accurate, parent-reported screening tools – the Ages & Stages Questionnaire (ASQ) and ASQ:Social-Emotional (ASQ:SE) – to measure developmental and behavioral skills in children aged 0-5 years. We found that routine and periodic ASQ and/or ASQ:SE screening is low cost, feasible, and increases early detection and referral rates, plus they connect at-risk children to early intervention programs at significantly younger ages.
Surprisingly, the United States and Scandinavia tend to use these same two screening questionnaires quite differently. U.S. pediatricians and family physicians commonly use the ASQ and/or ASQ:SE in clinic settings to swiftly identify developmental/behavioral red flags in children from general and at-risk populations (See video at end of article). Scandinavian studies more commonly report the use of the ASQ and ASQ:SE to track developmental/behavioral differences in children in an intervention/exposure group and how they compare with children in a control group over time. In other words, the United States uses these screens clinically, and Scandinavia mostly uses them for research purposes.
In Scandinavia, home visit nurses and general practitioners commonly administer more narrowly focused, “hands-on” screens during infancy. Different municipalities use different screens. Language-focused screening typically is not performed until ages 2.5-3 years in preschools or child health centers. That’s probably too late. Scandinavian countries, which boast bountiful and equitable early childhood resources, are not routinely using parent-centered screening tools that measure all of a child’s developmental domains, including social/emotional skills. One reason is probably that Danish and Swedish ASQ and ASQ:SE norming (standardization) and validation (reliability and accuracy) studies are lacking and because Norwegian norms are out-of-date. Therefore, they are primarily used just for research. Every decade, the “good” screening questionnaires have to be scientifically tweaked and improved as the characteristics of populations (like ethnicity, socioeconomic status, or percentage of new immigrants) and cultural norms (like rotary versus cell phones) change over time.
Scandinavia likely would benefit from nationwide screening initiatives, which played key roles in implementing and sustaining developmental and social/emotional screening in numerous U.S. states. The American Academy of Pediatrics recommends routinely administering a standardized developmental screening tool at ages 9, 18, and 24-30 months, along with many other action steps and decision-making points. In reality, only 30% of U.S. children received a parent-centered, standardized developmental screening, and state-level screening rates varied wildly from 59% (Oregon) to 17% (Mississippi) in 2017-2018 (JAMA Pediatr. 2018;172[9]:857-66). Statewide screening initiatives made a big difference.
One implementation lesson is that U.S. and Scandinavian health care clinics probably should not bother mailing out the ASQ or ASQ:SE paper questionnaires to family’s homes. They will end up getting suboptimal return rates, most especially for preschoolers. Instead, clinics should instruct parents to complete the online ASQ or ASQ:SE at home 1-2 weeks before the office visit or, alternatively, the paper ASQ or ASQ:SE about 20 minutes before the clinician walks into the exam room. A number of study results support this.
According to U.S. studies, when primary care doctors share office space with developmental specialists or psychologists, children with concerning screens are more reliably connected to early interventions. Children and families can benefit from care coordinators, who supervise and bring doctors together with different specialists while monitoring and evaluating the care delivered.
According to Scandinavian studies, when mothers screen positive for depression, their at-risk children generally benefit from a social-emotional/behavioral (ASQ:SE) screening at 2 years old or younger. Currently, this is not routinely happening in U.S. primary care practices.
America could do a much better job of screening, and as it turns out, ditto with Scandinavia. We hope our systematic review inspires policy makers, medical professionals, early childhood educators, mental health providers, social workers, and parents, to learn more about developmental and behavioral screening and to perform ongoing, high-quality research in the United States, Scandinavia, and many other developed nations.
Here is a video Dr. Marks has developed showing how to integrate ASQ screening into your practice.
Dr. Marks is a pediatrician, clinical researcher, and coauthor of Developmental Screening in Your Community. Dr. Madsen Sjö is a certified pediatric neuropsychologist in Copenhagen. Dr. Marks and his family moved from the United States to Denmark in 2017. Email him at [email protected].
Nearly every parent gets excited about their child’s first smile, steps, and words. Developmental and behavioral screening helps to better track young children’s progress in areas like communication, motor, cognitive, and social/emotional skills. Approximately one in four or five children are at risk for a developmental/behavioral delay, which might indicate an emerging developmental disability or mental health disorder.
Regular screenings raise awareness of children’s development, which makes it easier for parents to expect and celebrate milestones. They encourage parents and doctors to avoid the common pitfall of taking a “wait and see” approach. Regular screenings might even help doctors more easily diagnose co-occurring conditions like autism, sleep disorders, iron deficiencies, hearing impairment, metabolic disorders, genetic disorders, in utero drug/alcohol exposure, or child maltreatment.
High-quality interventions for children aged 0-5 years can decrease rates of special education, substance abuse, criminality/incarceration, suicidal attempts, and unemployment or welfare dependency. The trick is to swiftly identify and refer at-risk and delayed children to the most effective resources in a family-centered manner.
Our new study, which has been published online in Developmental Medicine and Child Neurology, investigated early childhood screening practices across the United States and Scandinavia (Denmark, Norway, and Sweden), which lie relatively far apart on the spectrum of preventive care models (2018 Sep 23. doi: 10.1111/dmcn.14044).
Just like many other developed areas of the world, the United States and Scandinavia are increasingly using two accurate, parent-reported screening tools – the Ages & Stages Questionnaire (ASQ) and ASQ:Social-Emotional (ASQ:SE) – to measure developmental and behavioral skills in children aged 0-5 years. We found that routine and periodic ASQ and/or ASQ:SE screening is low cost, feasible, and increases early detection and referral rates, plus they connect at-risk children to early intervention programs at significantly younger ages.
Surprisingly, the United States and Scandinavia tend to use these same two screening questionnaires quite differently. U.S. pediatricians and family physicians commonly use the ASQ and/or ASQ:SE in clinic settings to swiftly identify developmental/behavioral red flags in children from general and at-risk populations (See video at end of article). Scandinavian studies more commonly report the use of the ASQ and ASQ:SE to track developmental/behavioral differences in children in an intervention/exposure group and how they compare with children in a control group over time. In other words, the United States uses these screens clinically, and Scandinavia mostly uses them for research purposes.
In Scandinavia, home visit nurses and general practitioners commonly administer more narrowly focused, “hands-on” screens during infancy. Different municipalities use different screens. Language-focused screening typically is not performed until ages 2.5-3 years in preschools or child health centers. That’s probably too late. Scandinavian countries, which boast bountiful and equitable early childhood resources, are not routinely using parent-centered screening tools that measure all of a child’s developmental domains, including social/emotional skills. One reason is probably that Danish and Swedish ASQ and ASQ:SE norming (standardization) and validation (reliability and accuracy) studies are lacking and because Norwegian norms are out-of-date. Therefore, they are primarily used just for research. Every decade, the “good” screening questionnaires have to be scientifically tweaked and improved as the characteristics of populations (like ethnicity, socioeconomic status, or percentage of new immigrants) and cultural norms (like rotary versus cell phones) change over time.
Scandinavia likely would benefit from nationwide screening initiatives, which played key roles in implementing and sustaining developmental and social/emotional screening in numerous U.S. states. The American Academy of Pediatrics recommends routinely administering a standardized developmental screening tool at ages 9, 18, and 24-30 months, along with many other action steps and decision-making points. In reality, only 30% of U.S. children received a parent-centered, standardized developmental screening, and state-level screening rates varied wildly from 59% (Oregon) to 17% (Mississippi) in 2017-2018 (JAMA Pediatr. 2018;172[9]:857-66). Statewide screening initiatives made a big difference.
One implementation lesson is that U.S. and Scandinavian health care clinics probably should not bother mailing out the ASQ or ASQ:SE paper questionnaires to family’s homes. They will end up getting suboptimal return rates, most especially for preschoolers. Instead, clinics should instruct parents to complete the online ASQ or ASQ:SE at home 1-2 weeks before the office visit or, alternatively, the paper ASQ or ASQ:SE about 20 minutes before the clinician walks into the exam room. A number of study results support this.
According to U.S. studies, when primary care doctors share office space with developmental specialists or psychologists, children with concerning screens are more reliably connected to early interventions. Children and families can benefit from care coordinators, who supervise and bring doctors together with different specialists while monitoring and evaluating the care delivered.
According to Scandinavian studies, when mothers screen positive for depression, their at-risk children generally benefit from a social-emotional/behavioral (ASQ:SE) screening at 2 years old or younger. Currently, this is not routinely happening in U.S. primary care practices.
America could do a much better job of screening, and as it turns out, ditto with Scandinavia. We hope our systematic review inspires policy makers, medical professionals, early childhood educators, mental health providers, social workers, and parents, to learn more about developmental and behavioral screening and to perform ongoing, high-quality research in the United States, Scandinavia, and many other developed nations.
Here is a video Dr. Marks has developed showing how to integrate ASQ screening into your practice.
Dr. Marks is a pediatrician, clinical researcher, and coauthor of Developmental Screening in Your Community. Dr. Madsen Sjö is a certified pediatric neuropsychologist in Copenhagen. Dr. Marks and his family moved from the United States to Denmark in 2017. Email him at [email protected].
Nearly every parent gets excited about their child’s first smile, steps, and words. Developmental and behavioral screening helps to better track young children’s progress in areas like communication, motor, cognitive, and social/emotional skills. Approximately one in four or five children are at risk for a developmental/behavioral delay, which might indicate an emerging developmental disability or mental health disorder.
Regular screenings raise awareness of children’s development, which makes it easier for parents to expect and celebrate milestones. They encourage parents and doctors to avoid the common pitfall of taking a “wait and see” approach. Regular screenings might even help doctors more easily diagnose co-occurring conditions like autism, sleep disorders, iron deficiencies, hearing impairment, metabolic disorders, genetic disorders, in utero drug/alcohol exposure, or child maltreatment.
High-quality interventions for children aged 0-5 years can decrease rates of special education, substance abuse, criminality/incarceration, suicidal attempts, and unemployment or welfare dependency. The trick is to swiftly identify and refer at-risk and delayed children to the most effective resources in a family-centered manner.
Our new study, which has been published online in Developmental Medicine and Child Neurology, investigated early childhood screening practices across the United States and Scandinavia (Denmark, Norway, and Sweden), which lie relatively far apart on the spectrum of preventive care models (2018 Sep 23. doi: 10.1111/dmcn.14044).
Just like many other developed areas of the world, the United States and Scandinavia are increasingly using two accurate, parent-reported screening tools – the Ages & Stages Questionnaire (ASQ) and ASQ:Social-Emotional (ASQ:SE) – to measure developmental and behavioral skills in children aged 0-5 years. We found that routine and periodic ASQ and/or ASQ:SE screening is low cost, feasible, and increases early detection and referral rates, plus they connect at-risk children to early intervention programs at significantly younger ages.
Surprisingly, the United States and Scandinavia tend to use these same two screening questionnaires quite differently. U.S. pediatricians and family physicians commonly use the ASQ and/or ASQ:SE in clinic settings to swiftly identify developmental/behavioral red flags in children from general and at-risk populations (See video at end of article). Scandinavian studies more commonly report the use of the ASQ and ASQ:SE to track developmental/behavioral differences in children in an intervention/exposure group and how they compare with children in a control group over time. In other words, the United States uses these screens clinically, and Scandinavia mostly uses them for research purposes.
In Scandinavia, home visit nurses and general practitioners commonly administer more narrowly focused, “hands-on” screens during infancy. Different municipalities use different screens. Language-focused screening typically is not performed until ages 2.5-3 years in preschools or child health centers. That’s probably too late. Scandinavian countries, which boast bountiful and equitable early childhood resources, are not routinely using parent-centered screening tools that measure all of a child’s developmental domains, including social/emotional skills. One reason is probably that Danish and Swedish ASQ and ASQ:SE norming (standardization) and validation (reliability and accuracy) studies are lacking and because Norwegian norms are out-of-date. Therefore, they are primarily used just for research. Every decade, the “good” screening questionnaires have to be scientifically tweaked and improved as the characteristics of populations (like ethnicity, socioeconomic status, or percentage of new immigrants) and cultural norms (like rotary versus cell phones) change over time.
Scandinavia likely would benefit from nationwide screening initiatives, which played key roles in implementing and sustaining developmental and social/emotional screening in numerous U.S. states. The American Academy of Pediatrics recommends routinely administering a standardized developmental screening tool at ages 9, 18, and 24-30 months, along with many other action steps and decision-making points. In reality, only 30% of U.S. children received a parent-centered, standardized developmental screening, and state-level screening rates varied wildly from 59% (Oregon) to 17% (Mississippi) in 2017-2018 (JAMA Pediatr. 2018;172[9]:857-66). Statewide screening initiatives made a big difference.
One implementation lesson is that U.S. and Scandinavian health care clinics probably should not bother mailing out the ASQ or ASQ:SE paper questionnaires to family’s homes. They will end up getting suboptimal return rates, most especially for preschoolers. Instead, clinics should instruct parents to complete the online ASQ or ASQ:SE at home 1-2 weeks before the office visit or, alternatively, the paper ASQ or ASQ:SE about 20 minutes before the clinician walks into the exam room. A number of study results support this.
According to U.S. studies, when primary care doctors share office space with developmental specialists or psychologists, children with concerning screens are more reliably connected to early interventions. Children and families can benefit from care coordinators, who supervise and bring doctors together with different specialists while monitoring and evaluating the care delivered.
According to Scandinavian studies, when mothers screen positive for depression, their at-risk children generally benefit from a social-emotional/behavioral (ASQ:SE) screening at 2 years old or younger. Currently, this is not routinely happening in U.S. primary care practices.
America could do a much better job of screening, and as it turns out, ditto with Scandinavia. We hope our systematic review inspires policy makers, medical professionals, early childhood educators, mental health providers, social workers, and parents, to learn more about developmental and behavioral screening and to perform ongoing, high-quality research in the United States, Scandinavia, and many other developed nations.
Here is a video Dr. Marks has developed showing how to integrate ASQ screening into your practice.
Dr. Marks is a pediatrician, clinical researcher, and coauthor of Developmental Screening in Your Community. Dr. Madsen Sjö is a certified pediatric neuropsychologist in Copenhagen. Dr. Marks and his family moved from the United States to Denmark in 2017. Email him at [email protected].
Brexanolone injection quickly improves postpartum depression
BARCELONA – Brexanolone injection provided rapid and durable improvement in postpartum depression in an integrated analysis of three pivotal randomized trials collectively known as the Hummingbird trials, Christine Clemson, PhD, reported at the annual congress of the European College of Neuropsychopharmacology.
This was accomplished with a favorable safety experience. The most common treatment-emergent adverse events – dizziness and sleepiness – were roughly twice as common as with placebo in the 247-patient Hummingbird safety analysis.
On Dec. 19, 2018, the agency is expected to respond to SAGE Therapeutics’s application for marketing approval of intravenous brexanolone given as a continuous 60-hour infusion at 90 mcg/kg per hour, according to Dr. Clemson, senior medical director at Cambridge, Mass.–based SAGE Therapeutics, which is developing the therapy.
Brexanolone is a proprietary IV formulation of allopregnanolone, a metabolite of progesterone. The drug’s mechanism of action involves modulation of the neurotransmitter gamma-aminobutyric acid (GABA). The drug binds to both synaptic and extra-synaptic GABA A receptors, thereby increasing receptor functionality.
The decision to target GABA as a novel therapeutic strategy in PPD was based upon translational studies demonstrating that GABA is the chief neuroinhibitory mechanism in the brain, and its actions are mediated mainly by GABA A receptors. Brexanolone’s efficacy is consistent with a theory that the pathogenesis of PPD involves triggers such as inflammation, hormonal fluctuations, or chronic stress, which in some women cause GABA hypofunction, both at the receptors and in terms of tissue GABA levels. This, in turn, leads to an overactive HPA axis and dysregulated neural networks, with resultant PPD, Dr. Clemson explained.
The three Hummingbird clinical trials were double blind, randomized, and placebo controlled. Two were restricted to women with severe PPD. The third and largest focused on moderately affected patients as defined by a baseline Hamilton Depression Scale for Depression (HAM-D) score of 20-25.
The efficacy analysis included 207 patients who received brexanolone at 90 mcg/kg per hour or placebo for 60 hours in an inpatient setting and were followed for 30 days. The primary endpoint was the change in HAM-D total score from baseline to 60 hours. The mean 17-point reduction in the active treatment arm was significantly better than the 12.8-point decrease with placebo. The between-group difference was significant within the first 24 hours and remained so at all time points out to the study’s end at day 30. There was no individual item on the HAM-D in which the drug performed worse than placebo, and there were many in which brexanolone performed significantly better, including depressed mood, anxiety, insomnia, and feelings of guilt.
In terms of the rigorous secondary endpoint of HAM-D remission as defined by a total score of 7 or less, the brexanolone injection significantly outperformed placebo at every time point except for day 30.
There was a 2% rate of serious adverse events in both study arms. These included suicidal ideation, an intentional overdose attempt post discharge, altered state of consciousness, and syncope.
A vastly more convenient once-daily oral formulation of brexanolone is now in phase 3 clinical trials for PPD and major depressive disorder, and in phase 2 for insomnia and bipolar depression.
Elsewhere at the ECNP congress, other investigators from Sage Therapeutics presented for the first time the outcomes of an 89-patient, randomized, double-blind, multicenter, placebo-controlled, phase 2 clinical trial of SAGE-217 for treatment of major depressive disorder.
Participants received a nightly 30-mg dose of the drug or placebo for 2 weeks, with a primary study endpoint being the change in HAM-D total score from baseline to day 15. Patients on the oral GABA A receptor positive modulator averaged a 17.4-point improvement, significantly better than the 10.3-point spread in placebo-treated controls. A statistically significant between-group difference was noted on days 2 through 28. HAM-D remission at day 15 was documented in 64% of the oral brexanolone group, compared with 26% of controls.
Those improvements in depression were accompanied by significant gains in numerous domains of health-related quality of life as assessed via the 36-Item Short Form Health Survey. Indeed, day 15 health-related quality of life scores in the oral brexanolone group approached normative values for the general population.
The studies were funded by SAGE Therapeutics.
BARCELONA – Brexanolone injection provided rapid and durable improvement in postpartum depression in an integrated analysis of three pivotal randomized trials collectively known as the Hummingbird trials, Christine Clemson, PhD, reported at the annual congress of the European College of Neuropsychopharmacology.
This was accomplished with a favorable safety experience. The most common treatment-emergent adverse events – dizziness and sleepiness – were roughly twice as common as with placebo in the 247-patient Hummingbird safety analysis.
On Dec. 19, 2018, the agency is expected to respond to SAGE Therapeutics’s application for marketing approval of intravenous brexanolone given as a continuous 60-hour infusion at 90 mcg/kg per hour, according to Dr. Clemson, senior medical director at Cambridge, Mass.–based SAGE Therapeutics, which is developing the therapy.
Brexanolone is a proprietary IV formulation of allopregnanolone, a metabolite of progesterone. The drug’s mechanism of action involves modulation of the neurotransmitter gamma-aminobutyric acid (GABA). The drug binds to both synaptic and extra-synaptic GABA A receptors, thereby increasing receptor functionality.
The decision to target GABA as a novel therapeutic strategy in PPD was based upon translational studies demonstrating that GABA is the chief neuroinhibitory mechanism in the brain, and its actions are mediated mainly by GABA A receptors. Brexanolone’s efficacy is consistent with a theory that the pathogenesis of PPD involves triggers such as inflammation, hormonal fluctuations, or chronic stress, which in some women cause GABA hypofunction, both at the receptors and in terms of tissue GABA levels. This, in turn, leads to an overactive HPA axis and dysregulated neural networks, with resultant PPD, Dr. Clemson explained.
The three Hummingbird clinical trials were double blind, randomized, and placebo controlled. Two were restricted to women with severe PPD. The third and largest focused on moderately affected patients as defined by a baseline Hamilton Depression Scale for Depression (HAM-D) score of 20-25.
The efficacy analysis included 207 patients who received brexanolone at 90 mcg/kg per hour or placebo for 60 hours in an inpatient setting and were followed for 30 days. The primary endpoint was the change in HAM-D total score from baseline to 60 hours. The mean 17-point reduction in the active treatment arm was significantly better than the 12.8-point decrease with placebo. The between-group difference was significant within the first 24 hours and remained so at all time points out to the study’s end at day 30. There was no individual item on the HAM-D in which the drug performed worse than placebo, and there were many in which brexanolone performed significantly better, including depressed mood, anxiety, insomnia, and feelings of guilt.
In terms of the rigorous secondary endpoint of HAM-D remission as defined by a total score of 7 or less, the brexanolone injection significantly outperformed placebo at every time point except for day 30.
There was a 2% rate of serious adverse events in both study arms. These included suicidal ideation, an intentional overdose attempt post discharge, altered state of consciousness, and syncope.
A vastly more convenient once-daily oral formulation of brexanolone is now in phase 3 clinical trials for PPD and major depressive disorder, and in phase 2 for insomnia and bipolar depression.
Elsewhere at the ECNP congress, other investigators from Sage Therapeutics presented for the first time the outcomes of an 89-patient, randomized, double-blind, multicenter, placebo-controlled, phase 2 clinical trial of SAGE-217 for treatment of major depressive disorder.
Participants received a nightly 30-mg dose of the drug or placebo for 2 weeks, with a primary study endpoint being the change in HAM-D total score from baseline to day 15. Patients on the oral GABA A receptor positive modulator averaged a 17.4-point improvement, significantly better than the 10.3-point spread in placebo-treated controls. A statistically significant between-group difference was noted on days 2 through 28. HAM-D remission at day 15 was documented in 64% of the oral brexanolone group, compared with 26% of controls.
Those improvements in depression were accompanied by significant gains in numerous domains of health-related quality of life as assessed via the 36-Item Short Form Health Survey. Indeed, day 15 health-related quality of life scores in the oral brexanolone group approached normative values for the general population.
The studies were funded by SAGE Therapeutics.
BARCELONA – Brexanolone injection provided rapid and durable improvement in postpartum depression in an integrated analysis of three pivotal randomized trials collectively known as the Hummingbird trials, Christine Clemson, PhD, reported at the annual congress of the European College of Neuropsychopharmacology.
This was accomplished with a favorable safety experience. The most common treatment-emergent adverse events – dizziness and sleepiness – were roughly twice as common as with placebo in the 247-patient Hummingbird safety analysis.
On Dec. 19, 2018, the agency is expected to respond to SAGE Therapeutics’s application for marketing approval of intravenous brexanolone given as a continuous 60-hour infusion at 90 mcg/kg per hour, according to Dr. Clemson, senior medical director at Cambridge, Mass.–based SAGE Therapeutics, which is developing the therapy.
Brexanolone is a proprietary IV formulation of allopregnanolone, a metabolite of progesterone. The drug’s mechanism of action involves modulation of the neurotransmitter gamma-aminobutyric acid (GABA). The drug binds to both synaptic and extra-synaptic GABA A receptors, thereby increasing receptor functionality.
The decision to target GABA as a novel therapeutic strategy in PPD was based upon translational studies demonstrating that GABA is the chief neuroinhibitory mechanism in the brain, and its actions are mediated mainly by GABA A receptors. Brexanolone’s efficacy is consistent with a theory that the pathogenesis of PPD involves triggers such as inflammation, hormonal fluctuations, or chronic stress, which in some women cause GABA hypofunction, both at the receptors and in terms of tissue GABA levels. This, in turn, leads to an overactive HPA axis and dysregulated neural networks, with resultant PPD, Dr. Clemson explained.
The three Hummingbird clinical trials were double blind, randomized, and placebo controlled. Two were restricted to women with severe PPD. The third and largest focused on moderately affected patients as defined by a baseline Hamilton Depression Scale for Depression (HAM-D) score of 20-25.
The efficacy analysis included 207 patients who received brexanolone at 90 mcg/kg per hour or placebo for 60 hours in an inpatient setting and were followed for 30 days. The primary endpoint was the change in HAM-D total score from baseline to 60 hours. The mean 17-point reduction in the active treatment arm was significantly better than the 12.8-point decrease with placebo. The between-group difference was significant within the first 24 hours and remained so at all time points out to the study’s end at day 30. There was no individual item on the HAM-D in which the drug performed worse than placebo, and there were many in which brexanolone performed significantly better, including depressed mood, anxiety, insomnia, and feelings of guilt.
In terms of the rigorous secondary endpoint of HAM-D remission as defined by a total score of 7 or less, the brexanolone injection significantly outperformed placebo at every time point except for day 30.
There was a 2% rate of serious adverse events in both study arms. These included suicidal ideation, an intentional overdose attempt post discharge, altered state of consciousness, and syncope.
A vastly more convenient once-daily oral formulation of brexanolone is now in phase 3 clinical trials for PPD and major depressive disorder, and in phase 2 for insomnia and bipolar depression.
Elsewhere at the ECNP congress, other investigators from Sage Therapeutics presented for the first time the outcomes of an 89-patient, randomized, double-blind, multicenter, placebo-controlled, phase 2 clinical trial of SAGE-217 for treatment of major depressive disorder.
Participants received a nightly 30-mg dose of the drug or placebo for 2 weeks, with a primary study endpoint being the change in HAM-D total score from baseline to day 15. Patients on the oral GABA A receptor positive modulator averaged a 17.4-point improvement, significantly better than the 10.3-point spread in placebo-treated controls. A statistically significant between-group difference was noted on days 2 through 28. HAM-D remission at day 15 was documented in 64% of the oral brexanolone group, compared with 26% of controls.
Those improvements in depression were accompanied by significant gains in numerous domains of health-related quality of life as assessed via the 36-Item Short Form Health Survey. Indeed, day 15 health-related quality of life scores in the oral brexanolone group approached normative values for the general population.
The studies were funded by SAGE Therapeutics.
REPORTING FROM THE ECNP CONGRESS
Key clinical point: A novel investigational GABA modulator is turning heads for treatment of postpartum depression.
Major finding: At 60 hours, mean HAM-D total scores had dropped by 17 points with brexanolone, versus 12.8 with placebo.
Study details: A prespecified integrated safety and efficacy analysis incorporating three pivotal clinical trials.
Disclosures: The studies were funded by SAGE Therapeutics and presented by a company executive.
Paradigm shifts in palliative care
Better engagement with patients essential
A 57-year-old man is admitted to the hospital with new back pain, which has been getting worse over the past 6 days. He had been diagnosed with stage 4 lung cancer in mid-2017 and underwent treatment with a platinum-based double therapy.
The man also has a history of heroin use – as recently as two years earlier – and he was divorced not long ago. He has been using an old prescription for Vicodin to treat himself, taking as many as 10-12 tablets a day.
This man is an example of the kind of complicated patient hospitalists are called on to treat – complex pain in an era when opioid abuse is considered a public scourge. How is a hospitalist to handle a case like this?
Pain cases are far from the only types of increasingly complex, often palliative cases in which hospitalists are being asked to provide help. Care for the elderly is also becoming increasingly difficult as the U.S. population ages and as hospitalists step in to provide care in the absence of geriatricians. .
Pain management in the opioid era and the need for new approaches in elderly care were highlighted at the Hospital Medicine 2018 annual conference, with experts drawing attention to subtleties that are often overlooked in these sometimes desperate cases.
James Risser, MD, medical director of palliative care at Regions Hospital in Minneapolis, said the complex problems of the 57-year-old man with back pain amounted to an example of “pain’s greatest hits.”
That particular case underscores the need to identify individual types of pain, he said, because they all need to be handled differently. If hospitalists don’t consider all the different aspects of pain, a patient might endure more suffering than necessary.
“All of this pain is swirling around in a very complicated patient,” Dr. Risser said, noting that it is important to “tease out the individual parts” of a complex patient’s history.
“Pain is a very complicated construct, from the physical to the neurological to the emotional,” Dr. Risser said. “Pain is a subjective experience, and the way people interact with their pain really depends not just on physical pain but also their psychological state, their social state, and even their spiritual state.”
Understanding this array of causes has led Dr. Risser to approach the problem of pain from different angles – including perspectives that might not be traditional, he said.
“One of the things that I’ve gotten better at is taking a spiritual history,” he said. “I don’t know if that’s part of everybody’s armamentarium. But if you’re dealing with people who are very, very sick, sometimes that’s the fundamental fabric of how they live and how they die. If there are unresolved issues along those lines, it’s possible they could be experiencing their pain in a different or more severe way.”
Varieties of pain
Treatment depends on the pain type, Dr. Risser said. Somatic pain often responds to nonsteroidal anti-inflammatories or steroids.
Neuropathic pain usually responds poorly to anti-inflammatories and to opioids. There is some research suggesting methadone could be helpful, but the data are not very strong. The most common medications prescribed are antiseizure medications and antidepressants, such as gabapentin and serotonin, and norepinephrine reuptake inhibitors.
The question of cancer pain versus noncancer pain can be tricky, Dr. Risser said. If a person’s life expectancy is limited, there can be a reason, or even a requirement, to use higher-risk medications. But, he said, that doesn’t mean the patient still won’t have problems with overuse of pain medication.
“We have a lot of patients now living post cancer who have been put on methadone or have been put on Oxycontin, and now we’re trying to figure out what to do with them,” he said. “I don’t think it’s that clear anymore that there’s a massive difference between cancer and noncancer pain, especially for those survivors.”
Clinicians, he said, should “fix what can be fixed” – and with the right tools. “If you have a patient who’s got severe lower abdominal pain because they have a bladder full or urine, really the treatment would probably not be … opioids. It probably would be a Foley catheter,” he said.
Hospitalists should treat patients based on sound principles of pain management, Dr. Risser said, but “while you try to create a diagnostic framework, know that people continually defy the boxes we put them in.”
Indeed, in an era of pain-medication addiction, it might be a good idea to worry about prescribing opioids, but clinicians have to remember that their goal is to help patients get relief – and that they themselves bring biases to the table, said Amy Davis, DO, MS, of Drexel University, Philadelphia.
In a presentation at HM18, Dr. Davis displayed images of a variety of patients on a large screen – different races and genders, some in business attire, some rougher around the edges.
“Would pain decisions change based on what people look like?” she asked. “Can you really spot who the drug traffickers are? We need to remember that our biases play a huge role not only in the treatment of our patients but in their outcomes. I’m challenging everybody to start thinking about these folks not as drug-seekers but as comfort-seekers.”
When it comes right down to it, she said, patients want a better life, not their drug of choice.
“That is the nature of the disease. [The illegal drug] is not what they’re looking for in reality because that does not provide a good quality of life,” Dr. Davis said. “The [practice of medicine] is supposed to be about helping people live their lives, not just checking off boxes.”
People with an opioid use disorder are physically different, she said. The processing of pain stimuli by their brain and spinal cord is physically altered – they have an increased perception of pain and lower pain tolerance.
“This is not a character flaw,” Dr. Davis affirmed. The increased sensitivity to pain does not resolve with opioid cessation; it can last for decades. Clinicians may need to spend more time interacting with certain patients to get a sense of the physical and nonphysical pain from which they suffer.
“Consistent, open, nonjudgmental communication improves not only the information we gather from patients and families, but it actually changes the adherence,” Dr. Davis said. “Ultimately the treatment outcomes are what all of this is about.”
Paradigm shift
Another palliative care role that hospitalists often find themselves in is “comforter” of elderly patients.
Ryan Greysen, MD, MHS, chief of hospital medicine at the University of Pennsylvania, Philadelphia, said hospitals must respond to a shift in the paradigm of elderly care. To explain the nature of this change, he referenced the “paradigm shift” model devised by the philosopher of science Thomas Kuhn, PhD. According to Kuhn, science proceeds in a settled pattern for many years, but on the rare occasions, when there is a fundamental drift in thinking, new problems present themselves and put the old model in a crisis mode, which prompts an intellectual revolution and a shift in the paradigm itself.
“This is a way of thinking about changes in scientific paradigms, but I think it works in clinical practice as well,” Dr. Greysen said.
The need for a paradigm shift in the care of elderly inpatients has largely to do with demographics. By 2050, the number of people aged 65 years and older is expected to be about 80 million, roughly double what it was in 2000. The number of people aged 85 years and up is expected to be about 20 million, or about four times the total in 2000.
In 2010, 40% of the hospitalized population was over 65 years. In 2030, that will flip: Only 40% of inpatients will be under 65 years. This will mean that hospitalists must care for more patients who are older, and the patients themselves will have more complicated medical issues.
“To be ready for the aging century, we must be better able to adapt and address those things that affect seniors,” Dr. Greysen said. With the number of geriatricians falling, much more of this care will fall to hospitalists, he said.
More attention must be paid to the potential harms of hospital-based care to older patients: decreased muscle strength and aerobic capacity, vasomotor instability, lower bone density, poor ventilation, altered thirst and nutrition, and fragile skin, among others, Dr. Greysen said.
In a study published in 2015, Dr. Greysen assessed outcomes for elderly patients who were assessed before hospitalization for functional impairment. The more impaired they were, the more likely they were to be readmitted within 30 days of discharge – from a 13.5% readmission rate for those with no impairment up to 18.2% for those considered to have “dependency” in three or more activities of daily living.1
In another analysis, severe functional impairment – dependency in at least two activities of daily living – was associated with more post-acute care Medicare costs than neurological disorders or renal failure.2
Acute care for the elderly (ACE) programs, which have care specifically tailored to the needs of older patients, have been found to be associated with less functional decline, shorter lengths of stay, fewer adverse events, and lower costs and readmission rates, Dr. Greysen said.
These programs are becoming more common, but they are not spreading as quickly as perhaps they should, he said. In part, this is because of the “know-do” gap, in which practical steps that have been shown to work are not actually implemented because of assumptions that they are already in place or the mistaken belief that simple steps could not possibly make a difference.
Part of the paradigm shift that’s needed, Dr. Greysen said, is an appreciation of the concept of “posthospitalization syndrome,” which is composed of several domains: sleep, function, nutrition, symptom burden such as pain and discomfort, cognition, level of engagement, psychosocial status including emotional stress, and treatment burden including the adverse effects of medications.
Better patient engagement in discharge planning – including asking patients about whether they’ve had help reading hospital discharge–related documents, their level of education, and how often they are getting out of bed – is one necessary step toward change. Surveys of satisfaction using tablets and patient portals is another option, Dr. Greysen said.
The patients of the future will likely prompt their own change, he said, quoting from a 2013 publication.
“Possibly the most promising predictor for change in delivery of care is change in the patients themselves,” the authors wrote. “Baby boomers have redefined the norms at every stage of their lives. ... They will expect providers to engage them in shared decision making, elicit their health care goals and treatment preferences, communicate with providers across sites, and provide needed social supports.”3
References
1. Greysen SR et al. Functional impairment and hospital readmission in medicare seniors. JAMA Intern Med. 2015 Apr;175(4):559-65.
2. Greysen SR et al. Functional impairment: An unmeasured marker of medicare costs for postacute care of older adults. J Am Geriatr Soc. 2017 Sep;65(9):1996-2002.
3. Laura A. Levit, Erin P. Balogh, Sharyl J. Nass, and Patricia A. Ganz, eds. Delivering High-Quality Cancer Care: Charting a New Course for a System in Crisis. (Washington (DC): National Academies Press (US), 2013 Dec 27).
Better engagement with patients essential
Better engagement with patients essential
A 57-year-old man is admitted to the hospital with new back pain, which has been getting worse over the past 6 days. He had been diagnosed with stage 4 lung cancer in mid-2017 and underwent treatment with a platinum-based double therapy.
The man also has a history of heroin use – as recently as two years earlier – and he was divorced not long ago. He has been using an old prescription for Vicodin to treat himself, taking as many as 10-12 tablets a day.
This man is an example of the kind of complicated patient hospitalists are called on to treat – complex pain in an era when opioid abuse is considered a public scourge. How is a hospitalist to handle a case like this?
Pain cases are far from the only types of increasingly complex, often palliative cases in which hospitalists are being asked to provide help. Care for the elderly is also becoming increasingly difficult as the U.S. population ages and as hospitalists step in to provide care in the absence of geriatricians. .
Pain management in the opioid era and the need for new approaches in elderly care were highlighted at the Hospital Medicine 2018 annual conference, with experts drawing attention to subtleties that are often overlooked in these sometimes desperate cases.
James Risser, MD, medical director of palliative care at Regions Hospital in Minneapolis, said the complex problems of the 57-year-old man with back pain amounted to an example of “pain’s greatest hits.”
That particular case underscores the need to identify individual types of pain, he said, because they all need to be handled differently. If hospitalists don’t consider all the different aspects of pain, a patient might endure more suffering than necessary.
“All of this pain is swirling around in a very complicated patient,” Dr. Risser said, noting that it is important to “tease out the individual parts” of a complex patient’s history.
“Pain is a very complicated construct, from the physical to the neurological to the emotional,” Dr. Risser said. “Pain is a subjective experience, and the way people interact with their pain really depends not just on physical pain but also their psychological state, their social state, and even their spiritual state.”
Understanding this array of causes has led Dr. Risser to approach the problem of pain from different angles – including perspectives that might not be traditional, he said.
“One of the things that I’ve gotten better at is taking a spiritual history,” he said. “I don’t know if that’s part of everybody’s armamentarium. But if you’re dealing with people who are very, very sick, sometimes that’s the fundamental fabric of how they live and how they die. If there are unresolved issues along those lines, it’s possible they could be experiencing their pain in a different or more severe way.”
Varieties of pain
Treatment depends on the pain type, Dr. Risser said. Somatic pain often responds to nonsteroidal anti-inflammatories or steroids.
Neuropathic pain usually responds poorly to anti-inflammatories and to opioids. There is some research suggesting methadone could be helpful, but the data are not very strong. The most common medications prescribed are antiseizure medications and antidepressants, such as gabapentin and serotonin, and norepinephrine reuptake inhibitors.
The question of cancer pain versus noncancer pain can be tricky, Dr. Risser said. If a person’s life expectancy is limited, there can be a reason, or even a requirement, to use higher-risk medications. But, he said, that doesn’t mean the patient still won’t have problems with overuse of pain medication.
“We have a lot of patients now living post cancer who have been put on methadone or have been put on Oxycontin, and now we’re trying to figure out what to do with them,” he said. “I don’t think it’s that clear anymore that there’s a massive difference between cancer and noncancer pain, especially for those survivors.”
Clinicians, he said, should “fix what can be fixed” – and with the right tools. “If you have a patient who’s got severe lower abdominal pain because they have a bladder full or urine, really the treatment would probably not be … opioids. It probably would be a Foley catheter,” he said.
Hospitalists should treat patients based on sound principles of pain management, Dr. Risser said, but “while you try to create a diagnostic framework, know that people continually defy the boxes we put them in.”
Indeed, in an era of pain-medication addiction, it might be a good idea to worry about prescribing opioids, but clinicians have to remember that their goal is to help patients get relief – and that they themselves bring biases to the table, said Amy Davis, DO, MS, of Drexel University, Philadelphia.
In a presentation at HM18, Dr. Davis displayed images of a variety of patients on a large screen – different races and genders, some in business attire, some rougher around the edges.
“Would pain decisions change based on what people look like?” she asked. “Can you really spot who the drug traffickers are? We need to remember that our biases play a huge role not only in the treatment of our patients but in their outcomes. I’m challenging everybody to start thinking about these folks not as drug-seekers but as comfort-seekers.”
When it comes right down to it, she said, patients want a better life, not their drug of choice.
“That is the nature of the disease. [The illegal drug] is not what they’re looking for in reality because that does not provide a good quality of life,” Dr. Davis said. “The [practice of medicine] is supposed to be about helping people live their lives, not just checking off boxes.”
People with an opioid use disorder are physically different, she said. The processing of pain stimuli by their brain and spinal cord is physically altered – they have an increased perception of pain and lower pain tolerance.
“This is not a character flaw,” Dr. Davis affirmed. The increased sensitivity to pain does not resolve with opioid cessation; it can last for decades. Clinicians may need to spend more time interacting with certain patients to get a sense of the physical and nonphysical pain from which they suffer.
“Consistent, open, nonjudgmental communication improves not only the information we gather from patients and families, but it actually changes the adherence,” Dr. Davis said. “Ultimately the treatment outcomes are what all of this is about.”
Paradigm shift
Another palliative care role that hospitalists often find themselves in is “comforter” of elderly patients.
Ryan Greysen, MD, MHS, chief of hospital medicine at the University of Pennsylvania, Philadelphia, said hospitals must respond to a shift in the paradigm of elderly care. To explain the nature of this change, he referenced the “paradigm shift” model devised by the philosopher of science Thomas Kuhn, PhD. According to Kuhn, science proceeds in a settled pattern for many years, but on the rare occasions, when there is a fundamental drift in thinking, new problems present themselves and put the old model in a crisis mode, which prompts an intellectual revolution and a shift in the paradigm itself.
“This is a way of thinking about changes in scientific paradigms, but I think it works in clinical practice as well,” Dr. Greysen said.
The need for a paradigm shift in the care of elderly inpatients has largely to do with demographics. By 2050, the number of people aged 65 years and older is expected to be about 80 million, roughly double what it was in 2000. The number of people aged 85 years and up is expected to be about 20 million, or about four times the total in 2000.
In 2010, 40% of the hospitalized population was over 65 years. In 2030, that will flip: Only 40% of inpatients will be under 65 years. This will mean that hospitalists must care for more patients who are older, and the patients themselves will have more complicated medical issues.
“To be ready for the aging century, we must be better able to adapt and address those things that affect seniors,” Dr. Greysen said. With the number of geriatricians falling, much more of this care will fall to hospitalists, he said.
More attention must be paid to the potential harms of hospital-based care to older patients: decreased muscle strength and aerobic capacity, vasomotor instability, lower bone density, poor ventilation, altered thirst and nutrition, and fragile skin, among others, Dr. Greysen said.
In a study published in 2015, Dr. Greysen assessed outcomes for elderly patients who were assessed before hospitalization for functional impairment. The more impaired they were, the more likely they were to be readmitted within 30 days of discharge – from a 13.5% readmission rate for those with no impairment up to 18.2% for those considered to have “dependency” in three or more activities of daily living.1
In another analysis, severe functional impairment – dependency in at least two activities of daily living – was associated with more post-acute care Medicare costs than neurological disorders or renal failure.2
Acute care for the elderly (ACE) programs, which have care specifically tailored to the needs of older patients, have been found to be associated with less functional decline, shorter lengths of stay, fewer adverse events, and lower costs and readmission rates, Dr. Greysen said.
These programs are becoming more common, but they are not spreading as quickly as perhaps they should, he said. In part, this is because of the “know-do” gap, in which practical steps that have been shown to work are not actually implemented because of assumptions that they are already in place or the mistaken belief that simple steps could not possibly make a difference.
Part of the paradigm shift that’s needed, Dr. Greysen said, is an appreciation of the concept of “posthospitalization syndrome,” which is composed of several domains: sleep, function, nutrition, symptom burden such as pain and discomfort, cognition, level of engagement, psychosocial status including emotional stress, and treatment burden including the adverse effects of medications.
Better patient engagement in discharge planning – including asking patients about whether they’ve had help reading hospital discharge–related documents, their level of education, and how often they are getting out of bed – is one necessary step toward change. Surveys of satisfaction using tablets and patient portals is another option, Dr. Greysen said.
The patients of the future will likely prompt their own change, he said, quoting from a 2013 publication.
“Possibly the most promising predictor for change in delivery of care is change in the patients themselves,” the authors wrote. “Baby boomers have redefined the norms at every stage of their lives. ... They will expect providers to engage them in shared decision making, elicit their health care goals and treatment preferences, communicate with providers across sites, and provide needed social supports.”3
References
1. Greysen SR et al. Functional impairment and hospital readmission in medicare seniors. JAMA Intern Med. 2015 Apr;175(4):559-65.
2. Greysen SR et al. Functional impairment: An unmeasured marker of medicare costs for postacute care of older adults. J Am Geriatr Soc. 2017 Sep;65(9):1996-2002.
3. Laura A. Levit, Erin P. Balogh, Sharyl J. Nass, and Patricia A. Ganz, eds. Delivering High-Quality Cancer Care: Charting a New Course for a System in Crisis. (Washington (DC): National Academies Press (US), 2013 Dec 27).
A 57-year-old man is admitted to the hospital with new back pain, which has been getting worse over the past 6 days. He had been diagnosed with stage 4 lung cancer in mid-2017 and underwent treatment with a platinum-based double therapy.
The man also has a history of heroin use – as recently as two years earlier – and he was divorced not long ago. He has been using an old prescription for Vicodin to treat himself, taking as many as 10-12 tablets a day.
This man is an example of the kind of complicated patient hospitalists are called on to treat – complex pain in an era when opioid abuse is considered a public scourge. How is a hospitalist to handle a case like this?
Pain cases are far from the only types of increasingly complex, often palliative cases in which hospitalists are being asked to provide help. Care for the elderly is also becoming increasingly difficult as the U.S. population ages and as hospitalists step in to provide care in the absence of geriatricians. .
Pain management in the opioid era and the need for new approaches in elderly care were highlighted at the Hospital Medicine 2018 annual conference, with experts drawing attention to subtleties that are often overlooked in these sometimes desperate cases.
James Risser, MD, medical director of palliative care at Regions Hospital in Minneapolis, said the complex problems of the 57-year-old man with back pain amounted to an example of “pain’s greatest hits.”
That particular case underscores the need to identify individual types of pain, he said, because they all need to be handled differently. If hospitalists don’t consider all the different aspects of pain, a patient might endure more suffering than necessary.
“All of this pain is swirling around in a very complicated patient,” Dr. Risser said, noting that it is important to “tease out the individual parts” of a complex patient’s history.
“Pain is a very complicated construct, from the physical to the neurological to the emotional,” Dr. Risser said. “Pain is a subjective experience, and the way people interact with their pain really depends not just on physical pain but also their psychological state, their social state, and even their spiritual state.”
Understanding this array of causes has led Dr. Risser to approach the problem of pain from different angles – including perspectives that might not be traditional, he said.
“One of the things that I’ve gotten better at is taking a spiritual history,” he said. “I don’t know if that’s part of everybody’s armamentarium. But if you’re dealing with people who are very, very sick, sometimes that’s the fundamental fabric of how they live and how they die. If there are unresolved issues along those lines, it’s possible they could be experiencing their pain in a different or more severe way.”
Varieties of pain
Treatment depends on the pain type, Dr. Risser said. Somatic pain often responds to nonsteroidal anti-inflammatories or steroids.
Neuropathic pain usually responds poorly to anti-inflammatories and to opioids. There is some research suggesting methadone could be helpful, but the data are not very strong. The most common medications prescribed are antiseizure medications and antidepressants, such as gabapentin and serotonin, and norepinephrine reuptake inhibitors.
The question of cancer pain versus noncancer pain can be tricky, Dr. Risser said. If a person’s life expectancy is limited, there can be a reason, or even a requirement, to use higher-risk medications. But, he said, that doesn’t mean the patient still won’t have problems with overuse of pain medication.
“We have a lot of patients now living post cancer who have been put on methadone or have been put on Oxycontin, and now we’re trying to figure out what to do with them,” he said. “I don’t think it’s that clear anymore that there’s a massive difference between cancer and noncancer pain, especially for those survivors.”
Clinicians, he said, should “fix what can be fixed” – and with the right tools. “If you have a patient who’s got severe lower abdominal pain because they have a bladder full or urine, really the treatment would probably not be … opioids. It probably would be a Foley catheter,” he said.
Hospitalists should treat patients based on sound principles of pain management, Dr. Risser said, but “while you try to create a diagnostic framework, know that people continually defy the boxes we put them in.”
Indeed, in an era of pain-medication addiction, it might be a good idea to worry about prescribing opioids, but clinicians have to remember that their goal is to help patients get relief – and that they themselves bring biases to the table, said Amy Davis, DO, MS, of Drexel University, Philadelphia.
In a presentation at HM18, Dr. Davis displayed images of a variety of patients on a large screen – different races and genders, some in business attire, some rougher around the edges.
“Would pain decisions change based on what people look like?” she asked. “Can you really spot who the drug traffickers are? We need to remember that our biases play a huge role not only in the treatment of our patients but in their outcomes. I’m challenging everybody to start thinking about these folks not as drug-seekers but as comfort-seekers.”
When it comes right down to it, she said, patients want a better life, not their drug of choice.
“That is the nature of the disease. [The illegal drug] is not what they’re looking for in reality because that does not provide a good quality of life,” Dr. Davis said. “The [practice of medicine] is supposed to be about helping people live their lives, not just checking off boxes.”
People with an opioid use disorder are physically different, she said. The processing of pain stimuli by their brain and spinal cord is physically altered – they have an increased perception of pain and lower pain tolerance.
“This is not a character flaw,” Dr. Davis affirmed. The increased sensitivity to pain does not resolve with opioid cessation; it can last for decades. Clinicians may need to spend more time interacting with certain patients to get a sense of the physical and nonphysical pain from which they suffer.
“Consistent, open, nonjudgmental communication improves not only the information we gather from patients and families, but it actually changes the adherence,” Dr. Davis said. “Ultimately the treatment outcomes are what all of this is about.”
Paradigm shift
Another palliative care role that hospitalists often find themselves in is “comforter” of elderly patients.
Ryan Greysen, MD, MHS, chief of hospital medicine at the University of Pennsylvania, Philadelphia, said hospitals must respond to a shift in the paradigm of elderly care. To explain the nature of this change, he referenced the “paradigm shift” model devised by the philosopher of science Thomas Kuhn, PhD. According to Kuhn, science proceeds in a settled pattern for many years, but on the rare occasions, when there is a fundamental drift in thinking, new problems present themselves and put the old model in a crisis mode, which prompts an intellectual revolution and a shift in the paradigm itself.
“This is a way of thinking about changes in scientific paradigms, but I think it works in clinical practice as well,” Dr. Greysen said.
The need for a paradigm shift in the care of elderly inpatients has largely to do with demographics. By 2050, the number of people aged 65 years and older is expected to be about 80 million, roughly double what it was in 2000. The number of people aged 85 years and up is expected to be about 20 million, or about four times the total in 2000.
In 2010, 40% of the hospitalized population was over 65 years. In 2030, that will flip: Only 40% of inpatients will be under 65 years. This will mean that hospitalists must care for more patients who are older, and the patients themselves will have more complicated medical issues.
“To be ready for the aging century, we must be better able to adapt and address those things that affect seniors,” Dr. Greysen said. With the number of geriatricians falling, much more of this care will fall to hospitalists, he said.
More attention must be paid to the potential harms of hospital-based care to older patients: decreased muscle strength and aerobic capacity, vasomotor instability, lower bone density, poor ventilation, altered thirst and nutrition, and fragile skin, among others, Dr. Greysen said.
In a study published in 2015, Dr. Greysen assessed outcomes for elderly patients who were assessed before hospitalization for functional impairment. The more impaired they were, the more likely they were to be readmitted within 30 days of discharge – from a 13.5% readmission rate for those with no impairment up to 18.2% for those considered to have “dependency” in three or more activities of daily living.1
In another analysis, severe functional impairment – dependency in at least two activities of daily living – was associated with more post-acute care Medicare costs than neurological disorders or renal failure.2
Acute care for the elderly (ACE) programs, which have care specifically tailored to the needs of older patients, have been found to be associated with less functional decline, shorter lengths of stay, fewer adverse events, and lower costs and readmission rates, Dr. Greysen said.
These programs are becoming more common, but they are not spreading as quickly as perhaps they should, he said. In part, this is because of the “know-do” gap, in which practical steps that have been shown to work are not actually implemented because of assumptions that they are already in place or the mistaken belief that simple steps could not possibly make a difference.
Part of the paradigm shift that’s needed, Dr. Greysen said, is an appreciation of the concept of “posthospitalization syndrome,” which is composed of several domains: sleep, function, nutrition, symptom burden such as pain and discomfort, cognition, level of engagement, psychosocial status including emotional stress, and treatment burden including the adverse effects of medications.
Better patient engagement in discharge planning – including asking patients about whether they’ve had help reading hospital discharge–related documents, their level of education, and how often they are getting out of bed – is one necessary step toward change. Surveys of satisfaction using tablets and patient portals is another option, Dr. Greysen said.
The patients of the future will likely prompt their own change, he said, quoting from a 2013 publication.
“Possibly the most promising predictor for change in delivery of care is change in the patients themselves,” the authors wrote. “Baby boomers have redefined the norms at every stage of their lives. ... They will expect providers to engage them in shared decision making, elicit their health care goals and treatment preferences, communicate with providers across sites, and provide needed social supports.”3
References
1. Greysen SR et al. Functional impairment and hospital readmission in medicare seniors. JAMA Intern Med. 2015 Apr;175(4):559-65.
2. Greysen SR et al. Functional impairment: An unmeasured marker of medicare costs for postacute care of older adults. J Am Geriatr Soc. 2017 Sep;65(9):1996-2002.
3. Laura A. Levit, Erin P. Balogh, Sharyl J. Nass, and Patricia A. Ganz, eds. Delivering High-Quality Cancer Care: Charting a New Course for a System in Crisis. (Washington (DC): National Academies Press (US), 2013 Dec 27).
Poor outcomes for RCC with nodal involvement: Time to reconsider staging criteria?
Among patients with stage III renal cell carcinoma (RCC) by current staging criteria, survival outcomes are worse for those who have pathological nodal involvement, results of a retrospective study suggest.
Survival was significantly shorter for stage III patients with nodal involvement versus those with no involvement, and was “equivalent” to survival in stage IV RCC patients, according to study author Jose A. Karam, MD, of the University of Texas MD Anderson Cancer Center, Houston, and his coauthors.
“If these findings are validated in other studies, consideration should be given to reclassifying patients with stage III, pN1 disease as having stage IV disease,” Dr. Karam and his coauthors wrote in Cancer.
Dr. Karam and his colleagues looked at records for patients with RCC of any histologic subtype who had undergone radical or partial nephrectomy between 1993 and 2012. Their analysis included a total of 389 patients with stage III disease, including 274 with node-positive disease (pT3N0M0) and 115 with node-negative disease (pT123N1M0), along with 523 patients who had stage IV disease.
They found that median overall survival was just 2.4 years (95% confidence interval, 1.7-4.1) for stage III, node-positive disease patients, compared with 10.2 years (95% CI, 8.7-not estimable [NE]) for stage III, node-negative disease and 2.4 years (95% CI, 2.1-3.0) for stage IV disease.
There was a significant difference in overall survival between the three groups, but no significant difference between patients with stage III node-positive disease and stage IV disease, the investigators wrote.
Similarly, median cancer-specific survival was 2.8 years (95% CI, 1.8-4.8) for stage III node-positive disease, not reached (95% CI, 10.2-NE) for stage III node-negative disease, and 2.4 years (95% CI, 2.1-3.0) for stage IV disease, the investigators wrote.
In multivariate analysis, pathological lymph node involvement in the stage III patients was independently associated with worse overall and cancer-specific survival.
Dr. Karam and his coauthors wrote that it may be prudent to revise the current staging system to reclassify node-positive patients if further research confirms their findings. By the current American Joint Committee on Cancer tumor, nodes, and metastases staging manual, patients can be classified as stage III on the basis of either primary tumor status (pT3) or pathological lymph node involvement, they said.
The incidence of pathological, node-positive disease in RCC ranges from 2%-10% in studies, with 5-year survival rates that are “poor” at 5%-30%, the authors noted in their report.
“Even in the targeted therapy era, adjuvant therapy with tyrosine kinase inhibitors does not appear to improve on these outcomes in patients with pN-positive disease,” they wrote.
Funding support for the research came from the National Institutes of Health/National Cancer Institute. Dr. Karam reported serving as a consultant/advisory board member for Pfizer, EMD Serono, Novartis, and Roche/Genentech, and that the MD Anderson Cancer Center has received clinical trial research funding from Roche/Genentech, though none of these disclosures were related to the current report.
SOURCE: Karam JA et al. Cancer. 2018 Oct 1. doi: 10.1002/cncr.31661.
Among patients with stage III renal cell carcinoma (RCC) by current staging criteria, survival outcomes are worse for those who have pathological nodal involvement, results of a retrospective study suggest.
Survival was significantly shorter for stage III patients with nodal involvement versus those with no involvement, and was “equivalent” to survival in stage IV RCC patients, according to study author Jose A. Karam, MD, of the University of Texas MD Anderson Cancer Center, Houston, and his coauthors.
“If these findings are validated in other studies, consideration should be given to reclassifying patients with stage III, pN1 disease as having stage IV disease,” Dr. Karam and his coauthors wrote in Cancer.
Dr. Karam and his colleagues looked at records for patients with RCC of any histologic subtype who had undergone radical or partial nephrectomy between 1993 and 2012. Their analysis included a total of 389 patients with stage III disease, including 274 with node-positive disease (pT3N0M0) and 115 with node-negative disease (pT123N1M0), along with 523 patients who had stage IV disease.
They found that median overall survival was just 2.4 years (95% confidence interval, 1.7-4.1) for stage III, node-positive disease patients, compared with 10.2 years (95% CI, 8.7-not estimable [NE]) for stage III, node-negative disease and 2.4 years (95% CI, 2.1-3.0) for stage IV disease.
There was a significant difference in overall survival between the three groups, but no significant difference between patients with stage III node-positive disease and stage IV disease, the investigators wrote.
Similarly, median cancer-specific survival was 2.8 years (95% CI, 1.8-4.8) for stage III node-positive disease, not reached (95% CI, 10.2-NE) for stage III node-negative disease, and 2.4 years (95% CI, 2.1-3.0) for stage IV disease, the investigators wrote.
In multivariate analysis, pathological lymph node involvement in the stage III patients was independently associated with worse overall and cancer-specific survival.
Dr. Karam and his coauthors wrote that it may be prudent to revise the current staging system to reclassify node-positive patients if further research confirms their findings. By the current American Joint Committee on Cancer tumor, nodes, and metastases staging manual, patients can be classified as stage III on the basis of either primary tumor status (pT3) or pathological lymph node involvement, they said.
The incidence of pathological, node-positive disease in RCC ranges from 2%-10% in studies, with 5-year survival rates that are “poor” at 5%-30%, the authors noted in their report.
“Even in the targeted therapy era, adjuvant therapy with tyrosine kinase inhibitors does not appear to improve on these outcomes in patients with pN-positive disease,” they wrote.
Funding support for the research came from the National Institutes of Health/National Cancer Institute. Dr. Karam reported serving as a consultant/advisory board member for Pfizer, EMD Serono, Novartis, and Roche/Genentech, and that the MD Anderson Cancer Center has received clinical trial research funding from Roche/Genentech, though none of these disclosures were related to the current report.
SOURCE: Karam JA et al. Cancer. 2018 Oct 1. doi: 10.1002/cncr.31661.
Among patients with stage III renal cell carcinoma (RCC) by current staging criteria, survival outcomes are worse for those who have pathological nodal involvement, results of a retrospective study suggest.
Survival was significantly shorter for stage III patients with nodal involvement versus those with no involvement, and was “equivalent” to survival in stage IV RCC patients, according to study author Jose A. Karam, MD, of the University of Texas MD Anderson Cancer Center, Houston, and his coauthors.
“If these findings are validated in other studies, consideration should be given to reclassifying patients with stage III, pN1 disease as having stage IV disease,” Dr. Karam and his coauthors wrote in Cancer.
Dr. Karam and his colleagues looked at records for patients with RCC of any histologic subtype who had undergone radical or partial nephrectomy between 1993 and 2012. Their analysis included a total of 389 patients with stage III disease, including 274 with node-positive disease (pT3N0M0) and 115 with node-negative disease (pT123N1M0), along with 523 patients who had stage IV disease.
They found that median overall survival was just 2.4 years (95% confidence interval, 1.7-4.1) for stage III, node-positive disease patients, compared with 10.2 years (95% CI, 8.7-not estimable [NE]) for stage III, node-negative disease and 2.4 years (95% CI, 2.1-3.0) for stage IV disease.
There was a significant difference in overall survival between the three groups, but no significant difference between patients with stage III node-positive disease and stage IV disease, the investigators wrote.
Similarly, median cancer-specific survival was 2.8 years (95% CI, 1.8-4.8) for stage III node-positive disease, not reached (95% CI, 10.2-NE) for stage III node-negative disease, and 2.4 years (95% CI, 2.1-3.0) for stage IV disease, the investigators wrote.
In multivariate analysis, pathological lymph node involvement in the stage III patients was independently associated with worse overall and cancer-specific survival.
Dr. Karam and his coauthors wrote that it may be prudent to revise the current staging system to reclassify node-positive patients if further research confirms their findings. By the current American Joint Committee on Cancer tumor, nodes, and metastases staging manual, patients can be classified as stage III on the basis of either primary tumor status (pT3) or pathological lymph node involvement, they said.
The incidence of pathological, node-positive disease in RCC ranges from 2%-10% in studies, with 5-year survival rates that are “poor” at 5%-30%, the authors noted in their report.
“Even in the targeted therapy era, adjuvant therapy with tyrosine kinase inhibitors does not appear to improve on these outcomes in patients with pN-positive disease,” they wrote.
Funding support for the research came from the National Institutes of Health/National Cancer Institute. Dr. Karam reported serving as a consultant/advisory board member for Pfizer, EMD Serono, Novartis, and Roche/Genentech, and that the MD Anderson Cancer Center has received clinical trial research funding from Roche/Genentech, though none of these disclosures were related to the current report.
SOURCE: Karam JA et al. Cancer. 2018 Oct 1. doi: 10.1002/cncr.31661.
FROM CANCER
Key clinical point: Among patients with stage III renal cell carcinoma, survival outcomes for those with nodal involvement are worse than for those with no nodal involvement and comparable with patients with stage IV disease, suggesting a potential need to revisit current staging criteria.
Major finding: Overall survival was 2.4 years for stage III node-positive disease, 10.2 years for stage III, node-negative disease, and 2.4 years for stage IV disease.
Study details: A retrospective study including 912 patients with renal cell carcinoma who underwent radical or partial nephrectomy between 1993 and 2012.
Disclosures: Funding was reported from the National Institutes of Health/National Cancer Institute. One study author provided disclosures with Pfizer, EMD Serono, Novartis, and Roche/Genentech.
Source: Karam JA et al. Cancer. 2018 Oct 1. doi: 10.1002/cncr.31661.
What is your diagnosis?
Lichen nitidus, which literally means “shiny moss,” is a relatively rare, chronic skin eruption that is characterized clinically by asymptomatic, flat-topped, sharply-demarcated, skin-colored papules, which are sometimes described as being “pinpoint.”
Lichen nitidus mainly affects children and young adults. The most common sites of involvement are the trunk, flexor aspects of upper extremities, dorsal aspects of hands, and genitalia, but lesions can occur anywhere on the skin. The lesions also can develop in sites of trauma (Koebner phenomenon), and this can be a significant clinical clue to aid in the diagnosis of lichen nitidus in favor of other conditions which may present as many small papules.1 Nail changes can occur but are rare, presenting as dystrophy, pitting, riding, or loss of nail(s).2
Lichen nitidus can be a challenging diagnosis to make, especially if a practitioner is not used to seeing it. Many dermatologic conditions present with many fine papules, including the other answer choices in the given quiz question (molluscum contagiosum, keratosis pilaris, verruca vulgaris, papular eczema). What allows for a clearer diagnosis of lichen nitidus is the history provided by the patient as well as the exam. Lichen nitidus lesions typically arise without a known trigger and often persist for months while remaining asymptomatic.
Molluscum contagiosum tends to include papules that are larger and more substantial than lichen nitidus papules and may be accompanied by background hyperpigmentation or erythema, known as the “beginning of the end” sign. Keratosis pilaris is commonly thought of as a skin type more so than a skin condition, and is more commonly seen in fair-skinned individuals along the lateral arms and cheeks. It is commonly paired with a background of erythema and skin than tends to be more xerotic. Verruca are typically larger lesions, sometimes with a rough surface, and are not typically shiny. Verruca are more likely to present as a single lesion or a few lesions at a given location, as opposed to lichen nitidus which has many individual papules at a single location. Papular eczema typically is intensely pruritic and is associated with xerosis and atopy.
The cause of lichen nitidus is unknown, and there are no reported genetic factors that contribute to its presentation.3 It is thought to be a subtype of lichen planus, although this is still debated. There is more work that needs to be done to find answers to these questions and to assess what triggers these fine papules to present and in whom.
The dermatoscopic features of lichen nitidus were reported in a series of eight cases and include absent dermatoglyphics, radial ridges, ill-defined hypopigmentation, diffuse erythema, linear vessels within the lesion, and peripheral scaling.4 These features are distinctive in combination and can in some cases be used to clinically diagnose lichen nitidus without the need for a skin biopsy, which is an invasive procedure that should be avoided when possible, especially given the benign nature of lichen nitidus.
If a biopsy is performed, the histologic features that commonly are seen include well-circumscribed granuloma-like lymphohistiocytic infiltrates in the papillary dermis adjacent to ridges, mimicking a “ball-and-claw” formation.1,5
Lichen nitidus generally is self-limiting, with minimal cosmetic disruption; therefore, treatment usually is not necessary. The lesions typically resolve within 1 year of presentation – and often sooner. Topical steroids can be used for symptomatic relief of pruritus, but generally do not hasten resolution of the papules themselves. Additionally, there have been reports in the literature of the successful resolution of lesions using topical calcineurin inhibitors and UVB therapy.
In a case report of an 8-year-old child with histologically confirmed lichen nitidus that had been present for 2 years, pimecrolimus 1% cream was used twice daily for 2 months with improvement and flattening of the papules.6 This report is compelling because the lesions persisted for twice the expected time of resolution without improvement and then showed relatively quick response to pimecrolimus. In a case of a 32-year-old male with lichen nitidus on his penis, tacrolimus 0.1% was used for 4 weeks with resolution of the papules.7 Although given that lichen nitidus can self-resolve in this same time period, it is unclear in this case whether the tacrolimus was the independent cause of the resolution.
With regard to UVB therapy, there have been reports of lichen nitidus resolution after 17-30 irradiation sessions in patients with lesions present for 3-6 months, although again, it is possible that the resolution observed was simply the natural course of the lichen nitidus for these patients rather than a therapeutic benefit of UVB therapy.8,9
Given that lichen nitidus is benign and typically asymptomatic or with mild pruritus, it is reasonable to monitor the lesions without treating them. If the lesions persist beyond 1 year, it also is reasonable to trial therapies, such as topical calcineurin inhibitors and UVB therapy, although using these treatments earlier in the disease course has only limited supporting data and any improvement seen within 1 year of onset may be attributed to the natural disease course as opposed to an effect of the intervention. Considerations of the cost of therapy, as well as the degree to which the patient is bothered by the lesions and how long the lesions have persisted, should be undertaken when considering whether an intervention should be made.
Ms. Natsis is a medical student at the University of California, San Diego. Dr. Eichenfield is chief of pediatric and adolescent dermatology at Rady Children’s Hospital–San Diego. He is vice chair of the department of dermatology and professor of dermatology and pediatrics at the University of California, San Diego. There are no conflicts of interest or financial disclosures for Ms. Natsis or Dr. Eichenfield. Email them at [email protected].
References
1. Cutis. 1999 Aug 1;64(2):135-6.
2. J Am Acad Dermatol. 2004 Oct;51(4):606-24.
3. Papulosquamous diseases, in “Pediatric Dermatology,” 4th ed. (St Louis: Mosby; 2011, Vol. 2.
4. Pediatr Dermatol. 2018. doi: 10.1111/pde.13576.
5. Cutis. 2013 Dec;92(6):288, 297-8.
6. Dermatol Online J. 2011 Jul 15;17(7):11.
7. J Drugs Dermatol. 2004 Nov-Dec;3(6):683-4.
8. Int J Dermatol. 2004 Dec 23;45:615-7.
9. Photodermatol Photoimmunol Photomed. 2013 Aug;29(4):215-7.
Lichen nitidus, which literally means “shiny moss,” is a relatively rare, chronic skin eruption that is characterized clinically by asymptomatic, flat-topped, sharply-demarcated, skin-colored papules, which are sometimes described as being “pinpoint.”
Lichen nitidus mainly affects children and young adults. The most common sites of involvement are the trunk, flexor aspects of upper extremities, dorsal aspects of hands, and genitalia, but lesions can occur anywhere on the skin. The lesions also can develop in sites of trauma (Koebner phenomenon), and this can be a significant clinical clue to aid in the diagnosis of lichen nitidus in favor of other conditions which may present as many small papules.1 Nail changes can occur but are rare, presenting as dystrophy, pitting, riding, or loss of nail(s).2
Lichen nitidus can be a challenging diagnosis to make, especially if a practitioner is not used to seeing it. Many dermatologic conditions present with many fine papules, including the other answer choices in the given quiz question (molluscum contagiosum, keratosis pilaris, verruca vulgaris, papular eczema). What allows for a clearer diagnosis of lichen nitidus is the history provided by the patient as well as the exam. Lichen nitidus lesions typically arise without a known trigger and often persist for months while remaining asymptomatic.
Molluscum contagiosum tends to include papules that are larger and more substantial than lichen nitidus papules and may be accompanied by background hyperpigmentation or erythema, known as the “beginning of the end” sign. Keratosis pilaris is commonly thought of as a skin type more so than a skin condition, and is more commonly seen in fair-skinned individuals along the lateral arms and cheeks. It is commonly paired with a background of erythema and skin than tends to be more xerotic. Verruca are typically larger lesions, sometimes with a rough surface, and are not typically shiny. Verruca are more likely to present as a single lesion or a few lesions at a given location, as opposed to lichen nitidus which has many individual papules at a single location. Papular eczema typically is intensely pruritic and is associated with xerosis and atopy.
The cause of lichen nitidus is unknown, and there are no reported genetic factors that contribute to its presentation.3 It is thought to be a subtype of lichen planus, although this is still debated. There is more work that needs to be done to find answers to these questions and to assess what triggers these fine papules to present and in whom.
The dermatoscopic features of lichen nitidus were reported in a series of eight cases and include absent dermatoglyphics, radial ridges, ill-defined hypopigmentation, diffuse erythema, linear vessels within the lesion, and peripheral scaling.4 These features are distinctive in combination and can in some cases be used to clinically diagnose lichen nitidus without the need for a skin biopsy, which is an invasive procedure that should be avoided when possible, especially given the benign nature of lichen nitidus.
If a biopsy is performed, the histologic features that commonly are seen include well-circumscribed granuloma-like lymphohistiocytic infiltrates in the papillary dermis adjacent to ridges, mimicking a “ball-and-claw” formation.1,5
Lichen nitidus generally is self-limiting, with minimal cosmetic disruption; therefore, treatment usually is not necessary. The lesions typically resolve within 1 year of presentation – and often sooner. Topical steroids can be used for symptomatic relief of pruritus, but generally do not hasten resolution of the papules themselves. Additionally, there have been reports in the literature of the successful resolution of lesions using topical calcineurin inhibitors and UVB therapy.
In a case report of an 8-year-old child with histologically confirmed lichen nitidus that had been present for 2 years, pimecrolimus 1% cream was used twice daily for 2 months with improvement and flattening of the papules.6 This report is compelling because the lesions persisted for twice the expected time of resolution without improvement and then showed relatively quick response to pimecrolimus. In a case of a 32-year-old male with lichen nitidus on his penis, tacrolimus 0.1% was used for 4 weeks with resolution of the papules.7 Although given that lichen nitidus can self-resolve in this same time period, it is unclear in this case whether the tacrolimus was the independent cause of the resolution.
With regard to UVB therapy, there have been reports of lichen nitidus resolution after 17-30 irradiation sessions in patients with lesions present for 3-6 months, although again, it is possible that the resolution observed was simply the natural course of the lichen nitidus for these patients rather than a therapeutic benefit of UVB therapy.8,9
Given that lichen nitidus is benign and typically asymptomatic or with mild pruritus, it is reasonable to monitor the lesions without treating them. If the lesions persist beyond 1 year, it also is reasonable to trial therapies, such as topical calcineurin inhibitors and UVB therapy, although using these treatments earlier in the disease course has only limited supporting data and any improvement seen within 1 year of onset may be attributed to the natural disease course as opposed to an effect of the intervention. Considerations of the cost of therapy, as well as the degree to which the patient is bothered by the lesions and how long the lesions have persisted, should be undertaken when considering whether an intervention should be made.
Ms. Natsis is a medical student at the University of California, San Diego. Dr. Eichenfield is chief of pediatric and adolescent dermatology at Rady Children’s Hospital–San Diego. He is vice chair of the department of dermatology and professor of dermatology and pediatrics at the University of California, San Diego. There are no conflicts of interest or financial disclosures for Ms. Natsis or Dr. Eichenfield. Email them at [email protected].
References
1. Cutis. 1999 Aug 1;64(2):135-6.
2. J Am Acad Dermatol. 2004 Oct;51(4):606-24.
3. Papulosquamous diseases, in “Pediatric Dermatology,” 4th ed. (St Louis: Mosby; 2011, Vol. 2.
4. Pediatr Dermatol. 2018. doi: 10.1111/pde.13576.
5. Cutis. 2013 Dec;92(6):288, 297-8.
6. Dermatol Online J. 2011 Jul 15;17(7):11.
7. J Drugs Dermatol. 2004 Nov-Dec;3(6):683-4.
8. Int J Dermatol. 2004 Dec 23;45:615-7.
9. Photodermatol Photoimmunol Photomed. 2013 Aug;29(4):215-7.
Lichen nitidus, which literally means “shiny moss,” is a relatively rare, chronic skin eruption that is characterized clinically by asymptomatic, flat-topped, sharply-demarcated, skin-colored papules, which are sometimes described as being “pinpoint.”
Lichen nitidus mainly affects children and young adults. The most common sites of involvement are the trunk, flexor aspects of upper extremities, dorsal aspects of hands, and genitalia, but lesions can occur anywhere on the skin. The lesions also can develop in sites of trauma (Koebner phenomenon), and this can be a significant clinical clue to aid in the diagnosis of lichen nitidus in favor of other conditions which may present as many small papules.1 Nail changes can occur but are rare, presenting as dystrophy, pitting, riding, or loss of nail(s).2
Lichen nitidus can be a challenging diagnosis to make, especially if a practitioner is not used to seeing it. Many dermatologic conditions present with many fine papules, including the other answer choices in the given quiz question (molluscum contagiosum, keratosis pilaris, verruca vulgaris, papular eczema). What allows for a clearer diagnosis of lichen nitidus is the history provided by the patient as well as the exam. Lichen nitidus lesions typically arise without a known trigger and often persist for months while remaining asymptomatic.
Molluscum contagiosum tends to include papules that are larger and more substantial than lichen nitidus papules and may be accompanied by background hyperpigmentation or erythema, known as the “beginning of the end” sign. Keratosis pilaris is commonly thought of as a skin type more so than a skin condition, and is more commonly seen in fair-skinned individuals along the lateral arms and cheeks. It is commonly paired with a background of erythema and skin than tends to be more xerotic. Verruca are typically larger lesions, sometimes with a rough surface, and are not typically shiny. Verruca are more likely to present as a single lesion or a few lesions at a given location, as opposed to lichen nitidus which has many individual papules at a single location. Papular eczema typically is intensely pruritic and is associated with xerosis and atopy.
The cause of lichen nitidus is unknown, and there are no reported genetic factors that contribute to its presentation.3 It is thought to be a subtype of lichen planus, although this is still debated. There is more work that needs to be done to find answers to these questions and to assess what triggers these fine papules to present and in whom.
The dermatoscopic features of lichen nitidus were reported in a series of eight cases and include absent dermatoglyphics, radial ridges, ill-defined hypopigmentation, diffuse erythema, linear vessels within the lesion, and peripheral scaling.4 These features are distinctive in combination and can in some cases be used to clinically diagnose lichen nitidus without the need for a skin biopsy, which is an invasive procedure that should be avoided when possible, especially given the benign nature of lichen nitidus.
If a biopsy is performed, the histologic features that commonly are seen include well-circumscribed granuloma-like lymphohistiocytic infiltrates in the papillary dermis adjacent to ridges, mimicking a “ball-and-claw” formation.1,5
Lichen nitidus generally is self-limiting, with minimal cosmetic disruption; therefore, treatment usually is not necessary. The lesions typically resolve within 1 year of presentation – and often sooner. Topical steroids can be used for symptomatic relief of pruritus, but generally do not hasten resolution of the papules themselves. Additionally, there have been reports in the literature of the successful resolution of lesions using topical calcineurin inhibitors and UVB therapy.
In a case report of an 8-year-old child with histologically confirmed lichen nitidus that had been present for 2 years, pimecrolimus 1% cream was used twice daily for 2 months with improvement and flattening of the papules.6 This report is compelling because the lesions persisted for twice the expected time of resolution without improvement and then showed relatively quick response to pimecrolimus. In a case of a 32-year-old male with lichen nitidus on his penis, tacrolimus 0.1% was used for 4 weeks with resolution of the papules.7 Although given that lichen nitidus can self-resolve in this same time period, it is unclear in this case whether the tacrolimus was the independent cause of the resolution.
With regard to UVB therapy, there have been reports of lichen nitidus resolution after 17-30 irradiation sessions in patients with lesions present for 3-6 months, although again, it is possible that the resolution observed was simply the natural course of the lichen nitidus for these patients rather than a therapeutic benefit of UVB therapy.8,9
Given that lichen nitidus is benign and typically asymptomatic or with mild pruritus, it is reasonable to monitor the lesions without treating them. If the lesions persist beyond 1 year, it also is reasonable to trial therapies, such as topical calcineurin inhibitors and UVB therapy, although using these treatments earlier in the disease course has only limited supporting data and any improvement seen within 1 year of onset may be attributed to the natural disease course as opposed to an effect of the intervention. Considerations of the cost of therapy, as well as the degree to which the patient is bothered by the lesions and how long the lesions have persisted, should be undertaken when considering whether an intervention should be made.
Ms. Natsis is a medical student at the University of California, San Diego. Dr. Eichenfield is chief of pediatric and adolescent dermatology at Rady Children’s Hospital–San Diego. He is vice chair of the department of dermatology and professor of dermatology and pediatrics at the University of California, San Diego. There are no conflicts of interest or financial disclosures for Ms. Natsis or Dr. Eichenfield. Email them at [email protected].
References
1. Cutis. 1999 Aug 1;64(2):135-6.
2. J Am Acad Dermatol. 2004 Oct;51(4):606-24.
3. Papulosquamous diseases, in “Pediatric Dermatology,” 4th ed. (St Louis: Mosby; 2011, Vol. 2.
4. Pediatr Dermatol. 2018. doi: 10.1111/pde.13576.
5. Cutis. 2013 Dec;92(6):288, 297-8.
6. Dermatol Online J. 2011 Jul 15;17(7):11.
7. J Drugs Dermatol. 2004 Nov-Dec;3(6):683-4.
8. Int J Dermatol. 2004 Dec 23;45:615-7.
9. Photodermatol Photoimmunol Photomed. 2013 Aug;29(4):215-7.
Feds say ACA’s silver plan premiums will drop in 2019
, the second-lowest cost option – the first such decline since the marketplace’s start in 2014 under the Affordable Care Act.
The Centers for Medicare & Medicaid Services reported that premiums will drop 1.5% on average, after an average increase of 25.4% in 2017 and an increase of 36.9% in 2018.
Tennessee saw the greatest reduction for the 2019 plan year, dropping 26.2%. North Dakota was at the opposite end, seeing premiums increase by 20.2%. CMS provided a state-by-state breakdown of premium changes for states in the federally facilitated marketplace.
CMS Administrator Seema Verma credits the decline to market stabilization actions taken by the agency.
“Despite predictions that our actions would increase rates and destabilize the markets, the opposite has happened,” she said in a statement. “The drop in benchmark plan premiums for plan year 2019 and the increased choices for Americans seeking insurance on the exchanges is proof positive that our actions are working.”
While the agency is “encouraged by this progress, we aren’t satisfied,” Ms. Verma added. “Even with this reduction, average rates are still too high. If we are going to truly offer affordable, high-quality health care, ultimately, the law needs to change.”
Some experts, however, were quick to dismiss Ms. Verma’s assertions that federal government action caused the decline.
In fact, the trend is more of a market correction, said Sara Collins, PhD, vice president of health coverage and access at the Commonwealth Fund, New York. It follows 2 years of premium increases by insurers anticipating government actions to intentionally destabilize the market.
“We saw a correction in premiums in 2017, which reflected the phase-out of the reinsurance program, so insurers adjusted their premiums to reflect that,” Dr. Collins said. “Also, insurers are getting to know their risk pools better. So, the prediction was that the markets would stabilize in the out-years of implementation.”
The individual market “is weathering very well the attempts by the Trump administration and Congress over the past year to weaken it,” Dr. Collins added. Those include repealing the individual mandate penalties, ending federal cost-sharing reduction payments, and promoting the sale of short-term, limited-duration health policies.
Efforts at the state level also have been helpful in stabilizing the marketplace, she noted, particularly in those states that implemented reinsurance plans. CMS noted its role in approving reinsurance waivers in seven states as a reason for the overall decline.
Matthew Fiedler, PhD, a fellow at the Brookings Institution, Washington, concurred that the reduction was more of a market correction than anything else.
It “is not that the repeal of the individual mandate and various other policy changes implemented by the administration haven’t hurt rates,” he said. “It’s that rates were far higher than they needed to be in 2018. Even with the headwind of those policy games, rates are declining this year. Without those policy changes, rates would be declining by more in 2018.”
, the second-lowest cost option – the first such decline since the marketplace’s start in 2014 under the Affordable Care Act.
The Centers for Medicare & Medicaid Services reported that premiums will drop 1.5% on average, after an average increase of 25.4% in 2017 and an increase of 36.9% in 2018.
Tennessee saw the greatest reduction for the 2019 plan year, dropping 26.2%. North Dakota was at the opposite end, seeing premiums increase by 20.2%. CMS provided a state-by-state breakdown of premium changes for states in the federally facilitated marketplace.
CMS Administrator Seema Verma credits the decline to market stabilization actions taken by the agency.
“Despite predictions that our actions would increase rates and destabilize the markets, the opposite has happened,” she said in a statement. “The drop in benchmark plan premiums for plan year 2019 and the increased choices for Americans seeking insurance on the exchanges is proof positive that our actions are working.”
While the agency is “encouraged by this progress, we aren’t satisfied,” Ms. Verma added. “Even with this reduction, average rates are still too high. If we are going to truly offer affordable, high-quality health care, ultimately, the law needs to change.”
Some experts, however, were quick to dismiss Ms. Verma’s assertions that federal government action caused the decline.
In fact, the trend is more of a market correction, said Sara Collins, PhD, vice president of health coverage and access at the Commonwealth Fund, New York. It follows 2 years of premium increases by insurers anticipating government actions to intentionally destabilize the market.
“We saw a correction in premiums in 2017, which reflected the phase-out of the reinsurance program, so insurers adjusted their premiums to reflect that,” Dr. Collins said. “Also, insurers are getting to know their risk pools better. So, the prediction was that the markets would stabilize in the out-years of implementation.”
The individual market “is weathering very well the attempts by the Trump administration and Congress over the past year to weaken it,” Dr. Collins added. Those include repealing the individual mandate penalties, ending federal cost-sharing reduction payments, and promoting the sale of short-term, limited-duration health policies.
Efforts at the state level also have been helpful in stabilizing the marketplace, she noted, particularly in those states that implemented reinsurance plans. CMS noted its role in approving reinsurance waivers in seven states as a reason for the overall decline.
Matthew Fiedler, PhD, a fellow at the Brookings Institution, Washington, concurred that the reduction was more of a market correction than anything else.
It “is not that the repeal of the individual mandate and various other policy changes implemented by the administration haven’t hurt rates,” he said. “It’s that rates were far higher than they needed to be in 2018. Even with the headwind of those policy games, rates are declining this year. Without those policy changes, rates would be declining by more in 2018.”
, the second-lowest cost option – the first such decline since the marketplace’s start in 2014 under the Affordable Care Act.
The Centers for Medicare & Medicaid Services reported that premiums will drop 1.5% on average, after an average increase of 25.4% in 2017 and an increase of 36.9% in 2018.
Tennessee saw the greatest reduction for the 2019 plan year, dropping 26.2%. North Dakota was at the opposite end, seeing premiums increase by 20.2%. CMS provided a state-by-state breakdown of premium changes for states in the federally facilitated marketplace.
CMS Administrator Seema Verma credits the decline to market stabilization actions taken by the agency.
“Despite predictions that our actions would increase rates and destabilize the markets, the opposite has happened,” she said in a statement. “The drop in benchmark plan premiums for plan year 2019 and the increased choices for Americans seeking insurance on the exchanges is proof positive that our actions are working.”
While the agency is “encouraged by this progress, we aren’t satisfied,” Ms. Verma added. “Even with this reduction, average rates are still too high. If we are going to truly offer affordable, high-quality health care, ultimately, the law needs to change.”
Some experts, however, were quick to dismiss Ms. Verma’s assertions that federal government action caused the decline.
In fact, the trend is more of a market correction, said Sara Collins, PhD, vice president of health coverage and access at the Commonwealth Fund, New York. It follows 2 years of premium increases by insurers anticipating government actions to intentionally destabilize the market.
“We saw a correction in premiums in 2017, which reflected the phase-out of the reinsurance program, so insurers adjusted their premiums to reflect that,” Dr. Collins said. “Also, insurers are getting to know their risk pools better. So, the prediction was that the markets would stabilize in the out-years of implementation.”
The individual market “is weathering very well the attempts by the Trump administration and Congress over the past year to weaken it,” Dr. Collins added. Those include repealing the individual mandate penalties, ending federal cost-sharing reduction payments, and promoting the sale of short-term, limited-duration health policies.
Efforts at the state level also have been helpful in stabilizing the marketplace, she noted, particularly in those states that implemented reinsurance plans. CMS noted its role in approving reinsurance waivers in seven states as a reason for the overall decline.
Matthew Fiedler, PhD, a fellow at the Brookings Institution, Washington, concurred that the reduction was more of a market correction than anything else.
It “is not that the repeal of the individual mandate and various other policy changes implemented by the administration haven’t hurt rates,” he said. “It’s that rates were far higher than they needed to be in 2018. Even with the headwind of those policy games, rates are declining this year. Without those policy changes, rates would be declining by more in 2018.”