Clinical Review

BY JEFF BAUER

Use of a blood collection system that diverts and sequesters the initial 1.5 to 2 mL of blood was associated with a significant decrease in blood culture contamination compared to standard practice, according to an open-label trial conducted at a single ED. The results were published online in the journal Clinical Infectious Diseases.

An estimated 0.6% to 6% of blood cultures are contaminated. Some blood cultures may become contaminated by skin fragments colonized with bacteria that are dislodged during venipuncture. Such false-positive results lead to increased costs and harm associated with unnecessary additional testing and treatment.

Researchers at the University of Nebraska Medical Center evaluated a novel sterile blood collection system, the SteriPath initial specimen diversion device (ISDD), to determine if it could reduce contamination rates by diverting and excluding the initial portion of collected blood. Investigators evaluated 1,808 blood cultures from 904 adult ED patients at an urban 689-bed university hospital. The patients’ mean age was 59 years, and 55% were male. For each patient, the first 20-mL blood sample was obtained using a standard procedure in which blood was drawn into a syringe and then injected into blood culture vials. A second 20-mL sample was obtained using the ISDD; the initial 1.5 to 2 mL of blood was diverted into a holding chamber, and the rest of the sample was directed into the blood culture vials. A culture was determined to be contaminated if one or more of several skin-residing organisms, including coagulase-negative staphylococci, Propionibacterium species, Micrococcus species, viridans group streptococci, Corynebacterium species, or Bacillus species, was recovered from only one of the paired cultures.

Compared to standard practice, use of the ISDD was associated with a significant reduction in blood culture contamination. Overall, two of the 904 samples (0.22%) collected with the ISDD were contaminated, compared to 16 of the 904 samples (1.78%) collected via standard practice (P = .001). Sensitivity was not affected by use of the ISDD; true septicemia was observed in 65 of 904 samples (7.2%) collected via ISDD and 69 of 904 samples (7.6%) collected via standard procedure (P = .41).

Rupp ME, Cavalieri RJ, Marolf C, Lyden E. Reduction in blood culture contamination through use of initial specimen diversion device. Clin Infect Dis. 2017 Apr 3. [Epub ahead of print]. doi:10.1093/cid/cix304.

FDA: Fluoroquinolone Use Not Linked to Retinal Detachment, Aortic Problems

LUCAS FRANKI

FRONTLINE MEDICAL NEWS

The Food and Drug Administration (FDA) has found no evidence of a link between fluoroquinolone antibiotic use and retinal detachment or aortic aneurysm and dissection, according to a new Drug Safety Communication update on potential serious, disabling adverse effects of oral and injectable fluoroquinolones.

Fluoroquinolones are used to treat acute bacterial sinusitis, acute bacterial exacerbation of chronic bronchitis, and uncomplicated urinary tract infections.

In a Safety Communication published May 12, 2016, the FDA noted that serious adverse effects were possible from fluoroquinolone usage and that fluoroquinolones should be prescribed only when no other treatment options are possible. Serious adverse effects associated with fluoroquinolone use include hallucination, depression, suicidal thoughts, tendinitis and tendon rupture, a pins-and-needles feeling in the arms and legs, joint pain and swelling, skin rash, and severe diarrhea.

After reviewing patient cases and study findings, the FDA said the evidence did not support an association between fluoroquinolone use and potential retinal or aortic dangers, according to its May 10, 2017, Drug Safety Communication update.

“We will continue to assess safety issues with fluoroquinolones, and will update the public if additional actions are needed,” the FDA said in a statement.

US Food and Drug Administration. FDA Drug Safety Communication: FDA updates warnings for oral and injectable fluoroquinolone antibiotics due to disabling side effects. May 10, 2017. https://www.fda.gov/Drugs/DrugSafety/ucm511530.htm. Accessed May 25, 2017.

Intravenous tPA Increases Risk of Mortality in Children With Acute Ischemic Stroke

SHARON WORCESTER

FRONTLINE MEDICAL NEWS

Intravenous thrombolysis with tissue plasminogen activator (tPA) is associated with adverse outcomes, including an increased risk of death, in children with acute ischemic stroke, based on a review of cases from the 2006-2010 Nationwide Inpatient Survey.

Of 20,587 patients ages 0 to 17 years who were included in the survey, 198 received an intervention, including tPA in 169 patients, intra-arterial thrombectomy (IAT) in five patients, and both tPA and IAT in 24 patients. The overall mortality rate was 7.8%, but in those who received tPA, it was 13.8%, compared with 7.7% in those who did not, Kathryn Ess, MD, of Rush University Medical Center, Chicago, reported at the annual meeting of the American Academy of Neurology. No deaths occurred in those who underwent only IAT, said Dr Ess.

Other outcomes were also worse for those who received tPA. For example, untreated patients were more likely to be discharged home than were tPA-treated patients (67.8% vs 47.5%), and intracerebral hemorrhage was more common in treated vs untreated patients (10.1% vs 3.8%). Costs for treated patients averaged $200,346 vs $123,015 for untreated patients.

Children included in the review had a mean age of 6 years, 43.9% were girls, and 47.7% were white. Treated patients were older (10 years vs 5.9 years), and comorbidities included Moyamoya disease in 12.4% of patients, cardiac valvular disease in 6.6%, and sickle cell disease in 6.5%. Those who received tPA had a higher prevalence of procoagulable conditions (15.2% vs 2%). Of note, the higher prevalence of intracerebral hemorrhage in treated patients was not explained by Moyamoya or sickle cell disease, as patients with those comorbidities were less likely than those without those conditions to receive treatment, Dr Ess said.

Though limited by the retrospective study design, small numbers of treated patients, a lack of data on stroke severity or functional outcomes, and the inclusion of data from years before newer thrombectomy devices became available, the findings highlight concerns about the safety and efficacy of tPA in children with ischemic stroke, she said, noting that few studies have looked at the utility of tPA with or without IAT in the pediatric population.

“Studies of the efficacy of ischemic stroke treatment in adults can’t necessarily be extrapolated to children,” she said, adding that this is especially true given the difference in etiologies of pediatric acute ischemic stroke.

Indeed, the findings underscore “the age-old adage that children are not just little adults,” said Andrew Southerland, MD, of the University of Virginia, Charlottesville, who was the discussant for the session. “We need prospective clinical trials in children,” he said.

HCV Seroconversion Rate 0.1% After Occupational Exposure

BIANCA NOGRADY

FRONTLINE MEDICAL NEWS

An analysis of 13 years of accidental occupational exposures to hepatitis C virus (HCV)-contaminated fluids or instruments has revealed a seroconversion rate of just 0.1%, significantly lower than that previously reported in the literature. This finding is from a longitudinal analysis of data from a prospectively maintained database of 1,361 occupational injuries involving HCV-positive source that occurred between 2002 and 2015 conducted by Francesco M. Egro, MD, and his colleagues from the University of Pittsburgh Medical Center. Results were published online in the American Journal of Infection Control.

The two incidents of seroconversion occurred in patients who were exposed to blood from an HCV-positive patient via percutaneous injuries to the thumb from a hollow-bore needle, representing an overall seroconversion rate of 0.1%. In both cases, the source patients whose blood was involved were not coinfected with hepatitis B virus or human immunodeficiency virus.

Researchers also conducted a review of literature on needlestick injuries and occupational exposure to HCV-infected blood and fluids; from this review, they calculated an overall seroconversion rate average of 0.7%, with an average rate of 0.8% for percutaneous exposures. The review did not include mucomembranous exposure, as there were not enough data.

In this study, 65% of exposures were caused by percutaneous injuries and 34% were caused by mucocutaneous injuries; the cause of the remaining 1% was uncertain.

The hand was the most common site of injury (63%), followed by the face and neck (28%), and the arm, foot, leg, or trunk (4%). There was no record of the anatomical location of the injury in 5% of cases.

In nearly three-quarters of cases, blood was the source of exposure, while blood-containing saliva accounted for 3% of cases. The remaining 24% of cases were linked to other fluids, such as peritoneal fluid, tracheal secretions, amniotic fluid, bloody irrigation fluid, and blood-containing feces.

“The risk of transmission after exposure to HCV-positive patients’ fluids or tissues other than blood is expected to be low, but has not been formally quantified,” the authors wrote. “Although there have been reports of HCV seroconversion after human bites and after punching a HCV-positive individual in the teeth, percutaneous exposures to the blood of a HCV-positive source remain the most common cause of occupational HCV transmission.”

While the rate of seroconversion was low, the authors encouraged prompt reporting, testing, and follow-up of exposed individuals.

Egro FM, Nwaiwu CA, Smith S, Harper JD, Spiess AM. Seroconversion rates among health care workers exposed to hepatitis C virus-contaminated body fluids: The University of Pittsburgh 13-year experience. Am J Infect Control. 2017 Apr 24. [Epub ahead of print]. doi:10.1016/j.ajic.2017.03.011.

BY JEFF BAUER

Use of a blood collection system that diverts and sequesters the initial 1.5 to 2 mL of blood was associated with a significant decrease in blood culture contamination compared to standard practice, according to an open-label trial conducted at a single ED. The results were published online in the journal Clinical Infectious Diseases.

An estimated 0.6% to 6% of blood cultures are contaminated. Some blood cultures may become contaminated by skin fragments colonized with bacteria that are dislodged during venipuncture. Such false-positive results lead to increased costs and harm associated with unnecessary additional testing and treatment.

Researchers at the University of Nebraska Medical Center evaluated a novel sterile blood collection system, the SteriPath initial specimen diversion device (ISDD), to determine if it could reduce contamination rates by diverting and excluding the initial portion of collected blood. Investigators evaluated 1,808 blood cultures from 904 adult ED patients at an urban 689-bed university hospital. The patients’ mean age was 59 years, and 55% were male. For each patient, the first 20-mL blood sample was obtained using a standard procedure in which blood was drawn into a syringe and then injected into blood culture vials. A second 20-mL sample was obtained using the ISDD; the initial 1.5 to 2 mL of blood was diverted into a holding chamber, and the rest of the sample was directed into the blood culture vials. A culture was determined to be contaminated if one or more of several skin-residing organisms, including coagulase-negative staphylococci, Propionibacterium species, Micrococcus species, viridans group streptococci, Corynebacterium species, or Bacillus species, was recovered from only one of the paired cultures.

Compared to standard practice, use of the ISDD was associated with a significant reduction in blood culture contamination. Overall, two of the 904 samples (0.22%) collected with the ISDD were contaminated, compared to 16 of the 904 samples (1.78%) collected via standard practice (P = .001). Sensitivity was not affected by use of the ISDD; true septicemia was observed in 65 of 904 samples (7.2%) collected via ISDD and 69 of 904 samples (7.6%) collected via standard procedure (P = .41).

Rupp ME, Cavalieri RJ, Marolf C, Lyden E. Reduction in blood culture contamination through use of initial specimen diversion device. Clin Infect Dis. 2017 Apr 3. [Epub ahead of print]. doi:10.1093/cid/cix304.

FDA: Fluoroquinolone Use Not Linked to Retinal Detachment, Aortic Problems

LUCAS FRANKI

FRONTLINE MEDICAL NEWS

The Food and Drug Administration (FDA) has found no evidence of a link between fluoroquinolone antibiotic use and retinal detachment or aortic aneurysm and dissection, according to a new Drug Safety Communication update on potential serious, disabling adverse effects of oral and injectable fluoroquinolones.

Fluoroquinolones are used to treat acute bacterial sinusitis, acute bacterial exacerbation of chronic bronchitis, and uncomplicated urinary tract infections.

In a Safety Communication published May 12, 2016, the FDA noted that serious adverse effects were possible from fluoroquinolone usage and that fluoroquinolones should be prescribed only when no other treatment options are possible. Serious adverse effects associated with fluoroquinolone use include hallucination, depression, suicidal thoughts, tendinitis and tendon rupture, a pins-and-needles feeling in the arms and legs, joint pain and swelling, skin rash, and severe diarrhea.

After reviewing patient cases and study findings, the FDA said the evidence did not support an association between fluoroquinolone use and potential retinal or aortic dangers, according to its May 10, 2017, Drug Safety Communication update.

“We will continue to assess safety issues with fluoroquinolones, and will update the public if additional actions are needed,” the FDA said in a statement.

US Food and Drug Administration. FDA Drug Safety Communication: FDA updates warnings for oral and injectable fluoroquinolone antibiotics due to disabling side effects. May 10, 2017. https://www.fda.gov/Drugs/DrugSafety/ucm511530.htm. Accessed May 25, 2017.

Intravenous tPA Increases Risk of Mortality in Children With Acute Ischemic Stroke

SHARON WORCESTER

FRONTLINE MEDICAL NEWS

Intravenous thrombolysis with tissue plasminogen activator (tPA) is associated with adverse outcomes, including an increased risk of death, in children with acute ischemic stroke, based on a review of cases from the 2006-2010 Nationwide Inpatient Survey.

Of 20,587 patients ages 0 to 17 years who were included in the survey, 198 received an intervention, including tPA in 169 patients, intra-arterial thrombectomy (IAT) in five patients, and both tPA and IAT in 24 patients. The overall mortality rate was 7.8%, but in those who received tPA, it was 13.8%, compared with 7.7% in those who did not, Kathryn Ess, MD, of Rush University Medical Center, Chicago, reported at the annual meeting of the American Academy of Neurology. No deaths occurred in those who underwent only IAT, said Dr Ess.

Other outcomes were also worse for those who received tPA. For example, untreated patients were more likely to be discharged home than were tPA-treated patients (67.8% vs 47.5%), and intracerebral hemorrhage was more common in treated vs untreated patients (10.1% vs 3.8%). Costs for treated patients averaged $200,346 vs $123,015 for untreated patients.

Children included in the review had a mean age of 6 years, 43.9% were girls, and 47.7% were white. Treated patients were older (10 years vs 5.9 years), and comorbidities included Moyamoya disease in 12.4% of patients, cardiac valvular disease in 6.6%, and sickle cell disease in 6.5%. Those who received tPA had a higher prevalence of procoagulable conditions (15.2% vs 2%). Of note, the higher prevalence of intracerebral hemorrhage in treated patients was not explained by Moyamoya or sickle cell disease, as patients with those comorbidities were less likely than those without those conditions to receive treatment, Dr Ess said.

Though limited by the retrospective study design, small numbers of treated patients, a lack of data on stroke severity or functional outcomes, and the inclusion of data from years before newer thrombectomy devices became available, the findings highlight concerns about the safety and efficacy of tPA in children with ischemic stroke, she said, noting that few studies have looked at the utility of tPA with or without IAT in the pediatric population.

“Studies of the efficacy of ischemic stroke treatment in adults can’t necessarily be extrapolated to children,” she said, adding that this is especially true given the difference in etiologies of pediatric acute ischemic stroke.

Indeed, the findings underscore “the age-old adage that children are not just little adults,” said Andrew Southerland, MD, of the University of Virginia, Charlottesville, who was the discussant for the session. “We need prospective clinical trials in children,” he said.

HCV Seroconversion Rate 0.1% After Occupational Exposure

BIANCA NOGRADY

FRONTLINE MEDICAL NEWS

An analysis of 13 years of accidental occupational exposures to hepatitis C virus (HCV)-contaminated fluids or instruments has revealed a seroconversion rate of just 0.1%, significantly lower than that previously reported in the literature. This finding is from a longitudinal analysis of data from a prospectively maintained database of 1,361 occupational injuries involving HCV-positive source that occurred between 2002 and 2015 conducted by Francesco M. Egro, MD, and his colleagues from the University of Pittsburgh Medical Center. Results were published online in the American Journal of Infection Control.

The two incidents of seroconversion occurred in patients who were exposed to blood from an HCV-positive patient via percutaneous injuries to the thumb from a hollow-bore needle, representing an overall seroconversion rate of 0.1%. In both cases, the source patients whose blood was involved were not coinfected with hepatitis B virus or human immunodeficiency virus.

Researchers also conducted a review of literature on needlestick injuries and occupational exposure to HCV-infected blood and fluids; from this review, they calculated an overall seroconversion rate average of 0.7%, with an average rate of 0.8% for percutaneous exposures. The review did not include mucomembranous exposure, as there were not enough data.

In this study, 65% of exposures were caused by percutaneous injuries and 34% were caused by mucocutaneous injuries; the cause of the remaining 1% was uncertain.

The hand was the most common site of injury (63%), followed by the face and neck (28%), and the arm, foot, leg, or trunk (4%). There was no record of the anatomical location of the injury in 5% of cases.

In nearly three-quarters of cases, blood was the source of exposure, while blood-containing saliva accounted for 3% of cases. The remaining 24% of cases were linked to other fluids, such as peritoneal fluid, tracheal secretions, amniotic fluid, bloody irrigation fluid, and blood-containing feces.

“The risk of transmission after exposure to HCV-positive patients’ fluids or tissues other than blood is expected to be low, but has not been formally quantified,” the authors wrote. “Although there have been reports of HCV seroconversion after human bites and after punching a HCV-positive individual in the teeth, percutaneous exposures to the blood of a HCV-positive source remain the most common cause of occupational HCV transmission.”

While the rate of seroconversion was low, the authors encouraged prompt reporting, testing, and follow-up of exposed individuals.

Egro FM, Nwaiwu CA, Smith S, Harper JD, Spiess AM. Seroconversion rates among health care workers exposed to hepatitis C virus-contaminated body fluids: The University of Pittsburgh 13-year experience. Am J Infect Control. 2017 Apr 24. [Epub ahead of print]. doi:10.1016/j.ajic.2017.03.011.

BY JEFF BAUER

Use of a blood collection system that diverts and sequesters the initial 1.5 to 2 mL of blood was associated with a significant decrease in blood culture contamination compared to standard practice, according to an open-label trial conducted at a single ED. The results were published online in the journal Clinical Infectious Diseases.

An estimated 0.6% to 6% of blood cultures are contaminated. Some blood cultures may become contaminated by skin fragments colonized with bacteria that are dislodged during venipuncture. Such false-positive results lead to increased costs and harm associated with unnecessary additional testing and treatment.

Researchers at the University of Nebraska Medical Center evaluated a novel sterile blood collection system, the SteriPath initial specimen diversion device (ISDD), to determine if it could reduce contamination rates by diverting and excluding the initial portion of collected blood. Investigators evaluated 1,808 blood cultures from 904 adult ED patients at an urban 689-bed university hospital. The patients’ mean age was 59 years, and 55% were male. For each patient, the first 20-mL blood sample was obtained using a standard procedure in which blood was drawn into a syringe and then injected into blood culture vials. A second 20-mL sample was obtained using the ISDD; the initial 1.5 to 2 mL of blood was diverted into a holding chamber, and the rest of the sample was directed into the blood culture vials. A culture was determined to be contaminated if one or more of several skin-residing organisms, including coagulase-negative staphylococci, Propionibacterium species, Micrococcus species, viridans group streptococci, Corynebacterium species, or Bacillus species, was recovered from only one of the paired cultures.

Compared to standard practice, use of the ISDD was associated with a significant reduction in blood culture contamination. Overall, two of the 904 samples (0.22%) collected with the ISDD were contaminated, compared to 16 of the 904 samples (1.78%) collected via standard practice (P = .001). Sensitivity was not affected by use of the ISDD; true septicemia was observed in 65 of 904 samples (7.2%) collected via ISDD and 69 of 904 samples (7.6%) collected via standard procedure (P = .41).

Rupp ME, Cavalieri RJ, Marolf C, Lyden E. Reduction in blood culture contamination through use of initial specimen diversion device. Clin Infect Dis. 2017 Apr 3. [Epub ahead of print]. doi:10.1093/cid/cix304.

FDA: Fluoroquinolone Use Not Linked to Retinal Detachment, Aortic Problems

LUCAS FRANKI

FRONTLINE MEDICAL NEWS

The Food and Drug Administration (FDA) has found no evidence of a link between fluoroquinolone antibiotic use and retinal detachment or aortic aneurysm and dissection, according to a new Drug Safety Communication update on potential serious, disabling adverse effects of oral and injectable fluoroquinolones.

Fluoroquinolones are used to treat acute bacterial sinusitis, acute bacterial exacerbation of chronic bronchitis, and uncomplicated urinary tract infections.

In a Safety Communication published May 12, 2016, the FDA noted that serious adverse effects were possible from fluoroquinolone usage and that fluoroquinolones should be prescribed only when no other treatment options are possible. Serious adverse effects associated with fluoroquinolone use include hallucination, depression, suicidal thoughts, tendinitis and tendon rupture, a pins-and-needles feeling in the arms and legs, joint pain and swelling, skin rash, and severe diarrhea.

After reviewing patient cases and study findings, the FDA said the evidence did not support an association between fluoroquinolone use and potential retinal or aortic dangers, according to its May 10, 2017, Drug Safety Communication update.

“We will continue to assess safety issues with fluoroquinolones, and will update the public if additional actions are needed,” the FDA said in a statement.

US Food and Drug Administration. FDA Drug Safety Communication: FDA updates warnings for oral and injectable fluoroquinolone antibiotics due to disabling side effects. May 10, 2017. https://www.fda.gov/Drugs/DrugSafety/ucm511530.htm. Accessed May 25, 2017.

Intravenous tPA Increases Risk of Mortality in Children With Acute Ischemic Stroke

SHARON WORCESTER

FRONTLINE MEDICAL NEWS

Intravenous thrombolysis with tissue plasminogen activator (tPA) is associated with adverse outcomes, including an increased risk of death, in children with acute ischemic stroke, based on a review of cases from the 2006-2010 Nationwide Inpatient Survey.

Of 20,587 patients ages 0 to 17 years who were included in the survey, 198 received an intervention, including tPA in 169 patients, intra-arterial thrombectomy (IAT) in five patients, and both tPA and IAT in 24 patients. The overall mortality rate was 7.8%, but in those who received tPA, it was 13.8%, compared with 7.7% in those who did not, Kathryn Ess, MD, of Rush University Medical Center, Chicago, reported at the annual meeting of the American Academy of Neurology. No deaths occurred in those who underwent only IAT, said Dr Ess.

Other outcomes were also worse for those who received tPA. For example, untreated patients were more likely to be discharged home than were tPA-treated patients (67.8% vs 47.5%), and intracerebral hemorrhage was more common in treated vs untreated patients (10.1% vs 3.8%). Costs for treated patients averaged $200,346 vs $123,015 for untreated patients.

Children included in the review had a mean age of 6 years, 43.9% were girls, and 47.7% were white. Treated patients were older (10 years vs 5.9 years), and comorbidities included Moyamoya disease in 12.4% of patients, cardiac valvular disease in 6.6%, and sickle cell disease in 6.5%. Those who received tPA had a higher prevalence of procoagulable conditions (15.2% vs 2%). Of note, the higher prevalence of intracerebral hemorrhage in treated patients was not explained by Moyamoya or sickle cell disease, as patients with those comorbidities were less likely than those without those conditions to receive treatment, Dr Ess said.

Though limited by the retrospective study design, small numbers of treated patients, a lack of data on stroke severity or functional outcomes, and the inclusion of data from years before newer thrombectomy devices became available, the findings highlight concerns about the safety and efficacy of tPA in children with ischemic stroke, she said, noting that few studies have looked at the utility of tPA with or without IAT in the pediatric population.

“Studies of the efficacy of ischemic stroke treatment in adults can’t necessarily be extrapolated to children,” she said, adding that this is especially true given the difference in etiologies of pediatric acute ischemic stroke.

Indeed, the findings underscore “the age-old adage that children are not just little adults,” said Andrew Southerland, MD, of the University of Virginia, Charlottesville, who was the discussant for the session. “We need prospective clinical trials in children,” he said.

HCV Seroconversion Rate 0.1% After Occupational Exposure

BIANCA NOGRADY

FRONTLINE MEDICAL NEWS

An analysis of 13 years of accidental occupational exposures to hepatitis C virus (HCV)-contaminated fluids or instruments has revealed a seroconversion rate of just 0.1%, significantly lower than that previously reported in the literature. This finding is from a longitudinal analysis of data from a prospectively maintained database of 1,361 occupational injuries involving HCV-positive source that occurred between 2002 and 2015 conducted by Francesco M. Egro, MD, and his colleagues from the University of Pittsburgh Medical Center. Results were published online in the American Journal of Infection Control.

The two incidents of seroconversion occurred in patients who were exposed to blood from an HCV-positive patient via percutaneous injuries to the thumb from a hollow-bore needle, representing an overall seroconversion rate of 0.1%. In both cases, the source patients whose blood was involved were not coinfected with hepatitis B virus or human immunodeficiency virus.

Researchers also conducted a review of literature on needlestick injuries and occupational exposure to HCV-infected blood and fluids; from this review, they calculated an overall seroconversion rate average of 0.7%, with an average rate of 0.8% for percutaneous exposures. The review did not include mucomembranous exposure, as there were not enough data.

In this study, 65% of exposures were caused by percutaneous injuries and 34% were caused by mucocutaneous injuries; the cause of the remaining 1% was uncertain.

The hand was the most common site of injury (63%), followed by the face and neck (28%), and the arm, foot, leg, or trunk (4%). There was no record of the anatomical location of the injury in 5% of cases.

In nearly three-quarters of cases, blood was the source of exposure, while blood-containing saliva accounted for 3% of cases. The remaining 24% of cases were linked to other fluids, such as peritoneal fluid, tracheal secretions, amniotic fluid, bloody irrigation fluid, and blood-containing feces.

“The risk of transmission after exposure to HCV-positive patients’ fluids or tissues other than blood is expected to be low, but has not been formally quantified,” the authors wrote. “Although there have been reports of HCV seroconversion after human bites and after punching a HCV-positive individual in the teeth, percutaneous exposures to the blood of a HCV-positive source remain the most common cause of occupational HCV transmission.”

While the rate of seroconversion was low, the authors encouraged prompt reporting, testing, and follow-up of exposed individuals.

Egro FM, Nwaiwu CA, Smith S, Harper JD, Spiess AM. Seroconversion rates among health care workers exposed to hepatitis C virus-contaminated body fluids: The University of Pittsburgh 13-year experience. Am J Infect Control. 2017 Apr 24. [Epub ahead of print]. doi:10.1016/j.ajic.2017.03.011.

Illustration: Kimberly Martens for OBG Management

CASE: Transgender man consults gynecologist for fertility options

A 36-year-old transgender man considering the possibility of having his own biological children presents to the gynecology office to discuss hysterectomy as gender dysphoria treatment as well as his fertility preservation options. He has never had a gynecologic examination. Since age 24, he has been on testosterone therapy. Although his menses initially ceased, each month over the past 2 years he has had breakthrough spotting lasting 2 to 4 days, sometimes accompanied by pelvic pain and cramping. These symptoms have caused him distress and anxiety, which have led to his missing work 1 to 3 days each month. On presentation, he appears anxious and makes little eye contact. His girlfriend of 6 years has come in with him and is very supportive.

Over the past decade, transgender health care has moved to the forefront of the medical conversation. At many prominent medical centers across the United States, clinicians are forming multidisciplinary teams to help improve the health care of this patient population. Outcomes are being studied, and the literature is becoming more robust.

People tend to think of transgender women—male-assigned persons who self-identify as female—as the typical prototype for transgender people, but this focus is skewed in both society and the medical community. Transgender men—female-assigned persons who self-identify as male—remain underrepresented, mostly because they want to stay “under the radar,” especially with respect to medical care and, more specifically, routine gynecologic care.

Although the transgender woman has unique health needs and may present to a gynecologist for care after gender-affirmationsurgery, the transgender man’s many health care needs and their subtleties can be addressed only by a gynecologist. In this article, I review these intricacies of care to help increase clinician comfort in treating these patients.

Why transgender patients may delay seeking health care

Transgender patients remain underserved because of the health care barriers they encounter. Factors contributing to poor access include lack of health insurance, inability to pay for services, clinician insensitivity and hostility, and fear of exposure of transgender status during health care encounters.¹ In a recent large survey study, 30% of transgender respondents indicated that they delayed or did not seek medical care as a result of discrimination, and those who had needed to teach their clinicians about transgenderism were 4 times more likely to postpone or not seek care.²

In a 2015 survey of ObGyns’ current knowledge and practice regarding LGBT (lesbian, gay, bisexual, transgender) care, only one-third of respondents indicated they were comfortable caring for transgender patients.³ In addition, only one-third indicated being knowledgeable about the steps transgender patients must take to transition to their self-identified gender, and less than half were familiar with the recommendations for the routine health maintenance and screening of these patients.

Much of this discomfort derives from the lack of incorporation of LGBT-specific topics in medical curricula. In 2011, Obedin-Maliver and colleagues found that, at 176 US and Canadian allopathic and osteopathic medical schools, the median time dedicated to LGBT health care needs and related topics was unsatisfactory.⁴ This deficiency is slowly being reduced with changes in the curricula of many health care specialties. In ObGyn residency programs, for example, transgender-specific questions have been added to annual in-service examinations. The hope is that, as education initiatives improve, clinicians will become more comfortable caring for gender-minority patients, who with improved access to care will no longer need to seek subspecialists in transgender services.

Read about the need for gyn exams, managing benign disorders, and cervical cancer screening

Considerations for the gynecologic visit and examination

Transgender men visit the gynecology office for many reasons, including routine gynecologic care and health maintenance, care for acute and chronic gynecologic conditions (abnormal bleeding, pelvic pain, vaginitis), evaluation and management of pelvic floor disorders, consultation on hysterectomy for gender transition, and fertility counseling.

However, transgender men who reach their third, fourth, or fifth decade without having had a pelvic examination cite many reasons for avoiding the gynecology office. Most commonly, gynecologic visits and genital examination can severely exacerbate these patients’ gender dysphoria. In addition, many patients who do not engage in penetrative vaginal sex think their health risks are so low that they can forgo or delay pelvic exams. Patients who have stopped menstruating while on testosterone therapy may think there is no need for routine gynecologic care. Other reasons for avoiding pelvic exams are pain and traumatic sexual memories.⁵

Related Article:
Four pillars of a successful practice: 4. Motivate your staff

Transgender men need to receive the regular guideline-recommended pelvic exams and screenings used for cisgender women. (Cisgender refers to a person whose sense of gender identity corresponds with their birth sex.) We need to educate patients in this regard and to discuss several issues before performing an examination. First, take a thorough history and avoid making assumptions about sexual orientation and sex practices. Some patients have penetrative vaginal intercourse with either men or women. For some patients, the exam may cause dysphoria symptoms, and we need to validate patients’ fears. Discussing these issues ahead of time helps patients get used to the idea of undergoing an exam and assures them that the clinician is experienced in performing these exams for transgender men. In my practice, we explain the exam’s purpose (screening or diagnosis) and importance. We also counsel patients that they may experience some normal, and temporary, spotting after the exam. For those who experience severe dysphoria with vaginal bleeding of any kind, we acknowledge that postexam spotting may cause some anxiety. Patients with severe anxiety before the exam may be premedicated with an anxiolytic agent as long as someone can transport them to and from the office.

The bimanual exam should be performed with care and efficiency and with the patient given as much control as possible. In most cases, we ask patients to undress only from the waist down, and their genitals stay covered. Patients uncomfortable in stirrups are asked to show us the position that suits them best, and we try to accommodate them. Although speed is a goal, remember that many patients are nulliparous, have had limited or no vaginal penetration, or are on testosterone and have significant vaginal dryness. Use the smallest speculum possible, a pediatric or long and narrow adult speculum, and apply lubricant copiously. Pre-exam application of topical lidocaine jelly to the introitus can help reduce pain. To help a patient relax the pelvic floor muscles and habituate to the presence of a foreign object in the vagina, start the exam by inserting a single digit. In addition, ask the patient about speculum placement inside the vagina: Does he want to place the speculum himself or guide the clinician’s hand? Open the speculum only as much as needed to adequately visualize the cervix and then remove it with care.

Managing benign gynecologic disorders

The same algorithms are used to evaluate abnormal bleeding in all patients, but the differential diagnosis expands for those on testosterone therapy. Testosterone may no longer be suppressing their cycles, and abnormal bleeding could simply be the return of menses, which would present as regular cyclic bleeding. Increasing the testosterone dosing or changing the testosterone formulation may help, and the gynecologist should discuss these options with the patient’s prescribing clinician. In addition, progesterone in any form (for example, medroxyprogesterone acetate 5 to 30 mg daily) can be added to testosterone regimens to help suppress menses. The levonorgestrel-releasing intrauterine device (LNG-IUD) can be very effective, but placement can induce anxiety, and some patients decline this treatment option.

In patients with intermenstrual spotting, assess the vagina for atrophy. Both over-the-counter vaginal moisturizers and DHEA (dehydroepiandrosterone) suppositories (1% compounded) can help treat atrophy, but not all patients are comfortable using them. Most patients decline vaginal estrogen products for symptomatic vaginal atrophy even though the systemic effects are minimal.

The historic literature suggests that female-to-male patients’ long-term exposure to androgens leads to atrophic changes in the endometrium and myometrium, and clinical studies of menopausal women who take exogenous androgens have confirmed this effect.⁶ However, new data point to a different histologic scenario. A recent study found a possible association between long-term testosterone use in transgender men of reproductive age and a low proliferative active endometrium, as well as hypertrophic changes in the myometrium.⁷ The causes may be peripheral aromatization of androgens and expression and up-regulation of androgen receptors within the endometrial stroma and myometrial cells.⁸ Given these emerging data and anecdotal cases reported by clinicians who perform hysterectomies for transgender men, imaging and tissue sampling should be used to evaluate abnormal uterine bleeding, particularly in patients previously amenorrheic on testosterone. Be aware that transvaginal ultrasound or endometrial biopsy are challenging procedures for these patients. Counsel patients to ensure that they adhere to follow-up.

Related Article:
2017 Update on cervical disease

The ongoing need for cervical cancer screening

The concept of “original gender surveillance” was presented in a 2-case series of transgender men with uterine and cervical cancer that might have been detected earlier with better screening and routine care.⁹ There is no evidence, however, that long-term high-dose androgen therapy causes endometrial or cervical cancer,¹⁰ and the data on endometrial cancer in patients on cross-sex hormone therapy are limited such that a causal relationship between testosterone and these malignancies cannot be established.^9,11–14

The rate of unsatisfactory Pap smears is higher in transgender men than in cisgender women. The difference was anecdotally noted by clinicians who routinely cared for transgender patients over time and was confirmed with a retrospective chart review.¹⁵

Peitzmeier and colleagues reviewed the records of 233 transgender men and 3,625 cisgender women with Pap tests performed at an urban community health center over 6 years.¹⁵ The transgender cohort, with its prevalence rate of 10%, was 10 times more likely to have an unsatisfactory or inadequate Pap smear. Moreover, the transgender patients were more likely to have longer latency to follow-up for a repeat Pap test. In addition, testosterone therapy was more likely associated with inadequate Pap smears, and time on testosterone therapy was associated with higher odds of Pap smear inadequacy. Besides the exogenous hormone therapy, clinician comfort level and experience may have contributed to the high prevalence of inadequate Pap smears.

As mentioned earlier, it is important to become comfortable performing pelvic exams for transgender men and to prepare patients for the possibility that a Pap smear might be inadequate, making a follow-up visit and repeat Pap test necessary.¹⁶

Read about hysterectomy, oophorectomy, and vaginectomy choices

Consultation for hysterectomy: Perioperative considerations

Transgender men may undergo hysterectomy, oophorectomy, and/or vaginectomy. The TABLE summarizes the indications and perioperative considerations for each procedure.

Some transgender men undergo hysterectomy for benign gynecologic disease. Counseling and perioperative planning are the same for these patients as for cisgender women, although some of the considerations discussed here remain important.

Other patients undergo hysterectomy as part of transitioning to their self-affirmed gender. The World Professional Association for Transgender Health (WPATH) Standards of Care should be used to guide counseling and treatment.¹⁷ These guidelines were designed as a framework for performing hysterectomy and other gender-affirming procedures. According to the WPATH standards, the criteria for hysterectomy and oophorectomy are:

• 2 referral letters from qualified mental health professionals
• well-documented persistent gender dysphoria
• capacity to make fully informed decisions and to consent to treatment
• age of majority in given country
• good control of any concurrent medical or mental health concerns, and
• hormone therapy for 12 continuous months, as appropriate to gender goals, unless the patient has a medical contraindication or is otherwise unable or unwilling to take hormones.

As the guidelines emphasize, these criteria do not apply to patients undergoing either procedure for medical indications other than gender dysphoria.

Hysterectomy approach. Most surgeons perform gender-affirming hysterectomies laparoscopically. Many clinicians hesitate to perform these hysterectomies vaginally, as the patients are often nulliparous. In general, the best operative route is the one the surgeon feels most comfortable performing safely and efficiently. For a nulliparous patient with minimal pelvic organ descensus and a narrow pelvis, the laparoscopic approach is reasonable. A recent study in a small cohort of transgender men found that vaginal hysterectomy was successful in only 1 in 4 patients.¹⁸ Nevertheless, the American College of Obstetricians and Gynecologists (ACOG) recommends vaginal hysterectomy, when appropriate, for limiting complications and morbidity while maximizing cost-effectiveness.¹⁹ Although data are limited, vaginal hysterectomy seems feasible and should be considered in a subset of patients who pre‑sent for gender-affirming hysterectomy.

Related Article:
Total laparoscopic versus laparoscopic supracervical hysterectomy

The oophorectomy debate

Oophorectomy concurrent with hysterectomy remains a topic of debate among gynecologists who perform hysterectomy for gender transition. Some clinicians think gonadectomy poses a significant risk for bone health compromise at an early age. The long-term effects of testosterone on bone have not been well studied. Although bone metabolism is thought to increase over the short term, there are no major changes in bone density over the long term. In fact, in the setting of long-term testosterone therapy, cortical bone was found to be larger in transgender men than in cisgender women.²⁰ The issue is for patients who stop taking exogenous testosterone after oophorectomy. This subset of patients has not been well studied but clearly needs bone health surveillance and supplementation.

Another concern about oophorectomy is its effect on fertility. Because it is important to discuss fertility-preserving options, during consultation for a hysterectomy I spend a large portion of time addressing fertility goals. Patients who want to become a parent but do not want to carry a child (they want a current or future partner or surrogate to carry) are candidates for hysterectomy; those who do not want a genetic child are candidates for oophorectomy; and those who do not want to preserve their fertility (or have already ended it) and who meet the WPATH criteria for surgery are candidates for oophorectomy concurrent with hysterectomy. The discussion can be particularly challenging with young transgender men, since their ability to project their family planning goals may be compromised by their gender dysphoria. Clinicians can counsel patients about another option: isolated hysterectomy with subsequent staged oophorectomy.

Similar to cisgender women with polycystic ovary syndrome, transgender men on exogenous testosterone therapy are at risk for ovarian cysts,⁷ which can cause pain and should be evaluated and managed. As mentioned, these patients may find it difficult to visit a gynecologist and tolerate a vaginal examination, and many fear presenting to an emergency room, as they will need to disclose their transgender status and risk being discriminated against or, worse, not being triaged or cared for properly. Patients should be thoroughly counseled about the risks and benefits of having oophorectomy performed concurrently with hysterectomy.

Related Article:
Vaginal hysterectomy with basic instrumentation

The question of vaginectomy

Patients and clinicians often ask about concurrent vaginectomy procedures. In some cases, patients with severe gender dysphoria and absence of penetrative vaginal activity request excision or obliteration of the vagina. There is no standard of care, however. Vaginectomy can be done transvaginally or abdominally: open, laparoscopically, or robotically. It therefore should be performed by surgeons experienced in the procedure. Patients should be advised that a portion of the vaginal epithelium is sometimes used for certain phalloplasty procedures and that, if they are considering genital reconstruction in the future, it may be beneficial to preserve the vagina until that time.

There are no guidelines on stopping or continuing testosterone therapy perioperatively. Some clinicians are concerned about possible venous thromboembolic events related to perioperative use of testosterone, but there are no data supporting increased risk. The risk of postoperative vaginal cuff bleeding in patients on and off testosterone has not been well studied. Since patients who stop taking testosterone may develop severe mood swings and malaise, they should be counseled on recognizing and managing such changes. There are also no data on the risk of vaginal cuff dehiscence in this patient population. Testosterone usually causes the vagina to become very atrophic, so proper closure should be ensured to avoid cuff evisceration. In my practice, the vaginal cuff is closed in 2 layers using at least 1 layer of delayed absorbable suture.

Read about addressing fertility, contraception, OB care, and your role

Addressing fertility, contraception, and obstetric care

Most transgender men are able to conceive a child.²¹ Data in this area, however, are sparse. Most of the literature on reproductive health in this patient population is focused on human immunodeficiency virus (HIV) and other sexually transmitted infections.²² Nevertheless, patient-physician dialogue on fertility and reproductive health has increased since more patients started seeking surgical transition services (likely a result of improved coverage for these surgeries). In addition, we are learning more about patients’ ability and desire to conceive after long-term use of cross-sex hormone therapy. The importance of this dialogue is becoming apparent. One survey study found that more than half of the transgender men who had undergone affirmation surgery wanted to become parents.²³

Before initiating cross-sex hormone therapy or before undergoing hysterectomy and/or oophorectomy, patients must be counseled about their fertility options. Testosterone may affect fertility and fecundity, but there are case reports of successful pregnancy after discontinuation of testosterone.²¹ Reproductive endocrinology and fertility specialists have begun to recognize the importance of fertility preservation in this patient population and to apply the principles of oncofertility care beyond patients with cancer. In a 2015 opinion paper on access to fertility services by transgender persons, the Ethics Committee of the American Society for Reproductive Medicine focused on this population’s unique fertility needs.²⁴ Currently, oocyte and embryo cryopreservation are options for transgender men planning to start cross-sex hormones or undergo surgery.²⁵ Other methods being investigated may become options in the future.²⁵

There are even fewer data on transgender men’s contraceptive needs. Many clinicians mistakenly think these patients are at low risk for pregnancy. Some patients have male partners and engage in penetrative penile-vaginal intercourse; others are not on testosterone therapy; and still others, despite taking testosterone, are not always amenorrheic and may be ovulating. In a small cross-sectional study, Light and colleagues found that 12% of transgender men who were surveyed after conceiving had been amenorrheic on testosterone therapy, and 24% of these pregnancies were not planned.²¹

In a study by Cipres and colleagues, half of the 26 transgender men were considered at risk for pregnancy: These patients still had a uterus, not all were on testosterone, not all on testosterone were amenorrheic, they were having vaginal intercourse with cisgender men, and none were using condoms or other contraception.²⁶ The authors noted several potential underlying reasons for poor counseling on contraceptive needs: patients feel stigmatized, clinicians assume these patients are not candidates for “female” hormone therapy, patients fear these modalities may feminize them and compromise their affirmed identities, patients poorly understand how testosterone works and have mistaken ideas about its contraceptive properties, and clinician discomfort with broaching fertility and reproductive health discussions.

Data are also limited on pregnancy in transgender men. We do know that clinicians are not well equipped to help patients during the peripartum period and better resources are needed.²¹ Gender dysphoria can worsen during and immediately after pregnancy, and patients may be at significant risk for postpartum depression. More research is needed.

Related Article:
Care of the transgender patient: What is the gynecologist's role?

Gynecologists play key role in transgender care

Transgender men’s unique health care needs can be addressed only by gynecologists.It is important to become comfortable with and educated about these needs and their subtleties. This starts with understanding transgender patients’ gender dysphoria associated with the gynecologic visit and examination. Learning more about these patients and their needs will improve health care delivery.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Illustration: Kimberly Martens for OBG Management

CASE: Transgender man consults gynecologist for fertility options

A 36-year-old transgender man considering the possibility of having his own biological children presents to the gynecology office to discuss hysterectomy as gender dysphoria treatment as well as his fertility preservation options. He has never had a gynecologic examination. Since age 24, he has been on testosterone therapy. Although his menses initially ceased, each month over the past 2 years he has had breakthrough spotting lasting 2 to 4 days, sometimes accompanied by pelvic pain and cramping. These symptoms have caused him distress and anxiety, which have led to his missing work 1 to 3 days each month. On presentation, he appears anxious and makes little eye contact. His girlfriend of 6 years has come in with him and is very supportive.

Over the past decade, transgender health care has moved to the forefront of the medical conversation. At many prominent medical centers across the United States, clinicians are forming multidisciplinary teams to help improve the health care of this patient population. Outcomes are being studied, and the literature is becoming more robust.

People tend to think of transgender women—male-assigned persons who self-identify as female—as the typical prototype for transgender people, but this focus is skewed in both society and the medical community. Transgender men—female-assigned persons who self-identify as male—remain underrepresented, mostly because they want to stay “under the radar,” especially with respect to medical care and, more specifically, routine gynecologic care.

Although the transgender woman has unique health needs and may present to a gynecologist for care after gender-affirmationsurgery, the transgender man’s many health care needs and their subtleties can be addressed only by a gynecologist. In this article, I review these intricacies of care to help increase clinician comfort in treating these patients.

Why transgender patients may delay seeking health care

Transgender patients remain underserved because of the health care barriers they encounter. Factors contributing to poor access include lack of health insurance, inability to pay for services, clinician insensitivity and hostility, and fear of exposure of transgender status during health care encounters.¹ In a recent large survey study, 30% of transgender respondents indicated that they delayed or did not seek medical care as a result of discrimination, and those who had needed to teach their clinicians about transgenderism were 4 times more likely to postpone or not seek care.²

In a 2015 survey of ObGyns’ current knowledge and practice regarding LGBT (lesbian, gay, bisexual, transgender) care, only one-third of respondents indicated they were comfortable caring for transgender patients.³ In addition, only one-third indicated being knowledgeable about the steps transgender patients must take to transition to their self-identified gender, and less than half were familiar with the recommendations for the routine health maintenance and screening of these patients.

Much of this discomfort derives from the lack of incorporation of LGBT-specific topics in medical curricula. In 2011, Obedin-Maliver and colleagues found that, at 176 US and Canadian allopathic and osteopathic medical schools, the median time dedicated to LGBT health care needs and related topics was unsatisfactory.⁴ This deficiency is slowly being reduced with changes in the curricula of many health care specialties. In ObGyn residency programs, for example, transgender-specific questions have been added to annual in-service examinations. The hope is that, as education initiatives improve, clinicians will become more comfortable caring for gender-minority patients, who with improved access to care will no longer need to seek subspecialists in transgender services.

Read about the need for gyn exams, managing benign disorders, and cervical cancer screening

Considerations for the gynecologic visit and examination

Transgender men visit the gynecology office for many reasons, including routine gynecologic care and health maintenance, care for acute and chronic gynecologic conditions (abnormal bleeding, pelvic pain, vaginitis), evaluation and management of pelvic floor disorders, consultation on hysterectomy for gender transition, and fertility counseling.

However, transgender men who reach their third, fourth, or fifth decade without having had a pelvic examination cite many reasons for avoiding the gynecology office. Most commonly, gynecologic visits and genital examination can severely exacerbate these patients’ gender dysphoria. In addition, many patients who do not engage in penetrative vaginal sex think their health risks are so low that they can forgo or delay pelvic exams. Patients who have stopped menstruating while on testosterone therapy may think there is no need for routine gynecologic care. Other reasons for avoiding pelvic exams are pain and traumatic sexual memories.⁵

Related Article:
Four pillars of a successful practice: 4. Motivate your staff

Transgender men need to receive the regular guideline-recommended pelvic exams and screenings used for cisgender women. (Cisgender refers to a person whose sense of gender identity corresponds with their birth sex.) We need to educate patients in this regard and to discuss several issues before performing an examination. First, take a thorough history and avoid making assumptions about sexual orientation and sex practices. Some patients have penetrative vaginal intercourse with either men or women. For some patients, the exam may cause dysphoria symptoms, and we need to validate patients’ fears. Discussing these issues ahead of time helps patients get used to the idea of undergoing an exam and assures them that the clinician is experienced in performing these exams for transgender men. In my practice, we explain the exam’s purpose (screening or diagnosis) and importance. We also counsel patients that they may experience some normal, and temporary, spotting after the exam. For those who experience severe dysphoria with vaginal bleeding of any kind, we acknowledge that postexam spotting may cause some anxiety. Patients with severe anxiety before the exam may be premedicated with an anxiolytic agent as long as someone can transport them to and from the office.

The bimanual exam should be performed with care and efficiency and with the patient given as much control as possible. In most cases, we ask patients to undress only from the waist down, and their genitals stay covered. Patients uncomfortable in stirrups are asked to show us the position that suits them best, and we try to accommodate them. Although speed is a goal, remember that many patients are nulliparous, have had limited or no vaginal penetration, or are on testosterone and have significant vaginal dryness. Use the smallest speculum possible, a pediatric or long and narrow adult speculum, and apply lubricant copiously. Pre-exam application of topical lidocaine jelly to the introitus can help reduce pain. To help a patient relax the pelvic floor muscles and habituate to the presence of a foreign object in the vagina, start the exam by inserting a single digit. In addition, ask the patient about speculum placement inside the vagina: Does he want to place the speculum himself or guide the clinician’s hand? Open the speculum only as much as needed to adequately visualize the cervix and then remove it with care.

Managing benign gynecologic disorders

The same algorithms are used to evaluate abnormal bleeding in all patients, but the differential diagnosis expands for those on testosterone therapy. Testosterone may no longer be suppressing their cycles, and abnormal bleeding could simply be the return of menses, which would present as regular cyclic bleeding. Increasing the testosterone dosing or changing the testosterone formulation may help, and the gynecologist should discuss these options with the patient’s prescribing clinician. In addition, progesterone in any form (for example, medroxyprogesterone acetate 5 to 30 mg daily) can be added to testosterone regimens to help suppress menses. The levonorgestrel-releasing intrauterine device (LNG-IUD) can be very effective, but placement can induce anxiety, and some patients decline this treatment option.

In patients with intermenstrual spotting, assess the vagina for atrophy. Both over-the-counter vaginal moisturizers and DHEA (dehydroepiandrosterone) suppositories (1% compounded) can help treat atrophy, but not all patients are comfortable using them. Most patients decline vaginal estrogen products for symptomatic vaginal atrophy even though the systemic effects are minimal.

The historic literature suggests that female-to-male patients’ long-term exposure to androgens leads to atrophic changes in the endometrium and myometrium, and clinical studies of menopausal women who take exogenous androgens have confirmed this effect.⁶ However, new data point to a different histologic scenario. A recent study found a possible association between long-term testosterone use in transgender men of reproductive age and a low proliferative active endometrium, as well as hypertrophic changes in the myometrium.⁷ The causes may be peripheral aromatization of androgens and expression and up-regulation of androgen receptors within the endometrial stroma and myometrial cells.⁸ Given these emerging data and anecdotal cases reported by clinicians who perform hysterectomies for transgender men, imaging and tissue sampling should be used to evaluate abnormal uterine bleeding, particularly in patients previously amenorrheic on testosterone. Be aware that transvaginal ultrasound or endometrial biopsy are challenging procedures for these patients. Counsel patients to ensure that they adhere to follow-up.

Related Article:
2017 Update on cervical disease

The ongoing need for cervical cancer screening

The concept of “original gender surveillance” was presented in a 2-case series of transgender men with uterine and cervical cancer that might have been detected earlier with better screening and routine care.⁹ There is no evidence, however, that long-term high-dose androgen therapy causes endometrial or cervical cancer,¹⁰ and the data on endometrial cancer in patients on cross-sex hormone therapy are limited such that a causal relationship between testosterone and these malignancies cannot be established.^9,11–14

The rate of unsatisfactory Pap smears is higher in transgender men than in cisgender women. The difference was anecdotally noted by clinicians who routinely cared for transgender patients over time and was confirmed with a retrospective chart review.¹⁵

Peitzmeier and colleagues reviewed the records of 233 transgender men and 3,625 cisgender women with Pap tests performed at an urban community health center over 6 years.¹⁵ The transgender cohort, with its prevalence rate of 10%, was 10 times more likely to have an unsatisfactory or inadequate Pap smear. Moreover, the transgender patients were more likely to have longer latency to follow-up for a repeat Pap test. In addition, testosterone therapy was more likely associated with inadequate Pap smears, and time on testosterone therapy was associated with higher odds of Pap smear inadequacy. Besides the exogenous hormone therapy, clinician comfort level and experience may have contributed to the high prevalence of inadequate Pap smears.

As mentioned earlier, it is important to become comfortable performing pelvic exams for transgender men and to prepare patients for the possibility that a Pap smear might be inadequate, making a follow-up visit and repeat Pap test necessary.¹⁶

Read about hysterectomy, oophorectomy, and vaginectomy choices

Consultation for hysterectomy: Perioperative considerations

Transgender men may undergo hysterectomy, oophorectomy, and/or vaginectomy. The TABLE summarizes the indications and perioperative considerations for each procedure.

Some transgender men undergo hysterectomy for benign gynecologic disease. Counseling and perioperative planning are the same for these patients as for cisgender women, although some of the considerations discussed here remain important.

Other patients undergo hysterectomy as part of transitioning to their self-affirmed gender. The World Professional Association for Transgender Health (WPATH) Standards of Care should be used to guide counseling and treatment.¹⁷ These guidelines were designed as a framework for performing hysterectomy and other gender-affirming procedures. According to the WPATH standards, the criteria for hysterectomy and oophorectomy are:

• 2 referral letters from qualified mental health professionals
• well-documented persistent gender dysphoria
• capacity to make fully informed decisions and to consent to treatment
• age of majority in given country
• good control of any concurrent medical or mental health concerns, and
• hormone therapy for 12 continuous months, as appropriate to gender goals, unless the patient has a medical contraindication or is otherwise unable or unwilling to take hormones.

As the guidelines emphasize, these criteria do not apply to patients undergoing either procedure for medical indications other than gender dysphoria.

Hysterectomy approach. Most surgeons perform gender-affirming hysterectomies laparoscopically. Many clinicians hesitate to perform these hysterectomies vaginally, as the patients are often nulliparous. In general, the best operative route is the one the surgeon feels most comfortable performing safely and efficiently. For a nulliparous patient with minimal pelvic organ descensus and a narrow pelvis, the laparoscopic approach is reasonable. A recent study in a small cohort of transgender men found that vaginal hysterectomy was successful in only 1 in 4 patients.¹⁸ Nevertheless, the American College of Obstetricians and Gynecologists (ACOG) recommends vaginal hysterectomy, when appropriate, for limiting complications and morbidity while maximizing cost-effectiveness.¹⁹ Although data are limited, vaginal hysterectomy seems feasible and should be considered in a subset of patients who pre‑sent for gender-affirming hysterectomy.

Related Article:
Total laparoscopic versus laparoscopic supracervical hysterectomy

The oophorectomy debate

Oophorectomy concurrent with hysterectomy remains a topic of debate among gynecologists who perform hysterectomy for gender transition. Some clinicians think gonadectomy poses a significant risk for bone health compromise at an early age. The long-term effects of testosterone on bone have not been well studied. Although bone metabolism is thought to increase over the short term, there are no major changes in bone density over the long term. In fact, in the setting of long-term testosterone therapy, cortical bone was found to be larger in transgender men than in cisgender women.²⁰ The issue is for patients who stop taking exogenous testosterone after oophorectomy. This subset of patients has not been well studied but clearly needs bone health surveillance and supplementation.

Another concern about oophorectomy is its effect on fertility. Because it is important to discuss fertility-preserving options, during consultation for a hysterectomy I spend a large portion of time addressing fertility goals. Patients who want to become a parent but do not want to carry a child (they want a current or future partner or surrogate to carry) are candidates for hysterectomy; those who do not want a genetic child are candidates for oophorectomy; and those who do not want to preserve their fertility (or have already ended it) and who meet the WPATH criteria for surgery are candidates for oophorectomy concurrent with hysterectomy. The discussion can be particularly challenging with young transgender men, since their ability to project their family planning goals may be compromised by their gender dysphoria. Clinicians can counsel patients about another option: isolated hysterectomy with subsequent staged oophorectomy.

Similar to cisgender women with polycystic ovary syndrome, transgender men on exogenous testosterone therapy are at risk for ovarian cysts,⁷ which can cause pain and should be evaluated and managed. As mentioned, these patients may find it difficult to visit a gynecologist and tolerate a vaginal examination, and many fear presenting to an emergency room, as they will need to disclose their transgender status and risk being discriminated against or, worse, not being triaged or cared for properly. Patients should be thoroughly counseled about the risks and benefits of having oophorectomy performed concurrently with hysterectomy.

Related Article:
Vaginal hysterectomy with basic instrumentation

The question of vaginectomy

Patients and clinicians often ask about concurrent vaginectomy procedures. In some cases, patients with severe gender dysphoria and absence of penetrative vaginal activity request excision or obliteration of the vagina. There is no standard of care, however. Vaginectomy can be done transvaginally or abdominally: open, laparoscopically, or robotically. It therefore should be performed by surgeons experienced in the procedure. Patients should be advised that a portion of the vaginal epithelium is sometimes used for certain phalloplasty procedures and that, if they are considering genital reconstruction in the future, it may be beneficial to preserve the vagina until that time.

There are no guidelines on stopping or continuing testosterone therapy perioperatively. Some clinicians are concerned about possible venous thromboembolic events related to perioperative use of testosterone, but there are no data supporting increased risk. The risk of postoperative vaginal cuff bleeding in patients on and off testosterone has not been well studied. Since patients who stop taking testosterone may develop severe mood swings and malaise, they should be counseled on recognizing and managing such changes. There are also no data on the risk of vaginal cuff dehiscence in this patient population. Testosterone usually causes the vagina to become very atrophic, so proper closure should be ensured to avoid cuff evisceration. In my practice, the vaginal cuff is closed in 2 layers using at least 1 layer of delayed absorbable suture.

Read about addressing fertility, contraception, OB care, and your role

Addressing fertility, contraception, and obstetric care

Most transgender men are able to conceive a child.²¹ Data in this area, however, are sparse. Most of the literature on reproductive health in this patient population is focused on human immunodeficiency virus (HIV) and other sexually transmitted infections.²² Nevertheless, patient-physician dialogue on fertility and reproductive health has increased since more patients started seeking surgical transition services (likely a result of improved coverage for these surgeries). In addition, we are learning more about patients’ ability and desire to conceive after long-term use of cross-sex hormone therapy. The importance of this dialogue is becoming apparent. One survey study found that more than half of the transgender men who had undergone affirmation surgery wanted to become parents.²³

Before initiating cross-sex hormone therapy or before undergoing hysterectomy and/or oophorectomy, patients must be counseled about their fertility options. Testosterone may affect fertility and fecundity, but there are case reports of successful pregnancy after discontinuation of testosterone.²¹ Reproductive endocrinology and fertility specialists have begun to recognize the importance of fertility preservation in this patient population and to apply the principles of oncofertility care beyond patients with cancer. In a 2015 opinion paper on access to fertility services by transgender persons, the Ethics Committee of the American Society for Reproductive Medicine focused on this population’s unique fertility needs.²⁴ Currently, oocyte and embryo cryopreservation are options for transgender men planning to start cross-sex hormones or undergo surgery.²⁵ Other methods being investigated may become options in the future.²⁵

There are even fewer data on transgender men’s contraceptive needs. Many clinicians mistakenly think these patients are at low risk for pregnancy. Some patients have male partners and engage in penetrative penile-vaginal intercourse; others are not on testosterone therapy; and still others, despite taking testosterone, are not always amenorrheic and may be ovulating. In a small cross-sectional study, Light and colleagues found that 12% of transgender men who were surveyed after conceiving had been amenorrheic on testosterone therapy, and 24% of these pregnancies were not planned.²¹

In a study by Cipres and colleagues, half of the 26 transgender men were considered at risk for pregnancy: These patients still had a uterus, not all were on testosterone, not all on testosterone were amenorrheic, they were having vaginal intercourse with cisgender men, and none were using condoms or other contraception.²⁶ The authors noted several potential underlying reasons for poor counseling on contraceptive needs: patients feel stigmatized, clinicians assume these patients are not candidates for “female” hormone therapy, patients fear these modalities may feminize them and compromise their affirmed identities, patients poorly understand how testosterone works and have mistaken ideas about its contraceptive properties, and clinician discomfort with broaching fertility and reproductive health discussions.

Data are also limited on pregnancy in transgender men. We do know that clinicians are not well equipped to help patients during the peripartum period and better resources are needed.²¹ Gender dysphoria can worsen during and immediately after pregnancy, and patients may be at significant risk for postpartum depression. More research is needed.

Related Article:
Care of the transgender patient: What is the gynecologist's role?

Gynecologists play key role in transgender care

Transgender men’s unique health care needs can be addressed only by gynecologists.It is important to become comfortable with and educated about these needs and their subtleties. This starts with understanding transgender patients’ gender dysphoria associated with the gynecologic visit and examination. Learning more about these patients and their needs will improve health care delivery.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Illustration: Kimberly Martens for OBG Management

CASE: Transgender man consults gynecologist for fertility options

A 36-year-old transgender man considering the possibility of having his own biological children presents to the gynecology office to discuss hysterectomy as gender dysphoria treatment as well as his fertility preservation options. He has never had a gynecologic examination. Since age 24, he has been on testosterone therapy. Although his menses initially ceased, each month over the past 2 years he has had breakthrough spotting lasting 2 to 4 days, sometimes accompanied by pelvic pain and cramping. These symptoms have caused him distress and anxiety, which have led to his missing work 1 to 3 days each month. On presentation, he appears anxious and makes little eye contact. His girlfriend of 6 years has come in with him and is very supportive.

Over the past decade, transgender health care has moved to the forefront of the medical conversation. At many prominent medical centers across the United States, clinicians are forming multidisciplinary teams to help improve the health care of this patient population. Outcomes are being studied, and the literature is becoming more robust.

People tend to think of transgender women—male-assigned persons who self-identify as female—as the typical prototype for transgender people, but this focus is skewed in both society and the medical community. Transgender men—female-assigned persons who self-identify as male—remain underrepresented, mostly because they want to stay “under the radar,” especially with respect to medical care and, more specifically, routine gynecologic care.

Although the transgender woman has unique health needs and may present to a gynecologist for care after gender-affirmationsurgery, the transgender man’s many health care needs and their subtleties can be addressed only by a gynecologist. In this article, I review these intricacies of care to help increase clinician comfort in treating these patients.

Why transgender patients may delay seeking health care

Transgender patients remain underserved because of the health care barriers they encounter. Factors contributing to poor access include lack of health insurance, inability to pay for services, clinician insensitivity and hostility, and fear of exposure of transgender status during health care encounters.¹ In a recent large survey study, 30% of transgender respondents indicated that they delayed or did not seek medical care as a result of discrimination, and those who had needed to teach their clinicians about transgenderism were 4 times more likely to postpone or not seek care.²

In a 2015 survey of ObGyns’ current knowledge and practice regarding LGBT (lesbian, gay, bisexual, transgender) care, only one-third of respondents indicated they were comfortable caring for transgender patients.³ In addition, only one-third indicated being knowledgeable about the steps transgender patients must take to transition to their self-identified gender, and less than half were familiar with the recommendations for the routine health maintenance and screening of these patients.

Much of this discomfort derives from the lack of incorporation of LGBT-specific topics in medical curricula. In 2011, Obedin-Maliver and colleagues found that, at 176 US and Canadian allopathic and osteopathic medical schools, the median time dedicated to LGBT health care needs and related topics was unsatisfactory.⁴ This deficiency is slowly being reduced with changes in the curricula of many health care specialties. In ObGyn residency programs, for example, transgender-specific questions have been added to annual in-service examinations. The hope is that, as education initiatives improve, clinicians will become more comfortable caring for gender-minority patients, who with improved access to care will no longer need to seek subspecialists in transgender services.

Read about the need for gyn exams, managing benign disorders, and cervical cancer screening

Considerations for the gynecologic visit and examination

Transgender men visit the gynecology office for many reasons, including routine gynecologic care and health maintenance, care for acute and chronic gynecologic conditions (abnormal bleeding, pelvic pain, vaginitis), evaluation and management of pelvic floor disorders, consultation on hysterectomy for gender transition, and fertility counseling.

However, transgender men who reach their third, fourth, or fifth decade without having had a pelvic examination cite many reasons for avoiding the gynecology office. Most commonly, gynecologic visits and genital examination can severely exacerbate these patients’ gender dysphoria. In addition, many patients who do not engage in penetrative vaginal sex think their health risks are so low that they can forgo or delay pelvic exams. Patients who have stopped menstruating while on testosterone therapy may think there is no need for routine gynecologic care. Other reasons for avoiding pelvic exams are pain and traumatic sexual memories.⁵

Related Article:
Four pillars of a successful practice: 4. Motivate your staff

Transgender men need to receive the regular guideline-recommended pelvic exams and screenings used for cisgender women. (Cisgender refers to a person whose sense of gender identity corresponds with their birth sex.) We need to educate patients in this regard and to discuss several issues before performing an examination. First, take a thorough history and avoid making assumptions about sexual orientation and sex practices. Some patients have penetrative vaginal intercourse with either men or women. For some patients, the exam may cause dysphoria symptoms, and we need to validate patients’ fears. Discussing these issues ahead of time helps patients get used to the idea of undergoing an exam and assures them that the clinician is experienced in performing these exams for transgender men. In my practice, we explain the exam’s purpose (screening or diagnosis) and importance. We also counsel patients that they may experience some normal, and temporary, spotting after the exam. For those who experience severe dysphoria with vaginal bleeding of any kind, we acknowledge that postexam spotting may cause some anxiety. Patients with severe anxiety before the exam may be premedicated with an anxiolytic agent as long as someone can transport them to and from the office.

The bimanual exam should be performed with care and efficiency and with the patient given as much control as possible. In most cases, we ask patients to undress only from the waist down, and their genitals stay covered. Patients uncomfortable in stirrups are asked to show us the position that suits them best, and we try to accommodate them. Although speed is a goal, remember that many patients are nulliparous, have had limited or no vaginal penetration, or are on testosterone and have significant vaginal dryness. Use the smallest speculum possible, a pediatric or long and narrow adult speculum, and apply lubricant copiously. Pre-exam application of topical lidocaine jelly to the introitus can help reduce pain. To help a patient relax the pelvic floor muscles and habituate to the presence of a foreign object in the vagina, start the exam by inserting a single digit. In addition, ask the patient about speculum placement inside the vagina: Does he want to place the speculum himself or guide the clinician’s hand? Open the speculum only as much as needed to adequately visualize the cervix and then remove it with care.

Managing benign gynecologic disorders

The same algorithms are used to evaluate abnormal bleeding in all patients, but the differential diagnosis expands for those on testosterone therapy. Testosterone may no longer be suppressing their cycles, and abnormal bleeding could simply be the return of menses, which would present as regular cyclic bleeding. Increasing the testosterone dosing or changing the testosterone formulation may help, and the gynecologist should discuss these options with the patient’s prescribing clinician. In addition, progesterone in any form (for example, medroxyprogesterone acetate 5 to 30 mg daily) can be added to testosterone regimens to help suppress menses. The levonorgestrel-releasing intrauterine device (LNG-IUD) can be very effective, but placement can induce anxiety, and some patients decline this treatment option.

In patients with intermenstrual spotting, assess the vagina for atrophy. Both over-the-counter vaginal moisturizers and DHEA (dehydroepiandrosterone) suppositories (1% compounded) can help treat atrophy, but not all patients are comfortable using them. Most patients decline vaginal estrogen products for symptomatic vaginal atrophy even though the systemic effects are minimal.

The historic literature suggests that female-to-male patients’ long-term exposure to androgens leads to atrophic changes in the endometrium and myometrium, and clinical studies of menopausal women who take exogenous androgens have confirmed this effect.⁶ However, new data point to a different histologic scenario. A recent study found a possible association between long-term testosterone use in transgender men of reproductive age and a low proliferative active endometrium, as well as hypertrophic changes in the myometrium.⁷ The causes may be peripheral aromatization of androgens and expression and up-regulation of androgen receptors within the endometrial stroma and myometrial cells.⁸ Given these emerging data and anecdotal cases reported by clinicians who perform hysterectomies for transgender men, imaging and tissue sampling should be used to evaluate abnormal uterine bleeding, particularly in patients previously amenorrheic on testosterone. Be aware that transvaginal ultrasound or endometrial biopsy are challenging procedures for these patients. Counsel patients to ensure that they adhere to follow-up.

Related Article:
2017 Update on cervical disease

The ongoing need for cervical cancer screening

The concept of “original gender surveillance” was presented in a 2-case series of transgender men with uterine and cervical cancer that might have been detected earlier with better screening and routine care.⁹ There is no evidence, however, that long-term high-dose androgen therapy causes endometrial or cervical cancer,¹⁰ and the data on endometrial cancer in patients on cross-sex hormone therapy are limited such that a causal relationship between testosterone and these malignancies cannot be established.^9,11–14

The rate of unsatisfactory Pap smears is higher in transgender men than in cisgender women. The difference was anecdotally noted by clinicians who routinely cared for transgender patients over time and was confirmed with a retrospective chart review.¹⁵

Peitzmeier and colleagues reviewed the records of 233 transgender men and 3,625 cisgender women with Pap tests performed at an urban community health center over 6 years.¹⁵ The transgender cohort, with its prevalence rate of 10%, was 10 times more likely to have an unsatisfactory or inadequate Pap smear. Moreover, the transgender patients were more likely to have longer latency to follow-up for a repeat Pap test. In addition, testosterone therapy was more likely associated with inadequate Pap smears, and time on testosterone therapy was associated with higher odds of Pap smear inadequacy. Besides the exogenous hormone therapy, clinician comfort level and experience may have contributed to the high prevalence of inadequate Pap smears.

As mentioned earlier, it is important to become comfortable performing pelvic exams for transgender men and to prepare patients for the possibility that a Pap smear might be inadequate, making a follow-up visit and repeat Pap test necessary.¹⁶

Read about hysterectomy, oophorectomy, and vaginectomy choices

Consultation for hysterectomy: Perioperative considerations

Transgender men may undergo hysterectomy, oophorectomy, and/or vaginectomy. The TABLE summarizes the indications and perioperative considerations for each procedure.

Some transgender men undergo hysterectomy for benign gynecologic disease. Counseling and perioperative planning are the same for these patients as for cisgender women, although some of the considerations discussed here remain important.

Other patients undergo hysterectomy as part of transitioning to their self-affirmed gender. The World Professional Association for Transgender Health (WPATH) Standards of Care should be used to guide counseling and treatment.¹⁷ These guidelines were designed as a framework for performing hysterectomy and other gender-affirming procedures. According to the WPATH standards, the criteria for hysterectomy and oophorectomy are:

• 2 referral letters from qualified mental health professionals
• well-documented persistent gender dysphoria
• capacity to make fully informed decisions and to consent to treatment
• age of majority in given country
• good control of any concurrent medical or mental health concerns, and
• hormone therapy for 12 continuous months, as appropriate to gender goals, unless the patient has a medical contraindication or is otherwise unable or unwilling to take hormones.

As the guidelines emphasize, these criteria do not apply to patients undergoing either procedure for medical indications other than gender dysphoria.

Hysterectomy approach. Most surgeons perform gender-affirming hysterectomies laparoscopically. Many clinicians hesitate to perform these hysterectomies vaginally, as the patients are often nulliparous. In general, the best operative route is the one the surgeon feels most comfortable performing safely and efficiently. For a nulliparous patient with minimal pelvic organ descensus and a narrow pelvis, the laparoscopic approach is reasonable. A recent study in a small cohort of transgender men found that vaginal hysterectomy was successful in only 1 in 4 patients.¹⁸ Nevertheless, the American College of Obstetricians and Gynecologists (ACOG) recommends vaginal hysterectomy, when appropriate, for limiting complications and morbidity while maximizing cost-effectiveness.¹⁹ Although data are limited, vaginal hysterectomy seems feasible and should be considered in a subset of patients who pre‑sent for gender-affirming hysterectomy.

Related Article:
Total laparoscopic versus laparoscopic supracervical hysterectomy

The oophorectomy debate

Oophorectomy concurrent with hysterectomy remains a topic of debate among gynecologists who perform hysterectomy for gender transition. Some clinicians think gonadectomy poses a significant risk for bone health compromise at an early age. The long-term effects of testosterone on bone have not been well studied. Although bone metabolism is thought to increase over the short term, there are no major changes in bone density over the long term. In fact, in the setting of long-term testosterone therapy, cortical bone was found to be larger in transgender men than in cisgender women.²⁰ The issue is for patients who stop taking exogenous testosterone after oophorectomy. This subset of patients has not been well studied but clearly needs bone health surveillance and supplementation.

Another concern about oophorectomy is its effect on fertility. Because it is important to discuss fertility-preserving options, during consultation for a hysterectomy I spend a large portion of time addressing fertility goals. Patients who want to become a parent but do not want to carry a child (they want a current or future partner or surrogate to carry) are candidates for hysterectomy; those who do not want a genetic child are candidates for oophorectomy; and those who do not want to preserve their fertility (or have already ended it) and who meet the WPATH criteria for surgery are candidates for oophorectomy concurrent with hysterectomy. The discussion can be particularly challenging with young transgender men, since their ability to project their family planning goals may be compromised by their gender dysphoria. Clinicians can counsel patients about another option: isolated hysterectomy with subsequent staged oophorectomy.

Similar to cisgender women with polycystic ovary syndrome, transgender men on exogenous testosterone therapy are at risk for ovarian cysts,⁷ which can cause pain and should be evaluated and managed. As mentioned, these patients may find it difficult to visit a gynecologist and tolerate a vaginal examination, and many fear presenting to an emergency room, as they will need to disclose their transgender status and risk being discriminated against or, worse, not being triaged or cared for properly. Patients should be thoroughly counseled about the risks and benefits of having oophorectomy performed concurrently with hysterectomy.

Related Article:
Vaginal hysterectomy with basic instrumentation

The question of vaginectomy

Patients and clinicians often ask about concurrent vaginectomy procedures. In some cases, patients with severe gender dysphoria and absence of penetrative vaginal activity request excision or obliteration of the vagina. There is no standard of care, however. Vaginectomy can be done transvaginally or abdominally: open, laparoscopically, or robotically. It therefore should be performed by surgeons experienced in the procedure. Patients should be advised that a portion of the vaginal epithelium is sometimes used for certain phalloplasty procedures and that, if they are considering genital reconstruction in the future, it may be beneficial to preserve the vagina until that time.

There are no guidelines on stopping or continuing testosterone therapy perioperatively. Some clinicians are concerned about possible venous thromboembolic events related to perioperative use of testosterone, but there are no data supporting increased risk. The risk of postoperative vaginal cuff bleeding in patients on and off testosterone has not been well studied. Since patients who stop taking testosterone may develop severe mood swings and malaise, they should be counseled on recognizing and managing such changes. There are also no data on the risk of vaginal cuff dehiscence in this patient population. Testosterone usually causes the vagina to become very atrophic, so proper closure should be ensured to avoid cuff evisceration. In my practice, the vaginal cuff is closed in 2 layers using at least 1 layer of delayed absorbable suture.

Read about addressing fertility, contraception, OB care, and your role

Addressing fertility, contraception, and obstetric care

Most transgender men are able to conceive a child.²¹ Data in this area, however, are sparse. Most of the literature on reproductive health in this patient population is focused on human immunodeficiency virus (HIV) and other sexually transmitted infections.²² Nevertheless, patient-physician dialogue on fertility and reproductive health has increased since more patients started seeking surgical transition services (likely a result of improved coverage for these surgeries). In addition, we are learning more about patients’ ability and desire to conceive after long-term use of cross-sex hormone therapy. The importance of this dialogue is becoming apparent. One survey study found that more than half of the transgender men who had undergone affirmation surgery wanted to become parents.²³

Before initiating cross-sex hormone therapy or before undergoing hysterectomy and/or oophorectomy, patients must be counseled about their fertility options. Testosterone may affect fertility and fecundity, but there are case reports of successful pregnancy after discontinuation of testosterone.²¹ Reproductive endocrinology and fertility specialists have begun to recognize the importance of fertility preservation in this patient population and to apply the principles of oncofertility care beyond patients with cancer. In a 2015 opinion paper on access to fertility services by transgender persons, the Ethics Committee of the American Society for Reproductive Medicine focused on this population’s unique fertility needs.²⁴ Currently, oocyte and embryo cryopreservation are options for transgender men planning to start cross-sex hormones or undergo surgery.²⁵ Other methods being investigated may become options in the future.²⁵

There are even fewer data on transgender men’s contraceptive needs. Many clinicians mistakenly think these patients are at low risk for pregnancy. Some patients have male partners and engage in penetrative penile-vaginal intercourse; others are not on testosterone therapy; and still others, despite taking testosterone, are not always amenorrheic and may be ovulating. In a small cross-sectional study, Light and colleagues found that 12% of transgender men who were surveyed after conceiving had been amenorrheic on testosterone therapy, and 24% of these pregnancies were not planned.²¹

In a study by Cipres and colleagues, half of the 26 transgender men were considered at risk for pregnancy: These patients still had a uterus, not all were on testosterone, not all on testosterone were amenorrheic, they were having vaginal intercourse with cisgender men, and none were using condoms or other contraception.²⁶ The authors noted several potential underlying reasons for poor counseling on contraceptive needs: patients feel stigmatized, clinicians assume these patients are not candidates for “female” hormone therapy, patients fear these modalities may feminize them and compromise their affirmed identities, patients poorly understand how testosterone works and have mistaken ideas about its contraceptive properties, and clinician discomfort with broaching fertility and reproductive health discussions.

Data are also limited on pregnancy in transgender men. We do know that clinicians are not well equipped to help patients during the peripartum period and better resources are needed.²¹ Gender dysphoria can worsen during and immediately after pregnancy, and patients may be at significant risk for postpartum depression. More research is needed.

Related Article:
Care of the transgender patient: What is the gynecologist's role?

Gynecologists play key role in transgender care

Transgender men’s unique health care needs can be addressed only by gynecologists.It is important to become comfortable with and educated about these needs and their subtleties. This starts with understanding transgender patients’ gender dysphoria associated with the gynecologic visit and examination. Learning more about these patients and their needs will improve health care delivery.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Pyogenic flexor tenosynovitis (PFT) is a common closed space infection of the flexor tendon sheaths of the hand and remains one of the most challenging problems encountered in orthopedic and hand surgery (Figure 1). PFT also is known as septic flexor tenosynovitis and suppurative flexor tenosynovitis.

Kanavel¹ initially described 4 cardinal signs that characterize infection of the flexor tendon sheath: symmetric fusiform swelling of the entire digit, exquisite tenderness to palpation along the course of the tendon sheath, semiflexed posture at rest, and pain with attempted passive extension of the digit. The prevalence of this infection ranges from 2.5% to 9.4%.² Once the infection is established in a patient, it can cause significant morbidity and disability and produce an economic burden. It can also present a significant treatment dilemma for the treating surgeon, as there is no standardized protocol for managing this common but challenging hand infection. For treatment, many surgeons combine surgical decompression, sheath irrigation, and empiric intravenous (IV) antibiotic administration. However, despite prompt treatment, and regardless of the protocol used, complication rates as high as 38% have been reported.³ Moreover, even after infection eradication, a significant proportion of patients continue to have pain, swelling, stiffness, loss of composite flexion, weakness, and recurrence that potentially requires amputation.

1. What Causes Pyogenic Flexor Tenosynovitis?

PFT can result from hematogenous spread, but local inoculation by a laceration, a puncture, or a bite also is common^4-7 (Figure 1). As a consequence of these mechanisms of injury, the most common source of PFT is skin flora. Staphylococcus aureus has been found in up to 75% of positive cultures in several studies.^2,5,6,8,9 Methicillin-resistant S aureus (MRSA) has been found in up to 29% of cases, and the incidence continues to increase, particularly in urban areas.^2,9-12 Other common bacteria are Staphylococcus epidermidis, β-hemolytic Streptococcus species, and Pseudomonas aeruginosa.^5,6,10 Infection by more than 1 species of bacteria is also fairly prevalent. Of 62 patients in a study, 38% had infections with 1 organism, and 62% with 2 or more.⁶ Twenty-six percent of cultures grew mixed anaerobic and aerobic organisms.⁶ PFT is seldom caused by Eikenella corrodens from a human bite or Pasteurella multocida from an animal bite.¹⁰ Other rare causes of PFT are Listeria monocytogenes¹³ and Clostridium difficile from a gastrointestinal source.¹⁴Neisseria gonorrhea can cause acute tenosynovitis, usually in the setting of disseminated gonococcal infection.^15,16 Also reported is mycobacterial tenosynovitis, most commonly caused by Mycobacterium kansasii and Mycobacterium marinum.¹⁷

2. Which Antibiotics Are Best Suited to Empirical Management of PFT?

Management of PFT, regardless of the pathogen, includes prompt administration of empiric IV antibiotics, usually followed by surgical drainage.^7,18-20 While cultures are being tested, antibiotics should be selected—including antibiotics for empiric coverage against common gram-positive organisms, including Staphylococcus and Streptococcus species.¹² The Centers for Disease Control and Prevention recommends empiric coverage for MRSA if the local prevalence exceeds 10% to 15%. Recommended empiric antibiotics are trimethoprim-sulfamethoxazole (TMP-SMX) and clindamycin (both oral) and clindamycin, vancomycin, and daptomycin (all IV).

In addition, institutional and local antibiotic resistance patterns of bacteria should guide treatment and antibiotic selection. First-generation cephalosporins have long been the cornerstone of treatment for infections caused by S aureus, but increasing methicillin resistance has reduced their role in the treatment, particularly the empiric treatment, of MRSA infections. Methicillin resistance first appeared as nosocomial S aureus infections in 1961, only 1 year after the introduction of the semisynthetic penicillin class that includes methicillin. Over the past 2 decades, MRSA has emerged in the community in otherwise young and healthy individuals with no healthcare-associated risk factors. Fortunately, several readily available antibiotics have maintained their efficacy in managing these “community-acquired” MRSA hand infections. TMP-SMX provides adequate coverage for MRSA and is a relatively inexpensive medication, and clindamycin is an equally effective and cost-effective alternative.

Presumptive antibiotics should also cover gram-negative rods and anaerobes, including Clostridium species, especially in immunocompromised patients.^7,9 These patients may require additional antibiotics for presumptive coverage of other rarer bacterial causes, especially when unique mechanisms of injury (eg, aquatic injury, farm injury) are involved. Once culture results are ready, antibiotic regimens should be narrowed to cover the specific organisms identified.

3. What Are the Timing and Indications for Surgery?

Nonoperative treatment may be appropriate for PFT patients who present early, typically within 48 hours after penetrating trauma to the hand.²¹ In a 4-patient series, Neviaser and Gunther¹⁹ successfully treated PFT nonoperatively, with IV antibiotics, splinting, and elevation. During nonoperative treatment, the affected hand should be regularly examined. If this treatment is to be successful, clinical symptoms should improve within 48 hours; if they do not, surgical irrigation and débridement should be performed.

Regardless of timing and type of irrigation, surgical treatment remains the treatment of choice for the majority of PFT cases. Michon²² developed a 3-tier PFT classification system that is based on intraoperative findings (Table).

4. What Are the Surgical Techniques for PFT Drainage?

Several surgical methods have been developed to decompress and irrigate the flexor sheaths of the hand. However, debates about optimal timing of surgical intervention, surgery type (open surgery or closed catheter irrigation only), and irrigation method continue.

Open Irrigation and Débridement

Open irrigation and débridement procedures were originally described for surgical management of PFT.¹ Midaxial and palmar (Bruner zigzag) incisions can be used to expose and open the entire sheath for complete drainage and washout. Both incisions afford good access to the flexor sheath, but the midaxial approach may provide more coverage of the sheath after surgery. Open irrigation and débridement is the treatment of choice for the most advanced cases of PFT and for atypical or chronic tenosynovial infections.^4,23,24 The Bruner zigzag incision affords ease of surgical dissection, extension, and more exposure of the flexor tendon sheath at the expense of possible difficulty in closure or flap necrosis in the setting of a swollen digit. Alternatively, the midaxial incision has the advantage of a large, more robust skin flap for more reliable closure.

Closed Tendon Sheath Irrigation

In 1943, Dickson-Wright²⁵ first described catheter irrigation of tendon sheath infections. Later, Neviaser⁴ described this technique in detail. A proximal incision is made over the metacarpal neck. The tendon sheath is cut transversely at the proximal edge of the A1 pulley. An angiocatheter is inserted 1 cm to 2 cm antegrade into the flexor tendon sheath. Then, a distal midaxial incision is made dorsal to the neurovascular bundle at the level of the distal interphalangeal joint on the ulnar aspect of the finger or the radial aspect of the thumb. The distal edge of the flexor sheath is exposed and resected distal to the distal-most pulley. A Penrose drain can be threaded into the tendon sheath beneath the A4 pulley to keep the wound open and allow for fluid drainage. The sheath is flushed gently in the operating room. After surgery, intermittent bedside irrigation can be continued on the floor.

Neviaser⁴ reported excellent initial results with this technique; 18 of 20 patients regained complete active and passive range of motion (ROM) by 1 week after surgery. Similarly, Juliano and Eglseder,²⁶ using a similar method, reported 100% excellent results for mild PFT and 88.4% excellent results for more severe infection.

Gutowski and colleagues²³ reviewed 47 PFT cases to determine if there is a difference in outcomes between PFT treated with open irrigation and débridement and PFT treated with closed catheter irrigation. Between these groups, they found no significant differences in early postoperative outcomes, including resolution of infection, need for additional surgery, and hospital length of stay.

There are also many differing opinions regarding the best irrigation method. Some authors have asserted that normal saline is sufficient,^4,5,23 and others that local antibiotics provide added benefit.^27-29 Recently, Draeger and colleagues³⁰ reported promising results with local injection of antibiotics into the tendon sheath and the addition of locally administered corticosteroids in the treatment of PFT in an animal model.

Continuous Closed Irrigation

A continuous closed irrigation system with inlet and outlet tubes has yielded successful results.^8,31,32 This system consists of 2 fenestrated tubes placed within the infected space, with the tip of the smaller caliber inlet tube positioned just inside the larger outlet tube. Advantages of this system include the patient’s ability to participate in hand therapy with the system in place and avoidance of pain caused by the high pressures involved in intermittent closed irrigation. Duration of this system has ranged from 2 days to 3 weeks, and results have been good.^5,8

Postoperative Irrigation

Use of postoperative irrigation on the floor or at home is controversial, as leaving an indwelling catheter in the tendon sheath can lead to complications. Catheters may increase digital stiffness by decreasing the patient’s ability to participate in therapy or may cause additional injury and irritation to the sheath itself if left in place too long. Lille and colleagues⁶ retrospectively compared the results of intraoperative closed tendon sheath irrigation alone with those of intraoperative and postoperative closed tendon sheath irrigation. There were no significant differences in mean hospital length of stay, follow-up complication rates, or postoperative ROM—which suggests that postoperative intermittent or continuous irrigation is not necessary.

Our Preferred Technique

We recommend a palmar approach that begins with outlining a Bruner zigzag incision along the entire finger. Then, only the distal-most and proximal-most incision lines are opened, thereby exposing the A5 and A1 pulleys, respectively (Figure 2).

5. What Are the Long-Term Outcomes of PFT?

The principal complication associated with PFT is stiffness with loss of ROM, which can be caused by flexor tendon adhesions, joint capsular thickening, or destruction of the sheath and pulley system.²⁴ In several studies, up to one-fourth of patients with PFT did not obtain full ROM, despite adequate treatment.^4-6,27 Therefore, full active ROM exercises should be initiated immediately after surgery to counteract the development of stiffness.

The most severe complication of PFT is amputation of the affected digit (Figures 3A, 3B).

Conclusion

PFT is a common hand infection that can cause significant morbidity. Early treatment is crucial: this requires use of IV antibiotics, or surgical irrigation and débridement in more advanced cases. However, despite prompt and thorough treatment, severe infection can lead to long-term impaired function and even amputation of the affected digit. More research is needed to determine optimal timing and technique for surgical intervention and to elucidate the role of local antibiotics and corticosteroids in treating this infection and potentially preventing the morbid outcomes we currently see.

Am J Orthop. 2017;46(3):E207-E212. Copyright Frontline Medical Communications Inc. 2017. All rights reserved.

Pyogenic flexor tenosynovitis (PFT) is a common closed space infection of the flexor tendon sheaths of the hand and remains one of the most challenging problems encountered in orthopedic and hand surgery (Figure 1). PFT also is known as septic flexor tenosynovitis and suppurative flexor tenosynovitis.

Kanavel¹ initially described 4 cardinal signs that characterize infection of the flexor tendon sheath: symmetric fusiform swelling of the entire digit, exquisite tenderness to palpation along the course of the tendon sheath, semiflexed posture at rest, and pain with attempted passive extension of the digit. The prevalence of this infection ranges from 2.5% to 9.4%.² Once the infection is established in a patient, it can cause significant morbidity and disability and produce an economic burden. It can also present a significant treatment dilemma for the treating surgeon, as there is no standardized protocol for managing this common but challenging hand infection. For treatment, many surgeons combine surgical decompression, sheath irrigation, and empiric intravenous (IV) antibiotic administration. However, despite prompt treatment, and regardless of the protocol used, complication rates as high as 38% have been reported.³ Moreover, even after infection eradication, a significant proportion of patients continue to have pain, swelling, stiffness, loss of composite flexion, weakness, and recurrence that potentially requires amputation.

1. What Causes Pyogenic Flexor Tenosynovitis?

PFT can result from hematogenous spread, but local inoculation by a laceration, a puncture, or a bite also is common^4-7 (Figure 1). As a consequence of these mechanisms of injury, the most common source of PFT is skin flora. Staphylococcus aureus has been found in up to 75% of positive cultures in several studies.^2,5,6,8,9 Methicillin-resistant S aureus (MRSA) has been found in up to 29% of cases, and the incidence continues to increase, particularly in urban areas.^2,9-12 Other common bacteria are Staphylococcus epidermidis, β-hemolytic Streptococcus species, and Pseudomonas aeruginosa.^5,6,10 Infection by more than 1 species of bacteria is also fairly prevalent. Of 62 patients in a study, 38% had infections with 1 organism, and 62% with 2 or more.⁶ Twenty-six percent of cultures grew mixed anaerobic and aerobic organisms.⁶ PFT is seldom caused by Eikenella corrodens from a human bite or Pasteurella multocida from an animal bite.¹⁰ Other rare causes of PFT are Listeria monocytogenes¹³ and Clostridium difficile from a gastrointestinal source.¹⁴Neisseria gonorrhea can cause acute tenosynovitis, usually in the setting of disseminated gonococcal infection.^15,16 Also reported is mycobacterial tenosynovitis, most commonly caused by Mycobacterium kansasii and Mycobacterium marinum.¹⁷

2. Which Antibiotics Are Best Suited to Empirical Management of PFT?

Management of PFT, regardless of the pathogen, includes prompt administration of empiric IV antibiotics, usually followed by surgical drainage.^7,18-20 While cultures are being tested, antibiotics should be selected—including antibiotics for empiric coverage against common gram-positive organisms, including Staphylococcus and Streptococcus species.¹² The Centers for Disease Control and Prevention recommends empiric coverage for MRSA if the local prevalence exceeds 10% to 15%. Recommended empiric antibiotics are trimethoprim-sulfamethoxazole (TMP-SMX) and clindamycin (both oral) and clindamycin, vancomycin, and daptomycin (all IV).

In addition, institutional and local antibiotic resistance patterns of bacteria should guide treatment and antibiotic selection. First-generation cephalosporins have long been the cornerstone of treatment for infections caused by S aureus, but increasing methicillin resistance has reduced their role in the treatment, particularly the empiric treatment, of MRSA infections. Methicillin resistance first appeared as nosocomial S aureus infections in 1961, only 1 year after the introduction of the semisynthetic penicillin class that includes methicillin. Over the past 2 decades, MRSA has emerged in the community in otherwise young and healthy individuals with no healthcare-associated risk factors. Fortunately, several readily available antibiotics have maintained their efficacy in managing these “community-acquired” MRSA hand infections. TMP-SMX provides adequate coverage for MRSA and is a relatively inexpensive medication, and clindamycin is an equally effective and cost-effective alternative.

Presumptive antibiotics should also cover gram-negative rods and anaerobes, including Clostridium species, especially in immunocompromised patients.^7,9 These patients may require additional antibiotics for presumptive coverage of other rarer bacterial causes, especially when unique mechanisms of injury (eg, aquatic injury, farm injury) are involved. Once culture results are ready, antibiotic regimens should be narrowed to cover the specific organisms identified.

3. What Are the Timing and Indications for Surgery?

Nonoperative treatment may be appropriate for PFT patients who present early, typically within 48 hours after penetrating trauma to the hand.²¹ In a 4-patient series, Neviaser and Gunther¹⁹ successfully treated PFT nonoperatively, with IV antibiotics, splinting, and elevation. During nonoperative treatment, the affected hand should be regularly examined. If this treatment is to be successful, clinical symptoms should improve within 48 hours; if they do not, surgical irrigation and débridement should be performed.

Regardless of timing and type of irrigation, surgical treatment remains the treatment of choice for the majority of PFT cases. Michon²² developed a 3-tier PFT classification system that is based on intraoperative findings (Table).

4. What Are the Surgical Techniques for PFT Drainage?

Several surgical methods have been developed to decompress and irrigate the flexor sheaths of the hand. However, debates about optimal timing of surgical intervention, surgery type (open surgery or closed catheter irrigation only), and irrigation method continue.

Open Irrigation and Débridement

Open irrigation and débridement procedures were originally described for surgical management of PFT.¹ Midaxial and palmar (Bruner zigzag) incisions can be used to expose and open the entire sheath for complete drainage and washout. Both incisions afford good access to the flexor sheath, but the midaxial approach may provide more coverage of the sheath after surgery. Open irrigation and débridement is the treatment of choice for the most advanced cases of PFT and for atypical or chronic tenosynovial infections.^4,23,24 The Bruner zigzag incision affords ease of surgical dissection, extension, and more exposure of the flexor tendon sheath at the expense of possible difficulty in closure or flap necrosis in the setting of a swollen digit. Alternatively, the midaxial incision has the advantage of a large, more robust skin flap for more reliable closure.

Closed Tendon Sheath Irrigation

In 1943, Dickson-Wright²⁵ first described catheter irrigation of tendon sheath infections. Later, Neviaser⁴ described this technique in detail. A proximal incision is made over the metacarpal neck. The tendon sheath is cut transversely at the proximal edge of the A1 pulley. An angiocatheter is inserted 1 cm to 2 cm antegrade into the flexor tendon sheath. Then, a distal midaxial incision is made dorsal to the neurovascular bundle at the level of the distal interphalangeal joint on the ulnar aspect of the finger or the radial aspect of the thumb. The distal edge of the flexor sheath is exposed and resected distal to the distal-most pulley. A Penrose drain can be threaded into the tendon sheath beneath the A4 pulley to keep the wound open and allow for fluid drainage. The sheath is flushed gently in the operating room. After surgery, intermittent bedside irrigation can be continued on the floor.

Neviaser⁴ reported excellent initial results with this technique; 18 of 20 patients regained complete active and passive range of motion (ROM) by 1 week after surgery. Similarly, Juliano and Eglseder,²⁶ using a similar method, reported 100% excellent results for mild PFT and 88.4% excellent results for more severe infection.

Gutowski and colleagues²³ reviewed 47 PFT cases to determine if there is a difference in outcomes between PFT treated with open irrigation and débridement and PFT treated with closed catheter irrigation. Between these groups, they found no significant differences in early postoperative outcomes, including resolution of infection, need for additional surgery, and hospital length of stay.

There are also many differing opinions regarding the best irrigation method. Some authors have asserted that normal saline is sufficient,^4,5,23 and others that local antibiotics provide added benefit.^27-29 Recently, Draeger and colleagues³⁰ reported promising results with local injection of antibiotics into the tendon sheath and the addition of locally administered corticosteroids in the treatment of PFT in an animal model.

Continuous Closed Irrigation

A continuous closed irrigation system with inlet and outlet tubes has yielded successful results.^8,31,32 This system consists of 2 fenestrated tubes placed within the infected space, with the tip of the smaller caliber inlet tube positioned just inside the larger outlet tube. Advantages of this system include the patient’s ability to participate in hand therapy with the system in place and avoidance of pain caused by the high pressures involved in intermittent closed irrigation. Duration of this system has ranged from 2 days to 3 weeks, and results have been good.^5,8

Postoperative Irrigation

Use of postoperative irrigation on the floor or at home is controversial, as leaving an indwelling catheter in the tendon sheath can lead to complications. Catheters may increase digital stiffness by decreasing the patient’s ability to participate in therapy or may cause additional injury and irritation to the sheath itself if left in place too long. Lille and colleagues⁶ retrospectively compared the results of intraoperative closed tendon sheath irrigation alone with those of intraoperative and postoperative closed tendon sheath irrigation. There were no significant differences in mean hospital length of stay, follow-up complication rates, or postoperative ROM—which suggests that postoperative intermittent or continuous irrigation is not necessary.

Our Preferred Technique

We recommend a palmar approach that begins with outlining a Bruner zigzag incision along the entire finger. Then, only the distal-most and proximal-most incision lines are opened, thereby exposing the A5 and A1 pulleys, respectively (Figure 2).

5. What Are the Long-Term Outcomes of PFT?

The principal complication associated with PFT is stiffness with loss of ROM, which can be caused by flexor tendon adhesions, joint capsular thickening, or destruction of the sheath and pulley system.²⁴ In several studies, up to one-fourth of patients with PFT did not obtain full ROM, despite adequate treatment.^4-6,27 Therefore, full active ROM exercises should be initiated immediately after surgery to counteract the development of stiffness.

The most severe complication of PFT is amputation of the affected digit (Figures 3A, 3B).

Conclusion

PFT is a common hand infection that can cause significant morbidity. Early treatment is crucial: this requires use of IV antibiotics, or surgical irrigation and débridement in more advanced cases. However, despite prompt and thorough treatment, severe infection can lead to long-term impaired function and even amputation of the affected digit. More research is needed to determine optimal timing and technique for surgical intervention and to elucidate the role of local antibiotics and corticosteroids in treating this infection and potentially preventing the morbid outcomes we currently see.

Am J Orthop. 2017;46(3):E207-E212. Copyright Frontline Medical Communications Inc. 2017. All rights reserved.

Pyogenic flexor tenosynovitis (PFT) is a common closed space infection of the flexor tendon sheaths of the hand and remains one of the most challenging problems encountered in orthopedic and hand surgery (Figure 1). PFT also is known as septic flexor tenosynovitis and suppurative flexor tenosynovitis.

Kanavel¹ initially described 4 cardinal signs that characterize infection of the flexor tendon sheath: symmetric fusiform swelling of the entire digit, exquisite tenderness to palpation along the course of the tendon sheath, semiflexed posture at rest, and pain with attempted passive extension of the digit. The prevalence of this infection ranges from 2.5% to 9.4%.² Once the infection is established in a patient, it can cause significant morbidity and disability and produce an economic burden. It can also present a significant treatment dilemma for the treating surgeon, as there is no standardized protocol for managing this common but challenging hand infection. For treatment, many surgeons combine surgical decompression, sheath irrigation, and empiric intravenous (IV) antibiotic administration. However, despite prompt treatment, and regardless of the protocol used, complication rates as high as 38% have been reported.³ Moreover, even after infection eradication, a significant proportion of patients continue to have pain, swelling, stiffness, loss of composite flexion, weakness, and recurrence that potentially requires amputation.

1. What Causes Pyogenic Flexor Tenosynovitis?

PFT can result from hematogenous spread, but local inoculation by a laceration, a puncture, or a bite also is common^4-7 (Figure 1). As a consequence of these mechanisms of injury, the most common source of PFT is skin flora. Staphylococcus aureus has been found in up to 75% of positive cultures in several studies.^2,5,6,8,9 Methicillin-resistant S aureus (MRSA) has been found in up to 29% of cases, and the incidence continues to increase, particularly in urban areas.^2,9-12 Other common bacteria are Staphylococcus epidermidis, β-hemolytic Streptococcus species, and Pseudomonas aeruginosa.^5,6,10 Infection by more than 1 species of bacteria is also fairly prevalent. Of 62 patients in a study, 38% had infections with 1 organism, and 62% with 2 or more.⁶ Twenty-six percent of cultures grew mixed anaerobic and aerobic organisms.⁶ PFT is seldom caused by Eikenella corrodens from a human bite or Pasteurella multocida from an animal bite.¹⁰ Other rare causes of PFT are Listeria monocytogenes¹³ and Clostridium difficile from a gastrointestinal source.¹⁴Neisseria gonorrhea can cause acute tenosynovitis, usually in the setting of disseminated gonococcal infection.^15,16 Also reported is mycobacterial tenosynovitis, most commonly caused by Mycobacterium kansasii and Mycobacterium marinum.¹⁷

2. Which Antibiotics Are Best Suited to Empirical Management of PFT?

Management of PFT, regardless of the pathogen, includes prompt administration of empiric IV antibiotics, usually followed by surgical drainage.^7,18-20 While cultures are being tested, antibiotics should be selected—including antibiotics for empiric coverage against common gram-positive organisms, including Staphylococcus and Streptococcus species.¹² The Centers for Disease Control and Prevention recommends empiric coverage for MRSA if the local prevalence exceeds 10% to 15%. Recommended empiric antibiotics are trimethoprim-sulfamethoxazole (TMP-SMX) and clindamycin (both oral) and clindamycin, vancomycin, and daptomycin (all IV).

In addition, institutional and local antibiotic resistance patterns of bacteria should guide treatment and antibiotic selection. First-generation cephalosporins have long been the cornerstone of treatment for infections caused by S aureus, but increasing methicillin resistance has reduced their role in the treatment, particularly the empiric treatment, of MRSA infections. Methicillin resistance first appeared as nosocomial S aureus infections in 1961, only 1 year after the introduction of the semisynthetic penicillin class that includes methicillin. Over the past 2 decades, MRSA has emerged in the community in otherwise young and healthy individuals with no healthcare-associated risk factors. Fortunately, several readily available antibiotics have maintained their efficacy in managing these “community-acquired” MRSA hand infections. TMP-SMX provides adequate coverage for MRSA and is a relatively inexpensive medication, and clindamycin is an equally effective and cost-effective alternative.

Presumptive antibiotics should also cover gram-negative rods and anaerobes, including Clostridium species, especially in immunocompromised patients.^7,9 These patients may require additional antibiotics for presumptive coverage of other rarer bacterial causes, especially when unique mechanisms of injury (eg, aquatic injury, farm injury) are involved. Once culture results are ready, antibiotic regimens should be narrowed to cover the specific organisms identified.

3. What Are the Timing and Indications for Surgery?

Nonoperative treatment may be appropriate for PFT patients who present early, typically within 48 hours after penetrating trauma to the hand.²¹ In a 4-patient series, Neviaser and Gunther¹⁹ successfully treated PFT nonoperatively, with IV antibiotics, splinting, and elevation. During nonoperative treatment, the affected hand should be regularly examined. If this treatment is to be successful, clinical symptoms should improve within 48 hours; if they do not, surgical irrigation and débridement should be performed.

Regardless of timing and type of irrigation, surgical treatment remains the treatment of choice for the majority of PFT cases. Michon²² developed a 3-tier PFT classification system that is based on intraoperative findings (Table).

4. What Are the Surgical Techniques for PFT Drainage?

Several surgical methods have been developed to decompress and irrigate the flexor sheaths of the hand. However, debates about optimal timing of surgical intervention, surgery type (open surgery or closed catheter irrigation only), and irrigation method continue.

Open Irrigation and Débridement

Open irrigation and débridement procedures were originally described for surgical management of PFT.¹ Midaxial and palmar (Bruner zigzag) incisions can be used to expose and open the entire sheath for complete drainage and washout. Both incisions afford good access to the flexor sheath, but the midaxial approach may provide more coverage of the sheath after surgery. Open irrigation and débridement is the treatment of choice for the most advanced cases of PFT and for atypical or chronic tenosynovial infections.^4,23,24 The Bruner zigzag incision affords ease of surgical dissection, extension, and more exposure of the flexor tendon sheath at the expense of possible difficulty in closure or flap necrosis in the setting of a swollen digit. Alternatively, the midaxial incision has the advantage of a large, more robust skin flap for more reliable closure.

Closed Tendon Sheath Irrigation

In 1943, Dickson-Wright²⁵ first described catheter irrigation of tendon sheath infections. Later, Neviaser⁴ described this technique in detail. A proximal incision is made over the metacarpal neck. The tendon sheath is cut transversely at the proximal edge of the A1 pulley. An angiocatheter is inserted 1 cm to 2 cm antegrade into the flexor tendon sheath. Then, a distal midaxial incision is made dorsal to the neurovascular bundle at the level of the distal interphalangeal joint on the ulnar aspect of the finger or the radial aspect of the thumb. The distal edge of the flexor sheath is exposed and resected distal to the distal-most pulley. A Penrose drain can be threaded into the tendon sheath beneath the A4 pulley to keep the wound open and allow for fluid drainage. The sheath is flushed gently in the operating room. After surgery, intermittent bedside irrigation can be continued on the floor.

Neviaser⁴ reported excellent initial results with this technique; 18 of 20 patients regained complete active and passive range of motion (ROM) by 1 week after surgery. Similarly, Juliano and Eglseder,²⁶ using a similar method, reported 100% excellent results for mild PFT and 88.4% excellent results for more severe infection.

Gutowski and colleagues²³ reviewed 47 PFT cases to determine if there is a difference in outcomes between PFT treated with open irrigation and débridement and PFT treated with closed catheter irrigation. Between these groups, they found no significant differences in early postoperative outcomes, including resolution of infection, need for additional surgery, and hospital length of stay.

There are also many differing opinions regarding the best irrigation method. Some authors have asserted that normal saline is sufficient,^4,5,23 and others that local antibiotics provide added benefit.^27-29 Recently, Draeger and colleagues³⁰ reported promising results with local injection of antibiotics into the tendon sheath and the addition of locally administered corticosteroids in the treatment of PFT in an animal model.

Continuous Closed Irrigation

A continuous closed irrigation system with inlet and outlet tubes has yielded successful results.^8,31,32 This system consists of 2 fenestrated tubes placed within the infected space, with the tip of the smaller caliber inlet tube positioned just inside the larger outlet tube. Advantages of this system include the patient’s ability to participate in hand therapy with the system in place and avoidance of pain caused by the high pressures involved in intermittent closed irrigation. Duration of this system has ranged from 2 days to 3 weeks, and results have been good.^5,8

Postoperative Irrigation

Use of postoperative irrigation on the floor or at home is controversial, as leaving an indwelling catheter in the tendon sheath can lead to complications. Catheters may increase digital stiffness by decreasing the patient’s ability to participate in therapy or may cause additional injury and irritation to the sheath itself if left in place too long. Lille and colleagues⁶ retrospectively compared the results of intraoperative closed tendon sheath irrigation alone with those of intraoperative and postoperative closed tendon sheath irrigation. There were no significant differences in mean hospital length of stay, follow-up complication rates, or postoperative ROM—which suggests that postoperative intermittent or continuous irrigation is not necessary.

Our Preferred Technique

We recommend a palmar approach that begins with outlining a Bruner zigzag incision along the entire finger. Then, only the distal-most and proximal-most incision lines are opened, thereby exposing the A5 and A1 pulleys, respectively (Figure 2).

5. What Are the Long-Term Outcomes of PFT?

The principal complication associated with PFT is stiffness with loss of ROM, which can be caused by flexor tendon adhesions, joint capsular thickening, or destruction of the sheath and pulley system.²⁴ In several studies, up to one-fourth of patients with PFT did not obtain full ROM, despite adequate treatment.^4-6,27 Therefore, full active ROM exercises should be initiated immediately after surgery to counteract the development of stiffness.

The most severe complication of PFT is amputation of the affected digit (Figures 3A, 3B).

Conclusion

PFT is a common hand infection that can cause significant morbidity. Early treatment is crucial: this requires use of IV antibiotics, or surgical irrigation and débridement in more advanced cases. However, despite prompt and thorough treatment, severe infection can lead to long-term impaired function and even amputation of the affected digit. More research is needed to determine optimal timing and technique for surgical intervention and to elucidate the role of local antibiotics and corticosteroids in treating this infection and potentially preventing the morbid outcomes we currently see.

Am J Orthop. 2017;46(3):E207-E212. Copyright Frontline Medical Communications Inc. 2017. All rights reserved.

From the University of Texas MD Anderson Cancer Center, Houston, TX.

Abstract

• Objective: To review the evidence on interventions for managing cancer-related fatigue (CRF) and provide evidence-based guidance on approaches to its management.
• Methods: Nonsystematic review of the literature.
• Results: Several theories have been proposed to explain the biology of CRF, but there is no single clear mechanism that can be targeted for therapy. The approach to patients begins with screening for fatigue and assessing its intensity, followed by a thorough history and examination to determine whether any reversible medical conditions are contributing to fatigue. Management of underlying medical comorbidities may help some patients. For patients whose fatigue persists, pharmacologic and nonpharmacologic treatment options are available. Pharmacologic options include psychostimulants, such as methylphenidate and modafinil, and corticosteroids. Nonpharmacologic approaches include exercise, cognitive behavior therapy, yoga, acupuncture, and tai chi.
• Conclusion: We recommend an individualized approach, often with a combination of the available options. Patients need to be evaluated periodically to assess their fatigue, and since cancer-related fatigue affects survivors, long-term follow-up is needed.

Key words: fatigue; cancer; pro-inflammatory cytokines; nonpharmacologic; psychostimulants.

Fatigue is a common distressing effect of cancer [1].It impairs the quality of life of patients undergoing active cancer treatment and of post-treatment survivors. The National Comprehensive Cancer Network (NCCN) defines cancer-related fatigue (CRF) as “a distressing, persistent, subjective sense of physical, emotional and/or cognitive tiredness related to cancer or cancer treatment that is not proportional to recent activity and interferes with usual functioning [2].” Differences between CRF and fatigue reported by individuals without cancer are that CRF is more severe and is not relieved by rest. The prevalence of CRF in cancer patients and survivors is highly variable, ranging between 25% and 99% [2,3]. This variability may be secondary to methods used for screening fatigue and characteristics of the patient groups. In this article, we discuss recognition of CRF and approaches to its management.

Pathophysiology

The specific pathophysiologic mechanism underlying CRF is unknown, making targeted treatment a challenge. The multidimensional and subjective nature of CRF has limited the development of research methodologies to explain this condition. However, research has been done in both human and animal models, and several theories have been proposed to explain the pathophysiology of CRF. While pro-inflammatory cytokines remain the central factor playing a significant role at multiple levels in CRF, there may be a complex interplay of more than 1 mechanism contributing to fatigue in an individual patient.

Central Nervous System Disturbances

The basal ganglia are known to influence motivation. Lack of motivation and drive may cause failure to complete physical and mental tasks, even with preserved cognitive ability and motor function. In a study of melanoma patients receiving interferon, increased activity of the basal ganglia and the cerebellum resulted in higher fatigue scores [4]. Higher levels of cytokines may alter blood flow to the cerebellum and lead to the perception of fatigue. In a study of 12 patients and matched controls, when patients were asked to perform sustained elbow flexion until they perceived exhaustion, CRF patients perceived physical exhaustion sooner than controls. In CRF patients in this study, muscle fatigue measured by electromyogram was less than that in healthy individuals at the time of exhaustion, suggesting the role of the central nervous system in CRF [5]. However, there is not enough evidence at this time to support central nervous system disturbance as the main contributing factor to fatigue in cancer patients.

Circadian Rhythm Dysregulation

Circadian rhythm is regulated by the suprachiasmatic nucleus in the hypothalamus through cortisol and melatonin. Sleep disturbances occur with disruption of the circadian rhythm. Tumor-related peptides such as epidermal growth factor or alterations in serotonin and cortisol can influence the suprachiasmatic nucleus and the complex signaling pathways [2]. Positive feedback loops that are activated by cortisol under the influence of cytokines may lead to continuous cytokine production and altered circadian rhythm. Bower et al showed that changes in the cortisol curve influence fatigue in breast cancer survivors [6]. These patients had a late evening peak in cortisol levels, compared with an early morning peak in individuals without cancer.

Inhibition of Hypothalamic–Pituitary–Adrenal Axis

The hypothalamic–pituitary–adrenal (HPA) axis regulates the release of the stress hormone cortisol. One of several hypotheses advanced to explain the effect of serotonin and the HPA axis on CRF suggests that lower serotonin levels cause decreased activation of 5-hydroxytrytophan 1-a (5-HT1-a) receptors in the hypothalamus, leading to decreased activity of the HPA axis [6]. The inhibition of the HPA axis may occur with higher levels of serotonin as well [7]. The 5-HT1-a receptors are also triggered by cytokines. However, the correction of serotonin levels by antidepressants was not shown to improve fatigue [8]. Inhibition of the HPA axis can also lead to lower testosterone, progesterone, or estrogen levels, which may indirectly contribute to fatigue [2].

Skeletal Muscle Effect

Chemotherapy- and tumor-related cachexia have a direct effect on the metabolism of skeletal muscles. This effect may lead to impaired adenosine triphosphate (ATP) generation during muscle contraction [9]. ATP infusion improved muscle strength in one trial, but this was not confirmed in another trial [10,11]. Muscle contraction studies showed no differences in the contractile properties of muscles in fatigued patients who failed earlier in motor tasks and healthy controls [12]. This finding suggests that there could be a failure of skeletal muscle activation by the central nervous system or inhibition of skeletal muscle activity. Cytokines and other neurotransmitters activate vagal efferent nerve fibers, which may lead to reflex inhibition in skeletal muscles [13,14].

Pro-inflammatory Cytokines

Tumors or treatment of them may cause tissue injury, which triggers immune cells to release cytokines, signaling the brain to manifest the symptom fatigue. Inflammatory pathways are influenced by psychological, behavioral, and biological factors, which play a role as risk factors in CRF. Interleukin 6 (IL-6), interleukin-1 receptor antagonist, interleukin-1, and tumor necrosis factor (TNF) have been shown to be elevated in fatigued patients being treated for leukemia and non-Hodgkin lymphoma [15]. IL-6 was also associated with increased fatigue in breast cancer survivors [16]. Similar findings were reported in patients undergoing stem cell transplantation and high-dose chemotherapy [17]. Elevated levels of IL-6 and C-reactive protein were also linked to fatigue in terminally ill cancer patients [18,19]. Furthermore, TNF-α signaling was associated with post-chemotherapy fatigue in breast cancer patients [20]. Leukocytes in breast cancer survivors with fatigue also have increased gene expression of pro-inflammatory cytokines, emphasizing the role of cytokines and inflammation in the pathogenesis of CRF [21].

Other Hypotheses

Several other hypotheses for CRF pathogenesis have been proposed. Activation of latent viruses such as Epstein-Barr virus, lack of social support [22], genetic alterations in immune pathway [23], epigenetic changes [24], accumulation of neurotoxic metabolites and depletion of serotonin by indoleamine 2,3-dioxygenase pathway activation [25], elevated vascular endothelial growth factor levels [26], and hypoxia-related organ dysfunction due to anemia or hemoglobin dysfunction [13] all have been postulated to cause CRF.

Approach to Evaluation and Treatment

Screening

Because patients and health care professionals may be unaware of the treatment options available for CRF, patients may not report fatigue levels to their clinicians, and clinicians may not understand the impact of fatigue on their patients’ quality of life. This leads to underrecognition of the problem. The NCCN recommends screening every cancer patient and post-treatment survivor for fatigue [2]. Patients should be screened at their first visit and then at periodic intervals during and after cancer treatment.

Many scales are available to screen patients for CRF in clinical practice and clinical trials [27]. A single item that asks patients to rate their fatigue on a scale from 0 to 10—in which 0 indicates no fatigue, 1 to 3 indicates mild fatigue, 4 to 6 indicates moderate fatigue, 7 to 9 indicates severe fatigue, and 10 indicates the worst fatigue imaginable—is commonly used to screen for CRF [2]. This scale was adapted from the MD Anderson Symptom Inventory scale and is based on a large nationwide study of cancer patients and survivors [28]. The statistically derived cutoff points in this study are consistent with other scales such as the Brief Fatigue Inventory (BFI) and support the cutoff points (4–6 for moderate and ≥ 7 for severe fatigue) used in various fatigue management guidelines. Furthermore, studies of fatigue in cancer patients have revealed a marked decrease in physical function at levels of 7 or higher, suggesting 7 as an optimal cutoff to identify severe fatigue [29,30]. The Visual Analog Scale is another simple-to-use tool that helps in understanding variations in fatigue throughout the course of the day [31]. The 9-item BFI is often used in clinical trials [29]. It measures the severity of fatigue over the previous 24 hours and has been validated in non-English speaking patients [32].

CRF affects not only the somatic domain, but also the cognitive, behavioral, and affective domains; therefore, multidimensional scales have been developed for screening. One such tool is the Multidimensional Fatigue Inventory, which measures general, physical, mental, and emotional fatigue domains as well as activity and compares them with those of individuals without cancer [33,34]. The Functional Assessment of Cancer Therapy for Fatigue (FACT-F) is a 13-item questionnaire that has been used to measure CRF in clinical trials as well as in patients receiving various treatments [35].

Although many scales are available, the validity of self-reporting on simple fatigue-rating scales is equal to or better than most complex, lengthy scales [36]. Therefore, unidimensional tools such as the numeric rating scale of 0–10 are commonly used in clinical practice. Mild fatigue (0–3) requires periodic re-evaluation, and moderate and severe fatigue need further evaluation and management [37].

Primary Evaluation

This phase involves a focused history and physical examination and assessment of concurrent symptoms and contributing factors.

History and Physical Examination

A detailed history of the patient’s malignancy and type of previous and current treatment may help reveal the cause of fatigue. New-onset fatigue or increase in fatigue may be related to the progression of disease in patients with active malignancy or recurrence of cancer in survivors. These patients may require appropriate testing to assess the underlying disease pattern. A detailed review of systems may help identify some of the contributing factors, which are discussed below. A detailed history regarding medications, including over-the-counter drugs, complementary agents, and past and prior cancer therapies, is helpful as medications can contribute to fatigue. For example, opioids may cause drowsiness and fatigue, which could be improved by dose adjustments. A focused history of fatigue should be obtained in all patients with moderate to severe CRF, which includes the onset, pattern, duration, associated or alleviating factors, and interference with functioning, including activities of daily living [37]. Physical examination should focus on identifying signs of organ dysfunction and features of substance or alcohol abuse which may cause poor sleep and fatigue.

Assessment of Contributing Factors

The management of fatigue should be multifactorial, with a comprehensive assessment and treatment plan to address all modifiable fatigue etiologies. The Table lists potential contributing factors to fatigue that should be considered when evaluating patients for CRF; several common conditions are discussed below.

Anemia. Anemia has been correlated with fatigue and quality of life. In a study of 4382 cancer patients receiving chemotherapy, quality-of-life measures using FACT-Anemia scores improved with increased hemoglobin levels [38]. Cancer patients may have anemia due to marrow-suppressing effects of chemotherapy and may also have iron deficiency anemia due to blood loss or autoimmune hemolytic anemia. Therefore, a detailed work-up is required to identify the etiology of anemia. Patients with CRF whose anemia is related to chemotherapy or anemia of chronic disease may benefit from red blood cell transfusion or erythropoiesis-stimulating agents (ESAs). ESAs have been studied extensively; however, their use is controversial because of concerns about thromboembolic side effects leading to adverse outcomes [39]. Also, ESA therapy is not recommended in patients with hematologic malignancies. ESA use should be restricted to patients with chemotherapy-related anemia with hemoglobin below 10 mg/dL and should be discontinued in 6 to 8 weeks if patients do not respond [40]. Other patients may benefit from blood transfusions, which were shown to help in patients with hemoglobin levels between 7.5 and 8.5 g/dL [41].

Sleep disturbance. Poor sleep is common in fatigued cancer survivors [42]. Pro-inflammatory cytokines can disrupt the sleep–wake cycle, causing changes in the HPA axis and neuroendocrine system, which in turn may lead to increasing fatigue. Heckler et al showed that improvement in nighttime sleep leads to improvement of fatigue [43]. Cognitive behavioral therapy and sleep hygiene are important in caring for patients with CRF and poor sleep [44]. Taking a warm bath and/or drinking a glass of milk before bedtime, avoiding caffeinated drinks, and avoiding frequent napping in the day might help. Some patients may require medications such as benzodiazepines or non-benzodiazepine hypnotics (eg, zolpidem) to promote sleep [45]. Melatonin agonists are approved for insomnia in the United states, but not in Europe [46].

Malnutrition. Patients with advanced-stage cancer and with cancers affecting the gastrointestinal tract frequently develop mechanical bowel obstructions, especially at the end of their life, which cause malnutrition. Chemotherapy-related nausea and vomiting may also cause poor oral intake and malnutrition, causing fatigue from muscle weakness. Dehydration and electrolyte imbalances frequently occur as a result of poor oral intake, which might worsen fatigue. In our experience, modifying dietary intake with appropriate caloric exchanges with the help of a nutrition expert has lessened fatigue in some patients. However, terminally ill patients are advised to eat based on their comfort.

Medical comorbidities. Congestive heart failure from anthracycline chemotherapy, hypothyroidism after radiation therapy for head and neck cancers, renal failure, or hepatic failure from chemotherapy may indirectly lead to fatigue. Chemotherapy, opioids, and steroids may cause hypogonadism, which can contribute to fatigue in men [47].

Assessment of Concurrent Symptoms

Depression is common in cancer patients and coexists with pain, insomnia, fatigue, and anxiety as a symptom cluster [48]. A symptom cluster is defined as 2 or more concurrent and interrelated symptoms occurring together; treating of one of these symptoms without addressing other symptoms is not effective [49]. Therefore, screening for and management of depression, anxiety, and insomnia play an important role in the management of CRF.

Physical symptoms due to the tumor or to therapy—such as pain, dyspnea, nausea, and decreased physical activity—may also contribute to fatigue both directly and indirectly. Patients with lung cancer may have hypoxemia, which can contribute to dyspnea with activity and a perception of fatigue. Optimal management of pain and other physical symptoms in patients with cancer may significantly alleviate fatigue [50].

Management

Management of CRF is individualized based on the patient’s clinical status: active cancer treatment, survivor, or end of life. Education and counselling of patients and their caregivers play an important role in CRF. NCCN guidelines recommend focusing on pain control, distress management, energy conservation, physical activity, nutrition, and sleep hygiene.

Nonpharmacologic Interventions

Energy conservation. Energy conservation strategies, in which patients are advised to set priorities and realistic expectations, are highly recommended. Some energy-conserving strategies are to pace oneself, delegate and schedule activities at times of peak energy, postpone nonessential activities, attend to 1 activity at a time, structure daily routines, and maintain a diary to identify their peak energy period and structure activities around that time [51,52]. When patients approach the end of life, increasing fatigue may limit their activity level, and they may depend on caregivers for assistance with activities of daily living, monitoring treatment-related adverse effects, and taking medications, especially elderly patients [53].

Cognitive behavioral therapy. Cognitive behavioral therapy (CBT) has been shown to improve CRF during active treatment, and the benefits persist for a minimum of 2 years after therapy [54]. CBT interventions that optimize sleep quality may improve fatigue [55]. More studies are needed to understand whether referral to a psychologist for formal CBT is required. Randomized clinical trials (RCTs) showed patient fatigue education, learned self-care, coping techniques, and balancing rest and activity benefit patients with CRF [56].

Exercise. Physical activity is highly encouraged in patients with CRF. Exercise increases muscle protein synthesis, improves cytokine response, and decreases the rate of sarcopenia in healthy populations [57]. Studies have shown that exercise helps CRF at all phases of the cancer journey, including radiation therapy, chemotherapy, and survivorship [58]. Some patients may feel less motivated to exercise and may not believe that exercise is possible or could potentially help them. Counselling is needed for such patients.

Older cancer survivors have a decline in their functional capacity and reduced muscle mass. Exercise can improve cardiorespiratory fitness, muscle strength, and body composition [57]. Exercise not only helps at the cellular level but also has psychosocial benefits from improved self-esteem. Therefore, exercise may be recommended not only for younger patients, but also in the older population, who may have comorbidities and less motivation than younger patients.

In a meta-analysis of 56 randomized controlled trials involving 4068 participants, aerobic exercise was found to have beneficial effects on CRF for patients during and after chemotherapy, specifically for patients with solid tumors [59]. In another meta-analysis of breast and prostate cancer survivors, a combination of aerobic exercise with resistance training (3–6 metabolic equivalents, 60%–80% range of motion) was shown to reduce CRF more than aerobic exercise alone [60]. This effect was also shown in an RCT of 160 patients with stage 0 to III breast cancer undergoing radiation therapy [61]. The control group in this study had a group-based non-exercise intervention/relaxation; therefore, the study showed that the effect of resistance training extends beyond the psychosocial benefits of group-based interventions. The intervention comprised 8 progressive machine-based resistance exercises (3 sets, 8–12 repetitions at 60%–80% of 1 repetition maximum) for 60 minutes twice weekly for 12 weeks. However, fatigue assessment questionnaire scores showed benefits in the physical fatigue but not the affective and cognitive components.

The American Society of Clinical Oncology’s guidelines for cancer survivors with fatigue recommends 150 minutes of moderate aerobic exercise (eg, fast walking, cycling, or swimming) per week, with 2 or 3 sessions of strength training per week [62]. An individualized approach to exercise is recommended, as patients’ ability to perform certain types of exercises may be limited by thrombocytopenia, neutropenia, or lytic bone metastasis. Routine use of pre-exercise cardiovascular testing is not recommended but may be considered in high-risk populations, especially patients with risk factors for coronary heart disease and diabetes [63]. Patients withcomorbidities, substantial deconditioning, functional and anatomic defects, or recent major surgery may benefit from referral to physical therapy [37]. Patients near end of life may also benefit from an exercise program, as demonstrated in several studies that showed benefit in CRF and quality of life [64,65]. We recommend that physicians use their best clinical judgement in suggesting the type and intensity of exercise program, as it may not be feasible in some patients.

Mind-body interventions. Mindfulness-based stress reduction (MBSR) has shown promise in breast cancer survivors, who reported immediate improvements in fatigue severity that continued up to 6 weeks after cessation of the training [66]. Prior studies had similar findings, suggesting that MBSR modestly decreases fatigue and sleep disturbances and has a greater effect on the degree to which symptoms interfere with many facets of life [67].

Yoga. A study of a yoga intervention showed a benefit in older cancer survivors [68]. In breast cancer patients undergoing chemotherapy, yoga was shown to benefit not only physical fatigue, but also cognitive fatigue [69]. DVD-based yoga had benefits similar to strengthening exercises in a study of 34 early-stage breast cancer survivors with CRF [70]. More studies are needed in men and patients and survivors of other cancers, as most studies of yoga were conducted in women with breast cancer.

Tai chi/qigong. Like yoga, tai chi and qigong are practices of meditative movement. These practices use postures or movements with a focus on breath and a meditative state to bring about deep states of relaxation. Qigong is a series of simple, repeated practices including body posture/movement, breath practice, and meditation performed in synchrony. Tai chi easy (TCE) is a simplified set of common, repetitive tai chi movements. In a trial, qigong/TCE was compared with sham qigong, which had physical movements but no breathing or meditative practice. Breast cancer survivors in the qigong/TCE group had improved fatigue scores, and the effect persisted for 3 months [71]. Additional research is needed in this area.

Acupuncture. An RCT in breast cancer patients with CRF showed an improvement in the mean general fatigue score (per the Multidimensional Fatigue Inventory) in patients who received acupuncture versus those who did not (−3.11 [95% confidence interval −3.97 to −2.25]; P < 0.001) at 6 weeks. Improvements were seen in both the mental and physical aspects of fatigue [72]. However, Deng et al noted that true acupuncture was no more effective than sham acupuncture for reducing post-chemotherapy chronic fatigue [73]. Presently, there is not sufficient evidence to evaluate the benefits of acupuncture in CRF.

Other modalities. Massage therapy, music therapy, hypnosis, therapeutic touch, biofield therapies, relaxation, and reiki are other therapies for which few studies have been done, with mixed results, and additional research is needed [74]. Currently, there are not sufficient data to recommend any of these modalities.

Pharmacologic Interventions

Psychostimulants. Methylphenidate and modafinil are psychostimulants or wakefulness-promoting agents. Pilot studies showed benefit from methylphenidate and modafinil in CRF [75–77], but RCTs have yielded mixed results. Therefore, in patients with severe fatigue during cancer therapy, the initial management strategy involves evaluation and treatment of medical conditions such as anemia and a trial of non-pharmacological strategies as discussed above. If symptoms persist, then a therapeutic trial of a psychostimulant may be considered per NCCN guidelines for patients undergoing active cancer treatment [37].

Methylphenidate directly stimulates adrenergic receptors and indirectly releases dopamine and norepinephrine from presynaptic terminals, which may explain why the drug benefits patients receiving opioid-induced sedation. It is a commonly studied psychostimulant, though its mechanism of action in CRF is unclear. RCTs of methylphenidate have resulted in a wide range of findings due to the heterogeneity of study populations and variations in the dosage of methylphenidate. A meta-analysis of 7 studies indicates that methylphenidate benefitted the subgroup of patients with CRF [78]. Likewise, in an analysis of 5 RCTs, Minton et al showed a benefit of psychostimulants in fatigue compared with placebo [79]. However, another study of methylphenidate in patients with CRF showed a benefit only in patients with severe fatigue or advanced disease [80]. Methylphenidate was found to benefit cancer patients receiving opioid-induced sedation, as methylphenidate promotes wakefulness, though fatigue was not studied specifically [81]. In a trial with 30 hospice patients in which the methylphenidate dose was titrated based on response and adverse effects, Kerr at al found that the drug improved fatigue in a dose-dependent manner [82]. However, a study in patients with CRF at the University of Texas MD Anderson Cancer Center found no significant difference in BFI scores between patients receiving methylphenidate and those receiving placebo at the end of 2 weeks of treatment [83]. Also, other RCTs in patients undergoing adjuvant chemotherapy for breast cancer [84] and patients receiving radiation therapy for brain tumors [85] failed to demonstrate the efficacy of methylphenidate in CRF. It should be used cautiously after ruling out other causes of fatigue. The drug is overall well tolerated and side effects include headache and nausea.

Modafinil is a non-amphetamine psychostimulant that has been approved for the treatment of narcolepsy. In a trial studying the effect of modafinil on patients receiving docetaxel-based chemotherapy for metastatic breast or prostate cancer, there was a modest but not statistically significant improvement in fatigue scores on the MD Anderson Symptom Inventory compared with placebo. Nausea and vomiting were higher in the modafinil arm than in the placebo arm [86]. Similarly, modafinil was not superior to placebo for CRF in 208 patients with non-squamous cell lung cancer not undergoing chemotherapy or radiation [87]. A placebo effect was also noted in patients with multiple myeloma [88] and patients with primary brain tumors [89]. In a phase 3, multicenter, randomized, placebo-controlled, double-blind clinical trial of modafinil for CRF in 867 patients undergoing chemotherapy, there was a reduction in fatigue only for patients with severe baseline fatigue, with no significant effect on mild to moderate fatigue [90]. In another recent study, modafinil was shown to reduce depressive symptoms only in patients with severe fatigue (BFI item 3 score ≥ 7) [91]. This finding is consistent with previous studies showing benefit in patients with high baseline fatigue, but additional RCTs are needed to provide clarity. NCCN guidelines do not recommend the use of modafinil to treat CRF [37].

Other pharmacologic interventions. Corticosteroids are often used for symptom control in cancer patients. These drugs have anti-inflammatory effects through their modulation of pro-inflammatory cytokines [92]. In a RCT evaluating the efficacy of corticosteroids, patients receiving dexamethasone (4 mg twice daily) experienced significant improvement in their FACT-F scores compared with patients receiving placebo [93]. A similar benefit in fatigue was demonstrated in another study of methylprednisolone (32 mg daily) versus placebo [94]. Despite the benefits of steroids, their adverse effects, such as mood swings, gastritis, hyperglycemia, and immune suppression, limit their long-term use. Therefore, the use of steroids should be restricted to terminally ill fatigued patients with other symptoms such as anorexia, brain metastasis, or pain related to bone metastasis [37].

Testosterone replacement has been shown to diminish fatigue in non-cancer patients. Many men with advanced cancer have hypogonadism leading to low serum testosterone, which may cause fatigue. In a small trial in which cancer patients with hypogonadism received intramuscular testosterone every 14 days or placebo, the group receiving testosterone showed improvement in FACT-F scores, but there was no significant difference in FACT-F scores between the 2 groups [95].

Antidepressants have failed to demonstrate benefit in CRF without depression [8]. However, if a patient has both fatigue and depression, antidepressants may help [96]. A selective serotonin receptor inhibitor is recommended as a first-line antidepressant [97]. Patients with cancer are often receiving multiple medications, and medication interactions should be considered to prevent adverse events such as serotonin syndrome.

Complementary and Alternative Supplements

Studies using vitamin supplementation have been inconclusive in patients with CRF [74]. The use of other dietary supplements has yielded mixed results, and coenzyme Q has shown no benefit for patients with CRF [98].

The benefit of ginseng was studied in a RCT involving 364 patients with CRF. There was an improvement in Multidimensional Fatigue Symptom Inventory-short form (MFSI-SF) scores at 8 weeks in patients receiving 2000 mg of Wisconsin ginseng compared with patients receiving placebo [99]. Patients on active treatment had greater improvement as compared to the post-treatment group in this trial. In another study of high-dose panax ginseng (ginseng root) at 800 mg daily for 29 days, patients had improvement of CRF as well as overall quality of life, appetite, and sleep at night. It was also well tolerated with few adverse effects [100]. Interaction with warfarin, calcium channel blockers, antiplatelet agents, thrombolytic agents, imatinib, and other agents may occur; therefore, ginseng must be used with careful monitoring in selected patients. There is not enough evidence at this time to support the routine use of ginseng in CRF.

The seed extract of the guarana plant (Paullinia cupana) traditionally has been used as a stimulant. An improvement in fatigue scores was seen with the use of oral guarana (100 mg daily) at the end of 21 days in breast cancer patients receiving chemotherapy [101]. Further studies are needed for these results to be generalized and to understand the adverse effects and interaction profile of guarana.

Re-evaluation

Patients who have completed cancer treatment must be monitored for fatigue over the long term, as fatigue may exist beyond the period of active treatment. Many studies have shown fatigue in breast cancer survivors, and fatigue has been demonstrated in survivors of colorectal, lung, and prostate cancers as well as myeloproliferative neoplasms [28]. Therefore, it is important to screen patients for fatigue during follow-up visits. There are currently no studies evaluating the long-term treatment of fatigue. In our experience, the timing of follow-up depends on the level of fatigue and interventions prescribed. Once fatigue is stabilized to a level with which the patient is able to cope, the time interval for follow up may be lengthened. Annual visits may suffice in patients with mild fatigue. Follow-up of patients with moderate to severe fatigue depends on the level of fatigue, the ability to cope, choice of treatment, and presence of contributing factors.

Conclusion

CRF is a complex condition that places a significant burden on patients and caregivers, resulting in emotional distress, poor functioning, and suffering. Fatigue can occur before, during, and long after cancer treatment. The approach to CRF begins with screening for and educating patients and their caregivers about the symptoms. Many screening scales are available that may be used to follow patients’ progress over time. The evaluation and management of contributing conditions may help improve fatigue. If the fatigue persists, an individualized approach with a combination of nonpharmacologic and pharmacologic approaches should be considered. More research is needed to understand brain signaling pathways, cytokine changes, and genomic changes in cancer patients with fatigue. Though many hypotheses have been proposed, to date there is no biological marker to assess this condition. Biomarker research needs to be advanced to help to identify patients at risk for fatigue. As cytokines have a major role in CRF, targeted therapy to block cytokine pathways may also be explored in the future.

Acknowledgment: Bryan Tutt provided editorial assistance.

Corresponding author: Carmelita P. Escalante, MD, The University of Texas MD Anderson Cancer Center, 1400 Pressler St., Houston, TX 77030, [email protected].

Financial disclosures: None.

From the University of Texas MD Anderson Cancer Center, Houston, TX.

Abstract

• Objective: To review the evidence on interventions for managing cancer-related fatigue (CRF) and provide evidence-based guidance on approaches to its management.
• Methods: Nonsystematic review of the literature.
• Results: Several theories have been proposed to explain the biology of CRF, but there is no single clear mechanism that can be targeted for therapy. The approach to patients begins with screening for fatigue and assessing its intensity, followed by a thorough history and examination to determine whether any reversible medical conditions are contributing to fatigue. Management of underlying medical comorbidities may help some patients. For patients whose fatigue persists, pharmacologic and nonpharmacologic treatment options are available. Pharmacologic options include psychostimulants, such as methylphenidate and modafinil, and corticosteroids. Nonpharmacologic approaches include exercise, cognitive behavior therapy, yoga, acupuncture, and tai chi.
• Conclusion: We recommend an individualized approach, often with a combination of the available options. Patients need to be evaluated periodically to assess their fatigue, and since cancer-related fatigue affects survivors, long-term follow-up is needed.

Key words: fatigue; cancer; pro-inflammatory cytokines; nonpharmacologic; psychostimulants.

Fatigue is a common distressing effect of cancer [1].It impairs the quality of life of patients undergoing active cancer treatment and of post-treatment survivors. The National Comprehensive Cancer Network (NCCN) defines cancer-related fatigue (CRF) as “a distressing, persistent, subjective sense of physical, emotional and/or cognitive tiredness related to cancer or cancer treatment that is not proportional to recent activity and interferes with usual functioning [2].” Differences between CRF and fatigue reported by individuals without cancer are that CRF is more severe and is not relieved by rest. The prevalence of CRF in cancer patients and survivors is highly variable, ranging between 25% and 99% [2,3]. This variability may be secondary to methods used for screening fatigue and characteristics of the patient groups. In this article, we discuss recognition of CRF and approaches to its management.

Pathophysiology

The specific pathophysiologic mechanism underlying CRF is unknown, making targeted treatment a challenge. The multidimensional and subjective nature of CRF has limited the development of research methodologies to explain this condition. However, research has been done in both human and animal models, and several theories have been proposed to explain the pathophysiology of CRF. While pro-inflammatory cytokines remain the central factor playing a significant role at multiple levels in CRF, there may be a complex interplay of more than 1 mechanism contributing to fatigue in an individual patient.

Central Nervous System Disturbances

The basal ganglia are known to influence motivation. Lack of motivation and drive may cause failure to complete physical and mental tasks, even with preserved cognitive ability and motor function. In a study of melanoma patients receiving interferon, increased activity of the basal ganglia and the cerebellum resulted in higher fatigue scores [4]. Higher levels of cytokines may alter blood flow to the cerebellum and lead to the perception of fatigue. In a study of 12 patients and matched controls, when patients were asked to perform sustained elbow flexion until they perceived exhaustion, CRF patients perceived physical exhaustion sooner than controls. In CRF patients in this study, muscle fatigue measured by electromyogram was less than that in healthy individuals at the time of exhaustion, suggesting the role of the central nervous system in CRF [5]. However, there is not enough evidence at this time to support central nervous system disturbance as the main contributing factor to fatigue in cancer patients.

Circadian Rhythm Dysregulation

Circadian rhythm is regulated by the suprachiasmatic nucleus in the hypothalamus through cortisol and melatonin. Sleep disturbances occur with disruption of the circadian rhythm. Tumor-related peptides such as epidermal growth factor or alterations in serotonin and cortisol can influence the suprachiasmatic nucleus and the complex signaling pathways [2]. Positive feedback loops that are activated by cortisol under the influence of cytokines may lead to continuous cytokine production and altered circadian rhythm. Bower et al showed that changes in the cortisol curve influence fatigue in breast cancer survivors [6]. These patients had a late evening peak in cortisol levels, compared with an early morning peak in individuals without cancer.

Inhibition of Hypothalamic–Pituitary–Adrenal Axis

The hypothalamic–pituitary–adrenal (HPA) axis regulates the release of the stress hormone cortisol. One of several hypotheses advanced to explain the effect of serotonin and the HPA axis on CRF suggests that lower serotonin levels cause decreased activation of 5-hydroxytrytophan 1-a (5-HT1-a) receptors in the hypothalamus, leading to decreased activity of the HPA axis [6]. The inhibition of the HPA axis may occur with higher levels of serotonin as well [7]. The 5-HT1-a receptors are also triggered by cytokines. However, the correction of serotonin levels by antidepressants was not shown to improve fatigue [8]. Inhibition of the HPA axis can also lead to lower testosterone, progesterone, or estrogen levels, which may indirectly contribute to fatigue [2].

Skeletal Muscle Effect

Chemotherapy- and tumor-related cachexia have a direct effect on the metabolism of skeletal muscles. This effect may lead to impaired adenosine triphosphate (ATP) generation during muscle contraction [9]. ATP infusion improved muscle strength in one trial, but this was not confirmed in another trial [10,11]. Muscle contraction studies showed no differences in the contractile properties of muscles in fatigued patients who failed earlier in motor tasks and healthy controls [12]. This finding suggests that there could be a failure of skeletal muscle activation by the central nervous system or inhibition of skeletal muscle activity. Cytokines and other neurotransmitters activate vagal efferent nerve fibers, which may lead to reflex inhibition in skeletal muscles [13,14].

Pro-inflammatory Cytokines

Tumors or treatment of them may cause tissue injury, which triggers immune cells to release cytokines, signaling the brain to manifest the symptom fatigue. Inflammatory pathways are influenced by psychological, behavioral, and biological factors, which play a role as risk factors in CRF. Interleukin 6 (IL-6), interleukin-1 receptor antagonist, interleukin-1, and tumor necrosis factor (TNF) have been shown to be elevated in fatigued patients being treated for leukemia and non-Hodgkin lymphoma [15]. IL-6 was also associated with increased fatigue in breast cancer survivors [16]. Similar findings were reported in patients undergoing stem cell transplantation and high-dose chemotherapy [17]. Elevated levels of IL-6 and C-reactive protein were also linked to fatigue in terminally ill cancer patients [18,19]. Furthermore, TNF-α signaling was associated with post-chemotherapy fatigue in breast cancer patients [20]. Leukocytes in breast cancer survivors with fatigue also have increased gene expression of pro-inflammatory cytokines, emphasizing the role of cytokines and inflammation in the pathogenesis of CRF [21].

Other Hypotheses

Several other hypotheses for CRF pathogenesis have been proposed. Activation of latent viruses such as Epstein-Barr virus, lack of social support [22], genetic alterations in immune pathway [23], epigenetic changes [24], accumulation of neurotoxic metabolites and depletion of serotonin by indoleamine 2,3-dioxygenase pathway activation [25], elevated vascular endothelial growth factor levels [26], and hypoxia-related organ dysfunction due to anemia or hemoglobin dysfunction [13] all have been postulated to cause CRF.

Approach to Evaluation and Treatment

Screening

Because patients and health care professionals may be unaware of the treatment options available for CRF, patients may not report fatigue levels to their clinicians, and clinicians may not understand the impact of fatigue on their patients’ quality of life. This leads to underrecognition of the problem. The NCCN recommends screening every cancer patient and post-treatment survivor for fatigue [2]. Patients should be screened at their first visit and then at periodic intervals during and after cancer treatment.

Many scales are available to screen patients for CRF in clinical practice and clinical trials [27]. A single item that asks patients to rate their fatigue on a scale from 0 to 10—in which 0 indicates no fatigue, 1 to 3 indicates mild fatigue, 4 to 6 indicates moderate fatigue, 7 to 9 indicates severe fatigue, and 10 indicates the worst fatigue imaginable—is commonly used to screen for CRF [2]. This scale was adapted from the MD Anderson Symptom Inventory scale and is based on a large nationwide study of cancer patients and survivors [28]. The statistically derived cutoff points in this study are consistent with other scales such as the Brief Fatigue Inventory (BFI) and support the cutoff points (4–6 for moderate and ≥ 7 for severe fatigue) used in various fatigue management guidelines. Furthermore, studies of fatigue in cancer patients have revealed a marked decrease in physical function at levels of 7 or higher, suggesting 7 as an optimal cutoff to identify severe fatigue [29,30]. The Visual Analog Scale is another simple-to-use tool that helps in understanding variations in fatigue throughout the course of the day [31]. The 9-item BFI is often used in clinical trials [29]. It measures the severity of fatigue over the previous 24 hours and has been validated in non-English speaking patients [32].

CRF affects not only the somatic domain, but also the cognitive, behavioral, and affective domains; therefore, multidimensional scales have been developed for screening. One such tool is the Multidimensional Fatigue Inventory, which measures general, physical, mental, and emotional fatigue domains as well as activity and compares them with those of individuals without cancer [33,34]. The Functional Assessment of Cancer Therapy for Fatigue (FACT-F) is a 13-item questionnaire that has been used to measure CRF in clinical trials as well as in patients receiving various treatments [35].

Although many scales are available, the validity of self-reporting on simple fatigue-rating scales is equal to or better than most complex, lengthy scales [36]. Therefore, unidimensional tools such as the numeric rating scale of 0–10 are commonly used in clinical practice. Mild fatigue (0–3) requires periodic re-evaluation, and moderate and severe fatigue need further evaluation and management [37].

Primary Evaluation

This phase involves a focused history and physical examination and assessment of concurrent symptoms and contributing factors.

History and Physical Examination

A detailed history of the patient’s malignancy and type of previous and current treatment may help reveal the cause of fatigue. New-onset fatigue or increase in fatigue may be related to the progression of disease in patients with active malignancy or recurrence of cancer in survivors. These patients may require appropriate testing to assess the underlying disease pattern. A detailed review of systems may help identify some of the contributing factors, which are discussed below. A detailed history regarding medications, including over-the-counter drugs, complementary agents, and past and prior cancer therapies, is helpful as medications can contribute to fatigue. For example, opioids may cause drowsiness and fatigue, which could be improved by dose adjustments. A focused history of fatigue should be obtained in all patients with moderate to severe CRF, which includes the onset, pattern, duration, associated or alleviating factors, and interference with functioning, including activities of daily living [37]. Physical examination should focus on identifying signs of organ dysfunction and features of substance or alcohol abuse which may cause poor sleep and fatigue.

Assessment of Contributing Factors

The management of fatigue should be multifactorial, with a comprehensive assessment and treatment plan to address all modifiable fatigue etiologies. The Table lists potential contributing factors to fatigue that should be considered when evaluating patients for CRF; several common conditions are discussed below.

Anemia. Anemia has been correlated with fatigue and quality of life. In a study of 4382 cancer patients receiving chemotherapy, quality-of-life measures using FACT-Anemia scores improved with increased hemoglobin levels [38]. Cancer patients may have anemia due to marrow-suppressing effects of chemotherapy and may also have iron deficiency anemia due to blood loss or autoimmune hemolytic anemia. Therefore, a detailed work-up is required to identify the etiology of anemia. Patients with CRF whose anemia is related to chemotherapy or anemia of chronic disease may benefit from red blood cell transfusion or erythropoiesis-stimulating agents (ESAs). ESAs have been studied extensively; however, their use is controversial because of concerns about thromboembolic side effects leading to adverse outcomes [39]. Also, ESA therapy is not recommended in patients with hematologic malignancies. ESA use should be restricted to patients with chemotherapy-related anemia with hemoglobin below 10 mg/dL and should be discontinued in 6 to 8 weeks if patients do not respond [40]. Other patients may benefit from blood transfusions, which were shown to help in patients with hemoglobin levels between 7.5 and 8.5 g/dL [41].

Sleep disturbance. Poor sleep is common in fatigued cancer survivors [42]. Pro-inflammatory cytokines can disrupt the sleep–wake cycle, causing changes in the HPA axis and neuroendocrine system, which in turn may lead to increasing fatigue. Heckler et al showed that improvement in nighttime sleep leads to improvement of fatigue [43]. Cognitive behavioral therapy and sleep hygiene are important in caring for patients with CRF and poor sleep [44]. Taking a warm bath and/or drinking a glass of milk before bedtime, avoiding caffeinated drinks, and avoiding frequent napping in the day might help. Some patients may require medications such as benzodiazepines or non-benzodiazepine hypnotics (eg, zolpidem) to promote sleep [45]. Melatonin agonists are approved for insomnia in the United states, but not in Europe [46].

Malnutrition. Patients with advanced-stage cancer and with cancers affecting the gastrointestinal tract frequently develop mechanical bowel obstructions, especially at the end of their life, which cause malnutrition. Chemotherapy-related nausea and vomiting may also cause poor oral intake and malnutrition, causing fatigue from muscle weakness. Dehydration and electrolyte imbalances frequently occur as a result of poor oral intake, which might worsen fatigue. In our experience, modifying dietary intake with appropriate caloric exchanges with the help of a nutrition expert has lessened fatigue in some patients. However, terminally ill patients are advised to eat based on their comfort.

Medical comorbidities. Congestive heart failure from anthracycline chemotherapy, hypothyroidism after radiation therapy for head and neck cancers, renal failure, or hepatic failure from chemotherapy may indirectly lead to fatigue. Chemotherapy, opioids, and steroids may cause hypogonadism, which can contribute to fatigue in men [47].

Assessment of Concurrent Symptoms

Depression is common in cancer patients and coexists with pain, insomnia, fatigue, and anxiety as a symptom cluster [48]. A symptom cluster is defined as 2 or more concurrent and interrelated symptoms occurring together; treating of one of these symptoms without addressing other symptoms is not effective [49]. Therefore, screening for and management of depression, anxiety, and insomnia play an important role in the management of CRF.

Physical symptoms due to the tumor or to therapy—such as pain, dyspnea, nausea, and decreased physical activity—may also contribute to fatigue both directly and indirectly. Patients with lung cancer may have hypoxemia, which can contribute to dyspnea with activity and a perception of fatigue. Optimal management of pain and other physical symptoms in patients with cancer may significantly alleviate fatigue [50].

Management

Management of CRF is individualized based on the patient’s clinical status: active cancer treatment, survivor, or end of life. Education and counselling of patients and their caregivers play an important role in CRF. NCCN guidelines recommend focusing on pain control, distress management, energy conservation, physical activity, nutrition, and sleep hygiene.

Nonpharmacologic Interventions

Energy conservation. Energy conservation strategies, in which patients are advised to set priorities and realistic expectations, are highly recommended. Some energy-conserving strategies are to pace oneself, delegate and schedule activities at times of peak energy, postpone nonessential activities, attend to 1 activity at a time, structure daily routines, and maintain a diary to identify their peak energy period and structure activities around that time [51,52]. When patients approach the end of life, increasing fatigue may limit their activity level, and they may depend on caregivers for assistance with activities of daily living, monitoring treatment-related adverse effects, and taking medications, especially elderly patients [53].

Cognitive behavioral therapy. Cognitive behavioral therapy (CBT) has been shown to improve CRF during active treatment, and the benefits persist for a minimum of 2 years after therapy [54]. CBT interventions that optimize sleep quality may improve fatigue [55]. More studies are needed to understand whether referral to a psychologist for formal CBT is required. Randomized clinical trials (RCTs) showed patient fatigue education, learned self-care, coping techniques, and balancing rest and activity benefit patients with CRF [56].

Exercise. Physical activity is highly encouraged in patients with CRF. Exercise increases muscle protein synthesis, improves cytokine response, and decreases the rate of sarcopenia in healthy populations [57]. Studies have shown that exercise helps CRF at all phases of the cancer journey, including radiation therapy, chemotherapy, and survivorship [58]. Some patients may feel less motivated to exercise and may not believe that exercise is possible or could potentially help them. Counselling is needed for such patients.

Older cancer survivors have a decline in their functional capacity and reduced muscle mass. Exercise can improve cardiorespiratory fitness, muscle strength, and body composition [57]. Exercise not only helps at the cellular level but also has psychosocial benefits from improved self-esteem. Therefore, exercise may be recommended not only for younger patients, but also in the older population, who may have comorbidities and less motivation than younger patients.

In a meta-analysis of 56 randomized controlled trials involving 4068 participants, aerobic exercise was found to have beneficial effects on CRF for patients during and after chemotherapy, specifically for patients with solid tumors [59]. In another meta-analysis of breast and prostate cancer survivors, a combination of aerobic exercise with resistance training (3–6 metabolic equivalents, 60%–80% range of motion) was shown to reduce CRF more than aerobic exercise alone [60]. This effect was also shown in an RCT of 160 patients with stage 0 to III breast cancer undergoing radiation therapy [61]. The control group in this study had a group-based non-exercise intervention/relaxation; therefore, the study showed that the effect of resistance training extends beyond the psychosocial benefits of group-based interventions. The intervention comprised 8 progressive machine-based resistance exercises (3 sets, 8–12 repetitions at 60%–80% of 1 repetition maximum) for 60 minutes twice weekly for 12 weeks. However, fatigue assessment questionnaire scores showed benefits in the physical fatigue but not the affective and cognitive components.

The American Society of Clinical Oncology’s guidelines for cancer survivors with fatigue recommends 150 minutes of moderate aerobic exercise (eg, fast walking, cycling, or swimming) per week, with 2 or 3 sessions of strength training per week [62]. An individualized approach to exercise is recommended, as patients’ ability to perform certain types of exercises may be limited by thrombocytopenia, neutropenia, or lytic bone metastasis. Routine use of pre-exercise cardiovascular testing is not recommended but may be considered in high-risk populations, especially patients with risk factors for coronary heart disease and diabetes [63]. Patients withcomorbidities, substantial deconditioning, functional and anatomic defects, or recent major surgery may benefit from referral to physical therapy [37]. Patients near end of life may also benefit from an exercise program, as demonstrated in several studies that showed benefit in CRF and quality of life [64,65]. We recommend that physicians use their best clinical judgement in suggesting the type and intensity of exercise program, as it may not be feasible in some patients.

Mind-body interventions. Mindfulness-based stress reduction (MBSR) has shown promise in breast cancer survivors, who reported immediate improvements in fatigue severity that continued up to 6 weeks after cessation of the training [66]. Prior studies had similar findings, suggesting that MBSR modestly decreases fatigue and sleep disturbances and has a greater effect on the degree to which symptoms interfere with many facets of life [67].

Yoga. A study of a yoga intervention showed a benefit in older cancer survivors [68]. In breast cancer patients undergoing chemotherapy, yoga was shown to benefit not only physical fatigue, but also cognitive fatigue [69]. DVD-based yoga had benefits similar to strengthening exercises in a study of 34 early-stage breast cancer survivors with CRF [70]. More studies are needed in men and patients and survivors of other cancers, as most studies of yoga were conducted in women with breast cancer.

Tai chi/qigong. Like yoga, tai chi and qigong are practices of meditative movement. These practices use postures or movements with a focus on breath and a meditative state to bring about deep states of relaxation. Qigong is a series of simple, repeated practices including body posture/movement, breath practice, and meditation performed in synchrony. Tai chi easy (TCE) is a simplified set of common, repetitive tai chi movements. In a trial, qigong/TCE was compared with sham qigong, which had physical movements but no breathing or meditative practice. Breast cancer survivors in the qigong/TCE group had improved fatigue scores, and the effect persisted for 3 months [71]. Additional research is needed in this area.

Acupuncture. An RCT in breast cancer patients with CRF showed an improvement in the mean general fatigue score (per the Multidimensional Fatigue Inventory) in patients who received acupuncture versus those who did not (−3.11 [95% confidence interval −3.97 to −2.25]; P < 0.001) at 6 weeks. Improvements were seen in both the mental and physical aspects of fatigue [72]. However, Deng et al noted that true acupuncture was no more effective than sham acupuncture for reducing post-chemotherapy chronic fatigue [73]. Presently, there is not sufficient evidence to evaluate the benefits of acupuncture in CRF.

Other modalities. Massage therapy, music therapy, hypnosis, therapeutic touch, biofield therapies, relaxation, and reiki are other therapies for which few studies have been done, with mixed results, and additional research is needed [74]. Currently, there are not sufficient data to recommend any of these modalities.

Pharmacologic Interventions

Psychostimulants. Methylphenidate and modafinil are psychostimulants or wakefulness-promoting agents. Pilot studies showed benefit from methylphenidate and modafinil in CRF [75–77], but RCTs have yielded mixed results. Therefore, in patients with severe fatigue during cancer therapy, the initial management strategy involves evaluation and treatment of medical conditions such as anemia and a trial of non-pharmacological strategies as discussed above. If symptoms persist, then a therapeutic trial of a psychostimulant may be considered per NCCN guidelines for patients undergoing active cancer treatment [37].

Methylphenidate directly stimulates adrenergic receptors and indirectly releases dopamine and norepinephrine from presynaptic terminals, which may explain why the drug benefits patients receiving opioid-induced sedation. It is a commonly studied psychostimulant, though its mechanism of action in CRF is unclear. RCTs of methylphenidate have resulted in a wide range of findings due to the heterogeneity of study populations and variations in the dosage of methylphenidate. A meta-analysis of 7 studies indicates that methylphenidate benefitted the subgroup of patients with CRF [78]. Likewise, in an analysis of 5 RCTs, Minton et al showed a benefit of psychostimulants in fatigue compared with placebo [79]. However, another study of methylphenidate in patients with CRF showed a benefit only in patients with severe fatigue or advanced disease [80]. Methylphenidate was found to benefit cancer patients receiving opioid-induced sedation, as methylphenidate promotes wakefulness, though fatigue was not studied specifically [81]. In a trial with 30 hospice patients in which the methylphenidate dose was titrated based on response and adverse effects, Kerr at al found that the drug improved fatigue in a dose-dependent manner [82]. However, a study in patients with CRF at the University of Texas MD Anderson Cancer Center found no significant difference in BFI scores between patients receiving methylphenidate and those receiving placebo at the end of 2 weeks of treatment [83]. Also, other RCTs in patients undergoing adjuvant chemotherapy for breast cancer [84] and patients receiving radiation therapy for brain tumors [85] failed to demonstrate the efficacy of methylphenidate in CRF. It should be used cautiously after ruling out other causes of fatigue. The drug is overall well tolerated and side effects include headache and nausea.

Modafinil is a non-amphetamine psychostimulant that has been approved for the treatment of narcolepsy. In a trial studying the effect of modafinil on patients receiving docetaxel-based chemotherapy for metastatic breast or prostate cancer, there was a modest but not statistically significant improvement in fatigue scores on the MD Anderson Symptom Inventory compared with placebo. Nausea and vomiting were higher in the modafinil arm than in the placebo arm [86]. Similarly, modafinil was not superior to placebo for CRF in 208 patients with non-squamous cell lung cancer not undergoing chemotherapy or radiation [87]. A placebo effect was also noted in patients with multiple myeloma [88] and patients with primary brain tumors [89]. In a phase 3, multicenter, randomized, placebo-controlled, double-blind clinical trial of modafinil for CRF in 867 patients undergoing chemotherapy, there was a reduction in fatigue only for patients with severe baseline fatigue, with no significant effect on mild to moderate fatigue [90]. In another recent study, modafinil was shown to reduce depressive symptoms only in patients with severe fatigue (BFI item 3 score ≥ 7) [91]. This finding is consistent with previous studies showing benefit in patients with high baseline fatigue, but additional RCTs are needed to provide clarity. NCCN guidelines do not recommend the use of modafinil to treat CRF [37].

Other pharmacologic interventions. Corticosteroids are often used for symptom control in cancer patients. These drugs have anti-inflammatory effects through their modulation of pro-inflammatory cytokines [92]. In a RCT evaluating the efficacy of corticosteroids, patients receiving dexamethasone (4 mg twice daily) experienced significant improvement in their FACT-F scores compared with patients receiving placebo [93]. A similar benefit in fatigue was demonstrated in another study of methylprednisolone (32 mg daily) versus placebo [94]. Despite the benefits of steroids, their adverse effects, such as mood swings, gastritis, hyperglycemia, and immune suppression, limit their long-term use. Therefore, the use of steroids should be restricted to terminally ill fatigued patients with other symptoms such as anorexia, brain metastasis, or pain related to bone metastasis [37].

Testosterone replacement has been shown to diminish fatigue in non-cancer patients. Many men with advanced cancer have hypogonadism leading to low serum testosterone, which may cause fatigue. In a small trial in which cancer patients with hypogonadism received intramuscular testosterone every 14 days or placebo, the group receiving testosterone showed improvement in FACT-F scores, but there was no significant difference in FACT-F scores between the 2 groups [95].

Antidepressants have failed to demonstrate benefit in CRF without depression [8]. However, if a patient has both fatigue and depression, antidepressants may help [96]. A selective serotonin receptor inhibitor is recommended as a first-line antidepressant [97]. Patients with cancer are often receiving multiple medications, and medication interactions should be considered to prevent adverse events such as serotonin syndrome.

Complementary and Alternative Supplements

Studies using vitamin supplementation have been inconclusive in patients with CRF [74]. The use of other dietary supplements has yielded mixed results, and coenzyme Q has shown no benefit for patients with CRF [98].

The benefit of ginseng was studied in a RCT involving 364 patients with CRF. There was an improvement in Multidimensional Fatigue Symptom Inventory-short form (MFSI-SF) scores at 8 weeks in patients receiving 2000 mg of Wisconsin ginseng compared with patients receiving placebo [99]. Patients on active treatment had greater improvement as compared to the post-treatment group in this trial. In another study of high-dose panax ginseng (ginseng root) at 800 mg daily for 29 days, patients had improvement of CRF as well as overall quality of life, appetite, and sleep at night. It was also well tolerated with few adverse effects [100]. Interaction with warfarin, calcium channel blockers, antiplatelet agents, thrombolytic agents, imatinib, and other agents may occur; therefore, ginseng must be used with careful monitoring in selected patients. There is not enough evidence at this time to support the routine use of ginseng in CRF.

The seed extract of the guarana plant (Paullinia cupana) traditionally has been used as a stimulant. An improvement in fatigue scores was seen with the use of oral guarana (100 mg daily) at the end of 21 days in breast cancer patients receiving chemotherapy [101]. Further studies are needed for these results to be generalized and to understand the adverse effects and interaction profile of guarana.

Re-evaluation

Patients who have completed cancer treatment must be monitored for fatigue over the long term, as fatigue may exist beyond the period of active treatment. Many studies have shown fatigue in breast cancer survivors, and fatigue has been demonstrated in survivors of colorectal, lung, and prostate cancers as well as myeloproliferative neoplasms [28]. Therefore, it is important to screen patients for fatigue during follow-up visits. There are currently no studies evaluating the long-term treatment of fatigue. In our experience, the timing of follow-up depends on the level of fatigue and interventions prescribed. Once fatigue is stabilized to a level with which the patient is able to cope, the time interval for follow up may be lengthened. Annual visits may suffice in patients with mild fatigue. Follow-up of patients with moderate to severe fatigue depends on the level of fatigue, the ability to cope, choice of treatment, and presence of contributing factors.

Conclusion

CRF is a complex condition that places a significant burden on patients and caregivers, resulting in emotional distress, poor functioning, and suffering. Fatigue can occur before, during, and long after cancer treatment. The approach to CRF begins with screening for and educating patients and their caregivers about the symptoms. Many screening scales are available that may be used to follow patients’ progress over time. The evaluation and management of contributing conditions may help improve fatigue. If the fatigue persists, an individualized approach with a combination of nonpharmacologic and pharmacologic approaches should be considered. More research is needed to understand brain signaling pathways, cytokine changes, and genomic changes in cancer patients with fatigue. Though many hypotheses have been proposed, to date there is no biological marker to assess this condition. Biomarker research needs to be advanced to help to identify patients at risk for fatigue. As cytokines have a major role in CRF, targeted therapy to block cytokine pathways may also be explored in the future.

Acknowledgment: Bryan Tutt provided editorial assistance.

Corresponding author: Carmelita P. Escalante, MD, The University of Texas MD Anderson Cancer Center, 1400 Pressler St., Houston, TX 77030, [email protected].

Financial disclosures: None.

From the University of Texas MD Anderson Cancer Center, Houston, TX.

Abstract

• Objective: To review the evidence on interventions for managing cancer-related fatigue (CRF) and provide evidence-based guidance on approaches to its management.
• Methods: Nonsystematic review of the literature.
• Results: Several theories have been proposed to explain the biology of CRF, but there is no single clear mechanism that can be targeted for therapy. The approach to patients begins with screening for fatigue and assessing its intensity, followed by a thorough history and examination to determine whether any reversible medical conditions are contributing to fatigue. Management of underlying medical comorbidities may help some patients. For patients whose fatigue persists, pharmacologic and nonpharmacologic treatment options are available. Pharmacologic options include psychostimulants, such as methylphenidate and modafinil, and corticosteroids. Nonpharmacologic approaches include exercise, cognitive behavior therapy, yoga, acupuncture, and tai chi.
• Conclusion: We recommend an individualized approach, often with a combination of the available options. Patients need to be evaluated periodically to assess their fatigue, and since cancer-related fatigue affects survivors, long-term follow-up is needed.

Key words: fatigue; cancer; pro-inflammatory cytokines; nonpharmacologic; psychostimulants.

Fatigue is a common distressing effect of cancer [1].It impairs the quality of life of patients undergoing active cancer treatment and of post-treatment survivors. The National Comprehensive Cancer Network (NCCN) defines cancer-related fatigue (CRF) as “a distressing, persistent, subjective sense of physical, emotional and/or cognitive tiredness related to cancer or cancer treatment that is not proportional to recent activity and interferes with usual functioning [2].” Differences between CRF and fatigue reported by individuals without cancer are that CRF is more severe and is not relieved by rest. The prevalence of CRF in cancer patients and survivors is highly variable, ranging between 25% and 99% [2,3]. This variability may be secondary to methods used for screening fatigue and characteristics of the patient groups. In this article, we discuss recognition of CRF and approaches to its management.

Pathophysiology

The specific pathophysiologic mechanism underlying CRF is unknown, making targeted treatment a challenge. The multidimensional and subjective nature of CRF has limited the development of research methodologies to explain this condition. However, research has been done in both human and animal models, and several theories have been proposed to explain the pathophysiology of CRF. While pro-inflammatory cytokines remain the central factor playing a significant role at multiple levels in CRF, there may be a complex interplay of more than 1 mechanism contributing to fatigue in an individual patient.

Central Nervous System Disturbances

The basal ganglia are known to influence motivation. Lack of motivation and drive may cause failure to complete physical and mental tasks, even with preserved cognitive ability and motor function. In a study of melanoma patients receiving interferon, increased activity of the basal ganglia and the cerebellum resulted in higher fatigue scores [4]. Higher levels of cytokines may alter blood flow to the cerebellum and lead to the perception of fatigue. In a study of 12 patients and matched controls, when patients were asked to perform sustained elbow flexion until they perceived exhaustion, CRF patients perceived physical exhaustion sooner than controls. In CRF patients in this study, muscle fatigue measured by electromyogram was less than that in healthy individuals at the time of exhaustion, suggesting the role of the central nervous system in CRF [5]. However, there is not enough evidence at this time to support central nervous system disturbance as the main contributing factor to fatigue in cancer patients.

Circadian Rhythm Dysregulation

Circadian rhythm is regulated by the suprachiasmatic nucleus in the hypothalamus through cortisol and melatonin. Sleep disturbances occur with disruption of the circadian rhythm. Tumor-related peptides such as epidermal growth factor or alterations in serotonin and cortisol can influence the suprachiasmatic nucleus and the complex signaling pathways [2]. Positive feedback loops that are activated by cortisol under the influence of cytokines may lead to continuous cytokine production and altered circadian rhythm. Bower et al showed that changes in the cortisol curve influence fatigue in breast cancer survivors [6]. These patients had a late evening peak in cortisol levels, compared with an early morning peak in individuals without cancer.

Inhibition of Hypothalamic–Pituitary–Adrenal Axis

The hypothalamic–pituitary–adrenal (HPA) axis regulates the release of the stress hormone cortisol. One of several hypotheses advanced to explain the effect of serotonin and the HPA axis on CRF suggests that lower serotonin levels cause decreased activation of 5-hydroxytrytophan 1-a (5-HT1-a) receptors in the hypothalamus, leading to decreased activity of the HPA axis [6]. The inhibition of the HPA axis may occur with higher levels of serotonin as well [7]. The 5-HT1-a receptors are also triggered by cytokines. However, the correction of serotonin levels by antidepressants was not shown to improve fatigue [8]. Inhibition of the HPA axis can also lead to lower testosterone, progesterone, or estrogen levels, which may indirectly contribute to fatigue [2].

Skeletal Muscle Effect

Chemotherapy- and tumor-related cachexia have a direct effect on the metabolism of skeletal muscles. This effect may lead to impaired adenosine triphosphate (ATP) generation during muscle contraction [9]. ATP infusion improved muscle strength in one trial, but this was not confirmed in another trial [10,11]. Muscle contraction studies showed no differences in the contractile properties of muscles in fatigued patients who failed earlier in motor tasks and healthy controls [12]. This finding suggests that there could be a failure of skeletal muscle activation by the central nervous system or inhibition of skeletal muscle activity. Cytokines and other neurotransmitters activate vagal efferent nerve fibers, which may lead to reflex inhibition in skeletal muscles [13,14].

Pro-inflammatory Cytokines

Tumors or treatment of them may cause tissue injury, which triggers immune cells to release cytokines, signaling the brain to manifest the symptom fatigue. Inflammatory pathways are influenced by psychological, behavioral, and biological factors, which play a role as risk factors in CRF. Interleukin 6 (IL-6), interleukin-1 receptor antagonist, interleukin-1, and tumor necrosis factor (TNF) have been shown to be elevated in fatigued patients being treated for leukemia and non-Hodgkin lymphoma [15]. IL-6 was also associated with increased fatigue in breast cancer survivors [16]. Similar findings were reported in patients undergoing stem cell transplantation and high-dose chemotherapy [17]. Elevated levels of IL-6 and C-reactive protein were also linked to fatigue in terminally ill cancer patients [18,19]. Furthermore, TNF-α signaling was associated with post-chemotherapy fatigue in breast cancer patients [20]. Leukocytes in breast cancer survivors with fatigue also have increased gene expression of pro-inflammatory cytokines, emphasizing the role of cytokines and inflammation in the pathogenesis of CRF [21].

Other Hypotheses

Several other hypotheses for CRF pathogenesis have been proposed. Activation of latent viruses such as Epstein-Barr virus, lack of social support [22], genetic alterations in immune pathway [23], epigenetic changes [24], accumulation of neurotoxic metabolites and depletion of serotonin by indoleamine 2,3-dioxygenase pathway activation [25], elevated vascular endothelial growth factor levels [26], and hypoxia-related organ dysfunction due to anemia or hemoglobin dysfunction [13] all have been postulated to cause CRF.

Approach to Evaluation and Treatment

Screening

Because patients and health care professionals may be unaware of the treatment options available for CRF, patients may not report fatigue levels to their clinicians, and clinicians may not understand the impact of fatigue on their patients’ quality of life. This leads to underrecognition of the problem. The NCCN recommends screening every cancer patient and post-treatment survivor for fatigue [2]. Patients should be screened at their first visit and then at periodic intervals during and after cancer treatment.

Many scales are available to screen patients for CRF in clinical practice and clinical trials [27]. A single item that asks patients to rate their fatigue on a scale from 0 to 10—in which 0 indicates no fatigue, 1 to 3 indicates mild fatigue, 4 to 6 indicates moderate fatigue, 7 to 9 indicates severe fatigue, and 10 indicates the worst fatigue imaginable—is commonly used to screen for CRF [2]. This scale was adapted from the MD Anderson Symptom Inventory scale and is based on a large nationwide study of cancer patients and survivors [28]. The statistically derived cutoff points in this study are consistent with other scales such as the Brief Fatigue Inventory (BFI) and support the cutoff points (4–6 for moderate and ≥ 7 for severe fatigue) used in various fatigue management guidelines. Furthermore, studies of fatigue in cancer patients have revealed a marked decrease in physical function at levels of 7 or higher, suggesting 7 as an optimal cutoff to identify severe fatigue [29,30]. The Visual Analog Scale is another simple-to-use tool that helps in understanding variations in fatigue throughout the course of the day [31]. The 9-item BFI is often used in clinical trials [29]. It measures the severity of fatigue over the previous 24 hours and has been validated in non-English speaking patients [32].

CRF affects not only the somatic domain, but also the cognitive, behavioral, and affective domains; therefore, multidimensional scales have been developed for screening. One such tool is the Multidimensional Fatigue Inventory, which measures general, physical, mental, and emotional fatigue domains as well as activity and compares them with those of individuals without cancer [33,34]. The Functional Assessment of Cancer Therapy for Fatigue (FACT-F) is a 13-item questionnaire that has been used to measure CRF in clinical trials as well as in patients receiving various treatments [35].

Although many scales are available, the validity of self-reporting on simple fatigue-rating scales is equal to or better than most complex, lengthy scales [36]. Therefore, unidimensional tools such as the numeric rating scale of 0–10 are commonly used in clinical practice. Mild fatigue (0–3) requires periodic re-evaluation, and moderate and severe fatigue need further evaluation and management [37].

Primary Evaluation

This phase involves a focused history and physical examination and assessment of concurrent symptoms and contributing factors.

History and Physical Examination

A detailed history of the patient’s malignancy and type of previous and current treatment may help reveal the cause of fatigue. New-onset fatigue or increase in fatigue may be related to the progression of disease in patients with active malignancy or recurrence of cancer in survivors. These patients may require appropriate testing to assess the underlying disease pattern. A detailed review of systems may help identify some of the contributing factors, which are discussed below. A detailed history regarding medications, including over-the-counter drugs, complementary agents, and past and prior cancer therapies, is helpful as medications can contribute to fatigue. For example, opioids may cause drowsiness and fatigue, which could be improved by dose adjustments. A focused history of fatigue should be obtained in all patients with moderate to severe CRF, which includes the onset, pattern, duration, associated or alleviating factors, and interference with functioning, including activities of daily living [37]. Physical examination should focus on identifying signs of organ dysfunction and features of substance or alcohol abuse which may cause poor sleep and fatigue.

Assessment of Contributing Factors

The management of fatigue should be multifactorial, with a comprehensive assessment and treatment plan to address all modifiable fatigue etiologies. The Table lists potential contributing factors to fatigue that should be considered when evaluating patients for CRF; several common conditions are discussed below.

Anemia. Anemia has been correlated with fatigue and quality of life. In a study of 4382 cancer patients receiving chemotherapy, quality-of-life measures using FACT-Anemia scores improved with increased hemoglobin levels [38]. Cancer patients may have anemia due to marrow-suppressing effects of chemotherapy and may also have iron deficiency anemia due to blood loss or autoimmune hemolytic anemia. Therefore, a detailed work-up is required to identify the etiology of anemia. Patients with CRF whose anemia is related to chemotherapy or anemia of chronic disease may benefit from red blood cell transfusion or erythropoiesis-stimulating agents (ESAs). ESAs have been studied extensively; however, their use is controversial because of concerns about thromboembolic side effects leading to adverse outcomes [39]. Also, ESA therapy is not recommended in patients with hematologic malignancies. ESA use should be restricted to patients with chemotherapy-related anemia with hemoglobin below 10 mg/dL and should be discontinued in 6 to 8 weeks if patients do not respond [40]. Other patients may benefit from blood transfusions, which were shown to help in patients with hemoglobin levels between 7.5 and 8.5 g/dL [41].

Sleep disturbance. Poor sleep is common in fatigued cancer survivors [42]. Pro-inflammatory cytokines can disrupt the sleep–wake cycle, causing changes in the HPA axis and neuroendocrine system, which in turn may lead to increasing fatigue. Heckler et al showed that improvement in nighttime sleep leads to improvement of fatigue [43]. Cognitive behavioral therapy and sleep hygiene are important in caring for patients with CRF and poor sleep [44]. Taking a warm bath and/or drinking a glass of milk before bedtime, avoiding caffeinated drinks, and avoiding frequent napping in the day might help. Some patients may require medications such as benzodiazepines or non-benzodiazepine hypnotics (eg, zolpidem) to promote sleep [45]. Melatonin agonists are approved for insomnia in the United states, but not in Europe [46].

Malnutrition. Patients with advanced-stage cancer and with cancers affecting the gastrointestinal tract frequently develop mechanical bowel obstructions, especially at the end of their life, which cause malnutrition. Chemotherapy-related nausea and vomiting may also cause poor oral intake and malnutrition, causing fatigue from muscle weakness. Dehydration and electrolyte imbalances frequently occur as a result of poor oral intake, which might worsen fatigue. In our experience, modifying dietary intake with appropriate caloric exchanges with the help of a nutrition expert has lessened fatigue in some patients. However, terminally ill patients are advised to eat based on their comfort.

Medical comorbidities. Congestive heart failure from anthracycline chemotherapy, hypothyroidism after radiation therapy for head and neck cancers, renal failure, or hepatic failure from chemotherapy may indirectly lead to fatigue. Chemotherapy, opioids, and steroids may cause hypogonadism, which can contribute to fatigue in men [47].

Assessment of Concurrent Symptoms

Depression is common in cancer patients and coexists with pain, insomnia, fatigue, and anxiety as a symptom cluster [48]. A symptom cluster is defined as 2 or more concurrent and interrelated symptoms occurring together; treating of one of these symptoms without addressing other symptoms is not effective [49]. Therefore, screening for and management of depression, anxiety, and insomnia play an important role in the management of CRF.

Physical symptoms due to the tumor or to therapy—such as pain, dyspnea, nausea, and decreased physical activity—may also contribute to fatigue both directly and indirectly. Patients with lung cancer may have hypoxemia, which can contribute to dyspnea with activity and a perception of fatigue. Optimal management of pain and other physical symptoms in patients with cancer may significantly alleviate fatigue [50].

Management

Management of CRF is individualized based on the patient’s clinical status: active cancer treatment, survivor, or end of life. Education and counselling of patients and their caregivers play an important role in CRF. NCCN guidelines recommend focusing on pain control, distress management, energy conservation, physical activity, nutrition, and sleep hygiene.

Nonpharmacologic Interventions

Energy conservation. Energy conservation strategies, in which patients are advised to set priorities and realistic expectations, are highly recommended. Some energy-conserving strategies are to pace oneself, delegate and schedule activities at times of peak energy, postpone nonessential activities, attend to 1 activity at a time, structure daily routines, and maintain a diary to identify their peak energy period and structure activities around that time [51,52]. When patients approach the end of life, increasing fatigue may limit their activity level, and they may depend on caregivers for assistance with activities of daily living, monitoring treatment-related adverse effects, and taking medications, especially elderly patients [53].

Cognitive behavioral therapy. Cognitive behavioral therapy (CBT) has been shown to improve CRF during active treatment, and the benefits persist for a minimum of 2 years after therapy [54]. CBT interventions that optimize sleep quality may improve fatigue [55]. More studies are needed to understand whether referral to a psychologist for formal CBT is required. Randomized clinical trials (RCTs) showed patient fatigue education, learned self-care, coping techniques, and balancing rest and activity benefit patients with CRF [56].

Exercise. Physical activity is highly encouraged in patients with CRF. Exercise increases muscle protein synthesis, improves cytokine response, and decreases the rate of sarcopenia in healthy populations [57]. Studies have shown that exercise helps CRF at all phases of the cancer journey, including radiation therapy, chemotherapy, and survivorship [58]. Some patients may feel less motivated to exercise and may not believe that exercise is possible or could potentially help them. Counselling is needed for such patients.

Older cancer survivors have a decline in their functional capacity and reduced muscle mass. Exercise can improve cardiorespiratory fitness, muscle strength, and body composition [57]. Exercise not only helps at the cellular level but also has psychosocial benefits from improved self-esteem. Therefore, exercise may be recommended not only for younger patients, but also in the older population, who may have comorbidities and less motivation than younger patients.

In a meta-analysis of 56 randomized controlled trials involving 4068 participants, aerobic exercise was found to have beneficial effects on CRF for patients during and after chemotherapy, specifically for patients with solid tumors [59]. In another meta-analysis of breast and prostate cancer survivors, a combination of aerobic exercise with resistance training (3–6 metabolic equivalents, 60%–80% range of motion) was shown to reduce CRF more than aerobic exercise alone [60]. This effect was also shown in an RCT of 160 patients with stage 0 to III breast cancer undergoing radiation therapy [61]. The control group in this study had a group-based non-exercise intervention/relaxation; therefore, the study showed that the effect of resistance training extends beyond the psychosocial benefits of group-based interventions. The intervention comprised 8 progressive machine-based resistance exercises (3 sets, 8–12 repetitions at 60%–80% of 1 repetition maximum) for 60 minutes twice weekly for 12 weeks. However, fatigue assessment questionnaire scores showed benefits in the physical fatigue but not the affective and cognitive components.

The American Society of Clinical Oncology’s guidelines for cancer survivors with fatigue recommends 150 minutes of moderate aerobic exercise (eg, fast walking, cycling, or swimming) per week, with 2 or 3 sessions of strength training per week [62]. An individualized approach to exercise is recommended, as patients’ ability to perform certain types of exercises may be limited by thrombocytopenia, neutropenia, or lytic bone metastasis. Routine use of pre-exercise cardiovascular testing is not recommended but may be considered in high-risk populations, especially patients with risk factors for coronary heart disease and diabetes [63]. Patients withcomorbidities, substantial deconditioning, functional and anatomic defects, or recent major surgery may benefit from referral to physical therapy [37]. Patients near end of life may also benefit from an exercise program, as demonstrated in several studies that showed benefit in CRF and quality of life [64,65]. We recommend that physicians use their best clinical judgement in suggesting the type and intensity of exercise program, as it may not be feasible in some patients.

Mind-body interventions. Mindfulness-based stress reduction (MBSR) has shown promise in breast cancer survivors, who reported immediate improvements in fatigue severity that continued up to 6 weeks after cessation of the training [66]. Prior studies had similar findings, suggesting that MBSR modestly decreases fatigue and sleep disturbances and has a greater effect on the degree to which symptoms interfere with many facets of life [67].

Yoga. A study of a yoga intervention showed a benefit in older cancer survivors [68]. In breast cancer patients undergoing chemotherapy, yoga was shown to benefit not only physical fatigue, but also cognitive fatigue [69]. DVD-based yoga had benefits similar to strengthening exercises in a study of 34 early-stage breast cancer survivors with CRF [70]. More studies are needed in men and patients and survivors of other cancers, as most studies of yoga were conducted in women with breast cancer.

Tai chi/qigong. Like yoga, tai chi and qigong are practices of meditative movement. These practices use postures or movements with a focus on breath and a meditative state to bring about deep states of relaxation. Qigong is a series of simple, repeated practices including body posture/movement, breath practice, and meditation performed in synchrony. Tai chi easy (TCE) is a simplified set of common, repetitive tai chi movements. In a trial, qigong/TCE was compared with sham qigong, which had physical movements but no breathing or meditative practice. Breast cancer survivors in the qigong/TCE group had improved fatigue scores, and the effect persisted for 3 months [71]. Additional research is needed in this area.

Acupuncture. An RCT in breast cancer patients with CRF showed an improvement in the mean general fatigue score (per the Multidimensional Fatigue Inventory) in patients who received acupuncture versus those who did not (−3.11 [95% confidence interval −3.97 to −2.25]; P < 0.001) at 6 weeks. Improvements were seen in both the mental and physical aspects of fatigue [72]. However, Deng et al noted that true acupuncture was no more effective than sham acupuncture for reducing post-chemotherapy chronic fatigue [73]. Presently, there is not sufficient evidence to evaluate the benefits of acupuncture in CRF.

Other modalities. Massage therapy, music therapy, hypnosis, therapeutic touch, biofield therapies, relaxation, and reiki are other therapies for which few studies have been done, with mixed results, and additional research is needed [74]. Currently, there are not sufficient data to recommend any of these modalities.

Pharmacologic Interventions

Psychostimulants. Methylphenidate and modafinil are psychostimulants or wakefulness-promoting agents. Pilot studies showed benefit from methylphenidate and modafinil in CRF [75–77], but RCTs have yielded mixed results. Therefore, in patients with severe fatigue during cancer therapy, the initial management strategy involves evaluation and treatment of medical conditions such as anemia and a trial of non-pharmacological strategies as discussed above. If symptoms persist, then a therapeutic trial of a psychostimulant may be considered per NCCN guidelines for patients undergoing active cancer treatment [37].

Methylphenidate directly stimulates adrenergic receptors and indirectly releases dopamine and norepinephrine from presynaptic terminals, which may explain why the drug benefits patients receiving opioid-induced sedation. It is a commonly studied psychostimulant, though its mechanism of action in CRF is unclear. RCTs of methylphenidate have resulted in a wide range of findings due to the heterogeneity of study populations and variations in the dosage of methylphenidate. A meta-analysis of 7 studies indicates that methylphenidate benefitted the subgroup of patients with CRF [78]. Likewise, in an analysis of 5 RCTs, Minton et al showed a benefit of psychostimulants in fatigue compared with placebo [79]. However, another study of methylphenidate in patients with CRF showed a benefit only in patients with severe fatigue or advanced disease [80]. Methylphenidate was found to benefit cancer patients receiving opioid-induced sedation, as methylphenidate promotes wakefulness, though fatigue was not studied specifically [81]. In a trial with 30 hospice patients in which the methylphenidate dose was titrated based on response and adverse effects, Kerr at al found that the drug improved fatigue in a dose-dependent manner [82]. However, a study in patients with CRF at the University of Texas MD Anderson Cancer Center found no significant difference in BFI scores between patients receiving methylphenidate and those receiving placebo at the end of 2 weeks of treatment [83]. Also, other RCTs in patients undergoing adjuvant chemotherapy for breast cancer [84] and patients receiving radiation therapy for brain tumors [85] failed to demonstrate the efficacy of methylphenidate in CRF. It should be used cautiously after ruling out other causes of fatigue. The drug is overall well tolerated and side effects include headache and nausea.

Modafinil is a non-amphetamine psychostimulant that has been approved for the treatment of narcolepsy. In a trial studying the effect of modafinil on patients receiving docetaxel-based chemotherapy for metastatic breast or prostate cancer, there was a modest but not statistically significant improvement in fatigue scores on the MD Anderson Symptom Inventory compared with placebo. Nausea and vomiting were higher in the modafinil arm than in the placebo arm [86]. Similarly, modafinil was not superior to placebo for CRF in 208 patients with non-squamous cell lung cancer not undergoing chemotherapy or radiation [87]. A placebo effect was also noted in patients with multiple myeloma [88] and patients with primary brain tumors [89]. In a phase 3, multicenter, randomized, placebo-controlled, double-blind clinical trial of modafinil for CRF in 867 patients undergoing chemotherapy, there was a reduction in fatigue only for patients with severe baseline fatigue, with no significant effect on mild to moderate fatigue [90]. In another recent study, modafinil was shown to reduce depressive symptoms only in patients with severe fatigue (BFI item 3 score ≥ 7) [91]. This finding is consistent with previous studies showing benefit in patients with high baseline fatigue, but additional RCTs are needed to provide clarity. NCCN guidelines do not recommend the use of modafinil to treat CRF [37].

Other pharmacologic interventions. Corticosteroids are often used for symptom control in cancer patients. These drugs have anti-inflammatory effects through their modulation of pro-inflammatory cytokines [92]. In a RCT evaluating the efficacy of corticosteroids, patients receiving dexamethasone (4 mg twice daily) experienced significant improvement in their FACT-F scores compared with patients receiving placebo [93]. A similar benefit in fatigue was demonstrated in another study of methylprednisolone (32 mg daily) versus placebo [94]. Despite the benefits of steroids, their adverse effects, such as mood swings, gastritis, hyperglycemia, and immune suppression, limit their long-term use. Therefore, the use of steroids should be restricted to terminally ill fatigued patients with other symptoms such as anorexia, brain metastasis, or pain related to bone metastasis [37].

Testosterone replacement has been shown to diminish fatigue in non-cancer patients. Many men with advanced cancer have hypogonadism leading to low serum testosterone, which may cause fatigue. In a small trial in which cancer patients with hypogonadism received intramuscular testosterone every 14 days or placebo, the group receiving testosterone showed improvement in FACT-F scores, but there was no significant difference in FACT-F scores between the 2 groups [95].

Antidepressants have failed to demonstrate benefit in CRF without depression [8]. However, if a patient has both fatigue and depression, antidepressants may help [96]. A selective serotonin receptor inhibitor is recommended as a first-line antidepressant [97]. Patients with cancer are often receiving multiple medications, and medication interactions should be considered to prevent adverse events such as serotonin syndrome.

Complementary and Alternative Supplements

Studies using vitamin supplementation have been inconclusive in patients with CRF [74]. The use of other dietary supplements has yielded mixed results, and coenzyme Q has shown no benefit for patients with CRF [98].

The benefit of ginseng was studied in a RCT involving 364 patients with CRF. There was an improvement in Multidimensional Fatigue Symptom Inventory-short form (MFSI-SF) scores at 8 weeks in patients receiving 2000 mg of Wisconsin ginseng compared with patients receiving placebo [99]. Patients on active treatment had greater improvement as compared to the post-treatment group in this trial. In another study of high-dose panax ginseng (ginseng root) at 800 mg daily for 29 days, patients had improvement of CRF as well as overall quality of life, appetite, and sleep at night. It was also well tolerated with few adverse effects [100]. Interaction with warfarin, calcium channel blockers, antiplatelet agents, thrombolytic agents, imatinib, and other agents may occur; therefore, ginseng must be used with careful monitoring in selected patients. There is not enough evidence at this time to support the routine use of ginseng in CRF.

The seed extract of the guarana plant (Paullinia cupana) traditionally has been used as a stimulant. An improvement in fatigue scores was seen with the use of oral guarana (100 mg daily) at the end of 21 days in breast cancer patients receiving chemotherapy [101]. Further studies are needed for these results to be generalized and to understand the adverse effects and interaction profile of guarana.

Re-evaluation

Patients who have completed cancer treatment must be monitored for fatigue over the long term, as fatigue may exist beyond the period of active treatment. Many studies have shown fatigue in breast cancer survivors, and fatigue has been demonstrated in survivors of colorectal, lung, and prostate cancers as well as myeloproliferative neoplasms [28]. Therefore, it is important to screen patients for fatigue during follow-up visits. There are currently no studies evaluating the long-term treatment of fatigue. In our experience, the timing of follow-up depends on the level of fatigue and interventions prescribed. Once fatigue is stabilized to a level with which the patient is able to cope, the time interval for follow up may be lengthened. Annual visits may suffice in patients with mild fatigue. Follow-up of patients with moderate to severe fatigue depends on the level of fatigue, the ability to cope, choice of treatment, and presence of contributing factors.

Conclusion

CRF is a complex condition that places a significant burden on patients and caregivers, resulting in emotional distress, poor functioning, and suffering. Fatigue can occur before, during, and long after cancer treatment. The approach to CRF begins with screening for and educating patients and their caregivers about the symptoms. Many screening scales are available that may be used to follow patients’ progress over time. The evaluation and management of contributing conditions may help improve fatigue. If the fatigue persists, an individualized approach with a combination of nonpharmacologic and pharmacologic approaches should be considered. More research is needed to understand brain signaling pathways, cytokine changes, and genomic changes in cancer patients with fatigue. Though many hypotheses have been proposed, to date there is no biological marker to assess this condition. Biomarker research needs to be advanced to help to identify patients at risk for fatigue. As cytokines have a major role in CRF, targeted therapy to block cytokine pathways may also be explored in the future.

Acknowledgment: Bryan Tutt provided editorial assistance.

Corresponding author: Carmelita P. Escalante, MD, The University of Texas MD Anderson Cancer Center, 1400 Pressler St., Houston, TX 77030, [email protected].

Financial disclosures: None.

Take-Home Points

• Arthroplasty is a rarely utilized and, therefore, a rarely reported treatment for distal femur fractures.
• Arthroplasty carries certain advantages over fixation, including earlier weight-bearing, a benefit for elderly individuals.
• Arthroplasty is more often described in situations of comminution, often necessitating constrained prostheses.
• It is not unreasonable to utilize arthroplasty in extra-articular fractures in poor-quality bone, which can take the form of unconstrained prosthesis and supplemental fixation.

• The true complication rate is unclear, given that the few papers reporting high complication rates were in sicker populations.

Distal femur fractures (DFFs) in the elderly historically were difficult to treat because of osteoporotic bone, comminution, and intra-articular involvement. DFFs in minimally ambulatory patients were once treated nonoperatively, with traction or immobilization,^1,2 but surgery is now considered for displaced and unstable fractures, even in myelopathic and nonambulatory patients, to provide pain relief, ease mobility, and decrease the risks associated with prolonged bed rest.¹ Options are constantly evolving, but poor knee function, malunion, nonunion, prolonged immobilization, implant failure, and high morbidity and mortality rates have been reported in several studies regardless of fixation method.

Arthritis after DFF has been reported at rates of 36% to 50% by long-term follow-up.^3-5 However, total knee arthroplasty (TKA) for posttraumatic arthritis is more complex because of scarring, arthrofibrosis, malunion, nonunion, and the frequent need for hardware removal. These cases have a higher incidence of infection, aseptic loosening, stiffness,⁶ and skin necrosis.⁷ Primary TKA is a rarely used treatment for acute DFF. Several authors have recommended primary TKA for patients with intra-articular DFFs and preexisting osteoarthritis or rheumatoid arthritis, severe comminution, or poor bone stock.^7-22 Compared with open reduction and internal fixation (ORIF), primary TKA may allow for earlier mobility and weight-bearing and thereby reduce the rates of complications (eg, respiratory failure, deep vein thrombosis, pulmonary embolism) associated with prolonged immobilization.²³As the literature on TKA for acute DFF is scant, and to our knowledge there are no clear indications or guidelines, we performed a systematic review to determine whether TKA has been successful in relieving pain and restoring knee function. In this article, we discuss the indications, implant options, technical considerations, complications, and results (eg, range of motion [ROM], ambulatory status) associated with these procedures.

Methods

On December 1, 2015, we searched the major databases Medline, EMBASE (Excerpta Medica dataBASE), and the Cochrane Library for articles published since 1950. In our searches, we used the conjoint term knee arthroplasty with femur fracture, and knee replacement with femur fracture. Specifically, we queried: ((“knee replacement” OR “knee arthroplasty”) AND (intercondylar OR supracondylar OR femoral OR femur) AND fracture) NOT arthrodesis NOT periprosthetic NOT “posttraumatic arthritis” NOT osteotomy. We also hand-searched the current website of JBJS [Journal of Bone and Joint Surgery] Case Connector, a major case-report repository that was launched in 2011 but is not currently indexed by Medline.

All citations were imported to RefWorks for management and for removal of duplicates. Each article underwent screening and review by Dr. Chen and Dr. Li. Articles were included if titles were relevant to arthroplasty as treatment for acute (within 1 month) DFF. Articles and cases were excluded if they were reviews, published in languages other than English, animal studies, studies regarding nonacute (>3 months or nonunion) DFFs or periprosthetic fractures, or studies that considered only treatments other than TKA (ie, plate osteosynthesis).

Full-text publications were obtained and independently reviewed by Dr. Chen and Dr. Li for relevance and satisfaction of inclusion criteria. Disagreements were resolved by discussion. Given the rarity of publications on the treatment, all study designs from level I to level IV were included.

The same 2 reviewers extracted the data into prearranged summary tables. Data included study size, patient demographics, AO/OTA (Arbeitsgemeinschaft für Osteosynthesefragen/Orthopaedic Trauma Association) fracture type either reported or assessed by description and imaging (33A, extra-articular; 33B, partial articular with 1 intact condyle; 33C, complete articular with both condyles involved), baseline comorbidity, implant used and fracture treatment (if separate from arthroplasty), postoperative regimen, respective outcomes, and complication rates.

Results

We identified 728 articles: 389 through Medline, 294 through EMBASE, and 45 through the Cochrane Library (Figure 1).

The current evidence regarding primary TKA for acute DFF is primarily level IV (Table 1). Only 1 level III study¹⁶ compared TKA with ORIF. Three case series^11,19,24 met our inclusion criteria (Table 1, Table 2). In addition, 5 case series involved patients who met our criteria, but these studies did not separately report results for DFFs and proximal tibia fractures,^9,20-22 or separately for acute fractures and nonunions or ORIF failures.⁸

Discussion

DFFs in the elderly historically were difficult to treat. Reported outcomes are largely favorable, but, even with newer plate designs, catastrophic failures still occur in the absence of bony union.^26,27 After ORIF, patients’ weight-bearing is often restricted for 12 weeks or longer²⁸—a protocol that is undesirable in elderly patients, especially given that the rate of mortality 1 year after these fractures has been found to be as high as 25%.²⁹

Arthroplasty for DFFs—performed either with ORIF, or independently with a constrained implant—is a documented treatment modality, but the evidence is poor, and results have been mixed. Patients who received hinged TKA with major fracture resection had higher complication rates.^8,11,22,24 However, the problems were mostly medical, not associated with surgical technique. Appleton and colleagues²⁴ found a higher than expected 1-year mortality rate, 41%, but used an unhealthy baseline population (44% cognitive impairment, 17% nonambulatory before injury).Although Boureau and colleagues²² found a 1-year mortality rate of 30%, only 1 in 10 deaths was attributable to a perioperative complication. Among the remaining cases involving resection and megaprostheses for previously ambulatory patients, only 1 perioperative death was recorded (Table 2).^11,12,16,18 Therefore, the risks associated with patients’ baseline health and ambulatory status must be weighed against the benefits of aggressive arthroplasty.

An overwhelming majority of 33C fractures were treated with megaprostheses—a finding perhaps attributable to the higher likelihood that patients with osteoporosis have intra-articular, comminuted injuries. In addition, surgeons may have been more likely to indicate 33C fractures for joint replacement, whereas 33A and 33B patterns were more amenable to fracture fixation.^17,18 Interestingly, few type B fractures (0 in primary analysis and only 9 of 67 cases in Table 3) were treated with megaprostheses. In these situations, 1 condyle and ligamentous constraint remain intact, reducing the need for a constrained implant.

There were no reports of atraumatic or aseptic loosening, though use of rotating platforms with linked prostheses helps minimize this complication. Also surprising is the lack of nonunions in any of the reviewed studies, as nonunion is one of the most devastating complications of ORIF. Only 1 superficial and 2 deep infections were reported in all of the literature—representing 1.8% of all cases, which is comparable to the rate for elective primary TKA.³⁰In elderly patients with significant comorbidities, the main surgical goals are to minimize operative time and reduce time to mobility. It is therefore imperative to keep in mind that arthroplasty is elective. However, functional results of primary TKA for DFF may be more encouraging for healthier patients, as many can achieve satisfactory ROM and early weight-bearing. Therefore, TKA for DFF may benefit healthy and ambulatory patients in the setting of intra-articular comminution. Whether this treatment affects mortality rates remains to be seen.

There were several limitations to this study. First, the literature on the topic is scant. Second, exclusion criteria were kept lax to allow for inclusion of all treatments. This came at a cost to internal validity, given the heterogeneous population and differences in comorbidities between studies. Fracture classification was inconsistent as well: Although AO/OTA classification was dominant, descriptive classifications were used in several cases^7,10,12 (these descriptions, however, were sufficient for assigning equivalent AO/OTA classes). Details on preoperative functional status and comorbidity status and on postoperative protocols were also limited, though ROM and ambulatory status were provided in most studies. Last, most of these studies were single case reports or case series, so there may be reporting bias in the body of the literature, as reflected in the discrepancies between encouraging case reports and concerning case series with longer follow-up. Such bias can be avoided with larger, controlled sampling and adequate follow-up.

TKA should be considered for acute DFF in patients who have knee arthritis and are able to tolerate the physiological load of the surgery. In the choice of implant design, several factors should be considered, including bone quality, articular involvement, degree of comminution, and ligamentous injury. Unconstrained knee designs should be considered in cases in which the fracture pattern appears stable and the collateral ligaments are intact (eg, 33A and 33BB fractures). Megaprostheses, which may allow for immediate weight-bearing but require considerable bone resection, would be beneficial in 33C fractures and in fractures with ligamentous compromise. However, their complication rates are unclear, and comparative studies are needed to investigate whether the rates are higher for these patients than for patients treated more traditionally.

Am J Orthop. 2017;46(3):E163-E171. Copyright Frontline Medical Communications Inc. 2017. All rights reserved.

Take-Home Points

• Arthroplasty is a rarely utilized and, therefore, a rarely reported treatment for distal femur fractures.
• Arthroplasty carries certain advantages over fixation, including earlier weight-bearing, a benefit for elderly individuals.
• Arthroplasty is more often described in situations of comminution, often necessitating constrained prostheses.
• It is not unreasonable to utilize arthroplasty in extra-articular fractures in poor-quality bone, which can take the form of unconstrained prosthesis and supplemental fixation.

• The true complication rate is unclear, given that the few papers reporting high complication rates were in sicker populations.

Distal femur fractures (DFFs) in the elderly historically were difficult to treat because of osteoporotic bone, comminution, and intra-articular involvement. DFFs in minimally ambulatory patients were once treated nonoperatively, with traction or immobilization,^1,2 but surgery is now considered for displaced and unstable fractures, even in myelopathic and nonambulatory patients, to provide pain relief, ease mobility, and decrease the risks associated with prolonged bed rest.¹ Options are constantly evolving, but poor knee function, malunion, nonunion, prolonged immobilization, implant failure, and high morbidity and mortality rates have been reported in several studies regardless of fixation method.

Arthritis after DFF has been reported at rates of 36% to 50% by long-term follow-up.^3-5 However, total knee arthroplasty (TKA) for posttraumatic arthritis is more complex because of scarring, arthrofibrosis, malunion, nonunion, and the frequent need for hardware removal. These cases have a higher incidence of infection, aseptic loosening, stiffness,⁶ and skin necrosis.⁷ Primary TKA is a rarely used treatment for acute DFF. Several authors have recommended primary TKA for patients with intra-articular DFFs and preexisting osteoarthritis or rheumatoid arthritis, severe comminution, or poor bone stock.^7-22 Compared with open reduction and internal fixation (ORIF), primary TKA may allow for earlier mobility and weight-bearing and thereby reduce the rates of complications (eg, respiratory failure, deep vein thrombosis, pulmonary embolism) associated with prolonged immobilization.²³As the literature on TKA for acute DFF is scant, and to our knowledge there are no clear indications or guidelines, we performed a systematic review to determine whether TKA has been successful in relieving pain and restoring knee function. In this article, we discuss the indications, implant options, technical considerations, complications, and results (eg, range of motion [ROM], ambulatory status) associated with these procedures.

Methods

On December 1, 2015, we searched the major databases Medline, EMBASE (Excerpta Medica dataBASE), and the Cochrane Library for articles published since 1950. In our searches, we used the conjoint term knee arthroplasty with femur fracture, and knee replacement with femur fracture. Specifically, we queried: ((“knee replacement” OR “knee arthroplasty”) AND (intercondylar OR supracondylar OR femoral OR femur) AND fracture) NOT arthrodesis NOT periprosthetic NOT “posttraumatic arthritis” NOT osteotomy. We also hand-searched the current website of JBJS [Journal of Bone and Joint Surgery] Case Connector, a major case-report repository that was launched in 2011 but is not currently indexed by Medline.

All citations were imported to RefWorks for management and for removal of duplicates. Each article underwent screening and review by Dr. Chen and Dr. Li. Articles were included if titles were relevant to arthroplasty as treatment for acute (within 1 month) DFF. Articles and cases were excluded if they were reviews, published in languages other than English, animal studies, studies regarding nonacute (>3 months or nonunion) DFFs or periprosthetic fractures, or studies that considered only treatments other than TKA (ie, plate osteosynthesis).

Full-text publications were obtained and independently reviewed by Dr. Chen and Dr. Li for relevance and satisfaction of inclusion criteria. Disagreements were resolved by discussion. Given the rarity of publications on the treatment, all study designs from level I to level IV were included.

The same 2 reviewers extracted the data into prearranged summary tables. Data included study size, patient demographics, AO/OTA (Arbeitsgemeinschaft für Osteosynthesefragen/Orthopaedic Trauma Association) fracture type either reported or assessed by description and imaging (33A, extra-articular; 33B, partial articular with 1 intact condyle; 33C, complete articular with both condyles involved), baseline comorbidity, implant used and fracture treatment (if separate from arthroplasty), postoperative regimen, respective outcomes, and complication rates.

Results

We identified 728 articles: 389 through Medline, 294 through EMBASE, and 45 through the Cochrane Library (Figure 1).

The current evidence regarding primary TKA for acute DFF is primarily level IV (Table 1). Only 1 level III study¹⁶ compared TKA with ORIF. Three case series^11,19,24 met our inclusion criteria (Table 1, Table 2). In addition, 5 case series involved patients who met our criteria, but these studies did not separately report results for DFFs and proximal tibia fractures,^9,20-22 or separately for acute fractures and nonunions or ORIF failures.⁸

Discussion

DFFs in the elderly historically were difficult to treat. Reported outcomes are largely favorable, but, even with newer plate designs, catastrophic failures still occur in the absence of bony union.^26,27 After ORIF, patients’ weight-bearing is often restricted for 12 weeks or longer²⁸—a protocol that is undesirable in elderly patients, especially given that the rate of mortality 1 year after these fractures has been found to be as high as 25%.²⁹

Arthroplasty for DFFs—performed either with ORIF, or independently with a constrained implant—is a documented treatment modality, but the evidence is poor, and results have been mixed. Patients who received hinged TKA with major fracture resection had higher complication rates.^8,11,22,24 However, the problems were mostly medical, not associated with surgical technique. Appleton and colleagues²⁴ found a higher than expected 1-year mortality rate, 41%, but used an unhealthy baseline population (44% cognitive impairment, 17% nonambulatory before injury).Although Boureau and colleagues²² found a 1-year mortality rate of 30%, only 1 in 10 deaths was attributable to a perioperative complication. Among the remaining cases involving resection and megaprostheses for previously ambulatory patients, only 1 perioperative death was recorded (Table 2).^11,12,16,18 Therefore, the risks associated with patients’ baseline health and ambulatory status must be weighed against the benefits of aggressive arthroplasty.

An overwhelming majority of 33C fractures were treated with megaprostheses—a finding perhaps attributable to the higher likelihood that patients with osteoporosis have intra-articular, comminuted injuries. In addition, surgeons may have been more likely to indicate 33C fractures for joint replacement, whereas 33A and 33B patterns were more amenable to fracture fixation.^17,18 Interestingly, few type B fractures (0 in primary analysis and only 9 of 67 cases in Table 3) were treated with megaprostheses. In these situations, 1 condyle and ligamentous constraint remain intact, reducing the need for a constrained implant.

There were no reports of atraumatic or aseptic loosening, though use of rotating platforms with linked prostheses helps minimize this complication. Also surprising is the lack of nonunions in any of the reviewed studies, as nonunion is one of the most devastating complications of ORIF. Only 1 superficial and 2 deep infections were reported in all of the literature—representing 1.8% of all cases, which is comparable to the rate for elective primary TKA.³⁰In elderly patients with significant comorbidities, the main surgical goals are to minimize operative time and reduce time to mobility. It is therefore imperative to keep in mind that arthroplasty is elective. However, functional results of primary TKA for DFF may be more encouraging for healthier patients, as many can achieve satisfactory ROM and early weight-bearing. Therefore, TKA for DFF may benefit healthy and ambulatory patients in the setting of intra-articular comminution. Whether this treatment affects mortality rates remains to be seen.

There were several limitations to this study. First, the literature on the topic is scant. Second, exclusion criteria were kept lax to allow for inclusion of all treatments. This came at a cost to internal validity, given the heterogeneous population and differences in comorbidities between studies. Fracture classification was inconsistent as well: Although AO/OTA classification was dominant, descriptive classifications were used in several cases^7,10,12 (these descriptions, however, were sufficient for assigning equivalent AO/OTA classes). Details on preoperative functional status and comorbidity status and on postoperative protocols were also limited, though ROM and ambulatory status were provided in most studies. Last, most of these studies were single case reports or case series, so there may be reporting bias in the body of the literature, as reflected in the discrepancies between encouraging case reports and concerning case series with longer follow-up. Such bias can be avoided with larger, controlled sampling and adequate follow-up.

TKA should be considered for acute DFF in patients who have knee arthritis and are able to tolerate the physiological load of the surgery. In the choice of implant design, several factors should be considered, including bone quality, articular involvement, degree of comminution, and ligamentous injury. Unconstrained knee designs should be considered in cases in which the fracture pattern appears stable and the collateral ligaments are intact (eg, 33A and 33BB fractures). Megaprostheses, which may allow for immediate weight-bearing but require considerable bone resection, would be beneficial in 33C fractures and in fractures with ligamentous compromise. However, their complication rates are unclear, and comparative studies are needed to investigate whether the rates are higher for these patients than for patients treated more traditionally.

Am J Orthop. 2017;46(3):E163-E171. Copyright Frontline Medical Communications Inc. 2017. All rights reserved.

Take-Home Points

• Arthroplasty is a rarely utilized and, therefore, a rarely reported treatment for distal femur fractures.
• Arthroplasty carries certain advantages over fixation, including earlier weight-bearing, a benefit for elderly individuals.
• Arthroplasty is more often described in situations of comminution, often necessitating constrained prostheses.
• It is not unreasonable to utilize arthroplasty in extra-articular fractures in poor-quality bone, which can take the form of unconstrained prosthesis and supplemental fixation.

• The true complication rate is unclear, given that the few papers reporting high complication rates were in sicker populations.

Distal femur fractures (DFFs) in the elderly historically were difficult to treat because of osteoporotic bone, comminution, and intra-articular involvement. DFFs in minimally ambulatory patients were once treated nonoperatively, with traction or immobilization,^1,2 but surgery is now considered for displaced and unstable fractures, even in myelopathic and nonambulatory patients, to provide pain relief, ease mobility, and decrease the risks associated with prolonged bed rest.¹ Options are constantly evolving, but poor knee function, malunion, nonunion, prolonged immobilization, implant failure, and high morbidity and mortality rates have been reported in several studies regardless of fixation method.

Arthritis after DFF has been reported at rates of 36% to 50% by long-term follow-up.^3-5 However, total knee arthroplasty (TKA) for posttraumatic arthritis is more complex because of scarring, arthrofibrosis, malunion, nonunion, and the frequent need for hardware removal. These cases have a higher incidence of infection, aseptic loosening, stiffness,⁶ and skin necrosis.⁷ Primary TKA is a rarely used treatment for acute DFF. Several authors have recommended primary TKA for patients with intra-articular DFFs and preexisting osteoarthritis or rheumatoid arthritis, severe comminution, or poor bone stock.^7-22 Compared with open reduction and internal fixation (ORIF), primary TKA may allow for earlier mobility and weight-bearing and thereby reduce the rates of complications (eg, respiratory failure, deep vein thrombosis, pulmonary embolism) associated with prolonged immobilization.²³As the literature on TKA for acute DFF is scant, and to our knowledge there are no clear indications or guidelines, we performed a systematic review to determine whether TKA has been successful in relieving pain and restoring knee function. In this article, we discuss the indications, implant options, technical considerations, complications, and results (eg, range of motion [ROM], ambulatory status) associated with these procedures.

Methods

On December 1, 2015, we searched the major databases Medline, EMBASE (Excerpta Medica dataBASE), and the Cochrane Library for articles published since 1950. In our searches, we used the conjoint term knee arthroplasty with femur fracture, and knee replacement with femur fracture. Specifically, we queried: ((“knee replacement” OR “knee arthroplasty”) AND (intercondylar OR supracondylar OR femoral OR femur) AND fracture) NOT arthrodesis NOT periprosthetic NOT “posttraumatic arthritis” NOT osteotomy. We also hand-searched the current website of JBJS [Journal of Bone and Joint Surgery] Case Connector, a major case-report repository that was launched in 2011 but is not currently indexed by Medline.

All citations were imported to RefWorks for management and for removal of duplicates. Each article underwent screening and review by Dr. Chen and Dr. Li. Articles were included if titles were relevant to arthroplasty as treatment for acute (within 1 month) DFF. Articles and cases were excluded if they were reviews, published in languages other than English, animal studies, studies regarding nonacute (>3 months or nonunion) DFFs or periprosthetic fractures, or studies that considered only treatments other than TKA (ie, plate osteosynthesis).

Full-text publications were obtained and independently reviewed by Dr. Chen and Dr. Li for relevance and satisfaction of inclusion criteria. Disagreements were resolved by discussion. Given the rarity of publications on the treatment, all study designs from level I to level IV were included.

The same 2 reviewers extracted the data into prearranged summary tables. Data included study size, patient demographics, AO/OTA (Arbeitsgemeinschaft für Osteosynthesefragen/Orthopaedic Trauma Association) fracture type either reported or assessed by description and imaging (33A, extra-articular; 33B, partial articular with 1 intact condyle; 33C, complete articular with both condyles involved), baseline comorbidity, implant used and fracture treatment (if separate from arthroplasty), postoperative regimen, respective outcomes, and complication rates.

Results

We identified 728 articles: 389 through Medline, 294 through EMBASE, and 45 through the Cochrane Library (Figure 1).

The current evidence regarding primary TKA for acute DFF is primarily level IV (Table 1). Only 1 level III study¹⁶ compared TKA with ORIF. Three case series^11,19,24 met our inclusion criteria (Table 1, Table 2). In addition, 5 case series involved patients who met our criteria, but these studies did not separately report results for DFFs and proximal tibia fractures,^9,20-22 or separately for acute fractures and nonunions or ORIF failures.⁸

Discussion

DFFs in the elderly historically were difficult to treat. Reported outcomes are largely favorable, but, even with newer plate designs, catastrophic failures still occur in the absence of bony union.^26,27 After ORIF, patients’ weight-bearing is often restricted for 12 weeks or longer²⁸—a protocol that is undesirable in elderly patients, especially given that the rate of mortality 1 year after these fractures has been found to be as high as 25%.²⁹

Arthroplasty for DFFs—performed either with ORIF, or independently with a constrained implant—is a documented treatment modality, but the evidence is poor, and results have been mixed. Patients who received hinged TKA with major fracture resection had higher complication rates.^8,11,22,24 However, the problems were mostly medical, not associated with surgical technique. Appleton and colleagues²⁴ found a higher than expected 1-year mortality rate, 41%, but used an unhealthy baseline population (44% cognitive impairment, 17% nonambulatory before injury).Although Boureau and colleagues²² found a 1-year mortality rate of 30%, only 1 in 10 deaths was attributable to a perioperative complication. Among the remaining cases involving resection and megaprostheses for previously ambulatory patients, only 1 perioperative death was recorded (Table 2).^11,12,16,18 Therefore, the risks associated with patients’ baseline health and ambulatory status must be weighed against the benefits of aggressive arthroplasty.

An overwhelming majority of 33C fractures were treated with megaprostheses—a finding perhaps attributable to the higher likelihood that patients with osteoporosis have intra-articular, comminuted injuries. In addition, surgeons may have been more likely to indicate 33C fractures for joint replacement, whereas 33A and 33B patterns were more amenable to fracture fixation.^17,18 Interestingly, few type B fractures (0 in primary analysis and only 9 of 67 cases in Table 3) were treated with megaprostheses. In these situations, 1 condyle and ligamentous constraint remain intact, reducing the need for a constrained implant.

There were no reports of atraumatic or aseptic loosening, though use of rotating platforms with linked prostheses helps minimize this complication. Also surprising is the lack of nonunions in any of the reviewed studies, as nonunion is one of the most devastating complications of ORIF. Only 1 superficial and 2 deep infections were reported in all of the literature—representing 1.8% of all cases, which is comparable to the rate for elective primary TKA.³⁰In elderly patients with significant comorbidities, the main surgical goals are to minimize operative time and reduce time to mobility. It is therefore imperative to keep in mind that arthroplasty is elective. However, functional results of primary TKA for DFF may be more encouraging for healthier patients, as many can achieve satisfactory ROM and early weight-bearing. Therefore, TKA for DFF may benefit healthy and ambulatory patients in the setting of intra-articular comminution. Whether this treatment affects mortality rates remains to be seen.

There were several limitations to this study. First, the literature on the topic is scant. Second, exclusion criteria were kept lax to allow for inclusion of all treatments. This came at a cost to internal validity, given the heterogeneous population and differences in comorbidities between studies. Fracture classification was inconsistent as well: Although AO/OTA classification was dominant, descriptive classifications were used in several cases^7,10,12 (these descriptions, however, were sufficient for assigning equivalent AO/OTA classes). Details on preoperative functional status and comorbidity status and on postoperative protocols were also limited, though ROM and ambulatory status were provided in most studies. Last, most of these studies were single case reports or case series, so there may be reporting bias in the body of the literature, as reflected in the discrepancies between encouraging case reports and concerning case series with longer follow-up. Such bias can be avoided with larger, controlled sampling and adequate follow-up.

TKA should be considered for acute DFF in patients who have knee arthritis and are able to tolerate the physiological load of the surgery. In the choice of implant design, several factors should be considered, including bone quality, articular involvement, degree of comminution, and ligamentous injury. Unconstrained knee designs should be considered in cases in which the fracture pattern appears stable and the collateral ligaments are intact (eg, 33A and 33BB fractures). Megaprostheses, which may allow for immediate weight-bearing but require considerable bone resection, would be beneficial in 33C fractures and in fractures with ligamentous compromise. However, their complication rates are unclear, and comparative studies are needed to investigate whether the rates are higher for these patients than for patients treated more traditionally.

Am J Orthop. 2017;46(3):E163-E171. Copyright Frontline Medical Communications Inc. 2017. All rights reserved.

IN THIS ARTICLE

• Staging endometriosis
• Medications for treating endometriosis
• Complications

Endometriosis is a gynecologic disorder characterized by the presence and growth of endometrial tissue outside the uterine cavity (ie, endometrial implants), most commonly found on the ovaries. Although its pathophysiology is not completely understood, the disease is associated with dysmenorrhea, dyspareunia, and infertility.^1,2 Endometriosis is an estrogen-dependent disorder, predominantly affecting women of childbearing age. It occurs in 10% to 15% of the general female population, but prevalence is even higher (35% to 50%) among women who experience pelvic pain and/or infertility.^1-4 Although endometriosis mainly affects women in their mid-to-late 20s, it can also manifest in adolescence.^3,5 Nearly half of all adolescents with intractable dysmenorrhea are diagnosed with endometriosis.⁵

ETIOLOGY

The etiology of endometriosis, while not completely understood, is likely multifactorial. Factors that may influence its development include gene expression, tissue response to hormones, neuronal tissue involvement, lack of protective factors, inflammation, and cellular oxidative stress.^6,7

Several theories regarding the etiology of endometriosis have been proposed; the most widely accepted is the transplantation theory, which suggests that endometriosis results from retrograde flow of menstrual tissue through the fallopian tubes. During menstruation, fragments of the endometrium are driven through the fallopian tubes and into the pelvic cavity, where they can implant onto the pelvic structures, leading to further growth and invasion.^2,6,8 Women who have polymenorrhea, prolonged menses, and early menarche therefore have an increased risk for endometriosis.⁸ This theory does not account for the fact that although nearly 90% of women have some elements of retrograde menstrual flow, only a fraction of them develop endometriosis.⁶

Two other plausible explanations are the coelomic metaplasia and embryonic rest theories. In the coelomic metaplasia theory, the mesothelium (coelomic epithelium)—which encases the ovaries—invaginates into the ovaries and undergoes a metaplastic change to endometrial tissue. This could explain the development of endometriosis in patients with the congenital malformation Müllerian agenesis. In the embryonic rest theory, Müllerian remnants in the rectovaginal area, left behind by the Müllerian duct system, have the potential to differentiate into endometrial tissue.^2,5,6,8

Another theory involving lymphatic or hematologic spread has been proposed, which would explain the presence of endometrial implants at sites distant from the uterus (eg, the pleural cavity and brain). However, this theory is not widely understood.⁶

The two most recent hypotheses on endometriosis are associated with an abnormal immune system and a possible genetic predisposition. The peritoneal fluid of women with endometriosis has different levels of prostanoids, cytokines, growth factors, and interleukins than that of women who do not have the condition. It is uncertain whether the relationship between peritoneal fluid changes and endometriosis is causal.⁶ A genetic correlation has been suggested, based on an increased prevalence of endometriosis in women with an affected first-degree relative; in a case-control study on family incidence of endometriosis, 5.9% to 9.6% of first-degree relatives and 1.3% of second-degree relatives were affected.⁹ The Oxford Endometriosis Gene (OXEGENE) study is currently investigating susceptible loci for endometriosis genes, which could provide a better understanding of the disease process.⁶

CLINICAL PRESENTATION

The most common symptoms of endometriosis are dysmenorrhea, deep dyspareunia, chronic pelvic pain, and infertility, but 20% to 25% of affected women are asymptomatic.^4,10,11 Pelvic pain in women most often heralds onset of menses and worsens during menstruation.¹ Other symptoms include back pain, dyschezia, dysuria, nausea, lethargy, and chronic fatigue.^4,8,10

Endometriosis is concomitant with infertility; endometrial adhesions that attach to pelvic organs cause distortion of pelvic structures and impaired ovum release and pick-up, and are believed to reduce fecundity. Additionally, women with endometriosis have low ovarian reserve and low-quality oocytes.^6,8 Altered chemical elements (ie, prostanoids, cytokines, growth factors, and interleukins) may also contribute to endometrial-related infertility; intrapelvic growth factors could affect the fallopian tubes or pelvic environment, and thus the oocytes in a similar fashion.⁶

In adolescents, endometriosis can present as cyclic or acyclic pain; severe dysmenorrhea; dysmenorrhea that responds poorly to medications (eg, oral contraceptive pills [OCPs] or NSAIDs); and prolonged menstruation with premenstrual spotting.¹

The physical exam may reveal tender nodules in the posterior vaginal fornix; cervical motion tenderness; a fixed uterus, cervix, or adnexa; uterine motion tenderness; thickening, pain, tenderness, or nodularity of the uterosacral ligament; or tender adnexal masses due to endometriomas.^8,10

PATHOLOGIC CHARACTERISTICS AND STAGING

Gross pathology of endometriosis varies based on duration of disease and depth of implants or lesions. Implants range from punctate foci to small stellate patches that vary in color but typically measure less than 2 cm. They manifest most commonly in the ovaries, followed by the anterior and posterior cul-de-sac, posterior broad ligament, and uterosacral ligament. Implants can also be located on the uterus, fallopian tubes, sigmoid colon, ureter, small intestine, lungs, and brain (see Figure).³

Due to recurrent cyclic hemorrhage within a deep implant, endometriomas typically appear in the ovaries, entirely replacing normal ovarian tissue. Endometriomas are composed of dark, thick, degenerated blood products that result in a brown cyst—hence their designation as chocolate cysts. Microscopically, they are comprised of endometrial glands, stroma, and sometimes smooth muscle.³

Staging of endometriosis is determined by the volume, depth, location, and size of the implants (see Table 1). It is important to note that staging does not necessarily reflect symptom severity.¹²

DIAGNOSIS

There are several approaches to the diagnostic evaluation of endometriosis, all of which should be guided by the clinical presentation and physical examination. Clinical characteristics can be nonspecific and highly variable, warranting more reliable diagnostic methods.

Laparoscopy is the diagnostic gold standard for endometriosis, and biopsy of implants revealing endometrial tissue is confirmatory. Less invasive diagnostic methods include ultrasound and MRI—but without confirmatory histologic sampling, these only yield a presumptive diagnosis.

With ultrasonography, a transvaginal approach should be taken. While endometriomas have a variety of presentations on ultrasound, most appear as a homogenous, hypoechoic, focal lesion within the ovary. MRI has greater specificity than ultrasound for diagnosis of endometriomas. However, “shading,” or loss of signal, within an endometrioma is a feature commonly found on MRI.³

Other tests that aid in the diagnosis, but are not definitive, include sedimentation rate and tumor marker CA-125. These are both commonly elevated in patients with endometriosis. Measurement of CA-125 is helpful for identifying patients with infertility and severe endometriosis, who would therefore benefit from early surgical intervention.⁸

TREATMENT

There is no permanent cure for endometriosis; treatment entails nonsurgical and surgical approaches to symptom resolution. Treatment is directed by the patient’s desire to maintain fertility.

Conservative treatment of pelvic pain with NSAIDs is a common approach. Progestins are also used to treat pelvic pain; they create an acyclic, hypo-estrogenic environment by blocking ovarian estrogen secretion and subsequent endometrial cell proliferation. In addition to alleviating pain, progestins also prevent disease recurrence after surgery.^2,13 Options include combination OCPs, levonorgestrel intrauterine devices, medroxyprogesterone acetate, and etonogestrel implants. Combination OCPs and medroxyprogesterone acetate are considered to be firstline treatment.⁸

Gonadotropin-releasing hormone agonists (GnRH-a), such as leuprolide acetate, and androgenic agents, such as danocrine, are also indicated for relief of pain resulting from biopsy-confirmed endometriosis. Danocrine has been shown to ameliorate pain in up to 92% of patients.^3,8 Other unconventional treatment modalities include aromatase inhibitors, selective estrogen receptor modulators, anti-inflammatory agents, and immunomodulators.² For an outline of the medication choices and their mechanisms of action, see Table 2.

Surgery, or ablation of the implants, is another viable treatment option; it can be performed via laparoscopy or laparotomy. Although the success rate is high, implants recur in 28% of patients 18 months after surgery and in 40% of patients after nine years; 40% to 50% of patients have adhesion recurrence.³

Patients who have concomitant infertility can be treated with advanced reproductive techniques, including intrauterine insemination and ovarian hyperstimulation. The monthly fecundity rate with such techniques is 9% to 18%.³ Laparoscopic surgery with ablation of endometrial implants may increase fertility in patients with endometriosis.⁸

Hysterectomy and bilateral salpingo-oophorectomy are definitive treatment options reserved for patients with intractable pain and those who do not wish to maintain fertility.^3,8 Recurrent symptoms occur in 10% of patients 10 years after hysterectomy with bilateral salpingectomy, compared with 62% of those who have hysterectomy alone.⁸ Complete surgical removal of endometriomas, and ovary if affected, can reduce risk for epithelial ovarian cancer in the future.²

COMPLICATIONS

Adhesions are a common complication of endometriosis. Ultrasound can be used for diagnosis and to determine whether pelvic organs are fixed (ie, fixed retroverted uterus). MRI may also be used; adhesions appear as “speculated low-signal-intensity stranding that obscures organ interfaces.”³ Other suggestive findings on MRI include posterior displacement of the pelvic organs, elevation of the posterior vaginal fornix, hydrosalpinx, loculated fluid collections, and angulated bowel loops.³

Malignant transformation is rare, affecting fewer than 1% of patients with endometriosis. Most malignancies arise from ovarian endometriosis and can be related to unopposed estrogen therapy; they are typically large and have a solid component. The most common endometriosis-related malignant neoplasm is endometrioid carcinoma, followed by clear-cell carcinoma.³

CONCLUSION

Patients with endometriosis often present with complaints such as dysmenorrhea, deep dyspareunia, and chronic pelvic pain, but surgical and histologic findings indicate that symptom severity does not necessarily equate to disease severity. Definitive diagnosis requires an invasive surgical procedure.

In the absence of a cure, endometriosis treatment focuses on symptom control and improvement in quality of life. Familiarity with the disease process and knowledge of treatment options will help health care providers achieve this goal for patients who experience the potentially life-altering effects of endometriosis.

IN THIS ARTICLE

• Staging endometriosis
• Medications for treating endometriosis
• Complications

Endometriosis is a gynecologic disorder characterized by the presence and growth of endometrial tissue outside the uterine cavity (ie, endometrial implants), most commonly found on the ovaries. Although its pathophysiology is not completely understood, the disease is associated with dysmenorrhea, dyspareunia, and infertility.^1,2 Endometriosis is an estrogen-dependent disorder, predominantly affecting women of childbearing age. It occurs in 10% to 15% of the general female population, but prevalence is even higher (35% to 50%) among women who experience pelvic pain and/or infertility.^1-4 Although endometriosis mainly affects women in their mid-to-late 20s, it can also manifest in adolescence.^3,5 Nearly half of all adolescents with intractable dysmenorrhea are diagnosed with endometriosis.⁵

ETIOLOGY

The etiology of endometriosis, while not completely understood, is likely multifactorial. Factors that may influence its development include gene expression, tissue response to hormones, neuronal tissue involvement, lack of protective factors, inflammation, and cellular oxidative stress.^6,7

Several theories regarding the etiology of endometriosis have been proposed; the most widely accepted is the transplantation theory, which suggests that endometriosis results from retrograde flow of menstrual tissue through the fallopian tubes. During menstruation, fragments of the endometrium are driven through the fallopian tubes and into the pelvic cavity, where they can implant onto the pelvic structures, leading to further growth and invasion.^2,6,8 Women who have polymenorrhea, prolonged menses, and early menarche therefore have an increased risk for endometriosis.⁸ This theory does not account for the fact that although nearly 90% of women have some elements of retrograde menstrual flow, only a fraction of them develop endometriosis.⁶

Two other plausible explanations are the coelomic metaplasia and embryonic rest theories. In the coelomic metaplasia theory, the mesothelium (coelomic epithelium)—which encases the ovaries—invaginates into the ovaries and undergoes a metaplastic change to endometrial tissue. This could explain the development of endometriosis in patients with the congenital malformation Müllerian agenesis. In the embryonic rest theory, Müllerian remnants in the rectovaginal area, left behind by the Müllerian duct system, have the potential to differentiate into endometrial tissue.^2,5,6,8

Another theory involving lymphatic or hematologic spread has been proposed, which would explain the presence of endometrial implants at sites distant from the uterus (eg, the pleural cavity and brain). However, this theory is not widely understood.⁶

The two most recent hypotheses on endometriosis are associated with an abnormal immune system and a possible genetic predisposition. The peritoneal fluid of women with endometriosis has different levels of prostanoids, cytokines, growth factors, and interleukins than that of women who do not have the condition. It is uncertain whether the relationship between peritoneal fluid changes and endometriosis is causal.⁶ A genetic correlation has been suggested, based on an increased prevalence of endometriosis in women with an affected first-degree relative; in a case-control study on family incidence of endometriosis, 5.9% to 9.6% of first-degree relatives and 1.3% of second-degree relatives were affected.⁹ The Oxford Endometriosis Gene (OXEGENE) study is currently investigating susceptible loci for endometriosis genes, which could provide a better understanding of the disease process.⁶

CLINICAL PRESENTATION

The most common symptoms of endometriosis are dysmenorrhea, deep dyspareunia, chronic pelvic pain, and infertility, but 20% to 25% of affected women are asymptomatic.^4,10,11 Pelvic pain in women most often heralds onset of menses and worsens during menstruation.¹ Other symptoms include back pain, dyschezia, dysuria, nausea, lethargy, and chronic fatigue.^4,8,10

Endometriosis is concomitant with infertility; endometrial adhesions that attach to pelvic organs cause distortion of pelvic structures and impaired ovum release and pick-up, and are believed to reduce fecundity. Additionally, women with endometriosis have low ovarian reserve and low-quality oocytes.^6,8 Altered chemical elements (ie, prostanoids, cytokines, growth factors, and interleukins) may also contribute to endometrial-related infertility; intrapelvic growth factors could affect the fallopian tubes or pelvic environment, and thus the oocytes in a similar fashion.⁶

In adolescents, endometriosis can present as cyclic or acyclic pain; severe dysmenorrhea; dysmenorrhea that responds poorly to medications (eg, oral contraceptive pills [OCPs] or NSAIDs); and prolonged menstruation with premenstrual spotting.¹

The physical exam may reveal tender nodules in the posterior vaginal fornix; cervical motion tenderness; a fixed uterus, cervix, or adnexa; uterine motion tenderness; thickening, pain, tenderness, or nodularity of the uterosacral ligament; or tender adnexal masses due to endometriomas.^8,10

PATHOLOGIC CHARACTERISTICS AND STAGING

Gross pathology of endometriosis varies based on duration of disease and depth of implants or lesions. Implants range from punctate foci to small stellate patches that vary in color but typically measure less than 2 cm. They manifest most commonly in the ovaries, followed by the anterior and posterior cul-de-sac, posterior broad ligament, and uterosacral ligament. Implants can also be located on the uterus, fallopian tubes, sigmoid colon, ureter, small intestine, lungs, and brain (see Figure).³

Due to recurrent cyclic hemorrhage within a deep implant, endometriomas typically appear in the ovaries, entirely replacing normal ovarian tissue. Endometriomas are composed of dark, thick, degenerated blood products that result in a brown cyst—hence their designation as chocolate cysts. Microscopically, they are comprised of endometrial glands, stroma, and sometimes smooth muscle.³

Staging of endometriosis is determined by the volume, depth, location, and size of the implants (see Table 1). It is important to note that staging does not necessarily reflect symptom severity.¹²

DIAGNOSIS

There are several approaches to the diagnostic evaluation of endometriosis, all of which should be guided by the clinical presentation and physical examination. Clinical characteristics can be nonspecific and highly variable, warranting more reliable diagnostic methods.

Laparoscopy is the diagnostic gold standard for endometriosis, and biopsy of implants revealing endometrial tissue is confirmatory. Less invasive diagnostic methods include ultrasound and MRI—but without confirmatory histologic sampling, these only yield a presumptive diagnosis.

With ultrasonography, a transvaginal approach should be taken. While endometriomas have a variety of presentations on ultrasound, most appear as a homogenous, hypoechoic, focal lesion within the ovary. MRI has greater specificity than ultrasound for diagnosis of endometriomas. However, “shading,” or loss of signal, within an endometrioma is a feature commonly found on MRI.³

Other tests that aid in the diagnosis, but are not definitive, include sedimentation rate and tumor marker CA-125. These are both commonly elevated in patients with endometriosis. Measurement of CA-125 is helpful for identifying patients with infertility and severe endometriosis, who would therefore benefit from early surgical intervention.⁸

TREATMENT

There is no permanent cure for endometriosis; treatment entails nonsurgical and surgical approaches to symptom resolution. Treatment is directed by the patient’s desire to maintain fertility.

Conservative treatment of pelvic pain with NSAIDs is a common approach. Progestins are also used to treat pelvic pain; they create an acyclic, hypo-estrogenic environment by blocking ovarian estrogen secretion and subsequent endometrial cell proliferation. In addition to alleviating pain, progestins also prevent disease recurrence after surgery.^2,13 Options include combination OCPs, levonorgestrel intrauterine devices, medroxyprogesterone acetate, and etonogestrel implants. Combination OCPs and medroxyprogesterone acetate are considered to be firstline treatment.⁸

Gonadotropin-releasing hormone agonists (GnRH-a), such as leuprolide acetate, and androgenic agents, such as danocrine, are also indicated for relief of pain resulting from biopsy-confirmed endometriosis. Danocrine has been shown to ameliorate pain in up to 92% of patients.^3,8 Other unconventional treatment modalities include aromatase inhibitors, selective estrogen receptor modulators, anti-inflammatory agents, and immunomodulators.² For an outline of the medication choices and their mechanisms of action, see Table 2.

Surgery, or ablation of the implants, is another viable treatment option; it can be performed via laparoscopy or laparotomy. Although the success rate is high, implants recur in 28% of patients 18 months after surgery and in 40% of patients after nine years; 40% to 50% of patients have adhesion recurrence.³

Patients who have concomitant infertility can be treated with advanced reproductive techniques, including intrauterine insemination and ovarian hyperstimulation. The monthly fecundity rate with such techniques is 9% to 18%.³ Laparoscopic surgery with ablation of endometrial implants may increase fertility in patients with endometriosis.⁸

Hysterectomy and bilateral salpingo-oophorectomy are definitive treatment options reserved for patients with intractable pain and those who do not wish to maintain fertility.^3,8 Recurrent symptoms occur in 10% of patients 10 years after hysterectomy with bilateral salpingectomy, compared with 62% of those who have hysterectomy alone.⁸ Complete surgical removal of endometriomas, and ovary if affected, can reduce risk for epithelial ovarian cancer in the future.²

COMPLICATIONS

Adhesions are a common complication of endometriosis. Ultrasound can be used for diagnosis and to determine whether pelvic organs are fixed (ie, fixed retroverted uterus). MRI may also be used; adhesions appear as “speculated low-signal-intensity stranding that obscures organ interfaces.”³ Other suggestive findings on MRI include posterior displacement of the pelvic organs, elevation of the posterior vaginal fornix, hydrosalpinx, loculated fluid collections, and angulated bowel loops.³

Malignant transformation is rare, affecting fewer than 1% of patients with endometriosis. Most malignancies arise from ovarian endometriosis and can be related to unopposed estrogen therapy; they are typically large and have a solid component. The most common endometriosis-related malignant neoplasm is endometrioid carcinoma, followed by clear-cell carcinoma.³

CONCLUSION

Patients with endometriosis often present with complaints such as dysmenorrhea, deep dyspareunia, and chronic pelvic pain, but surgical and histologic findings indicate that symptom severity does not necessarily equate to disease severity. Definitive diagnosis requires an invasive surgical procedure.

In the absence of a cure, endometriosis treatment focuses on symptom control and improvement in quality of life. Familiarity with the disease process and knowledge of treatment options will help health care providers achieve this goal for patients who experience the potentially life-altering effects of endometriosis.

IN THIS ARTICLE

• Staging endometriosis
• Medications for treating endometriosis
• Complications

Endometriosis is a gynecologic disorder characterized by the presence and growth of endometrial tissue outside the uterine cavity (ie, endometrial implants), most commonly found on the ovaries. Although its pathophysiology is not completely understood, the disease is associated with dysmenorrhea, dyspareunia, and infertility.^1,2 Endometriosis is an estrogen-dependent disorder, predominantly affecting women of childbearing age. It occurs in 10% to 15% of the general female population, but prevalence is even higher (35% to 50%) among women who experience pelvic pain and/or infertility.^1-4 Although endometriosis mainly affects women in their mid-to-late 20s, it can also manifest in adolescence.^3,5 Nearly half of all adolescents with intractable dysmenorrhea are diagnosed with endometriosis.⁵

ETIOLOGY

The etiology of endometriosis, while not completely understood, is likely multifactorial. Factors that may influence its development include gene expression, tissue response to hormones, neuronal tissue involvement, lack of protective factors, inflammation, and cellular oxidative stress.^6,7

Several theories regarding the etiology of endometriosis have been proposed; the most widely accepted is the transplantation theory, which suggests that endometriosis results from retrograde flow of menstrual tissue through the fallopian tubes. During menstruation, fragments of the endometrium are driven through the fallopian tubes and into the pelvic cavity, where they can implant onto the pelvic structures, leading to further growth and invasion.^2,6,8 Women who have polymenorrhea, prolonged menses, and early menarche therefore have an increased risk for endometriosis.⁸ This theory does not account for the fact that although nearly 90% of women have some elements of retrograde menstrual flow, only a fraction of them develop endometriosis.⁶

Two other plausible explanations are the coelomic metaplasia and embryonic rest theories. In the coelomic metaplasia theory, the mesothelium (coelomic epithelium)—which encases the ovaries—invaginates into the ovaries and undergoes a metaplastic change to endometrial tissue. This could explain the development of endometriosis in patients with the congenital malformation Müllerian agenesis. In the embryonic rest theory, Müllerian remnants in the rectovaginal area, left behind by the Müllerian duct system, have the potential to differentiate into endometrial tissue.^2,5,6,8

Another theory involving lymphatic or hematologic spread has been proposed, which would explain the presence of endometrial implants at sites distant from the uterus (eg, the pleural cavity and brain). However, this theory is not widely understood.⁶

The two most recent hypotheses on endometriosis are associated with an abnormal immune system and a possible genetic predisposition. The peritoneal fluid of women with endometriosis has different levels of prostanoids, cytokines, growth factors, and interleukins than that of women who do not have the condition. It is uncertain whether the relationship between peritoneal fluid changes and endometriosis is causal.⁶ A genetic correlation has been suggested, based on an increased prevalence of endometriosis in women with an affected first-degree relative; in a case-control study on family incidence of endometriosis, 5.9% to 9.6% of first-degree relatives and 1.3% of second-degree relatives were affected.⁹ The Oxford Endometriosis Gene (OXEGENE) study is currently investigating susceptible loci for endometriosis genes, which could provide a better understanding of the disease process.⁶

CLINICAL PRESENTATION

The most common symptoms of endometriosis are dysmenorrhea, deep dyspareunia, chronic pelvic pain, and infertility, but 20% to 25% of affected women are asymptomatic.^4,10,11 Pelvic pain in women most often heralds onset of menses and worsens during menstruation.¹ Other symptoms include back pain, dyschezia, dysuria, nausea, lethargy, and chronic fatigue.^4,8,10

Endometriosis is concomitant with infertility; endometrial adhesions that attach to pelvic organs cause distortion of pelvic structures and impaired ovum release and pick-up, and are believed to reduce fecundity. Additionally, women with endometriosis have low ovarian reserve and low-quality oocytes.^6,8 Altered chemical elements (ie, prostanoids, cytokines, growth factors, and interleukins) may also contribute to endometrial-related infertility; intrapelvic growth factors could affect the fallopian tubes or pelvic environment, and thus the oocytes in a similar fashion.⁶

In adolescents, endometriosis can present as cyclic or acyclic pain; severe dysmenorrhea; dysmenorrhea that responds poorly to medications (eg, oral contraceptive pills [OCPs] or NSAIDs); and prolonged menstruation with premenstrual spotting.¹

The physical exam may reveal tender nodules in the posterior vaginal fornix; cervical motion tenderness; a fixed uterus, cervix, or adnexa; uterine motion tenderness; thickening, pain, tenderness, or nodularity of the uterosacral ligament; or tender adnexal masses due to endometriomas.^8,10

PATHOLOGIC CHARACTERISTICS AND STAGING

Gross pathology of endometriosis varies based on duration of disease and depth of implants or lesions. Implants range from punctate foci to small stellate patches that vary in color but typically measure less than 2 cm. They manifest most commonly in the ovaries, followed by the anterior and posterior cul-de-sac, posterior broad ligament, and uterosacral ligament. Implants can also be located on the uterus, fallopian tubes, sigmoid colon, ureter, small intestine, lungs, and brain (see Figure).³

Due to recurrent cyclic hemorrhage within a deep implant, endometriomas typically appear in the ovaries, entirely replacing normal ovarian tissue. Endometriomas are composed of dark, thick, degenerated blood products that result in a brown cyst—hence their designation as chocolate cysts. Microscopically, they are comprised of endometrial glands, stroma, and sometimes smooth muscle.³

Staging of endometriosis is determined by the volume, depth, location, and size of the implants (see Table 1). It is important to note that staging does not necessarily reflect symptom severity.¹²

DIAGNOSIS

There are several approaches to the diagnostic evaluation of endometriosis, all of which should be guided by the clinical presentation and physical examination. Clinical characteristics can be nonspecific and highly variable, warranting more reliable diagnostic methods.

Laparoscopy is the diagnostic gold standard for endometriosis, and biopsy of implants revealing endometrial tissue is confirmatory. Less invasive diagnostic methods include ultrasound and MRI—but without confirmatory histologic sampling, these only yield a presumptive diagnosis.

With ultrasonography, a transvaginal approach should be taken. While endometriomas have a variety of presentations on ultrasound, most appear as a homogenous, hypoechoic, focal lesion within the ovary. MRI has greater specificity than ultrasound for diagnosis of endometriomas. However, “shading,” or loss of signal, within an endometrioma is a feature commonly found on MRI.³

Other tests that aid in the diagnosis, but are not definitive, include sedimentation rate and tumor marker CA-125. These are both commonly elevated in patients with endometriosis. Measurement of CA-125 is helpful for identifying patients with infertility and severe endometriosis, who would therefore benefit from early surgical intervention.⁸

TREATMENT

There is no permanent cure for endometriosis; treatment entails nonsurgical and surgical approaches to symptom resolution. Treatment is directed by the patient’s desire to maintain fertility.

Conservative treatment of pelvic pain with NSAIDs is a common approach. Progestins are also used to treat pelvic pain; they create an acyclic, hypo-estrogenic environment by blocking ovarian estrogen secretion and subsequent endometrial cell proliferation. In addition to alleviating pain, progestins also prevent disease recurrence after surgery.^2,13 Options include combination OCPs, levonorgestrel intrauterine devices, medroxyprogesterone acetate, and etonogestrel implants. Combination OCPs and medroxyprogesterone acetate are considered to be firstline treatment.⁸

Gonadotropin-releasing hormone agonists (GnRH-a), such as leuprolide acetate, and androgenic agents, such as danocrine, are also indicated for relief of pain resulting from biopsy-confirmed endometriosis. Danocrine has been shown to ameliorate pain in up to 92% of patients.^3,8 Other unconventional treatment modalities include aromatase inhibitors, selective estrogen receptor modulators, anti-inflammatory agents, and immunomodulators.² For an outline of the medication choices and their mechanisms of action, see Table 2.

Surgery, or ablation of the implants, is another viable treatment option; it can be performed via laparoscopy or laparotomy. Although the success rate is high, implants recur in 28% of patients 18 months after surgery and in 40% of patients after nine years; 40% to 50% of patients have adhesion recurrence.³

Patients who have concomitant infertility can be treated with advanced reproductive techniques, including intrauterine insemination and ovarian hyperstimulation. The monthly fecundity rate with such techniques is 9% to 18%.³ Laparoscopic surgery with ablation of endometrial implants may increase fertility in patients with endometriosis.⁸

Hysterectomy and bilateral salpingo-oophorectomy are definitive treatment options reserved for patients with intractable pain and those who do not wish to maintain fertility.^3,8 Recurrent symptoms occur in 10% of patients 10 years after hysterectomy with bilateral salpingectomy, compared with 62% of those who have hysterectomy alone.⁸ Complete surgical removal of endometriomas, and ovary if affected, can reduce risk for epithelial ovarian cancer in the future.²

COMPLICATIONS

Adhesions are a common complication of endometriosis. Ultrasound can be used for diagnosis and to determine whether pelvic organs are fixed (ie, fixed retroverted uterus). MRI may also be used; adhesions appear as “speculated low-signal-intensity stranding that obscures organ interfaces.”³ Other suggestive findings on MRI include posterior displacement of the pelvic organs, elevation of the posterior vaginal fornix, hydrosalpinx, loculated fluid collections, and angulated bowel loops.³

Malignant transformation is rare, affecting fewer than 1% of patients with endometriosis. Most malignancies arise from ovarian endometriosis and can be related to unopposed estrogen therapy; they are typically large and have a solid component. The most common endometriosis-related malignant neoplasm is endometrioid carcinoma, followed by clear-cell carcinoma.³

CONCLUSION

Patients with endometriosis often present with complaints such as dysmenorrhea, deep dyspareunia, and chronic pelvic pain, but surgical and histologic findings indicate that symptom severity does not necessarily equate to disease severity. Definitive diagnosis requires an invasive surgical procedure.

In the absence of a cure, endometriosis treatment focuses on symptom control and improvement in quality of life. Familiarity with the disease process and knowledge of treatment options will help health care providers achieve this goal for patients who experience the potentially life-altering effects of endometriosis.

Vaccination against human papillomavirus (HPV) infection and periodic cervical screening have significantly decreased the incidence of invasive cervical cancer. But cancers still exist despite the availability of these useful clinical tools, especially in women of reproductive age in developing regions of the world. In the 2016 update on cervical disease, I reviewed studies on 2 promising and novel immunotherapies for cervical cancer: HPV therapeutic vaccine and adoptive T-cell therapy. This year the focus is on remarkable advances in the field of genomics and related studies that are rapidly expanding our understanding of the molecular characteristics of cervical cancer. Rewards of this research already being explored include novel immunotherapeutic agents as well as the repurposed use of existing drugs.

But first, with regard to cervical screening and follow-up, 2 recent large studies have yielded findings that have important implications for patient management. One pertains to the monitoring of women who have persistent infection with high-risk HPV but cytology results that are negative. Its conclusion was unequivocal and very useful in the management of our patients. The other study tracked HPV screening performed every 3 years and reported on the diagnostic efficiency of this shorter interval screening strategy.

Read about persistent HPV infection and CIN

Persistent HPV infection has a higher risk than most clinicians might think

Elfgren K, Elfström KM, Naucler P, Arnheim-Dahlström L, Dillner J. Management of women with human papillomavirus persistence: long-term follow-up of a randomized clinical trial. Am J Obstet Gynecol. 2017;216(3):264.e1-e7.

It is well known that most cases of cervical cancer arise from persistent HPV infection, with the highest percentage of cancers caused by high-risk types 16 or 18. What has been uncertain, however, is the actual degree of risk that persistent infection confers over time for the development of cervical intraepithelial neoplasia (CIN) or worse when a woman's repeated cytology reports are negative. In an analysis of a long-term double-blind, randomized, controlled screening study, Elfgren and colleagues showed that all women whose HPV infection persisted up to 7 years developed CIN grade 2 (CIN2+), while those whose infection cleared in that period, or changed genotype, had no precancerous lesions out to 13 years of follow-up.

Related Article:
It is time for HPV vaccination to be considered part of routine preventive health care

Details of the study

Between 1997 and 2000, 12,527 Swedish women between the ages of 32 and 38 years who were undergoing organized cervical cancer screening agreed to participate in a 1:1-randomized prospective trial to determine the benefit of screening with HPV and cytology (intervention group) compared with cytology screening alone (control group). However, brush sampling for HPV was performed even on women in the control group, with the samples frozen for later testing. All participants were identified in the Swedish National Cervical Screening Registry.

Women in the intervention group who initially tested positive for HPV but whose cytology test results were negative (n = 341) were invited to return a year later for repeat HPV testing; 270 women returned and 119 had type-specific HPV persistence. Of those with persistent infection, 100 agreed to undergo colposcopy; 111 women from the control group were randomly selected to undergo sham HPV testing and colposcopy, and 95 attended. Women with evident cytologic abnormalities received treatment per protocol. Those with negative cytology results were offered annual HPV testing thereafter, and each follow-up with documented type-specific HPV persistence led to repeat colposcopy. A comparable number of women from the control group had repeat colposcopies.

Although some women were lost to clinical follow-up throughout the trial, all 195 who attended the first colposcopy were followed for at least 5 years in the Swedish registry, and 191 were followed in the registry for 13 years. Of 102 women with known HPV persistence at baseline (100 in the treatment group; 2 in the randomly selected control group), 31 became HPV negative, 4 evidenced a switch in HPV type but cleared the initial infection, 27 had unknown persistence status due to missed HPV tests, and 40 had continuously type-specific persistence. Of note, persistent HPV16 infection seemed to impart a higher risk of CIN development than did persistent HPV18 infection.

All 40 participants with clinically verified continuously persistent HPV infection developed CIN2+ within 7 years of baseline documentation of persistence (FIGURE 1). Among the 27 women with unknown persistence status, risk of CIN2+ occurrence within 7 years was 50%. None of the 35 women who cleared their infection or switched HPV type developed CIN2+.

Read about HPV-cytology cotesting

HPV−cytology cotesting every 3 years lowers population rates of cervical precancer and cancer

Silver MI, Schiffman M, Fetterman B, et al. The population impact of human papillomavirus/cytology cervical cotesting at 3-year intervals: reduced cervical cancer risk and decreased yield of precancer per screen. Cancer. 2016;122(23):3682−3686.

Current guidelines on screening for cervical cancer in women 30 to 65 years of age advise the preferred strategy of using cytology alone every 3 years or combining HPV testing and cytology every 5 years.¹ These guidelines, based on data available at the time they were written, were meant to offer a reasonable balance between timely detection of abnormalities and avoidance of potential harms from screening too frequently. However, many patients are reluctant to postpone repeat testing to the extent recommended. Several authorities have in fact asked that screening intervals be revisited, perhaps allowing for a range of strategies, contending that the level of protection once provided by annual screening should be the benchmark by which evolving strategies are judged.² Today, they point out, the risk of cancer doubles in the 3 years following an initial negative cytology result, and it also increases by lengthening the cotesting interval from 3 to 5 years. They additionally question the validity of using frequency of colposcopies as a surrogate to measure harms of screening, and suggest that many women would willingly accept the procedure's minimal discomfort and inconvenience to gain peace of mind.

The study by Silver and colleagues gives credence to considering a shorter cotesting interval. Since 2003, Kaiser Permanente Northern California (KPNC) has implemented 3-year cotesting. To determine actual clinical outcomes of cotesting at this interval, KPNC analyzed data on more than 1 million women in its care between 2003 and 2012. Although investigators expected that they might see decreasing efficiency in cotesting over time, they instead found an increased detection rate of precancerous lesions per woman screened in the larger of 2 study cohorts.

Related Article:
Women’s Preventive Services Initiative Guidelines provide consensus for practicing ObGyns

Details of the study

Included were all women 30 years of age or older enrolled in this study at KPNC between 2003 and 2012 who underwent HPV−cytology cotesting every 3 years. The population in its entirety (1,065,273 women) was deemed the "open cohort" and represented KPNC's total annual experience. A subset of this population, the "closed cohort," was designed to gauge the effect of repeated screening on a fixed population and comprised only those women enrolled and initially screened between 2003 and 2004 and then followed longitudinally until 2012.

For each cohort, investigators calculated the ratios of precancer and cancer diagnoses to the total number of cotests performed on the cohort's population. The 3-year testing periods were 2004−2006, 2007−2009, and 2010−2012. Also calculated in these periods were the ratios of colposcopic biopsies to cotests and the rates of precancer diagnoses (TABLE). 

In the open cohort, the biopsy rate nearly doubled over the course of the study. Precancer diagnoses per number of cotests rose by 71.5% between the first and second testing periods (P = .001) and then eased off by 10% in the third period (P<.001). These corresponding increases throughout the study yielded a stable number of biopsies (16 to 22) needed to detect precancer.

In the closed long-term cohort, the biopsy rate rose, but not as much as in the open cohort. Precancer diagnoses per number of cotests rose by 47% between the first and second periods (P≤.001), but in the third period fell back by 28% (P<.001) to a level just above the first period results. The number of biopsies needed to detect a precancerous lesion in the closed cohort rose from 19 to 33 over the course of the study, suggesting there may have been some loss of screening efficiency in the fixed group.

Read about molecular profiling of cervical cancer

Molecular profiling of cervical cancer is revolutionizing treatment

The Cancer Genome Atlas Research Network. Integratedgenomic and molecular characterization of cervical cancer. Nature. 2017;543(7645):378−384.

Effective treatments for cervical cancer could be close at hand, thanks to a recent explosion of knowledge at the molecular level about how specific cancers arise and what drives them other than HPV. The Cancer Genome Atlas Research Network (TCGA) recently published the results of its genomic and proteomic analyses, which yielded distinct profiles for 178 cervical cancers with important patterns common to other cancers, such as uterine and breast cancer. These recently published findings on cervical cancer highlight areas of gene and protein dysfunction it shares with these other cancers, which could open the doors for new targets for treatments already developed or in the pipeline.

Related Article:
2016 Update on cervical disease

How molecular profiling is paying off for cervical cancer

Cancers develop in any given tissue through the altered function of different genes and signaling pathways in the tissue's cells. The latest extensive investigation conducted by the TCGA network has identified significant mutations in 5 genes previously unrecognized in association with cervical cancer, bringing the total now to 14.

Several highlights are featured in the TCGA's recently published work. One discovery is the amplification of genes CD274 and PDCD1LG2, which are involved with the expression of 2 cytolytic effector genes and are therefore likely targets for immunotherapeutic strategies. Another line of exploration, whole-genome sequencing, has detected an aberration in some cervical cancer tissue with the potential for immediate application. Duplication and copy number gain of BCAR4, a noncoding RNA, facilitates cell proliferation through the HER2/HER3 pathway, a target of the tyrosine-kinase inhibitor, lapatinib, which is currently used to treat breast cancer.

The integration of data from multiple layers of analysis (FIGURE 2) is helping investigators identify variations in cancers. DNA methylation, for instance, is a means by which cells control gene expression. An analysis of this process in cervical tumor tissue has revealed additional cancer subgroups in which messenger RNA increases the transition of epithelial cells to invasive mesenchymal cells. Targeting that process in these subgroups would likely enhance the effectiveness of novel small-molecule inhibitors and some standard cytotoxic chemotherapy.  

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Vaccination against human papillomavirus (HPV) infection and periodic cervical screening have significantly decreased the incidence of invasive cervical cancer. But cancers still exist despite the availability of these useful clinical tools, especially in women of reproductive age in developing regions of the world. In the 2016 update on cervical disease, I reviewed studies on 2 promising and novel immunotherapies for cervical cancer: HPV therapeutic vaccine and adoptive T-cell therapy. This year the focus is on remarkable advances in the field of genomics and related studies that are rapidly expanding our understanding of the molecular characteristics of cervical cancer. Rewards of this research already being explored include novel immunotherapeutic agents as well as the repurposed use of existing drugs.

But first, with regard to cervical screening and follow-up, 2 recent large studies have yielded findings that have important implications for patient management. One pertains to the monitoring of women who have persistent infection with high-risk HPV but cytology results that are negative. Its conclusion was unequivocal and very useful in the management of our patients. The other study tracked HPV screening performed every 3 years and reported on the diagnostic efficiency of this shorter interval screening strategy.

Read about persistent HPV infection and CIN

Persistent HPV infection has a higher risk than most clinicians might think

Elfgren K, Elfström KM, Naucler P, Arnheim-Dahlström L, Dillner J. Management of women with human papillomavirus persistence: long-term follow-up of a randomized clinical trial. Am J Obstet Gynecol. 2017;216(3):264.e1-e7.

It is well known that most cases of cervical cancer arise from persistent HPV infection, with the highest percentage of cancers caused by high-risk types 16 or 18. What has been uncertain, however, is the actual degree of risk that persistent infection confers over time for the development of cervical intraepithelial neoplasia (CIN) or worse when a woman's repeated cytology reports are negative. In an analysis of a long-term double-blind, randomized, controlled screening study, Elfgren and colleagues showed that all women whose HPV infection persisted up to 7 years developed CIN grade 2 (CIN2+), while those whose infection cleared in that period, or changed genotype, had no precancerous lesions out to 13 years of follow-up.

Related Article:
It is time for HPV vaccination to be considered part of routine preventive health care

Details of the study

Between 1997 and 2000, 12,527 Swedish women between the ages of 32 and 38 years who were undergoing organized cervical cancer screening agreed to participate in a 1:1-randomized prospective trial to determine the benefit of screening with HPV and cytology (intervention group) compared with cytology screening alone (control group). However, brush sampling for HPV was performed even on women in the control group, with the samples frozen for later testing. All participants were identified in the Swedish National Cervical Screening Registry.

Women in the intervention group who initially tested positive for HPV but whose cytology test results were negative (n = 341) were invited to return a year later for repeat HPV testing; 270 women returned and 119 had type-specific HPV persistence. Of those with persistent infection, 100 agreed to undergo colposcopy; 111 women from the control group were randomly selected to undergo sham HPV testing and colposcopy, and 95 attended. Women with evident cytologic abnormalities received treatment per protocol. Those with negative cytology results were offered annual HPV testing thereafter, and each follow-up with documented type-specific HPV persistence led to repeat colposcopy. A comparable number of women from the control group had repeat colposcopies.

Although some women were lost to clinical follow-up throughout the trial, all 195 who attended the first colposcopy were followed for at least 5 years in the Swedish registry, and 191 were followed in the registry for 13 years. Of 102 women with known HPV persistence at baseline (100 in the treatment group; 2 in the randomly selected control group), 31 became HPV negative, 4 evidenced a switch in HPV type but cleared the initial infection, 27 had unknown persistence status due to missed HPV tests, and 40 had continuously type-specific persistence. Of note, persistent HPV16 infection seemed to impart a higher risk of CIN development than did persistent HPV18 infection.

All 40 participants with clinically verified continuously persistent HPV infection developed CIN2+ within 7 years of baseline documentation of persistence (FIGURE 1). Among the 27 women with unknown persistence status, risk of CIN2+ occurrence within 7 years was 50%. None of the 35 women who cleared their infection or switched HPV type developed CIN2+.

Read about HPV-cytology cotesting

HPV−cytology cotesting every 3 years lowers population rates of cervical precancer and cancer

Silver MI, Schiffman M, Fetterman B, et al. The population impact of human papillomavirus/cytology cervical cotesting at 3-year intervals: reduced cervical cancer risk and decreased yield of precancer per screen. Cancer. 2016;122(23):3682−3686.

Current guidelines on screening for cervical cancer in women 30 to 65 years of age advise the preferred strategy of using cytology alone every 3 years or combining HPV testing and cytology every 5 years.¹ These guidelines, based on data available at the time they were written, were meant to offer a reasonable balance between timely detection of abnormalities and avoidance of potential harms from screening too frequently. However, many patients are reluctant to postpone repeat testing to the extent recommended. Several authorities have in fact asked that screening intervals be revisited, perhaps allowing for a range of strategies, contending that the level of protection once provided by annual screening should be the benchmark by which evolving strategies are judged.² Today, they point out, the risk of cancer doubles in the 3 years following an initial negative cytology result, and it also increases by lengthening the cotesting interval from 3 to 5 years. They additionally question the validity of using frequency of colposcopies as a surrogate to measure harms of screening, and suggest that many women would willingly accept the procedure's minimal discomfort and inconvenience to gain peace of mind.

The study by Silver and colleagues gives credence to considering a shorter cotesting interval. Since 2003, Kaiser Permanente Northern California (KPNC) has implemented 3-year cotesting. To determine actual clinical outcomes of cotesting at this interval, KPNC analyzed data on more than 1 million women in its care between 2003 and 2012. Although investigators expected that they might see decreasing efficiency in cotesting over time, they instead found an increased detection rate of precancerous lesions per woman screened in the larger of 2 study cohorts.

Related Article:
Women’s Preventive Services Initiative Guidelines provide consensus for practicing ObGyns

Details of the study

Included were all women 30 years of age or older enrolled in this study at KPNC between 2003 and 2012 who underwent HPV−cytology cotesting every 3 years. The population in its entirety (1,065,273 women) was deemed the "open cohort" and represented KPNC's total annual experience. A subset of this population, the "closed cohort," was designed to gauge the effect of repeated screening on a fixed population and comprised only those women enrolled and initially screened between 2003 and 2004 and then followed longitudinally until 2012.

For each cohort, investigators calculated the ratios of precancer and cancer diagnoses to the total number of cotests performed on the cohort's population. The 3-year testing periods were 2004−2006, 2007−2009, and 2010−2012. Also calculated in these periods were the ratios of colposcopic biopsies to cotests and the rates of precancer diagnoses (TABLE). 

In the open cohort, the biopsy rate nearly doubled over the course of the study. Precancer diagnoses per number of cotests rose by 71.5% between the first and second testing periods (P = .001) and then eased off by 10% in the third period (P<.001). These corresponding increases throughout the study yielded a stable number of biopsies (16 to 22) needed to detect precancer.

In the closed long-term cohort, the biopsy rate rose, but not as much as in the open cohort. Precancer diagnoses per number of cotests rose by 47% between the first and second periods (P≤.001), but in the third period fell back by 28% (P<.001) to a level just above the first period results. The number of biopsies needed to detect a precancerous lesion in the closed cohort rose from 19 to 33 over the course of the study, suggesting there may have been some loss of screening efficiency in the fixed group.

Read about molecular profiling of cervical cancer

Molecular profiling of cervical cancer is revolutionizing treatment

The Cancer Genome Atlas Research Network. Integratedgenomic and molecular characterization of cervical cancer. Nature. 2017;543(7645):378−384.

Effective treatments for cervical cancer could be close at hand, thanks to a recent explosion of knowledge at the molecular level about how specific cancers arise and what drives them other than HPV. The Cancer Genome Atlas Research Network (TCGA) recently published the results of its genomic and proteomic analyses, which yielded distinct profiles for 178 cervical cancers with important patterns common to other cancers, such as uterine and breast cancer. These recently published findings on cervical cancer highlight areas of gene and protein dysfunction it shares with these other cancers, which could open the doors for new targets for treatments already developed or in the pipeline.

Related Article:
2016 Update on cervical disease

How molecular profiling is paying off for cervical cancer

Cancers develop in any given tissue through the altered function of different genes and signaling pathways in the tissue's cells. The latest extensive investigation conducted by the TCGA network has identified significant mutations in 5 genes previously unrecognized in association with cervical cancer, bringing the total now to 14.

Several highlights are featured in the TCGA's recently published work. One discovery is the amplification of genes CD274 and PDCD1LG2, which are involved with the expression of 2 cytolytic effector genes and are therefore likely targets for immunotherapeutic strategies. Another line of exploration, whole-genome sequencing, has detected an aberration in some cervical cancer tissue with the potential for immediate application. Duplication and copy number gain of BCAR4, a noncoding RNA, facilitates cell proliferation through the HER2/HER3 pathway, a target of the tyrosine-kinase inhibitor, lapatinib, which is currently used to treat breast cancer.

The integration of data from multiple layers of analysis (FIGURE 2) is helping investigators identify variations in cancers. DNA methylation, for instance, is a means by which cells control gene expression. An analysis of this process in cervical tumor tissue has revealed additional cancer subgroups in which messenger RNA increases the transition of epithelial cells to invasive mesenchymal cells. Targeting that process in these subgroups would likely enhance the effectiveness of novel small-molecule inhibitors and some standard cytotoxic chemotherapy.  

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Vaccination against human papillomavirus (HPV) infection and periodic cervical screening have significantly decreased the incidence of invasive cervical cancer. But cancers still exist despite the availability of these useful clinical tools, especially in women of reproductive age in developing regions of the world. In the 2016 update on cervical disease, I reviewed studies on 2 promising and novel immunotherapies for cervical cancer: HPV therapeutic vaccine and adoptive T-cell therapy. This year the focus is on remarkable advances in the field of genomics and related studies that are rapidly expanding our understanding of the molecular characteristics of cervical cancer. Rewards of this research already being explored include novel immunotherapeutic agents as well as the repurposed use of existing drugs.

But first, with regard to cervical screening and follow-up, 2 recent large studies have yielded findings that have important implications for patient management. One pertains to the monitoring of women who have persistent infection with high-risk HPV but cytology results that are negative. Its conclusion was unequivocal and very useful in the management of our patients. The other study tracked HPV screening performed every 3 years and reported on the diagnostic efficiency of this shorter interval screening strategy.

Read about persistent HPV infection and CIN

Persistent HPV infection has a higher risk than most clinicians might think

Elfgren K, Elfström KM, Naucler P, Arnheim-Dahlström L, Dillner J. Management of women with human papillomavirus persistence: long-term follow-up of a randomized clinical trial. Am J Obstet Gynecol. 2017;216(3):264.e1-e7.

It is well known that most cases of cervical cancer arise from persistent HPV infection, with the highest percentage of cancers caused by high-risk types 16 or 18. What has been uncertain, however, is the actual degree of risk that persistent infection confers over time for the development of cervical intraepithelial neoplasia (CIN) or worse when a woman's repeated cytology reports are negative. In an analysis of a long-term double-blind, randomized, controlled screening study, Elfgren and colleagues showed that all women whose HPV infection persisted up to 7 years developed CIN grade 2 (CIN2+), while those whose infection cleared in that period, or changed genotype, had no precancerous lesions out to 13 years of follow-up.

Related Article:
It is time for HPV vaccination to be considered part of routine preventive health care

Details of the study

Between 1997 and 2000, 12,527 Swedish women between the ages of 32 and 38 years who were undergoing organized cervical cancer screening agreed to participate in a 1:1-randomized prospective trial to determine the benefit of screening with HPV and cytology (intervention group) compared with cytology screening alone (control group). However, brush sampling for HPV was performed even on women in the control group, with the samples frozen for later testing. All participants were identified in the Swedish National Cervical Screening Registry.

Women in the intervention group who initially tested positive for HPV but whose cytology test results were negative (n = 341) were invited to return a year later for repeat HPV testing; 270 women returned and 119 had type-specific HPV persistence. Of those with persistent infection, 100 agreed to undergo colposcopy; 111 women from the control group were randomly selected to undergo sham HPV testing and colposcopy, and 95 attended. Women with evident cytologic abnormalities received treatment per protocol. Those with negative cytology results were offered annual HPV testing thereafter, and each follow-up with documented type-specific HPV persistence led to repeat colposcopy. A comparable number of women from the control group had repeat colposcopies.

Although some women were lost to clinical follow-up throughout the trial, all 195 who attended the first colposcopy were followed for at least 5 years in the Swedish registry, and 191 were followed in the registry for 13 years. Of 102 women with known HPV persistence at baseline (100 in the treatment group; 2 in the randomly selected control group), 31 became HPV negative, 4 evidenced a switch in HPV type but cleared the initial infection, 27 had unknown persistence status due to missed HPV tests, and 40 had continuously type-specific persistence. Of note, persistent HPV16 infection seemed to impart a higher risk of CIN development than did persistent HPV18 infection.

All 40 participants with clinically verified continuously persistent HPV infection developed CIN2+ within 7 years of baseline documentation of persistence (FIGURE 1). Among the 27 women with unknown persistence status, risk of CIN2+ occurrence within 7 years was 50%. None of the 35 women who cleared their infection or switched HPV type developed CIN2+.

Read about HPV-cytology cotesting

HPV−cytology cotesting every 3 years lowers population rates of cervical precancer and cancer

Silver MI, Schiffman M, Fetterman B, et al. The population impact of human papillomavirus/cytology cervical cotesting at 3-year intervals: reduced cervical cancer risk and decreased yield of precancer per screen. Cancer. 2016;122(23):3682−3686.

Current guidelines on screening for cervical cancer in women 30 to 65 years of age advise the preferred strategy of using cytology alone every 3 years or combining HPV testing and cytology every 5 years.¹ These guidelines, based on data available at the time they were written, were meant to offer a reasonable balance between timely detection of abnormalities and avoidance of potential harms from screening too frequently. However, many patients are reluctant to postpone repeat testing to the extent recommended. Several authorities have in fact asked that screening intervals be revisited, perhaps allowing for a range of strategies, contending that the level of protection once provided by annual screening should be the benchmark by which evolving strategies are judged.² Today, they point out, the risk of cancer doubles in the 3 years following an initial negative cytology result, and it also increases by lengthening the cotesting interval from 3 to 5 years. They additionally question the validity of using frequency of colposcopies as a surrogate to measure harms of screening, and suggest that many women would willingly accept the procedure's minimal discomfort and inconvenience to gain peace of mind.

The study by Silver and colleagues gives credence to considering a shorter cotesting interval. Since 2003, Kaiser Permanente Northern California (KPNC) has implemented 3-year cotesting. To determine actual clinical outcomes of cotesting at this interval, KPNC analyzed data on more than 1 million women in its care between 2003 and 2012. Although investigators expected that they might see decreasing efficiency in cotesting over time, they instead found an increased detection rate of precancerous lesions per woman screened in the larger of 2 study cohorts.

Related Article:
Women’s Preventive Services Initiative Guidelines provide consensus for practicing ObGyns

Details of the study

Included were all women 30 years of age or older enrolled in this study at KPNC between 2003 and 2012 who underwent HPV−cytology cotesting every 3 years. The population in its entirety (1,065,273 women) was deemed the "open cohort" and represented KPNC's total annual experience. A subset of this population, the "closed cohort," was designed to gauge the effect of repeated screening on a fixed population and comprised only those women enrolled and initially screened between 2003 and 2004 and then followed longitudinally until 2012.

For each cohort, investigators calculated the ratios of precancer and cancer diagnoses to the total number of cotests performed on the cohort's population. The 3-year testing periods were 2004−2006, 2007−2009, and 2010−2012. Also calculated in these periods were the ratios of colposcopic biopsies to cotests and the rates of precancer diagnoses (TABLE). 

In the open cohort, the biopsy rate nearly doubled over the course of the study. Precancer diagnoses per number of cotests rose by 71.5% between the first and second testing periods (P = .001) and then eased off by 10% in the third period (P<.001). These corresponding increases throughout the study yielded a stable number of biopsies (16 to 22) needed to detect precancer.

In the closed long-term cohort, the biopsy rate rose, but not as much as in the open cohort. Precancer diagnoses per number of cotests rose by 47% between the first and second periods (P≤.001), but in the third period fell back by 28% (P<.001) to a level just above the first period results. The number of biopsies needed to detect a precancerous lesion in the closed cohort rose from 19 to 33 over the course of the study, suggesting there may have been some loss of screening efficiency in the fixed group.

Read about molecular profiling of cervical cancer

Molecular profiling of cervical cancer is revolutionizing treatment

The Cancer Genome Atlas Research Network. Integratedgenomic and molecular characterization of cervical cancer. Nature. 2017;543(7645):378−384.

Effective treatments for cervical cancer could be close at hand, thanks to a recent explosion of knowledge at the molecular level about how specific cancers arise and what drives them other than HPV. The Cancer Genome Atlas Research Network (TCGA) recently published the results of its genomic and proteomic analyses, which yielded distinct profiles for 178 cervical cancers with important patterns common to other cancers, such as uterine and breast cancer. These recently published findings on cervical cancer highlight areas of gene and protein dysfunction it shares with these other cancers, which could open the doors for new targets for treatments already developed or in the pipeline.

Related Article:
2016 Update on cervical disease

How molecular profiling is paying off for cervical cancer

Cancers develop in any given tissue through the altered function of different genes and signaling pathways in the tissue's cells. The latest extensive investigation conducted by the TCGA network has identified significant mutations in 5 genes previously unrecognized in association with cervical cancer, bringing the total now to 14.

Several highlights are featured in the TCGA's recently published work. One discovery is the amplification of genes CD274 and PDCD1LG2, which are involved with the expression of 2 cytolytic effector genes and are therefore likely targets for immunotherapeutic strategies. Another line of exploration, whole-genome sequencing, has detected an aberration in some cervical cancer tissue with the potential for immediate application. Duplication and copy number gain of BCAR4, a noncoding RNA, facilitates cell proliferation through the HER2/HER3 pathway, a target of the tyrosine-kinase inhibitor, lapatinib, which is currently used to treat breast cancer.

The integration of data from multiple layers of analysis (FIGURE 2) is helping investigators identify variations in cancers. DNA methylation, for instance, is a means by which cells control gene expression. An analysis of this process in cervical tumor tissue has revealed additional cancer subgroups in which messenger RNA increases the transition of epithelial cells to invasive mesenchymal cells. Targeting that process in these subgroups would likely enhance the effectiveness of novel small-molecule inhibitors and some standard cytotoxic chemotherapy.  

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Case

An 85-year-old right-handed woman who recently had been diagnosed with mild cognitive impairment arrived at the ED via emergency medical services (EMS) for evaluation of a reported fall. She was accompanied by her daughter, who resided with the patient and was her primary caregiver. The patient stated that she had tripped on a wet rug in the bathroom of her home, striking her head and face on the edge of the sink without losing consciousness. Her daughter reported that she was not assisting her mother when the fall occurred, but had witnessed the fall from the hallway and called EMS. At the patient’s home, EMS found the patient to be alert, oriented, and ambulatory with normal vital signs that remained stable throughout prehospital transport.

The remainder of the patient’s history was provided almost entirely by her daughter, who constantly interrupted her mother whenever she attempted to directly answer a question or provide information. On physical examination, the patient had bilateral tenderness, edema, and periorbital ecchymoses, and a left eye that was nearly swollen shut. Extraocular movements were normal, visual acuity was intact, and sclerae were noninjected. The patient had tenderness over both maxillary sinuses, and edema and ecchymosis of her left cheek. There was also tenderness, ecchymoses, and edema on the lateral aspects of both forearms, and decreased range of motion of her right lower arm and wrist. With the exception of the patient not knowing the date during the orientation part of the thorough neurological examination, the remainder of the physical examination was unremarkable.

Radiological evaluation found no evidence of traumatic brain injury, but did reveal an acute fracture of the left zygomatic arch, an acute displaced nasal bone fracture, an age-indeterminate fracture of the right zygomatic arch, and an acute right ulnar fracture. Considering all of these findings, particularly the pattern of acute injuries, the emergency physician (EP) considered elder abuse as the possible etiology of the patient’s acute and chronic injuries.

Although the patient had initially agreed with her daughter’s description of the events—including her claim that she had fallen—when the EP questioned the patient alone, she related a history of frequent verbal and less frequent physical abuse by her daughter. The patient further noted that immediately before sustaining the injuries that brought her to the ED, her daughter had been insisting that she sign documents to give her control of her banking and finances. After refusing to sign the papers, the patient said that she and her daughter got into an argument, which she noted “they tended to do frequently.” The patient admitted that during this argument, her daughter struck her in the face repeatedly with the cane that the daughter had grabbed with her right hand.

The EP admitted the patient to the hospital for management of her orthopedic injuries and related pain, and to formulate a safe discharge plan. During admission, additional diagnostic testing revealed multiple old rib fractures, anemia, and a low-serum albumin, which suggested poor nutritional status.

Epidemiology

The term elder abuse refers to harm or the risk of harm to an older adult from either action or negligence committed by someone in a relationship of trust, or when a victim has been targeted because of age or disability. Elder abuse encompasses physical, sexual, or psychological abuse, neglect, and financial exploitation.^1-5 Identified victims of elder abuse typically suffer from multiple forms of abuse.^1-5

At present, elder abuse annually affects 5% to 10% of community-dwelling older adults,^1-6 and nursing-home residents are at increased risk of abuse.^7-10 Poor medical outcomes, including depression and dementia,¹¹ and much higher mortality^6,12,13 have been linked to victims of elder abuse.

Etiology

When treating older adults, it is critically important for EPs and the ED staff to consider and identify elder abuse in the differential diagnosis.^14,15 Presently, only an estimated 1 in 24 cases of abuse is recognized and reported to the authorities,² and much of the subsequent morbidity and mortality of elder abuse results from poor detection. A visit to the ED for an acute injury or illness may be the only time socially isolated older adults leave their homes.^15-17 Additionally, the ED setting is uniquely suited to identify mistreatment, as a patient typically may be evaluated for several hours by providers from multiple disciplines who are able to observe, interact with, and examine the patient.¹⁵ The ED already exercises a similar essential role in the identification and initial intervention for both child abuse^18,19 and intimate partner violence among younger adults.^20,21

Recognition

Unfortunately, at present, ED providers rarely recognize and report elder abuse.^22-24 Though the reasons for this are not entirely understood, inadequate training, lack of time and space to conduct complete evaluations, reluctance to become involved with the legal system, and challenges to distinguishing intentional from unintentional injuries may be contributing factors.^24,25 A focus on improving EP and ED staff approaches to elder abuse is relevant and timely given the growing elderly population.

Risk Factors

When evaluating elderly patients, providers should consider research suggesting that some older adults may be at particularly high risk for abuse.^4,26-29 Notably, individuals who have cognitive impairment are more likely to be victims of abuse.^30-32 Health-related demographic characteristics such as poor physical and mental health, substance abuse, low income/socioeconomic status, and social isolation all may increase the potential for mistreatment.

Family History

Similar to situations resulting in intimate partner violence, a family history of abuse and exposure to traumatic events may increase risk, and those responsible for elder abuse often turn out to be spouses, romantic partners, or an adult child living with the elderly parent—though paid caregivers also can be abusive.

Suspicion of abuse should be increased when individuals in caregiving roles have a history or show signs of mental illness, substance abuse, financial dependence on the victim, or caregiver stress. Considering that a caregiver may be overwhelmed is particularly relevant when an elderly patient exhibits behavioral issues.

Medical History

Obtaining a clear and thorough medical history from the patient and caregiver, both together and alone, is paramount to assessing the potential for abuse. Many indicators from the history may suggest the possibility of mistreatment (Table 1)^33-37 and although challenging in a busy ED, a comprehensive head-to-toe examination is crucial to adequately assess abuse. Suspicious physical findings and injury patterns of physical abuse, sexual abuse, and neglect are listed in Table 2.^33-37 Ongoing research is aimed at improving ED providers’ ability to differentiate accidental injuries, such as fall injuries, from injuries caused by physical elder abuse.

Injury Patterns

Preliminary studies have indicated that physical abuse injuries most commonly occur on the head, neck, and upper extremities.^38,39 A study comparing abuse victims to accidental injury sufferers found that abuse victims often had large bruises (>5 cm) on the face, lateral right arm, or posterior torso.⁴⁰ Preliminary results from a study in progress suggest that injuries to the left periorbital area, neck, and ulnar forearm may be much more common in abuse than in accident.

Imaging Studies

Emergency radiologists are contributing additional concerning findings indicative of elder abuse,^38,41,42 such as the concomitant presence of old and new fractures, high-energy fractures inconsistent with the purported mechanism, and distal ulnar diaphyseal fractures.^41,42 The ultimate goal is to identify pathognomonic injury patterns similar to those found in child abuse cases, to assist ED providers.

Laboratory Studies

Although there are no laboratory tests to definitively identify abuse or neglect, specific findings that may indicate abuse include anemia, dehydration, malnutrition, hypothermia/hyperthermia, and rhabdomyolysis.⁴³ In addition, inappropriately high- or low-medication levels and the presence of illicit drugs, which are not often checked in elderly patients in the ED, may be a sign of abuse.⁴³

Laboratory studies that reveal undetectable levels of a patient’s prescription medications may indicate a caregiver’s intentional or neglectful withholding of such medications—especially diversion of opioid medications prescribed for painful conditions.⁴³ Likewise, elevated levels of prescribed drugs may point to intentional or unintentional overdose, whereas the presence of nonprescribed drugs or toxins may suggest poisoning.⁴³

Screening Tools

To improve identification of elder abuse in the ED, universal or targeted screening tools are under consideration. Though several screening tools for elder abuse are already available, none have been validated in the ED.^15,44,45 Research sponsored by the National Institute of Justice to identify an ED-specific screening tool is ongoing.¹⁵

Elder Abuse Suspicion Index

The Elder Abuse Suspicion Index (EASI) is a short screening tool that has been validated for cognitively intact patients being treated in family practice and ambulatory care settings, and may be used in EDs.⁴⁴ The tool comprises six questions: five for patient response, and a sixth question for clinician response. This tool is available at http://www.nicenet.ca/tools-easi-elder-abuse-suspicion-index.⁴⁶

Interventional Measures

When elder mistreatment is suspected or confirmed, health care providers must first address any acute medical, traumatic, or psychological issues. Bleeding, orthopedic injuries, metabolic abnormalities, infections, and agitation must be treated and/or stabilized, while neglected or inappropriately managed chronic medical conditions may require treatment.

Hospitalization should be considered for an older adult who needs extended treatment or observation and, in cases of immediate or continued danger of abuse, separation from contact with the suspected abuser. These measures present several challenges, particularly if the suspected abuser is the patient’s health care proxy, in which case early involvement of the hospital’s legal department, social services, and administration may be necessary—especially in navigating the guardianship process.

Engaging security also may be necessary if the patient requires one-to-one patient watch or when the perpetrator must be removed from the ED. Social workers, patient services representatives, and law enforcement officials should be informed when such intervention is necessary.

In instances when a patient is not at risk of immediate harm, interventions can be more individualized. Coordination with primary care physicians (PCPs) must also be facilitated prior to discharge, to ensure consistent longitudinal follow-up care, and social workers should provide any needed out-of-hospital resources to the patient—and caregiver—such as Meals-on-Wheels, medical transportation services, adult day care/senior center participation, and substance abuse treatment.

Patient Decision-Making Capacity

When a patient experiencing abuse declines interventions or services, the EP must evaluate the patient’s decision-making capacity. In unclear cases, a psychiatric evaluation can help to assess decision-making capacity. If the victim is deemed to have capacity with regard to care and/or discharge, the patient’s choice of returning to an unsafe environment must be respected, as is true in instances of intimate partner violence among younger adults—but not in child abuse cases. In such situations, the EP should nevertheless discuss safety planning, offer psychoeducation about violence and abuse, suggest appropriate community referrals, and encourage abused patients to return or call a contact person whenever they desire or feel the need to talk further. For a victim who is deemed not to possess capacity, providers should proceed with treatment considered to be in the best interest of the patient.

Reporting Abuse

Emergency department providers should notify the appropriate authorities when elder abuse is suspected or identified. A report may be made to the local Adult Protective Services (APS), but this agency operates much differently than Child Protective Services. Case workers with APS will not open a case while a patient is in the ED or hospital, as it is deemed a safe environment and any investigation they undertake will only commence upon discharge. Because of this, contacting the local police department prior to discharge should be considered.

Mandatory elder abuse-reporting laws vary from state to state. Health care providers should therefore contact their respective state or city department of health to obtain local legislation.

Multidisciplinary Approach

Ideally, a multidisciplinary, ED-based intervention team modeled on child abuse teams^18,19 would help to optimize treatment and ensure the safety and treatment of vulnerable older adults. These teams could conduct thorough medical, forensic, and social work assessments, allowing ED providers to attend to other patients. The team could also assist in arranging for appropriate and safe dispositions. An innovative Vulnerable Elder Protection Team was recently launched at New York-Presbyterian Weill Cornell Medical Center to provide these services, and its impact is currently being evaluated.

Case Conclusion

The EP who treated the patient realized that blows from a blunt object held by a right-handed person would tend to land on the left side of the victim’s face and upper torso, and that a right-handed victim who successfully blocked the blows intended for her face would instead sustain an isolated right ulna or radius midshaft fracture. These findings, together with the concomitant presence of both old and new fractures, led the EP to question the patient alone and, after obtaining a different history of the events that led to the injuries, admit her for further evaluation, treatment, and interventions to prevent continuing abuse.

Summary

Elder abuse has the potential to affect an increasing number of older adults in this growing population, and an ED visit may offer the only opportunity to identify victims and provide intervention, in turn reducing morbidity and mortality. The results of ongoing research will improve the ability of EPs and ED staff to accurately assess the presence or risk of elder abuse and respond more effectively. It is essential that EPs always consider elder abuse and neglect as a possible etiology when evaluating injuries in this population. Moreover, when identified, addressing elder mistreatment may dramatically improve quality of life or save the lives of these vulnerable patients.


Case

An 85-year-old right-handed woman who recently had been diagnosed with mild cognitive impairment arrived at the ED via emergency medical services (EMS) for evaluation of a reported fall. She was accompanied by her daughter, who resided with the patient and was her primary caregiver. The patient stated that she had tripped on a wet rug in the bathroom of her home, striking her head and face on the edge of the sink without losing consciousness. Her daughter reported that she was not assisting her mother when the fall occurred, but had witnessed the fall from the hallway and called EMS. At the patient’s home, EMS found the patient to be alert, oriented, and ambulatory with normal vital signs that remained stable throughout prehospital transport.

The remainder of the patient’s history was provided almost entirely by her daughter, who constantly interrupted her mother whenever she attempted to directly answer a question or provide information. On physical examination, the patient had bilateral tenderness, edema, and periorbital ecchymoses, and a left eye that was nearly swollen shut. Extraocular movements were normal, visual acuity was intact, and sclerae were noninjected. The patient had tenderness over both maxillary sinuses, and edema and ecchymosis of her left cheek. There was also tenderness, ecchymoses, and edema on the lateral aspects of both forearms, and decreased range of motion of her right lower arm and wrist. With the exception of the patient not knowing the date during the orientation part of the thorough neurological examination, the remainder of the physical examination was unremarkable.

Radiological evaluation found no evidence of traumatic brain injury, but did reveal an acute fracture of the left zygomatic arch, an acute displaced nasal bone fracture, an age-indeterminate fracture of the right zygomatic arch, and an acute right ulnar fracture. Considering all of these findings, particularly the pattern of acute injuries, the emergency physician (EP) considered elder abuse as the possible etiology of the patient’s acute and chronic injuries.

Although the patient had initially agreed with her daughter’s description of the events—including her claim that she had fallen—when the EP questioned the patient alone, she related a history of frequent verbal and less frequent physical abuse by her daughter. The patient further noted that immediately before sustaining the injuries that brought her to the ED, her daughter had been insisting that she sign documents to give her control of her banking and finances. After refusing to sign the papers, the patient said that she and her daughter got into an argument, which she noted “they tended to do frequently.” The patient admitted that during this argument, her daughter struck her in the face repeatedly with the cane that the daughter had grabbed with her right hand.

The EP admitted the patient to the hospital for management of her orthopedic injuries and related pain, and to formulate a safe discharge plan. During admission, additional diagnostic testing revealed multiple old rib fractures, anemia, and a low-serum albumin, which suggested poor nutritional status.

Epidemiology

The term elder abuse refers to harm or the risk of harm to an older adult from either action or negligence committed by someone in a relationship of trust, or when a victim has been targeted because of age or disability. Elder abuse encompasses physical, sexual, or psychological abuse, neglect, and financial exploitation.^1-5 Identified victims of elder abuse typically suffer from multiple forms of abuse.^1-5

At present, elder abuse annually affects 5% to 10% of community-dwelling older adults,^1-6 and nursing-home residents are at increased risk of abuse.^7-10 Poor medical outcomes, including depression and dementia,¹¹ and much higher mortality^6,12,13 have been linked to victims of elder abuse.

Etiology

When treating older adults, it is critically important for EPs and the ED staff to consider and identify elder abuse in the differential diagnosis.^14,15 Presently, only an estimated 1 in 24 cases of abuse is recognized and reported to the authorities,² and much of the subsequent morbidity and mortality of elder abuse results from poor detection. A visit to the ED for an acute injury or illness may be the only time socially isolated older adults leave their homes.^15-17 Additionally, the ED setting is uniquely suited to identify mistreatment, as a patient typically may be evaluated for several hours by providers from multiple disciplines who are able to observe, interact with, and examine the patient.¹⁵ The ED already exercises a similar essential role in the identification and initial intervention for both child abuse^18,19 and intimate partner violence among younger adults.^20,21

Recognition

Unfortunately, at present, ED providers rarely recognize and report elder abuse.^22-24 Though the reasons for this are not entirely understood, inadequate training, lack of time and space to conduct complete evaluations, reluctance to become involved with the legal system, and challenges to distinguishing intentional from unintentional injuries may be contributing factors.^24,25 A focus on improving EP and ED staff approaches to elder abuse is relevant and timely given the growing elderly population.

Risk Factors

When evaluating elderly patients, providers should consider research suggesting that some older adults may be at particularly high risk for abuse.^4,26-29 Notably, individuals who have cognitive impairment are more likely to be victims of abuse.^30-32 Health-related demographic characteristics such as poor physical and mental health, substance abuse, low income/socioeconomic status, and social isolation all may increase the potential for mistreatment.

Family History

Similar to situations resulting in intimate partner violence, a family history of abuse and exposure to traumatic events may increase risk, and those responsible for elder abuse often turn out to be spouses, romantic partners, or an adult child living with the elderly parent—though paid caregivers also can be abusive.

Suspicion of abuse should be increased when individuals in caregiving roles have a history or show signs of mental illness, substance abuse, financial dependence on the victim, or caregiver stress. Considering that a caregiver may be overwhelmed is particularly relevant when an elderly patient exhibits behavioral issues.

Medical History

Obtaining a clear and thorough medical history from the patient and caregiver, both together and alone, is paramount to assessing the potential for abuse. Many indicators from the history may suggest the possibility of mistreatment (Table 1)^33-37 and although challenging in a busy ED, a comprehensive head-to-toe examination is crucial to adequately assess abuse. Suspicious physical findings and injury patterns of physical abuse, sexual abuse, and neglect are listed in Table 2.^33-37 Ongoing research is aimed at improving ED providers’ ability to differentiate accidental injuries, such as fall injuries, from injuries caused by physical elder abuse.

Injury Patterns

Preliminary studies have indicated that physical abuse injuries most commonly occur on the head, neck, and upper extremities.^38,39 A study comparing abuse victims to accidental injury sufferers found that abuse victims often had large bruises (>5 cm) on the face, lateral right arm, or posterior torso.⁴⁰ Preliminary results from a study in progress suggest that injuries to the left periorbital area, neck, and ulnar forearm may be much more common in abuse than in accident.

Imaging Studies

Emergency radiologists are contributing additional concerning findings indicative of elder abuse,^38,41,42 such as the concomitant presence of old and new fractures, high-energy fractures inconsistent with the purported mechanism, and distal ulnar diaphyseal fractures.^41,42 The ultimate goal is to identify pathognomonic injury patterns similar to those found in child abuse cases, to assist ED providers.

Laboratory Studies

Although there are no laboratory tests to definitively identify abuse or neglect, specific findings that may indicate abuse include anemia, dehydration, malnutrition, hypothermia/hyperthermia, and rhabdomyolysis.⁴³ In addition, inappropriately high- or low-medication levels and the presence of illicit drugs, which are not often checked in elderly patients in the ED, may be a sign of abuse.⁴³

Laboratory studies that reveal undetectable levels of a patient’s prescription medications may indicate a caregiver’s intentional or neglectful withholding of such medications—especially diversion of opioid medications prescribed for painful conditions.⁴³ Likewise, elevated levels of prescribed drugs may point to intentional or unintentional overdose, whereas the presence of nonprescribed drugs or toxins may suggest poisoning.⁴³

Screening Tools

To improve identification of elder abuse in the ED, universal or targeted screening tools are under consideration. Though several screening tools for elder abuse are already available, none have been validated in the ED.^15,44,45 Research sponsored by the National Institute of Justice to identify an ED-specific screening tool is ongoing.¹⁵

Elder Abuse Suspicion Index

The Elder Abuse Suspicion Index (EASI) is a short screening tool that has been validated for cognitively intact patients being treated in family practice and ambulatory care settings, and may be used in EDs.⁴⁴ The tool comprises six questions: five for patient response, and a sixth question for clinician response. This tool is available at http://www.nicenet.ca/tools-easi-elder-abuse-suspicion-index.⁴⁶

Interventional Measures

When elder mistreatment is suspected or confirmed, health care providers must first address any acute medical, traumatic, or psychological issues. Bleeding, orthopedic injuries, metabolic abnormalities, infections, and agitation must be treated and/or stabilized, while neglected or inappropriately managed chronic medical conditions may require treatment.

Hospitalization should be considered for an older adult who needs extended treatment or observation and, in cases of immediate or continued danger of abuse, separation from contact with the suspected abuser. These measures present several challenges, particularly if the suspected abuser is the patient’s health care proxy, in which case early involvement of the hospital’s legal department, social services, and administration may be necessary—especially in navigating the guardianship process.

Engaging security also may be necessary if the patient requires one-to-one patient watch or when the perpetrator must be removed from the ED. Social workers, patient services representatives, and law enforcement officials should be informed when such intervention is necessary.

In instances when a patient is not at risk of immediate harm, interventions can be more individualized. Coordination with primary care physicians (PCPs) must also be facilitated prior to discharge, to ensure consistent longitudinal follow-up care, and social workers should provide any needed out-of-hospital resources to the patient—and caregiver—such as Meals-on-Wheels, medical transportation services, adult day care/senior center participation, and substance abuse treatment.

Patient Decision-Making Capacity

When a patient experiencing abuse declines interventions or services, the EP must evaluate the patient’s decision-making capacity. In unclear cases, a psychiatric evaluation can help to assess decision-making capacity. If the victim is deemed to have capacity with regard to care and/or discharge, the patient’s choice of returning to an unsafe environment must be respected, as is true in instances of intimate partner violence among younger adults—but not in child abuse cases. In such situations, the EP should nevertheless discuss safety planning, offer psychoeducation about violence and abuse, suggest appropriate community referrals, and encourage abused patients to return or call a contact person whenever they desire or feel the need to talk further. For a victim who is deemed not to possess capacity, providers should proceed with treatment considered to be in the best interest of the patient.

Reporting Abuse

Emergency department providers should notify the appropriate authorities when elder abuse is suspected or identified. A report may be made to the local Adult Protective Services (APS), but this agency operates much differently than Child Protective Services. Case workers with APS will not open a case while a patient is in the ED or hospital, as it is deemed a safe environment and any investigation they undertake will only commence upon discharge. Because of this, contacting the local police department prior to discharge should be considered.

Mandatory elder abuse-reporting laws vary from state to state. Health care providers should therefore contact their respective state or city department of health to obtain local legislation.

Multidisciplinary Approach

Ideally, a multidisciplinary, ED-based intervention team modeled on child abuse teams^18,19 would help to optimize treatment and ensure the safety and treatment of vulnerable older adults. These teams could conduct thorough medical, forensic, and social work assessments, allowing ED providers to attend to other patients. The team could also assist in arranging for appropriate and safe dispositions. An innovative Vulnerable Elder Protection Team was recently launched at New York-Presbyterian Weill Cornell Medical Center to provide these services, and its impact is currently being evaluated.

Case Conclusion

The EP who treated the patient realized that blows from a blunt object held by a right-handed person would tend to land on the left side of the victim’s face and upper torso, and that a right-handed victim who successfully blocked the blows intended for her face would instead sustain an isolated right ulna or radius midshaft fracture. These findings, together with the concomitant presence of both old and new fractures, led the EP to question the patient alone and, after obtaining a different history of the events that led to the injuries, admit her for further evaluation, treatment, and interventions to prevent continuing abuse.

Summary

Elder abuse has the potential to affect an increasing number of older adults in this growing population, and an ED visit may offer the only opportunity to identify victims and provide intervention, in turn reducing morbidity and mortality. The results of ongoing research will improve the ability of EPs and ED staff to accurately assess the presence or risk of elder abuse and respond more effectively. It is essential that EPs always consider elder abuse and neglect as a possible etiology when evaluating injuries in this population. Moreover, when identified, addressing elder mistreatment may dramatically improve quality of life or save the lives of these vulnerable patients.


Case

An 85-year-old right-handed woman who recently had been diagnosed with mild cognitive impairment arrived at the ED via emergency medical services (EMS) for evaluation of a reported fall. She was accompanied by her daughter, who resided with the patient and was her primary caregiver. The patient stated that she had tripped on a wet rug in the bathroom of her home, striking her head and face on the edge of the sink without losing consciousness. Her daughter reported that she was not assisting her mother when the fall occurred, but had witnessed the fall from the hallway and called EMS. At the patient’s home, EMS found the patient to be alert, oriented, and ambulatory with normal vital signs that remained stable throughout prehospital transport.

The remainder of the patient’s history was provided almost entirely by her daughter, who constantly interrupted her mother whenever she attempted to directly answer a question or provide information. On physical examination, the patient had bilateral tenderness, edema, and periorbital ecchymoses, and a left eye that was nearly swollen shut. Extraocular movements were normal, visual acuity was intact, and sclerae were noninjected. The patient had tenderness over both maxillary sinuses, and edema and ecchymosis of her left cheek. There was also tenderness, ecchymoses, and edema on the lateral aspects of both forearms, and decreased range of motion of her right lower arm and wrist. With the exception of the patient not knowing the date during the orientation part of the thorough neurological examination, the remainder of the physical examination was unremarkable.

Radiological evaluation found no evidence of traumatic brain injury, but did reveal an acute fracture of the left zygomatic arch, an acute displaced nasal bone fracture, an age-indeterminate fracture of the right zygomatic arch, and an acute right ulnar fracture. Considering all of these findings, particularly the pattern of acute injuries, the emergency physician (EP) considered elder abuse as the possible etiology of the patient’s acute and chronic injuries.

Although the patient had initially agreed with her daughter’s description of the events—including her claim that she had fallen—when the EP questioned the patient alone, she related a history of frequent verbal and less frequent physical abuse by her daughter. The patient further noted that immediately before sustaining the injuries that brought her to the ED, her daughter had been insisting that she sign documents to give her control of her banking and finances. After refusing to sign the papers, the patient said that she and her daughter got into an argument, which she noted “they tended to do frequently.” The patient admitted that during this argument, her daughter struck her in the face repeatedly with the cane that the daughter had grabbed with her right hand.

The EP admitted the patient to the hospital for management of her orthopedic injuries and related pain, and to formulate a safe discharge plan. During admission, additional diagnostic testing revealed multiple old rib fractures, anemia, and a low-serum albumin, which suggested poor nutritional status.

Epidemiology

The term elder abuse refers to harm or the risk of harm to an older adult from either action or negligence committed by someone in a relationship of trust, or when a victim has been targeted because of age or disability. Elder abuse encompasses physical, sexual, or psychological abuse, neglect, and financial exploitation.^1-5 Identified victims of elder abuse typically suffer from multiple forms of abuse.^1-5

At present, elder abuse annually affects 5% to 10% of community-dwelling older adults,^1-6 and nursing-home residents are at increased risk of abuse.^7-10 Poor medical outcomes, including depression and dementia,¹¹ and much higher mortality^6,12,13 have been linked to victims of elder abuse.

Etiology

When treating older adults, it is critically important for EPs and the ED staff to consider and identify elder abuse in the differential diagnosis.^14,15 Presently, only an estimated 1 in 24 cases of abuse is recognized and reported to the authorities,² and much of the subsequent morbidity and mortality of elder abuse results from poor detection. A visit to the ED for an acute injury or illness may be the only time socially isolated older adults leave their homes.^15-17 Additionally, the ED setting is uniquely suited to identify mistreatment, as a patient typically may be evaluated for several hours by providers from multiple disciplines who are able to observe, interact with, and examine the patient.¹⁵ The ED already exercises a similar essential role in the identification and initial intervention for both child abuse^18,19 and intimate partner violence among younger adults.^20,21

Recognition

Unfortunately, at present, ED providers rarely recognize and report elder abuse.^22-24 Though the reasons for this are not entirely understood, inadequate training, lack of time and space to conduct complete evaluations, reluctance to become involved with the legal system, and challenges to distinguishing intentional from unintentional injuries may be contributing factors.^24,25 A focus on improving EP and ED staff approaches to elder abuse is relevant and timely given the growing elderly population.

Risk Factors

When evaluating elderly patients, providers should consider research suggesting that some older adults may be at particularly high risk for abuse.^4,26-29 Notably, individuals who have cognitive impairment are more likely to be victims of abuse.^30-32 Health-related demographic characteristics such as poor physical and mental health, substance abuse, low income/socioeconomic status, and social isolation all may increase the potential for mistreatment.

Family History

Similar to situations resulting in intimate partner violence, a family history of abuse and exposure to traumatic events may increase risk, and those responsible for elder abuse often turn out to be spouses, romantic partners, or an adult child living with the elderly parent—though paid caregivers also can be abusive.

Suspicion of abuse should be increased when individuals in caregiving roles have a history or show signs of mental illness, substance abuse, financial dependence on the victim, or caregiver stress. Considering that a caregiver may be overwhelmed is particularly relevant when an elderly patient exhibits behavioral issues.

Medical History

Obtaining a clear and thorough medical history from the patient and caregiver, both together and alone, is paramount to assessing the potential for abuse. Many indicators from the history may suggest the possibility of mistreatment (Table 1)^33-37 and although challenging in a busy ED, a comprehensive head-to-toe examination is crucial to adequately assess abuse. Suspicious physical findings and injury patterns of physical abuse, sexual abuse, and neglect are listed in Table 2.^33-37 Ongoing research is aimed at improving ED providers’ ability to differentiate accidental injuries, such as fall injuries, from injuries caused by physical elder abuse.

Injury Patterns

Preliminary studies have indicated that physical abuse injuries most commonly occur on the head, neck, and upper extremities.^38,39 A study comparing abuse victims to accidental injury sufferers found that abuse victims often had large bruises (>5 cm) on the face, lateral right arm, or posterior torso.⁴⁰ Preliminary results from a study in progress suggest that injuries to the left periorbital area, neck, and ulnar forearm may be much more common in abuse than in accident.

Imaging Studies

Emergency radiologists are contributing additional concerning findings indicative of elder abuse,^38,41,42 such as the concomitant presence of old and new fractures, high-energy fractures inconsistent with the purported mechanism, and distal ulnar diaphyseal fractures.^41,42 The ultimate goal is to identify pathognomonic injury patterns similar to those found in child abuse cases, to assist ED providers.

Laboratory Studies

Although there are no laboratory tests to definitively identify abuse or neglect, specific findings that may indicate abuse include anemia, dehydration, malnutrition, hypothermia/hyperthermia, and rhabdomyolysis.⁴³ In addition, inappropriately high- or low-medication levels and the presence of illicit drugs, which are not often checked in elderly patients in the ED, may be a sign of abuse.⁴³

Laboratory studies that reveal undetectable levels of a patient’s prescription medications may indicate a caregiver’s intentional or neglectful withholding of such medications—especially diversion of opioid medications prescribed for painful conditions.⁴³ Likewise, elevated levels of prescribed drugs may point to intentional or unintentional overdose, whereas the presence of nonprescribed drugs or toxins may suggest poisoning.⁴³

Screening Tools

To improve identification of elder abuse in the ED, universal or targeted screening tools are under consideration. Though several screening tools for elder abuse are already available, none have been validated in the ED.^15,44,45 Research sponsored by the National Institute of Justice to identify an ED-specific screening tool is ongoing.¹⁵

Elder Abuse Suspicion Index

The Elder Abuse Suspicion Index (EASI) is a short screening tool that has been validated for cognitively intact patients being treated in family practice and ambulatory care settings, and may be used in EDs.⁴⁴ The tool comprises six questions: five for patient response, and a sixth question for clinician response. This tool is available at http://www.nicenet.ca/tools-easi-elder-abuse-suspicion-index.⁴⁶

Interventional Measures

When elder mistreatment is suspected or confirmed, health care providers must first address any acute medical, traumatic, or psychological issues. Bleeding, orthopedic injuries, metabolic abnormalities, infections, and agitation must be treated and/or stabilized, while neglected or inappropriately managed chronic medical conditions may require treatment.

Hospitalization should be considered for an older adult who needs extended treatment or observation and, in cases of immediate or continued danger of abuse, separation from contact with the suspected abuser. These measures present several challenges, particularly if the suspected abuser is the patient’s health care proxy, in which case early involvement of the hospital’s legal department, social services, and administration may be necessary—especially in navigating the guardianship process.

Engaging security also may be necessary if the patient requires one-to-one patient watch or when the perpetrator must be removed from the ED. Social workers, patient services representatives, and law enforcement officials should be informed when such intervention is necessary.

In instances when a patient is not at risk of immediate harm, interventions can be more individualized. Coordination with primary care physicians (PCPs) must also be facilitated prior to discharge, to ensure consistent longitudinal follow-up care, and social workers should provide any needed out-of-hospital resources to the patient—and caregiver—such as Meals-on-Wheels, medical transportation services, adult day care/senior center participation, and substance abuse treatment.

Patient Decision-Making Capacity

When a patient experiencing abuse declines interventions or services, the EP must evaluate the patient’s decision-making capacity. In unclear cases, a psychiatric evaluation can help to assess decision-making capacity. If the victim is deemed to have capacity with regard to care and/or discharge, the patient’s choice of returning to an unsafe environment must be respected, as is true in instances of intimate partner violence among younger adults—but not in child abuse cases. In such situations, the EP should nevertheless discuss safety planning, offer psychoeducation about violence and abuse, suggest appropriate community referrals, and encourage abused patients to return or call a contact person whenever they desire or feel the need to talk further. For a victim who is deemed not to possess capacity, providers should proceed with treatment considered to be in the best interest of the patient.

Reporting Abuse

Emergency department providers should notify the appropriate authorities when elder abuse is suspected or identified. A report may be made to the local Adult Protective Services (APS), but this agency operates much differently than Child Protective Services. Case workers with APS will not open a case while a patient is in the ED or hospital, as it is deemed a safe environment and any investigation they undertake will only commence upon discharge. Because of this, contacting the local police department prior to discharge should be considered.

Mandatory elder abuse-reporting laws vary from state to state. Health care providers should therefore contact their respective state or city department of health to obtain local legislation.

Multidisciplinary Approach

Ideally, a multidisciplinary, ED-based intervention team modeled on child abuse teams^18,19 would help to optimize treatment and ensure the safety and treatment of vulnerable older adults. These teams could conduct thorough medical, forensic, and social work assessments, allowing ED providers to attend to other patients. The team could also assist in arranging for appropriate and safe dispositions. An innovative Vulnerable Elder Protection Team was recently launched at New York-Presbyterian Weill Cornell Medical Center to provide these services, and its impact is currently being evaluated.

Case Conclusion

The EP who treated the patient realized that blows from a blunt object held by a right-handed person would tend to land on the left side of the victim’s face and upper torso, and that a right-handed victim who successfully blocked the blows intended for her face would instead sustain an isolated right ulna or radius midshaft fracture. These findings, together with the concomitant presence of both old and new fractures, led the EP to question the patient alone and, after obtaining a different history of the events that led to the injuries, admit her for further evaluation, treatment, and interventions to prevent continuing abuse.

Summary

Elder abuse has the potential to affect an increasing number of older adults in this growing population, and an ED visit may offer the only opportunity to identify victims and provide intervention, in turn reducing morbidity and mortality. The results of ongoing research will improve the ability of EPs and ED staff to accurately assess the presence or risk of elder abuse and respond more effectively. It is essential that EPs always consider elder abuse and neglect as a possible etiology when evaluating injuries in this population. Moreover, when identified, addressing elder mistreatment may dramatically improve quality of life or save the lives of these vulnerable patients.


Artificial dermal fillers and autologous fat grafting have become increasingly popular in recent years, primarily because they augment existing soft tissue volumes, thus producing aesthetic improvements at a lower cost than traditional plastic surgery (ie, facelift), and with nearly no recovery time. According to the American Society for Aesthetic Plastic Surgery, more than 2 million hyaluronic acid (HA) dermal filler procedures were performed in 2016, an increase of 3% from 2015.¹ In addition, 80,000 autologous fat grafting procedures were performed in 2016, an increase of 13% from 2015. In total, there were 2.6 million soft tissue filler procedures in 2016, an increase of 2% from 2015.¹

With the increased demand and access to both artificial dermal fillers and autologous fat grafting, there has been a plethora of reported adverse events, ranging from expected erythema to acute blindness and stroke. Emergency physicians should have a thorough understanding of facial vascular anatomy, as well as the effects of available facial volumization products, including potential complications and treatment options. Through our review of two patient cases, we propose a simplified protocol for the treatment of patients with acute arterial occlusion secondary to facial volumization procedures.

Case 1

A 38-year-old white woman presented to the ED for evaluation of transient blurred vision and blanching of the left cheek and upper lip, which began approximately 40 minutes prior to presentation, immediately after her primary care physician (PCP) injected her left nasolabial fold with calcium hydroxyapatite (CaHA). The patient stated that her vision became blurry and her eyes began to tear within 1 minute of receiving the injection. She further noted that these visual changes were painless and lasted for approximately 30 seconds.

The patient’s PCP believed these symptoms were due to pain at the injection site. While the patient was at her PCP’s office, the reception clerk noticed the blanching of the patient’s left cheek and informed the PCP, who referred the patient to our ED for evaluation.

Workup

The patient’s vital signs at presentation were normal. Her medical history was unremarkable and negative for smoking, alcohol, or drug use. She was not taking any medications and had no known drug allergies. The patient’s history was negative for any prior cosmetic procedures, and she confirmed this was the first and only time had a facial revolumization.

Facial examination revealed a Fitzpatrick scale (FS; a numerical scoring system used to assess a patient’s reaction to ultraviolet radiation) score of type 3. She also had left-sided blanching that extended from the midpoint of the nose diagonally to the lateral midbuccal cheek to the level of the oral commissure, including the cutaneous upper lip, alar, and nasal side wall. There was minimal capillary refill with compression at the affected site, and sensation was diminished to fine touch and pinprick. The facial muscles were intact, and, with the exception of puncture marks along both nasolabial folds, the remainder of the facial examination was normal.

The ophthalmic examination revealed a reactive pupil at 2 mm, white sclera, pink conjunctiva, red reflex, and normal fundoscopic vessels. The patient’s bedside Snellen visual acuity and visual field assessments were normal. The neurological examination was likewise normal, and no other physical findings were noted.

Laboratory evaluation included complete blood count (CBC), Chem 7 panel (creatinine, blood urea nitrogen [BUN], carbon dioxide, chloride, glucose, sodium, and potassium), and international normalized ratio (INR), which were all within normal limits.

Diagnosis and Treatment

The patient was diagnosed with acute angular arterial occlusion and transient retinal artery embolism secondary to facial volumization with CaHA. She was treated with oral acetylsalicylic acid aspirin (ASA) 325 mg, prednisone 40 mg, and sildenafil 50 mg; and subcutaneous (SC) enoxaparin 60 mg (1 mg/kg). Topical nitroglycerin paste 2% was applied to the affected area.

Ophthalmology and plastic surgery services were contacted for consultation. Based on no acute findings on examination, the ophthalmologist provided no additional treatment recommendations. The patient was observed in the ED for 4 hours, during which time the facial blanching resolved and her capillary refill time returned to normal at 2 seconds.

After evaluating the patient, the plastic surgeon recommended discharge home with instructions to continue taking the oral ASA and sildenafil, as well as a methylprednisolone dose pack for 6 days. He also recommended the patient begin hyperbaric oxygen (HBO) therapy the day after discharge, since there was no HBO chamber available during her hospital stay.

The patient complied with all discharge instructions, including HBO therapy. At plastic surgery follow-up, the patient had no long-term adverse effects from the CaHA injection.

Case 2

A 54-year-old Asian woman presented to the ED for evaluation of a 24-hour history of progressive and persistent pain, swelling, and discoloration of the nasolabial and upper lip region. She stated her symptoms began within 1 hour of receiving a fat graft injection into the affected area by her cosmetic surgeon. After examining the patient, the cosmetic surgeon referred her to the ED for further evaluation. The patient stated that she had undergone six prior facial revolumization procedures, but noted the recent procedure was her first autologous fat graft.

Workup

The patient’s medical history was unremarkable. Her social history was positive for one glass of wine per day and negative for smoking. The patient was not taking any medications and had no known drug allergies.

The patient’s vital signs at presentation were normal. She was evaluated approximately 30 hours after the fat graft procedure. Facial examination revealed an FS of type 4 with right-sided ischemia along the cutaneous upper lip, alar, and cheek (Figure 1).

Capillary refill time with compression was 0 in the affected area. Sensation to fine touch and pinprick was 0. The facial muscles were intact and, with the exception of puncture marks along both nasolabial folds, the remainder of the facial examination was normal. The neurological examination was likewise normal, and no other physical findings were noted. Laboratory evaluation included CBC, Chem 7 panel, and INR, which were all within normal limits.

Diagnosis and Treatment

The patient was diagnosed with acute angular arterial occlusion with soft tissue ischemia secondary to facial revolumization with autologous fat grafting. She was given oral acyclovir 800 mg, ASA 325 mg, cephalexin 500 mg, prednisone 40 mg, and sildenafil 50 mg; and SC enoxaparin 60 mg (1 mg/kg). Topical nitroglycerin paste 2% was applied to the affected area.

Plastic surgery services were contacted for consultation. After evaluating the patient, the plastic surgeon recommended discharge home with instructions to continue taking the oral acyclovir, ASA, cephalexin, prednisone, and sildenafil for 6 days. He also recommended the patient start HBO therapy the day after discharge home.

The patient refused HBO therapy, but did visit a plastic surgeon for a follow-up examination 3 days after discharge from the ED. A photograph of the patient’s nasolabial and upper lip region taken during this visit is presented in Figure 2.

Five days after discharge from the ED, the patient presented to a plastic surgery clinic for evaluation; a photograph was also obtained at this visit (Figure 3). The plastic surgeon at this clinic referred the patient to a tertiary center for a second opinion regarding the need for HBO therapy. The plastic surgeon at the tertiary center affirmed the initial plastic surgeon’s diagnosis and recommendation for HBO therapy. Although the patient did not return for further evaluation, she underwent 10 HBO treatments at the tertiary center with an acceptable aesthetic result.

Noninvasive Injectable Cosmetic Facial Augmentation

Facial augmentation procedures include the use of autologous adipose bovine collagen, HA gels, CaHA, and plastic compounds to fill wrinkles, folds, or soft tissue defects due to normal aging or trauma. Plastic surgeons traditionally use adipose and manufactured products for scar revision, midfacial restoration of volume loss from aging or trauma, cheek and chin augmentation, tear-trough correction (the diagonal crease running from the inner eye canthus to the maxilla resulting in a groove that creates a tired appearance), nose reshaping, lip enhancement, and correction of facial asymmetry.

Today the use of manufactured soft tissue revolumization products (ie, fillers) is no longer solely in the purview of plastic surgeons, but rather has become ubiquitous with nonsurgeons and allied health care professionals. As the overall number of revolumization procedures increases, so too does the risk for local and distant vascular complications.

Dermal Fillers

Dermal fillers vary widely in their respective properties, solubility, injection-technique flow requirements, and inherent complication risks. Regardless of type, all dermal fillers have the potential to cause serious complications. Most adverse events are related to substance type, volume, and injection technique. Bruising and trauma-related edema following dermal filler procedures are considered normal.

Though complications from dermal filler injections are rarely lethal, serious adverse events can result in permanent functional and aesthetic deficits. With proper physician training, planning, and injection technique, most adverse events can be avoided.

Hyaluronic Acid. Hyaluronic acid (HA)-containing injectable gel fillers (eg, Belotero, Juvederm, Perlane, and Restylane) are one of the most commonly used volumization products—especially by nonplastic surgeons. These gel fillers, which vary in viscosity and elasticity, may be injected from the superficial dermis to the periosteum. Dilution, dispersion, and degradation may be achieved in vivo either by high arterial flow or hyaluronidase.

Calcium Hydroxylapatite. Calcium hydroxylapatite (Radiesse) microsphere fillers consist of a very viscous paste that is mixed with lidocaine prior to injection to increase its flowability. The CaHA solution is injected at the deep dermis to periosteum level. Since CaHA is not easily diluted, dispersed, or degraded by high arterial flow, it tends to retain its consistency. When this procedure is performed by a novice, it can result in complete occlusion at the injection site or through embolization via antegrade or retrograde flow.

Poly-L-lactic Acid. Poly-L-lactic acid (PLLA; Sculptra) is a low-viscosity fluid comprised of synthetic polymer beads. The PLLA microparticles are not dissolvable or degradable by high arterial flow, and are designed to induce an inflammatory response with neocollagenesis.

Polymethyl Methacrylate. Polymethyl methacrylate (PMMA; Bellafil) consists of a combination of microscopic synthetic polymer beads suspended in a variety of substances. For facial enhancement, PMMA is usually suspended in HA or bovine collagen. Off-label use of silicon oils and gels such as PMMA are gaining in popularity—often with disastrous consequences such as acute arterial occlusion, bone erosion, and skin ulcerations.^2,3

Autologous Adipose Tissue. Plastic surgeons primarily use autologous adipose tissue to volumize the face, breasts, buttocks, and scars. Autologous fat grafts are typically placed in fat, superficial and deep muscles, and deep fat pads through a 2- to 2.5-mm facial fat grafting cannula using a multichannel technique that leaves minute amounts of fat in each channel. Fat embolization may occur when a nonfacial fat graft cannula or needle used to transplant the fat graft enters an artery either through direct sharp puncture or traumatic tear cannulation.^4-9

Adverse Events

The first recorded manufactured adverse event from an injectable dermal filler was in 1991. At that time, the US Food and Drug Administration warned of adverse events secondary to collagen injections, including open sores, abscess formation associated with delayed healing of the skin, and partial blindness.¹⁰

Arterial Embolization and Cannulation. The most serious complications from dermal fillers are accidental injection and/or embolization of the filler into the arterial system. Since 1991, an increased number of cases of soft tissue necrosis, blindness, and stroke have been reported as a result of injection of fillers in the glabella, forehead creases, temple, crow’s feet, nose, cheeks, nasolabial folds, and lower lip.^11-15

Accidental cannulation and inadvertent injection of fillers into the arterial vessels can have catastrophic complications. The potential of such inadvertent complications occurs despite skill level of the practitioner or surgeon. Therefore, recognition and treatment of a vascular occlusion must be immediate and aggressive to avoid devastating and potentially irreversible complications including blindness, stroke, and death.^11-15

Acute Blindness and Stroke. The issues and concerns associated with local intra-arterial dermal filler injection and distal embolism are well described in the literature. However, the mechanism of retinal artery occlusion is much more complex given the need for deep placement of products and the force necessary to cause distention and elevation of the dermis. Hence, higher g-forces are applied via the plunger, forcing the intra-arterial filler proximally past the origin of the retinal artery. When the clinician stops the injection, the arterial systolic pressure immediately embolizes the filler into the distal branches of the ophthalmic artery. This causes acute pain and blindness (Figure 5). Depending on the g-force applied, filler can enter into the internal carotid artery and embolize resulting in cerebral ischemia. Signs of cerebral ischemia may be mild or overt.^4-9

Management

Patients with intra-arterial dermal filler injection constitute a medical emergency requiring immediate intervention. We recommend clinicians initiate the treatment protocols outlined in the Box and Table 1.

Hyaluronidase. Injection of hyaluronidase may assist in degrading the HA around the arterial puncture site, relieving compression, which may increase blood flow. There is a risk of distal embolization from a dislodged HA emboli.

Fat Graft Injections. There are no known degradation products for fat, CaHA, PLLA, or PMMA products. The use of normal saline or hyaluronidase has no proven efficacy and may increase the compression pressure in the artery and surrounding tissue, causing further ischemia.

Long-term Sequelae

Despite aggressive intervention, permanent complications of cerebral ischemia, blindness, and severe soft tissue necrosis may occur. In six cases in the literature, patients treated with ocular massage therapy,^7,14 carbon dioxide rebreathing,¹⁴ HBO therapy,^7,14 oral and IV corticosteroids,^6-9 antiplatelet drugs,⁶ and fibrinolytic agents,^7,16 or mechanical thrombolysis¹⁶ showed no clinical effects. Neither the treated nor the untreated patients in any of these case studies had any return of vision.^4-7,9,20-27

Conclusion

Although artificial dermal fillers such as HA, CaHA, PLLA, and PMMA, and autologous adipose tissue grafts offer a minimally invasive alternative to plastic surgical procedures, they are not without complication or adverse effects, such as the acute arterial occlusion experienced by both of our patients. Patients presenting to the ED with adverse effects from such procedures must be managed promptly, employing the suggested management and treatment protocol, including consultation with ophthalmology, plastic surgery, and neurological services as indicated, to avoid permanent sequela and damage.

Artificial dermal fillers and autologous fat grafting have become increasingly popular in recent years, primarily because they augment existing soft tissue volumes, thus producing aesthetic improvements at a lower cost than traditional plastic surgery (ie, facelift), and with nearly no recovery time. According to the American Society for Aesthetic Plastic Surgery, more than 2 million hyaluronic acid (HA) dermal filler procedures were performed in 2016, an increase of 3% from 2015.¹ In addition, 80,000 autologous fat grafting procedures were performed in 2016, an increase of 13% from 2015. In total, there were 2.6 million soft tissue filler procedures in 2016, an increase of 2% from 2015.¹

With the increased demand and access to both artificial dermal fillers and autologous fat grafting, there has been a plethora of reported adverse events, ranging from expected erythema to acute blindness and stroke. Emergency physicians should have a thorough understanding of facial vascular anatomy, as well as the effects of available facial volumization products, including potential complications and treatment options. Through our review of two patient cases, we propose a simplified protocol for the treatment of patients with acute arterial occlusion secondary to facial volumization procedures.

Case 1

A 38-year-old white woman presented to the ED for evaluation of transient blurred vision and blanching of the left cheek and upper lip, which began approximately 40 minutes prior to presentation, immediately after her primary care physician (PCP) injected her left nasolabial fold with calcium hydroxyapatite (CaHA). The patient stated that her vision became blurry and her eyes began to tear within 1 minute of receiving the injection. She further noted that these visual changes were painless and lasted for approximately 30 seconds.

The patient’s PCP believed these symptoms were due to pain at the injection site. While the patient was at her PCP’s office, the reception clerk noticed the blanching of the patient’s left cheek and informed the PCP, who referred the patient to our ED for evaluation.

Workup

The patient’s vital signs at presentation were normal. Her medical history was unremarkable and negative for smoking, alcohol, or drug use. She was not taking any medications and had no known drug allergies. The patient’s history was negative for any prior cosmetic procedures, and she confirmed this was the first and only time had a facial revolumization.

Facial examination revealed a Fitzpatrick scale (FS; a numerical scoring system used to assess a patient’s reaction to ultraviolet radiation) score of type 3. She also had left-sided blanching that extended from the midpoint of the nose diagonally to the lateral midbuccal cheek to the level of the oral commissure, including the cutaneous upper lip, alar, and nasal side wall. There was minimal capillary refill with compression at the affected site, and sensation was diminished to fine touch and pinprick. The facial muscles were intact, and, with the exception of puncture marks along both nasolabial folds, the remainder of the facial examination was normal.

The ophthalmic examination revealed a reactive pupil at 2 mm, white sclera, pink conjunctiva, red reflex, and normal fundoscopic vessels. The patient’s bedside Snellen visual acuity and visual field assessments were normal. The neurological examination was likewise normal, and no other physical findings were noted.

Laboratory evaluation included complete blood count (CBC), Chem 7 panel (creatinine, blood urea nitrogen [BUN], carbon dioxide, chloride, glucose, sodium, and potassium), and international normalized ratio (INR), which were all within normal limits.

Diagnosis and Treatment

The patient was diagnosed with acute angular arterial occlusion and transient retinal artery embolism secondary to facial volumization with CaHA. She was treated with oral acetylsalicylic acid aspirin (ASA) 325 mg, prednisone 40 mg, and sildenafil 50 mg; and subcutaneous (SC) enoxaparin 60 mg (1 mg/kg). Topical nitroglycerin paste 2% was applied to the affected area.

Ophthalmology and plastic surgery services were contacted for consultation. Based on no acute findings on examination, the ophthalmologist provided no additional treatment recommendations. The patient was observed in the ED for 4 hours, during which time the facial blanching resolved and her capillary refill time returned to normal at 2 seconds.

After evaluating the patient, the plastic surgeon recommended discharge home with instructions to continue taking the oral ASA and sildenafil, as well as a methylprednisolone dose pack for 6 days. He also recommended the patient begin hyperbaric oxygen (HBO) therapy the day after discharge, since there was no HBO chamber available during her hospital stay.

The patient complied with all discharge instructions, including HBO therapy. At plastic surgery follow-up, the patient had no long-term adverse effects from the CaHA injection.

Case 2

A 54-year-old Asian woman presented to the ED for evaluation of a 24-hour history of progressive and persistent pain, swelling, and discoloration of the nasolabial and upper lip region. She stated her symptoms began within 1 hour of receiving a fat graft injection into the affected area by her cosmetic surgeon. After examining the patient, the cosmetic surgeon referred her to the ED for further evaluation. The patient stated that she had undergone six prior facial revolumization procedures, but noted the recent procedure was her first autologous fat graft.

Workup

The patient’s medical history was unremarkable. Her social history was positive for one glass of wine per day and negative for smoking. The patient was not taking any medications and had no known drug allergies.

The patient’s vital signs at presentation were normal. She was evaluated approximately 30 hours after the fat graft procedure. Facial examination revealed an FS of type 4 with right-sided ischemia along the cutaneous upper lip, alar, and cheek (Figure 1).

Capillary refill time with compression was 0 in the affected area. Sensation to fine touch and pinprick was 0. The facial muscles were intact and, with the exception of puncture marks along both nasolabial folds, the remainder of the facial examination was normal. The neurological examination was likewise normal, and no other physical findings were noted. Laboratory evaluation included CBC, Chem 7 panel, and INR, which were all within normal limits.

Diagnosis and Treatment

The patient was diagnosed with acute angular arterial occlusion with soft tissue ischemia secondary to facial revolumization with autologous fat grafting. She was given oral acyclovir 800 mg, ASA 325 mg, cephalexin 500 mg, prednisone 40 mg, and sildenafil 50 mg; and SC enoxaparin 60 mg (1 mg/kg). Topical nitroglycerin paste 2% was applied to the affected area.

Plastic surgery services were contacted for consultation. After evaluating the patient, the plastic surgeon recommended discharge home with instructions to continue taking the oral acyclovir, ASA, cephalexin, prednisone, and sildenafil for 6 days. He also recommended the patient start HBO therapy the day after discharge home.

The patient refused HBO therapy, but did visit a plastic surgeon for a follow-up examination 3 days after discharge from the ED. A photograph of the patient’s nasolabial and upper lip region taken during this visit is presented in Figure 2.

Five days after discharge from the ED, the patient presented to a plastic surgery clinic for evaluation; a photograph was also obtained at this visit (Figure 3). The plastic surgeon at this clinic referred the patient to a tertiary center for a second opinion regarding the need for HBO therapy. The plastic surgeon at the tertiary center affirmed the initial plastic surgeon’s diagnosis and recommendation for HBO therapy. Although the patient did not return for further evaluation, she underwent 10 HBO treatments at the tertiary center with an acceptable aesthetic result.

Noninvasive Injectable Cosmetic Facial Augmentation

Facial augmentation procedures include the use of autologous adipose bovine collagen, HA gels, CaHA, and plastic compounds to fill wrinkles, folds, or soft tissue defects due to normal aging or trauma. Plastic surgeons traditionally use adipose and manufactured products for scar revision, midfacial restoration of volume loss from aging or trauma, cheek and chin augmentation, tear-trough correction (the diagonal crease running from the inner eye canthus to the maxilla resulting in a groove that creates a tired appearance), nose reshaping, lip enhancement, and correction of facial asymmetry.

Today the use of manufactured soft tissue revolumization products (ie, fillers) is no longer solely in the purview of plastic surgeons, but rather has become ubiquitous with nonsurgeons and allied health care professionals. As the overall number of revolumization procedures increases, so too does the risk for local and distant vascular complications.

Dermal Fillers

Dermal fillers vary widely in their respective properties, solubility, injection-technique flow requirements, and inherent complication risks. Regardless of type, all dermal fillers have the potential to cause serious complications. Most adverse events are related to substance type, volume, and injection technique. Bruising and trauma-related edema following dermal filler procedures are considered normal.

Though complications from dermal filler injections are rarely lethal, serious adverse events can result in permanent functional and aesthetic deficits. With proper physician training, planning, and injection technique, most adverse events can be avoided.

Hyaluronic Acid. Hyaluronic acid (HA)-containing injectable gel fillers (eg, Belotero, Juvederm, Perlane, and Restylane) are one of the most commonly used volumization products—especially by nonplastic surgeons. These gel fillers, which vary in viscosity and elasticity, may be injected from the superficial dermis to the periosteum. Dilution, dispersion, and degradation may be achieved in vivo either by high arterial flow or hyaluronidase.

Calcium Hydroxylapatite. Calcium hydroxylapatite (Radiesse) microsphere fillers consist of a very viscous paste that is mixed with lidocaine prior to injection to increase its flowability. The CaHA solution is injected at the deep dermis to periosteum level. Since CaHA is not easily diluted, dispersed, or degraded by high arterial flow, it tends to retain its consistency. When this procedure is performed by a novice, it can result in complete occlusion at the injection site or through embolization via antegrade or retrograde flow.

Poly-L-lactic Acid. Poly-L-lactic acid (PLLA; Sculptra) is a low-viscosity fluid comprised of synthetic polymer beads. The PLLA microparticles are not dissolvable or degradable by high arterial flow, and are designed to induce an inflammatory response with neocollagenesis.

Polymethyl Methacrylate. Polymethyl methacrylate (PMMA; Bellafil) consists of a combination of microscopic synthetic polymer beads suspended in a variety of substances. For facial enhancement, PMMA is usually suspended in HA or bovine collagen. Off-label use of silicon oils and gels such as PMMA are gaining in popularity—often with disastrous consequences such as acute arterial occlusion, bone erosion, and skin ulcerations.^2,3

Autologous Adipose Tissue. Plastic surgeons primarily use autologous adipose tissue to volumize the face, breasts, buttocks, and scars. Autologous fat grafts are typically placed in fat, superficial and deep muscles, and deep fat pads through a 2- to 2.5-mm facial fat grafting cannula using a multichannel technique that leaves minute amounts of fat in each channel. Fat embolization may occur when a nonfacial fat graft cannula or needle used to transplant the fat graft enters an artery either through direct sharp puncture or traumatic tear cannulation.^4-9

Adverse Events

The first recorded manufactured adverse event from an injectable dermal filler was in 1991. At that time, the US Food and Drug Administration warned of adverse events secondary to collagen injections, including open sores, abscess formation associated with delayed healing of the skin, and partial blindness.¹⁰

Arterial Embolization and Cannulation. The most serious complications from dermal fillers are accidental injection and/or embolization of the filler into the arterial system. Since 1991, an increased number of cases of soft tissue necrosis, blindness, and stroke have been reported as a result of injection of fillers in the glabella, forehead creases, temple, crow’s feet, nose, cheeks, nasolabial folds, and lower lip.^11-15

Accidental cannulation and inadvertent injection of fillers into the arterial vessels can have catastrophic complications. The potential of such inadvertent complications occurs despite skill level of the practitioner or surgeon. Therefore, recognition and treatment of a vascular occlusion must be immediate and aggressive to avoid devastating and potentially irreversible complications including blindness, stroke, and death.^11-15

Acute Blindness and Stroke. The issues and concerns associated with local intra-arterial dermal filler injection and distal embolism are well described in the literature. However, the mechanism of retinal artery occlusion is much more complex given the need for deep placement of products and the force necessary to cause distention and elevation of the dermis. Hence, higher g-forces are applied via the plunger, forcing the intra-arterial filler proximally past the origin of the retinal artery. When the clinician stops the injection, the arterial systolic pressure immediately embolizes the filler into the distal branches of the ophthalmic artery. This causes acute pain and blindness (Figure 5). Depending on the g-force applied, filler can enter into the internal carotid artery and embolize resulting in cerebral ischemia. Signs of cerebral ischemia may be mild or overt.^4-9

Management

Patients with intra-arterial dermal filler injection constitute a medical emergency requiring immediate intervention. We recommend clinicians initiate the treatment protocols outlined in the Box and Table 1.

Hyaluronidase. Injection of hyaluronidase may assist in degrading the HA around the arterial puncture site, relieving compression, which may increase blood flow. There is a risk of distal embolization from a dislodged HA emboli.

Fat Graft Injections. There are no known degradation products for fat, CaHA, PLLA, or PMMA products. The use of normal saline or hyaluronidase has no proven efficacy and may increase the compression pressure in the artery and surrounding tissue, causing further ischemia.

Long-term Sequelae

Despite aggressive intervention, permanent complications of cerebral ischemia, blindness, and severe soft tissue necrosis may occur. In six cases in the literature, patients treated with ocular massage therapy,^7,14 carbon dioxide rebreathing,¹⁴ HBO therapy,^7,14 oral and IV corticosteroids,^6-9 antiplatelet drugs,⁶ and fibrinolytic agents,^7,16 or mechanical thrombolysis¹⁶ showed no clinical effects. Neither the treated nor the untreated patients in any of these case studies had any return of vision.^4-7,9,20-27

Conclusion

Although artificial dermal fillers such as HA, CaHA, PLLA, and PMMA, and autologous adipose tissue grafts offer a minimally invasive alternative to plastic surgical procedures, they are not without complication or adverse effects, such as the acute arterial occlusion experienced by both of our patients. Patients presenting to the ED with adverse effects from such procedures must be managed promptly, employing the suggested management and treatment protocol, including consultation with ophthalmology, plastic surgery, and neurological services as indicated, to avoid permanent sequela and damage.

Artificial dermal fillers and autologous fat grafting have become increasingly popular in recent years, primarily because they augment existing soft tissue volumes, thus producing aesthetic improvements at a lower cost than traditional plastic surgery (ie, facelift), and with nearly no recovery time. According to the American Society for Aesthetic Plastic Surgery, more than 2 million hyaluronic acid (HA) dermal filler procedures were performed in 2016, an increase of 3% from 2015.¹ In addition, 80,000 autologous fat grafting procedures were performed in 2016, an increase of 13% from 2015. In total, there were 2.6 million soft tissue filler procedures in 2016, an increase of 2% from 2015.¹

With the increased demand and access to both artificial dermal fillers and autologous fat grafting, there has been a plethora of reported adverse events, ranging from expected erythema to acute blindness and stroke. Emergency physicians should have a thorough understanding of facial vascular anatomy, as well as the effects of available facial volumization products, including potential complications and treatment options. Through our review of two patient cases, we propose a simplified protocol for the treatment of patients with acute arterial occlusion secondary to facial volumization procedures.

Case 1

A 38-year-old white woman presented to the ED for evaluation of transient blurred vision and blanching of the left cheek and upper lip, which began approximately 40 minutes prior to presentation, immediately after her primary care physician (PCP) injected her left nasolabial fold with calcium hydroxyapatite (CaHA). The patient stated that her vision became blurry and her eyes began to tear within 1 minute of receiving the injection. She further noted that these visual changes were painless and lasted for approximately 30 seconds.

The patient’s PCP believed these symptoms were due to pain at the injection site. While the patient was at her PCP’s office, the reception clerk noticed the blanching of the patient’s left cheek and informed the PCP, who referred the patient to our ED for evaluation.

Workup

The patient’s vital signs at presentation were normal. Her medical history was unremarkable and negative for smoking, alcohol, or drug use. She was not taking any medications and had no known drug allergies. The patient’s history was negative for any prior cosmetic procedures, and she confirmed this was the first and only time had a facial revolumization.

Facial examination revealed a Fitzpatrick scale (FS; a numerical scoring system used to assess a patient’s reaction to ultraviolet radiation) score of type 3. She also had left-sided blanching that extended from the midpoint of the nose diagonally to the lateral midbuccal cheek to the level of the oral commissure, including the cutaneous upper lip, alar, and nasal side wall. There was minimal capillary refill with compression at the affected site, and sensation was diminished to fine touch and pinprick. The facial muscles were intact, and, with the exception of puncture marks along both nasolabial folds, the remainder of the facial examination was normal.

The ophthalmic examination revealed a reactive pupil at 2 mm, white sclera, pink conjunctiva, red reflex, and normal fundoscopic vessels. The patient’s bedside Snellen visual acuity and visual field assessments were normal. The neurological examination was likewise normal, and no other physical findings were noted.

Laboratory evaluation included complete blood count (CBC), Chem 7 panel (creatinine, blood urea nitrogen [BUN], carbon dioxide, chloride, glucose, sodium, and potassium), and international normalized ratio (INR), which were all within normal limits.

Diagnosis and Treatment

The patient was diagnosed with acute angular arterial occlusion and transient retinal artery embolism secondary to facial volumization with CaHA. She was treated with oral acetylsalicylic acid aspirin (ASA) 325 mg, prednisone 40 mg, and sildenafil 50 mg; and subcutaneous (SC) enoxaparin 60 mg (1 mg/kg). Topical nitroglycerin paste 2% was applied to the affected area.

Ophthalmology and plastic surgery services were contacted for consultation. Based on no acute findings on examination, the ophthalmologist provided no additional treatment recommendations. The patient was observed in the ED for 4 hours, during which time the facial blanching resolved and her capillary refill time returned to normal at 2 seconds.

After evaluating the patient, the plastic surgeon recommended discharge home with instructions to continue taking the oral ASA and sildenafil, as well as a methylprednisolone dose pack for 6 days. He also recommended the patient begin hyperbaric oxygen (HBO) therapy the day after discharge, since there was no HBO chamber available during her hospital stay.

The patient complied with all discharge instructions, including HBO therapy. At plastic surgery follow-up, the patient had no long-term adverse effects from the CaHA injection.

Case 2

A 54-year-old Asian woman presented to the ED for evaluation of a 24-hour history of progressive and persistent pain, swelling, and discoloration of the nasolabial and upper lip region. She stated her symptoms began within 1 hour of receiving a fat graft injection into the affected area by her cosmetic surgeon. After examining the patient, the cosmetic surgeon referred her to the ED for further evaluation. The patient stated that she had undergone six prior facial revolumization procedures, but noted the recent procedure was her first autologous fat graft.

Workup

The patient’s medical history was unremarkable. Her social history was positive for one glass of wine per day and negative for smoking. The patient was not taking any medications and had no known drug allergies.

The patient’s vital signs at presentation were normal. She was evaluated approximately 30 hours after the fat graft procedure. Facial examination revealed an FS of type 4 with right-sided ischemia along the cutaneous upper lip, alar, and cheek (Figure 1).

Capillary refill time with compression was 0 in the affected area. Sensation to fine touch and pinprick was 0. The facial muscles were intact and, with the exception of puncture marks along both nasolabial folds, the remainder of the facial examination was normal. The neurological examination was likewise normal, and no other physical findings were noted. Laboratory evaluation included CBC, Chem 7 panel, and INR, which were all within normal limits.

Diagnosis and Treatment

The patient was diagnosed with acute angular arterial occlusion with soft tissue ischemia secondary to facial revolumization with autologous fat grafting. She was given oral acyclovir 800 mg, ASA 325 mg, cephalexin 500 mg, prednisone 40 mg, and sildenafil 50 mg; and SC enoxaparin 60 mg (1 mg/kg). Topical nitroglycerin paste 2% was applied to the affected area.

Plastic surgery services were contacted for consultation. After evaluating the patient, the plastic surgeon recommended discharge home with instructions to continue taking the oral acyclovir, ASA, cephalexin, prednisone, and sildenafil for 6 days. He also recommended the patient start HBO therapy the day after discharge home.

The patient refused HBO therapy, but did visit a plastic surgeon for a follow-up examination 3 days after discharge from the ED. A photograph of the patient’s nasolabial and upper lip region taken during this visit is presented in Figure 2.

Five days after discharge from the ED, the patient presented to a plastic surgery clinic for evaluation; a photograph was also obtained at this visit (Figure 3). The plastic surgeon at this clinic referred the patient to a tertiary center for a second opinion regarding the need for HBO therapy. The plastic surgeon at the tertiary center affirmed the initial plastic surgeon’s diagnosis and recommendation for HBO therapy. Although the patient did not return for further evaluation, she underwent 10 HBO treatments at the tertiary center with an acceptable aesthetic result.

Noninvasive Injectable Cosmetic Facial Augmentation

Facial augmentation procedures include the use of autologous adipose bovine collagen, HA gels, CaHA, and plastic compounds to fill wrinkles, folds, or soft tissue defects due to normal aging or trauma. Plastic surgeons traditionally use adipose and manufactured products for scar revision, midfacial restoration of volume loss from aging or trauma, cheek and chin augmentation, tear-trough correction (the diagonal crease running from the inner eye canthus to the maxilla resulting in a groove that creates a tired appearance), nose reshaping, lip enhancement, and correction of facial asymmetry.

Today the use of manufactured soft tissue revolumization products (ie, fillers) is no longer solely in the purview of plastic surgeons, but rather has become ubiquitous with nonsurgeons and allied health care professionals. As the overall number of revolumization procedures increases, so too does the risk for local and distant vascular complications.

Dermal Fillers

Dermal fillers vary widely in their respective properties, solubility, injection-technique flow requirements, and inherent complication risks. Regardless of type, all dermal fillers have the potential to cause serious complications. Most adverse events are related to substance type, volume, and injection technique. Bruising and trauma-related edema following dermal filler procedures are considered normal.

Though complications from dermal filler injections are rarely lethal, serious adverse events can result in permanent functional and aesthetic deficits. With proper physician training, planning, and injection technique, most adverse events can be avoided.

Hyaluronic Acid. Hyaluronic acid (HA)-containing injectable gel fillers (eg, Belotero, Juvederm, Perlane, and Restylane) are one of the most commonly used volumization products—especially by nonplastic surgeons. These gel fillers, which vary in viscosity and elasticity, may be injected from the superficial dermis to the periosteum. Dilution, dispersion, and degradation may be achieved in vivo either by high arterial flow or hyaluronidase.

Calcium Hydroxylapatite. Calcium hydroxylapatite (Radiesse) microsphere fillers consist of a very viscous paste that is mixed with lidocaine prior to injection to increase its flowability. The CaHA solution is injected at the deep dermis to periosteum level. Since CaHA is not easily diluted, dispersed, or degraded by high arterial flow, it tends to retain its consistency. When this procedure is performed by a novice, it can result in complete occlusion at the injection site or through embolization via antegrade or retrograde flow.

Poly-L-lactic Acid. Poly-L-lactic acid (PLLA; Sculptra) is a low-viscosity fluid comprised of synthetic polymer beads. The PLLA microparticles are not dissolvable or degradable by high arterial flow, and are designed to induce an inflammatory response with neocollagenesis.

Polymethyl Methacrylate. Polymethyl methacrylate (PMMA; Bellafil) consists of a combination of microscopic synthetic polymer beads suspended in a variety of substances. For facial enhancement, PMMA is usually suspended in HA or bovine collagen. Off-label use of silicon oils and gels such as PMMA are gaining in popularity—often with disastrous consequences such as acute arterial occlusion, bone erosion, and skin ulcerations.^2,3

Autologous Adipose Tissue. Plastic surgeons primarily use autologous adipose tissue to volumize the face, breasts, buttocks, and scars. Autologous fat grafts are typically placed in fat, superficial and deep muscles, and deep fat pads through a 2- to 2.5-mm facial fat grafting cannula using a multichannel technique that leaves minute amounts of fat in each channel. Fat embolization may occur when a nonfacial fat graft cannula or needle used to transplant the fat graft enters an artery either through direct sharp puncture or traumatic tear cannulation.^4-9

Adverse Events

The first recorded manufactured adverse event from an injectable dermal filler was in 1991. At that time, the US Food and Drug Administration warned of adverse events secondary to collagen injections, including open sores, abscess formation associated with delayed healing of the skin, and partial blindness.¹⁰

Arterial Embolization and Cannulation. The most serious complications from dermal fillers are accidental injection and/or embolization of the filler into the arterial system. Since 1991, an increased number of cases of soft tissue necrosis, blindness, and stroke have been reported as a result of injection of fillers in the glabella, forehead creases, temple, crow’s feet, nose, cheeks, nasolabial folds, and lower lip.^11-15

Accidental cannulation and inadvertent injection of fillers into the arterial vessels can have catastrophic complications. The potential of such inadvertent complications occurs despite skill level of the practitioner or surgeon. Therefore, recognition and treatment of a vascular occlusion must be immediate and aggressive to avoid devastating and potentially irreversible complications including blindness, stroke, and death.^11-15

Acute Blindness and Stroke. The issues and concerns associated with local intra-arterial dermal filler injection and distal embolism are well described in the literature. However, the mechanism of retinal artery occlusion is much more complex given the need for deep placement of products and the force necessary to cause distention and elevation of the dermis. Hence, higher g-forces are applied via the plunger, forcing the intra-arterial filler proximally past the origin of the retinal artery. When the clinician stops the injection, the arterial systolic pressure immediately embolizes the filler into the distal branches of the ophthalmic artery. This causes acute pain and blindness (Figure 5). Depending on the g-force applied, filler can enter into the internal carotid artery and embolize resulting in cerebral ischemia. Signs of cerebral ischemia may be mild or overt.^4-9

Management

Patients with intra-arterial dermal filler injection constitute a medical emergency requiring immediate intervention. We recommend clinicians initiate the treatment protocols outlined in the Box and Table 1.

Hyaluronidase. Injection of hyaluronidase may assist in degrading the HA around the arterial puncture site, relieving compression, which may increase blood flow. There is a risk of distal embolization from a dislodged HA emboli.

Fat Graft Injections. There are no known degradation products for fat, CaHA, PLLA, or PMMA products. The use of normal saline or hyaluronidase has no proven efficacy and may increase the compression pressure in the artery and surrounding tissue, causing further ischemia.

Long-term Sequelae

Despite aggressive intervention, permanent complications of cerebral ischemia, blindness, and severe soft tissue necrosis may occur. In six cases in the literature, patients treated with ocular massage therapy,^7,14 carbon dioxide rebreathing,¹⁴ HBO therapy,^7,14 oral and IV corticosteroids,^6-9 antiplatelet drugs,⁶ and fibrinolytic agents,^7,16 or mechanical thrombolysis¹⁶ showed no clinical effects. Neither the treated nor the untreated patients in any of these case studies had any return of vision.^4-7,9,20-27

Conclusion

Although artificial dermal fillers such as HA, CaHA, PLLA, and PMMA, and autologous adipose tissue grafts offer a minimally invasive alternative to plastic surgical procedures, they are not without complication or adverse effects, such as the acute arterial occlusion experienced by both of our patients. Patients presenting to the ED with adverse effects from such procedures must be managed promptly, employing the suggested management and treatment protocol, including consultation with ophthalmology, plastic surgery, and neurological services as indicated, to avoid permanent sequela and damage.