Clinical Review

In this Update, I outline important findings from several studies published in the past year. First and foremost, what are best practices for performing colposcopy in the United States? The American Society for Colposcopy and Cervical Pathology (ASCCP) released guidelines addressing such practices. Second, what are the implications of repeated negative screening and patients’ acceptance of extended screening intervals? A recent observational cohort study and a large study of Kaiser Permanente’s practices since 2003 shed light on these questions. Last, where do we stand with HPV vaccination? Two studies shed light on the efficacy of vaccination against human papillomavirus (HPV), and subsequent cervical intraepithelial neoplasia (CIN) and cervical cancer.

ASCCP releases updated quality guidelines for performing colposcopy

Khan MJ, Werner CL, Darragh TM, et al. ASCCP colposcopy standards: Role of colposcopy, benefits, potential harms, and terminology for colposcopic practice. J Low Genit Tract Dis. 2017;21(4):223-229.

Waxman AG, Conageski C, Silver MI, et al. ASCCP colposcopy standards: How do we perform colposcopy? Implications for establishing standards. J Low Genit Tract Dis. 2017;21(4):235-241.

Wentzensen N, Schiffman M, Silver MI, et al. ASCCP colposcopy standards: Risk-based colposcopy practice. J Low Genit Tract Dis. 2017;21(4):230-234.

In October 2017, the ASCCP released a set of standards on the role and performance of colposcopy that represents best practices in women's health care in the United States. The work of these groups comprised a literature search, a national survey of ASCCP members, public comment, and expert consensus, and addressed:

• establishment of a common understanding of 1) the benefits of colposcopy in health maintenance and risk prevention, 2) risks presented by the procedure, and 3) terminology and criteria for reporting results that reduce subjectivity in reporting  
• the rationale for, approach to, and recommendations regarding assessment of cervical precancer at colposcopy
• both minimum and comprehensive guidelines for the colposcopic examination, from preprocedure evaluation to follow-up.

Each Working Group performed the analysis and produced its own report and recommendations, published sequentially in a 2017 issue of the Journal of Lower Urinary Tract Disease. The findings and standards that they produced 1) offer essential insight for high- and low-volume coloposcopists and 2) are intended to improve the quality of colposcopy, reduce subjectivity in reporting findings, and improve the sensitivity of the procedure. Aware of the concerns and objectives of payers and hospital credentialing committees, the ASCCP found it important to establish what would be considered US-based minimum quality standards and to present goals that providers and systems could strive to achieve.

Selected details of the 3 guideline reports

The past 6 years have brought us through a great deal of transition in the prevention of cervical precancer, with regard to screening intervals and types of screening (for example, see "HPV−cytology co-testing every 3 years lowers population rates of cervical precancer and cancer," in the 2017 "Cervical Disease Update," OBG Management, May 2017). The most significant change was in 2012, when American Cancer Society/ASCCP guidelines were revised to abandon screening with annual Pap testing on most patients--an effort to strike a balance between the lifesaving value of identifying precancer and the potential harm of excessive colposcopy.

If, as the US Preventive Services Task Force (USPSTF) has declared, excessive colposcopy is a harm of screening, then we should be adapting our practices, especially in terms of the frequency of screening, to 1) reduce the risk of unnecessarily screening and potentially triaging patients to colposcopy and 2) bring the highest standards of performance and reporting to colposcopic practice (see "Why aren't you doing a Pap on me?"). In other words, "This is the way I've always done it" shouldn't characterize efforts to detect disease, when the data are clear that doing less might be more beneficial for our patients. Adherence to extended screening intervals is not yet good enough to balance benefit and risk of harm, as Rendle and colleagues showed in an article this year in Preventive Medicine (discussed in the next section of this "Update"). We need to do better.

Here is a limited encapsulation of the 3 wide-ranging reports on the ASCCP colposcopy recommendations:

Role of colposcopy; benefits, potential harms, terminology (Khan et al; Working Group 1). The authors provide reinforcement: The strategic benefit of colposcopy is clear--a "drastic" reduction in excisional procedures by limiting them to patients in whom cervical cancer precursors have been confirmed or who present a high risk of occult invasive cervical cancer. Furthermore, the rate of adverse events for colposcopy−including significant bleeding and infection−is low.

Nevertheless, the potential for harm exists when an unskilled provider performs colposcopy; the Working Group emphasizes that proficiency comes with training and experience. Even in skilled hands, however, anxiety and the discomfort of a speculum examination and from acetic acid, as well as cramping and pain, might dissuade some women from receiving regular cervical screening subsequently. The authors cite research showing that educational interventions can help soothe anxiety about colposcopy and potential findings,^1,2 although consensus is lacking on the value of such interventions.

The Working Group 1) developed recommended terminology for reporting findings in colposcopy practice in the United States and 2) defined the comprehensive documentation of the procedure as comprising cervix and squamocolumnar junction visibility; acetowhitening; presence of a lesion; lesion visibility, size and location of lesion(s); vascular changes; other features; and colposcopic impression (TABLE 1).³ Minimum criteria for reporting colposcopy results were also proposed, extracted from the comprehensive standards.

Risk-based colposcopy practice (Wentzensen et al). Women referred to colposcopy present with a range of underlying risk of precancer. Assessing that risk at the colposcopy visit allows the provider to modify and individualize the procedure. Risk can be estimated by referral screening tests (eg, cytology, HPV testing) performed in conjunction with the colposcopic impression. As opposed to a lack of standards for a minimum number of biopsies, the Working Group recommends that, as a standard, multiple targeted biopsies (≥2, as many as 4) are needed to improve detection of prevalent precancers. Colposcopic impression alone is not enough to diagnose precancerous cells. Let's face it: Our eyes with a colposcopic magnification of 15X do not make a microscope.

Implementing the Working Group's recommendations is expected to lead to improved detection of cervical precancers at colposcopy and to provide stronger reassurance of negative colposcopy results. Regarding biopsy of lesions, ASCCP did not find added benefit to taking random (nondirected) biopsies for women at low risk for precancer. The sensitivity of biopsy is increased by taking multiple biopsies of suspicious lesions, based on a risk-based approach detailed in the ASCCP guidelines. So, depending on underlying risk (estimated from screening and triage tests), colposcopy practice can be adapted in a useful manner to account for differences in risk:

• When risk of precancer is very high, for example, immediate treatment might reduce cost and prevent the patient from being lost to follow-up. When risk is very low, consider expectant management (serial cytology and HPV testing) with limited need for biopsy. In a setting of intermediate risk, the Working Group proposes, "multiple biopsies of acetowhite lesions lead to increased detection of precancer."
• Perform multiple biopsies that target all areas characterized by 1) acetowhitening, 2) metaplasia, and 3) higher abnormalities.
• Do not perform nontargeted biopsies on patients at the lowest end of risk who have been referred to colposcopy−ie, those with cytology that is less than HSIL; no evidence of HPV types 16/18; and a normal colposcopic impression (ie, no acetowhitening or metaplasia, or other visible abnormality).  
• Immediate excision without biopsy confirmation or colposcopy with multiple targeted biopsies is acceptable in nonpregnant women 25 years and older whose risk of precancer is very high (≥2 of the following: HSIL cytology, HPV 16- or HPV 18-positive(or both), and high-grade colposcopy impression). Endocervical sampling should be conducted according to ASCCP's 2012 management guidelines. If biopsies do not show precancer, manage the patient using ASCCP's 2012 management guidelines, the Working Group recommends.

How do we perform colposcopy? Implications for establishing standards (Waxman et al; Working Group 3). To serve as a guide to standardizing colposcopy across the United States, the authors defined and delineated 6 major components (and their constituent parts) of a comprehensive colposcopy:

• precolposcopy evaluation
• the examination
• use of colposcopy adjuncts
• documentation
• biopsy sampling
• postcolposcopy procedures.

The constituent parts of these components are laid out in TABLE 2.⁴ A set of components for a minimum colposcopy procedure is drawn mostly from the comprehensive protocol.

The Working Group acknowledges that, in the United States, "the accuracy and reproducibility of colposcopy with biopsy as a diagnostic tool are limited." Why? Three contributing factors, the authors write, might be the absence of practice recommendations for colposcopy-biopsy procedures; of measures of quality assurance; and of standardized terminology.

Standards arrive for practice

Minimum quality standards are becoming part of almost everything US health care providers do−whether it is documentation, billing practices, or good care. Our work in gynecology, including colposcopy, is now being assessed as it is in much of the world, where minimum standards are already in place and guidelines must be followed. (In some countries standards require performing a minimum number of colposcopies per year to be identified as a "certified" colposcopist.)

What should be considered "minimum standards" for colposcopy in the United States? These ASCCP reports ask, and deliver answers to that question, bringing a broad range of concerns about high-quality practice into focus. Physicians and advanced-practice clinicians in this country who perform colposcopies have been trained to do so, but they have never had minimum standards by which to model and assess their performance. A procedure that has the potential to lead to additional testing for either cervical cancer, or to surveillance, should have minimum standards by which it is performed and documented in the United States as it is for much of the world that has widespread cervical cancer screening.

Read about adherence to cervical cancer screening.

Cervical screening adherence is relatively low, but safe. Extended intervals are very safe.

Castle PE, Kinney WK, Xue X, et al. Effect of several negative rounds of human papillomavirus and cytology co-testing on safety against cervical cancer: an observational cohort study. Ann Intern Med. 2018;168(1):20-29.

Rendle KA, Schiffman M, Cheung LC, et al. Adherence patterns to extended cervical screening intervals in women undergoing human papillomavirus (HPV) and cytology cotesting. Prev Med. 2018;109:44-50.

Patients who have been screened for cervical cancer for a long time--decades, even--have a diminishing likelihood that cancer will ever be detected. Furthermore, highest-risk patients already have been triaged into further testing or procedures, such as a loop excision electrosurgical procedure or hysterectomy. Two recent studies examined the implications of repeated negative screening and patients' acceptance of extended screening intervals.

Details of the studies

Several negative rounds of cotesting (HPV and cytology) might justify changes to the screening interval. To determine the rate of detection of CIN3, adenocarcinoma in situ, and cervical cancer (≥CIN3) in routine practice after successive negative screening at 3-year intervals, Castle and colleagues looked at records of more than 990,000 women in an integrated health care system who underwent cotesting (HPV and cytology) between 2003 and 2014. They determined that the risk of invasive cervical cancer and ≥CIN3 declined with each round of cotesting; the absolute risk fell more between first and second rounds than between second and third rounds.

At any given round of cotesting, Castle found that the ability to reassure a patient about cancer and cancer risk was similar when looking at an HPV result alone, whatever the cytology or HPV-cytology cotest result was. The investigators concluded that similar patterns of risk would have been seen had stand-alone HPV testing been used, instead of co-testing, (HPV testing alone might have missed a few cases of CIN3 and adenocarcinoma in situ leading to cancer). A single negative cotest was so effective at ruling out ≥CIN3 and cervical cancer that, after a second round of cotesting, they found that no interval cancer cases were detected among women who had a negative HPV result.

Women aged 50 years or older had a 5- to 6-fold lower risk after their third consecutive negative cotest than women aged 30 to 39 years had after their first negative cotest. These data support the ideas, Castle noted, that 1) assigning screening intervals based on both age and number of previous negative screens and 2) extending the screening interval even further than 3 years after 2--perhaps even after 1--negative cotests or HPV tests are worth entertaining. Screening women of this age becomes inefficient and cost-ineffective, even at 5-year intervals.

Is patients' adherence to an extended interval of cotesting reliable enough to change practice? Rendle and colleagues examined the records of more than 491,000 women (in the same integrated health care system that Castle studied) who had undergone routine cervical cancer screening between 2003 and 2015. Their goal was to determine how high adherence had become to the system's recommendation of an every-3-year screening interval--an interval that mirrors long-standing guidelines elsewhere.

In short, researchers observed increasing and relatively rapid clinical adoption of every-3-year cotesting for routine cervical screening over time; between 2003 and 2009, the cohort grew significantly less likely overall to come in early for screening. In this setting, adoption of an extended screeninginterval appears to run counter to earlier understanding that patients are likely to resist such extension.

Women aged 60 to 64 were most likely to screen early across 2 consecutive intervals. What Rendle termed a "modest" decrease in the percentage of late screeners (but still within a 5-year interval) was also noted during adoption of the 3-year interval.

What next?

Molecular-based testing. Research, mostly outside of the United States, is taking us in the direction of molecular-based technologies as at least a component of cervical cancer screening. Today, we rely mostly on Pap tests and colposcopy, but these are subjective screens, with a human operator. With molecular testing (mostly of components of HPV), results are objective--a "Yes" or "No" finding based on clinically validated thresholds. Methods such as genotyping, P16^INK4a/Ki-67 gene product dual-stain cytology, and testing for E6 and E7 HPV mRNA transcripts are in development, and hold promise to allow us to screen safely using almost completely molecular testing, thus eliminating human error and subjectivity and enriching the population that needs further management with very sensitive and potentially specific testing.

We are being presented with the possibility that almost all aspects of screening can be done without a provider, until the patient needs treatment.

Access to screening. Research is also looking at improving access, such as self-sampling for primary screening. That includes home cervical and vaginal sampling, with specimens mailed to the laboratory, from where results and follow-up instructions as communicated to patients. The Netherlands and the United Kingdom are moving to self-sampling primary screens; the United States is not--yet. But that is the direction research is taking us.

Modified guidelines. Eyes are on the work of the USPSTF. Last year, the Task Force issued draft recommendations (https://www.uspre ventiveservicestaskforce.org/Page/Document/draft-recommendation-statement/cervical-cancer-screening2#clinical), followed by a comment period (now closed), for updating 2012 cervical cancer screening guidelines in a way that would trigger a major change in clinical practice. Those draft recommendations and public comments are under review; final recommendations are possible within this calendar year.  

Read about the safety and efficacy of HPV vaccination.

Primary prevention of cervical cancer with vaccination is critical in any cancer prevention program

Benard VB, Castle PE, Jenison SA, et al; New Mexico HPV Pap Registry Steering Committee. Population-based incidence rates of cervical intraepithelial neoplasia in the human papillomavirus vaccine era. JAMA Oncol. 2017;3(6):833-837.

Luostarinen T, Apter D, Dillner J, et al. Vaccination protects against invasive HPV-associated cancers. Int J Cancer. 2018;142(10):2186-2187.

The success story of HPV vaccination, after more than a decade of use, continued to unfold in important ways over the past year.

Safety. With tens of millions of doses delivered, we know that the vaccine is safe, and we have retreated on some of the precautions that we once took: For example, we no longer perform a routine pregnancy test before vaccination on reproductive-age women.

Efficacy. We have learned, based on what we see in Australia and Western Europe, that vaccination is highly effective. We are also starting to see evidence of efficacy in areas of the United States, even though the vaccine is voluntary and there are no school-based recommendations. And we know that herd vaccination is very effective. The 2 studies described here add to our understanding of how vaccination is having an impact on endpoints.

Findings of the 2 studies

HPV vaccination has a direct impact on the precursor of cancer, CIN. Benard and colleagues examined data from the New Mexico HPV Pap Registry, a mandatory statewide surveillance system of cervical cancer screening that captured estimates of both screening prevalence and CIN since the time HPV vaccination was introduced in 2007 to 2014. The investigators examined registry data to gauge trends in the rate of CIN and to estimate the effect of HPV vaccination on that rate when adjusted for changes in screening for cervical cancer.

The incidence of CIN declined significantly across all grades in 2 groups between 2007 and 2015: females aged 15 to 19 years and females aged 20 to 24 years (but not in females 25 to 29 years of age). During those years, mean uptake of HPV vaccination among females 13 to 17 years of age reached as high as 40% (in 2014).

Although a reduction in CIN2 and CIN3 precancers "are early benchmarks for achieving this aim [of reducing the rate of cancer]," the investigators note, a reduction in CIN1 is "a direct measure of reductions in HPV infections requisite to the development of almost all invasive cervical cancer."

Benard moves on to conclude that a reduction in clinical outcomes of CIN among groups who are partially vaccinated for HPV is going to change clinical practice and reduce the cost-effectiveness of clinical care that supports prevention of cervical cancer. Of greatest importance, modalities and strategies for screening, and management algorithms, are going to need to evolve as HPV vaccination and cervical screening are integrated in a rational manner. Furthermore, it might be feasible to factor in population-level decreases in CIN among cohorts who are partially vaccinated for HPV when reassessing clinical practice guidelines for cervical cancer screening.

What does this mean? As we start to eliminate HPV from the population, any positive screening result will be that much more meaningful because the outcome--cervical cancer--will be much rarer. The onus will be on providers and public health officials to re-strategize how to screen what is going to be a widely-vaccinated population; more and more, we will be looking for needles in a haystack.

How are we going to someday screen women in their 20s who were vaccinated at 11 or 12 years of age? Likely, screening will start at a later age, and screening will be conducted at longer intervals. Any finding of HPV or disease is going to be highly significant, and likely, far less frequent.

HPV vaccination protects against invasive HPV-associated cancer. Luostarinen and colleagues report proof of highly efficacious protection offered by a population-based HPV vaccination program in Finland, in the form of a decrease in the key endpoint: cases of invasive HPV-associated cancer. Examining vaccinated (3,331 females) and unvaccinated (15,665 females) cohorts in the nationwide Finnish Cancer Registry, the investigators identified 10 cases of HPV-caused cancer (8 cervical, 1 oropharyngeal, 1 vulvar) in the unvaccinated females and 0 cases in vaccinated females--a statistically significant difference.

From the evidence gathered in this first intention-to-treat trial, the investigators conclude that vaccination protects against invasive HPV-associated cancer--what they call "an awaited, pivotal corollary" to high vaccine efficacy against HPV infection.

Summing up

This success story continues to unfold, despite well-organized, antivaccine campaigns. The HPV vaccine has been an easy target: It is novel, it involves a sexually transmitted infection, and the endpoint of protecting against invasive HPV-associated cancer is years--decades--away. But antivaccine groups can no longer argue the point that studies have not been designed to yield evidence of the impact of the vaccine on decisive endpoints, including cervical cancer.

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.

In this Update, I outline important findings from several studies published in the past year. First and foremost, what are best practices for performing colposcopy in the United States? The American Society for Colposcopy and Cervical Pathology (ASCCP) released guidelines addressing such practices. Second, what are the implications of repeated negative screening and patients’ acceptance of extended screening intervals? A recent observational cohort study and a large study of Kaiser Permanente’s practices since 2003 shed light on these questions. Last, where do we stand with HPV vaccination? Two studies shed light on the efficacy of vaccination against human papillomavirus (HPV), and subsequent cervical intraepithelial neoplasia (CIN) and cervical cancer.

ASCCP releases updated quality guidelines for performing colposcopy

Khan MJ, Werner CL, Darragh TM, et al. ASCCP colposcopy standards: Role of colposcopy, benefits, potential harms, and terminology for colposcopic practice. J Low Genit Tract Dis. 2017;21(4):223-229.

Waxman AG, Conageski C, Silver MI, et al. ASCCP colposcopy standards: How do we perform colposcopy? Implications for establishing standards. J Low Genit Tract Dis. 2017;21(4):235-241.

Wentzensen N, Schiffman M, Silver MI, et al. ASCCP colposcopy standards: Risk-based colposcopy practice. J Low Genit Tract Dis. 2017;21(4):230-234.

In October 2017, the ASCCP released a set of standards on the role and performance of colposcopy that represents best practices in women's health care in the United States. The work of these groups comprised a literature search, a national survey of ASCCP members, public comment, and expert consensus, and addressed:

• establishment of a common understanding of 1) the benefits of colposcopy in health maintenance and risk prevention, 2) risks presented by the procedure, and 3) terminology and criteria for reporting results that reduce subjectivity in reporting  
• the rationale for, approach to, and recommendations regarding assessment of cervical precancer at colposcopy
• both minimum and comprehensive guidelines for the colposcopic examination, from preprocedure evaluation to follow-up.

Each Working Group performed the analysis and produced its own report and recommendations, published sequentially in a 2017 issue of the Journal of Lower Urinary Tract Disease. The findings and standards that they produced 1) offer essential insight for high- and low-volume coloposcopists and 2) are intended to improve the quality of colposcopy, reduce subjectivity in reporting findings, and improve the sensitivity of the procedure. Aware of the concerns and objectives of payers and hospital credentialing committees, the ASCCP found it important to establish what would be considered US-based minimum quality standards and to present goals that providers and systems could strive to achieve.

Selected details of the 3 guideline reports

The past 6 years have brought us through a great deal of transition in the prevention of cervical precancer, with regard to screening intervals and types of screening (for example, see "HPV−cytology co-testing every 3 years lowers population rates of cervical precancer and cancer," in the 2017 "Cervical Disease Update," OBG Management, May 2017). The most significant change was in 2012, when American Cancer Society/ASCCP guidelines were revised to abandon screening with annual Pap testing on most patients--an effort to strike a balance between the lifesaving value of identifying precancer and the potential harm of excessive colposcopy.

If, as the US Preventive Services Task Force (USPSTF) has declared, excessive colposcopy is a harm of screening, then we should be adapting our practices, especially in terms of the frequency of screening, to 1) reduce the risk of unnecessarily screening and potentially triaging patients to colposcopy and 2) bring the highest standards of performance and reporting to colposcopic practice (see "Why aren't you doing a Pap on me?"). In other words, "This is the way I've always done it" shouldn't characterize efforts to detect disease, when the data are clear that doing less might be more beneficial for our patients. Adherence to extended screening intervals is not yet good enough to balance benefit and risk of harm, as Rendle and colleagues showed in an article this year in Preventive Medicine (discussed in the next section of this "Update"). We need to do better.

Here is a limited encapsulation of the 3 wide-ranging reports on the ASCCP colposcopy recommendations:

Role of colposcopy; benefits, potential harms, terminology (Khan et al; Working Group 1). The authors provide reinforcement: The strategic benefit of colposcopy is clear--a "drastic" reduction in excisional procedures by limiting them to patients in whom cervical cancer precursors have been confirmed or who present a high risk of occult invasive cervical cancer. Furthermore, the rate of adverse events for colposcopy−including significant bleeding and infection−is low.

Nevertheless, the potential for harm exists when an unskilled provider performs colposcopy; the Working Group emphasizes that proficiency comes with training and experience. Even in skilled hands, however, anxiety and the discomfort of a speculum examination and from acetic acid, as well as cramping and pain, might dissuade some women from receiving regular cervical screening subsequently. The authors cite research showing that educational interventions can help soothe anxiety about colposcopy and potential findings,^1,2 although consensus is lacking on the value of such interventions.

The Working Group 1) developed recommended terminology for reporting findings in colposcopy practice in the United States and 2) defined the comprehensive documentation of the procedure as comprising cervix and squamocolumnar junction visibility; acetowhitening; presence of a lesion; lesion visibility, size and location of lesion(s); vascular changes; other features; and colposcopic impression (TABLE 1).³ Minimum criteria for reporting colposcopy results were also proposed, extracted from the comprehensive standards.

Risk-based colposcopy practice (Wentzensen et al). Women referred to colposcopy present with a range of underlying risk of precancer. Assessing that risk at the colposcopy visit allows the provider to modify and individualize the procedure. Risk can be estimated by referral screening tests (eg, cytology, HPV testing) performed in conjunction with the colposcopic impression. As opposed to a lack of standards for a minimum number of biopsies, the Working Group recommends that, as a standard, multiple targeted biopsies (≥2, as many as 4) are needed to improve detection of prevalent precancers. Colposcopic impression alone is not enough to diagnose precancerous cells. Let's face it: Our eyes with a colposcopic magnification of 15X do not make a microscope.

Implementing the Working Group's recommendations is expected to lead to improved detection of cervical precancers at colposcopy and to provide stronger reassurance of negative colposcopy results. Regarding biopsy of lesions, ASCCP did not find added benefit to taking random (nondirected) biopsies for women at low risk for precancer. The sensitivity of biopsy is increased by taking multiple biopsies of suspicious lesions, based on a risk-based approach detailed in the ASCCP guidelines. So, depending on underlying risk (estimated from screening and triage tests), colposcopy practice can be adapted in a useful manner to account for differences in risk:

• When risk of precancer is very high, for example, immediate treatment might reduce cost and prevent the patient from being lost to follow-up. When risk is very low, consider expectant management (serial cytology and HPV testing) with limited need for biopsy. In a setting of intermediate risk, the Working Group proposes, "multiple biopsies of acetowhite lesions lead to increased detection of precancer."
• Perform multiple biopsies that target all areas characterized by 1) acetowhitening, 2) metaplasia, and 3) higher abnormalities.
• Do not perform nontargeted biopsies on patients at the lowest end of risk who have been referred to colposcopy−ie, those with cytology that is less than HSIL; no evidence of HPV types 16/18; and a normal colposcopic impression (ie, no acetowhitening or metaplasia, or other visible abnormality).  
• Immediate excision without biopsy confirmation or colposcopy with multiple targeted biopsies is acceptable in nonpregnant women 25 years and older whose risk of precancer is very high (≥2 of the following: HSIL cytology, HPV 16- or HPV 18-positive(or both), and high-grade colposcopy impression). Endocervical sampling should be conducted according to ASCCP's 2012 management guidelines. If biopsies do not show precancer, manage the patient using ASCCP's 2012 management guidelines, the Working Group recommends.

How do we perform colposcopy? Implications for establishing standards (Waxman et al; Working Group 3). To serve as a guide to standardizing colposcopy across the United States, the authors defined and delineated 6 major components (and their constituent parts) of a comprehensive colposcopy:

• precolposcopy evaluation
• the examination
• use of colposcopy adjuncts
• documentation
• biopsy sampling
• postcolposcopy procedures.

The constituent parts of these components are laid out in TABLE 2.⁴ A set of components for a minimum colposcopy procedure is drawn mostly from the comprehensive protocol.

The Working Group acknowledges that, in the United States, "the accuracy and reproducibility of colposcopy with biopsy as a diagnostic tool are limited." Why? Three contributing factors, the authors write, might be the absence of practice recommendations for colposcopy-biopsy procedures; of measures of quality assurance; and of standardized terminology.

Standards arrive for practice

Minimum quality standards are becoming part of almost everything US health care providers do−whether it is documentation, billing practices, or good care. Our work in gynecology, including colposcopy, is now being assessed as it is in much of the world, where minimum standards are already in place and guidelines must be followed. (In some countries standards require performing a minimum number of colposcopies per year to be identified as a "certified" colposcopist.)

What should be considered "minimum standards" for colposcopy in the United States? These ASCCP reports ask, and deliver answers to that question, bringing a broad range of concerns about high-quality practice into focus. Physicians and advanced-practice clinicians in this country who perform colposcopies have been trained to do so, but they have never had minimum standards by which to model and assess their performance. A procedure that has the potential to lead to additional testing for either cervical cancer, or to surveillance, should have minimum standards by which it is performed and documented in the United States as it is for much of the world that has widespread cervical cancer screening.

Read about adherence to cervical cancer screening.

Cervical screening adherence is relatively low, but safe. Extended intervals are very safe.

Castle PE, Kinney WK, Xue X, et al. Effect of several negative rounds of human papillomavirus and cytology co-testing on safety against cervical cancer: an observational cohort study. Ann Intern Med. 2018;168(1):20-29.

Rendle KA, Schiffman M, Cheung LC, et al. Adherence patterns to extended cervical screening intervals in women undergoing human papillomavirus (HPV) and cytology cotesting. Prev Med. 2018;109:44-50.

Patients who have been screened for cervical cancer for a long time--decades, even--have a diminishing likelihood that cancer will ever be detected. Furthermore, highest-risk patients already have been triaged into further testing or procedures, such as a loop excision electrosurgical procedure or hysterectomy. Two recent studies examined the implications of repeated negative screening and patients' acceptance of extended screening intervals.

Details of the studies

Several negative rounds of cotesting (HPV and cytology) might justify changes to the screening interval. To determine the rate of detection of CIN3, adenocarcinoma in situ, and cervical cancer (≥CIN3) in routine practice after successive negative screening at 3-year intervals, Castle and colleagues looked at records of more than 990,000 women in an integrated health care system who underwent cotesting (HPV and cytology) between 2003 and 2014. They determined that the risk of invasive cervical cancer and ≥CIN3 declined with each round of cotesting; the absolute risk fell more between first and second rounds than between second and third rounds.

At any given round of cotesting, Castle found that the ability to reassure a patient about cancer and cancer risk was similar when looking at an HPV result alone, whatever the cytology or HPV-cytology cotest result was. The investigators concluded that similar patterns of risk would have been seen had stand-alone HPV testing been used, instead of co-testing, (HPV testing alone might have missed a few cases of CIN3 and adenocarcinoma in situ leading to cancer). A single negative cotest was so effective at ruling out ≥CIN3 and cervical cancer that, after a second round of cotesting, they found that no interval cancer cases were detected among women who had a negative HPV result.

Women aged 50 years or older had a 5- to 6-fold lower risk after their third consecutive negative cotest than women aged 30 to 39 years had after their first negative cotest. These data support the ideas, Castle noted, that 1) assigning screening intervals based on both age and number of previous negative screens and 2) extending the screening interval even further than 3 years after 2--perhaps even after 1--negative cotests or HPV tests are worth entertaining. Screening women of this age becomes inefficient and cost-ineffective, even at 5-year intervals.

Is patients' adherence to an extended interval of cotesting reliable enough to change practice? Rendle and colleagues examined the records of more than 491,000 women (in the same integrated health care system that Castle studied) who had undergone routine cervical cancer screening between 2003 and 2015. Their goal was to determine how high adherence had become to the system's recommendation of an every-3-year screening interval--an interval that mirrors long-standing guidelines elsewhere.

In short, researchers observed increasing and relatively rapid clinical adoption of every-3-year cotesting for routine cervical screening over time; between 2003 and 2009, the cohort grew significantly less likely overall to come in early for screening. In this setting, adoption of an extended screeninginterval appears to run counter to earlier understanding that patients are likely to resist such extension.

Women aged 60 to 64 were most likely to screen early across 2 consecutive intervals. What Rendle termed a "modest" decrease in the percentage of late screeners (but still within a 5-year interval) was also noted during adoption of the 3-year interval.

What next?

Molecular-based testing. Research, mostly outside of the United States, is taking us in the direction of molecular-based technologies as at least a component of cervical cancer screening. Today, we rely mostly on Pap tests and colposcopy, but these are subjective screens, with a human operator. With molecular testing (mostly of components of HPV), results are objective--a "Yes" or "No" finding based on clinically validated thresholds. Methods such as genotyping, P16^INK4a/Ki-67 gene product dual-stain cytology, and testing for E6 and E7 HPV mRNA transcripts are in development, and hold promise to allow us to screen safely using almost completely molecular testing, thus eliminating human error and subjectivity and enriching the population that needs further management with very sensitive and potentially specific testing.

We are being presented with the possibility that almost all aspects of screening can be done without a provider, until the patient needs treatment.

Access to screening. Research is also looking at improving access, such as self-sampling for primary screening. That includes home cervical and vaginal sampling, with specimens mailed to the laboratory, from where results and follow-up instructions as communicated to patients. The Netherlands and the United Kingdom are moving to self-sampling primary screens; the United States is not--yet. But that is the direction research is taking us.

Modified guidelines. Eyes are on the work of the USPSTF. Last year, the Task Force issued draft recommendations (https://www.uspre ventiveservicestaskforce.org/Page/Document/draft-recommendation-statement/cervical-cancer-screening2#clinical), followed by a comment period (now closed), for updating 2012 cervical cancer screening guidelines in a way that would trigger a major change in clinical practice. Those draft recommendations and public comments are under review; final recommendations are possible within this calendar year.  

Read about the safety and efficacy of HPV vaccination.

Primary prevention of cervical cancer with vaccination is critical in any cancer prevention program

Benard VB, Castle PE, Jenison SA, et al; New Mexico HPV Pap Registry Steering Committee. Population-based incidence rates of cervical intraepithelial neoplasia in the human papillomavirus vaccine era. JAMA Oncol. 2017;3(6):833-837.

Luostarinen T, Apter D, Dillner J, et al. Vaccination protects against invasive HPV-associated cancers. Int J Cancer. 2018;142(10):2186-2187.

The success story of HPV vaccination, after more than a decade of use, continued to unfold in important ways over the past year.

Safety. With tens of millions of doses delivered, we know that the vaccine is safe, and we have retreated on some of the precautions that we once took: For example, we no longer perform a routine pregnancy test before vaccination on reproductive-age women.

Efficacy. We have learned, based on what we see in Australia and Western Europe, that vaccination is highly effective. We are also starting to see evidence of efficacy in areas of the United States, even though the vaccine is voluntary and there are no school-based recommendations. And we know that herd vaccination is very effective. The 2 studies described here add to our understanding of how vaccination is having an impact on endpoints.

Findings of the 2 studies

HPV vaccination has a direct impact on the precursor of cancer, CIN. Benard and colleagues examined data from the New Mexico HPV Pap Registry, a mandatory statewide surveillance system of cervical cancer screening that captured estimates of both screening prevalence and CIN since the time HPV vaccination was introduced in 2007 to 2014. The investigators examined registry data to gauge trends in the rate of CIN and to estimate the effect of HPV vaccination on that rate when adjusted for changes in screening for cervical cancer.

The incidence of CIN declined significantly across all grades in 2 groups between 2007 and 2015: females aged 15 to 19 years and females aged 20 to 24 years (but not in females 25 to 29 years of age). During those years, mean uptake of HPV vaccination among females 13 to 17 years of age reached as high as 40% (in 2014).

Although a reduction in CIN2 and CIN3 precancers "are early benchmarks for achieving this aim [of reducing the rate of cancer]," the investigators note, a reduction in CIN1 is "a direct measure of reductions in HPV infections requisite to the development of almost all invasive cervical cancer."

Benard moves on to conclude that a reduction in clinical outcomes of CIN among groups who are partially vaccinated for HPV is going to change clinical practice and reduce the cost-effectiveness of clinical care that supports prevention of cervical cancer. Of greatest importance, modalities and strategies for screening, and management algorithms, are going to need to evolve as HPV vaccination and cervical screening are integrated in a rational manner. Furthermore, it might be feasible to factor in population-level decreases in CIN among cohorts who are partially vaccinated for HPV when reassessing clinical practice guidelines for cervical cancer screening.

What does this mean? As we start to eliminate HPV from the population, any positive screening result will be that much more meaningful because the outcome--cervical cancer--will be much rarer. The onus will be on providers and public health officials to re-strategize how to screen what is going to be a widely-vaccinated population; more and more, we will be looking for needles in a haystack.

How are we going to someday screen women in their 20s who were vaccinated at 11 or 12 years of age? Likely, screening will start at a later age, and screening will be conducted at longer intervals. Any finding of HPV or disease is going to be highly significant, and likely, far less frequent.

HPV vaccination protects against invasive HPV-associated cancer. Luostarinen and colleagues report proof of highly efficacious protection offered by a population-based HPV vaccination program in Finland, in the form of a decrease in the key endpoint: cases of invasive HPV-associated cancer. Examining vaccinated (3,331 females) and unvaccinated (15,665 females) cohorts in the nationwide Finnish Cancer Registry, the investigators identified 10 cases of HPV-caused cancer (8 cervical, 1 oropharyngeal, 1 vulvar) in the unvaccinated females and 0 cases in vaccinated females--a statistically significant difference.

From the evidence gathered in this first intention-to-treat trial, the investigators conclude that vaccination protects against invasive HPV-associated cancer--what they call "an awaited, pivotal corollary" to high vaccine efficacy against HPV infection.

Summing up

This success story continues to unfold, despite well-organized, antivaccine campaigns. The HPV vaccine has been an easy target: It is novel, it involves a sexually transmitted infection, and the endpoint of protecting against invasive HPV-associated cancer is years--decades--away. But antivaccine groups can no longer argue the point that studies have not been designed to yield evidence of the impact of the vaccine on decisive endpoints, including cervical cancer.

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.

In this Update, I outline important findings from several studies published in the past year. First and foremost, what are best practices for performing colposcopy in the United States? The American Society for Colposcopy and Cervical Pathology (ASCCP) released guidelines addressing such practices. Second, what are the implications of repeated negative screening and patients’ acceptance of extended screening intervals? A recent observational cohort study and a large study of Kaiser Permanente’s practices since 2003 shed light on these questions. Last, where do we stand with HPV vaccination? Two studies shed light on the efficacy of vaccination against human papillomavirus (HPV), and subsequent cervical intraepithelial neoplasia (CIN) and cervical cancer.

ASCCP releases updated quality guidelines for performing colposcopy

Khan MJ, Werner CL, Darragh TM, et al. ASCCP colposcopy standards: Role of colposcopy, benefits, potential harms, and terminology for colposcopic practice. J Low Genit Tract Dis. 2017;21(4):223-229.

Waxman AG, Conageski C, Silver MI, et al. ASCCP colposcopy standards: How do we perform colposcopy? Implications for establishing standards. J Low Genit Tract Dis. 2017;21(4):235-241.

Wentzensen N, Schiffman M, Silver MI, et al. ASCCP colposcopy standards: Risk-based colposcopy practice. J Low Genit Tract Dis. 2017;21(4):230-234.

In October 2017, the ASCCP released a set of standards on the role and performance of colposcopy that represents best practices in women's health care in the United States. The work of these groups comprised a literature search, a national survey of ASCCP members, public comment, and expert consensus, and addressed:

• establishment of a common understanding of 1) the benefits of colposcopy in health maintenance and risk prevention, 2) risks presented by the procedure, and 3) terminology and criteria for reporting results that reduce subjectivity in reporting  
• the rationale for, approach to, and recommendations regarding assessment of cervical precancer at colposcopy
• both minimum and comprehensive guidelines for the colposcopic examination, from preprocedure evaluation to follow-up.

Each Working Group performed the analysis and produced its own report and recommendations, published sequentially in a 2017 issue of the Journal of Lower Urinary Tract Disease. The findings and standards that they produced 1) offer essential insight for high- and low-volume coloposcopists and 2) are intended to improve the quality of colposcopy, reduce subjectivity in reporting findings, and improve the sensitivity of the procedure. Aware of the concerns and objectives of payers and hospital credentialing committees, the ASCCP found it important to establish what would be considered US-based minimum quality standards and to present goals that providers and systems could strive to achieve.

Selected details of the 3 guideline reports

The past 6 years have brought us through a great deal of transition in the prevention of cervical precancer, with regard to screening intervals and types of screening (for example, see "HPV−cytology co-testing every 3 years lowers population rates of cervical precancer and cancer," in the 2017 "Cervical Disease Update," OBG Management, May 2017). The most significant change was in 2012, when American Cancer Society/ASCCP guidelines were revised to abandon screening with annual Pap testing on most patients--an effort to strike a balance between the lifesaving value of identifying precancer and the potential harm of excessive colposcopy.

If, as the US Preventive Services Task Force (USPSTF) has declared, excessive colposcopy is a harm of screening, then we should be adapting our practices, especially in terms of the frequency of screening, to 1) reduce the risk of unnecessarily screening and potentially triaging patients to colposcopy and 2) bring the highest standards of performance and reporting to colposcopic practice (see "Why aren't you doing a Pap on me?"). In other words, "This is the way I've always done it" shouldn't characterize efforts to detect disease, when the data are clear that doing less might be more beneficial for our patients. Adherence to extended screening intervals is not yet good enough to balance benefit and risk of harm, as Rendle and colleagues showed in an article this year in Preventive Medicine (discussed in the next section of this "Update"). We need to do better.

Here is a limited encapsulation of the 3 wide-ranging reports on the ASCCP colposcopy recommendations:

Role of colposcopy; benefits, potential harms, terminology (Khan et al; Working Group 1). The authors provide reinforcement: The strategic benefit of colposcopy is clear--a "drastic" reduction in excisional procedures by limiting them to patients in whom cervical cancer precursors have been confirmed or who present a high risk of occult invasive cervical cancer. Furthermore, the rate of adverse events for colposcopy−including significant bleeding and infection−is low.

Nevertheless, the potential for harm exists when an unskilled provider performs colposcopy; the Working Group emphasizes that proficiency comes with training and experience. Even in skilled hands, however, anxiety and the discomfort of a speculum examination and from acetic acid, as well as cramping and pain, might dissuade some women from receiving regular cervical screening subsequently. The authors cite research showing that educational interventions can help soothe anxiety about colposcopy and potential findings,^1,2 although consensus is lacking on the value of such interventions.

The Working Group 1) developed recommended terminology for reporting findings in colposcopy practice in the United States and 2) defined the comprehensive documentation of the procedure as comprising cervix and squamocolumnar junction visibility; acetowhitening; presence of a lesion; lesion visibility, size and location of lesion(s); vascular changes; other features; and colposcopic impression (TABLE 1).³ Minimum criteria for reporting colposcopy results were also proposed, extracted from the comprehensive standards.

Risk-based colposcopy practice (Wentzensen et al). Women referred to colposcopy present with a range of underlying risk of precancer. Assessing that risk at the colposcopy visit allows the provider to modify and individualize the procedure. Risk can be estimated by referral screening tests (eg, cytology, HPV testing) performed in conjunction with the colposcopic impression. As opposed to a lack of standards for a minimum number of biopsies, the Working Group recommends that, as a standard, multiple targeted biopsies (≥2, as many as 4) are needed to improve detection of prevalent precancers. Colposcopic impression alone is not enough to diagnose precancerous cells. Let's face it: Our eyes with a colposcopic magnification of 15X do not make a microscope.

Implementing the Working Group's recommendations is expected to lead to improved detection of cervical precancers at colposcopy and to provide stronger reassurance of negative colposcopy results. Regarding biopsy of lesions, ASCCP did not find added benefit to taking random (nondirected) biopsies for women at low risk for precancer. The sensitivity of biopsy is increased by taking multiple biopsies of suspicious lesions, based on a risk-based approach detailed in the ASCCP guidelines. So, depending on underlying risk (estimated from screening and triage tests), colposcopy practice can be adapted in a useful manner to account for differences in risk:

• When risk of precancer is very high, for example, immediate treatment might reduce cost and prevent the patient from being lost to follow-up. When risk is very low, consider expectant management (serial cytology and HPV testing) with limited need for biopsy. In a setting of intermediate risk, the Working Group proposes, "multiple biopsies of acetowhite lesions lead to increased detection of precancer."
• Perform multiple biopsies that target all areas characterized by 1) acetowhitening, 2) metaplasia, and 3) higher abnormalities.
• Do not perform nontargeted biopsies on patients at the lowest end of risk who have been referred to colposcopy−ie, those with cytology that is less than HSIL; no evidence of HPV types 16/18; and a normal colposcopic impression (ie, no acetowhitening or metaplasia, or other visible abnormality).  
• Immediate excision without biopsy confirmation or colposcopy with multiple targeted biopsies is acceptable in nonpregnant women 25 years and older whose risk of precancer is very high (≥2 of the following: HSIL cytology, HPV 16- or HPV 18-positive(or both), and high-grade colposcopy impression). Endocervical sampling should be conducted according to ASCCP's 2012 management guidelines. If biopsies do not show precancer, manage the patient using ASCCP's 2012 management guidelines, the Working Group recommends.

How do we perform colposcopy? Implications for establishing standards (Waxman et al; Working Group 3). To serve as a guide to standardizing colposcopy across the United States, the authors defined and delineated 6 major components (and their constituent parts) of a comprehensive colposcopy:

• precolposcopy evaluation
• the examination
• use of colposcopy adjuncts
• documentation
• biopsy sampling
• postcolposcopy procedures.

The constituent parts of these components are laid out in TABLE 2.⁴ A set of components for a minimum colposcopy procedure is drawn mostly from the comprehensive protocol.

The Working Group acknowledges that, in the United States, "the accuracy and reproducibility of colposcopy with biopsy as a diagnostic tool are limited." Why? Three contributing factors, the authors write, might be the absence of practice recommendations for colposcopy-biopsy procedures; of measures of quality assurance; and of standardized terminology.

Standards arrive for practice

Minimum quality standards are becoming part of almost everything US health care providers do−whether it is documentation, billing practices, or good care. Our work in gynecology, including colposcopy, is now being assessed as it is in much of the world, where minimum standards are already in place and guidelines must be followed. (In some countries standards require performing a minimum number of colposcopies per year to be identified as a "certified" colposcopist.)

What should be considered "minimum standards" for colposcopy in the United States? These ASCCP reports ask, and deliver answers to that question, bringing a broad range of concerns about high-quality practice into focus. Physicians and advanced-practice clinicians in this country who perform colposcopies have been trained to do so, but they have never had minimum standards by which to model and assess their performance. A procedure that has the potential to lead to additional testing for either cervical cancer, or to surveillance, should have minimum standards by which it is performed and documented in the United States as it is for much of the world that has widespread cervical cancer screening.

Read about adherence to cervical cancer screening.

Cervical screening adherence is relatively low, but safe. Extended intervals are very safe.

Castle PE, Kinney WK, Xue X, et al. Effect of several negative rounds of human papillomavirus and cytology co-testing on safety against cervical cancer: an observational cohort study. Ann Intern Med. 2018;168(1):20-29.

Rendle KA, Schiffman M, Cheung LC, et al. Adherence patterns to extended cervical screening intervals in women undergoing human papillomavirus (HPV) and cytology cotesting. Prev Med. 2018;109:44-50.

Patients who have been screened for cervical cancer for a long time--decades, even--have a diminishing likelihood that cancer will ever be detected. Furthermore, highest-risk patients already have been triaged into further testing or procedures, such as a loop excision electrosurgical procedure or hysterectomy. Two recent studies examined the implications of repeated negative screening and patients' acceptance of extended screening intervals.

Details of the studies

Several negative rounds of cotesting (HPV and cytology) might justify changes to the screening interval. To determine the rate of detection of CIN3, adenocarcinoma in situ, and cervical cancer (≥CIN3) in routine practice after successive negative screening at 3-year intervals, Castle and colleagues looked at records of more than 990,000 women in an integrated health care system who underwent cotesting (HPV and cytology) between 2003 and 2014. They determined that the risk of invasive cervical cancer and ≥CIN3 declined with each round of cotesting; the absolute risk fell more between first and second rounds than between second and third rounds.

At any given round of cotesting, Castle found that the ability to reassure a patient about cancer and cancer risk was similar when looking at an HPV result alone, whatever the cytology or HPV-cytology cotest result was. The investigators concluded that similar patterns of risk would have been seen had stand-alone HPV testing been used, instead of co-testing, (HPV testing alone might have missed a few cases of CIN3 and adenocarcinoma in situ leading to cancer). A single negative cotest was so effective at ruling out ≥CIN3 and cervical cancer that, after a second round of cotesting, they found that no interval cancer cases were detected among women who had a negative HPV result.

Women aged 50 years or older had a 5- to 6-fold lower risk after their third consecutive negative cotest than women aged 30 to 39 years had after their first negative cotest. These data support the ideas, Castle noted, that 1) assigning screening intervals based on both age and number of previous negative screens and 2) extending the screening interval even further than 3 years after 2--perhaps even after 1--negative cotests or HPV tests are worth entertaining. Screening women of this age becomes inefficient and cost-ineffective, even at 5-year intervals.

Is patients' adherence to an extended interval of cotesting reliable enough to change practice? Rendle and colleagues examined the records of more than 491,000 women (in the same integrated health care system that Castle studied) who had undergone routine cervical cancer screening between 2003 and 2015. Their goal was to determine how high adherence had become to the system's recommendation of an every-3-year screening interval--an interval that mirrors long-standing guidelines elsewhere.

In short, researchers observed increasing and relatively rapid clinical adoption of every-3-year cotesting for routine cervical screening over time; between 2003 and 2009, the cohort grew significantly less likely overall to come in early for screening. In this setting, adoption of an extended screeninginterval appears to run counter to earlier understanding that patients are likely to resist such extension.

Women aged 60 to 64 were most likely to screen early across 2 consecutive intervals. What Rendle termed a "modest" decrease in the percentage of late screeners (but still within a 5-year interval) was also noted during adoption of the 3-year interval.

What next?

Molecular-based testing. Research, mostly outside of the United States, is taking us in the direction of molecular-based technologies as at least a component of cervical cancer screening. Today, we rely mostly on Pap tests and colposcopy, but these are subjective screens, with a human operator. With molecular testing (mostly of components of HPV), results are objective--a "Yes" or "No" finding based on clinically validated thresholds. Methods such as genotyping, P16^INK4a/Ki-67 gene product dual-stain cytology, and testing for E6 and E7 HPV mRNA transcripts are in development, and hold promise to allow us to screen safely using almost completely molecular testing, thus eliminating human error and subjectivity and enriching the population that needs further management with very sensitive and potentially specific testing.

We are being presented with the possibility that almost all aspects of screening can be done without a provider, until the patient needs treatment.

Access to screening. Research is also looking at improving access, such as self-sampling for primary screening. That includes home cervical and vaginal sampling, with specimens mailed to the laboratory, from where results and follow-up instructions as communicated to patients. The Netherlands and the United Kingdom are moving to self-sampling primary screens; the United States is not--yet. But that is the direction research is taking us.

Modified guidelines. Eyes are on the work of the USPSTF. Last year, the Task Force issued draft recommendations (https://www.uspre ventiveservicestaskforce.org/Page/Document/draft-recommendation-statement/cervical-cancer-screening2#clinical), followed by a comment period (now closed), for updating 2012 cervical cancer screening guidelines in a way that would trigger a major change in clinical practice. Those draft recommendations and public comments are under review; final recommendations are possible within this calendar year.  

Read about the safety and efficacy of HPV vaccination.

Primary prevention of cervical cancer with vaccination is critical in any cancer prevention program

Benard VB, Castle PE, Jenison SA, et al; New Mexico HPV Pap Registry Steering Committee. Population-based incidence rates of cervical intraepithelial neoplasia in the human papillomavirus vaccine era. JAMA Oncol. 2017;3(6):833-837.

Luostarinen T, Apter D, Dillner J, et al. Vaccination protects against invasive HPV-associated cancers. Int J Cancer. 2018;142(10):2186-2187.

The success story of HPV vaccination, after more than a decade of use, continued to unfold in important ways over the past year.

Safety. With tens of millions of doses delivered, we know that the vaccine is safe, and we have retreated on some of the precautions that we once took: For example, we no longer perform a routine pregnancy test before vaccination on reproductive-age women.

Efficacy. We have learned, based on what we see in Australia and Western Europe, that vaccination is highly effective. We are also starting to see evidence of efficacy in areas of the United States, even though the vaccine is voluntary and there are no school-based recommendations. And we know that herd vaccination is very effective. The 2 studies described here add to our understanding of how vaccination is having an impact on endpoints.

Findings of the 2 studies

HPV vaccination has a direct impact on the precursor of cancer, CIN. Benard and colleagues examined data from the New Mexico HPV Pap Registry, a mandatory statewide surveillance system of cervical cancer screening that captured estimates of both screening prevalence and CIN since the time HPV vaccination was introduced in 2007 to 2014. The investigators examined registry data to gauge trends in the rate of CIN and to estimate the effect of HPV vaccination on that rate when adjusted for changes in screening for cervical cancer.

The incidence of CIN declined significantly across all grades in 2 groups between 2007 and 2015: females aged 15 to 19 years and females aged 20 to 24 years (but not in females 25 to 29 years of age). During those years, mean uptake of HPV vaccination among females 13 to 17 years of age reached as high as 40% (in 2014).

Although a reduction in CIN2 and CIN3 precancers "are early benchmarks for achieving this aim [of reducing the rate of cancer]," the investigators note, a reduction in CIN1 is "a direct measure of reductions in HPV infections requisite to the development of almost all invasive cervical cancer."

Benard moves on to conclude that a reduction in clinical outcomes of CIN among groups who are partially vaccinated for HPV is going to change clinical practice and reduce the cost-effectiveness of clinical care that supports prevention of cervical cancer. Of greatest importance, modalities and strategies for screening, and management algorithms, are going to need to evolve as HPV vaccination and cervical screening are integrated in a rational manner. Furthermore, it might be feasible to factor in population-level decreases in CIN among cohorts who are partially vaccinated for HPV when reassessing clinical practice guidelines for cervical cancer screening.

What does this mean? As we start to eliminate HPV from the population, any positive screening result will be that much more meaningful because the outcome--cervical cancer--will be much rarer. The onus will be on providers and public health officials to re-strategize how to screen what is going to be a widely-vaccinated population; more and more, we will be looking for needles in a haystack.

How are we going to someday screen women in their 20s who were vaccinated at 11 or 12 years of age? Likely, screening will start at a later age, and screening will be conducted at longer intervals. Any finding of HPV or disease is going to be highly significant, and likely, far less frequent.

HPV vaccination protects against invasive HPV-associated cancer. Luostarinen and colleagues report proof of highly efficacious protection offered by a population-based HPV vaccination program in Finland, in the form of a decrease in the key endpoint: cases of invasive HPV-associated cancer. Examining vaccinated (3,331 females) and unvaccinated (15,665 females) cohorts in the nationwide Finnish Cancer Registry, the investigators identified 10 cases of HPV-caused cancer (8 cervical, 1 oropharyngeal, 1 vulvar) in the unvaccinated females and 0 cases in vaccinated females--a statistically significant difference.

From the evidence gathered in this first intention-to-treat trial, the investigators conclude that vaccination protects against invasive HPV-associated cancer--what they call "an awaited, pivotal corollary" to high vaccine efficacy against HPV infection.

Summing up

This success story continues to unfold, despite well-organized, antivaccine campaigns. The HPV vaccine has been an easy target: It is novel, it involves a sexually transmitted infection, and the endpoint of protecting against invasive HPV-associated cancer is years--decades--away. But antivaccine groups can no longer argue the point that studies have not been designed to yield evidence of the impact of the vaccine on decisive endpoints, including cervical cancer.

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.

IN THIS ARTICLE

• Confirming the diagnosis
• Pirfenidone treatment
• Nintedanib treatment

A 64-year-old man has a one-year history of dyspnea on exertion and a nonproductive cough. His symptoms are gradually worsening and increasingly bothersome to him.

His medical history includes mild seasonal allergies and GERD, which is well-controlled by oral antihistamines and proton pump inhibitors. He has spent the past 30 years working a desk job as an accountant. He denies a history of smoking, exposure to secondhand smoke, and initiation of new medication.

He admits to increased fatigue, but denies fever, chills, lymphadenopathy, weight change, chest pain, wheezing, abdominal pain, diarrhea, vomiting, claudication, and swelling in the extremities. The rest of the review of systems is negative.

Lab results—complete blood count, comprehensive metabolic panel, TSH, antinuclear antibodies, erythrocyte sedimentation rate, and C-reactive protein—are within normal limits. Spirometry shows very mild restriction. A chest x-ray is abnormal but nonspecific, showing peripheral opacities. An ECG shows normal sinus rhythm.

The patient is given a trial of an inhaled steroid, which yields no improvement. Six months later, the patient is seen by a pulmonologist. Idiopathic pulmonary fibrosis (IPF) is diagnosed based on high-resolution CT (HRCT) and lung biopsy results.

IPF is a chronic, progressive, fibrosing interstitial disease that is limited to lung tissue. It most commonly manifests in older adults with vague symptoms of dyspnea on exertion and nonproductive cough, but symptoms can also include fatigue, muscle and joint aches, clubbing of the fingernails, and weight loss.¹ The average life expectancy following diagnosis of IPF is two to five years, and the mortality rate is estimated at 64.3 per million men and 58.4 per million women per year.^2,3

Continue to: DIAGNOSIS

IPF belongs in the general class of idiopathic interstitial pneumonias (IIPs), which are characterized by varying degrees of inflammation and fibrosis of lung interstitium.⁴ All subtypes of IIPs cause dyspnea and diffuse abnormalities on HRCT, and all vary from each other histologically. Table 1 outlines the key features of each.^5-8

Because of its vague symptomology and the extensive workup needed to rule out other diseases, patients with IPF often have symptoms for one to two years before a diagnosis is made.¹ Physical exam may reveal fine inspiratory rales in both lung bases and digital clubbing; eventual signs of pulmonary hypertension and right-sided heart failure may be appreciated.^1,9

There are no specific diagnostic laboratory tests to confirm IPF; however, baseline labwork (as outlined in the case presentation) is typically ordered to rule out infection, thyroid disease, or connective tissue disease.¹⁰ Many patients are referred to a cardiologist before being seen by a pulmonologist; cardiac stress testing may be done, and an echocardiogram may be performed to rule out heart failure.

Diagnostic testing may include pulmonary function testing, HRCT of the chest, and lung biopsy.¹⁰ Tissue samples from patients with IPF reveal different stages of disease, including dense fibrosis with honeycombing, subpleural or paraseptal distribution, fibroblast foci, and normal tissue.¹¹ Pulmonary function test results will show a restrictive pattern. Both forced expiratory volume in one second (FEV₁) and forced vital capacity (FVC) will be reduced, and the FEV₁/FVC ratio preserved. Due to decreased functional lung volume, diffusing capacity of the lung for carbon monoxide (DL_CO) will also be reduced.^4,12

The differential is broad and includes allergic asthma, bronchitis, COPD, lung cancer, hypersensitivity pneumonitis, asbestosis, or pulmonary embolism.

Continue to: TREATMENT HISTORY

IPF has a long history of tried and failed treatment options. The American Thoracic Society (ATS), in concert with other professional organizations, has published comprehensive guidelines and recommendations pertaining to the use of pharmacologic medications to control disease progression. Warfarin and other anticoagulants have been studied, based on the observation that a procoagulant state promotes fibrotic changes in the lung tissue.¹³ However, anticoagulant use is not recommended in patients with IPF due to lack of efficacy and high potential for harm.¹³

Immunosuppressants have also been in the spotlight as possible treatment for IPF, but a clinical study investigating the efficacy of a three-drug regimen including prednisone, azathioprine, and N-acetylcysteine was stopped early due to increased risk for harm. Endothelin antagonists and potent tyrosine kinase inhibitors are also not recommended in the most recent edition of IPF guidelines, as they lack benefit.¹³

In fact, prior to the 2015 edition of the guidelines, no single medication was routinely recommended for patients with IPF. But this is now changing, following the 2014 FDA approval of two new drugs, nintedanib and pirfenidone, designed specifically to treat IPF.¹⁴ These drugs have shown promise in clinical trials (results of which are summarized in Table 2).

Continue to: NEW PHARMACOLOGIC OPTIONS

NEW PHARMACOLOGIC OPTIONS

Pirfenidone

In 2008, a study was conducted in Japan to determine the mechanism of action of pirfenidone.¹⁵ Through in vitro studies of healthy adult lung fibroblasts with added pro-fibrotic factor and transforming growth factor (TGF-ß 1), the researchers found that pirfenidone was effective at decreasing the production of a collagen-binding protein called HSP47. This protein is ubiquitous in fibrotic tissue. The study also showed that pirfenidone decreased the production of collagen type 1, which, when uninhibited, increases fibrosis.¹⁵

CAPACITY trials. In the CAPACITY trials, two phase 3 multinational studies conducted from 2006 to 2008, patients were given either pirfenidone or placebo.¹⁶ In the first study arm, patients were assigned to pirfenidone 2,403 mg/d (n = 174), pirfenidone 1,197 mg/d (n = 87), or placebo (n = 174). In the second study arm, 171 patients received pirfenidone 2,403 mg/d and 173 patients received placebo. Endpoints were measured at baseline and up to week 72.

The first study arm found that the mean rate of decline of FVC—the primary endpoint—was 4.4% less in the treatment group than in the placebo group (p = 0.001), and there was a 36% decrease in risk for death or disease progression in the treatment group (HR, 0.64; p, 0.023). (Endpoints were defined as: time to confirmed > 10% decline in percentage predicted FVC, > 15% decline in percentage predicted DL_CO, or death.) The researchers found no clinically significant change in the six-minute walk test—a secondary endpoint of the study.¹⁶

The second study arm, however, found no statistically significant change in FVC between the treatment and placebo groups (with a 0.6% smaller decrease in FVC in the pirfenidone group), nor did they see a difference in progression-free survival. However, there was a significant change in the six-minute walk test between the treatment and placebo groups (p = 0.0009). Throughout the study, the most common adverse effects included nausea (36%), rash (32%), and dyspepsia (19%).¹⁶

ASCEND trial. The 2014 Assessment of Pirfenidone to Confirm Efficacy and Safety in Idiopathic Pulmonary Fibrosis (ASCEND) trial was a phase 3, multinational, randomized, double-blind, placebo-controlled study of the use of pirfenidone 2,403 mg/d.¹⁷ The study was conducted from 2012 to 2013. Of the total number of patients (N = 522), half received pirfenidone and half received placebo. After 52 weeks of treatment (the end of the study), the researchers found a smaller decline in FVC—the primary endpoint—in the treatment group compared to placebo (mean decline, 235 mL vs 428 mL, respectively [p < 0.001]). Regarding the six-minute walk test, the investigators found that 25.9% of the treatment group exhibited a decrease of ≥ 50 meters, compared to 35.7% of the placebo group (p = 0.04). (Progression-free survival was defined as a confirmed ≥ 10% decrease in predicted FVC, a confirmed decrease of 50 meters in the six-minute walk test, or death.)

The pirfenidone group in the ASCEND trial showed a 43% reduced risk for death or disease progression (HR, 0.57; p, < 0.001).^16,17 All-cause mortality was lower in the pirfenidone group (4%) than in the placebo group (7.2%), but this was not statistically significant. Deaths from IPF in the pirfenidone group totaled three patients (1.1%) versus seven patients (2.5%) in the placebo group; this was also not statistically significant. The most common adverse effects seen during the study were nausea (36%), rash (28.1%), and headache (25.9%).¹⁷

Recommendations for use. Liver function testing should be performed at baseline, monthly for six months, and every three months afterward, as elevations in liver enzymes have been observed.¹⁸ Pirfenidone is a CYP1A2 substrate; moderate-to-strong CYP1A2 inhibitors should therefore be discontinued prior to initiation, as they are likely to decrease exposure and efficacy of pirfenidone. There are currently no black box warnings.¹⁸

Continue to: Nintedanib

Hostettler et al studied lung samples from patients with IPF to determine the mechanism of action of nintedanib.¹⁹ Evaluation of fibroblasts derived from IPF samples revealed that they contained higher levels of platelet-derived growth factor (PDGF) than did nonfibrotic control cells. They also found that nintedanib, a tyrosine kinase inhibitor, significantly inhibited the phosphorylation of fibrotic-inducing growth factors—PDGF as well as vascular endothelial growth factor (VEGF).

INPULSIS trials. A phase 3 replicate of randomized, double-blind, multinational studies, the INPULSIS trials were performed between 2011 and 2012.²⁰ Two study arms were used to evaluate a total of 638 patients who received nintedanib 150 mg bid for 52 weeks. The primary endpoint was annual rate of decline of FVC.

The researchers also evaluated efficacy through two other endpoints: patient-reported quality of life and symptoms via the St. George’s Respiratory Questionnaire (SGRQ) and evaluation of time to acute exacerbation. The latter was defined as worsening or new dyspnea, new diffuse pulmonary infiltrates visualized on chest radiography and/or HRCT, or the development of parenchymal abnormalities with no pneumothorax or pleural effusion since the preceding visit; and exclusion of any known causes of acute worsening, including infection, heart failure, pulmonary embolism, and any identifiable cause of acute lung injury.²⁰

INPULSIS 1 (first arm) included 309 patients in the treatment group. Results showed an adjusted annual rate of decline in FVC of 114.7 mL/year, versus 239.9 mL/year in the placebo group (p < 0.001). In the treatment group, 52.8% exhibited ≤ 5% decline in FVC, compared to 38.2% in the placebo group (p = 0.001). No significant between-group differences were found in SGRQ score or time to acute exacerbation.²⁰

INPULSIS 2 had 329 patients receiving nintedanib. An annual rate of decline in FVC of 113.6 mL/year from baseline was observed in the treatment group, compared to 207.3 mL/year in the placebo group (p < 0.001). In the treatment group, 53.2% showed ≤ 5% decline in FVC, versus 39.3% in the placebo group (p = 0.001). There was also a significantly smaller increase in total SGRQ score (meaning, less deterioration in quality of life) in the nintedanib group versus the placebo group (p = 0.02). A statistically significant increase in time to first acute exacerbation was observed in the nintedanib group (p = 0.005).²⁰

There was no significant difference between groups in death from any cause, death from respiratory causation, or death that occurred between randomization and 28 days post treatment. The most common adverse effects seen throughout the two trials included diarrhea (trial 1, 61.5%; trial 2, 63.2%), nausea (trial 1, 22.7%; trial 2, 26.1%), and nasopharyngitis (trial 1, 12.6%; trial 2, 14.6%).²⁰

Recommendations for use. Liver function testing should be performed at baseline, at regular intervals during the first three months, then periodically thereafter; patients in the treatment group of both INPULSIS trials had elevated liver enzymes, and cases of drug-induced liver injury have been observed with use of nintedanib.²¹ This medication may increase risk for bleeding due to its mechanism of action (VEGFR inhibition). Coadministration with CYP3A4 inhibitors may increase concentration of nintedanib; therefore, close monitoring is recommended. Avoid coadministration with CYP3A4 inducers, as this may decrease concentration of nintedanib by 50%. There are currently no black box warnings.²¹

Continue to: Patient monitoring

Patient monitoring

The ATS recommends measuring FVC and DL_CO every three to six months, or sooner if clinically indicated.¹³ Pulse oximetry should be measured at rest and on exertion in all patients, regardless of symptoms, to assure proper saturation and identify the need for supplemental oxygen; this should also be done every three to six months.

The ATS recommends prompt detection and treatment of comorbidities such as pulmonary hypertension, emphysema, airflow obstruction, GERD, sleep apnea, and coronary artery disease.¹³ These recommendations are based on the organization’s 2015 guidelines.

OUTCOME FOR THE CASE PATIENT

The patient was started on pirfenidone (2,403 mg/d). He is continuing treatment and showing improvements in quality of life and slowed deterioration of lung function.

CONCLUSION

IPF causes progressive fibrosis of lung interstitium. The etiology is unknown, the symptoms and signs are vague, and mean life expectancy following diagnosis is two to five years. The most recent IPF guidelines recommend avoiding use of anticoagulants and immunosuppressants (eg, steroids, azathioprine, and N-acetylcysteine), due to their proven ineffectiveness and harm to patients with IPF.

Since the FDA’s approval of pirfenidone and nintedanib, the ATS has made recommendations for their use in patients with IPF. Despite mixed results in clinical trials, both drugs have demonstrated the ability to slow the decline in FVC over time, with relatively benign adverse effects. It is difficult to compare pirfenidone and nintedanib, or to recommend use of one drug over the other. However, it is promising that patients with this routinely fatal disease now have treatment options that can potentially modulate their disease progression.

IN THIS ARTICLE

• Confirming the diagnosis
• Pirfenidone treatment
• Nintedanib treatment

A 64-year-old man has a one-year history of dyspnea on exertion and a nonproductive cough. His symptoms are gradually worsening and increasingly bothersome to him.

His medical history includes mild seasonal allergies and GERD, which is well-controlled by oral antihistamines and proton pump inhibitors. He has spent the past 30 years working a desk job as an accountant. He denies a history of smoking, exposure to secondhand smoke, and initiation of new medication.

He admits to increased fatigue, but denies fever, chills, lymphadenopathy, weight change, chest pain, wheezing, abdominal pain, diarrhea, vomiting, claudication, and swelling in the extremities. The rest of the review of systems is negative.

Lab results—complete blood count, comprehensive metabolic panel, TSH, antinuclear antibodies, erythrocyte sedimentation rate, and C-reactive protein—are within normal limits. Spirometry shows very mild restriction. A chest x-ray is abnormal but nonspecific, showing peripheral opacities. An ECG shows normal sinus rhythm.

The patient is given a trial of an inhaled steroid, which yields no improvement. Six months later, the patient is seen by a pulmonologist. Idiopathic pulmonary fibrosis (IPF) is diagnosed based on high-resolution CT (HRCT) and lung biopsy results.

IPF is a chronic, progressive, fibrosing interstitial disease that is limited to lung tissue. It most commonly manifests in older adults with vague symptoms of dyspnea on exertion and nonproductive cough, but symptoms can also include fatigue, muscle and joint aches, clubbing of the fingernails, and weight loss.¹ The average life expectancy following diagnosis of IPF is two to five years, and the mortality rate is estimated at 64.3 per million men and 58.4 per million women per year.^2,3

Continue to: DIAGNOSIS

IPF belongs in the general class of idiopathic interstitial pneumonias (IIPs), which are characterized by varying degrees of inflammation and fibrosis of lung interstitium.⁴ All subtypes of IIPs cause dyspnea and diffuse abnormalities on HRCT, and all vary from each other histologically. Table 1 outlines the key features of each.^5-8

Because of its vague symptomology and the extensive workup needed to rule out other diseases, patients with IPF often have symptoms for one to two years before a diagnosis is made.¹ Physical exam may reveal fine inspiratory rales in both lung bases and digital clubbing; eventual signs of pulmonary hypertension and right-sided heart failure may be appreciated.^1,9

There are no specific diagnostic laboratory tests to confirm IPF; however, baseline labwork (as outlined in the case presentation) is typically ordered to rule out infection, thyroid disease, or connective tissue disease.¹⁰ Many patients are referred to a cardiologist before being seen by a pulmonologist; cardiac stress testing may be done, and an echocardiogram may be performed to rule out heart failure.

Diagnostic testing may include pulmonary function testing, HRCT of the chest, and lung biopsy.¹⁰ Tissue samples from patients with IPF reveal different stages of disease, including dense fibrosis with honeycombing, subpleural or paraseptal distribution, fibroblast foci, and normal tissue.¹¹ Pulmonary function test results will show a restrictive pattern. Both forced expiratory volume in one second (FEV₁) and forced vital capacity (FVC) will be reduced, and the FEV₁/FVC ratio preserved. Due to decreased functional lung volume, diffusing capacity of the lung for carbon monoxide (DL_CO) will also be reduced.^4,12

The differential is broad and includes allergic asthma, bronchitis, COPD, lung cancer, hypersensitivity pneumonitis, asbestosis, or pulmonary embolism.

Continue to: TREATMENT HISTORY

IPF has a long history of tried and failed treatment options. The American Thoracic Society (ATS), in concert with other professional organizations, has published comprehensive guidelines and recommendations pertaining to the use of pharmacologic medications to control disease progression. Warfarin and other anticoagulants have been studied, based on the observation that a procoagulant state promotes fibrotic changes in the lung tissue.¹³ However, anticoagulant use is not recommended in patients with IPF due to lack of efficacy and high potential for harm.¹³

Immunosuppressants have also been in the spotlight as possible treatment for IPF, but a clinical study investigating the efficacy of a three-drug regimen including prednisone, azathioprine, and N-acetylcysteine was stopped early due to increased risk for harm. Endothelin antagonists and potent tyrosine kinase inhibitors are also not recommended in the most recent edition of IPF guidelines, as they lack benefit.¹³

In fact, prior to the 2015 edition of the guidelines, no single medication was routinely recommended for patients with IPF. But this is now changing, following the 2014 FDA approval of two new drugs, nintedanib and pirfenidone, designed specifically to treat IPF.¹⁴ These drugs have shown promise in clinical trials (results of which are summarized in Table 2).

Continue to: NEW PHARMACOLOGIC OPTIONS

NEW PHARMACOLOGIC OPTIONS

Pirfenidone

In 2008, a study was conducted in Japan to determine the mechanism of action of pirfenidone.¹⁵ Through in vitro studies of healthy adult lung fibroblasts with added pro-fibrotic factor and transforming growth factor (TGF-ß 1), the researchers found that pirfenidone was effective at decreasing the production of a collagen-binding protein called HSP47. This protein is ubiquitous in fibrotic tissue. The study also showed that pirfenidone decreased the production of collagen type 1, which, when uninhibited, increases fibrosis.¹⁵

CAPACITY trials. In the CAPACITY trials, two phase 3 multinational studies conducted from 2006 to 2008, patients were given either pirfenidone or placebo.¹⁶ In the first study arm, patients were assigned to pirfenidone 2,403 mg/d (n = 174), pirfenidone 1,197 mg/d (n = 87), or placebo (n = 174). In the second study arm, 171 patients received pirfenidone 2,403 mg/d and 173 patients received placebo. Endpoints were measured at baseline and up to week 72.

The first study arm found that the mean rate of decline of FVC—the primary endpoint—was 4.4% less in the treatment group than in the placebo group (p = 0.001), and there was a 36% decrease in risk for death or disease progression in the treatment group (HR, 0.64; p, 0.023). (Endpoints were defined as: time to confirmed > 10% decline in percentage predicted FVC, > 15% decline in percentage predicted DL_CO, or death.) The researchers found no clinically significant change in the six-minute walk test—a secondary endpoint of the study.¹⁶

The second study arm, however, found no statistically significant change in FVC between the treatment and placebo groups (with a 0.6% smaller decrease in FVC in the pirfenidone group), nor did they see a difference in progression-free survival. However, there was a significant change in the six-minute walk test between the treatment and placebo groups (p = 0.0009). Throughout the study, the most common adverse effects included nausea (36%), rash (32%), and dyspepsia (19%).¹⁶

ASCEND trial. The 2014 Assessment of Pirfenidone to Confirm Efficacy and Safety in Idiopathic Pulmonary Fibrosis (ASCEND) trial was a phase 3, multinational, randomized, double-blind, placebo-controlled study of the use of pirfenidone 2,403 mg/d.¹⁷ The study was conducted from 2012 to 2013. Of the total number of patients (N = 522), half received pirfenidone and half received placebo. After 52 weeks of treatment (the end of the study), the researchers found a smaller decline in FVC—the primary endpoint—in the treatment group compared to placebo (mean decline, 235 mL vs 428 mL, respectively [p < 0.001]). Regarding the six-minute walk test, the investigators found that 25.9% of the treatment group exhibited a decrease of ≥ 50 meters, compared to 35.7% of the placebo group (p = 0.04). (Progression-free survival was defined as a confirmed ≥ 10% decrease in predicted FVC, a confirmed decrease of 50 meters in the six-minute walk test, or death.)

The pirfenidone group in the ASCEND trial showed a 43% reduced risk for death or disease progression (HR, 0.57; p, < 0.001).^16,17 All-cause mortality was lower in the pirfenidone group (4%) than in the placebo group (7.2%), but this was not statistically significant. Deaths from IPF in the pirfenidone group totaled three patients (1.1%) versus seven patients (2.5%) in the placebo group; this was also not statistically significant. The most common adverse effects seen during the study were nausea (36%), rash (28.1%), and headache (25.9%).¹⁷

Recommendations for use. Liver function testing should be performed at baseline, monthly for six months, and every three months afterward, as elevations in liver enzymes have been observed.¹⁸ Pirfenidone is a CYP1A2 substrate; moderate-to-strong CYP1A2 inhibitors should therefore be discontinued prior to initiation, as they are likely to decrease exposure and efficacy of pirfenidone. There are currently no black box warnings.¹⁸

Continue to: Nintedanib

Hostettler et al studied lung samples from patients with IPF to determine the mechanism of action of nintedanib.¹⁹ Evaluation of fibroblasts derived from IPF samples revealed that they contained higher levels of platelet-derived growth factor (PDGF) than did nonfibrotic control cells. They also found that nintedanib, a tyrosine kinase inhibitor, significantly inhibited the phosphorylation of fibrotic-inducing growth factors—PDGF as well as vascular endothelial growth factor (VEGF).

INPULSIS trials. A phase 3 replicate of randomized, double-blind, multinational studies, the INPULSIS trials were performed between 2011 and 2012.²⁰ Two study arms were used to evaluate a total of 638 patients who received nintedanib 150 mg bid for 52 weeks. The primary endpoint was annual rate of decline of FVC.

The researchers also evaluated efficacy through two other endpoints: patient-reported quality of life and symptoms via the St. George’s Respiratory Questionnaire (SGRQ) and evaluation of time to acute exacerbation. The latter was defined as worsening or new dyspnea, new diffuse pulmonary infiltrates visualized on chest radiography and/or HRCT, or the development of parenchymal abnormalities with no pneumothorax or pleural effusion since the preceding visit; and exclusion of any known causes of acute worsening, including infection, heart failure, pulmonary embolism, and any identifiable cause of acute lung injury.²⁰

INPULSIS 1 (first arm) included 309 patients in the treatment group. Results showed an adjusted annual rate of decline in FVC of 114.7 mL/year, versus 239.9 mL/year in the placebo group (p < 0.001). In the treatment group, 52.8% exhibited ≤ 5% decline in FVC, compared to 38.2% in the placebo group (p = 0.001). No significant between-group differences were found in SGRQ score or time to acute exacerbation.²⁰

INPULSIS 2 had 329 patients receiving nintedanib. An annual rate of decline in FVC of 113.6 mL/year from baseline was observed in the treatment group, compared to 207.3 mL/year in the placebo group (p < 0.001). In the treatment group, 53.2% showed ≤ 5% decline in FVC, versus 39.3% in the placebo group (p = 0.001). There was also a significantly smaller increase in total SGRQ score (meaning, less deterioration in quality of life) in the nintedanib group versus the placebo group (p = 0.02). A statistically significant increase in time to first acute exacerbation was observed in the nintedanib group (p = 0.005).²⁰

There was no significant difference between groups in death from any cause, death from respiratory causation, or death that occurred between randomization and 28 days post treatment. The most common adverse effects seen throughout the two trials included diarrhea (trial 1, 61.5%; trial 2, 63.2%), nausea (trial 1, 22.7%; trial 2, 26.1%), and nasopharyngitis (trial 1, 12.6%; trial 2, 14.6%).²⁰

Recommendations for use. Liver function testing should be performed at baseline, at regular intervals during the first three months, then periodically thereafter; patients in the treatment group of both INPULSIS trials had elevated liver enzymes, and cases of drug-induced liver injury have been observed with use of nintedanib.²¹ This medication may increase risk for bleeding due to its mechanism of action (VEGFR inhibition). Coadministration with CYP3A4 inhibitors may increase concentration of nintedanib; therefore, close monitoring is recommended. Avoid coadministration with CYP3A4 inducers, as this may decrease concentration of nintedanib by 50%. There are currently no black box warnings.²¹

Continue to: Patient monitoring

Patient monitoring

The ATS recommends measuring FVC and DL_CO every three to six months, or sooner if clinically indicated.¹³ Pulse oximetry should be measured at rest and on exertion in all patients, regardless of symptoms, to assure proper saturation and identify the need for supplemental oxygen; this should also be done every three to six months.

The ATS recommends prompt detection and treatment of comorbidities such as pulmonary hypertension, emphysema, airflow obstruction, GERD, sleep apnea, and coronary artery disease.¹³ These recommendations are based on the organization’s 2015 guidelines.

OUTCOME FOR THE CASE PATIENT

The patient was started on pirfenidone (2,403 mg/d). He is continuing treatment and showing improvements in quality of life and slowed deterioration of lung function.

CONCLUSION

IPF causes progressive fibrosis of lung interstitium. The etiology is unknown, the symptoms and signs are vague, and mean life expectancy following diagnosis is two to five years. The most recent IPF guidelines recommend avoiding use of anticoagulants and immunosuppressants (eg, steroids, azathioprine, and N-acetylcysteine), due to their proven ineffectiveness and harm to patients with IPF.

Since the FDA’s approval of pirfenidone and nintedanib, the ATS has made recommendations for their use in patients with IPF. Despite mixed results in clinical trials, both drugs have demonstrated the ability to slow the decline in FVC over time, with relatively benign adverse effects. It is difficult to compare pirfenidone and nintedanib, or to recommend use of one drug over the other. However, it is promising that patients with this routinely fatal disease now have treatment options that can potentially modulate their disease progression.

IN THIS ARTICLE

• Confirming the diagnosis
• Pirfenidone treatment
• Nintedanib treatment

A 64-year-old man has a one-year history of dyspnea on exertion and a nonproductive cough. His symptoms are gradually worsening and increasingly bothersome to him.

His medical history includes mild seasonal allergies and GERD, which is well-controlled by oral antihistamines and proton pump inhibitors. He has spent the past 30 years working a desk job as an accountant. He denies a history of smoking, exposure to secondhand smoke, and initiation of new medication.

He admits to increased fatigue, but denies fever, chills, lymphadenopathy, weight change, chest pain, wheezing, abdominal pain, diarrhea, vomiting, claudication, and swelling in the extremities. The rest of the review of systems is negative.

Lab results—complete blood count, comprehensive metabolic panel, TSH, antinuclear antibodies, erythrocyte sedimentation rate, and C-reactive protein—are within normal limits. Spirometry shows very mild restriction. A chest x-ray is abnormal but nonspecific, showing peripheral opacities. An ECG shows normal sinus rhythm.

The patient is given a trial of an inhaled steroid, which yields no improvement. Six months later, the patient is seen by a pulmonologist. Idiopathic pulmonary fibrosis (IPF) is diagnosed based on high-resolution CT (HRCT) and lung biopsy results.

IPF is a chronic, progressive, fibrosing interstitial disease that is limited to lung tissue. It most commonly manifests in older adults with vague symptoms of dyspnea on exertion and nonproductive cough, but symptoms can also include fatigue, muscle and joint aches, clubbing of the fingernails, and weight loss.¹ The average life expectancy following diagnosis of IPF is two to five years, and the mortality rate is estimated at 64.3 per million men and 58.4 per million women per year.^2,3

Continue to: DIAGNOSIS

IPF belongs in the general class of idiopathic interstitial pneumonias (IIPs), which are characterized by varying degrees of inflammation and fibrosis of lung interstitium.⁴ All subtypes of IIPs cause dyspnea and diffuse abnormalities on HRCT, and all vary from each other histologically. Table 1 outlines the key features of each.^5-8

Because of its vague symptomology and the extensive workup needed to rule out other diseases, patients with IPF often have symptoms for one to two years before a diagnosis is made.¹ Physical exam may reveal fine inspiratory rales in both lung bases and digital clubbing; eventual signs of pulmonary hypertension and right-sided heart failure may be appreciated.^1,9

There are no specific diagnostic laboratory tests to confirm IPF; however, baseline labwork (as outlined in the case presentation) is typically ordered to rule out infection, thyroid disease, or connective tissue disease.¹⁰ Many patients are referred to a cardiologist before being seen by a pulmonologist; cardiac stress testing may be done, and an echocardiogram may be performed to rule out heart failure.

Diagnostic testing may include pulmonary function testing, HRCT of the chest, and lung biopsy.¹⁰ Tissue samples from patients with IPF reveal different stages of disease, including dense fibrosis with honeycombing, subpleural or paraseptal distribution, fibroblast foci, and normal tissue.¹¹ Pulmonary function test results will show a restrictive pattern. Both forced expiratory volume in one second (FEV₁) and forced vital capacity (FVC) will be reduced, and the FEV₁/FVC ratio preserved. Due to decreased functional lung volume, diffusing capacity of the lung for carbon monoxide (DL_CO) will also be reduced.^4,12

The differential is broad and includes allergic asthma, bronchitis, COPD, lung cancer, hypersensitivity pneumonitis, asbestosis, or pulmonary embolism.

Continue to: TREATMENT HISTORY

IPF has a long history of tried and failed treatment options. The American Thoracic Society (ATS), in concert with other professional organizations, has published comprehensive guidelines and recommendations pertaining to the use of pharmacologic medications to control disease progression. Warfarin and other anticoagulants have been studied, based on the observation that a procoagulant state promotes fibrotic changes in the lung tissue.¹³ However, anticoagulant use is not recommended in patients with IPF due to lack of efficacy and high potential for harm.¹³

Immunosuppressants have also been in the spotlight as possible treatment for IPF, but a clinical study investigating the efficacy of a three-drug regimen including prednisone, azathioprine, and N-acetylcysteine was stopped early due to increased risk for harm. Endothelin antagonists and potent tyrosine kinase inhibitors are also not recommended in the most recent edition of IPF guidelines, as they lack benefit.¹³

In fact, prior to the 2015 edition of the guidelines, no single medication was routinely recommended for patients with IPF. But this is now changing, following the 2014 FDA approval of two new drugs, nintedanib and pirfenidone, designed specifically to treat IPF.¹⁴ These drugs have shown promise in clinical trials (results of which are summarized in Table 2).

Continue to: NEW PHARMACOLOGIC OPTIONS

NEW PHARMACOLOGIC OPTIONS

Pirfenidone

In 2008, a study was conducted in Japan to determine the mechanism of action of pirfenidone.¹⁵ Through in vitro studies of healthy adult lung fibroblasts with added pro-fibrotic factor and transforming growth factor (TGF-ß 1), the researchers found that pirfenidone was effective at decreasing the production of a collagen-binding protein called HSP47. This protein is ubiquitous in fibrotic tissue. The study also showed that pirfenidone decreased the production of collagen type 1, which, when uninhibited, increases fibrosis.¹⁵

CAPACITY trials. In the CAPACITY trials, two phase 3 multinational studies conducted from 2006 to 2008, patients were given either pirfenidone or placebo.¹⁶ In the first study arm, patients were assigned to pirfenidone 2,403 mg/d (n = 174), pirfenidone 1,197 mg/d (n = 87), or placebo (n = 174). In the second study arm, 171 patients received pirfenidone 2,403 mg/d and 173 patients received placebo. Endpoints were measured at baseline and up to week 72.

The first study arm found that the mean rate of decline of FVC—the primary endpoint—was 4.4% less in the treatment group than in the placebo group (p = 0.001), and there was a 36% decrease in risk for death or disease progression in the treatment group (HR, 0.64; p, 0.023). (Endpoints were defined as: time to confirmed > 10% decline in percentage predicted FVC, > 15% decline in percentage predicted DL_CO, or death.) The researchers found no clinically significant change in the six-minute walk test—a secondary endpoint of the study.¹⁶

The second study arm, however, found no statistically significant change in FVC between the treatment and placebo groups (with a 0.6% smaller decrease in FVC in the pirfenidone group), nor did they see a difference in progression-free survival. However, there was a significant change in the six-minute walk test between the treatment and placebo groups (p = 0.0009). Throughout the study, the most common adverse effects included nausea (36%), rash (32%), and dyspepsia (19%).¹⁶

ASCEND trial. The 2014 Assessment of Pirfenidone to Confirm Efficacy and Safety in Idiopathic Pulmonary Fibrosis (ASCEND) trial was a phase 3, multinational, randomized, double-blind, placebo-controlled study of the use of pirfenidone 2,403 mg/d.¹⁷ The study was conducted from 2012 to 2013. Of the total number of patients (N = 522), half received pirfenidone and half received placebo. After 52 weeks of treatment (the end of the study), the researchers found a smaller decline in FVC—the primary endpoint—in the treatment group compared to placebo (mean decline, 235 mL vs 428 mL, respectively [p < 0.001]). Regarding the six-minute walk test, the investigators found that 25.9% of the treatment group exhibited a decrease of ≥ 50 meters, compared to 35.7% of the placebo group (p = 0.04). (Progression-free survival was defined as a confirmed ≥ 10% decrease in predicted FVC, a confirmed decrease of 50 meters in the six-minute walk test, or death.)

The pirfenidone group in the ASCEND trial showed a 43% reduced risk for death or disease progression (HR, 0.57; p, < 0.001).^16,17 All-cause mortality was lower in the pirfenidone group (4%) than in the placebo group (7.2%), but this was not statistically significant. Deaths from IPF in the pirfenidone group totaled three patients (1.1%) versus seven patients (2.5%) in the placebo group; this was also not statistically significant. The most common adverse effects seen during the study were nausea (36%), rash (28.1%), and headache (25.9%).¹⁷

Recommendations for use. Liver function testing should be performed at baseline, monthly for six months, and every three months afterward, as elevations in liver enzymes have been observed.¹⁸ Pirfenidone is a CYP1A2 substrate; moderate-to-strong CYP1A2 inhibitors should therefore be discontinued prior to initiation, as they are likely to decrease exposure and efficacy of pirfenidone. There are currently no black box warnings.¹⁸

Continue to: Nintedanib

Hostettler et al studied lung samples from patients with IPF to determine the mechanism of action of nintedanib.¹⁹ Evaluation of fibroblasts derived from IPF samples revealed that they contained higher levels of platelet-derived growth factor (PDGF) than did nonfibrotic control cells. They also found that nintedanib, a tyrosine kinase inhibitor, significantly inhibited the phosphorylation of fibrotic-inducing growth factors—PDGF as well as vascular endothelial growth factor (VEGF).

INPULSIS trials. A phase 3 replicate of randomized, double-blind, multinational studies, the INPULSIS trials were performed between 2011 and 2012.²⁰ Two study arms were used to evaluate a total of 638 patients who received nintedanib 150 mg bid for 52 weeks. The primary endpoint was annual rate of decline of FVC.

The researchers also evaluated efficacy through two other endpoints: patient-reported quality of life and symptoms via the St. George’s Respiratory Questionnaire (SGRQ) and evaluation of time to acute exacerbation. The latter was defined as worsening or new dyspnea, new diffuse pulmonary infiltrates visualized on chest radiography and/or HRCT, or the development of parenchymal abnormalities with no pneumothorax or pleural effusion since the preceding visit; and exclusion of any known causes of acute worsening, including infection, heart failure, pulmonary embolism, and any identifiable cause of acute lung injury.²⁰

INPULSIS 1 (first arm) included 309 patients in the treatment group. Results showed an adjusted annual rate of decline in FVC of 114.7 mL/year, versus 239.9 mL/year in the placebo group (p < 0.001). In the treatment group, 52.8% exhibited ≤ 5% decline in FVC, compared to 38.2% in the placebo group (p = 0.001). No significant between-group differences were found in SGRQ score or time to acute exacerbation.²⁰

INPULSIS 2 had 329 patients receiving nintedanib. An annual rate of decline in FVC of 113.6 mL/year from baseline was observed in the treatment group, compared to 207.3 mL/year in the placebo group (p < 0.001). In the treatment group, 53.2% showed ≤ 5% decline in FVC, versus 39.3% in the placebo group (p = 0.001). There was also a significantly smaller increase in total SGRQ score (meaning, less deterioration in quality of life) in the nintedanib group versus the placebo group (p = 0.02). A statistically significant increase in time to first acute exacerbation was observed in the nintedanib group (p = 0.005).²⁰

There was no significant difference between groups in death from any cause, death from respiratory causation, or death that occurred between randomization and 28 days post treatment. The most common adverse effects seen throughout the two trials included diarrhea (trial 1, 61.5%; trial 2, 63.2%), nausea (trial 1, 22.7%; trial 2, 26.1%), and nasopharyngitis (trial 1, 12.6%; trial 2, 14.6%).²⁰

Recommendations for use. Liver function testing should be performed at baseline, at regular intervals during the first three months, then periodically thereafter; patients in the treatment group of both INPULSIS trials had elevated liver enzymes, and cases of drug-induced liver injury have been observed with use of nintedanib.²¹ This medication may increase risk for bleeding due to its mechanism of action (VEGFR inhibition). Coadministration with CYP3A4 inhibitors may increase concentration of nintedanib; therefore, close monitoring is recommended. Avoid coadministration with CYP3A4 inducers, as this may decrease concentration of nintedanib by 50%. There are currently no black box warnings.²¹

Continue to: Patient monitoring

Patient monitoring

The ATS recommends measuring FVC and DL_CO every three to six months, or sooner if clinically indicated.¹³ Pulse oximetry should be measured at rest and on exertion in all patients, regardless of symptoms, to assure proper saturation and identify the need for supplemental oxygen; this should also be done every three to six months.

The ATS recommends prompt detection and treatment of comorbidities such as pulmonary hypertension, emphysema, airflow obstruction, GERD, sleep apnea, and coronary artery disease.¹³ These recommendations are based on the organization’s 2015 guidelines.

OUTCOME FOR THE CASE PATIENT

The patient was started on pirfenidone (2,403 mg/d). He is continuing treatment and showing improvements in quality of life and slowed deterioration of lung function.

CONCLUSION

IPF causes progressive fibrosis of lung interstitium. The etiology is unknown, the symptoms and signs are vague, and mean life expectancy following diagnosis is two to five years. The most recent IPF guidelines recommend avoiding use of anticoagulants and immunosuppressants (eg, steroids, azathioprine, and N-acetylcysteine), due to their proven ineffectiveness and harm to patients with IPF.

Since the FDA’s approval of pirfenidone and nintedanib, the ATS has made recommendations for their use in patients with IPF. Despite mixed results in clinical trials, both drugs have demonstrated the ability to slow the decline in FVC over time, with relatively benign adverse effects. It is difficult to compare pirfenidone and nintedanib, or to recommend use of one drug over the other. However, it is promising that patients with this routinely fatal disease now have treatment options that can potentially modulate their disease progression.

From the Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA.

Abstract

• Objective: To review and summarize the literature regarding current approaches to secondary prevention of low-trauma osteoporotic fractures.
• Methods: PubMed search and summary of existing literature related to complications and secondary prevention of osteoporotic fractures was performed.
• Results: Fragility fractures are associated with high rates of short and long term morbidities and carry a high risk of mortality and fracture recurrence. Several of the currently available anti-osteoporosis medications have been shown to decrease the risk of fracture recurrence in patients with prevalent osteoporotic fractures and some may even decrease mortality. However, only a minority of patients with fragility fractures are adequately evaluated and treated for osteoporosis. Fracture liaison services that ensure identification and risk stratification of patients with fragility fractures and proper evaluation and treatment of osteoporosis have proven effective at enhancing osteoporosis care in these patients, decreasing fracture recurrence and possibly even decreasing long-term mortality, while providing long-term cost savings. Unfortunately, however, this model of care has not been widely adopted and implemented.
• Conclusion: Fragility fractures represent a major health care problem for aging populations. Unfortunately, most patients with low-trauma fractures still receive suboptimal osteoporosis care.

Key words: osteoporosis; fracture; fragility; low-trauma; bone density.

Low-trauma fractures are fractures that occur from a trauma equivalent to a fall from standing height or less [1,2]. They can involve any skeletal site, but the most significant are vertebral, pelvic, wrist and hip fractures, which together represent close to 90% of all low-trauma fractures [3,4]. The overall burden of low-trauma fractures is quite high worldwide and is projected to increase over time [3–6]. In 2010, 3.5 million new low-trauma fractures were reported in the European Union [3]. In the United States, there were more than 2 million fractures in 2005, and it is estimated that more than 3 million fractures will occur in year 2025 [4].

Low-trauma fractures are generally indicative of compromised bone strength—especially when they involve the hip—and are thus often referred to as fragility fractures. While the traditional definition of osteoporosis is a bone mineral density (BMD) T-score of -2.5 or lower, low-trauma fractures of the hip are also diagnostic of osteoporosis, regardless of bone mineral density [2,7–9]. In addition, low-trauma fractures of the vertebrae, the proximal humerus, and the pelvis are considered diagnostic of osteoporosis when combined with T-scores between -1 and -2.5 [2,7]. Bone biopsies and high-resolution peripheral quantitative computed tomography (HR-pQCT) in patients with low-trauma fractures and normal BMD suggest microarchitectural alterations and abnormalities of collagen orientation and crosslinking within the bone matrix [10-12], leading to decreased bone strength.

This review will address the individual and societal costs of low-trauma fractures and issues related to secondary prevention of fractures, with specific emphasis on pharmacotherapy and fracture liaison services.

Impact of Low-Trauma Fractures

Acute and Long-Term Complications

Of all fragility fractures, hip fractures are the ones most likely to result in serious acute complications. The most common acute complications are delirium in up to 50% of patients and malnutrition in up to 60%, both of which predict slower and less complete recovery [13–16]. Other complications include urinary tract infections in up to 60% of patients in certain reports [17], thromboembolic disease with deep venous thrombosis in around 27% of patients and pulmonary embolism in up to 7% [16], and acute kidney injury in about 15% [18].

In addition, it is not uncommon for patients to suffer from significant long-term functional limitations following fragility fractures. While vertebral fractures do not frequently lead to hospitalization or institutionalization, they often lead to significant physical limitations and chronic pain [19,20] and to negative effects on self-esteem, mood, and body image [21,22]. However, the most remarkable functional decline and limitations are seen after hip fractures [23–25]. In a study of 2800 women and men with hip fracture, Beringer et al found that more than 30% were still institutionalized, and only 40% were able to walk outdoors independently 1 year later. Predictors of poor outcome included male sex, advanced age, cognitive impairment, and presence of comorbidities [23].

It is not surprising then that a fracture is often associated with an overall decline in the individual’s quality of life and this has been demonstrated in several studies [26–28]. In the largest study of this type, Tarride et al examined over 23,000 patients with fragility fractures and found a sharp decline in health-related quality of life (HRQOL) immediately after the fracture, which remained below baseline for up to 3 years [26]. The decline was worse in patients with hip and spine fractures compared to other fractures [27].

Mortality Following Fragility Fractures

Perhaps the most concerning complication, however, is the excess mortality seen after fractures. Several studies have demonstrated excess mortality after vertebral fractures, especially in the year following the fracture [29–33], but the highest increase in mortality was observed following hip fractures. In fact, the 30-day mortality after a hip fracture approximates 7% [23] and the excess 1-year mortality is estimated at 8% to 36% [34,35]. While the highest risk of mortality is seen in the first year following the fracture, the increased risk persists for at least 5 to 6 years [36]. Malnutrition, decreased mobility, male sex, and the number of coexisting medical comorbidities further increase the risk of mortality [29,32,34,36,37].

Risk of Fracture Recurrence

In both men and women, a fragility fracture at any site increases the risk of subsequent fractures [38–41], and the risk increases with the number of prevalent fractures [42]. Gehlbach et al estimated an 80% increase in the risk of fracture recurrence after 1 fracture, a threefold increase after 2 fractures, and an almost fivefold increase after 3 fractures [42]. The increase in risk is even more pronounced following vertebral fractures specifically, doubling after the first fracture an increasing by up to ninefold after 3 fractures [42, 43]. This increase in risk is highest in the first year following the fracture but may persist for up to 10 years [39,43].

Fracture Impact on Society

Fractures are associated with a high financial burden to society, in terms of direct acute care costs and long-term rehabilitation [3,4,44–48]. In 2010, the direct cost from fractures in the EU was estimated at €24.6 billion [3]. In the US, this cost was around $14.0 billion in 2002 and $16.9 billion in 2005 [4,48], and in Canada it was $1.5 billion in 2011 [47]. These numbers increase substantially when costs associated with long-term post-fracture rehabilitation are included, with an additional estimated yearly cost of €10.7 billion in the EU and $1.03 billion in Canada [3,47].

While hip fractures account for only about 18% of all low-trauma fractures, they are associated with the highest cost burden, accounting for about 50% to 70% of the total fracture-associated expenditures [3,4,44]. This is likely due to the fact almost all hip fractures require hospitalization, most require surgical repair and rehabilitation, and because they lead to the highest rates of morbidity and mortality.

Can Fracture Recurrence After a Low-Trauma Fracture Be Prevented?

Many approaches to secondary fracture prevention have been proposed, including but not limited to fall prevention, exercise therapy, nutrition therapy, prevention and treatment of sarcopenia, vitamin D and calcium supplementation, and osteoporosis pharmacotherapy [49–53]. Of those, osteoporosis pharmacotherapy has the strongest and most compelling efficacy data and will be reviewed in the following sections.

Effect of Antiresorptive Therapy After a Fracture

In the Fracture Intervention Trial (FIT), alendronate decreased the risk of new vertebral fractures by about 47% and of hip fractures by about 50% in women with preexisting vertebral fractures [54,55]. Similar fracture protection benefits were demonstrated in the Hip Intervention Program (HIP), where risedronate decreased the risk of hip fractures by 60% in women with prior history of vertebral fractures [56].

The best data regarding secondary prevention of hip fractures however comes from the Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly (HORIZON) trial, where patients were randomized to zoledronic acid or placebo within 90 days of a hip fracture. Over a median duration of therapy of about 2 years, zoledronic acid decreased the risk of any new clinical fracture by 35%, of new vertebral fractures by 46%, and of recurrent hip fractures by 30% [57].

Effect of Anabolic Therapy After a Fracture

The Fracture Prevention Trial (FPT) compared the effect of teriparatide to placebo in women with at least 1 moderate or 2 mild atraumatic vertebral fractures and showed a 65% reduction in the risk of new vertebral fractures and a 53% reduction in the risk of new non-vertebral fractures [58]. Likewise, the Abaloparatide Comparator Trial In Vertebral Endpoints (ACTIVE) enrolled women with at least 2 mild vertebral fractures, 1 moderate vertebral fracture or history of a low trauma fracture of the forearm, humerus, sacrum, pelvis, hip, femur, or tibia. In this trial, abaloparatide decreased the risk of new vertebral fractures by 85% and of new non-vertebral fractures by 43% compared to placebo [59].

Will Anti-Osteoporosis Therapy After a Low-Trauma Fracture Impact Fracture Healing?

One major question regarding the use of anti-osteoporosis drugs in patients with a recent fracture is the effect that treatment might have on bone healing after fracture or fracture-repair surgery. With antiresorptive agents in particular, the main concern is whether suppression of bone turnover may lead to delayed bone healing, since healing requires callus remodeling. A small prospective study evaluated fracture healing in 196 patients treated for a distal radius fracture, 153 of whom were on a bisphosphonate at the time of the fracture. While bisphosphonate use was associated with a longer time to radiographic union, the time to union was only 6 days longer in the bisphosphonate group (55 days versus 49 days to union in the bisphosphonate and control groups, respectively), and has generally not been felt to be clinically significant [60]. The most reassuring data regarding this question however, comes from the HORIZON trial where 2127 men and women were randomized to zoledronic acid or placebo within 90 days of a hip fracture. No difference in healing between the 2 groups was seen, regardless of the time of initiation of zoledronic acid (within 2 weeks of fracture, between 2 and 4 weeks, between 4 and 6 weeks or after 6 weeks) [61].

The stimulation of bone turnover that occurs with anabolic agents is generally thought to accelerate bone healing. In animal studies, teriparatide has been found to enhance callus formation and mechanical strength [62–64], but there is no definitive data in humans to prove this effect [65].

In summary, there is strong evidence demonstrating the effectiveness of bisphosphonates and anabolic agents at decreasing the risk of fracture recurrence in patients with preexisting vertebral fractures. Zoledronic acid has also been shown to decrease the risk of fracture recurrence after a hip fracture. Anti-osteoporosis therapy after a fracture has no clinically significant effect on fracture healing.

The Gap Between Science and Practice

Practice Guidelines Versus Actual Practice

Based on the data presented above, multiple professional societies and expert groups have developed guidelines emphasizing the importance of evaluation and treatment for osteoporosis following a low-trauma fracture, especially those of the hip and spine [8,9,66–69]. In a 2009 multidisciplinary workshop of the International Society of Fracture Repair, an in-depth review of existing data showed no evidence for a negative effect of anti-osteoporosis drugs on fracture healing. As a result, it was recommended not to withhold osteoporosis therapy until fracture healing has occurred, and to initiate treatment before patient discharge from the fracture ward in order to improve follow-up [70].

However, despite these expert guidelines and the availability of several effective agents to decrease the risk of fracture and fracture recurrence, evaluation and treatment of patients for osteoporosis after a low-trauma fracture are very low. Several large-scale studies involving older patients with fractures in North America, Europe, Asia, and Australia have shown that the rates of BMD measurement or drug therapy for osteoporosis after a fragility fracture do not exceed 25% to 30% [71–80]. While treatment trends over time may have shown some improvement, they remain overall disappointing. For example, in a study of over 150,000 patients who sustained a fracture between 1997 and 2004, Roerholt et al found that around 20% of women were started on therapy after a vertebral fracture in 1997, while 40% received therapy in 2004. Among women with hip fracture, 3% received treatment in 1997 and 9% in 2004 [71]. Furthermore, when osteoporosis treatment rates are examined more closely, most of the patients who receive treatment after a fracture are those who were being treated prior to the fracture, so treatment is simply continued in them. New osteoporosis therapy is initiated in only 5% to 15% of patients who are not already on osteoporosis therapy at the time of fracture [72,73,77,81,82].

Analyses of prescription patterns suggest that patients with vertebral fractures are more likely to receive treatment compared to those with hip fractures [71,82], and that women are much more likely to receive therapy than men [71,74,77,83–88]. Other factors that decrease the chance of receiving therapy include black race [84], low income [74], older age, presence of multiple comorbidities, and polypharmacy [83].

Barriers to Care: Where Are We Failing?

The large discrepancy between science and practice when it comes to secondary prevention of fractures is quite puzzling and has been the subject of several investigations. A major barrier to proper care seems to be the lack of ownership of the problem by the orthopedic surgeons and medical providers, and the less than ideal collaboration between the 2 services in coordinating and providing secondary prevention [89–94]. The orthopedic surgeons are one of the first points of contact with health care for a patient with a low-trauma hip fracture. They are mainly charged with providing acute fracture care and often cannot provide long-term osteoporosis care, which would be more suitable for a medical specialist. However, while the acute care surgical team is not best suited to treat osteoporosis, it is still very important that they initiate patient referral to a provider who can provide long-term osteoporosis care. This transition of care–of lack of it–seems to be one of the major missing links, leading to patient loss [88] and suboptimal secondary prevention.

However, patient referral may not be a sufficient solution and interestingly, a medical consultation during an acute admission for hip fracture does not seem to increase the frequency of osteoporosis diagnosis [95]. This points to a deficiency in knowledge, and as a matter of fact, studies do suggest a problem with under-recognition of the connection between low-trauma fractures and underlying osteoporosis among medical and surgical providers alike [92,93,96]. In a survey of orthopedic surgeons and consultant physicians involved in the care of patients with low-trauma hip fractures, only 24% of respondents felt that osteoporosis therapy was indicated. The majority of providers thought that treatment with a bisphosphonate was indicated only if low BMD was present, rather than in all patients with low-trauma hip fractures [92]. This is further illustrated by the fact that only a minority of patients with a low-trauma fracture are formally given the diagnosis of osteoporosis [75,80,97] or are told that they have osteoporosis [79].

Fracture Liaison Services—A Potential Solution to Enhance Secondary Fracture Prevention

What is a Fracture Liaison Service?

Several solutions have been proposed to remedy the main barriers that interfere with proper secondary treatment of osteoporosis, namely patient education, provider education, and the initiation of programs to enhance coordination and continuity of care between treating teams. Taken together, these interventions have been modestly effective at increasing the odds of BMD measurement and initiation of osteoporosis therapy [98, 99]. Interventions that focused mainly on provider and/or patient education were the least effective, especially when they did not rely on direct in-person interactions, and programs intended to enhance transitions of care were more effective [96,99,100].

These programs are commonly referred to as fracture liaison services (FLS). They aim to identify patients with low-trauma fractures, provide risk assessment and education to the patient, and in some cases provide the patient with post-fracture osteoporosis care. These services typically require a dedicated case manager, who is often a clinical nurse specialist, ideally supported by a medical practitioner with expertise in the treatment of osteoporosis. The FLS case manager uses predetermined protocols that facilitate patient identification, risk assessment and management [101]. Some programs are hospital-based, identifying and evaluating patients while still hospitalized for their hip fracture, and others are based in clinics, aiming to provide services after discharge from the initial acute hospitalization [96,99–101].

How Effective Are Fracture Liaison Services?

Several FLS models have been proposed and tested, with some limited to patient identification and risk stratification, and others more intensive, involving initiation of BMD testing or BMD testing and osteoporosis treatment. In a meta-analysis of FLS programs, Ganda et al grouped programs into 3 categories: Type A programs involved patient identification, assessment and treatment, type B programs involved patient identification and assessment only without treatment, and type C programs involved patient identification combined with alerting of the patients and providers to the need to assess and treat. The effectiveness of the programs in terms of BMD testing and initiation of therapy increased with intensity. Type A programs were the most effective with BMD testing and treatment initiation rates of 79.4% and 46.4% respectively, followed by type B programs which had BMD testing and treatment initiation rates of 59.5% and 40.6% respectively, then type C programs which had BMD testing and treatment initiation rates of 43.4% and 23.4% respectively [100].

The most intensive programs have also been shown to significantly decrease the risk of fracture recurrence, with a reduction in the rate of re-fracture from 19.7% to 4.1% within 4 weeks [102], and a 37.2 % reduction within 3 years [103,104]. Additionally, intensive FLS programs involving pharmacotherapy with a bisphosphonate may be associated with a reduction in mortality after a hip fracture. Beaupre et al evaluated the mortality benefit associated with oral bisphosphonate therapy in the setting of a FLS and demonstrated an 8% decline in mortality per month of oral bisphosphonate use, and an approximate 60% reduction per year of use in comparison to patients who did not receive treatment [105]. This finding was consistent with the reduction in mortality seen with zoledronic acid in the HORIZON trial, which was in part attributable to decreased re-fracture rates, but primarily due to reduction in the occurrence of pneumonia and arrhythmias in patients receiving the drug [57,106].

While fracture liaison services may be associated with increased immediate costs—such as the costs of hiring a case manager, BMD testing and pharmacotherapy, and in some cases a data management system—several cost-effectiveness analyses have shown associated long-term cost savings [107–109]. This is not surprising given that they decrease re-fracture rates, leading to a decline in the very costly immediate and long-term fracture care costs.

Summary

In summary, fragility fractures present a major health care problem for aging populations, leading to significant costs and high morbidity and mortality. Assessment and treatment of osteoporosis following a fragility fracture can decrease the risk of fracture recurrence, long-term costs, morbidities, and possibly mortality. In the last decade, several national and international initiatives have been created to promote and encourage secondary prevention of fragility fractures [110–113]. However, these programs have all been voluntary and there are currently no reliable mechanisms to ensure broad implementation of secondary fracture prevention interventions. As a result, and while several isolated secondary prevention programs have shown great success, most patients with low-trauma fractures still receive suboptimal osteoporosis care.

Corresponding author: Amal Shibli-Rahhal, MD, MS, Dept. of Internal Medicine, University of Iowa Hospitals and Clinics, Iowa City, IA 52242.

Financial disclosures:

From the Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA.

Abstract

• Objective: To review and summarize the literature regarding current approaches to secondary prevention of low-trauma osteoporotic fractures.
• Methods: PubMed search and summary of existing literature related to complications and secondary prevention of osteoporotic fractures was performed.
• Results: Fragility fractures are associated with high rates of short and long term morbidities and carry a high risk of mortality and fracture recurrence. Several of the currently available anti-osteoporosis medications have been shown to decrease the risk of fracture recurrence in patients with prevalent osteoporotic fractures and some may even decrease mortality. However, only a minority of patients with fragility fractures are adequately evaluated and treated for osteoporosis. Fracture liaison services that ensure identification and risk stratification of patients with fragility fractures and proper evaluation and treatment of osteoporosis have proven effective at enhancing osteoporosis care in these patients, decreasing fracture recurrence and possibly even decreasing long-term mortality, while providing long-term cost savings. Unfortunately, however, this model of care has not been widely adopted and implemented.
• Conclusion: Fragility fractures represent a major health care problem for aging populations. Unfortunately, most patients with low-trauma fractures still receive suboptimal osteoporosis care.

Key words: osteoporosis; fracture; fragility; low-trauma; bone density.

Low-trauma fractures are fractures that occur from a trauma equivalent to a fall from standing height or less [1,2]. They can involve any skeletal site, but the most significant are vertebral, pelvic, wrist and hip fractures, which together represent close to 90% of all low-trauma fractures [3,4]. The overall burden of low-trauma fractures is quite high worldwide and is projected to increase over time [3–6]. In 2010, 3.5 million new low-trauma fractures were reported in the European Union [3]. In the United States, there were more than 2 million fractures in 2005, and it is estimated that more than 3 million fractures will occur in year 2025 [4].

Low-trauma fractures are generally indicative of compromised bone strength—especially when they involve the hip—and are thus often referred to as fragility fractures. While the traditional definition of osteoporosis is a bone mineral density (BMD) T-score of -2.5 or lower, low-trauma fractures of the hip are also diagnostic of osteoporosis, regardless of bone mineral density [2,7–9]. In addition, low-trauma fractures of the vertebrae, the proximal humerus, and the pelvis are considered diagnostic of osteoporosis when combined with T-scores between -1 and -2.5 [2,7]. Bone biopsies and high-resolution peripheral quantitative computed tomography (HR-pQCT) in patients with low-trauma fractures and normal BMD suggest microarchitectural alterations and abnormalities of collagen orientation and crosslinking within the bone matrix [10-12], leading to decreased bone strength.

This review will address the individual and societal costs of low-trauma fractures and issues related to secondary prevention of fractures, with specific emphasis on pharmacotherapy and fracture liaison services.

Impact of Low-Trauma Fractures

Acute and Long-Term Complications

Of all fragility fractures, hip fractures are the ones most likely to result in serious acute complications. The most common acute complications are delirium in up to 50% of patients and malnutrition in up to 60%, both of which predict slower and less complete recovery [13–16]. Other complications include urinary tract infections in up to 60% of patients in certain reports [17], thromboembolic disease with deep venous thrombosis in around 27% of patients and pulmonary embolism in up to 7% [16], and acute kidney injury in about 15% [18].

In addition, it is not uncommon for patients to suffer from significant long-term functional limitations following fragility fractures. While vertebral fractures do not frequently lead to hospitalization or institutionalization, they often lead to significant physical limitations and chronic pain [19,20] and to negative effects on self-esteem, mood, and body image [21,22]. However, the most remarkable functional decline and limitations are seen after hip fractures [23–25]. In a study of 2800 women and men with hip fracture, Beringer et al found that more than 30% were still institutionalized, and only 40% were able to walk outdoors independently 1 year later. Predictors of poor outcome included male sex, advanced age, cognitive impairment, and presence of comorbidities [23].

It is not surprising then that a fracture is often associated with an overall decline in the individual’s quality of life and this has been demonstrated in several studies [26–28]. In the largest study of this type, Tarride et al examined over 23,000 patients with fragility fractures and found a sharp decline in health-related quality of life (HRQOL) immediately after the fracture, which remained below baseline for up to 3 years [26]. The decline was worse in patients with hip and spine fractures compared to other fractures [27].

Mortality Following Fragility Fractures

Perhaps the most concerning complication, however, is the excess mortality seen after fractures. Several studies have demonstrated excess mortality after vertebral fractures, especially in the year following the fracture [29–33], but the highest increase in mortality was observed following hip fractures. In fact, the 30-day mortality after a hip fracture approximates 7% [23] and the excess 1-year mortality is estimated at 8% to 36% [34,35]. While the highest risk of mortality is seen in the first year following the fracture, the increased risk persists for at least 5 to 6 years [36]. Malnutrition, decreased mobility, male sex, and the number of coexisting medical comorbidities further increase the risk of mortality [29,32,34,36,37].

Risk of Fracture Recurrence

In both men and women, a fragility fracture at any site increases the risk of subsequent fractures [38–41], and the risk increases with the number of prevalent fractures [42]. Gehlbach et al estimated an 80% increase in the risk of fracture recurrence after 1 fracture, a threefold increase after 2 fractures, and an almost fivefold increase after 3 fractures [42]. The increase in risk is even more pronounced following vertebral fractures specifically, doubling after the first fracture an increasing by up to ninefold after 3 fractures [42, 43]. This increase in risk is highest in the first year following the fracture but may persist for up to 10 years [39,43].

Fracture Impact on Society

Fractures are associated with a high financial burden to society, in terms of direct acute care costs and long-term rehabilitation [3,4,44–48]. In 2010, the direct cost from fractures in the EU was estimated at €24.6 billion [3]. In the US, this cost was around $14.0 billion in 2002 and $16.9 billion in 2005 [4,48], and in Canada it was $1.5 billion in 2011 [47]. These numbers increase substantially when costs associated with long-term post-fracture rehabilitation are included, with an additional estimated yearly cost of €10.7 billion in the EU and $1.03 billion in Canada [3,47].

While hip fractures account for only about 18% of all low-trauma fractures, they are associated with the highest cost burden, accounting for about 50% to 70% of the total fracture-associated expenditures [3,4,44]. This is likely due to the fact almost all hip fractures require hospitalization, most require surgical repair and rehabilitation, and because they lead to the highest rates of morbidity and mortality.

Can Fracture Recurrence After a Low-Trauma Fracture Be Prevented?

Many approaches to secondary fracture prevention have been proposed, including but not limited to fall prevention, exercise therapy, nutrition therapy, prevention and treatment of sarcopenia, vitamin D and calcium supplementation, and osteoporosis pharmacotherapy [49–53]. Of those, osteoporosis pharmacotherapy has the strongest and most compelling efficacy data and will be reviewed in the following sections.

Effect of Antiresorptive Therapy After a Fracture

In the Fracture Intervention Trial (FIT), alendronate decreased the risk of new vertebral fractures by about 47% and of hip fractures by about 50% in women with preexisting vertebral fractures [54,55]. Similar fracture protection benefits were demonstrated in the Hip Intervention Program (HIP), where risedronate decreased the risk of hip fractures by 60% in women with prior history of vertebral fractures [56].

The best data regarding secondary prevention of hip fractures however comes from the Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly (HORIZON) trial, where patients were randomized to zoledronic acid or placebo within 90 days of a hip fracture. Over a median duration of therapy of about 2 years, zoledronic acid decreased the risk of any new clinical fracture by 35%, of new vertebral fractures by 46%, and of recurrent hip fractures by 30% [57].

Effect of Anabolic Therapy After a Fracture

The Fracture Prevention Trial (FPT) compared the effect of teriparatide to placebo in women with at least 1 moderate or 2 mild atraumatic vertebral fractures and showed a 65% reduction in the risk of new vertebral fractures and a 53% reduction in the risk of new non-vertebral fractures [58]. Likewise, the Abaloparatide Comparator Trial In Vertebral Endpoints (ACTIVE) enrolled women with at least 2 mild vertebral fractures, 1 moderate vertebral fracture or history of a low trauma fracture of the forearm, humerus, sacrum, pelvis, hip, femur, or tibia. In this trial, abaloparatide decreased the risk of new vertebral fractures by 85% and of new non-vertebral fractures by 43% compared to placebo [59].

Will Anti-Osteoporosis Therapy After a Low-Trauma Fracture Impact Fracture Healing?

One major question regarding the use of anti-osteoporosis drugs in patients with a recent fracture is the effect that treatment might have on bone healing after fracture or fracture-repair surgery. With antiresorptive agents in particular, the main concern is whether suppression of bone turnover may lead to delayed bone healing, since healing requires callus remodeling. A small prospective study evaluated fracture healing in 196 patients treated for a distal radius fracture, 153 of whom were on a bisphosphonate at the time of the fracture. While bisphosphonate use was associated with a longer time to radiographic union, the time to union was only 6 days longer in the bisphosphonate group (55 days versus 49 days to union in the bisphosphonate and control groups, respectively), and has generally not been felt to be clinically significant [60]. The most reassuring data regarding this question however, comes from the HORIZON trial where 2127 men and women were randomized to zoledronic acid or placebo within 90 days of a hip fracture. No difference in healing between the 2 groups was seen, regardless of the time of initiation of zoledronic acid (within 2 weeks of fracture, between 2 and 4 weeks, between 4 and 6 weeks or after 6 weeks) [61].

The stimulation of bone turnover that occurs with anabolic agents is generally thought to accelerate bone healing. In animal studies, teriparatide has been found to enhance callus formation and mechanical strength [62–64], but there is no definitive data in humans to prove this effect [65].

In summary, there is strong evidence demonstrating the effectiveness of bisphosphonates and anabolic agents at decreasing the risk of fracture recurrence in patients with preexisting vertebral fractures. Zoledronic acid has also been shown to decrease the risk of fracture recurrence after a hip fracture. Anti-osteoporosis therapy after a fracture has no clinically significant effect on fracture healing.

The Gap Between Science and Practice

Practice Guidelines Versus Actual Practice

Based on the data presented above, multiple professional societies and expert groups have developed guidelines emphasizing the importance of evaluation and treatment for osteoporosis following a low-trauma fracture, especially those of the hip and spine [8,9,66–69]. In a 2009 multidisciplinary workshop of the International Society of Fracture Repair, an in-depth review of existing data showed no evidence for a negative effect of anti-osteoporosis drugs on fracture healing. As a result, it was recommended not to withhold osteoporosis therapy until fracture healing has occurred, and to initiate treatment before patient discharge from the fracture ward in order to improve follow-up [70].

However, despite these expert guidelines and the availability of several effective agents to decrease the risk of fracture and fracture recurrence, evaluation and treatment of patients for osteoporosis after a low-trauma fracture are very low. Several large-scale studies involving older patients with fractures in North America, Europe, Asia, and Australia have shown that the rates of BMD measurement or drug therapy for osteoporosis after a fragility fracture do not exceed 25% to 30% [71–80]. While treatment trends over time may have shown some improvement, they remain overall disappointing. For example, in a study of over 150,000 patients who sustained a fracture between 1997 and 2004, Roerholt et al found that around 20% of women were started on therapy after a vertebral fracture in 1997, while 40% received therapy in 2004. Among women with hip fracture, 3% received treatment in 1997 and 9% in 2004 [71]. Furthermore, when osteoporosis treatment rates are examined more closely, most of the patients who receive treatment after a fracture are those who were being treated prior to the fracture, so treatment is simply continued in them. New osteoporosis therapy is initiated in only 5% to 15% of patients who are not already on osteoporosis therapy at the time of fracture [72,73,77,81,82].

Analyses of prescription patterns suggest that patients with vertebral fractures are more likely to receive treatment compared to those with hip fractures [71,82], and that women are much more likely to receive therapy than men [71,74,77,83–88]. Other factors that decrease the chance of receiving therapy include black race [84], low income [74], older age, presence of multiple comorbidities, and polypharmacy [83].

Barriers to Care: Where Are We Failing?

The large discrepancy between science and practice when it comes to secondary prevention of fractures is quite puzzling and has been the subject of several investigations. A major barrier to proper care seems to be the lack of ownership of the problem by the orthopedic surgeons and medical providers, and the less than ideal collaboration between the 2 services in coordinating and providing secondary prevention [89–94]. The orthopedic surgeons are one of the first points of contact with health care for a patient with a low-trauma hip fracture. They are mainly charged with providing acute fracture care and often cannot provide long-term osteoporosis care, which would be more suitable for a medical specialist. However, while the acute care surgical team is not best suited to treat osteoporosis, it is still very important that they initiate patient referral to a provider who can provide long-term osteoporosis care. This transition of care–of lack of it–seems to be one of the major missing links, leading to patient loss [88] and suboptimal secondary prevention.

However, patient referral may not be a sufficient solution and interestingly, a medical consultation during an acute admission for hip fracture does not seem to increase the frequency of osteoporosis diagnosis [95]. This points to a deficiency in knowledge, and as a matter of fact, studies do suggest a problem with under-recognition of the connection between low-trauma fractures and underlying osteoporosis among medical and surgical providers alike [92,93,96]. In a survey of orthopedic surgeons and consultant physicians involved in the care of patients with low-trauma hip fractures, only 24% of respondents felt that osteoporosis therapy was indicated. The majority of providers thought that treatment with a bisphosphonate was indicated only if low BMD was present, rather than in all patients with low-trauma hip fractures [92]. This is further illustrated by the fact that only a minority of patients with a low-trauma fracture are formally given the diagnosis of osteoporosis [75,80,97] or are told that they have osteoporosis [79].

Fracture Liaison Services—A Potential Solution to Enhance Secondary Fracture Prevention

What is a Fracture Liaison Service?

Several solutions have been proposed to remedy the main barriers that interfere with proper secondary treatment of osteoporosis, namely patient education, provider education, and the initiation of programs to enhance coordination and continuity of care between treating teams. Taken together, these interventions have been modestly effective at increasing the odds of BMD measurement and initiation of osteoporosis therapy [98, 99]. Interventions that focused mainly on provider and/or patient education were the least effective, especially when they did not rely on direct in-person interactions, and programs intended to enhance transitions of care were more effective [96,99,100].

These programs are commonly referred to as fracture liaison services (FLS). They aim to identify patients with low-trauma fractures, provide risk assessment and education to the patient, and in some cases provide the patient with post-fracture osteoporosis care. These services typically require a dedicated case manager, who is often a clinical nurse specialist, ideally supported by a medical practitioner with expertise in the treatment of osteoporosis. The FLS case manager uses predetermined protocols that facilitate patient identification, risk assessment and management [101]. Some programs are hospital-based, identifying and evaluating patients while still hospitalized for their hip fracture, and others are based in clinics, aiming to provide services after discharge from the initial acute hospitalization [96,99–101].

How Effective Are Fracture Liaison Services?

Several FLS models have been proposed and tested, with some limited to patient identification and risk stratification, and others more intensive, involving initiation of BMD testing or BMD testing and osteoporosis treatment. In a meta-analysis of FLS programs, Ganda et al grouped programs into 3 categories: Type A programs involved patient identification, assessment and treatment, type B programs involved patient identification and assessment only without treatment, and type C programs involved patient identification combined with alerting of the patients and providers to the need to assess and treat. The effectiveness of the programs in terms of BMD testing and initiation of therapy increased with intensity. Type A programs were the most effective with BMD testing and treatment initiation rates of 79.4% and 46.4% respectively, followed by type B programs which had BMD testing and treatment initiation rates of 59.5% and 40.6% respectively, then type C programs which had BMD testing and treatment initiation rates of 43.4% and 23.4% respectively [100].

The most intensive programs have also been shown to significantly decrease the risk of fracture recurrence, with a reduction in the rate of re-fracture from 19.7% to 4.1% within 4 weeks [102], and a 37.2 % reduction within 3 years [103,104]. Additionally, intensive FLS programs involving pharmacotherapy with a bisphosphonate may be associated with a reduction in mortality after a hip fracture. Beaupre et al evaluated the mortality benefit associated with oral bisphosphonate therapy in the setting of a FLS and demonstrated an 8% decline in mortality per month of oral bisphosphonate use, and an approximate 60% reduction per year of use in comparison to patients who did not receive treatment [105]. This finding was consistent with the reduction in mortality seen with zoledronic acid in the HORIZON trial, which was in part attributable to decreased re-fracture rates, but primarily due to reduction in the occurrence of pneumonia and arrhythmias in patients receiving the drug [57,106].

While fracture liaison services may be associated with increased immediate costs—such as the costs of hiring a case manager, BMD testing and pharmacotherapy, and in some cases a data management system—several cost-effectiveness analyses have shown associated long-term cost savings [107–109]. This is not surprising given that they decrease re-fracture rates, leading to a decline in the very costly immediate and long-term fracture care costs.

Summary

In summary, fragility fractures present a major health care problem for aging populations, leading to significant costs and high morbidity and mortality. Assessment and treatment of osteoporosis following a fragility fracture can decrease the risk of fracture recurrence, long-term costs, morbidities, and possibly mortality. In the last decade, several national and international initiatives have been created to promote and encourage secondary prevention of fragility fractures [110–113]. However, these programs have all been voluntary and there are currently no reliable mechanisms to ensure broad implementation of secondary fracture prevention interventions. As a result, and while several isolated secondary prevention programs have shown great success, most patients with low-trauma fractures still receive suboptimal osteoporosis care.

Corresponding author: Amal Shibli-Rahhal, MD, MS, Dept. of Internal Medicine, University of Iowa Hospitals and Clinics, Iowa City, IA 52242.

Financial disclosures:

From the Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA.

Abstract

• Objective: To review and summarize the literature regarding current approaches to secondary prevention of low-trauma osteoporotic fractures.
• Methods: PubMed search and summary of existing literature related to complications and secondary prevention of osteoporotic fractures was performed.
• Results: Fragility fractures are associated with high rates of short and long term morbidities and carry a high risk of mortality and fracture recurrence. Several of the currently available anti-osteoporosis medications have been shown to decrease the risk of fracture recurrence in patients with prevalent osteoporotic fractures and some may even decrease mortality. However, only a minority of patients with fragility fractures are adequately evaluated and treated for osteoporosis. Fracture liaison services that ensure identification and risk stratification of patients with fragility fractures and proper evaluation and treatment of osteoporosis have proven effective at enhancing osteoporosis care in these patients, decreasing fracture recurrence and possibly even decreasing long-term mortality, while providing long-term cost savings. Unfortunately, however, this model of care has not been widely adopted and implemented.
• Conclusion: Fragility fractures represent a major health care problem for aging populations. Unfortunately, most patients with low-trauma fractures still receive suboptimal osteoporosis care.

Key words: osteoporosis; fracture; fragility; low-trauma; bone density.

Low-trauma fractures are fractures that occur from a trauma equivalent to a fall from standing height or less [1,2]. They can involve any skeletal site, but the most significant are vertebral, pelvic, wrist and hip fractures, which together represent close to 90% of all low-trauma fractures [3,4]. The overall burden of low-trauma fractures is quite high worldwide and is projected to increase over time [3–6]. In 2010, 3.5 million new low-trauma fractures were reported in the European Union [3]. In the United States, there were more than 2 million fractures in 2005, and it is estimated that more than 3 million fractures will occur in year 2025 [4].

Low-trauma fractures are generally indicative of compromised bone strength—especially when they involve the hip—and are thus often referred to as fragility fractures. While the traditional definition of osteoporosis is a bone mineral density (BMD) T-score of -2.5 or lower, low-trauma fractures of the hip are also diagnostic of osteoporosis, regardless of bone mineral density [2,7–9]. In addition, low-trauma fractures of the vertebrae, the proximal humerus, and the pelvis are considered diagnostic of osteoporosis when combined with T-scores between -1 and -2.5 [2,7]. Bone biopsies and high-resolution peripheral quantitative computed tomography (HR-pQCT) in patients with low-trauma fractures and normal BMD suggest microarchitectural alterations and abnormalities of collagen orientation and crosslinking within the bone matrix [10-12], leading to decreased bone strength.

This review will address the individual and societal costs of low-trauma fractures and issues related to secondary prevention of fractures, with specific emphasis on pharmacotherapy and fracture liaison services.

Impact of Low-Trauma Fractures

Acute and Long-Term Complications

Of all fragility fractures, hip fractures are the ones most likely to result in serious acute complications. The most common acute complications are delirium in up to 50% of patients and malnutrition in up to 60%, both of which predict slower and less complete recovery [13–16]. Other complications include urinary tract infections in up to 60% of patients in certain reports [17], thromboembolic disease with deep venous thrombosis in around 27% of patients and pulmonary embolism in up to 7% [16], and acute kidney injury in about 15% [18].

In addition, it is not uncommon for patients to suffer from significant long-term functional limitations following fragility fractures. While vertebral fractures do not frequently lead to hospitalization or institutionalization, they often lead to significant physical limitations and chronic pain [19,20] and to negative effects on self-esteem, mood, and body image [21,22]. However, the most remarkable functional decline and limitations are seen after hip fractures [23–25]. In a study of 2800 women and men with hip fracture, Beringer et al found that more than 30% were still institutionalized, and only 40% were able to walk outdoors independently 1 year later. Predictors of poor outcome included male sex, advanced age, cognitive impairment, and presence of comorbidities [23].

It is not surprising then that a fracture is often associated with an overall decline in the individual’s quality of life and this has been demonstrated in several studies [26–28]. In the largest study of this type, Tarride et al examined over 23,000 patients with fragility fractures and found a sharp decline in health-related quality of life (HRQOL) immediately after the fracture, which remained below baseline for up to 3 years [26]. The decline was worse in patients with hip and spine fractures compared to other fractures [27].

Mortality Following Fragility Fractures

Perhaps the most concerning complication, however, is the excess mortality seen after fractures. Several studies have demonstrated excess mortality after vertebral fractures, especially in the year following the fracture [29–33], but the highest increase in mortality was observed following hip fractures. In fact, the 30-day mortality after a hip fracture approximates 7% [23] and the excess 1-year mortality is estimated at 8% to 36% [34,35]. While the highest risk of mortality is seen in the first year following the fracture, the increased risk persists for at least 5 to 6 years [36]. Malnutrition, decreased mobility, male sex, and the number of coexisting medical comorbidities further increase the risk of mortality [29,32,34,36,37].

Risk of Fracture Recurrence

In both men and women, a fragility fracture at any site increases the risk of subsequent fractures [38–41], and the risk increases with the number of prevalent fractures [42]. Gehlbach et al estimated an 80% increase in the risk of fracture recurrence after 1 fracture, a threefold increase after 2 fractures, and an almost fivefold increase after 3 fractures [42]. The increase in risk is even more pronounced following vertebral fractures specifically, doubling after the first fracture an increasing by up to ninefold after 3 fractures [42, 43]. This increase in risk is highest in the first year following the fracture but may persist for up to 10 years [39,43].

Fracture Impact on Society

Fractures are associated with a high financial burden to society, in terms of direct acute care costs and long-term rehabilitation [3,4,44–48]. In 2010, the direct cost from fractures in the EU was estimated at €24.6 billion [3]. In the US, this cost was around $14.0 billion in 2002 and $16.9 billion in 2005 [4,48], and in Canada it was $1.5 billion in 2011 [47]. These numbers increase substantially when costs associated with long-term post-fracture rehabilitation are included, with an additional estimated yearly cost of €10.7 billion in the EU and $1.03 billion in Canada [3,47].

While hip fractures account for only about 18% of all low-trauma fractures, they are associated with the highest cost burden, accounting for about 50% to 70% of the total fracture-associated expenditures [3,4,44]. This is likely due to the fact almost all hip fractures require hospitalization, most require surgical repair and rehabilitation, and because they lead to the highest rates of morbidity and mortality.

Can Fracture Recurrence After a Low-Trauma Fracture Be Prevented?

Many approaches to secondary fracture prevention have been proposed, including but not limited to fall prevention, exercise therapy, nutrition therapy, prevention and treatment of sarcopenia, vitamin D and calcium supplementation, and osteoporosis pharmacotherapy [49–53]. Of those, osteoporosis pharmacotherapy has the strongest and most compelling efficacy data and will be reviewed in the following sections.

Effect of Antiresorptive Therapy After a Fracture

In the Fracture Intervention Trial (FIT), alendronate decreased the risk of new vertebral fractures by about 47% and of hip fractures by about 50% in women with preexisting vertebral fractures [54,55]. Similar fracture protection benefits were demonstrated in the Hip Intervention Program (HIP), where risedronate decreased the risk of hip fractures by 60% in women with prior history of vertebral fractures [56].

The best data regarding secondary prevention of hip fractures however comes from the Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly (HORIZON) trial, where patients were randomized to zoledronic acid or placebo within 90 days of a hip fracture. Over a median duration of therapy of about 2 years, zoledronic acid decreased the risk of any new clinical fracture by 35%, of new vertebral fractures by 46%, and of recurrent hip fractures by 30% [57].

Effect of Anabolic Therapy After a Fracture

The Fracture Prevention Trial (FPT) compared the effect of teriparatide to placebo in women with at least 1 moderate or 2 mild atraumatic vertebral fractures and showed a 65% reduction in the risk of new vertebral fractures and a 53% reduction in the risk of new non-vertebral fractures [58]. Likewise, the Abaloparatide Comparator Trial In Vertebral Endpoints (ACTIVE) enrolled women with at least 2 mild vertebral fractures, 1 moderate vertebral fracture or history of a low trauma fracture of the forearm, humerus, sacrum, pelvis, hip, femur, or tibia. In this trial, abaloparatide decreased the risk of new vertebral fractures by 85% and of new non-vertebral fractures by 43% compared to placebo [59].

Will Anti-Osteoporosis Therapy After a Low-Trauma Fracture Impact Fracture Healing?

One major question regarding the use of anti-osteoporosis drugs in patients with a recent fracture is the effect that treatment might have on bone healing after fracture or fracture-repair surgery. With antiresorptive agents in particular, the main concern is whether suppression of bone turnover may lead to delayed bone healing, since healing requires callus remodeling. A small prospective study evaluated fracture healing in 196 patients treated for a distal radius fracture, 153 of whom were on a bisphosphonate at the time of the fracture. While bisphosphonate use was associated with a longer time to radiographic union, the time to union was only 6 days longer in the bisphosphonate group (55 days versus 49 days to union in the bisphosphonate and control groups, respectively), and has generally not been felt to be clinically significant [60]. The most reassuring data regarding this question however, comes from the HORIZON trial where 2127 men and women were randomized to zoledronic acid or placebo within 90 days of a hip fracture. No difference in healing between the 2 groups was seen, regardless of the time of initiation of zoledronic acid (within 2 weeks of fracture, between 2 and 4 weeks, between 4 and 6 weeks or after 6 weeks) [61].

The stimulation of bone turnover that occurs with anabolic agents is generally thought to accelerate bone healing. In animal studies, teriparatide has been found to enhance callus formation and mechanical strength [62–64], but there is no definitive data in humans to prove this effect [65].

In summary, there is strong evidence demonstrating the effectiveness of bisphosphonates and anabolic agents at decreasing the risk of fracture recurrence in patients with preexisting vertebral fractures. Zoledronic acid has also been shown to decrease the risk of fracture recurrence after a hip fracture. Anti-osteoporosis therapy after a fracture has no clinically significant effect on fracture healing.

The Gap Between Science and Practice

Practice Guidelines Versus Actual Practice

Based on the data presented above, multiple professional societies and expert groups have developed guidelines emphasizing the importance of evaluation and treatment for osteoporosis following a low-trauma fracture, especially those of the hip and spine [8,9,66–69]. In a 2009 multidisciplinary workshop of the International Society of Fracture Repair, an in-depth review of existing data showed no evidence for a negative effect of anti-osteoporosis drugs on fracture healing. As a result, it was recommended not to withhold osteoporosis therapy until fracture healing has occurred, and to initiate treatment before patient discharge from the fracture ward in order to improve follow-up [70].

However, despite these expert guidelines and the availability of several effective agents to decrease the risk of fracture and fracture recurrence, evaluation and treatment of patients for osteoporosis after a low-trauma fracture are very low. Several large-scale studies involving older patients with fractures in North America, Europe, Asia, and Australia have shown that the rates of BMD measurement or drug therapy for osteoporosis after a fragility fracture do not exceed 25% to 30% [71–80]. While treatment trends over time may have shown some improvement, they remain overall disappointing. For example, in a study of over 150,000 patients who sustained a fracture between 1997 and 2004, Roerholt et al found that around 20% of women were started on therapy after a vertebral fracture in 1997, while 40% received therapy in 2004. Among women with hip fracture, 3% received treatment in 1997 and 9% in 2004 [71]. Furthermore, when osteoporosis treatment rates are examined more closely, most of the patients who receive treatment after a fracture are those who were being treated prior to the fracture, so treatment is simply continued in them. New osteoporosis therapy is initiated in only 5% to 15% of patients who are not already on osteoporosis therapy at the time of fracture [72,73,77,81,82].

Analyses of prescription patterns suggest that patients with vertebral fractures are more likely to receive treatment compared to those with hip fractures [71,82], and that women are much more likely to receive therapy than men [71,74,77,83–88]. Other factors that decrease the chance of receiving therapy include black race [84], low income [74], older age, presence of multiple comorbidities, and polypharmacy [83].

Barriers to Care: Where Are We Failing?

The large discrepancy between science and practice when it comes to secondary prevention of fractures is quite puzzling and has been the subject of several investigations. A major barrier to proper care seems to be the lack of ownership of the problem by the orthopedic surgeons and medical providers, and the less than ideal collaboration between the 2 services in coordinating and providing secondary prevention [89–94]. The orthopedic surgeons are one of the first points of contact with health care for a patient with a low-trauma hip fracture. They are mainly charged with providing acute fracture care and often cannot provide long-term osteoporosis care, which would be more suitable for a medical specialist. However, while the acute care surgical team is not best suited to treat osteoporosis, it is still very important that they initiate patient referral to a provider who can provide long-term osteoporosis care. This transition of care–of lack of it–seems to be one of the major missing links, leading to patient loss [88] and suboptimal secondary prevention.

However, patient referral may not be a sufficient solution and interestingly, a medical consultation during an acute admission for hip fracture does not seem to increase the frequency of osteoporosis diagnosis [95]. This points to a deficiency in knowledge, and as a matter of fact, studies do suggest a problem with under-recognition of the connection between low-trauma fractures and underlying osteoporosis among medical and surgical providers alike [92,93,96]. In a survey of orthopedic surgeons and consultant physicians involved in the care of patients with low-trauma hip fractures, only 24% of respondents felt that osteoporosis therapy was indicated. The majority of providers thought that treatment with a bisphosphonate was indicated only if low BMD was present, rather than in all patients with low-trauma hip fractures [92]. This is further illustrated by the fact that only a minority of patients with a low-trauma fracture are formally given the diagnosis of osteoporosis [75,80,97] or are told that they have osteoporosis [79].

Fracture Liaison Services—A Potential Solution to Enhance Secondary Fracture Prevention

What is a Fracture Liaison Service?

Several solutions have been proposed to remedy the main barriers that interfere with proper secondary treatment of osteoporosis, namely patient education, provider education, and the initiation of programs to enhance coordination and continuity of care between treating teams. Taken together, these interventions have been modestly effective at increasing the odds of BMD measurement and initiation of osteoporosis therapy [98, 99]. Interventions that focused mainly on provider and/or patient education were the least effective, especially when they did not rely on direct in-person interactions, and programs intended to enhance transitions of care were more effective [96,99,100].

These programs are commonly referred to as fracture liaison services (FLS). They aim to identify patients with low-trauma fractures, provide risk assessment and education to the patient, and in some cases provide the patient with post-fracture osteoporosis care. These services typically require a dedicated case manager, who is often a clinical nurse specialist, ideally supported by a medical practitioner with expertise in the treatment of osteoporosis. The FLS case manager uses predetermined protocols that facilitate patient identification, risk assessment and management [101]. Some programs are hospital-based, identifying and evaluating patients while still hospitalized for their hip fracture, and others are based in clinics, aiming to provide services after discharge from the initial acute hospitalization [96,99–101].

How Effective Are Fracture Liaison Services?

Several FLS models have been proposed and tested, with some limited to patient identification and risk stratification, and others more intensive, involving initiation of BMD testing or BMD testing and osteoporosis treatment. In a meta-analysis of FLS programs, Ganda et al grouped programs into 3 categories: Type A programs involved patient identification, assessment and treatment, type B programs involved patient identification and assessment only without treatment, and type C programs involved patient identification combined with alerting of the patients and providers to the need to assess and treat. The effectiveness of the programs in terms of BMD testing and initiation of therapy increased with intensity. Type A programs were the most effective with BMD testing and treatment initiation rates of 79.4% and 46.4% respectively, followed by type B programs which had BMD testing and treatment initiation rates of 59.5% and 40.6% respectively, then type C programs which had BMD testing and treatment initiation rates of 43.4% and 23.4% respectively [100].

The most intensive programs have also been shown to significantly decrease the risk of fracture recurrence, with a reduction in the rate of re-fracture from 19.7% to 4.1% within 4 weeks [102], and a 37.2 % reduction within 3 years [103,104]. Additionally, intensive FLS programs involving pharmacotherapy with a bisphosphonate may be associated with a reduction in mortality after a hip fracture. Beaupre et al evaluated the mortality benefit associated with oral bisphosphonate therapy in the setting of a FLS and demonstrated an 8% decline in mortality per month of oral bisphosphonate use, and an approximate 60% reduction per year of use in comparison to patients who did not receive treatment [105]. This finding was consistent with the reduction in mortality seen with zoledronic acid in the HORIZON trial, which was in part attributable to decreased re-fracture rates, but primarily due to reduction in the occurrence of pneumonia and arrhythmias in patients receiving the drug [57,106].

While fracture liaison services may be associated with increased immediate costs—such as the costs of hiring a case manager, BMD testing and pharmacotherapy, and in some cases a data management system—several cost-effectiveness analyses have shown associated long-term cost savings [107–109]. This is not surprising given that they decrease re-fracture rates, leading to a decline in the very costly immediate and long-term fracture care costs.

Summary

In summary, fragility fractures present a major health care problem for aging populations, leading to significant costs and high morbidity and mortality. Assessment and treatment of osteoporosis following a fragility fracture can decrease the risk of fracture recurrence, long-term costs, morbidities, and possibly mortality. In the last decade, several national and international initiatives have been created to promote and encourage secondary prevention of fragility fractures [110–113]. However, these programs have all been voluntary and there are currently no reliable mechanisms to ensure broad implementation of secondary fracture prevention interventions. As a result, and while several isolated secondary prevention programs have shown great success, most patients with low-trauma fractures still receive suboptimal osteoporosis care.

Corresponding author: Amal Shibli-Rahhal, MD, MS, Dept. of Internal Medicine, University of Iowa Hospitals and Clinics, Iowa City, IA 52242.

Financial disclosures:

IN THIS ARTICLE

• Causes of pain
• Screening
• Multimodal treatment

Care of women with sexual disorders has made great strides since Masters and Johnson began their study in 1957. In 2000, the Sexual Function Health Council of the American Foundation for Urologic Disease devised the classification system for female sexual dysfunction, which was officially defined in the Diagnostic and Statistical Manual of Mental Disorders-IV-TR.¹ There are now definitions for sexual desire disorders, sexual arousal disorders, orgasmic disorder, and sexual pain disorders.

Female sexual dysfunction (FSD) has complex physiologic and psychologic components that require a detailed screening, history, and physical examination. Our goal in this review is to provide primary care providers with insights and practical advice to help screen, diagnose, and treat FSD, which can have a profound impact on patients’ most intimate relationships.

UNDERSTANDING THE TYPES OF FSD

Most women consider sexual health an important part of their overall health.² Factors that can disrupt normal sexual function include aging, socioeconomics, and other medical comorbidities. FSD is common in women throughout their lives and refers to various sexual dysfunctions including diminished arousal, problems achieving orgasm, dyspareunia, and low desire. Its prevalence is reported to be as high as 20% to 43%.^3,4

The World Health Organization and the US Surgeon General have released statements encouraging health care providers to address sexual health during a patient’s annual visits.⁵ Unfortunately, despite this call to action, many patients and providers are initially hesitant to discuss these problems.⁶

The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) provides the definition and diagnostic guidelines for the different components of FSD. Its classification of sexual disorders was simplified and published in May 2013.⁷ There are now only three female dysfunctions (as opposed to five in DSM-IV):

• Female hypoactive desire dysfunction and female arousal dysfunction were merged into a single syndrome labeled female sexual interest/arousal disorder.
• The formerly separate dyspareunia (painful intercourse) and vaginismus are now called genitopelvic pain/penetration disorder.
• Female orgasmic disorder remains as a category and is unchanged.

To qualify as a dysfunction, the problem must be present more than 75% of the time, for more than six months, causing significant distress, and must not be explained by a nonsexual mental disorder, relationship distress, substance abuse, or a medical condition.

Substance- or medication-induced sexual dysfunction falls under “Other Dysfunctions” and is defined as a clinically significant disturbance in sexual function that is predominant in the clinical picture. The criteria for substance- and medication-induced sexual dysfunction are unchanged and include neither the 75% nor the six-month requirement. The diagnosis of sexual dysfunction due to a general medical condition and sexual aversion disorder are absent from the DSM-5.⁷

Continue to: A common symptom

A common symptom. Female sexual disorders can be caused by several complex physiologic and psychologic factors. A common symptom among many women is dyspareunia. It is seen more often in postmenopausal women, and its prevalence ranges from 8% to 22%.⁸ Pain on vaginal entry usually indicates vaginal atrophy, vaginal dermatitis, or provoked vestibulodynia. Pain on deep penetration could be caused by endometriosis, interstitial cystitis, or uterine leiomyomas.⁹

The physical examination will reproduce the pain when the vulva or vagina is touched with a cotton swab or when you insert a finger into the vagina. The differential diagnosis is listed in the Table.^9-11

EVALUATING THE PATIENT

Initially, many patients and providers may hesitate to discuss sexual dysfunction, but the annual exam is a good opportunity to broach the topic of sexual health.

Screening and history

Clinicians can screen all patients, regardless of age, with the help of a validated sex questionnaire or during a routine review of systems. There are many validated screening tools available. A simple, integrated screening tool to use is the Brief Sexual Symptom Checklist for Women (BSSC-W), created by the International Consultation on Sexual Medicine.¹² Although recommended by the American Congress of Obstetricians and Gynecologists, the BSSC-W is not validated.⁹ The four items in the questionnaire ascertain personal information regarding an individual’s overall sexual function satisfaction, the problem causing dysfunction, how bothersome the symptoms are, and whether the patient is interested in discussing it with her provider.¹²

It’s important to obtain a detailed obstetric and gynecologic history that includes any sexually transmitted diseases, sexual abuse, urinary and bowel complaints, or surgeries. In addition, you’ll want to differentiate between various types of dysfunctions. A thorough physical examination, including an external and internal pelvic exam, can help to rule out other causes of sexual dysfunction.

Continue to: General exam: What to look for

General exam: What to look for

The external pelvic examination begins with visual inspection of the vulva, labia majora, and labia minora. Often, this is best accomplished gently with a gloved hand and a cotton swab. This inspection may reveal changes in pubic hair distribution, vulvar skin disorders, lesions, masses, cracks, or fissures. Inspection may also reveal redness and pain typical of vestibulitis, a flattening and pallor of the labia that suggests estrogen deficiency, or pelvic organ prolapse.

The internal pelvic examination begins with a manual evaluation of the muscles of the pelvic floor, uterus, bladder, urethra, anus, and adnexa. Make careful note of any unusual tenderness or pelvic masses. Pelvic floor muscles (PFMs) should voluntarily contract and relax and are not normally tender to palpation. Pelvic organ prolapse and/or hypermobility of the bladder may indicate a weakening of the endopelvic fascia and may cause sexual pain. The size and flexion of the uterus, tenderness in the vaginal fornix possibly indicating endometriosis, and adnexal fullness and/or masses should be identified and evaluated.

Neurologic exam of the pelvis will involve evaluation of sensory and motor function of both lower extremities and include a screening lumbosacral neurologic examination. Lumbosacral examination includes assessment of PFM strength, anal sphincter resting tone, voluntary anal contraction, and perineal sensation. If abnormalities are noted in the screening assessment, a complete comprehensive neurologic examination should be performed.

It’s important to assess pelvic floor muscle strength

Sexual function is associated with normal PFM function.^13,14 The PFMs, particularly the pubococcygeus and iliococcygeus, are responsible for involuntary contractions during orgasm.¹³ Orgasm has been considered a reflex, which is preceded by increased blood flow to the genital organs, tumescence of the vulva and vagina, increased secretions during sexual arousal, and increased tension and contractions of the PFMs.¹⁵

Lowenstein et al found that women with strong or moderate PFM contractions scored significantly higher on both orgasm and arousal domains of the Female Sexual Function Index (FSFI), compared with women with weak PFM contractions.¹⁶ Orgasm and arousal functions may be associated with PFM strength, with a positive association between pelvic floor strength and sexual activity and function.^17,18

The function and dysfunction of the PFMs have been characterized as normal, overactive (high tone), underactive (low tone), and nonfunctioning.

Continue to: Normal PFMs

Normal PFMs are those that can voluntarily and involuntarily contract and relax.^19,20

Overactive (high-tone) muscles are those that do not relax and possibly contract during times of relaxation for micturition or defecation. This type of dysfunction can lead to voiding dysfunction, defecatory dysfunction, and dyspareunia.¹⁹

Underactive, or low-tone, PFMs cannot contract voluntarily. This can be associated with urinary and anal incontinence and pelvic organ prolapse.

Nonfunctioning muscles are completely inactive.¹⁹

How to assess. There are several ways to assess PFM tone and strength.²⁰ The first is intravaginal or intrarectal digital palpation, which can be performed when the patient is in a supine or standing position. This examination evaluates PFM tone, squeeze pressure during contraction, symmetry, and relaxation. However, there is no validated scale to quantify PFM strength. Contractions can be further divided into voluntary and involuntary.¹⁹

During the exam, ask the patient to contract as much as she can to evaluate the maximum strength and sustained contraction for endurance. This measurement can be done with digital palpation or with pressure manometry or dynamometry.

Examination can be focused on the levator ani, piriformis, and internal obturator muscles bilaterally and rated by the patient’s reactions. Pelvic muscle tenderness, which can be highly prevalent in women with chronic pelvic pain, is associated with higher degrees of dyspareunia.²¹ Digital evaluation of the pelvic floor musculature varies in scale, number of fingers used, and parameters evaluated.

Lukban et al have described a 0 to 4 numbered scale that evaluates tenderness in the pelvic floor.²² The scale denotes “1” as comfortable pressure associated with the exam, “2” as uncomfortable pressure associated with the exam, “3” as moderate pain associated with the exam that intensifies with contraction, and “4” indicating severe pain with the exam and inability to perform the contraction maneuver due to pain.

Continue to: EFFECTIVE TREATMENT INCLUDES MULTIPLE OPTIONS

Lifestyle modifications can help

Lifestyle changes may help improve sexual function. These modifications include physical activity, healthy diet, nutrition counseling, and adequate sleep.^23,24

Identifying medical conditions such as depression and anxiety will help delineate differential diagnoses of sexual dysfunction. Cardiovascular diseases may contribute to arousal disorder as a result of atherosclerosis of the vessels supplying the vagina and clitoris. Neurologic diseases such as multiple sclerosis and diabetes can affect sexual dysfunction by impairing arousal and orgasm.

Identification of concurrent comorbidities and implementation of lifestyle changes will help improve overall health and may improve sexual function.²⁵

In addition, Herati et al found food sensitivities to grapefruit juice, spicy foods, alcohol, and caffeine were more prevalent in patients with interstitial cystitis and chronic pelvic pain.²⁶ Avoiding irritants such as soap and other detergents in the perineal region may help decrease dysfunction.²⁷ Finally, foods high in oxalate and other acidic items may cause bladder pain and worsening symptoms of vulvodynia.²⁸

Topical therapies worth considering

Lubricants and moisturizers may help women with dyspareunia or symptoms of vaginal atrophy. For instance

Zestra, which contains a patented blend of botanical oils and extracts and is applied to the vulva prior to sexual activity, has been proven more effective than placebo for improving desire and arousal.²⁹

Neogyn, a nonhormonal cream containing cutaneous lysate, has been shown to improve vulvar pain in women with vulvodynia. A double-blind placebo-controlled randomized crossover trial followed 30 patients for three months and found a significant reduction in pain during sexual activity and a significant reduction in erythema.³⁰

Alprostadil, a prostaglandin E1 analogue that increases genital vasodilation when applied topically, is currently undergoing investigational trials.^31,32

Patients can also choose from many OTC lubricants that contain water-based, oil-based, or silicone-based ingredients.

Continue to: Don't overlook physical therapy

Manual therapies, including the transvaginal technique, are used for FSD that results from a variety of causes, including high-tone pelvic floor dysfunction. The transvaginal technique can identify myofascial pain; treatment involves internal release of the PFMs and external trigger-point identification and alleviation.

One pilot study examined use of transvaginal Thiele massage twice a week for five weeks in 21 symptomatic women with interstitial cystitis and high-tone pelvic floor dysfunction. The researchers found it decreased hypertonicity of the pelvic floor and generated statistically significant improvement in the Symptom and Problem Indexes of the O’Leary-Sant Questionnaire, Likert Visual Analogue Scales for urgency and pain, and the Physical and Mental Component Summary from the SF-12 Quality-of-Life Scale.³³ Transvaginal physical therapy is also an effective treatment for myofascial pelvic pain.³⁴

Biofeedback, which can be used in combination with pelvic floor physical therapy, teaches the patient to control the PFMs by visualizing the activity to achieve conscious control over contraction of the pelvic floor and ceasing the cycle of spasm.³⁵ Ger et al investigated patients with levator spasm and found biofeedback decreased pain; relief was rated as good or excellent at 15-month follow-up in six of 14 patients (43%).³⁶

Home devices such as Eros Therapy, an FDA-approved, nonpharmacologic battery-operated device, provide vacuum suction to the clitoris with vibratory sensation. Eros Therapy has been shown to increase blood flow to the clitoris, vagina, and pelvic floor and increase sensation, orgasm, lubrication, and satisfaction.³⁷

Vaginal dilators allow increasing lengths and girths designed to treat vaginal and pelvic floor pain.³⁸ In our practice, we encourage pelvic muscle strengthening tools in the form of Kegel trainers and other insertion devices that may improve PFM coordination and strength.

Continue to: Pharmacotherapy has its place

The treatment of FSD may require a multimodal systematic approach targeting genitopelvic pain. But before the best options can be found, it is important to first establish the cause of the pain. Several drug formulations have been effectively used, including hormonal and nonhormonal options.

Conjugated estrogens are FDA approved for the treatment of dyspareunia, which can contribute to decreased desire. Systemic estrogen in oral form, transdermal preparations, and topical formulations may increase sexual desire and arousal and decrease dyspareunia.³⁹ Even synthetic steroid compounds such as tibolone may improve sexual function, although it is not FDA approved for that purpose.⁴⁰

Ospemifene is a selective estrogen receptor modulator that acts as an estrogen agonist in select tissues, including vaginal epithelium. It is FDA approved for dyspareunia in postmenopausal women.^41,42 A daily dose of 60 mg is effective and safe, with minimal adverse effects.⁴² Studies suggest that testosterone, although not FDA approved in the United States for this purpose, improves sexual desire, pleasure, orgasm, and arousal satisfaction.³⁹ The hormone has not gained FDA approval because of concerns about long-term safety and efficacy.⁴²

Nonhormonal drugs including flibanserin, a well-tolerated serotonin receptor 1A agonist, 2A antagonist shown to improve sexual desire, increase the number of satisfying sexual events and reduce distress associated with low sexual desire when compared with placebo.⁴³ The FDA has approved flibanserin as the first treatment targeted for women with hypoactive sexual desire disorder (HSDD). It can, however, cause severe hypotension and syncope, is not well tolerated with alcohol, and is contraindicated in patients who take strong CYP3A4 inhibitors, such as fluconazole, verapamil, and erythromycin, or who have liver impairment.

Bupropion, a mild dopamine and norepinephrine reuptake inhibitor and acetylcholine receptor antagonist, has been shown to improve desire in women with and without depression. Although it is FDA approved for major depressive disorder, it is not approved for female sexual dysfunction and is still under investigation.

Tricyclic antidepressants, such as nortriptyline and amitriptyline, may be effective in treating neuropathic pain. Starting doses of both amitriptyline and nortriptyline are 10 mg/d and can be increased to a maximum of 100 mg/d.⁴⁴ Tricyclic antidepressants are still under investigation for the treatment of FSD.

Muscle relaxants in oral and topical compounded form are used to treat increased pelvic floor tension and spasticity. Cyclobenzaprine and tizanidine are FDA-approved muscle relaxants indicated for muscle spasticity.

Cyclobenzaprine, at a starting dose of 10 mg, can be taken up to three times a day for pelvic floor tension. Tizanidine is a centrally active alpha 2 agonist that’s superior to placebo in treating high-tone pelvic floor dysfunction.⁴⁴

Other medications include benzodiazepines, such as oral clonazepam and intravaginal diazepam, although they are not FDA approved for high-tone pelvic floor dysfunction. Rogalski et al evaluated data for 26 patients who received vaginal diazepam for bladder pain, sexual pain, and levator hypertonus.⁴⁵ They found subjective and sexual pain improvement assessed on FSFI and the visual analog pain scale. PFM tone significantly improved during resting, squeezing, and relaxation phases. Multimodal therapy can be used for muscle spasticity and high-tone pelvic floor dysfunction.

Continue to: Trigger point and Botox injections

Although drug therapy has its place in the management of sexual dysfunction, other modalities that involve trigger-point injections or botulinum toxin injections to the PFMs may prove helpful for patients with high-tone pelvic floor dysfunction.

A prospective study investigated the role of trigger-point injections in 18 women with levator ani muscle spasm using a mixture of 0.25% bupivacaine in 10 mL, 2% lidocaine in 10 mL, and 40 mg of triamcinolone in 1 mL combined and used for injection of 5 mL per trigger point.⁴⁶ Three months after injections, 13 of the 18 women showed improvement, resulting in a success rate of 72%. Trigger point injections can be applied externally or transvaginally.

OnabotulinumtoxinA (Botox) has also been tested for relief of levator ani muscle spasm. Botox is FDA approved for upper and lower limb spasticity but is not approved for pelvic floor spasticity or tension. It may reduce pressure in the PFMs and may be useful in women with high-tone pelvic floor dysfunction.⁴⁷

In a prospective six-month pilot study, 28 patients with pelvic pain for whom conservative treatment did not work received up to 300 U Botox into the pelvic floor.¹¹ The study, which used needle electromyography guidance and a transperineal approach, found that the dyspareunia visual analog scale improved significantly at weeks 12 and 24. Keep in mind, however, that onabotulinumtoxinA should be reserved for patients for whom conventional treatments fail.^47,48

Addressing psychologic issues

Sex therapy is a traditional approach that aims to improve individual or couples’ sexual experiences and help reduce anxiety related to sex.⁴² Cognitive behavioral sex therapy includes traditional sex therapy components but puts greater emphasis on modifying thought patterns that interfere with intimacy and sex.⁴²

Mindfulness-based cognitive behavioral treatments have shown promise for sexual desire problems. It is an ancient eastern practice with Buddhist roots. This therapy is a nonjudgmental, present-moment awareness comprised of self-regulation of attention and accepting orientation to the present.⁴⁹ Although there is little evidence from prospective studies, it may benefit women with sexual dysfunction after intervention with sex therapy and cognitive behavioral therapy.

CONCLUSION

Female sexual dysfunction is common and affects women of all ages. It can negatively impact a woman’s quality of life and overall well-being. The etiology of FSD is complex, and treatments are based on the causes of the dysfunction. Difficult cases warrant referral to a specialist in sexual health and female pelvic medicine. Future prospective trials, randomized controlled trials, the use of validated questionnaires, and meta-analyses will continue to move us forward as we find better ways to understand, identify, and treat female sexual dysfunction.

IN THIS ARTICLE

• Causes of pain
• Screening
• Multimodal treatment

Care of women with sexual disorders has made great strides since Masters and Johnson began their study in 1957. In 2000, the Sexual Function Health Council of the American Foundation for Urologic Disease devised the classification system for female sexual dysfunction, which was officially defined in the Diagnostic and Statistical Manual of Mental Disorders-IV-TR.¹ There are now definitions for sexual desire disorders, sexual arousal disorders, orgasmic disorder, and sexual pain disorders.

Female sexual dysfunction (FSD) has complex physiologic and psychologic components that require a detailed screening, history, and physical examination. Our goal in this review is to provide primary care providers with insights and practical advice to help screen, diagnose, and treat FSD, which can have a profound impact on patients’ most intimate relationships.

UNDERSTANDING THE TYPES OF FSD

Most women consider sexual health an important part of their overall health.² Factors that can disrupt normal sexual function include aging, socioeconomics, and other medical comorbidities. FSD is common in women throughout their lives and refers to various sexual dysfunctions including diminished arousal, problems achieving orgasm, dyspareunia, and low desire. Its prevalence is reported to be as high as 20% to 43%.^3,4

The World Health Organization and the US Surgeon General have released statements encouraging health care providers to address sexual health during a patient’s annual visits.⁵ Unfortunately, despite this call to action, many patients and providers are initially hesitant to discuss these problems.⁶

The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) provides the definition and diagnostic guidelines for the different components of FSD. Its classification of sexual disorders was simplified and published in May 2013.⁷ There are now only three female dysfunctions (as opposed to five in DSM-IV):

• Female hypoactive desire dysfunction and female arousal dysfunction were merged into a single syndrome labeled female sexual interest/arousal disorder.
• The formerly separate dyspareunia (painful intercourse) and vaginismus are now called genitopelvic pain/penetration disorder.
• Female orgasmic disorder remains as a category and is unchanged.

To qualify as a dysfunction, the problem must be present more than 75% of the time, for more than six months, causing significant distress, and must not be explained by a nonsexual mental disorder, relationship distress, substance abuse, or a medical condition.

Substance- or medication-induced sexual dysfunction falls under “Other Dysfunctions” and is defined as a clinically significant disturbance in sexual function that is predominant in the clinical picture. The criteria for substance- and medication-induced sexual dysfunction are unchanged and include neither the 75% nor the six-month requirement. The diagnosis of sexual dysfunction due to a general medical condition and sexual aversion disorder are absent from the DSM-5.⁷

Continue to: A common symptom

A common symptom. Female sexual disorders can be caused by several complex physiologic and psychologic factors. A common symptom among many women is dyspareunia. It is seen more often in postmenopausal women, and its prevalence ranges from 8% to 22%.⁸ Pain on vaginal entry usually indicates vaginal atrophy, vaginal dermatitis, or provoked vestibulodynia. Pain on deep penetration could be caused by endometriosis, interstitial cystitis, or uterine leiomyomas.⁹

The physical examination will reproduce the pain when the vulva or vagina is touched with a cotton swab or when you insert a finger into the vagina. The differential diagnosis is listed in the Table.^9-11

EVALUATING THE PATIENT

Initially, many patients and providers may hesitate to discuss sexual dysfunction, but the annual exam is a good opportunity to broach the topic of sexual health.

Screening and history

Clinicians can screen all patients, regardless of age, with the help of a validated sex questionnaire or during a routine review of systems. There are many validated screening tools available. A simple, integrated screening tool to use is the Brief Sexual Symptom Checklist for Women (BSSC-W), created by the International Consultation on Sexual Medicine.¹² Although recommended by the American Congress of Obstetricians and Gynecologists, the BSSC-W is not validated.⁹ The four items in the questionnaire ascertain personal information regarding an individual’s overall sexual function satisfaction, the problem causing dysfunction, how bothersome the symptoms are, and whether the patient is interested in discussing it with her provider.¹²

It’s important to obtain a detailed obstetric and gynecologic history that includes any sexually transmitted diseases, sexual abuse, urinary and bowel complaints, or surgeries. In addition, you’ll want to differentiate between various types of dysfunctions. A thorough physical examination, including an external and internal pelvic exam, can help to rule out other causes of sexual dysfunction.

Continue to: General exam: What to look for

General exam: What to look for

The external pelvic examination begins with visual inspection of the vulva, labia majora, and labia minora. Often, this is best accomplished gently with a gloved hand and a cotton swab. This inspection may reveal changes in pubic hair distribution, vulvar skin disorders, lesions, masses, cracks, or fissures. Inspection may also reveal redness and pain typical of vestibulitis, a flattening and pallor of the labia that suggests estrogen deficiency, or pelvic organ prolapse.

The internal pelvic examination begins with a manual evaluation of the muscles of the pelvic floor, uterus, bladder, urethra, anus, and adnexa. Make careful note of any unusual tenderness or pelvic masses. Pelvic floor muscles (PFMs) should voluntarily contract and relax and are not normally tender to palpation. Pelvic organ prolapse and/or hypermobility of the bladder may indicate a weakening of the endopelvic fascia and may cause sexual pain. The size and flexion of the uterus, tenderness in the vaginal fornix possibly indicating endometriosis, and adnexal fullness and/or masses should be identified and evaluated.

Neurologic exam of the pelvis will involve evaluation of sensory and motor function of both lower extremities and include a screening lumbosacral neurologic examination. Lumbosacral examination includes assessment of PFM strength, anal sphincter resting tone, voluntary anal contraction, and perineal sensation. If abnormalities are noted in the screening assessment, a complete comprehensive neurologic examination should be performed.

It’s important to assess pelvic floor muscle strength

Sexual function is associated with normal PFM function.^13,14 The PFMs, particularly the pubococcygeus and iliococcygeus, are responsible for involuntary contractions during orgasm.¹³ Orgasm has been considered a reflex, which is preceded by increased blood flow to the genital organs, tumescence of the vulva and vagina, increased secretions during sexual arousal, and increased tension and contractions of the PFMs.¹⁵

Lowenstein et al found that women with strong or moderate PFM contractions scored significantly higher on both orgasm and arousal domains of the Female Sexual Function Index (FSFI), compared with women with weak PFM contractions.¹⁶ Orgasm and arousal functions may be associated with PFM strength, with a positive association between pelvic floor strength and sexual activity and function.^17,18

The function and dysfunction of the PFMs have been characterized as normal, overactive (high tone), underactive (low tone), and nonfunctioning.

Continue to: Normal PFMs

Normal PFMs are those that can voluntarily and involuntarily contract and relax.^19,20

Overactive (high-tone) muscles are those that do not relax and possibly contract during times of relaxation for micturition or defecation. This type of dysfunction can lead to voiding dysfunction, defecatory dysfunction, and dyspareunia.¹⁹

Underactive, or low-tone, PFMs cannot contract voluntarily. This can be associated with urinary and anal incontinence and pelvic organ prolapse.

Nonfunctioning muscles are completely inactive.¹⁹

How to assess. There are several ways to assess PFM tone and strength.²⁰ The first is intravaginal or intrarectal digital palpation, which can be performed when the patient is in a supine or standing position. This examination evaluates PFM tone, squeeze pressure during contraction, symmetry, and relaxation. However, there is no validated scale to quantify PFM strength. Contractions can be further divided into voluntary and involuntary.¹⁹

During the exam, ask the patient to contract as much as she can to evaluate the maximum strength and sustained contraction for endurance. This measurement can be done with digital palpation or with pressure manometry or dynamometry.

Examination can be focused on the levator ani, piriformis, and internal obturator muscles bilaterally and rated by the patient’s reactions. Pelvic muscle tenderness, which can be highly prevalent in women with chronic pelvic pain, is associated with higher degrees of dyspareunia.²¹ Digital evaluation of the pelvic floor musculature varies in scale, number of fingers used, and parameters evaluated.

Lukban et al have described a 0 to 4 numbered scale that evaluates tenderness in the pelvic floor.²² The scale denotes “1” as comfortable pressure associated with the exam, “2” as uncomfortable pressure associated with the exam, “3” as moderate pain associated with the exam that intensifies with contraction, and “4” indicating severe pain with the exam and inability to perform the contraction maneuver due to pain.

Continue to: EFFECTIVE TREATMENT INCLUDES MULTIPLE OPTIONS

Lifestyle modifications can help

Lifestyle changes may help improve sexual function. These modifications include physical activity, healthy diet, nutrition counseling, and adequate sleep.^23,24

Identifying medical conditions such as depression and anxiety will help delineate differential diagnoses of sexual dysfunction. Cardiovascular diseases may contribute to arousal disorder as a result of atherosclerosis of the vessels supplying the vagina and clitoris. Neurologic diseases such as multiple sclerosis and diabetes can affect sexual dysfunction by impairing arousal and orgasm.

Identification of concurrent comorbidities and implementation of lifestyle changes will help improve overall health and may improve sexual function.²⁵

In addition, Herati et al found food sensitivities to grapefruit juice, spicy foods, alcohol, and caffeine were more prevalent in patients with interstitial cystitis and chronic pelvic pain.²⁶ Avoiding irritants such as soap and other detergents in the perineal region may help decrease dysfunction.²⁷ Finally, foods high in oxalate and other acidic items may cause bladder pain and worsening symptoms of vulvodynia.²⁸

Topical therapies worth considering

Lubricants and moisturizers may help women with dyspareunia or symptoms of vaginal atrophy. For instance

Zestra, which contains a patented blend of botanical oils and extracts and is applied to the vulva prior to sexual activity, has been proven more effective than placebo for improving desire and arousal.²⁹

Neogyn, a nonhormonal cream containing cutaneous lysate, has been shown to improve vulvar pain in women with vulvodynia. A double-blind placebo-controlled randomized crossover trial followed 30 patients for three months and found a significant reduction in pain during sexual activity and a significant reduction in erythema.³⁰

Alprostadil, a prostaglandin E1 analogue that increases genital vasodilation when applied topically, is currently undergoing investigational trials.^31,32

Patients can also choose from many OTC lubricants that contain water-based, oil-based, or silicone-based ingredients.

Continue to: Don't overlook physical therapy

Manual therapies, including the transvaginal technique, are used for FSD that results from a variety of causes, including high-tone pelvic floor dysfunction. The transvaginal technique can identify myofascial pain; treatment involves internal release of the PFMs and external trigger-point identification and alleviation.

One pilot study examined use of transvaginal Thiele massage twice a week for five weeks in 21 symptomatic women with interstitial cystitis and high-tone pelvic floor dysfunction. The researchers found it decreased hypertonicity of the pelvic floor and generated statistically significant improvement in the Symptom and Problem Indexes of the O’Leary-Sant Questionnaire, Likert Visual Analogue Scales for urgency and pain, and the Physical and Mental Component Summary from the SF-12 Quality-of-Life Scale.³³ Transvaginal physical therapy is also an effective treatment for myofascial pelvic pain.³⁴

Biofeedback, which can be used in combination with pelvic floor physical therapy, teaches the patient to control the PFMs by visualizing the activity to achieve conscious control over contraction of the pelvic floor and ceasing the cycle of spasm.³⁵ Ger et al investigated patients with levator spasm and found biofeedback decreased pain; relief was rated as good or excellent at 15-month follow-up in six of 14 patients (43%).³⁶

Home devices such as Eros Therapy, an FDA-approved, nonpharmacologic battery-operated device, provide vacuum suction to the clitoris with vibratory sensation. Eros Therapy has been shown to increase blood flow to the clitoris, vagina, and pelvic floor and increase sensation, orgasm, lubrication, and satisfaction.³⁷

Vaginal dilators allow increasing lengths and girths designed to treat vaginal and pelvic floor pain.³⁸ In our practice, we encourage pelvic muscle strengthening tools in the form of Kegel trainers and other insertion devices that may improve PFM coordination and strength.

Continue to: Pharmacotherapy has its place

The treatment of FSD may require a multimodal systematic approach targeting genitopelvic pain. But before the best options can be found, it is important to first establish the cause of the pain. Several drug formulations have been effectively used, including hormonal and nonhormonal options.

Conjugated estrogens are FDA approved for the treatment of dyspareunia, which can contribute to decreased desire. Systemic estrogen in oral form, transdermal preparations, and topical formulations may increase sexual desire and arousal and decrease dyspareunia.³⁹ Even synthetic steroid compounds such as tibolone may improve sexual function, although it is not FDA approved for that purpose.⁴⁰

Ospemifene is a selective estrogen receptor modulator that acts as an estrogen agonist in select tissues, including vaginal epithelium. It is FDA approved for dyspareunia in postmenopausal women.^41,42 A daily dose of 60 mg is effective and safe, with minimal adverse effects.⁴² Studies suggest that testosterone, although not FDA approved in the United States for this purpose, improves sexual desire, pleasure, orgasm, and arousal satisfaction.³⁹ The hormone has not gained FDA approval because of concerns about long-term safety and efficacy.⁴²

Nonhormonal drugs including flibanserin, a well-tolerated serotonin receptor 1A agonist, 2A antagonist shown to improve sexual desire, increase the number of satisfying sexual events and reduce distress associated with low sexual desire when compared with placebo.⁴³ The FDA has approved flibanserin as the first treatment targeted for women with hypoactive sexual desire disorder (HSDD). It can, however, cause severe hypotension and syncope, is not well tolerated with alcohol, and is contraindicated in patients who take strong CYP3A4 inhibitors, such as fluconazole, verapamil, and erythromycin, or who have liver impairment.

Bupropion, a mild dopamine and norepinephrine reuptake inhibitor and acetylcholine receptor antagonist, has been shown to improve desire in women with and without depression. Although it is FDA approved for major depressive disorder, it is not approved for female sexual dysfunction and is still under investigation.

Tricyclic antidepressants, such as nortriptyline and amitriptyline, may be effective in treating neuropathic pain. Starting doses of both amitriptyline and nortriptyline are 10 mg/d and can be increased to a maximum of 100 mg/d.⁴⁴ Tricyclic antidepressants are still under investigation for the treatment of FSD.

Muscle relaxants in oral and topical compounded form are used to treat increased pelvic floor tension and spasticity. Cyclobenzaprine and tizanidine are FDA-approved muscle relaxants indicated for muscle spasticity.

Cyclobenzaprine, at a starting dose of 10 mg, can be taken up to three times a day for pelvic floor tension. Tizanidine is a centrally active alpha 2 agonist that’s superior to placebo in treating high-tone pelvic floor dysfunction.⁴⁴

Other medications include benzodiazepines, such as oral clonazepam and intravaginal diazepam, although they are not FDA approved for high-tone pelvic floor dysfunction. Rogalski et al evaluated data for 26 patients who received vaginal diazepam for bladder pain, sexual pain, and levator hypertonus.⁴⁵ They found subjective and sexual pain improvement assessed on FSFI and the visual analog pain scale. PFM tone significantly improved during resting, squeezing, and relaxation phases. Multimodal therapy can be used for muscle spasticity and high-tone pelvic floor dysfunction.

Continue to: Trigger point and Botox injections

Although drug therapy has its place in the management of sexual dysfunction, other modalities that involve trigger-point injections or botulinum toxin injections to the PFMs may prove helpful for patients with high-tone pelvic floor dysfunction.

A prospective study investigated the role of trigger-point injections in 18 women with levator ani muscle spasm using a mixture of 0.25% bupivacaine in 10 mL, 2% lidocaine in 10 mL, and 40 mg of triamcinolone in 1 mL combined and used for injection of 5 mL per trigger point.⁴⁶ Three months after injections, 13 of the 18 women showed improvement, resulting in a success rate of 72%. Trigger point injections can be applied externally or transvaginally.

OnabotulinumtoxinA (Botox) has also been tested for relief of levator ani muscle spasm. Botox is FDA approved for upper and lower limb spasticity but is not approved for pelvic floor spasticity or tension. It may reduce pressure in the PFMs and may be useful in women with high-tone pelvic floor dysfunction.⁴⁷

In a prospective six-month pilot study, 28 patients with pelvic pain for whom conservative treatment did not work received up to 300 U Botox into the pelvic floor.¹¹ The study, which used needle electromyography guidance and a transperineal approach, found that the dyspareunia visual analog scale improved significantly at weeks 12 and 24. Keep in mind, however, that onabotulinumtoxinA should be reserved for patients for whom conventional treatments fail.^47,48

Addressing psychologic issues

Sex therapy is a traditional approach that aims to improve individual or couples’ sexual experiences and help reduce anxiety related to sex.⁴² Cognitive behavioral sex therapy includes traditional sex therapy components but puts greater emphasis on modifying thought patterns that interfere with intimacy and sex.⁴²

Mindfulness-based cognitive behavioral treatments have shown promise for sexual desire problems. It is an ancient eastern practice with Buddhist roots. This therapy is a nonjudgmental, present-moment awareness comprised of self-regulation of attention and accepting orientation to the present.⁴⁹ Although there is little evidence from prospective studies, it may benefit women with sexual dysfunction after intervention with sex therapy and cognitive behavioral therapy.

CONCLUSION

Female sexual dysfunction is common and affects women of all ages. It can negatively impact a woman’s quality of life and overall well-being. The etiology of FSD is complex, and treatments are based on the causes of the dysfunction. Difficult cases warrant referral to a specialist in sexual health and female pelvic medicine. Future prospective trials, randomized controlled trials, the use of validated questionnaires, and meta-analyses will continue to move us forward as we find better ways to understand, identify, and treat female sexual dysfunction.

IN THIS ARTICLE

• Causes of pain
• Screening
• Multimodal treatment

Care of women with sexual disorders has made great strides since Masters and Johnson began their study in 1957. In 2000, the Sexual Function Health Council of the American Foundation for Urologic Disease devised the classification system for female sexual dysfunction, which was officially defined in the Diagnostic and Statistical Manual of Mental Disorders-IV-TR.¹ There are now definitions for sexual desire disorders, sexual arousal disorders, orgasmic disorder, and sexual pain disorders.

Female sexual dysfunction (FSD) has complex physiologic and psychologic components that require a detailed screening, history, and physical examination. Our goal in this review is to provide primary care providers with insights and practical advice to help screen, diagnose, and treat FSD, which can have a profound impact on patients’ most intimate relationships.

UNDERSTANDING THE TYPES OF FSD

Most women consider sexual health an important part of their overall health.² Factors that can disrupt normal sexual function include aging, socioeconomics, and other medical comorbidities. FSD is common in women throughout their lives and refers to various sexual dysfunctions including diminished arousal, problems achieving orgasm, dyspareunia, and low desire. Its prevalence is reported to be as high as 20% to 43%.^3,4

The World Health Organization and the US Surgeon General have released statements encouraging health care providers to address sexual health during a patient’s annual visits.⁵ Unfortunately, despite this call to action, many patients and providers are initially hesitant to discuss these problems.⁶

The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) provides the definition and diagnostic guidelines for the different components of FSD. Its classification of sexual disorders was simplified and published in May 2013.⁷ There are now only three female dysfunctions (as opposed to five in DSM-IV):

• Female hypoactive desire dysfunction and female arousal dysfunction were merged into a single syndrome labeled female sexual interest/arousal disorder.
• The formerly separate dyspareunia (painful intercourse) and vaginismus are now called genitopelvic pain/penetration disorder.
• Female orgasmic disorder remains as a category and is unchanged.

To qualify as a dysfunction, the problem must be present more than 75% of the time, for more than six months, causing significant distress, and must not be explained by a nonsexual mental disorder, relationship distress, substance abuse, or a medical condition.

Substance- or medication-induced sexual dysfunction falls under “Other Dysfunctions” and is defined as a clinically significant disturbance in sexual function that is predominant in the clinical picture. The criteria for substance- and medication-induced sexual dysfunction are unchanged and include neither the 75% nor the six-month requirement. The diagnosis of sexual dysfunction due to a general medical condition and sexual aversion disorder are absent from the DSM-5.⁷

Continue to: A common symptom

A common symptom. Female sexual disorders can be caused by several complex physiologic and psychologic factors. A common symptom among many women is dyspareunia. It is seen more often in postmenopausal women, and its prevalence ranges from 8% to 22%.⁸ Pain on vaginal entry usually indicates vaginal atrophy, vaginal dermatitis, or provoked vestibulodynia. Pain on deep penetration could be caused by endometriosis, interstitial cystitis, or uterine leiomyomas.⁹

The physical examination will reproduce the pain when the vulva or vagina is touched with a cotton swab or when you insert a finger into the vagina. The differential diagnosis is listed in the Table.^9-11

EVALUATING THE PATIENT

Initially, many patients and providers may hesitate to discuss sexual dysfunction, but the annual exam is a good opportunity to broach the topic of sexual health.

Screening and history

Clinicians can screen all patients, regardless of age, with the help of a validated sex questionnaire or during a routine review of systems. There are many validated screening tools available. A simple, integrated screening tool to use is the Brief Sexual Symptom Checklist for Women (BSSC-W), created by the International Consultation on Sexual Medicine.¹² Although recommended by the American Congress of Obstetricians and Gynecologists, the BSSC-W is not validated.⁹ The four items in the questionnaire ascertain personal information regarding an individual’s overall sexual function satisfaction, the problem causing dysfunction, how bothersome the symptoms are, and whether the patient is interested in discussing it with her provider.¹²

It’s important to obtain a detailed obstetric and gynecologic history that includes any sexually transmitted diseases, sexual abuse, urinary and bowel complaints, or surgeries. In addition, you’ll want to differentiate between various types of dysfunctions. A thorough physical examination, including an external and internal pelvic exam, can help to rule out other causes of sexual dysfunction.

Continue to: General exam: What to look for

General exam: What to look for

The external pelvic examination begins with visual inspection of the vulva, labia majora, and labia minora. Often, this is best accomplished gently with a gloved hand and a cotton swab. This inspection may reveal changes in pubic hair distribution, vulvar skin disorders, lesions, masses, cracks, or fissures. Inspection may also reveal redness and pain typical of vestibulitis, a flattening and pallor of the labia that suggests estrogen deficiency, or pelvic organ prolapse.

The internal pelvic examination begins with a manual evaluation of the muscles of the pelvic floor, uterus, bladder, urethra, anus, and adnexa. Make careful note of any unusual tenderness or pelvic masses. Pelvic floor muscles (PFMs) should voluntarily contract and relax and are not normally tender to palpation. Pelvic organ prolapse and/or hypermobility of the bladder may indicate a weakening of the endopelvic fascia and may cause sexual pain. The size and flexion of the uterus, tenderness in the vaginal fornix possibly indicating endometriosis, and adnexal fullness and/or masses should be identified and evaluated.

Neurologic exam of the pelvis will involve evaluation of sensory and motor function of both lower extremities and include a screening lumbosacral neurologic examination. Lumbosacral examination includes assessment of PFM strength, anal sphincter resting tone, voluntary anal contraction, and perineal sensation. If abnormalities are noted in the screening assessment, a complete comprehensive neurologic examination should be performed.

It’s important to assess pelvic floor muscle strength

Sexual function is associated with normal PFM function.^13,14 The PFMs, particularly the pubococcygeus and iliococcygeus, are responsible for involuntary contractions during orgasm.¹³ Orgasm has been considered a reflex, which is preceded by increased blood flow to the genital organs, tumescence of the vulva and vagina, increased secretions during sexual arousal, and increased tension and contractions of the PFMs.¹⁵

Lowenstein et al found that women with strong or moderate PFM contractions scored significantly higher on both orgasm and arousal domains of the Female Sexual Function Index (FSFI), compared with women with weak PFM contractions.¹⁶ Orgasm and arousal functions may be associated with PFM strength, with a positive association between pelvic floor strength and sexual activity and function.^17,18

The function and dysfunction of the PFMs have been characterized as normal, overactive (high tone), underactive (low tone), and nonfunctioning.

Continue to: Normal PFMs

Normal PFMs are those that can voluntarily and involuntarily contract and relax.^19,20

Overactive (high-tone) muscles are those that do not relax and possibly contract during times of relaxation for micturition or defecation. This type of dysfunction can lead to voiding dysfunction, defecatory dysfunction, and dyspareunia.¹⁹

Underactive, or low-tone, PFMs cannot contract voluntarily. This can be associated with urinary and anal incontinence and pelvic organ prolapse.

Nonfunctioning muscles are completely inactive.¹⁹

How to assess. There are several ways to assess PFM tone and strength.²⁰ The first is intravaginal or intrarectal digital palpation, which can be performed when the patient is in a supine or standing position. This examination evaluates PFM tone, squeeze pressure during contraction, symmetry, and relaxation. However, there is no validated scale to quantify PFM strength. Contractions can be further divided into voluntary and involuntary.¹⁹

During the exam, ask the patient to contract as much as she can to evaluate the maximum strength and sustained contraction for endurance. This measurement can be done with digital palpation or with pressure manometry or dynamometry.

Examination can be focused on the levator ani, piriformis, and internal obturator muscles bilaterally and rated by the patient’s reactions. Pelvic muscle tenderness, which can be highly prevalent in women with chronic pelvic pain, is associated with higher degrees of dyspareunia.²¹ Digital evaluation of the pelvic floor musculature varies in scale, number of fingers used, and parameters evaluated.

Lukban et al have described a 0 to 4 numbered scale that evaluates tenderness in the pelvic floor.²² The scale denotes “1” as comfortable pressure associated with the exam, “2” as uncomfortable pressure associated with the exam, “3” as moderate pain associated with the exam that intensifies with contraction, and “4” indicating severe pain with the exam and inability to perform the contraction maneuver due to pain.

Continue to: EFFECTIVE TREATMENT INCLUDES MULTIPLE OPTIONS

Lifestyle modifications can help

Lifestyle changes may help improve sexual function. These modifications include physical activity, healthy diet, nutrition counseling, and adequate sleep.^23,24

Identifying medical conditions such as depression and anxiety will help delineate differential diagnoses of sexual dysfunction. Cardiovascular diseases may contribute to arousal disorder as a result of atherosclerosis of the vessels supplying the vagina and clitoris. Neurologic diseases such as multiple sclerosis and diabetes can affect sexual dysfunction by impairing arousal and orgasm.

Identification of concurrent comorbidities and implementation of lifestyle changes will help improve overall health and may improve sexual function.²⁵

In addition, Herati et al found food sensitivities to grapefruit juice, spicy foods, alcohol, and caffeine were more prevalent in patients with interstitial cystitis and chronic pelvic pain.²⁶ Avoiding irritants such as soap and other detergents in the perineal region may help decrease dysfunction.²⁷ Finally, foods high in oxalate and other acidic items may cause bladder pain and worsening symptoms of vulvodynia.²⁸

Topical therapies worth considering

Lubricants and moisturizers may help women with dyspareunia or symptoms of vaginal atrophy. For instance

Zestra, which contains a patented blend of botanical oils and extracts and is applied to the vulva prior to sexual activity, has been proven more effective than placebo for improving desire and arousal.²⁹

Neogyn, a nonhormonal cream containing cutaneous lysate, has been shown to improve vulvar pain in women with vulvodynia. A double-blind placebo-controlled randomized crossover trial followed 30 patients for three months and found a significant reduction in pain during sexual activity and a significant reduction in erythema.³⁰

Alprostadil, a prostaglandin E1 analogue that increases genital vasodilation when applied topically, is currently undergoing investigational trials.^31,32

Patients can also choose from many OTC lubricants that contain water-based, oil-based, or silicone-based ingredients.

Continue to: Don't overlook physical therapy

Manual therapies, including the transvaginal technique, are used for FSD that results from a variety of causes, including high-tone pelvic floor dysfunction. The transvaginal technique can identify myofascial pain; treatment involves internal release of the PFMs and external trigger-point identification and alleviation.

One pilot study examined use of transvaginal Thiele massage twice a week for five weeks in 21 symptomatic women with interstitial cystitis and high-tone pelvic floor dysfunction. The researchers found it decreased hypertonicity of the pelvic floor and generated statistically significant improvement in the Symptom and Problem Indexes of the O’Leary-Sant Questionnaire, Likert Visual Analogue Scales for urgency and pain, and the Physical and Mental Component Summary from the SF-12 Quality-of-Life Scale.³³ Transvaginal physical therapy is also an effective treatment for myofascial pelvic pain.³⁴

Biofeedback, which can be used in combination with pelvic floor physical therapy, teaches the patient to control the PFMs by visualizing the activity to achieve conscious control over contraction of the pelvic floor and ceasing the cycle of spasm.³⁵ Ger et al investigated patients with levator spasm and found biofeedback decreased pain; relief was rated as good or excellent at 15-month follow-up in six of 14 patients (43%).³⁶

Home devices such as Eros Therapy, an FDA-approved, nonpharmacologic battery-operated device, provide vacuum suction to the clitoris with vibratory sensation. Eros Therapy has been shown to increase blood flow to the clitoris, vagina, and pelvic floor and increase sensation, orgasm, lubrication, and satisfaction.³⁷

Vaginal dilators allow increasing lengths and girths designed to treat vaginal and pelvic floor pain.³⁸ In our practice, we encourage pelvic muscle strengthening tools in the form of Kegel trainers and other insertion devices that may improve PFM coordination and strength.

Continue to: Pharmacotherapy has its place

The treatment of FSD may require a multimodal systematic approach targeting genitopelvic pain. But before the best options can be found, it is important to first establish the cause of the pain. Several drug formulations have been effectively used, including hormonal and nonhormonal options.

Conjugated estrogens are FDA approved for the treatment of dyspareunia, which can contribute to decreased desire. Systemic estrogen in oral form, transdermal preparations, and topical formulations may increase sexual desire and arousal and decrease dyspareunia.³⁹ Even synthetic steroid compounds such as tibolone may improve sexual function, although it is not FDA approved for that purpose.⁴⁰

Ospemifene is a selective estrogen receptor modulator that acts as an estrogen agonist in select tissues, including vaginal epithelium. It is FDA approved for dyspareunia in postmenopausal women.^41,42 A daily dose of 60 mg is effective and safe, with minimal adverse effects.⁴² Studies suggest that testosterone, although not FDA approved in the United States for this purpose, improves sexual desire, pleasure, orgasm, and arousal satisfaction.³⁹ The hormone has not gained FDA approval because of concerns about long-term safety and efficacy.⁴²

Nonhormonal drugs including flibanserin, a well-tolerated serotonin receptor 1A agonist, 2A antagonist shown to improve sexual desire, increase the number of satisfying sexual events and reduce distress associated with low sexual desire when compared with placebo.⁴³ The FDA has approved flibanserin as the first treatment targeted for women with hypoactive sexual desire disorder (HSDD). It can, however, cause severe hypotension and syncope, is not well tolerated with alcohol, and is contraindicated in patients who take strong CYP3A4 inhibitors, such as fluconazole, verapamil, and erythromycin, or who have liver impairment.

Bupropion, a mild dopamine and norepinephrine reuptake inhibitor and acetylcholine receptor antagonist, has been shown to improve desire in women with and without depression. Although it is FDA approved for major depressive disorder, it is not approved for female sexual dysfunction and is still under investigation.

Tricyclic antidepressants, such as nortriptyline and amitriptyline, may be effective in treating neuropathic pain. Starting doses of both amitriptyline and nortriptyline are 10 mg/d and can be increased to a maximum of 100 mg/d.⁴⁴ Tricyclic antidepressants are still under investigation for the treatment of FSD.

Muscle relaxants in oral and topical compounded form are used to treat increased pelvic floor tension and spasticity. Cyclobenzaprine and tizanidine are FDA-approved muscle relaxants indicated for muscle spasticity.

Cyclobenzaprine, at a starting dose of 10 mg, can be taken up to three times a day for pelvic floor tension. Tizanidine is a centrally active alpha 2 agonist that’s superior to placebo in treating high-tone pelvic floor dysfunction.⁴⁴

Other medications include benzodiazepines, such as oral clonazepam and intravaginal diazepam, although they are not FDA approved for high-tone pelvic floor dysfunction. Rogalski et al evaluated data for 26 patients who received vaginal diazepam for bladder pain, sexual pain, and levator hypertonus.⁴⁵ They found subjective and sexual pain improvement assessed on FSFI and the visual analog pain scale. PFM tone significantly improved during resting, squeezing, and relaxation phases. Multimodal therapy can be used for muscle spasticity and high-tone pelvic floor dysfunction.

Continue to: Trigger point and Botox injections

Although drug therapy has its place in the management of sexual dysfunction, other modalities that involve trigger-point injections or botulinum toxin injections to the PFMs may prove helpful for patients with high-tone pelvic floor dysfunction.

A prospective study investigated the role of trigger-point injections in 18 women with levator ani muscle spasm using a mixture of 0.25% bupivacaine in 10 mL, 2% lidocaine in 10 mL, and 40 mg of triamcinolone in 1 mL combined and used for injection of 5 mL per trigger point.⁴⁶ Three months after injections, 13 of the 18 women showed improvement, resulting in a success rate of 72%. Trigger point injections can be applied externally or transvaginally.

OnabotulinumtoxinA (Botox) has also been tested for relief of levator ani muscle spasm. Botox is FDA approved for upper and lower limb spasticity but is not approved for pelvic floor spasticity or tension. It may reduce pressure in the PFMs and may be useful in women with high-tone pelvic floor dysfunction.⁴⁷

In a prospective six-month pilot study, 28 patients with pelvic pain for whom conservative treatment did not work received up to 300 U Botox into the pelvic floor.¹¹ The study, which used needle electromyography guidance and a transperineal approach, found that the dyspareunia visual analog scale improved significantly at weeks 12 and 24. Keep in mind, however, that onabotulinumtoxinA should be reserved for patients for whom conventional treatments fail.^47,48

Addressing psychologic issues

Sex therapy is a traditional approach that aims to improve individual or couples’ sexual experiences and help reduce anxiety related to sex.⁴² Cognitive behavioral sex therapy includes traditional sex therapy components but puts greater emphasis on modifying thought patterns that interfere with intimacy and sex.⁴²

Mindfulness-based cognitive behavioral treatments have shown promise for sexual desire problems. It is an ancient eastern practice with Buddhist roots. This therapy is a nonjudgmental, present-moment awareness comprised of self-regulation of attention and accepting orientation to the present.⁴⁹ Although there is little evidence from prospective studies, it may benefit women with sexual dysfunction after intervention with sex therapy and cognitive behavioral therapy.

CONCLUSION

Female sexual dysfunction is common and affects women of all ages. It can negatively impact a woman’s quality of life and overall well-being. The etiology of FSD is complex, and treatments are based on the causes of the dysfunction. Difficult cases warrant referral to a specialist in sexual health and female pelvic medicine. Future prospective trials, randomized controlled trials, the use of validated questionnaires, and meta-analyses will continue to move us forward as we find better ways to understand, identify, and treat female sexual dysfunction.

Increased risk of suicide among veterans with posttraumatic stress disorder (PTSD) is well established. Posttraumatic stress disorder and related consequences are associated with higher rates of suicidal ideation and suicidal self-directed violence (S-SDV).¹ Based on a systematic review, several explanations for this relationship have been hypothesized.¹ Particular emphasis has been placed on trauma type (eg, premilitary childhood abuse, combat exposure), frequency of trauma exposure (ie, a single traumatic episode vs multiple traumatic experiences), specific PTSD symptoms (eg, avoidance, sleep disturbance, alteration in mood and cognitions, risky behaviors), and other psychosocial consequences associated with PTSD (eg, low social support, psychiatric comorbidity, substance use). However, there is limited understanding regarding how to conceptualize and assess risk for suicide when treating veterans who have PTSD.

PTSD and the Interpersonal-Psychological Theory of Suicide

Although PTSD is associated with risk for S-SDV among veterans, a diagnosis-specific approach to conceptualizing risk of suicide (ie, an explanation specific to PTSD) might not be enough because most individuals with a psychiatric diagnosis do not engage in S-SDV.² Rather, theories that are able to conceptualize suicide risk across many different psychiatric diagnoses are likely to improve mental health providers’ ability to understand risk of suicide. Although many theories attempt to understand suicide risk, the Interpersonal-Psychological Theory of Suicide (IPTS) has robust empirical support.³

The IPTS proposes that suicidal ideation is driven by perceptions of stable and unchanging thwarted belongingness (TB), defined as an unmet psychological need to socially belong, and perceived burdensomeness (PB), defined as the perception that one is a burden on others.⁴ However, PB and TB are not considered sufficient for S-SDV to occur unless an individual also has acquired the capability for suicide. Capability for suicide is thought to happen when an individual loses the fear of dying by suicide and develops tolerance to physical pain, which is proposed to occur through habituation or repeated exposure to painful stimuli.³

Several studies have examined the IPTS in a number of clinical populations, including veterans and active-duty service members; yet limited research has applied the IPTS to veterans with PTSD.³ However, a recent article proposed that a number of PTSD-related factors increase risk of suicide through the lens of the IPTS.⁵ In particular, repeated exposure to painful and provocative events—especially those characterized by violence and aggression—might increase acquired capability for suicide by causing habituation to physical pain and discomfort and reducing fear of injury and death. This concept is especially concerning because of the frequent occurrence of both military- (eg, combat, military sexual trauma) and nonmilitary-related (eg, childhood abuse, intimate partner violence) stressful and traumatic events among veterans, especially individuals with PTSD.

Moreover, the acquired capability for suicide correlates highly with anxious, intrusive, and hyperarousal symptoms of PTSD.^5-7 Over time, these PTSD symptoms are thought to increase habituation to the physically painful and frightening aspects of S-SDV, resulting in increased pain tolerance and fearlessness about death.³

In addition, PTSD-related cognitive-affective states (ie, thoughts and emotions), such as guilt, shame, and self-deprecation, might drive beliefs of PB and TB.^5,8 Repeated exposure to such trauma-related thoughts and emotions could further reinforce beliefs of self-hate or inadequacy (PB).² Trauma-related beliefs that the world or others are unsafe also might reduce the likelihood of seeking social support, thereby increasing TB.² The PTSD symptoms of avoidance and self-blame also are likely to reinforce beliefs of PB and TB.²

Assessing Suicide Risk in the Context of PTSD

The IPTS framework is one that can be used by mental health providers to conceptualize risk of suicide across populations and psychiatric diagnoses, including veterans with PTSD. However, integrating additional risk assessment and management techniques is essential to guide appropriate risk stratification and treatment.

One such method of suicide risk assessment and management is therapeutic risk management (TRM).⁹ Therapeutic risk management involves a stratification process by which temporal aspects (ie, acute and chronic) and severity (ie, low, moderate, and high) of suicide risk are assessed using a combination of clinical interview and psychometrically sound self-report measures, such as the Beck Scale for Suicide Ideation, Beck Hopelessness Scale, and Reasons for Living Inventory. Appropriate clinical interventions that correspond to acute and chronic suicide risk stratification are then implemented (eg, safety planning, lethal means counseling, increasing frequency of care, hospitalization if warranted).

Therapeutic risk management emphasizes the necessity of assessing current and past suicidal ideation, intent, plan, and access to means. Moreover, additional considerations might be indicated when assessing and conceptualizing suicide risk among veterans with PTSD. Assessing lifetime trauma history, including traumas that occurred before, during, and after military service, is important for understanding whether traumatic experiences influence acute and chronic risks of suicide. As previously described, careful attention to stressful and traumatic experiences with violent and aggressive characteristics is recommended because research suggests that these experiences are associated with increased capability for suicide.⁵ Awareness of the diversity of traumatic experiences and the importance of contextual factors surrounding such experiences also are essential. For example, the nature of violence and proximity to violence (eg, directly involved in a firefight vs hearing a mortar explosion in the distance) are key components of military-related combat trauma that might differentially influence risk of suicide.¹⁰

Similarly, although military sexual trauma can include repeated threatening sexual harassment or sexual assault, research suggests that military sexual assault is particularly important for understanding suicidal ideation, and experiences of military sexual harassment are less important.¹¹ Therefore, a careful and nuanced understanding of how contextual aspects of a veteran’s trauma history might relate to his or her chronic and acute risk of suicide is critical.

Also important is considering the individual and institutional reactions to trauma. For example, veterans whose behaviors during traumatic experiences violated their values and moral code (ie, moral injury) might be at increased risk for S-SDV. Similarly, veterans who believe that the military institution did not adequately protect them from or support them in the aftermath of traumatic experience(s) (ie, institutional betrayal) might be at higher risk of suicide.

During a clinical interview, mental health providers should pay attention to beliefs and behaviors the veteran is reporting. For example, endorsement of perceptions of low social support (eg, “no one likes me”) or self-esteem (eg, “I’m just not as good as I used to be”) might be indicative of TB or PB, respectively. Additionally, providers should be aware of current or lifetime exposure to painful stimuli (eg, nonsuicidal self-injury, such as cutting or burning, previous suicide attempts) because these exposures might increase the veteran’s acquired capability of future S-SDV.

Although unstructured clinical interviews are a common suicide risk assessment approach, TRM proposes that using a thorough clinical interview along with valid self-report measures could further illuminate a patient’s risk of suicide.⁹ Implementing brief measures allows mental health providers to quickly assess several risk factors and decrease the likelihood of missing important aspects of suicide risk assessment. Providers can use a number of measures to inform their suicide risk assessment, including augmenting a clinical interview of suicide risk with a valid self-report measure of recent suicidal ideation (eg, Beck Scale for Suicide Ideation, which assesses the severity of suicidal ideation in the past week).

Additionally for veterans with PTSD, mental health providers can include measures of PTSD symptoms (eg, PTSD checklist in the Diagnostic and Statistical Manual of Mental Disorders–5) and common PTSD comorbidities (eg, Beck Depression Inventory-II for depressive symptoms) that might contribute to current risk of suicide. Based on previous research, providers also might consider adding measures of trauma-related beliefs (eg, Posttraumatic Cognitions Inventory) and emotions, such as guilt (eg, Trauma-Related Guilt Inventory).⁵

These measures could aid in identifying modifiable risk factors of suicide among veterans with PTSD, such as the extent to which certain beliefs or emotions relate to an individual’s risk of suicide. In addition to asking about characteristics of traumatic events during the clinical interview, measures of moral injury (eg, Moral Injury Events Scale) and institutional betrayal (eg, Institutional Betrayal Questionnaire) might further inform understanding of contextual aspects of trauma that could help explain an individual’s risk of suicide.

Finally, interpersonal measures also could be helpful. For example, because avoidance and social isolation are risk factors for suicidal ideation among veterans with PTSD, measures of perceived interpersonal functioning (eg, Interpersonal Needs Questionnaire) might add further data to assist in suicide risk conceptualization. Although the selection of specific measures likely varies based on the specific needs of an individual patient, these are examples of measures that can be used with veterans with PTSD to inform suicide risk assessment and conceptualization.

By combining data from various measures across multiple domains with a thorough clinical interview, mental health providers can use a TRM approach to understand and conceptualize suicide risk among veterans with PTSD. This approach can facilitate mental health providers’ ability to provide optimal care and guide intervention(s) for veterans with PTSD. One brief intervention that has been used with veterans is safety planning. During safety planning, the provider assists the veteran in identifying warning signs, internal and external coping strategies, and individuals the veteran can reach out to for help (eg, friends and family, providers, Veterans Crisis Line), in addition to collaboratively brainstorming ways the veteran can make his or her environment safer (eg, reducing access to lethal means, identifying reminders of their reasons for living).

Specific to veterans with PTSD, symptoms such as avoidance, hyperarousal, social isolation, and beliefs that others and the world are unsafe might affect safety planning. Such symptoms could hinder identification and use of coping strategies while deterring openness to reach out to others for help. A collaborative method can be used to identify alternate means of coping that take into account PTSD-related avoidance and hyperarousal (eg, rather than going to a crowded store or isolating at home, taking a walk in a quiet park with few people). Similarly, because substance use and risky behaviors are common among veterans with PTSD and might further increase risk of suicide, exploring healthy (eg, exercise) vs unhealthy (eg, substance use; unprotected sex) coping strategies could be helpful.

Further, based on their lived experience, veterans with PTSD could experience difficulty identifying a support system or be reluctant to reach out to others during acute crisis. This might be particularly daunting in the presence of PB and TB. In these situations, it is important to validate the veteran’s difficulty with reaching out while simultaneously encouraging the veteran to examine the accuracy of such beliefs and/or helping the veteran develop skills to overcome these obstacles.

The mental health provider also can work with the individual to ensure that the veteran understands that if he or she does engage emergency resources (eg, Veterans Crisis Line), information likely will be held confidential. Providers can tell their patients that breaks in confidentiality are rare and occur only in circumstances in which it is necessary to protect the veteran. In doing so, the provider facilitates the veteran’s understanding of the role of crisis resources and clarifies any misconceptions the veteran might have (eg, calling the crisis line will always result in hospitalization or police presence).

Conclusion

Several PTSD-related factors might increase PB, TB, and the acquired capability for suicide among veterans with PTSD. Because suicide risk assessment and management can be time sensitive and anxiety provoking, mental health providers can use a TRM approach to increase their confidence in instituting optimal care and mitigating risk by having a structured, therapeutic assessment process that gathers appropriate suicide- and PTSD-related data to assist in developing suicide risk-related treatment. However, more research is needed to determine the most useful self-report measures and effective interventions when working with veterans with PTSD at risk of suicide.

Increased risk of suicide among veterans with posttraumatic stress disorder (PTSD) is well established. Posttraumatic stress disorder and related consequences are associated with higher rates of suicidal ideation and suicidal self-directed violence (S-SDV).¹ Based on a systematic review, several explanations for this relationship have been hypothesized.¹ Particular emphasis has been placed on trauma type (eg, premilitary childhood abuse, combat exposure), frequency of trauma exposure (ie, a single traumatic episode vs multiple traumatic experiences), specific PTSD symptoms (eg, avoidance, sleep disturbance, alteration in mood and cognitions, risky behaviors), and other psychosocial consequences associated with PTSD (eg, low social support, psychiatric comorbidity, substance use). However, there is limited understanding regarding how to conceptualize and assess risk for suicide when treating veterans who have PTSD.

PTSD and the Interpersonal-Psychological Theory of Suicide

Although PTSD is associated with risk for S-SDV among veterans, a diagnosis-specific approach to conceptualizing risk of suicide (ie, an explanation specific to PTSD) might not be enough because most individuals with a psychiatric diagnosis do not engage in S-SDV.² Rather, theories that are able to conceptualize suicide risk across many different psychiatric diagnoses are likely to improve mental health providers’ ability to understand risk of suicide. Although many theories attempt to understand suicide risk, the Interpersonal-Psychological Theory of Suicide (IPTS) has robust empirical support.³

The IPTS proposes that suicidal ideation is driven by perceptions of stable and unchanging thwarted belongingness (TB), defined as an unmet psychological need to socially belong, and perceived burdensomeness (PB), defined as the perception that one is a burden on others.⁴ However, PB and TB are not considered sufficient for S-SDV to occur unless an individual also has acquired the capability for suicide. Capability for suicide is thought to happen when an individual loses the fear of dying by suicide and develops tolerance to physical pain, which is proposed to occur through habituation or repeated exposure to painful stimuli.³

Several studies have examined the IPTS in a number of clinical populations, including veterans and active-duty service members; yet limited research has applied the IPTS to veterans with PTSD.³ However, a recent article proposed that a number of PTSD-related factors increase risk of suicide through the lens of the IPTS.⁵ In particular, repeated exposure to painful and provocative events—especially those characterized by violence and aggression—might increase acquired capability for suicide by causing habituation to physical pain and discomfort and reducing fear of injury and death. This concept is especially concerning because of the frequent occurrence of both military- (eg, combat, military sexual trauma) and nonmilitary-related (eg, childhood abuse, intimate partner violence) stressful and traumatic events among veterans, especially individuals with PTSD.

Moreover, the acquired capability for suicide correlates highly with anxious, intrusive, and hyperarousal symptoms of PTSD.^5-7 Over time, these PTSD symptoms are thought to increase habituation to the physically painful and frightening aspects of S-SDV, resulting in increased pain tolerance and fearlessness about death.³

In addition, PTSD-related cognitive-affective states (ie, thoughts and emotions), such as guilt, shame, and self-deprecation, might drive beliefs of PB and TB.^5,8 Repeated exposure to such trauma-related thoughts and emotions could further reinforce beliefs of self-hate or inadequacy (PB).² Trauma-related beliefs that the world or others are unsafe also might reduce the likelihood of seeking social support, thereby increasing TB.² The PTSD symptoms of avoidance and self-blame also are likely to reinforce beliefs of PB and TB.²

Assessing Suicide Risk in the Context of PTSD

The IPTS framework is one that can be used by mental health providers to conceptualize risk of suicide across populations and psychiatric diagnoses, including veterans with PTSD. However, integrating additional risk assessment and management techniques is essential to guide appropriate risk stratification and treatment.

One such method of suicide risk assessment and management is therapeutic risk management (TRM).⁹ Therapeutic risk management involves a stratification process by which temporal aspects (ie, acute and chronic) and severity (ie, low, moderate, and high) of suicide risk are assessed using a combination of clinical interview and psychometrically sound self-report measures, such as the Beck Scale for Suicide Ideation, Beck Hopelessness Scale, and Reasons for Living Inventory. Appropriate clinical interventions that correspond to acute and chronic suicide risk stratification are then implemented (eg, safety planning, lethal means counseling, increasing frequency of care, hospitalization if warranted).

Therapeutic risk management emphasizes the necessity of assessing current and past suicidal ideation, intent, plan, and access to means. Moreover, additional considerations might be indicated when assessing and conceptualizing suicide risk among veterans with PTSD. Assessing lifetime trauma history, including traumas that occurred before, during, and after military service, is important for understanding whether traumatic experiences influence acute and chronic risks of suicide. As previously described, careful attention to stressful and traumatic experiences with violent and aggressive characteristics is recommended because research suggests that these experiences are associated with increased capability for suicide.⁵ Awareness of the diversity of traumatic experiences and the importance of contextual factors surrounding such experiences also are essential. For example, the nature of violence and proximity to violence (eg, directly involved in a firefight vs hearing a mortar explosion in the distance) are key components of military-related combat trauma that might differentially influence risk of suicide.¹⁰

Similarly, although military sexual trauma can include repeated threatening sexual harassment or sexual assault, research suggests that military sexual assault is particularly important for understanding suicidal ideation, and experiences of military sexual harassment are less important.¹¹ Therefore, a careful and nuanced understanding of how contextual aspects of a veteran’s trauma history might relate to his or her chronic and acute risk of suicide is critical.

Also important is considering the individual and institutional reactions to trauma. For example, veterans whose behaviors during traumatic experiences violated their values and moral code (ie, moral injury) might be at increased risk for S-SDV. Similarly, veterans who believe that the military institution did not adequately protect them from or support them in the aftermath of traumatic experience(s) (ie, institutional betrayal) might be at higher risk of suicide.

During a clinical interview, mental health providers should pay attention to beliefs and behaviors the veteran is reporting. For example, endorsement of perceptions of low social support (eg, “no one likes me”) or self-esteem (eg, “I’m just not as good as I used to be”) might be indicative of TB or PB, respectively. Additionally, providers should be aware of current or lifetime exposure to painful stimuli (eg, nonsuicidal self-injury, such as cutting or burning, previous suicide attempts) because these exposures might increase the veteran’s acquired capability of future S-SDV.

Although unstructured clinical interviews are a common suicide risk assessment approach, TRM proposes that using a thorough clinical interview along with valid self-report measures could further illuminate a patient’s risk of suicide.⁹ Implementing brief measures allows mental health providers to quickly assess several risk factors and decrease the likelihood of missing important aspects of suicide risk assessment. Providers can use a number of measures to inform their suicide risk assessment, including augmenting a clinical interview of suicide risk with a valid self-report measure of recent suicidal ideation (eg, Beck Scale for Suicide Ideation, which assesses the severity of suicidal ideation in the past week).

Additionally for veterans with PTSD, mental health providers can include measures of PTSD symptoms (eg, PTSD checklist in the Diagnostic and Statistical Manual of Mental Disorders–5) and common PTSD comorbidities (eg, Beck Depression Inventory-II for depressive symptoms) that might contribute to current risk of suicide. Based on previous research, providers also might consider adding measures of trauma-related beliefs (eg, Posttraumatic Cognitions Inventory) and emotions, such as guilt (eg, Trauma-Related Guilt Inventory).⁵

These measures could aid in identifying modifiable risk factors of suicide among veterans with PTSD, such as the extent to which certain beliefs or emotions relate to an individual’s risk of suicide. In addition to asking about characteristics of traumatic events during the clinical interview, measures of moral injury (eg, Moral Injury Events Scale) and institutional betrayal (eg, Institutional Betrayal Questionnaire) might further inform understanding of contextual aspects of trauma that could help explain an individual’s risk of suicide.

Finally, interpersonal measures also could be helpful. For example, because avoidance and social isolation are risk factors for suicidal ideation among veterans with PTSD, measures of perceived interpersonal functioning (eg, Interpersonal Needs Questionnaire) might add further data to assist in suicide risk conceptualization. Although the selection of specific measures likely varies based on the specific needs of an individual patient, these are examples of measures that can be used with veterans with PTSD to inform suicide risk assessment and conceptualization.

By combining data from various measures across multiple domains with a thorough clinical interview, mental health providers can use a TRM approach to understand and conceptualize suicide risk among veterans with PTSD. This approach can facilitate mental health providers’ ability to provide optimal care and guide intervention(s) for veterans with PTSD. One brief intervention that has been used with veterans is safety planning. During safety planning, the provider assists the veteran in identifying warning signs, internal and external coping strategies, and individuals the veteran can reach out to for help (eg, friends and family, providers, Veterans Crisis Line), in addition to collaboratively brainstorming ways the veteran can make his or her environment safer (eg, reducing access to lethal means, identifying reminders of their reasons for living).

Specific to veterans with PTSD, symptoms such as avoidance, hyperarousal, social isolation, and beliefs that others and the world are unsafe might affect safety planning. Such symptoms could hinder identification and use of coping strategies while deterring openness to reach out to others for help. A collaborative method can be used to identify alternate means of coping that take into account PTSD-related avoidance and hyperarousal (eg, rather than going to a crowded store or isolating at home, taking a walk in a quiet park with few people). Similarly, because substance use and risky behaviors are common among veterans with PTSD and might further increase risk of suicide, exploring healthy (eg, exercise) vs unhealthy (eg, substance use; unprotected sex) coping strategies could be helpful.

Further, based on their lived experience, veterans with PTSD could experience difficulty identifying a support system or be reluctant to reach out to others during acute crisis. This might be particularly daunting in the presence of PB and TB. In these situations, it is important to validate the veteran’s difficulty with reaching out while simultaneously encouraging the veteran to examine the accuracy of such beliefs and/or helping the veteran develop skills to overcome these obstacles.

The mental health provider also can work with the individual to ensure that the veteran understands that if he or she does engage emergency resources (eg, Veterans Crisis Line), information likely will be held confidential. Providers can tell their patients that breaks in confidentiality are rare and occur only in circumstances in which it is necessary to protect the veteran. In doing so, the provider facilitates the veteran’s understanding of the role of crisis resources and clarifies any misconceptions the veteran might have (eg, calling the crisis line will always result in hospitalization or police presence).

Conclusion

Several PTSD-related factors might increase PB, TB, and the acquired capability for suicide among veterans with PTSD. Because suicide risk assessment and management can be time sensitive and anxiety provoking, mental health providers can use a TRM approach to increase their confidence in instituting optimal care and mitigating risk by having a structured, therapeutic assessment process that gathers appropriate suicide- and PTSD-related data to assist in developing suicide risk-related treatment. However, more research is needed to determine the most useful self-report measures and effective interventions when working with veterans with PTSD at risk of suicide.

Increased risk of suicide among veterans with posttraumatic stress disorder (PTSD) is well established. Posttraumatic stress disorder and related consequences are associated with higher rates of suicidal ideation and suicidal self-directed violence (S-SDV).¹ Based on a systematic review, several explanations for this relationship have been hypothesized.¹ Particular emphasis has been placed on trauma type (eg, premilitary childhood abuse, combat exposure), frequency of trauma exposure (ie, a single traumatic episode vs multiple traumatic experiences), specific PTSD symptoms (eg, avoidance, sleep disturbance, alteration in mood and cognitions, risky behaviors), and other psychosocial consequences associated with PTSD (eg, low social support, psychiatric comorbidity, substance use). However, there is limited understanding regarding how to conceptualize and assess risk for suicide when treating veterans who have PTSD.

PTSD and the Interpersonal-Psychological Theory of Suicide

Although PTSD is associated with risk for S-SDV among veterans, a diagnosis-specific approach to conceptualizing risk of suicide (ie, an explanation specific to PTSD) might not be enough because most individuals with a psychiatric diagnosis do not engage in S-SDV.² Rather, theories that are able to conceptualize suicide risk across many different psychiatric diagnoses are likely to improve mental health providers’ ability to understand risk of suicide. Although many theories attempt to understand suicide risk, the Interpersonal-Psychological Theory of Suicide (IPTS) has robust empirical support.³

The IPTS proposes that suicidal ideation is driven by perceptions of stable and unchanging thwarted belongingness (TB), defined as an unmet psychological need to socially belong, and perceived burdensomeness (PB), defined as the perception that one is a burden on others.⁴ However, PB and TB are not considered sufficient for S-SDV to occur unless an individual also has acquired the capability for suicide. Capability for suicide is thought to happen when an individual loses the fear of dying by suicide and develops tolerance to physical pain, which is proposed to occur through habituation or repeated exposure to painful stimuli.³

Several studies have examined the IPTS in a number of clinical populations, including veterans and active-duty service members; yet limited research has applied the IPTS to veterans with PTSD.³ However, a recent article proposed that a number of PTSD-related factors increase risk of suicide through the lens of the IPTS.⁵ In particular, repeated exposure to painful and provocative events—especially those characterized by violence and aggression—might increase acquired capability for suicide by causing habituation to physical pain and discomfort and reducing fear of injury and death. This concept is especially concerning because of the frequent occurrence of both military- (eg, combat, military sexual trauma) and nonmilitary-related (eg, childhood abuse, intimate partner violence) stressful and traumatic events among veterans, especially individuals with PTSD.

Moreover, the acquired capability for suicide correlates highly with anxious, intrusive, and hyperarousal symptoms of PTSD.^5-7 Over time, these PTSD symptoms are thought to increase habituation to the physically painful and frightening aspects of S-SDV, resulting in increased pain tolerance and fearlessness about death.³

In addition, PTSD-related cognitive-affective states (ie, thoughts and emotions), such as guilt, shame, and self-deprecation, might drive beliefs of PB and TB.^5,8 Repeated exposure to such trauma-related thoughts and emotions could further reinforce beliefs of self-hate or inadequacy (PB).² Trauma-related beliefs that the world or others are unsafe also might reduce the likelihood of seeking social support, thereby increasing TB.² The PTSD symptoms of avoidance and self-blame also are likely to reinforce beliefs of PB and TB.²

Assessing Suicide Risk in the Context of PTSD

The IPTS framework is one that can be used by mental health providers to conceptualize risk of suicide across populations and psychiatric diagnoses, including veterans with PTSD. However, integrating additional risk assessment and management techniques is essential to guide appropriate risk stratification and treatment.

One such method of suicide risk assessment and management is therapeutic risk management (TRM).⁹ Therapeutic risk management involves a stratification process by which temporal aspects (ie, acute and chronic) and severity (ie, low, moderate, and high) of suicide risk are assessed using a combination of clinical interview and psychometrically sound self-report measures, such as the Beck Scale for Suicide Ideation, Beck Hopelessness Scale, and Reasons for Living Inventory. Appropriate clinical interventions that correspond to acute and chronic suicide risk stratification are then implemented (eg, safety planning, lethal means counseling, increasing frequency of care, hospitalization if warranted).

Therapeutic risk management emphasizes the necessity of assessing current and past suicidal ideation, intent, plan, and access to means. Moreover, additional considerations might be indicated when assessing and conceptualizing suicide risk among veterans with PTSD. Assessing lifetime trauma history, including traumas that occurred before, during, and after military service, is important for understanding whether traumatic experiences influence acute and chronic risks of suicide. As previously described, careful attention to stressful and traumatic experiences with violent and aggressive characteristics is recommended because research suggests that these experiences are associated with increased capability for suicide.⁵ Awareness of the diversity of traumatic experiences and the importance of contextual factors surrounding such experiences also are essential. For example, the nature of violence and proximity to violence (eg, directly involved in a firefight vs hearing a mortar explosion in the distance) are key components of military-related combat trauma that might differentially influence risk of suicide.¹⁰

Similarly, although military sexual trauma can include repeated threatening sexual harassment or sexual assault, research suggests that military sexual assault is particularly important for understanding suicidal ideation, and experiences of military sexual harassment are less important.¹¹ Therefore, a careful and nuanced understanding of how contextual aspects of a veteran’s trauma history might relate to his or her chronic and acute risk of suicide is critical.

Also important is considering the individual and institutional reactions to trauma. For example, veterans whose behaviors during traumatic experiences violated their values and moral code (ie, moral injury) might be at increased risk for S-SDV. Similarly, veterans who believe that the military institution did not adequately protect them from or support them in the aftermath of traumatic experience(s) (ie, institutional betrayal) might be at higher risk of suicide.

During a clinical interview, mental health providers should pay attention to beliefs and behaviors the veteran is reporting. For example, endorsement of perceptions of low social support (eg, “no one likes me”) or self-esteem (eg, “I’m just not as good as I used to be”) might be indicative of TB or PB, respectively. Additionally, providers should be aware of current or lifetime exposure to painful stimuli (eg, nonsuicidal self-injury, such as cutting or burning, previous suicide attempts) because these exposures might increase the veteran’s acquired capability of future S-SDV.

Although unstructured clinical interviews are a common suicide risk assessment approach, TRM proposes that using a thorough clinical interview along with valid self-report measures could further illuminate a patient’s risk of suicide.⁹ Implementing brief measures allows mental health providers to quickly assess several risk factors and decrease the likelihood of missing important aspects of suicide risk assessment. Providers can use a number of measures to inform their suicide risk assessment, including augmenting a clinical interview of suicide risk with a valid self-report measure of recent suicidal ideation (eg, Beck Scale for Suicide Ideation, which assesses the severity of suicidal ideation in the past week).

Additionally for veterans with PTSD, mental health providers can include measures of PTSD symptoms (eg, PTSD checklist in the Diagnostic and Statistical Manual of Mental Disorders–5) and common PTSD comorbidities (eg, Beck Depression Inventory-II for depressive symptoms) that might contribute to current risk of suicide. Based on previous research, providers also might consider adding measures of trauma-related beliefs (eg, Posttraumatic Cognitions Inventory) and emotions, such as guilt (eg, Trauma-Related Guilt Inventory).⁵

These measures could aid in identifying modifiable risk factors of suicide among veterans with PTSD, such as the extent to which certain beliefs or emotions relate to an individual’s risk of suicide. In addition to asking about characteristics of traumatic events during the clinical interview, measures of moral injury (eg, Moral Injury Events Scale) and institutional betrayal (eg, Institutional Betrayal Questionnaire) might further inform understanding of contextual aspects of trauma that could help explain an individual’s risk of suicide.

Finally, interpersonal measures also could be helpful. For example, because avoidance and social isolation are risk factors for suicidal ideation among veterans with PTSD, measures of perceived interpersonal functioning (eg, Interpersonal Needs Questionnaire) might add further data to assist in suicide risk conceptualization. Although the selection of specific measures likely varies based on the specific needs of an individual patient, these are examples of measures that can be used with veterans with PTSD to inform suicide risk assessment and conceptualization.

By combining data from various measures across multiple domains with a thorough clinical interview, mental health providers can use a TRM approach to understand and conceptualize suicide risk among veterans with PTSD. This approach can facilitate mental health providers’ ability to provide optimal care and guide intervention(s) for veterans with PTSD. One brief intervention that has been used with veterans is safety planning. During safety planning, the provider assists the veteran in identifying warning signs, internal and external coping strategies, and individuals the veteran can reach out to for help (eg, friends and family, providers, Veterans Crisis Line), in addition to collaboratively brainstorming ways the veteran can make his or her environment safer (eg, reducing access to lethal means, identifying reminders of their reasons for living).

Specific to veterans with PTSD, symptoms such as avoidance, hyperarousal, social isolation, and beliefs that others and the world are unsafe might affect safety planning. Such symptoms could hinder identification and use of coping strategies while deterring openness to reach out to others for help. A collaborative method can be used to identify alternate means of coping that take into account PTSD-related avoidance and hyperarousal (eg, rather than going to a crowded store or isolating at home, taking a walk in a quiet park with few people). Similarly, because substance use and risky behaviors are common among veterans with PTSD and might further increase risk of suicide, exploring healthy (eg, exercise) vs unhealthy (eg, substance use; unprotected sex) coping strategies could be helpful.

Further, based on their lived experience, veterans with PTSD could experience difficulty identifying a support system or be reluctant to reach out to others during acute crisis. This might be particularly daunting in the presence of PB and TB. In these situations, it is important to validate the veteran’s difficulty with reaching out while simultaneously encouraging the veteran to examine the accuracy of such beliefs and/or helping the veteran develop skills to overcome these obstacles.

The mental health provider also can work with the individual to ensure that the veteran understands that if he or she does engage emergency resources (eg, Veterans Crisis Line), information likely will be held confidential. Providers can tell their patients that breaks in confidentiality are rare and occur only in circumstances in which it is necessary to protect the veteran. In doing so, the provider facilitates the veteran’s understanding of the role of crisis resources and clarifies any misconceptions the veteran might have (eg, calling the crisis line will always result in hospitalization or police presence).

Conclusion

Several PTSD-related factors might increase PB, TB, and the acquired capability for suicide among veterans with PTSD. Because suicide risk assessment and management can be time sensitive and anxiety provoking, mental health providers can use a TRM approach to increase their confidence in instituting optimal care and mitigating risk by having a structured, therapeutic assessment process that gathers appropriate suicide- and PTSD-related data to assist in developing suicide risk-related treatment. However, more research is needed to determine the most useful self-report measures and effective interventions when working with veterans with PTSD at risk of suicide.

Prenatal care has long included carrier screening for genetic diseases, such as cystic fibrosis and Tay-Sachs disease. Recently, advances in genetics technologies led to the development of multiplex panels that can be used to test for hundreds of genetic disorders simultaneously, and can be used to assess carrier status for expectant couples or those planning a pregnancy. Although such screening covers many more conditions than those recommended in traditional guidelines, the benefit of expanded carrier screening (ECS) over standard gene-by-gene testing is not clear.

In this Update, I review recent ECS research that can be helpful to those who practice reproductive endocrinology and infertility medicine, maternal–fetal medicine, and general ObGyn. This research considered some of the many complexities of ECS:

• number and type of severe autosomal recessive conditions identified by an ECS panel, or by panethnic screening for 3 common conditions (cystic fibrosis, fragile X syndrome, spinal muscular atrophy)
• whether the disorders covered by ECS panels meet recommended criteria regarding severity, prevalence, and test accuracy
• women’s thoughts and perspectives on ECS
• whether the marketing materials disseminated by commercial providers of ECS are accurate and balanced.

Genetic diseases identified by expanded carrier screening

Haque IS, Lazarin GA, Kang HP, Evans EA, Goldberg JD, Wapner RJ. Modeled fetal risk of genetic diseases identified by expanded carrier screening. JAMA. 2016;316(7):734-742.

Screening during pregnancy to determine if one or both parents are carriers of genetic disorders historically has involved testing for a limited number of conditions, such as cystic fibrosis, hemoglobinopathies, and Tay-Sachs disease. Patients usually are offered testing for 1 or 2 disorders, with test choices primarily based on patient race and ethnicity. Unfortunately, ancestry-based screening may result in inequitable distribution of genetic testing and resources, as it has significant limitations in our increasingly multicultural society, which includes many people of uncertain or mixed race and ethnicity.

Advantages of expanded carrier screening

Several commercial laboratories now offer ECS. Haque and colleagues used data from one of these laboratories and modeled the predicted number of potentially affected fetuses that would be identified with traditional, ethnicity-based screening as compared with ECS. In one of their hypothetical cohorts, of Northern European couples, traditional screening would identify 55 affected fetuses per 100,000 (1 in 1,800), and ECS would identify 159 per 100,000 (almost 3 times more). The numbers identified with ECS varied with race or ethnicity and ranged from 94 per 100,000 (about 1 in 1,000) for Hispanic couples to 392 per 100,000 (about 1 in 250) for Ashkenazi Jewish couples.

In Australia, Archibald and colleagues conducted a similar study, of panethnic screening of 12,000 women for cystic fibrosis, fragile X syndrome, and spinal muscular atrophy.¹ The number of affected fetuses identified was about 1 per 1,000 screened couples--not much different from the ECS number, though comparison is difficult given the likely very different racial and ethnic backgrounds of the 2 cohorts.

Although these data suggest ECS increases detection of genetic disorders, and it seems almost self-evident that more screening is better, there are concerns about ECS.² Traditional carrier screening methods focus on conditions that significantly affect quality of life--owing to cognitive or physical disabilities or required lifelong medical therapies--and that have a fetal, neonatal, or early-childhood onset and well-defined phenotype. In ECS panels, additional conditions may vary significantly in severity or age of onset. Although some genetic variants on ECS panels have a consistent phenotype, the natural history of others is less well understood. Panels often include conditions for which carrier screening of the general population is not recommended by current guidelines--for example, hemochromatosis and factor V Leiden. Moreover, almost by definition, ECS panels include rare conditions for which the natural history may not be well understood, and the carrier frequency as well as the proportion of condition-causing variants that can be detected may be unclear, leaving the residual risk unknown.

Read about the ideal expanded carrier screening panel.

The ideal expanded carrier screening panel

Stevens B, Krstic N, Jones M, Murphy L, Hoskovec J. Finding middle ground in constructing a clinically useful expanded carrier screening panel. Obstet Gynecol. 2017;130(2):279-284.

Both the American College of Obstetricians and Gynecologists (ACOG) and the American College of Medical Genetics and Genomics (ACMG) have proposed criteria for including specific disorders on ECS panels.^3,4 These criteria consider disorder characteristics, such as carrier prevalence, which should be at least 1 in 100; severity; early-childhood onset; and complete penetrance. In addition, they consider test characteristics, such as sensitivity, which should be at least 70%.

Details of the study

Stevens and colleagues evaluated the ECS panels offered by 6 commercial laboratories in the United States. They found that only 27% of included conditions met the recommended criteria, and concluded that these panels are putting patients at risk for undue anxiety, and that time and money are being spent on follow-up testing for rare and mild conditions for which the benefits of testing are unclear or unlikely. The potential benefits of the extra screening should be weighed against the significant resulting harms.

Across the 6 ECS panels, 96 conditions met the criteria. As some laboratories allow providers to customize their panels, members of my practice, after reviewing this thought-provoking article, agreed we should create a custom panel that includes only these 96 conditions. Unfortunately, no commercial laboratory includes all 96 conditions, so it is not feasible to create an "ideal" panel at this time.

Arguments favoring ECS include its low cost and the efficiency of screening with multigene panels. In a 2013 study, however, 24% of patients were identified as carriers, and in most cases this finding led to screening for the reproductive partner as well.⁵ If the rate of detection of the disorder is low, the utility of screening with the same panel may be limited, and couples may require more extensive testing, such as gene sequencing, which is far more expensive. These findings and the additional testing also will increase the need for genetic counseling, and may lead to invasive prenatal diagnostic testing with further increases in costs. If counseling and prenatal testing yield improved outcomes--increased detection of important findings--the benefit will justify the higher costs. However, if the increased costs are largely generated chasing down and explaining findings that are not important to patients or providers, the costs may be incurred without benefit.

Read about the pregnant women’s perspectives on ECS.

Pregnant women's perspectives on expanded carrier screening

Propst L, Connor G, Hinton M, Poorvu T, Dungan J. Pregnant women's perspectives on expanded carrier screening [published online February 23, 2018]. J Genet Couns. doi:10.1007/s10897-018-0232-x.

Although several authors have discussed ECS detection rates, less has been reported on how women perceive ECS or how they elect or decline screening. Studies have found that the decision to undergo screening for cystic fibrosis is influenced by factors that include age, sex, ethnicity, socioeconomic status, lack of family history, cost, fear of a blood test, lack of knowledge about the condition, already having children, wanting to avoid having a disabled child, abortion preferences, and feeling pressured by health care providers.^6,7 Propst and colleagues asked women for their perspectives on ECS, on electing or declining screening, and on any anxiety associated with their decision.

Details of the study

Women who declined ECS said they did so because they:

• had no family history
• knew there was a very small chance their partner carried the same condition  
• would not change the course of their pregnancy on the basis of the test results.

Women who elected ECS said they did so because they wanted to:

• know their risk of having a child with a genetic condition
• have all available information about their genetic risks
• be able to make decisions about continuing or terminating their pregnancy.

Women also were asked what they would do if they discovered their fetus had a genetic disorder. About 42% said they were unsure what they would do, 34% said they would continue their pregnancy and prepare for the birth of an affected child, and 24% said they likely would terminate their pregnancy.

The most common reason women gave for declining ECS was that they had no family history. However, ECS is not a good option for women with a positive family history, as they need genetic counseling and specific consideration of their own risks and what testing should be done. The majority of couples who have a child with a genetic disease have no other family history of the disorder. In a study of reproductive carrier screening in Australia, 88% of carriers had no family history.¹ Careful pretest counseling is needed to explain the distinction between, on one hand, genetic counseling and testing for those with a family history of genetic disease and, on the other hand, population screening performed to identify unsuspecting individuals who are healthy carriers of genetic disorders.

Another crucial point about carrier screening is the need to consider how its results will be used, and what options the carrier couple will have. For women who are pregnant when a risk is identified, options include expectant management, with diagnosis after birth, or prenatal diagnosis with termination of an affected fetus, out-adoption of an affected fetus, or expectant management with preparation for caring for an affected child. For women who are not pregnant when they have ECS, additional options include use of a gamete (ovum or sperm) donor to achieve pregnancy, or preimplantation genetic diagnosis with implantation of only unaffected embryos.

Read about the marketing of ECS.

Marketing of expanded carrier screening

Chokoshvili D, Borry P, Vears DF. A systematic analysis of online marketing materials used by providers of expanded carrier screening [published online December 14, 2017]. Genet Med. doi:10.1038/gim.2017.222.

Prenatal carrier screening can be helpful to women and their families, but it is also a high-volume, lucrative business, with many commercial laboratories competing for the growing ECS market. Professional medical societies recommend making all screening candidates aware of the purpose, characteristics, and limitations of the tests, and of the potential significance of their results. As becoming familiar and comfortable with the tests and explaining them to each patient can be time-consuming, and daunting, many busy clinicians have started relying on marketing materials and other information from the commercial laboratories. Therefore analysis of the accuracy of such materials is in order.

Details of the study

Chokoshvili and colleagues performed a systematic analysis of the quality and accuracy of online marketing materials for ECS. They identified 18 providers: 16 commercial laboratories and 2 medical services providers. All described ECS as a useful tool for family planning, and some were very directive in stating that this testing is "one of the most important steps in preparing for parenthood." In their materials, most of the companies cover some limitations, such as residual risk, but none of the commercial laboratories indicate that ECS can overestimate risk (many variants have incomplete penetrance, meaning that some individuals with a positive test result may in fact be asymptomatic throughout their lifetime).

In addition, whereas a large amount of the marketing materials implies the test was developed in line with professional recommendations, none in fact complies with ACOG and ACMG guidance. Finally, though some of the online information provided by laboratories can be helpful, it is important for clinicians to remember that reproductive genetic counseling should be nondirective and balanced. Carrier testing should be based on patient (not provider) values regarding reproductive autonomy.

Summary

ECS increasingly is being adopted into clinical practice. According to ACOG, traditional ethnicity-based screening, panethnic screening (the same limited panel of tests for all patients), and ECS are all acceptable alternatives for prenatal carrier screening.³ For providers who offer ECS, it is important to have a good understanding of each selected test and its limitations. Providers should have a plan for following up patients who have positive test results; this plan may include having genetic counseling and prenatal genetic diagnostic testing in place. Although treatment is available for a few genetic conditions, for the large majority, prenatal screening has not been proved to lead to improved therapeutic options. Providers should try to make sure that patients do not have unrealistic expectations of the outcomes of carrier screening.

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.

Prenatal care has long included carrier screening for genetic diseases, such as cystic fibrosis and Tay-Sachs disease. Recently, advances in genetics technologies led to the development of multiplex panels that can be used to test for hundreds of genetic disorders simultaneously, and can be used to assess carrier status for expectant couples or those planning a pregnancy. Although such screening covers many more conditions than those recommended in traditional guidelines, the benefit of expanded carrier screening (ECS) over standard gene-by-gene testing is not clear.

In this Update, I review recent ECS research that can be helpful to those who practice reproductive endocrinology and infertility medicine, maternal–fetal medicine, and general ObGyn. This research considered some of the many complexities of ECS:

• number and type of severe autosomal recessive conditions identified by an ECS panel, or by panethnic screening for 3 common conditions (cystic fibrosis, fragile X syndrome, spinal muscular atrophy)
• whether the disorders covered by ECS panels meet recommended criteria regarding severity, prevalence, and test accuracy
• women’s thoughts and perspectives on ECS
• whether the marketing materials disseminated by commercial providers of ECS are accurate and balanced.

Genetic diseases identified by expanded carrier screening

Haque IS, Lazarin GA, Kang HP, Evans EA, Goldberg JD, Wapner RJ. Modeled fetal risk of genetic diseases identified by expanded carrier screening. JAMA. 2016;316(7):734-742.

Screening during pregnancy to determine if one or both parents are carriers of genetic disorders historically has involved testing for a limited number of conditions, such as cystic fibrosis, hemoglobinopathies, and Tay-Sachs disease. Patients usually are offered testing for 1 or 2 disorders, with test choices primarily based on patient race and ethnicity. Unfortunately, ancestry-based screening may result in inequitable distribution of genetic testing and resources, as it has significant limitations in our increasingly multicultural society, which includes many people of uncertain or mixed race and ethnicity.

Advantages of expanded carrier screening

Several commercial laboratories now offer ECS. Haque and colleagues used data from one of these laboratories and modeled the predicted number of potentially affected fetuses that would be identified with traditional, ethnicity-based screening as compared with ECS. In one of their hypothetical cohorts, of Northern European couples, traditional screening would identify 55 affected fetuses per 100,000 (1 in 1,800), and ECS would identify 159 per 100,000 (almost 3 times more). The numbers identified with ECS varied with race or ethnicity and ranged from 94 per 100,000 (about 1 in 1,000) for Hispanic couples to 392 per 100,000 (about 1 in 250) for Ashkenazi Jewish couples.

In Australia, Archibald and colleagues conducted a similar study, of panethnic screening of 12,000 women for cystic fibrosis, fragile X syndrome, and spinal muscular atrophy.¹ The number of affected fetuses identified was about 1 per 1,000 screened couples--not much different from the ECS number, though comparison is difficult given the likely very different racial and ethnic backgrounds of the 2 cohorts.

Although these data suggest ECS increases detection of genetic disorders, and it seems almost self-evident that more screening is better, there are concerns about ECS.² Traditional carrier screening methods focus on conditions that significantly affect quality of life--owing to cognitive or physical disabilities or required lifelong medical therapies--and that have a fetal, neonatal, or early-childhood onset and well-defined phenotype. In ECS panels, additional conditions may vary significantly in severity or age of onset. Although some genetic variants on ECS panels have a consistent phenotype, the natural history of others is less well understood. Panels often include conditions for which carrier screening of the general population is not recommended by current guidelines--for example, hemochromatosis and factor V Leiden. Moreover, almost by definition, ECS panels include rare conditions for which the natural history may not be well understood, and the carrier frequency as well as the proportion of condition-causing variants that can be detected may be unclear, leaving the residual risk unknown.

Read about the ideal expanded carrier screening panel.

The ideal expanded carrier screening panel

Stevens B, Krstic N, Jones M, Murphy L, Hoskovec J. Finding middle ground in constructing a clinically useful expanded carrier screening panel. Obstet Gynecol. 2017;130(2):279-284.

Both the American College of Obstetricians and Gynecologists (ACOG) and the American College of Medical Genetics and Genomics (ACMG) have proposed criteria for including specific disorders on ECS panels.^3,4 These criteria consider disorder characteristics, such as carrier prevalence, which should be at least 1 in 100; severity; early-childhood onset; and complete penetrance. In addition, they consider test characteristics, such as sensitivity, which should be at least 70%.

Details of the study

Stevens and colleagues evaluated the ECS panels offered by 6 commercial laboratories in the United States. They found that only 27% of included conditions met the recommended criteria, and concluded that these panels are putting patients at risk for undue anxiety, and that time and money are being spent on follow-up testing for rare and mild conditions for which the benefits of testing are unclear or unlikely. The potential benefits of the extra screening should be weighed against the significant resulting harms.

Across the 6 ECS panels, 96 conditions met the criteria. As some laboratories allow providers to customize their panels, members of my practice, after reviewing this thought-provoking article, agreed we should create a custom panel that includes only these 96 conditions. Unfortunately, no commercial laboratory includes all 96 conditions, so it is not feasible to create an "ideal" panel at this time.

Arguments favoring ECS include its low cost and the efficiency of screening with multigene panels. In a 2013 study, however, 24% of patients were identified as carriers, and in most cases this finding led to screening for the reproductive partner as well.⁵ If the rate of detection of the disorder is low, the utility of screening with the same panel may be limited, and couples may require more extensive testing, such as gene sequencing, which is far more expensive. These findings and the additional testing also will increase the need for genetic counseling, and may lead to invasive prenatal diagnostic testing with further increases in costs. If counseling and prenatal testing yield improved outcomes--increased detection of important findings--the benefit will justify the higher costs. However, if the increased costs are largely generated chasing down and explaining findings that are not important to patients or providers, the costs may be incurred without benefit.

Read about the pregnant women’s perspectives on ECS.

Pregnant women's perspectives on expanded carrier screening

Propst L, Connor G, Hinton M, Poorvu T, Dungan J. Pregnant women's perspectives on expanded carrier screening [published online February 23, 2018]. J Genet Couns. doi:10.1007/s10897-018-0232-x.

Although several authors have discussed ECS detection rates, less has been reported on how women perceive ECS or how they elect or decline screening. Studies have found that the decision to undergo screening for cystic fibrosis is influenced by factors that include age, sex, ethnicity, socioeconomic status, lack of family history, cost, fear of a blood test, lack of knowledge about the condition, already having children, wanting to avoid having a disabled child, abortion preferences, and feeling pressured by health care providers.^6,7 Propst and colleagues asked women for their perspectives on ECS, on electing or declining screening, and on any anxiety associated with their decision.

Details of the study

Women who declined ECS said they did so because they:

• had no family history
• knew there was a very small chance their partner carried the same condition  
• would not change the course of their pregnancy on the basis of the test results.

Women who elected ECS said they did so because they wanted to:

• know their risk of having a child with a genetic condition
• have all available information about their genetic risks
• be able to make decisions about continuing or terminating their pregnancy.

Women also were asked what they would do if they discovered their fetus had a genetic disorder. About 42% said they were unsure what they would do, 34% said they would continue their pregnancy and prepare for the birth of an affected child, and 24% said they likely would terminate their pregnancy.

The most common reason women gave for declining ECS was that they had no family history. However, ECS is not a good option for women with a positive family history, as they need genetic counseling and specific consideration of their own risks and what testing should be done. The majority of couples who have a child with a genetic disease have no other family history of the disorder. In a study of reproductive carrier screening in Australia, 88% of carriers had no family history.¹ Careful pretest counseling is needed to explain the distinction between, on one hand, genetic counseling and testing for those with a family history of genetic disease and, on the other hand, population screening performed to identify unsuspecting individuals who are healthy carriers of genetic disorders.

Another crucial point about carrier screening is the need to consider how its results will be used, and what options the carrier couple will have. For women who are pregnant when a risk is identified, options include expectant management, with diagnosis after birth, or prenatal diagnosis with termination of an affected fetus, out-adoption of an affected fetus, or expectant management with preparation for caring for an affected child. For women who are not pregnant when they have ECS, additional options include use of a gamete (ovum or sperm) donor to achieve pregnancy, or preimplantation genetic diagnosis with implantation of only unaffected embryos.

Read about the marketing of ECS.

Marketing of expanded carrier screening

Chokoshvili D, Borry P, Vears DF. A systematic analysis of online marketing materials used by providers of expanded carrier screening [published online December 14, 2017]. Genet Med. doi:10.1038/gim.2017.222.

Prenatal carrier screening can be helpful to women and their families, but it is also a high-volume, lucrative business, with many commercial laboratories competing for the growing ECS market. Professional medical societies recommend making all screening candidates aware of the purpose, characteristics, and limitations of the tests, and of the potential significance of their results. As becoming familiar and comfortable with the tests and explaining them to each patient can be time-consuming, and daunting, many busy clinicians have started relying on marketing materials and other information from the commercial laboratories. Therefore analysis of the accuracy of such materials is in order.

Details of the study

Chokoshvili and colleagues performed a systematic analysis of the quality and accuracy of online marketing materials for ECS. They identified 18 providers: 16 commercial laboratories and 2 medical services providers. All described ECS as a useful tool for family planning, and some were very directive in stating that this testing is "one of the most important steps in preparing for parenthood." In their materials, most of the companies cover some limitations, such as residual risk, but none of the commercial laboratories indicate that ECS can overestimate risk (many variants have incomplete penetrance, meaning that some individuals with a positive test result may in fact be asymptomatic throughout their lifetime).

In addition, whereas a large amount of the marketing materials implies the test was developed in line with professional recommendations, none in fact complies with ACOG and ACMG guidance. Finally, though some of the online information provided by laboratories can be helpful, it is important for clinicians to remember that reproductive genetic counseling should be nondirective and balanced. Carrier testing should be based on patient (not provider) values regarding reproductive autonomy.

Summary

ECS increasingly is being adopted into clinical practice. According to ACOG, traditional ethnicity-based screening, panethnic screening (the same limited panel of tests for all patients), and ECS are all acceptable alternatives for prenatal carrier screening.³ For providers who offer ECS, it is important to have a good understanding of each selected test and its limitations. Providers should have a plan for following up patients who have positive test results; this plan may include having genetic counseling and prenatal genetic diagnostic testing in place. Although treatment is available for a few genetic conditions, for the large majority, prenatal screening has not been proved to lead to improved therapeutic options. Providers should try to make sure that patients do not have unrealistic expectations of the outcomes of carrier screening.

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.

Prenatal care has long included carrier screening for genetic diseases, such as cystic fibrosis and Tay-Sachs disease. Recently, advances in genetics technologies led to the development of multiplex panels that can be used to test for hundreds of genetic disorders simultaneously, and can be used to assess carrier status for expectant couples or those planning a pregnancy. Although such screening covers many more conditions than those recommended in traditional guidelines, the benefit of expanded carrier screening (ECS) over standard gene-by-gene testing is not clear.

In this Update, I review recent ECS research that can be helpful to those who practice reproductive endocrinology and infertility medicine, maternal–fetal medicine, and general ObGyn. This research considered some of the many complexities of ECS:

• number and type of severe autosomal recessive conditions identified by an ECS panel, or by panethnic screening for 3 common conditions (cystic fibrosis, fragile X syndrome, spinal muscular atrophy)
• whether the disorders covered by ECS panels meet recommended criteria regarding severity, prevalence, and test accuracy
• women’s thoughts and perspectives on ECS
• whether the marketing materials disseminated by commercial providers of ECS are accurate and balanced.

Genetic diseases identified by expanded carrier screening

Haque IS, Lazarin GA, Kang HP, Evans EA, Goldberg JD, Wapner RJ. Modeled fetal risk of genetic diseases identified by expanded carrier screening. JAMA. 2016;316(7):734-742.

Screening during pregnancy to determine if one or both parents are carriers of genetic disorders historically has involved testing for a limited number of conditions, such as cystic fibrosis, hemoglobinopathies, and Tay-Sachs disease. Patients usually are offered testing for 1 or 2 disorders, with test choices primarily based on patient race and ethnicity. Unfortunately, ancestry-based screening may result in inequitable distribution of genetic testing and resources, as it has significant limitations in our increasingly multicultural society, which includes many people of uncertain or mixed race and ethnicity.

Advantages of expanded carrier screening

Several commercial laboratories now offer ECS. Haque and colleagues used data from one of these laboratories and modeled the predicted number of potentially affected fetuses that would be identified with traditional, ethnicity-based screening as compared with ECS. In one of their hypothetical cohorts, of Northern European couples, traditional screening would identify 55 affected fetuses per 100,000 (1 in 1,800), and ECS would identify 159 per 100,000 (almost 3 times more). The numbers identified with ECS varied with race or ethnicity and ranged from 94 per 100,000 (about 1 in 1,000) for Hispanic couples to 392 per 100,000 (about 1 in 250) for Ashkenazi Jewish couples.

In Australia, Archibald and colleagues conducted a similar study, of panethnic screening of 12,000 women for cystic fibrosis, fragile X syndrome, and spinal muscular atrophy.¹ The number of affected fetuses identified was about 1 per 1,000 screened couples--not much different from the ECS number, though comparison is difficult given the likely very different racial and ethnic backgrounds of the 2 cohorts.

Although these data suggest ECS increases detection of genetic disorders, and it seems almost self-evident that more screening is better, there are concerns about ECS.² Traditional carrier screening methods focus on conditions that significantly affect quality of life--owing to cognitive or physical disabilities or required lifelong medical therapies--and that have a fetal, neonatal, or early-childhood onset and well-defined phenotype. In ECS panels, additional conditions may vary significantly in severity or age of onset. Although some genetic variants on ECS panels have a consistent phenotype, the natural history of others is less well understood. Panels often include conditions for which carrier screening of the general population is not recommended by current guidelines--for example, hemochromatosis and factor V Leiden. Moreover, almost by definition, ECS panels include rare conditions for which the natural history may not be well understood, and the carrier frequency as well as the proportion of condition-causing variants that can be detected may be unclear, leaving the residual risk unknown.

Read about the ideal expanded carrier screening panel.

The ideal expanded carrier screening panel

Stevens B, Krstic N, Jones M, Murphy L, Hoskovec J. Finding middle ground in constructing a clinically useful expanded carrier screening panel. Obstet Gynecol. 2017;130(2):279-284.

Both the American College of Obstetricians and Gynecologists (ACOG) and the American College of Medical Genetics and Genomics (ACMG) have proposed criteria for including specific disorders on ECS panels.^3,4 These criteria consider disorder characteristics, such as carrier prevalence, which should be at least 1 in 100; severity; early-childhood onset; and complete penetrance. In addition, they consider test characteristics, such as sensitivity, which should be at least 70%.

Details of the study

Stevens and colleagues evaluated the ECS panels offered by 6 commercial laboratories in the United States. They found that only 27% of included conditions met the recommended criteria, and concluded that these panels are putting patients at risk for undue anxiety, and that time and money are being spent on follow-up testing for rare and mild conditions for which the benefits of testing are unclear or unlikely. The potential benefits of the extra screening should be weighed against the significant resulting harms.

Across the 6 ECS panels, 96 conditions met the criteria. As some laboratories allow providers to customize their panels, members of my practice, after reviewing this thought-provoking article, agreed we should create a custom panel that includes only these 96 conditions. Unfortunately, no commercial laboratory includes all 96 conditions, so it is not feasible to create an "ideal" panel at this time.

Arguments favoring ECS include its low cost and the efficiency of screening with multigene panels. In a 2013 study, however, 24% of patients were identified as carriers, and in most cases this finding led to screening for the reproductive partner as well.⁵ If the rate of detection of the disorder is low, the utility of screening with the same panel may be limited, and couples may require more extensive testing, such as gene sequencing, which is far more expensive. These findings and the additional testing also will increase the need for genetic counseling, and may lead to invasive prenatal diagnostic testing with further increases in costs. If counseling and prenatal testing yield improved outcomes--increased detection of important findings--the benefit will justify the higher costs. However, if the increased costs are largely generated chasing down and explaining findings that are not important to patients or providers, the costs may be incurred without benefit.

Read about the pregnant women’s perspectives on ECS.

Pregnant women's perspectives on expanded carrier screening

Propst L, Connor G, Hinton M, Poorvu T, Dungan J. Pregnant women's perspectives on expanded carrier screening [published online February 23, 2018]. J Genet Couns. doi:10.1007/s10897-018-0232-x.

Although several authors have discussed ECS detection rates, less has been reported on how women perceive ECS or how they elect or decline screening. Studies have found that the decision to undergo screening for cystic fibrosis is influenced by factors that include age, sex, ethnicity, socioeconomic status, lack of family history, cost, fear of a blood test, lack of knowledge about the condition, already having children, wanting to avoid having a disabled child, abortion preferences, and feeling pressured by health care providers.^6,7 Propst and colleagues asked women for their perspectives on ECS, on electing or declining screening, and on any anxiety associated with their decision.

Details of the study

Women who declined ECS said they did so because they:

• had no family history
• knew there was a very small chance their partner carried the same condition  
• would not change the course of their pregnancy on the basis of the test results.

Women who elected ECS said they did so because they wanted to:

• know their risk of having a child with a genetic condition
• have all available information about their genetic risks
• be able to make decisions about continuing or terminating their pregnancy.

Women also were asked what they would do if they discovered their fetus had a genetic disorder. About 42% said they were unsure what they would do, 34% said they would continue their pregnancy and prepare for the birth of an affected child, and 24% said they likely would terminate their pregnancy.

The most common reason women gave for declining ECS was that they had no family history. However, ECS is not a good option for women with a positive family history, as they need genetic counseling and specific consideration of their own risks and what testing should be done. The majority of couples who have a child with a genetic disease have no other family history of the disorder. In a study of reproductive carrier screening in Australia, 88% of carriers had no family history.¹ Careful pretest counseling is needed to explain the distinction between, on one hand, genetic counseling and testing for those with a family history of genetic disease and, on the other hand, population screening performed to identify unsuspecting individuals who are healthy carriers of genetic disorders.

Another crucial point about carrier screening is the need to consider how its results will be used, and what options the carrier couple will have. For women who are pregnant when a risk is identified, options include expectant management, with diagnosis after birth, or prenatal diagnosis with termination of an affected fetus, out-adoption of an affected fetus, or expectant management with preparation for caring for an affected child. For women who are not pregnant when they have ECS, additional options include use of a gamete (ovum or sperm) donor to achieve pregnancy, or preimplantation genetic diagnosis with implantation of only unaffected embryos.

Read about the marketing of ECS.

Marketing of expanded carrier screening

Chokoshvili D, Borry P, Vears DF. A systematic analysis of online marketing materials used by providers of expanded carrier screening [published online December 14, 2017]. Genet Med. doi:10.1038/gim.2017.222.

Prenatal carrier screening can be helpful to women and their families, but it is also a high-volume, lucrative business, with many commercial laboratories competing for the growing ECS market. Professional medical societies recommend making all screening candidates aware of the purpose, characteristics, and limitations of the tests, and of the potential significance of their results. As becoming familiar and comfortable with the tests and explaining them to each patient can be time-consuming, and daunting, many busy clinicians have started relying on marketing materials and other information from the commercial laboratories. Therefore analysis of the accuracy of such materials is in order.

Details of the study

Chokoshvili and colleagues performed a systematic analysis of the quality and accuracy of online marketing materials for ECS. They identified 18 providers: 16 commercial laboratories and 2 medical services providers. All described ECS as a useful tool for family planning, and some were very directive in stating that this testing is "one of the most important steps in preparing for parenthood." In their materials, most of the companies cover some limitations, such as residual risk, but none of the commercial laboratories indicate that ECS can overestimate risk (many variants have incomplete penetrance, meaning that some individuals with a positive test result may in fact be asymptomatic throughout their lifetime).

In addition, whereas a large amount of the marketing materials implies the test was developed in line with professional recommendations, none in fact complies with ACOG and ACMG guidance. Finally, though some of the online information provided by laboratories can be helpful, it is important for clinicians to remember that reproductive genetic counseling should be nondirective and balanced. Carrier testing should be based on patient (not provider) values regarding reproductive autonomy.

Summary

ECS increasingly is being adopted into clinical practice. According to ACOG, traditional ethnicity-based screening, panethnic screening (the same limited panel of tests for all patients), and ECS are all acceptable alternatives for prenatal carrier screening.³ For providers who offer ECS, it is important to have a good understanding of each selected test and its limitations. Providers should have a plan for following up patients who have positive test results; this plan may include having genetic counseling and prenatal genetic diagnostic testing in place. Although treatment is available for a few genetic conditions, for the large majority, prenatal screening has not been proved to lead to improved therapeutic options. Providers should try to make sure that patients do not have unrealistic expectations of the outcomes of carrier screening.

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.

ABSTRACT

This article aims to provide the information necessary to prevent femoral trial head loss and to offer information regarding retrieval of the trial head if it is lost within the surgical field. These techniques can be used to help guide practice in the future. A review of the literature was conducted using a computerized search of PubMed in regard to this issue to investigate how such an occurrence can be prevented and what steps can be taken if preventative measures fail.

Continue to: Total hip arthroplasty...

Total hip arthroplasty (THA) is becoming an increasingly common procedure. Although this procedure is frequently performed, intraoperative complications still arise; therefore, methods of preventing and ameliorating these complications must be devised. One such complication is the loss of the femoral trial head component within the patient.

Loss of the trial head has been documented in THA cases that have used a number of different surgical approaches.¹ Although it is uncommon to lose the trial within the pelvis, it is not an entirely unlikely phenomenon. The possibility of such an event makes prevention important, especially given the associated morbidity that loss of the component could cause. Fortunately, there are preventative measures that can be taken to minimize the probability of losing the femoral trial head, in addition to techniques that can be utilized if prevention fails.

SURGICAL TECHNIQUE

PREVENTION

Firstly, it is important to avoid the use of worn-out femoral trial components. It is thought that the incidence of femoral trial head loss is increased when the trunnion is older and has been used repeatedly.^2,3 Therefore, it is advised that the use of worn femoral trial stems and other older trial components be avoided.

When the femoral trial head disengages anteriorly, it has the potential to enter the pelvis/retroperitoneal space.^2,4 The femoral trial head may move more freely in the absence of resistance offered by the anterior capsule.⁴ Therefore, when extensive anterior capsular dissection has taken place, such as during extensive capsulectomy, caution should be exercised when manipulating the hip. This emphasizes the necessity to closely monitor the head during any manipulation, particularly in the presence of significant anterior capsule disruption.

Modular hip arthroplasty prosthetics allow for various intraoperative changes to be made to the femoral component, providing greater specificity to the prosthesis.⁵ However, the modularity of the femoral component has been described as a factor contributing to loss of the femoral trial head.⁴ This also has been discussed with respect to the implantable prosthetic femoral head itself because of disengagement from the femoral stem during reduction and dislocation.⁴

Continue to: Case reports have cited...

Case reports have cited the tension of the soft tissues as a definitive factor in trial head loss.^1,4,6 These reports discuss the notion that more tension within the soft tissue can increase the likelihood that the trial head will dislodge during reduction or dislocation. Surgeons should therefore consider taking special care when manipulating the trial joint when the soft tissues are particularly tight and offer significant resistance. It has been suggested that the incision be packed with gauze during reductions when the soft tissue is under significant tension in order to keep the femoral trial head from entering the pelvis.⁶

A simple technique that can be utilized in the prevention of femoral trial head loss is the placement of a suture through the apical hole in the trial head to aid in the retrieval of the implant if it is lost.¹ Madsen and colleagues¹ suggest the placement of a No.1 (or thicker) suture through this hole. Although this takes some time to perform, it could prove useful in the prevention of complicated implant loss.

Lastly, and perhaps most importantly, it is essential that there is communication and understanding between the surgeon and any assistants. This has been noted to be particularly important during posterior or lateral surgical approaches when the trial head can be lost during attempts at reduction with traction and internal rotation.² Given the possibility of losing the trial head during this reduction maneuver, communication between the team during the reduction is instrumental.

RETRIEVAL

If the femoral trial head dissociates from the trunnion of the femoral trial manipulation, there are some techniques that can be used to aid in retrieval. It has been described that when the trial head is lost within the surgical wound, it can travel underneath the rectus femoris muscle and cross the pelvic brim, subsequently entering the pelvis along the psoas tendon, as the psoas bursa offers little resistance to the smooth femoral trial head.¹ The trial head has been found to follow this path along the psoas tendon until it is located in the posterior pelvis within the retroperitoneal space.^1,7 What follows is a compilation of techniques for approaching loss of the femoral trial head when it occurs.

The femoral trial head is round and smooth, which complicates its retrieval. If the surgeon tries to simply grab the component with fingers, it may slip away into the pelvis. When trialing the hip to assess for anterior stability, if the femoral trial head is lost, the leg should not be moved.⁷ At this point, a manual attempt to recover the trial head before it moves into the pelvis along the psoas tendon should be made.⁷ It is possible that the femoral trial head may spin when trying to retrieve it, however this should still be attempted before a formal additional surgical approach is employed.⁷ It has also been noted that one can manually simultaneously press down on the hypogastrium toward the iliac fossa in order to inhibit the movement of the disarticulated trial head from advancing proximally.³ After performing this maneuver, the femoral trial head can be retrieved through the inguinal canal.³

Continue to: Additional surgical approaches...

Additional surgical approaches can also be utilized for retrieval of the femoral trial head if other measures fail. Callaghan and colleagues⁷ describe a separate surgical approach that can be used to retrieve the trial component after losing the trial head during a posterolateral approach for THA. This technique is commenced by making a 6-cm to 7-cm incision along the iliac crest to the anteromedial aspect of the anterior superior iliac spine.⁷ The interval between the iliacus and the inner table of the iliac wing is developed, and an attempt is made to locate the femoral trial head and guide it distally along the pelvis toward the hip. Fingers or napkin forceps can be used to accomplish this advancement of the trial head distally toward the hip, and once reaching surgical site, the trial can then be retrieved.⁷ Further extension of the incision can be made distally if this limited approach is unsuccessful.⁷ In the event the femoral trial head is still unable to be retrieved, the authors suggest considering a dedicated retroperitoneal approach for trial retrieval after the arthroplasty procedure has been completed.⁷

Another method for retrieval of the femoral trial head has been described specifically in the setting of a direct lateral approach.⁸ Kalra and colleagues⁸ describe a case in which the trial femoral head dislocated anteriorly, and although it was unable to be visualized, the component was able to be palpated posterior to the superior pubic ramus. With the trial head still disassociated within the pelvis, the final implants were implanted. Although the trial was unable to be viewed, using the same incision for the direct lateral approach, the trial femoral head was guided posteriorly toward the sciatic notch. A posterior approach to the hip was then performed using the same initial direct lateral incision used. Subsequent exposure and release of the external rotators and posterior capsule was performed, as was release of the insertion of the gluteus maximus in order to facilitate better visualization and to prevent excessive tension on the sciatic nerve. Blunt finger dissection of the soft tissues was then performed, and the trial head was retrieved from the sciatic notch with a Kocher clamp.⁸

Madsen and colleagues¹ highlight two different cases in which the trial head was lost into the pelvis when using an anterolateral (modified Watson-Jones) approach to the hip to perform THA. As previously alluded to, the trial heads traveled along the patients’ psoas muscle and stopped directly anterior to their sacroiliac joint. In both cases, the trial head was retrieved using a large Satinsky aortic clamp, which enabled the surgeons to drag the trial head to the pelvic brim where it could be removed with a hemostat.¹

Multiple authors have discussed the decision to leave the component within the pelvis if the femoral trial head cannot be retrieved.^2,4,7 Batouk and colleagues⁴ noted that in a case of loss of the femoral trial head, the component would be unlikely to disrupt any of the structures within the pelvis, and in the absence of compression of any vital structures, leaving the implant in the patient could be considered. Although the short-term follow-up of 3 months noted in this particular case did not yield any obvious detriment to the patient in regard to symptomatology, the authors note that the long-term effects of such a practice is unclear.⁴ In another case, in which the decision was made to leave the femoral trial head, the patient at postoperative week 6 began to hear clicking in the hip with an associated loss of range of motion.⁷ This subsequently prompted removal of the trial component.

DISCUSSION

Although not a particularly common complication, loss of the femoral trial head can occur; therefore, a plan of action should be in place to prevent its loss or to retrieve it if prevention is ineffective. Given the modularity of various arthroplasty systems in regard to the different trial components or even the final implantable prosthetic devices, component loss is a possibility. An understanding of this complication and the appropriate steps to approaching it could aid in preventing patient morbidity. Because of this, it is imperative that surgeons who perform THA be aware of the potential complications and the measures that can be taken to address them.

Continue to: CONCLUSION

The femoral trial head often can be quickly and easily recovered; however, trial component recovery can sometimes be more complicated. Loss of the trial femoral head could potentially occur during dislocation, reduction, or any of the trial positions. An example of a more complicated recovery is when the femoral trial head is lost into the retroperitoneal space, which could occur when trialing the hip in extension to assess the anterior stability of the hip. Loss of the femoral trial head is an avoidable occurrence, and it has the potential to cause a number of complications as well as the need for additional incisions/surgery to retrieve the femoral trial head. The subsequent issues that could arise after loss occurs can not only lead to extensive surgical complications, but can also foster patient dissatisfaction regarding surgical outcomes. Therefore, consistent attempts to utilize preventative techniques are essential. As discussed, simple measures such as placement of a suture through the apical hole of the trial component and adequate communication between those involved in reduction and trialing maneuvers, can serve to avert femoral trial head loss.

ABSTRACT

This article aims to provide the information necessary to prevent femoral trial head loss and to offer information regarding retrieval of the trial head if it is lost within the surgical field. These techniques can be used to help guide practice in the future. A review of the literature was conducted using a computerized search of PubMed in regard to this issue to investigate how such an occurrence can be prevented and what steps can be taken if preventative measures fail.

Continue to: Total hip arthroplasty...

Total hip arthroplasty (THA) is becoming an increasingly common procedure. Although this procedure is frequently performed, intraoperative complications still arise; therefore, methods of preventing and ameliorating these complications must be devised. One such complication is the loss of the femoral trial head component within the patient.

Loss of the trial head has been documented in THA cases that have used a number of different surgical approaches.¹ Although it is uncommon to lose the trial within the pelvis, it is not an entirely unlikely phenomenon. The possibility of such an event makes prevention important, especially given the associated morbidity that loss of the component could cause. Fortunately, there are preventative measures that can be taken to minimize the probability of losing the femoral trial head, in addition to techniques that can be utilized if prevention fails.

SURGICAL TECHNIQUE

PREVENTION

Firstly, it is important to avoid the use of worn-out femoral trial components. It is thought that the incidence of femoral trial head loss is increased when the trunnion is older and has been used repeatedly.^2,3 Therefore, it is advised that the use of worn femoral trial stems and other older trial components be avoided.

When the femoral trial head disengages anteriorly, it has the potential to enter the pelvis/retroperitoneal space.^2,4 The femoral trial head may move more freely in the absence of resistance offered by the anterior capsule.⁴ Therefore, when extensive anterior capsular dissection has taken place, such as during extensive capsulectomy, caution should be exercised when manipulating the hip. This emphasizes the necessity to closely monitor the head during any manipulation, particularly in the presence of significant anterior capsule disruption.

Modular hip arthroplasty prosthetics allow for various intraoperative changes to be made to the femoral component, providing greater specificity to the prosthesis.⁵ However, the modularity of the femoral component has been described as a factor contributing to loss of the femoral trial head.⁴ This also has been discussed with respect to the implantable prosthetic femoral head itself because of disengagement from the femoral stem during reduction and dislocation.⁴

Continue to: Case reports have cited...

Case reports have cited the tension of the soft tissues as a definitive factor in trial head loss.^1,4,6 These reports discuss the notion that more tension within the soft tissue can increase the likelihood that the trial head will dislodge during reduction or dislocation. Surgeons should therefore consider taking special care when manipulating the trial joint when the soft tissues are particularly tight and offer significant resistance. It has been suggested that the incision be packed with gauze during reductions when the soft tissue is under significant tension in order to keep the femoral trial head from entering the pelvis.⁶

A simple technique that can be utilized in the prevention of femoral trial head loss is the placement of a suture through the apical hole in the trial head to aid in the retrieval of the implant if it is lost.¹ Madsen and colleagues¹ suggest the placement of a No.1 (or thicker) suture through this hole. Although this takes some time to perform, it could prove useful in the prevention of complicated implant loss.

Lastly, and perhaps most importantly, it is essential that there is communication and understanding between the surgeon and any assistants. This has been noted to be particularly important during posterior or lateral surgical approaches when the trial head can be lost during attempts at reduction with traction and internal rotation.² Given the possibility of losing the trial head during this reduction maneuver, communication between the team during the reduction is instrumental.

RETRIEVAL

If the femoral trial head dissociates from the trunnion of the femoral trial manipulation, there are some techniques that can be used to aid in retrieval. It has been described that when the trial head is lost within the surgical wound, it can travel underneath the rectus femoris muscle and cross the pelvic brim, subsequently entering the pelvis along the psoas tendon, as the psoas bursa offers little resistance to the smooth femoral trial head.¹ The trial head has been found to follow this path along the psoas tendon until it is located in the posterior pelvis within the retroperitoneal space.^1,7 What follows is a compilation of techniques for approaching loss of the femoral trial head when it occurs.

The femoral trial head is round and smooth, which complicates its retrieval. If the surgeon tries to simply grab the component with fingers, it may slip away into the pelvis. When trialing the hip to assess for anterior stability, if the femoral trial head is lost, the leg should not be moved.⁷ At this point, a manual attempt to recover the trial head before it moves into the pelvis along the psoas tendon should be made.⁷ It is possible that the femoral trial head may spin when trying to retrieve it, however this should still be attempted before a formal additional surgical approach is employed.⁷ It has also been noted that one can manually simultaneously press down on the hypogastrium toward the iliac fossa in order to inhibit the movement of the disarticulated trial head from advancing proximally.³ After performing this maneuver, the femoral trial head can be retrieved through the inguinal canal.³

Continue to: Additional surgical approaches...

Additional surgical approaches can also be utilized for retrieval of the femoral trial head if other measures fail. Callaghan and colleagues⁷ describe a separate surgical approach that can be used to retrieve the trial component after losing the trial head during a posterolateral approach for THA. This technique is commenced by making a 6-cm to 7-cm incision along the iliac crest to the anteromedial aspect of the anterior superior iliac spine.⁷ The interval between the iliacus and the inner table of the iliac wing is developed, and an attempt is made to locate the femoral trial head and guide it distally along the pelvis toward the hip. Fingers or napkin forceps can be used to accomplish this advancement of the trial head distally toward the hip, and once reaching surgical site, the trial can then be retrieved.⁷ Further extension of the incision can be made distally if this limited approach is unsuccessful.⁷ In the event the femoral trial head is still unable to be retrieved, the authors suggest considering a dedicated retroperitoneal approach for trial retrieval after the arthroplasty procedure has been completed.⁷

Another method for retrieval of the femoral trial head has been described specifically in the setting of a direct lateral approach.⁸ Kalra and colleagues⁸ describe a case in which the trial femoral head dislocated anteriorly, and although it was unable to be visualized, the component was able to be palpated posterior to the superior pubic ramus. With the trial head still disassociated within the pelvis, the final implants were implanted. Although the trial was unable to be viewed, using the same incision for the direct lateral approach, the trial femoral head was guided posteriorly toward the sciatic notch. A posterior approach to the hip was then performed using the same initial direct lateral incision used. Subsequent exposure and release of the external rotators and posterior capsule was performed, as was release of the insertion of the gluteus maximus in order to facilitate better visualization and to prevent excessive tension on the sciatic nerve. Blunt finger dissection of the soft tissues was then performed, and the trial head was retrieved from the sciatic notch with a Kocher clamp.⁸

Madsen and colleagues¹ highlight two different cases in which the trial head was lost into the pelvis when using an anterolateral (modified Watson-Jones) approach to the hip to perform THA. As previously alluded to, the trial heads traveled along the patients’ psoas muscle and stopped directly anterior to their sacroiliac joint. In both cases, the trial head was retrieved using a large Satinsky aortic clamp, which enabled the surgeons to drag the trial head to the pelvic brim where it could be removed with a hemostat.¹

Multiple authors have discussed the decision to leave the component within the pelvis if the femoral trial head cannot be retrieved.^2,4,7 Batouk and colleagues⁴ noted that in a case of loss of the femoral trial head, the component would be unlikely to disrupt any of the structures within the pelvis, and in the absence of compression of any vital structures, leaving the implant in the patient could be considered. Although the short-term follow-up of 3 months noted in this particular case did not yield any obvious detriment to the patient in regard to symptomatology, the authors note that the long-term effects of such a practice is unclear.⁴ In another case, in which the decision was made to leave the femoral trial head, the patient at postoperative week 6 began to hear clicking in the hip with an associated loss of range of motion.⁷ This subsequently prompted removal of the trial component.

DISCUSSION

Although not a particularly common complication, loss of the femoral trial head can occur; therefore, a plan of action should be in place to prevent its loss or to retrieve it if prevention is ineffective. Given the modularity of various arthroplasty systems in regard to the different trial components or even the final implantable prosthetic devices, component loss is a possibility. An understanding of this complication and the appropriate steps to approaching it could aid in preventing patient morbidity. Because of this, it is imperative that surgeons who perform THA be aware of the potential complications and the measures that can be taken to address them.

Continue to: CONCLUSION

The femoral trial head often can be quickly and easily recovered; however, trial component recovery can sometimes be more complicated. Loss of the trial femoral head could potentially occur during dislocation, reduction, or any of the trial positions. An example of a more complicated recovery is when the femoral trial head is lost into the retroperitoneal space, which could occur when trialing the hip in extension to assess the anterior stability of the hip. Loss of the femoral trial head is an avoidable occurrence, and it has the potential to cause a number of complications as well as the need for additional incisions/surgery to retrieve the femoral trial head. The subsequent issues that could arise after loss occurs can not only lead to extensive surgical complications, but can also foster patient dissatisfaction regarding surgical outcomes. Therefore, consistent attempts to utilize preventative techniques are essential. As discussed, simple measures such as placement of a suture through the apical hole of the trial component and adequate communication between those involved in reduction and trialing maneuvers, can serve to avert femoral trial head loss.

ABSTRACT

This article aims to provide the information necessary to prevent femoral trial head loss and to offer information regarding retrieval of the trial head if it is lost within the surgical field. These techniques can be used to help guide practice in the future. A review of the literature was conducted using a computerized search of PubMed in regard to this issue to investigate how such an occurrence can be prevented and what steps can be taken if preventative measures fail.

Continue to: Total hip arthroplasty...

Total hip arthroplasty (THA) is becoming an increasingly common procedure. Although this procedure is frequently performed, intraoperative complications still arise; therefore, methods of preventing and ameliorating these complications must be devised. One such complication is the loss of the femoral trial head component within the patient.

Loss of the trial head has been documented in THA cases that have used a number of different surgical approaches.¹ Although it is uncommon to lose the trial within the pelvis, it is not an entirely unlikely phenomenon. The possibility of such an event makes prevention important, especially given the associated morbidity that loss of the component could cause. Fortunately, there are preventative measures that can be taken to minimize the probability of losing the femoral trial head, in addition to techniques that can be utilized if prevention fails.

SURGICAL TECHNIQUE

PREVENTION

Firstly, it is important to avoid the use of worn-out femoral trial components. It is thought that the incidence of femoral trial head loss is increased when the trunnion is older and has been used repeatedly.^2,3 Therefore, it is advised that the use of worn femoral trial stems and other older trial components be avoided.

When the femoral trial head disengages anteriorly, it has the potential to enter the pelvis/retroperitoneal space.^2,4 The femoral trial head may move more freely in the absence of resistance offered by the anterior capsule.⁴ Therefore, when extensive anterior capsular dissection has taken place, such as during extensive capsulectomy, caution should be exercised when manipulating the hip. This emphasizes the necessity to closely monitor the head during any manipulation, particularly in the presence of significant anterior capsule disruption.

Modular hip arthroplasty prosthetics allow for various intraoperative changes to be made to the femoral component, providing greater specificity to the prosthesis.⁵ However, the modularity of the femoral component has been described as a factor contributing to loss of the femoral trial head.⁴ This also has been discussed with respect to the implantable prosthetic femoral head itself because of disengagement from the femoral stem during reduction and dislocation.⁴

Continue to: Case reports have cited...

Case reports have cited the tension of the soft tissues as a definitive factor in trial head loss.^1,4,6 These reports discuss the notion that more tension within the soft tissue can increase the likelihood that the trial head will dislodge during reduction or dislocation. Surgeons should therefore consider taking special care when manipulating the trial joint when the soft tissues are particularly tight and offer significant resistance. It has been suggested that the incision be packed with gauze during reductions when the soft tissue is under significant tension in order to keep the femoral trial head from entering the pelvis.⁶

A simple technique that can be utilized in the prevention of femoral trial head loss is the placement of a suture through the apical hole in the trial head to aid in the retrieval of the implant if it is lost.¹ Madsen and colleagues¹ suggest the placement of a No.1 (or thicker) suture through this hole. Although this takes some time to perform, it could prove useful in the prevention of complicated implant loss.

Lastly, and perhaps most importantly, it is essential that there is communication and understanding between the surgeon and any assistants. This has been noted to be particularly important during posterior or lateral surgical approaches when the trial head can be lost during attempts at reduction with traction and internal rotation.² Given the possibility of losing the trial head during this reduction maneuver, communication between the team during the reduction is instrumental.

RETRIEVAL

If the femoral trial head dissociates from the trunnion of the femoral trial manipulation, there are some techniques that can be used to aid in retrieval. It has been described that when the trial head is lost within the surgical wound, it can travel underneath the rectus femoris muscle and cross the pelvic brim, subsequently entering the pelvis along the psoas tendon, as the psoas bursa offers little resistance to the smooth femoral trial head.¹ The trial head has been found to follow this path along the psoas tendon until it is located in the posterior pelvis within the retroperitoneal space.^1,7 What follows is a compilation of techniques for approaching loss of the femoral trial head when it occurs.

The femoral trial head is round and smooth, which complicates its retrieval. If the surgeon tries to simply grab the component with fingers, it may slip away into the pelvis. When trialing the hip to assess for anterior stability, if the femoral trial head is lost, the leg should not be moved.⁷ At this point, a manual attempt to recover the trial head before it moves into the pelvis along the psoas tendon should be made.⁷ It is possible that the femoral trial head may spin when trying to retrieve it, however this should still be attempted before a formal additional surgical approach is employed.⁷ It has also been noted that one can manually simultaneously press down on the hypogastrium toward the iliac fossa in order to inhibit the movement of the disarticulated trial head from advancing proximally.³ After performing this maneuver, the femoral trial head can be retrieved through the inguinal canal.³

Continue to: Additional surgical approaches...

Additional surgical approaches can also be utilized for retrieval of the femoral trial head if other measures fail. Callaghan and colleagues⁷ describe a separate surgical approach that can be used to retrieve the trial component after losing the trial head during a posterolateral approach for THA. This technique is commenced by making a 6-cm to 7-cm incision along the iliac crest to the anteromedial aspect of the anterior superior iliac spine.⁷ The interval between the iliacus and the inner table of the iliac wing is developed, and an attempt is made to locate the femoral trial head and guide it distally along the pelvis toward the hip. Fingers or napkin forceps can be used to accomplish this advancement of the trial head distally toward the hip, and once reaching surgical site, the trial can then be retrieved.⁷ Further extension of the incision can be made distally if this limited approach is unsuccessful.⁷ In the event the femoral trial head is still unable to be retrieved, the authors suggest considering a dedicated retroperitoneal approach for trial retrieval after the arthroplasty procedure has been completed.⁷

Another method for retrieval of the femoral trial head has been described specifically in the setting of a direct lateral approach.⁸ Kalra and colleagues⁸ describe a case in which the trial femoral head dislocated anteriorly, and although it was unable to be visualized, the component was able to be palpated posterior to the superior pubic ramus. With the trial head still disassociated within the pelvis, the final implants were implanted. Although the trial was unable to be viewed, using the same incision for the direct lateral approach, the trial femoral head was guided posteriorly toward the sciatic notch. A posterior approach to the hip was then performed using the same initial direct lateral incision used. Subsequent exposure and release of the external rotators and posterior capsule was performed, as was release of the insertion of the gluteus maximus in order to facilitate better visualization and to prevent excessive tension on the sciatic nerve. Blunt finger dissection of the soft tissues was then performed, and the trial head was retrieved from the sciatic notch with a Kocher clamp.⁸

Madsen and colleagues¹ highlight two different cases in which the trial head was lost into the pelvis when using an anterolateral (modified Watson-Jones) approach to the hip to perform THA. As previously alluded to, the trial heads traveled along the patients’ psoas muscle and stopped directly anterior to their sacroiliac joint. In both cases, the trial head was retrieved using a large Satinsky aortic clamp, which enabled the surgeons to drag the trial head to the pelvic brim where it could be removed with a hemostat.¹

Multiple authors have discussed the decision to leave the component within the pelvis if the femoral trial head cannot be retrieved.^2,4,7 Batouk and colleagues⁴ noted that in a case of loss of the femoral trial head, the component would be unlikely to disrupt any of the structures within the pelvis, and in the absence of compression of any vital structures, leaving the implant in the patient could be considered. Although the short-term follow-up of 3 months noted in this particular case did not yield any obvious detriment to the patient in regard to symptomatology, the authors note that the long-term effects of such a practice is unclear.⁴ In another case, in which the decision was made to leave the femoral trial head, the patient at postoperative week 6 began to hear clicking in the hip with an associated loss of range of motion.⁷ This subsequently prompted removal of the trial component.

DISCUSSION

Although not a particularly common complication, loss of the femoral trial head can occur; therefore, a plan of action should be in place to prevent its loss or to retrieve it if prevention is ineffective. Given the modularity of various arthroplasty systems in regard to the different trial components or even the final implantable prosthetic devices, component loss is a possibility. An understanding of this complication and the appropriate steps to approaching it could aid in preventing patient morbidity. Because of this, it is imperative that surgeons who perform THA be aware of the potential complications and the measures that can be taken to address them.

Continue to: CONCLUSION

The femoral trial head often can be quickly and easily recovered; however, trial component recovery can sometimes be more complicated. Loss of the trial femoral head could potentially occur during dislocation, reduction, or any of the trial positions. An example of a more complicated recovery is when the femoral trial head is lost into the retroperitoneal space, which could occur when trialing the hip in extension to assess the anterior stability of the hip. Loss of the femoral trial head is an avoidable occurrence, and it has the potential to cause a number of complications as well as the need for additional incisions/surgery to retrieve the femoral trial head. The subsequent issues that could arise after loss occurs can not only lead to extensive surgical complications, but can also foster patient dissatisfaction regarding surgical outcomes. Therefore, consistent attempts to utilize preventative techniques are essential. As discussed, simple measures such as placement of a suture through the apical hole of the trial component and adequate communication between those involved in reduction and trialing maneuvers, can serve to avert femoral trial head loss.

ABSTRACT

Patellar instability in children and adolescents is a challenging subset to treat. Varied forms of instability, ranging from episodic dislocation to fixed dislocation, have been recognized. It is of utmost importance for the treating physician to recognize these different patterns of instability and their associated risk factors, as more complex patterns of instability would require more extensive surgical procedures. Medial patellofemoral ligament (MPFL) reconstruction, by itself, may not suffice or may not be appropriate for the more complex instability patterns. Appropriate and early treatment of such instability in children would allow for functional progression and possible remodeling of the trochlea. However, early treatment has the associated risk of growth disturbances when surgical procedures are performed around open physis or if adult-type bony procedures are performed in children. Recent knowledge about the relationship between trochlea, MPFL femoral attachment, and distal femoral physis could help to advance safe surgical care for these patients. This article reviews the pathophysiology, risk factors, and the existing classification systems for patellar instability in children and adolescents. It focuses on varied surgical techniques, which are unique to the pediatric population, and summarizes the outcomes of these surgical techniques.

Continue to: EPIDEMIOLOGY

EPIDEMIOLOGY

In a prospective 2-year study of Finnish children, the annual incidence rate of patellar instability was 43/100,000 pediatric population.¹ In patients 9 to 15 years of age, the incidence was approximately 1/1000.¹ In another study, patients at highest risk for a first-time patellar dislocation were females aged 10 to 17 years.² In a study in patients with traumatic hemarthrosis, 36% in the younger age group (10-14 years) and 28% in the older age group (15-18 years) had sustained patellar dislocation. In contrast, 22% in the younger age group and 40% in the older age group had sustained an anterior cruciate ligament tear.³

Approximately one-half of patients who dislocate their patella suffer from long-term complications.^4,5 These complications include recurrent instability, patellofemoral pain, osteochondral lesions, and eventual arthritis.^1,4,5 Young, active individuals are more prone to these issues.⁶ Also, 39% or more of patellar dislocation patients have an associated osteochondral fracture that might influence the management.¹ Thus, patellar instability in young patients is an area of concern.

DEVELOPMENTAL ANATOMY

At 4-week gestation, the patellofemoral joint is an ectodermal sac filled with mesenchyme of the somatic mesoderm.⁷ Mesenchymal condensations then appear at 4 to 5 weeks gestation, followed by chondrification of both the femur and patella.⁷ The joint space is present by 6 weeks, and the patellar and distal femoral condyles are present at 7 weeks gestation.⁷ By 8 weeks gestation, the basic knee anatomy resembles that of an adult with the chondroepiphysis forming the articular surfaces of the femur, tibia, and patella.⁷ By this time, the extensor mechanism is formed, and active joint motion has begun, facilitating the development of the trochlear sulcus.⁷ The secondary ossification center in the distal femoral epiphysis forms around 36 weeks gestation.⁸ Postnatally, both the patella and distal femur grow through endochondral ossification.^9,10

The patella is the largest sesamoid bone in the human body.¹¹ The patella begins as a dense consolidation of cells that differentiate as the quadriceps mechanisms develop.^12,13 The patellar anlage becomes distinguishable within the quadriceps tendon around 7.5-week gestation.¹² The morphology of the patella conforms to the distal femur.¹² The patella molds or re-models as the knee begins to move in response to mechanical stresses.⁷ The patella increases in relative size during the first 6 months of gestation, then enlarges proportionately to the rest of the bones.⁷ Ossification begins around 3 years of age for females and 4 to 5 years of age for males.^8,14 The ossification center may appear irregular as it rapidly expands.¹⁴ Ossification proceeds in a proximal to distal direction, thus giving a spurious estimation of patellar height on radiographs in children. The overall morphology of the cartilaginous patella during development is comparable to the final mature shape.¹⁴ Abnormal contact stresses on the articular surface of the patella during skeletal immaturity can lead to deformation.⁷

Ultrasonographic measurements in normal patients show that trochlear groove (TG) morphology is present early and becomes more radiographically apparent as distal femoral ossification is completed.¹⁵ Anatomic dissections of aborted fetuses have verified the morphology of the TG as it remains constant during growth and the groove morphology is the same for both fetuses and adults.¹⁶ An ultrasound study performed on patients aged 12 to 18 years showed the cartilaginous sulcus angle (CSA) remained constant throughout all age groups (146°).¹⁷ The CSA however, differed in patients who suffered a patellar dislocation (average, 164°; range, 154°-195°) compared with normal knees (average CSA, 145°; range, 131°-158°).^15,17,18 The osseous sulcus angle, on the other hand, appears flat at birth and the TG deepens with age. This increase in depth is more of a reflection of progressive ossification of a well-formed cartilaginous trochlea, rather than a true deepening of the sulcus.¹⁷ Thus, the axial radiographic view of the patella provides misleading information about the sulcus angle in children and should not be used to define trochlear morphology.

Continue to: MEDIAL PATELLOFEMORAL LIGAMENT ANATOMY

The medial patellofemoral ligament (MPFL) functions to limit the lateral translation of the patella.¹⁹ The attachment sites on the femur and patella for the MPFL have been studied in children.^20-23 Cadaveric dissections in specimens aged 2 to 11 years have noted the patellar attachment to be an average of 12 mm in length with the midpoint approximately 5 mm superior to the mid-pole of the patella.²² The patellar footprint of the MPFL insertion was a mean 41% of the entire patellar length.²²

It is important to be aware of the characteristic anatomy of the MPFL, as fixation points should mimic the anatomic insertion as best as possible while also avoiding violation of the nearby physis. The MPFL originates between the adductor tubercle and the medial femoral epicondyle just distal to the distal femoral physis and attaches to the superomedial aspect of the patella.^20-25 In relation to the physis in pediatric patients, the midpoint of MPFL insertion has been measured to be 4 mm to 9 mm distal to the femoral physis.^21,24,25 These measurements represent averages as cadaveric studies have reported that some part of MPFL femoral insertion extends proximal to the distal femoral physis.²¹ A recent report of physeal injury to the posterior distal femoral physis during MPFL reconstruction leading to femoral flexion deformity highlights the importance of physeal-respecting surgery.²⁶

TROCHLEA AND ANTERIOR DISTAL FEMORAL PHYSIS

The relationship between the proximal aspect of the trochlea and the anterior distal femoral physis has been recently studied in 175 knees with dysplastic trochlea.²⁷ Based on magnetic resonance imaging evaluation, the lateral aspect of the trochlea extended proximal to the anterior distal femoral physis in 13% of patients and was at the level of the anterior physis in another 13% of patients (Figure 1).²⁷ Hence, a cautious approach is recommended for any surgery to address trochlear dysplasia or trochlear bump in younger patients to prevent iatrogenic injury to anterior distal femoral physis and resultant genu recurvatum. The distance between the trochlea and the physis increased with increasing age.

LIMB ALIGNMENT

Physiologically, the quadriceps angle (Q angle) changes through the course of growth. As children begin standing and walking, they stand with their feet wider apart and in genu varum.²⁸ Physiologic genu varum can reach 15°.²⁸ This degree lessens during the first 1.5 to 2 years of life, transitioning to physiologic valgus of nearly 12° by 3 years of age.²⁸ Genu valgum, thereafter, gradually decreases to reach the adult value of around 7° to 8° by age 7 years.²⁸ Increased genu valgum is a risk factor for patellar instability. In skeletally immature patients, correction of genu valgum through guided growth may be desirable in patients undergoing patellar stabilization surgery (Figures 2A, 2B).²⁹

PATHOPHYSIOLOGY OF PEDIATRIC PATELLAR DISLOCATION

TROCHLEAR DYSPLASIA

Trochlear dysplasia is an abnormal shape and depth of the TG.³⁰ Up to 96% of patients with patellar dislocation have trochlear dysplasia.^30-33 In a study of patellar instability in children, at least 1 of the 3 signs of trochlear dysplasia (the crossing sign, supratrochlear bump, and double contour sign) was present on lateral radiographs.³⁴ In another study on the growth of trochlear dysplasia in children and adolescents, all grades of trochlear dysplasia were present at all ages (ie, the dysplasia was most likely present at birth and did not necessarily worsen with age and growth).³⁵ The linear dimensions of lateral and medial condylar height as well as trochlear bump increased with age but both the sulcus angle and shape of the trochlea did not change significantly.³⁵ Remodeling of a dysplastic trochlea can happen if the patella is stabilized and appropriately located at a younger age, preferably before 10 years of age.^36,37

Continue to: PATELLAR HEIGHT

The role of patellar height in patellar instability has been well established.³⁸ In patients with patella alta, the patella remains proximal to the TG during the greater arc of knee motion, which predisposes it to patellar instability. Calculation of patellar height in children could be challenging due to incomplete ossification, as well as asymmetric ossification of the patella and the tibial tubercle (TT). Since the patella ossifies from proximal to distal, most radiographic methods that measure the patellar height from the distal aspect of the patella provide a spurious elevation of the measurement.

The Caton-Deschamps (CD) method measures the length of the patellar articular surface and the distance from the inferior edge of the articular surface to the anterosuperior corner of the tibial plateau.³⁹ A ratio >1.3 signifies patella alta. The CD ratio has been verified as a simple and reliable index for measuring patellar height in children.⁴⁰ Two other methods have been described for determining patellar height in children.^41,42 Based on anteroposterior (AP) radiographs of the knee in full extension, Micheli and colleagues⁴¹ calculated the difference between the distance from the superior pole of the patella to the tibial plateau and the length of the patella. A positive difference signified patella alta. The Koshino method involves the ratio between a reference line from the midpoint of the patella to the midpoint of the proximal tibial physis and a second distance from the midpoint of the distal femoral physis to the midpoint of the proximal tibial physis on lateral knee radiographs.⁴² Normal values range from 0.99 to 1.20 with the knee in >30° flexion, in children 3 to 18 years of age.

HYPERLAXITY

In contrast to adults, children have increased levels of collagen III compared with collagen I, which is responsible for tissue elasticity.⁴³ Tissue elasticity leads to increased joint mobility, which is more common in children. Joint hypermobility or hyperlaxity has to be differentiated from symptomatic instability. The traditional Beighton score identifies individuals as having joint hypermobility with a score of 5/9 or higher in school-aged children.^44-46 Smits-Engelsman and colleagues⁴⁴ suggested using stricter criteria with scores of 7/9 or higher being indicative of hyperlaxity in school-aged children. A study of 1845 Swedish school children noted that females have a higher degree of joint laxity.⁴⁵ Maximal laxity was noted in females at 15 years of age.⁴⁵ Hyperlaxity has been demonstrated to be greater on the left side of the body⁴⁴ and can be part of generalized syndromes including Down’s syndrome, Marfan’s syndrome, or Ehlers-Danlos syndrome.

LIMB TORSION

Staheli and colleagues⁴⁷ described the normative values of a lower extremity rotational profile, including femoral anteversion and tibial torsion. Children normally have increased femoral anteversion, which decreases with growth. Miserable malalignment is a term used to denote increased femoral anteversion and increased external tibial torsion.^48,49 These rotational abnormalities can increase the Q angle and the lateral forces on the patella. Femoral anteversion or internal rotation of the femur of 30° significantly increases strain in all areas of the MPFL.⁴⁸ This increased strain may lead to MPFL failure and patellar instability.⁴⁸ Increased internal rotation of the femur also increases contact pressure on the lateral aspect of the patellofemoral joint.⁴⁸ Miserable malalignment frequently manifests following a pubertal growth spurt and may require femoral and tibial osteotomy.⁵⁰

SYNDROMIC ASSOCIATIONS

Several syndromes have patellar instability as a part of their manifestation. The more common syndromes include nail-patella syndrome, Kabuki syndrome, Down’s syndrome, and Rubinstein-Taybi syndrome.^51-54 Other syndromes less commonly associated with patellar instability include Turner syndrome, patella aplasia, or absent patella syndrome. Since many patients with syndromic patellar instability are functionally limited, they may not require an aggressive approach to treatment. When treating these patients, it is important to recognize the unique features of a specific syndrome, which may affect the anesthesia risk profile, management decisions, rehabilitation, and prognosis.

Continue to: MPFL TEAR PATTERN

The MPFL serves as an important constraint to the patella to prevent lateral dislocation, primarily during the first 20° to 30° of knee flexion.^55,56 Injury to the MPFL is noted in over 90% of patients who suffer a patellar dislocation.⁵⁷ The location of MPFL tears in pediatric patients is variably reported at the patellar attachment (10%-61%), femoral attachment (12%-73%), both (12%-35%) or mid-substance (2.5%-15%).^25,57 The most common tear patterns in pediatric patients are tears at the patellar attachment.^25,57 This tear pattern may be accompanied by an avulsion fracture of the medial rim of the patella, though this fracture, being extra-articular, seldom needs treatment.

CLASSIFICATION

While several authors have established extensive classification systems of patellar dislocation based on both clinical and radiographic presentation and reviews of the literature, a single classification system has not been recognized as the gold standard. In this section, in addition to presenting our preferred methods of classification, we will review some of the more recent and extensive classification systems for patellar dislocation and patellar instability.

Dejour and colleagues³¹ initially used both the presence of patellofemoral anatomic abnormalities and pain to define 3 types of patellar instability: major, objective, and potential patellar instability. Major patellar instability indicates that the patient has experienced more than 1 documented dislocation, objective instability involves one dislocation in addition to an associated anatomic abnormality, and potential patellar instability refers to cases in which the patient has radiographic abnormalities and patellar pain.³¹ Garin and colleagues⁵⁸ more simplistically divided patellar dislocation patients into 2 groups: major (permanent or habitual) dislocation of the patella and recurrent dislocation. Sillanpaa⁵⁹ stressed the distinction between first-time dislocation and recurrent dislocation specifically in the context of acute injuries. These classification systems were formulated with adults as the most relevant population; however, classifications targeted specifically to pediatric patients have recently been presented in the literature.

Historically, pediatric patella dislocations were simply categorized as traumatic or congenital.⁶⁰ In 2014, Chotel and colleagues⁶¹ focused on classifying patellar dislocation by extensively reviewing anatomic, biomechanical, pathophysiological, and clinical patterns seen most commonly in children. They included 5 categories: congenital dislocation, permanent dislocation, habitual dislocation during knee flexion, habitual dislocation during knee extension, and recurrent dislocation; however, they did not address traumatic dislocations.⁶¹ Congenital dislocation is a rare condition, typically presenting at birth, which produces a pattern of functional genu valgum.⁶² Permanent dislocation typically presents after the child has started walking, but before the age of 5 years.⁶¹ The 2 variations of habitual dislocation typically present between ages 5 and 8 years.⁶¹ The final category is the most common and typically occurs during pre-adolescence or adolescence as a result of an atraumatic or trivial traumatic event or sports injury.¹ Using more specific terminology, Hiemstra and colleagues⁶³ modeled a classification system based on the traumatic, unilateral, bankart lesion, surgery (TUBS)/atraumatic, multidirectional, bilateral, rehabilitation, inferior shift (AMBRI) for shoulder dislocation classifications. The patellar dislocation system is used to identify 2 distinct subsets of patients in the patellofemoral instability population. One subset is defined by the acronym WARPS (weak, atraumatic, risky anatomy, pain, and subluxation), the other is STAID (strong, traumatic, anatomy normal, instability, and dislocation).⁶⁴ Patients categorized by the WARPS acronym tend to experience atraumatic onsets of patellofemoral instability and demonstrate anatomic issues that increase this instability. These underlying anatomic issues include valgus alignment, ligamentous laxity, rotational abnormalities, shallow and short TG, and patella alta. On the other hand, STAID patients describe a traumatic dislocation event and do not have underlying anatomic abnormalities that predispose them to instability.⁶⁴

Taking into account these previous classifications, Frosch and colleagues⁶⁵ added specific pathologies including “instability,” “maltracking,” and “loss of patellar tracking,” in addition to both clinical and radiographic factors to define 5 types of patellar dislocation and their specific treatment recommendations.⁶⁵ Type 1 involves simple dislocation with neither maltracking nor instability and a low risk of redislocation.⁶⁵ Type 2 is defined as primary dislocation followed by subsequent high risk of dislocation and no maltracking.⁶⁵ Type 3 is divided into 5 subcategories of instability and maltracking issues involving soft tissue contracture, patella alta, pathological tibial tuberosity, and TG distance.⁶⁵ Type 4 is defined as the highly unstable “floating patella,” and type 5 involves patellar maltracking without instability ⁶⁵. In terms of treatment, conservative rehabilitation is recommended for type 1 whereas MPFL reconstruction tends to show positive outcomes for both types 2 and 3.^66-70

Continue to: Parikh and Lykissas recently published...

Parikh and Lykissas recently published a comprehensive classification system of 4 defined types of patellar dislocation in addition to voluntary patellar instability and syndromic patellar instability (Table).⁶⁰ The 4 types are Type 1, first-time patellar dislocation; Type 2, recurrent patellar instability; Type 3, dislocatable; and Type 4, dislocated. Type 2 is further subdivided into Type 2A, which presents with positive apprehension signs, and Type 2B, which involves instabilities related to anatomic abnormalities.⁶⁰ A distinction is also made between Type 3A or passive patellar dislocation and Type 3B habitual patellar dislocation.⁶⁰

The classification system proposed by Green and colleagues is more simplified with 3 main categories (Table) of pediatric patellar dislocation: traumatic (acute or recurrent), obligatory (either in flexion or extension), and fixed laterally.^71,72 The acute traumatic categorization refers to patients who experienced an initial dislocation event due to trauma whereas recurrent traumatic involves repeated patella dislocations following an initial incident. Studies report that between 60% to 70% of these acute traumatic dislocations occur as a result of a sports-related incident.^2,33,73 Obligatory dislocations occur with every episode of either knee flexion or extension, depending on the subtype. Obligatory patella dislocation in flexion typically cannot be manipulated or relocated into the trochlea while the knee is fixed but does reduce into the trochlea in full extension. Fixed lateral dislocations are rare, irreducible dislocations in which the patella stays dislocated laterally in flexion and extension. These dislocations often present with other congenital abnormalities. Each of these categories can be further specified as syndromic if the dislocation is associated with genetic or congenital conditions including skeletal dysplasia, Ehlers-Danlos syndrome, cerebral palsy, Marfan disease, nail-patella syndrome, Down syndrome, Rubenstein-Taybi syndrome, and Kabuki syndrome.^{51-54,61,74-76}

SURGICAL TECHNIQUES IN SKELETALLY IMMATURE PATIENTS

While nonsurgical, conservative treatment involving physical therapy and activity modification is recommended for most patients who experience first-time traumatic patellar dislocations, many patients experience complicating factors that indicate them for surgery. These factors include recurrent dislocation, risk factors for patellofemoral instability, underlying malalignment issues, and congenital deformities. When evaluating these factors, particularly patellofemoral instability, the authors recommend assessing osteochondral lesions, age, skeletal maturity, number of previous dislocations, family history, and anatomic risk factors.^2,5,77-79 Extra care should be taken when considering surgical treatment for skeletally immature patients at elevated risk for recurrent instability as the risk of cartilage damage in these cases is high.^80-82

Recently, there has been a reported increase in surgical treatment for patellar instability in the skeletally immature.⁸³ This finding may be attributed to heightened awareness of factors that indicate patients for surgical treatment and increased familiarity of surgeons with newer techniques.⁸³ Many surgical techniques have been described to address patellar instability involving both soft-tissue procedures and bony corrections.⁸⁴ In this article, we discuss the various surgical techniques for MPFL reconstruction, quadricepsplasty, and distal realignment. These procedures can be paired with any number of additional procedures including, but not limited to, lateral retinacular release or lengthening, chondroplasty, TT osteotomy (in skeletally mature patients), and removal of loose bodies.⁸³

There is a need for more comprehensive studies, particularly randomized controlled trials, to evaluate the outcomes for both surgical and nonsurgical treatments for first-time dislocations. In the current literature, only very recently have surgical treatments shown outcomes that are more positive. In 2009, Nietosvaara and colleagues⁸⁵ conducted a randomized controlled trial of nonoperative and operative treatment of primary acute patellar dislocation in both children and adolescents. After a long-term mean follow-up of 14 years, there was not a significant difference between the groups in recurrent dislocation and instability, subjective outcome, or activity scores.⁸⁵ In a subsequent review of 5 studies including 339 knees, Hing and colleagues⁸⁶ also found similar results in both the operative and nonoperative cohorts at risk of recurrent dislocations, Kujala scores, and reoperations. However, a recent systematic review comparing redislocation rates and clinical outcomes between surgical and conservative management of acute patellar dislocation reported more positive outcomes for the surgical cohort.⁸⁷ This review included 627 knees, 470 of which received conservative management, 157 of which received operative treatment. The conservative cohort was followed for an average of 3.9 years and had a 31% rate of recurrent dislocation while the surgical group was followed for a mean 4.7 years and experienced a 22% redislocation rate.⁸⁷ This study indicates that operative management for acute first-time dislocations may be the preferred treatment option.

Continue to: A potential reason some of these studies...

A potential reason some of these studies did not show any significant difference between the operative and nonoperative cohort could be that the surgical cohorts included a wide range of procedures including lateral releases and MPFL repairs. Recent publications have indicated that these techniques do not produce overall positive outcomes. While each surgical treatment plan is unique depending on the patient; recently, MPFL reconstruction has been shown to have better outcomes than both nonoperative management and simple medial repair and/or lateral
release.^67,88-90

MPFL RECONSTRUCTION

INDICATIONS/OVERVIEW

The MPFL is an important stabilizer for the knee that primarily resists lateral translation of the patella. Damage to the MPFL is very common in acute patellar dislocations with up to 90% of first-time dislocations resulting in injury to the MPFL.^91,92 Historically, simple medial and/or lateral MPFL repairs have not been shown to improve patellofemoral kinematics significantly and often result in recurrence.^90,93 To address this issue, during the past few decades, numerous MPFL reconstruction techniques have been developed to reconstruct a stronger ligament with the same kinematics as the anatomic MPFL.^{2,19,69,81,94-106} The ultimate goal of MPFL reconstruction is to reestablish the anatomic “checkrein” to guide the patella into the trochlea between 0° and 30° of knee flexion.^107,108 An essential secondary surgical goal in skeletally immature patients is to avoid damaging the distal femoral physis.

There are many variations in both the grafts used to replace the MPFL and the means by which to secure them. The ones discussed below include free semitendinosus or gracilis autografts or grafts constructed from a pedicled adductor, patellar, or quadriceps tendon.^69,105,109 While not used as frequently, allografts have also been used.¹¹⁰ Methods to secure these grafts in osseous tunnels include suture anchors or tenodesis screws. Incomplete osseous sockets or medial-sided bone tunnels have also been used as a method to decrease patellar fractures as they preserve the lateral patellar cortex.^111-114

DOUBLE-BUNDLE HAMSTRING AUTOGRAFT

The technique most often used by the author is a double-bundle hamstring autograft harvested from either the semitendinosus or the gracilis secured by short patellar and femoral sockets (Figure 3). After harvesting the hamstring graft from a posteromedial incision, an approximately 90-mm graft is prepared with Krackow stitches to secure 15 mm of the tendon in each socket.¹¹⁵ Lateral radiographs are used intraoperatively to ensure the guidewire for the femoral drill hole falls along the posterior cortex of the diaphysis of the femur while AP radiographs confirm placement distal to the physis. It is important to take both AP and lateral radiographs intraoperatively due to the concave curvature of the distal femoral physis. This unique anatomy can make a point that is located distally to the physis on the AP view appear on or proximal to it on the lateral cross reference view.^24,116 For the patellar socket, 2 short sockets are made in the superior half of the patella. Once the sockets have been drilled, the graft is adjusted so that the patella stays seated in the center of the trochlea between 20° and 30° of flexion. This anchoring is accomplished by securing the graft while the knee is kept at 30° of flexion. Proper tension is confirmed by ensuring that the graft does not allow lateral patella movement over one-fourth the width of the patella in extension while crepitation must not appear throughout the ROM.⁹²

QUADRICPETS TENDON TRANSFER

A combination of techniques by Steensen and colleagues,¹⁰⁵ Goyal,¹⁰⁹ Noyes and Albright,¹¹⁷ and Pinkowsky and Hennrikus¹¹⁸ describe an MPFL reconstruction in which the proximal end of a small medial portion of the quadriceps tendon is released and then attached to the medial epicondyle through a subcutaneous tunnel (Figure 4). This technique is particularly useful for cases in which the extra strength provided by the bone-quadriceps tendon is necessary to correct more severe dysplasia. Leaving the distal end of the quadriceps tendon intact at its patellar insertion, a graft of about 8 mm x 70 mm thickness is harvested from the tendon. The free distal end of the tendon is then run anatomically through the synovium and retinaculum to be either sutured to the medial intermuscular septum at the medial femoral epicondyle or fixed in femoral tunnel using interference screw.^105,109,118 The placement of the femoral fixation point is essential to ensure positive surgical outcomes. If the graft is secured too anteriorly, it may be too loose in extension and too tight in flexion, both of which can lead to postoperative pain, loss of normal kinematics, and overload of the medial patellofemoral cartilage.^119-121 Once the ideal placement of the femoral fixation point has been confirmed by intraoperative radiographs, the graft is secured with a small absorbable suture.^122,123 While this technique has good clinical results, the longitudinal scar that results from graft harvesting is cosmetically unappealing, and it is technically challenging to harvest a consistent strip of the quadriceps tendon. To address some of these concerns, Fink and colleagues¹²⁴ described a new harvesting technique that produces more consistent grafts and requires a smaller incision.

Continue to: ADDUCTOR MAGNUS TENDON TRANSFER

This technique is a double-bundle MPFL reconstruction that uses a pedicled graft of the distal adductor magnus tendon and suture anchors or incomplete osseous sockets to recreate the MPFL anatomically (Figure 5). Avikainen and colleagues⁹⁶ and Sillanpää and colleagues¹²⁵ described this procedure as a progression from the original single-strand adductor magnus transfer technique. First, maintaining the distal insertion, a graft of approximately 14 cm to 18 cm is harvested from the adductor tendon and then passed through a subcutaneous tunnel between the distal vastus medialis obliquus and the superficial joint capsule. The graft is then looped at the medial patella so that the distal bundle runs back to the adductor tubercle.¹²⁵ With the knee at 30° of flexion to assure proper tension, the graft is secured at both the patella and near the adductor tubercle with suture anchors.¹²⁵ Hambridge and colleagues¹²⁶ compared a similar adductor magnus transfer with other pedicled techniques including bone-quadriceps tendon autograft and bone-patellar tendon allograft and found positive results for all 3 methods of reconstruction.

HEMI-PATELLA TENDON TRANSFER

In a similar technique to the adductor tendon transfer, the medial section of the patellar tendon is harvested from the TT and run from its proximal insertion at the medial patella to the medial femoral attachment via a subcutaneous tunnel. The free end of the graft is then secured with suture anchors or incomplete osseous sockets with the knee at 30° of flexion.¹²⁷

HAMSTRING GRAFT WITH ADDUCTOR TENDON AS A PULLEY

Several techniques opt to use a more dynamic model of MPFL reconstruction in which the adductor tendon or medial collateral ligament (MCL) is used as a pulley for the hamstring graft (Figure 6).^128,129 The site of the pulley approximates the normal attachment of the MPFL to the femur and so acts as an effective anatomic replica of the MPFL origin. A semitendinosus graft is harvested and is prepared with continuous sutures, and 2 tunnels to secure the graft are drilled into the patella. The graft is then run subcutaneously from the medial side of the patella to the adductor magnus tubercle into which an osteoperiosteal tunnel is drilled at its distal femoral insertion. The graft is looped through the adductor tunnel and secured with sutures. Proper knee kinematics was ensured by placing the knee at 30° of flexion as the ends of the tendon are secured to the patella.^114,130

HAMSTRING GRAFT WITH MCL AS A PULLEY

The MCL can also be used as a pulley rather than the adductor tendon. The semitendinosus graft is harvested and prepared and the patella drilled as it is in the previous technique. The MCL was fashioned into a pulley by making a slit in its posterior one-third. The semitendinosus graft is looped through this slit, and both ends of the graft are held in place with suture anchors on the surface of the patella.¹²⁹

ADDITIONAL PROCEDURAL COMBINATIONS

Depending on the needs of the individual patient, MPFL reconstruction, and other patellar stabilization techniques can also be combined with additional procedures. Arshi and colleagues⁸³ conducted a review of 6190 adolescents surgically treated for patellar instability and reported the most common additional procedures performed at the time of the stabilization. They found 43.7% of the population underwent lateral retinacular release, which while not effective as an isolated technique to treat patellar instability, has often been used in combination with MPFL reconstruction.^131-133 There is currently a lack of consensus regarding the success of adding a lateral release to the reconstruction. Some studies report no difference while others report a decrease in stability after lateral release.^90,134-136 While lateral retinacular release has been shown to decrease the force required to displace the patella, it can be surgically indicated in certain patients undergoing MPFL reconstruction.¹³¹ The authors advocate that if the lateral retinaculum is tight such that centralized patellar tracking is inhibited following the reconstruction, or if the patella cannot be pushed passively from a laterally tilted position to the neutral horizontal position, lateral retinacular lengthening should be performed to improve kinematics.¹³²

Continue to: Arshi and colleagues...

Arshi and colleagues⁸³ also reported a high rate of cartilage procedures, with chondroplasty performed in 31.1% and chondral fragment/loose body removal in 10.2%. These statistics suggest that a significant level of cartilage damage has occurred by the time of surgery.⁸³

COMPLICATIONS

As MPFL reconstruction techniques have only recently been popularized and developed, there are not many comprehensive studies evaluating the outcomes and complications associated with these procedures. However, in the current literature, there is a general consensus that patients usually experience positive short-term clinical outcomes and relatively low complication rates.^68,77 In one of the largest retrospective cohort studies of pediatric patients undergoing MPFL reconstruction, Parikh and colleagues¹¹⁴ reported both the type and rate of complications. They found complications occurred in 16.2% of patients, and the most common complications were recurrent patellar instability, patellar fractures, patellofemoral arthrosis, motion deficits, and stiffness with over half classified as avoidable. Most of these complications were due to technical errors with episodes of recurrent instability only reported in 4.5% of patients.¹¹⁴ In a comprehensive meta-analysis of MPFL reconstruction studies, Shah and colleagues¹³⁷ reported a complication rate of 26% in both pediatric and adult patients. The cohort was not stratified by age, yet complications were similar to those reported by Parikh and colleagues,¹¹⁴ including pain, loss of knee flexion, wound complications, and patellar fracture.¹³⁷

As indicated by the frequency of technical complications reported by Parikh and colleagues,¹¹⁴ extra caution should be taken in the operating room to minimize potential errors. In techniques that require drilling of femoral sockets, proper length for and placement of the graft is essential to reestablish proper kinematics. Studies have reported that placing the femoral socket too proximally can result in loss of ROM during flexion and increased compressive forces across the patella.¹³⁸ A graft that is too short can have similar negative outcomes, and a graft that is too long can result in recurrent instability. Positioning the graft while the knee is in 30° of flexion can help ensure the proper length and tension is achieved. Once the graft is in place, it is important to ensure the ROM and isometry before completing the fixation.⁷² It is also essential to be vigilant about potential violation of the physes and subsequent growth disturbances. To establish the safest angles for drilling the distal femoral epiphysis for graft placement, Nguyen and colleagues¹³⁹ conducted a study using high-resolution 3-dimensional images of cadaveric distal femoral epiphyses. By recording which tunnels disrupted the physis before reaching 20 mm of depth, the authors concluded that it is safest to drill distally and anteriorly at an angle between 15° and 20°.¹³⁹ This technique should minimize damage to the physis, notch, and distal femoral cartilage and decrease potential complications.¹³⁹

OUTCOMES

In general, the literature reports positive outcomes for MPFL reconstruction—in both studies that address a specific technique and all-encompassing studies. Outcomes are typically reported as Kujala and Tegner scores, results from clinical examinations, and rates of subsequence recurrences. Several recent studies have also evaluated the ability of MPFL reconstruction to restore proper kinematics. Edmonds and colleagues¹⁴⁰ evaluated the difference in patellofemoral joint reaction forces and load experienced by 3 groups of adolescents: a cohort treated with MPFL reconstruction, a cohort treated with soft-tissue realignment of the extensor mechanism (the Insall method), and controls. While both surgical techniques were able to restore medial constraints to the patella, the study showed that only the MPFL reconstruction cohort experienced joint reaction forces that were analogous to the control group. In comparison, the cohort that was treated with soft-tissue realignment alone experienced higher patellofemoral joint reaction forces and did not regain normal joint mechanics.¹⁴⁰ These results can be used to advocate for the further use of MPFL reconstruction as an effective anatomic replacement of the native ligament. Radiographic studies have similarly reported MPFL reconstruction as an effective means to restore anatomic normality. Fabricant and colleagues¹⁴¹ conducted a radiographic study in which patella alta was corrected to normal childhood ranges in patients who underwent MPFL reconstruction technique using a hamstring autograft. Lykissas and colleagues¹⁴² corroborated these results with another radiographic study that reported small but significant decreases in the Blackburne-Peel index and CD index following MPFL reconstruction in 25 adolescents. As correction of patella alta allows the patella to rest in a deeper, more secure position in the TG, these results indicate that effective early MPFL reconstruction can correct for patellar anatomic abnormalities that could be future risk factors.^143,144 Several studies have also reported outcomes addressing specific MPFL techniques; these are reported and discussed in this article.

OUTCOMES BY TECHNIQUE

HAMSTRING AUTOGRAFT

Reports on outcomes following MPFL reconstructions using hamstring autografts have been particularly promising. A cohort of 21 skeletally immature patients who underwent MPFL reconstruction was evaluated pre- and postoperatively with an average of a 2.8-year follow-up. The authors of the study reported no redislocation events and significant improvement in the Kujala scores, and patients were able to return to athletic activities safely.¹⁴⁵ Previous studies report similar positive increases in Kujala scores, subjective patient reports, and lack of subsequent redislocation for patients who underwent either semitendinosus or gracilis autograft MPFL reconstructions. One such study further documented an average patellar inclination angle decrease from 34.3° to 18.6° following MPFL reconstruction.¹⁴⁶ However, while the literature typically reports positive Kujala scores and subjective outcomes for the hamstring autograft procedure, a study arthroscopically evaluating patellar tracking immediately following surgery and then at 6 to 26 months follow-up found that patellar tracking correction was not maintained for all patients who underwent this type of MPFL reconstruction.¹⁴⁷

Continue to: QUADRICEPS TENDON TRANSFER OUTCOMES

Studies specifically evaluating the quadriceps tendon transfer technique for MPFL reconstruction in children are sparse, but authors have reported positive clinical outcomes and low complication rates in adults. After following 32 young adults who underwent this MPFL reconstruction technique for 3 years, Goyal¹⁰⁹ reported a significant increase in mean Kujala scores from 49.31 to 91.25 and no complications or redislocation. He argues this type of quadriceps graft has a high success rate because it is anatomically more similar to the MPFL than other grafts and does not require additional patellar fixation.^101,109 Similar positive Kujala scores and minimal complications have been reported in adult patient populations.¹⁴⁸ Abouelsoud and colleagues¹⁴⁹ conducted one of the few studies in skeletally immature patients and reported similarly positive results with no redislocations and significantly improved Kujala scores at a mean follow-up of 29.25 months in their 16-patient cohorts.

ADDUCTOR MAGNUS TENDON TRANSFER

After initially describing this technique in 14 adult patients, Avikainen and colleagues⁹⁶ followed this cohort and reported positive subjective results and only 1 redislocation. In a more recent study in which the adductor tendon transfer technique was compared with the quadriceps tendon transfer described above and the bone-patellar tendon allograft, Steiner and colleagues⁶⁹ reported similarly significant improvement in all cohorts in Lysholm, Kujala, and Tegner scores with no redislocations. Additionally, Malecki and colleagues¹⁵⁰ followed a cohort of 33 children with 39 knees diagnosed with recurrent patellar dislocation, who underwent MPFL reconstruction using the adductor magnus tendon. After evaluating this cohort functionally and radiographically, the authors reported improvements in Lysholm and Kujala scores, patellar tilt and congruence angles, and peak torque of the quadriceps muscle and flexor.¹⁵⁰ However, this cohort did report postoperative redislocations in 36.4% of patients (4 of 11).¹⁵⁰

HEMI-PATELLA TENDON TRANSFER

In 2012, in the first randomized controlled trial, Bitar and colleagues⁶⁷ compared the outcomes of patients who underwent MPFL reconstruction via the hemi-patellar tendon technique with those who were managed nonoperatively with immobilization and physiotherapy after first-time patellar dislocation. At 2-year follow-up, the surgical cohort presented positive results with a significantly higher mean Kujala score (88.9 to 70.8) and no redislocations or subluxations. In contrast, 35% of nonoperative cases presented with recurrences and subluxations over the 2-year period.⁶⁷

MCL OR ADDUCTOR TENDON AS A PULLEY

Studies have reported good postoperative results and low complication rates for these dynamic techniques.^128,129 In terms of kinematics, while hypermobility and patellar height were not fully corrected, improvements in patellar tilt and lateral shift were reported in a cohort of 6 patients with a minimum 4-year follow-up.¹²⁹ To further evaluate whether the more dynamic pulley reconstruction technique resulted in better outcomes, Gomes and colleagues¹²⁸ compared the subjective reports, clinical evaluations, and complication rates of patients who underwent MPFL reconstruction with a rigid adductor magnus fixation vs a semitendinosus tendon dynamic femoral fixation. One case in the rigid cohort experienced a subsequent subluxation, while patients in the semitendinosus group had better subjective reports and a higher rate of return to sport.¹²⁸ More recently, Kumahashi and colleagues¹⁵¹ specifically studied the outcomes of the MCL tendon as a pulley in 5 patients aged 14 to 15 years. They reported similar successful results as no patients experienced recurrence, and all patients exhibited improvement in radiographic measures of patellar tilt and congruence angle, lateral shift ratio, and both Kujala and Lysholm scores.¹⁵¹

While there has yet to be a randomized controlled trial comparing all of these different techniques, there is a general consensus in the literature that patients tend to perform better following MPFL reconstruction vs MPFL repair.

OTHER STABILIZATION PROCEDURES, INCLUDING DISTAL REALIGNMENT

Patients with additional underlying deficits and malalignment issues such as significant trochlear dysplasia, increased TT-TG distance, patella alta, increased Q angle, and/or positive J sign may require stabilization procedures beyond MPFL reconstruction.^152,153 TT osteotomies are often used to correct alignment issues in the adult patient population; however, these procedures are typically contraindicated in skeletally immature patients. Alternative realignment procedures for the pediatric population include both proximal and distal realignment, with proximal realignment performed primarily in children under the age of 12 years.¹⁵³ Many variations on these procedures exist, some of which are no longer regularly performed due to poor reported outcomes. In this article, we discuss several of the techniques, focusing primarily on those that have demonstrated higher success rates.

Continue to: GALEAZZI TECHNIQUE

One of the first and most famous soft-tissue techniques to address patellar instability was the semitendinosus tenodesis, published by Galeazzi¹⁵⁴ in 1922 (Figure 7). This technique stabilizes the patella without altering the TT. In the original technique, a portion of the semitendinosus tendon is harvested with its tibial insertion left intact. The free end of the tendon is then secured with sutures at the periosteal groove of the medial patella.^154,155 Fiume¹⁵⁶ modified this technique by adding a lateral release and medial retinacular reefing. The most recent addition to this procedure was introduced by Baker and colleagues,¹⁵⁷ in which a tunnel is drilled from the medial to the lateral border of the patella. Tension placed on the grafted tendon is used to reposition the patella medially and draw it downward. Preliminary literature on this modified procedure reported fair clinical results with success rates of approximately 75%.^155,158-160 A recent study evaluating both the clinical and radiographic outcomes of this technique also indicated that while clinical results were excellent in 62.5% of patients, this technique alone was unsuccessful in fully addressing patellar instability in patients with underlying anatomic abnormalities such as patellar alta.¹⁶¹ In light of these less than ideal reports, the authors no longer recommend this technique for patellofemoral instability cases.

ROUX-GOLDTHWAIT PROCEDURE

The Roux-Goldthwait procedure, first described by both Roux¹⁶² and Goldthwait¹⁶³ in 1888 and 1895 respectively, was later modified in 1985 to involve a lateral release, plication of the medial retinaculum, medial transfer of the lateral patellar tendon without advancement, and advancement of the vastus medialis (Figure 8).¹⁶⁴ More recently, Marsh and colleagues¹⁵² introduced an addition to aligning the extensor mechanism with the femoral shaft better. In this technique modification, the patellar tendon is split longitudinally, and its lateral half is detached and transferred distally beneath its medial half. The free end is then sutured to the periosteum on the medial side of the tibia.¹⁵² With a mean long-term follow-up of 6.2 years, Marsh and colleagues¹⁵² reported excellent results in 65%, good in 11%, and fair in 3% of the knees operated on with this modified technique. Of the patients in this cohort whose strength was evaluated, 80% had their strength returned to 90% of preoperative levels in the operated leg.¹⁵² While this study and others report improved outcomes, an increasing body of literature has found high rates of recurrence, patella infera, and other complications following the modified Roux-Goldthwait procedure.^36,165-171 Also, a study comparing MPFL reconstruction using adductus magnus transfer with the Roux-Goldthwait procedure reported that patients in the MPFL cohort reported less pain postoperatively.¹⁵⁰ In addition, whereas the Kujala and Lysholm scores, recurrence rates, patellofemoral angles, and apprehension test results did not demonstrate significant differences between these 2 groups, the MPFL group had significantly fewer abnormal congruence angles, better patellar medialization, and higher peak torque of the hamstring.¹⁵⁰

COMBINED MPFL AND MEDIAL PATELLOTIBIAL LIGAMENT RECONSTRUCTION

While the medial patellotibial ligament (MPTL) has not received much attention with regard to patellar stability, recent studies have indicated its role during higher degrees of both flexion and extension.¹⁷² The MPTL acts as a secondary restrictor ligament which helps release stress on the MPFL by decreasing the Q angle and further normalizing patellar kinematics.¹⁷³ Patients who present with hyperlaxity or knee hyperextension combined with extension subluxation and flexion instability could be indicated for this additional stabilizing procedure. Both Nietosvaara and colleagues⁸⁵ and Brown and Ahmad¹⁷⁴ have described a dual MPTL and MPFL reconstruction technique using a semitendinosus hamstring graft. More recently Hinckel and colleagues¹⁷² described a combined MPFL and MPTL reconstruction, using a graft from the quadriceps tendon to reconstruct the MPFL and one from the patellar tendon to reconstruct the MPTL. In this technique, once the respective grafts have been harvested, a femoral insertion for the graft recreating the MPFL is fluoroscopically established so that an anchor can be inserted distal to the femoral physeal growth plate. For the MPTL insertion, attachment to the tibia below the joint line and 2 cm medial to the patellar tendon is established fluoroscopically just above the physeal growth plate on the proximal epiphysis.^19,175 The MPTL graft is sutured first with the knee at 90° of flexion to establish tension similar to that of the patellar tendon.¹⁷⁶ Then, the knee is placed in 30° of flexion to fix the MPFL graft to the medial patella to prevent excessive lateral translation of the patella.

PATELLAR TENDON TRANSFER

Patellar tendon transfer with proximal realignment is a technique used in particularly young patients to address cases of patellofemoral instability involving concomitant bony or anatomic abnormalities. This procedure is effective for young children with substantial amounts of remaining growth as it better mimics native anatomy than other realignment procedures and does not require bony remodeling.^152-154 It is important to familiarize with surgical techniques to address malalignment issues in young patients as neglected alignment issues can lead to worsening of trochlear dysplasia and instability, which are very difficult to treat later on when patients are older.¹⁵³

The patellar tendon transfer technique (Figure 9), as described by Gordon and Schoenecker,¹⁷⁷ starts with an extensive lateral retinacular release. The patellar tendon is then released from its distal insertion at the TT so that it can be moved medially without moving it inferiorly. After confirming patellar tracking and alignment by flexing the knee from 0° to 90° with the graft in place, the patellar tendon graft is secured with multiple nonabsorbable horizontal sutures.¹⁷⁷ Of note, in skeletally mature patients, a TT osteotomy is used to accomplish the same goal. This osteotomy has been shown to improve both patellar height and TT-TG distance in skeletally mature patients, but is contraindicated in skeletally immature patients.^92,178

Continue to: Initial studies conducted on patellar tendon...

Initial studies conducted on patellar tendon transfer have positive outcomes.¹⁷⁹ At a mean follow-up of 5.1 years, patients reported a decrease in pain and increased the ROM and activity, and only 1 reported a postoperative redislocation.¹⁷⁹ In more recent studies, both Benoit and colleagues³⁶ and Garin and colleagues⁵⁸ reviewed cases of patellar instability treated with patellar tendon transfer to address concomitant patellar alignment and anatomic abnormalities. They reported good functional, clinical, and radiographic outcomes with 12.5% and 16% recurrence rates, respectively.^36,58 They also noted radiographic improvements in femoral sulcus angle, particularly in younger patients, which indicate this procedure is effective in addressing bony abnormalities that can result from neglected malalignment issues.^36,58,154

QUADRICEPSPLASTY

Quadricepsplasty is a lengthening and remodeling technique not frequently used in the pediatric population. The goal of this procedure in patients with significant amounts of growth remaining is to reposition the patella to ameliorate trochlear remodeling and prevent worsening symptoms and anatomic abnormalities.³⁶ A quadricepsplasty accomplishes this by de-rotating and/or lengthening the extensor mechanism and may or may not involve a concomitant MPFL reconstruction. This procedure is particularly effective in young patients who experience obligatory dislocation.^60,72 Several quadricepsplasty techniques have been described including Thompson, Curtis and Fisher, Judet, Stanisavljevic, and V-Y technique.^180-186 Most techniques initially involve sharp dissection of the vastus medialis and lateralis from the rectus femoral tendon. A tongue is then fashioned out of the rectus femoral tendon. Once the vastus medialis and lateralis are detached from the margins of the patella, the knee is extended, and the distal ends of the vasti are sutured to the tongue of the rectus tendon. Effective extension facilitates flexion to 90°.¹⁸⁴ The authors recommend a modification of this technique in which a Z lengthening of the quadriceps tendon is performed after the vastus lateralis is removed distally from the patella and the quadriceps tendon.

Several series and case reports evaluating quadricepsplasty in adult patients report positive outcomes with most patients achieving good or excellent flexion with minimal complications.^{183,185,187-189} Reports on quadricepsplasty used to treat conditions other than patellofemoral instability in children have reported similar positive outcomes.^190-192 As quadricepsplasty for patellar instability is relatively rare in pediatric patients, there is not much relevant literature. However, Kocon and colleagues¹⁹³ reported results of quadricepsplasty and quadricepsplasty combined with the modified Galeazzi procedure in 8 children (10 knees) with a mean follow-up of 3.25 years. Seventy percent of cases resulted in stabilization and correction of patellar position, and only 2 postoperative redislocations were noted.¹⁹³ Additionally, in a study evaluating 6 patients suffering from patellar instability, 2 of whom were obligate dislocators, quadricepsplasty resulted in patellar stability, satisfaction, and near normal gait patterns.¹⁹⁴

Figure 10 shows the surgical algorithm used for patellar instability characteristics.

CONCLUSION

Patellofemoral joint stability relies on a complex interplay of musculotendinous units, ligaments and the osteocartilaginous morphology of the patellofemoral joint. Patellar instability in pediatric patients is different from adults. Having an in-depth understanding of the remodeling potential, the insertion sites for the MPFL and its relationship to the physis are of utmost importance when planning surgery. Reducing and maintaining the patella within the patellofemoral joint early enough can allow for remodeling of the patella and/or the trochlea to provide for lasting stability. Appropriate surgical principles, such as tensioning, can help both prevent continued pain and minimize future complications.

ABSTRACT

Patellar instability in children and adolescents is a challenging subset to treat. Varied forms of instability, ranging from episodic dislocation to fixed dislocation, have been recognized. It is of utmost importance for the treating physician to recognize these different patterns of instability and their associated risk factors, as more complex patterns of instability would require more extensive surgical procedures. Medial patellofemoral ligament (MPFL) reconstruction, by itself, may not suffice or may not be appropriate for the more complex instability patterns. Appropriate and early treatment of such instability in children would allow for functional progression and possible remodeling of the trochlea. However, early treatment has the associated risk of growth disturbances when surgical procedures are performed around open physis or if adult-type bony procedures are performed in children. Recent knowledge about the relationship between trochlea, MPFL femoral attachment, and distal femoral physis could help to advance safe surgical care for these patients. This article reviews the pathophysiology, risk factors, and the existing classification systems for patellar instability in children and adolescents. It focuses on varied surgical techniques, which are unique to the pediatric population, and summarizes the outcomes of these surgical techniques.

Continue to: EPIDEMIOLOGY

EPIDEMIOLOGY

In a prospective 2-year study of Finnish children, the annual incidence rate of patellar instability was 43/100,000 pediatric population.¹ In patients 9 to 15 years of age, the incidence was approximately 1/1000.¹ In another study, patients at highest risk for a first-time patellar dislocation were females aged 10 to 17 years.² In a study in patients with traumatic hemarthrosis, 36% in the younger age group (10-14 years) and 28% in the older age group (15-18 years) had sustained patellar dislocation. In contrast, 22% in the younger age group and 40% in the older age group had sustained an anterior cruciate ligament tear.³

Approximately one-half of patients who dislocate their patella suffer from long-term complications.^4,5 These complications include recurrent instability, patellofemoral pain, osteochondral lesions, and eventual arthritis.^1,4,5 Young, active individuals are more prone to these issues.⁶ Also, 39% or more of patellar dislocation patients have an associated osteochondral fracture that might influence the management.¹ Thus, patellar instability in young patients is an area of concern.

DEVELOPMENTAL ANATOMY

At 4-week gestation, the patellofemoral joint is an ectodermal sac filled with mesenchyme of the somatic mesoderm.⁷ Mesenchymal condensations then appear at 4 to 5 weeks gestation, followed by chondrification of both the femur and patella.⁷ The joint space is present by 6 weeks, and the patellar and distal femoral condyles are present at 7 weeks gestation.⁷ By 8 weeks gestation, the basic knee anatomy resembles that of an adult with the chondroepiphysis forming the articular surfaces of the femur, tibia, and patella.⁷ By this time, the extensor mechanism is formed, and active joint motion has begun, facilitating the development of the trochlear sulcus.⁷ The secondary ossification center in the distal femoral epiphysis forms around 36 weeks gestation.⁸ Postnatally, both the patella and distal femur grow through endochondral ossification.^9,10

The patella is the largest sesamoid bone in the human body.¹¹ The patella begins as a dense consolidation of cells that differentiate as the quadriceps mechanisms develop.^12,13 The patellar anlage becomes distinguishable within the quadriceps tendon around 7.5-week gestation.¹² The morphology of the patella conforms to the distal femur.¹² The patella molds or re-models as the knee begins to move in response to mechanical stresses.⁷ The patella increases in relative size during the first 6 months of gestation, then enlarges proportionately to the rest of the bones.⁷ Ossification begins around 3 years of age for females and 4 to 5 years of age for males.^8,14 The ossification center may appear irregular as it rapidly expands.¹⁴ Ossification proceeds in a proximal to distal direction, thus giving a spurious estimation of patellar height on radiographs in children. The overall morphology of the cartilaginous patella during development is comparable to the final mature shape.¹⁴ Abnormal contact stresses on the articular surface of the patella during skeletal immaturity can lead to deformation.⁷

Ultrasonographic measurements in normal patients show that trochlear groove (TG) morphology is present early and becomes more radiographically apparent as distal femoral ossification is completed.¹⁵ Anatomic dissections of aborted fetuses have verified the morphology of the TG as it remains constant during growth and the groove morphology is the same for both fetuses and adults.¹⁶ An ultrasound study performed on patients aged 12 to 18 years showed the cartilaginous sulcus angle (CSA) remained constant throughout all age groups (146°).¹⁷ The CSA however, differed in patients who suffered a patellar dislocation (average, 164°; range, 154°-195°) compared with normal knees (average CSA, 145°; range, 131°-158°).^15,17,18 The osseous sulcus angle, on the other hand, appears flat at birth and the TG deepens with age. This increase in depth is more of a reflection of progressive ossification of a well-formed cartilaginous trochlea, rather than a true deepening of the sulcus.¹⁷ Thus, the axial radiographic view of the patella provides misleading information about the sulcus angle in children and should not be used to define trochlear morphology.

Continue to: MEDIAL PATELLOFEMORAL LIGAMENT ANATOMY

The medial patellofemoral ligament (MPFL) functions to limit the lateral translation of the patella.¹⁹ The attachment sites on the femur and patella for the MPFL have been studied in children.^20-23 Cadaveric dissections in specimens aged 2 to 11 years have noted the patellar attachment to be an average of 12 mm in length with the midpoint approximately 5 mm superior to the mid-pole of the patella.²² The patellar footprint of the MPFL insertion was a mean 41% of the entire patellar length.²²

It is important to be aware of the characteristic anatomy of the MPFL, as fixation points should mimic the anatomic insertion as best as possible while also avoiding violation of the nearby physis. The MPFL originates between the adductor tubercle and the medial femoral epicondyle just distal to the distal femoral physis and attaches to the superomedial aspect of the patella.^20-25 In relation to the physis in pediatric patients, the midpoint of MPFL insertion has been measured to be 4 mm to 9 mm distal to the femoral physis.^21,24,25 These measurements represent averages as cadaveric studies have reported that some part of MPFL femoral insertion extends proximal to the distal femoral physis.²¹ A recent report of physeal injury to the posterior distal femoral physis during MPFL reconstruction leading to femoral flexion deformity highlights the importance of physeal-respecting surgery.²⁶

TROCHLEA AND ANTERIOR DISTAL FEMORAL PHYSIS

The relationship between the proximal aspect of the trochlea and the anterior distal femoral physis has been recently studied in 175 knees with dysplastic trochlea.²⁷ Based on magnetic resonance imaging evaluation, the lateral aspect of the trochlea extended proximal to the anterior distal femoral physis in 13% of patients and was at the level of the anterior physis in another 13% of patients (Figure 1).²⁷ Hence, a cautious approach is recommended for any surgery to address trochlear dysplasia or trochlear bump in younger patients to prevent iatrogenic injury to anterior distal femoral physis and resultant genu recurvatum. The distance between the trochlea and the physis increased with increasing age.

LIMB ALIGNMENT

Physiologically, the quadriceps angle (Q angle) changes through the course of growth. As children begin standing and walking, they stand with their feet wider apart and in genu varum.²⁸ Physiologic genu varum can reach 15°.²⁸ This degree lessens during the first 1.5 to 2 years of life, transitioning to physiologic valgus of nearly 12° by 3 years of age.²⁸ Genu valgum, thereafter, gradually decreases to reach the adult value of around 7° to 8° by age 7 years.²⁸ Increased genu valgum is a risk factor for patellar instability. In skeletally immature patients, correction of genu valgum through guided growth may be desirable in patients undergoing patellar stabilization surgery (Figures 2A, 2B).²⁹

PATHOPHYSIOLOGY OF PEDIATRIC PATELLAR DISLOCATION

TROCHLEAR DYSPLASIA

Trochlear dysplasia is an abnormal shape and depth of the TG.³⁰ Up to 96% of patients with patellar dislocation have trochlear dysplasia.^30-33 In a study of patellar instability in children, at least 1 of the 3 signs of trochlear dysplasia (the crossing sign, supratrochlear bump, and double contour sign) was present on lateral radiographs.³⁴ In another study on the growth of trochlear dysplasia in children and adolescents, all grades of trochlear dysplasia were present at all ages (ie, the dysplasia was most likely present at birth and did not necessarily worsen with age and growth).³⁵ The linear dimensions of lateral and medial condylar height as well as trochlear bump increased with age but both the sulcus angle and shape of the trochlea did not change significantly.³⁵ Remodeling of a dysplastic trochlea can happen if the patella is stabilized and appropriately located at a younger age, preferably before 10 years of age.^36,37

Continue to: PATELLAR HEIGHT

The role of patellar height in patellar instability has been well established.³⁸ In patients with patella alta, the patella remains proximal to the TG during the greater arc of knee motion, which predisposes it to patellar instability. Calculation of patellar height in children could be challenging due to incomplete ossification, as well as asymmetric ossification of the patella and the tibial tubercle (TT). Since the patella ossifies from proximal to distal, most radiographic methods that measure the patellar height from the distal aspect of the patella provide a spurious elevation of the measurement.

The Caton-Deschamps (CD) method measures the length of the patellar articular surface and the distance from the inferior edge of the articular surface to the anterosuperior corner of the tibial plateau.³⁹ A ratio >1.3 signifies patella alta. The CD ratio has been verified as a simple and reliable index for measuring patellar height in children.⁴⁰ Two other methods have been described for determining patellar height in children.^41,42 Based on anteroposterior (AP) radiographs of the knee in full extension, Micheli and colleagues⁴¹ calculated the difference between the distance from the superior pole of the patella to the tibial plateau and the length of the patella. A positive difference signified patella alta. The Koshino method involves the ratio between a reference line from the midpoint of the patella to the midpoint of the proximal tibial physis and a second distance from the midpoint of the distal femoral physis to the midpoint of the proximal tibial physis on lateral knee radiographs.⁴² Normal values range from 0.99 to 1.20 with the knee in >30° flexion, in children 3 to 18 years of age.

HYPERLAXITY

In contrast to adults, children have increased levels of collagen III compared with collagen I, which is responsible for tissue elasticity.⁴³ Tissue elasticity leads to increased joint mobility, which is more common in children. Joint hypermobility or hyperlaxity has to be differentiated from symptomatic instability. The traditional Beighton score identifies individuals as having joint hypermobility with a score of 5/9 or higher in school-aged children.^44-46 Smits-Engelsman and colleagues⁴⁴ suggested using stricter criteria with scores of 7/9 or higher being indicative of hyperlaxity in school-aged children. A study of 1845 Swedish school children noted that females have a higher degree of joint laxity.⁴⁵ Maximal laxity was noted in females at 15 years of age.⁴⁵ Hyperlaxity has been demonstrated to be greater on the left side of the body⁴⁴ and can be part of generalized syndromes including Down’s syndrome, Marfan’s syndrome, or Ehlers-Danlos syndrome.

LIMB TORSION

Staheli and colleagues⁴⁷ described the normative values of a lower extremity rotational profile, including femoral anteversion and tibial torsion. Children normally have increased femoral anteversion, which decreases with growth. Miserable malalignment is a term used to denote increased femoral anteversion and increased external tibial torsion.^48,49 These rotational abnormalities can increase the Q angle and the lateral forces on the patella. Femoral anteversion or internal rotation of the femur of 30° significantly increases strain in all areas of the MPFL.⁴⁸ This increased strain may lead to MPFL failure and patellar instability.⁴⁸ Increased internal rotation of the femur also increases contact pressure on the lateral aspect of the patellofemoral joint.⁴⁸ Miserable malalignment frequently manifests following a pubertal growth spurt and may require femoral and tibial osteotomy.⁵⁰

SYNDROMIC ASSOCIATIONS

Several syndromes have patellar instability as a part of their manifestation. The more common syndromes include nail-patella syndrome, Kabuki syndrome, Down’s syndrome, and Rubinstein-Taybi syndrome.^51-54 Other syndromes less commonly associated with patellar instability include Turner syndrome, patella aplasia, or absent patella syndrome. Since many patients with syndromic patellar instability are functionally limited, they may not require an aggressive approach to treatment. When treating these patients, it is important to recognize the unique features of a specific syndrome, which may affect the anesthesia risk profile, management decisions, rehabilitation, and prognosis.

Continue to: MPFL TEAR PATTERN

The MPFL serves as an important constraint to the patella to prevent lateral dislocation, primarily during the first 20° to 30° of knee flexion.^55,56 Injury to the MPFL is noted in over 90% of patients who suffer a patellar dislocation.⁵⁷ The location of MPFL tears in pediatric patients is variably reported at the patellar attachment (10%-61%), femoral attachment (12%-73%), both (12%-35%) or mid-substance (2.5%-15%).^25,57 The most common tear patterns in pediatric patients are tears at the patellar attachment.^25,57 This tear pattern may be accompanied by an avulsion fracture of the medial rim of the patella, though this fracture, being extra-articular, seldom needs treatment.

CLASSIFICATION

While several authors have established extensive classification systems of patellar dislocation based on both clinical and radiographic presentation and reviews of the literature, a single classification system has not been recognized as the gold standard. In this section, in addition to presenting our preferred methods of classification, we will review some of the more recent and extensive classification systems for patellar dislocation and patellar instability.

Dejour and colleagues³¹ initially used both the presence of patellofemoral anatomic abnormalities and pain to define 3 types of patellar instability: major, objective, and potential patellar instability. Major patellar instability indicates that the patient has experienced more than 1 documented dislocation, objective instability involves one dislocation in addition to an associated anatomic abnormality, and potential patellar instability refers to cases in which the patient has radiographic abnormalities and patellar pain.³¹ Garin and colleagues⁵⁸ more simplistically divided patellar dislocation patients into 2 groups: major (permanent or habitual) dislocation of the patella and recurrent dislocation. Sillanpaa⁵⁹ stressed the distinction between first-time dislocation and recurrent dislocation specifically in the context of acute injuries. These classification systems were formulated with adults as the most relevant population; however, classifications targeted specifically to pediatric patients have recently been presented in the literature.

Historically, pediatric patella dislocations were simply categorized as traumatic or congenital.⁶⁰ In 2014, Chotel and colleagues⁶¹ focused on classifying patellar dislocation by extensively reviewing anatomic, biomechanical, pathophysiological, and clinical patterns seen most commonly in children. They included 5 categories: congenital dislocation, permanent dislocation, habitual dislocation during knee flexion, habitual dislocation during knee extension, and recurrent dislocation; however, they did not address traumatic dislocations.⁶¹ Congenital dislocation is a rare condition, typically presenting at birth, which produces a pattern of functional genu valgum.⁶² Permanent dislocation typically presents after the child has started walking, but before the age of 5 years.⁶¹ The 2 variations of habitual dislocation typically present between ages 5 and 8 years.⁶¹ The final category is the most common and typically occurs during pre-adolescence or adolescence as a result of an atraumatic or trivial traumatic event or sports injury.¹ Using more specific terminology, Hiemstra and colleagues⁶³ modeled a classification system based on the traumatic, unilateral, bankart lesion, surgery (TUBS)/atraumatic, multidirectional, bilateral, rehabilitation, inferior shift (AMBRI) for shoulder dislocation classifications. The patellar dislocation system is used to identify 2 distinct subsets of patients in the patellofemoral instability population. One subset is defined by the acronym WARPS (weak, atraumatic, risky anatomy, pain, and subluxation), the other is STAID (strong, traumatic, anatomy normal, instability, and dislocation).⁶⁴ Patients categorized by the WARPS acronym tend to experience atraumatic onsets of patellofemoral instability and demonstrate anatomic issues that increase this instability. These underlying anatomic issues include valgus alignment, ligamentous laxity, rotational abnormalities, shallow and short TG, and patella alta. On the other hand, STAID patients describe a traumatic dislocation event and do not have underlying anatomic abnormalities that predispose them to instability.⁶⁴

Taking into account these previous classifications, Frosch and colleagues⁶⁵ added specific pathologies including “instability,” “maltracking,” and “loss of patellar tracking,” in addition to both clinical and radiographic factors to define 5 types of patellar dislocation and their specific treatment recommendations.⁶⁵ Type 1 involves simple dislocation with neither maltracking nor instability and a low risk of redislocation.⁶⁵ Type 2 is defined as primary dislocation followed by subsequent high risk of dislocation and no maltracking.⁶⁵ Type 3 is divided into 5 subcategories of instability and maltracking issues involving soft tissue contracture, patella alta, pathological tibial tuberosity, and TG distance.⁶⁵ Type 4 is defined as the highly unstable “floating patella,” and type 5 involves patellar maltracking without instability ⁶⁵. In terms of treatment, conservative rehabilitation is recommended for type 1 whereas MPFL reconstruction tends to show positive outcomes for both types 2 and 3.^66-70

Continue to: Parikh and Lykissas recently published...

Parikh and Lykissas recently published a comprehensive classification system of 4 defined types of patellar dislocation in addition to voluntary patellar instability and syndromic patellar instability (Table).⁶⁰ The 4 types are Type 1, first-time patellar dislocation; Type 2, recurrent patellar instability; Type 3, dislocatable; and Type 4, dislocated. Type 2 is further subdivided into Type 2A, which presents with positive apprehension signs, and Type 2B, which involves instabilities related to anatomic abnormalities.⁶⁰ A distinction is also made between Type 3A or passive patellar dislocation and Type 3B habitual patellar dislocation.⁶⁰

The classification system proposed by Green and colleagues is more simplified with 3 main categories (Table) of pediatric patellar dislocation: traumatic (acute or recurrent), obligatory (either in flexion or extension), and fixed laterally.^71,72 The acute traumatic categorization refers to patients who experienced an initial dislocation event due to trauma whereas recurrent traumatic involves repeated patella dislocations following an initial incident. Studies report that between 60% to 70% of these acute traumatic dislocations occur as a result of a sports-related incident.^2,33,73 Obligatory dislocations occur with every episode of either knee flexion or extension, depending on the subtype. Obligatory patella dislocation in flexion typically cannot be manipulated or relocated into the trochlea while the knee is fixed but does reduce into the trochlea in full extension. Fixed lateral dislocations are rare, irreducible dislocations in which the patella stays dislocated laterally in flexion and extension. These dislocations often present with other congenital abnormalities. Each of these categories can be further specified as syndromic if the dislocation is associated with genetic or congenital conditions including skeletal dysplasia, Ehlers-Danlos syndrome, cerebral palsy, Marfan disease, nail-patella syndrome, Down syndrome, Rubenstein-Taybi syndrome, and Kabuki syndrome.^{51-54,61,74-76}

SURGICAL TECHNIQUES IN SKELETALLY IMMATURE PATIENTS

While nonsurgical, conservative treatment involving physical therapy and activity modification is recommended for most patients who experience first-time traumatic patellar dislocations, many patients experience complicating factors that indicate them for surgery. These factors include recurrent dislocation, risk factors for patellofemoral instability, underlying malalignment issues, and congenital deformities. When evaluating these factors, particularly patellofemoral instability, the authors recommend assessing osteochondral lesions, age, skeletal maturity, number of previous dislocations, family history, and anatomic risk factors.^2,5,77-79 Extra care should be taken when considering surgical treatment for skeletally immature patients at elevated risk for recurrent instability as the risk of cartilage damage in these cases is high.^80-82

Recently, there has been a reported increase in surgical treatment for patellar instability in the skeletally immature.⁸³ This finding may be attributed to heightened awareness of factors that indicate patients for surgical treatment and increased familiarity of surgeons with newer techniques.⁸³ Many surgical techniques have been described to address patellar instability involving both soft-tissue procedures and bony corrections.⁸⁴ In this article, we discuss the various surgical techniques for MPFL reconstruction, quadricepsplasty, and distal realignment. These procedures can be paired with any number of additional procedures including, but not limited to, lateral retinacular release or lengthening, chondroplasty, TT osteotomy (in skeletally mature patients), and removal of loose bodies.⁸³

There is a need for more comprehensive studies, particularly randomized controlled trials, to evaluate the outcomes for both surgical and nonsurgical treatments for first-time dislocations. In the current literature, only very recently have surgical treatments shown outcomes that are more positive. In 2009, Nietosvaara and colleagues⁸⁵ conducted a randomized controlled trial of nonoperative and operative treatment of primary acute patellar dislocation in both children and adolescents. After a long-term mean follow-up of 14 years, there was not a significant difference between the groups in recurrent dislocation and instability, subjective outcome, or activity scores.⁸⁵ In a subsequent review of 5 studies including 339 knees, Hing and colleagues⁸⁶ also found similar results in both the operative and nonoperative cohorts at risk of recurrent dislocations, Kujala scores, and reoperations. However, a recent systematic review comparing redislocation rates and clinical outcomes between surgical and conservative management of acute patellar dislocation reported more positive outcomes for the surgical cohort.⁸⁷ This review included 627 knees, 470 of which received conservative management, 157 of which received operative treatment. The conservative cohort was followed for an average of 3.9 years and had a 31% rate of recurrent dislocation while the surgical group was followed for a mean 4.7 years and experienced a 22% redislocation rate.⁸⁷ This study indicates that operative management for acute first-time dislocations may be the preferred treatment option.

Continue to: A potential reason some of these studies...

A potential reason some of these studies did not show any significant difference between the operative and nonoperative cohort could be that the surgical cohorts included a wide range of procedures including lateral releases and MPFL repairs. Recent publications have indicated that these techniques do not produce overall positive outcomes. While each surgical treatment plan is unique depending on the patient; recently, MPFL reconstruction has been shown to have better outcomes than both nonoperative management and simple medial repair and/or lateral
release.^67,88-90

MPFL RECONSTRUCTION

INDICATIONS/OVERVIEW

The MPFL is an important stabilizer for the knee that primarily resists lateral translation of the patella. Damage to the MPFL is very common in acute patellar dislocations with up to 90% of first-time dislocations resulting in injury to the MPFL.^91,92 Historically, simple medial and/or lateral MPFL repairs have not been shown to improve patellofemoral kinematics significantly and often result in recurrence.^90,93 To address this issue, during the past few decades, numerous MPFL reconstruction techniques have been developed to reconstruct a stronger ligament with the same kinematics as the anatomic MPFL.^{2,19,69,81,94-106} The ultimate goal of MPFL reconstruction is to reestablish the anatomic “checkrein” to guide the patella into the trochlea between 0° and 30° of knee flexion.^107,108 An essential secondary surgical goal in skeletally immature patients is to avoid damaging the distal femoral physis.

There are many variations in both the grafts used to replace the MPFL and the means by which to secure them. The ones discussed below include free semitendinosus or gracilis autografts or grafts constructed from a pedicled adductor, patellar, or quadriceps tendon.^69,105,109 While not used as frequently, allografts have also been used.¹¹⁰ Methods to secure these grafts in osseous tunnels include suture anchors or tenodesis screws. Incomplete osseous sockets or medial-sided bone tunnels have also been used as a method to decrease patellar fractures as they preserve the lateral patellar cortex.^111-114

DOUBLE-BUNDLE HAMSTRING AUTOGRAFT

The technique most often used by the author is a double-bundle hamstring autograft harvested from either the semitendinosus or the gracilis secured by short patellar and femoral sockets (Figure 3). After harvesting the hamstring graft from a posteromedial incision, an approximately 90-mm graft is prepared with Krackow stitches to secure 15 mm of the tendon in each socket.¹¹⁵ Lateral radiographs are used intraoperatively to ensure the guidewire for the femoral drill hole falls along the posterior cortex of the diaphysis of the femur while AP radiographs confirm placement distal to the physis. It is important to take both AP and lateral radiographs intraoperatively due to the concave curvature of the distal femoral physis. This unique anatomy can make a point that is located distally to the physis on the AP view appear on or proximal to it on the lateral cross reference view.^24,116 For the patellar socket, 2 short sockets are made in the superior half of the patella. Once the sockets have been drilled, the graft is adjusted so that the patella stays seated in the center of the trochlea between 20° and 30° of flexion. This anchoring is accomplished by securing the graft while the knee is kept at 30° of flexion. Proper tension is confirmed by ensuring that the graft does not allow lateral patella movement over one-fourth the width of the patella in extension while crepitation must not appear throughout the ROM.⁹²

QUADRICPETS TENDON TRANSFER

A combination of techniques by Steensen and colleagues,¹⁰⁵ Goyal,¹⁰⁹ Noyes and Albright,¹¹⁷ and Pinkowsky and Hennrikus¹¹⁸ describe an MPFL reconstruction in which the proximal end of a small medial portion of the quadriceps tendon is released and then attached to the medial epicondyle through a subcutaneous tunnel (Figure 4). This technique is particularly useful for cases in which the extra strength provided by the bone-quadriceps tendon is necessary to correct more severe dysplasia. Leaving the distal end of the quadriceps tendon intact at its patellar insertion, a graft of about 8 mm x 70 mm thickness is harvested from the tendon. The free distal end of the tendon is then run anatomically through the synovium and retinaculum to be either sutured to the medial intermuscular septum at the medial femoral epicondyle or fixed in femoral tunnel using interference screw.^105,109,118 The placement of the femoral fixation point is essential to ensure positive surgical outcomes. If the graft is secured too anteriorly, it may be too loose in extension and too tight in flexion, both of which can lead to postoperative pain, loss of normal kinematics, and overload of the medial patellofemoral cartilage.^119-121 Once the ideal placement of the femoral fixation point has been confirmed by intraoperative radiographs, the graft is secured with a small absorbable suture.^122,123 While this technique has good clinical results, the longitudinal scar that results from graft harvesting is cosmetically unappealing, and it is technically challenging to harvest a consistent strip of the quadriceps tendon. To address some of these concerns, Fink and colleagues¹²⁴ described a new harvesting technique that produces more consistent grafts and requires a smaller incision.

Continue to: ADDUCTOR MAGNUS TENDON TRANSFER

This technique is a double-bundle MPFL reconstruction that uses a pedicled graft of the distal adductor magnus tendon and suture anchors or incomplete osseous sockets to recreate the MPFL anatomically (Figure 5). Avikainen and colleagues⁹⁶ and Sillanpää and colleagues¹²⁵ described this procedure as a progression from the original single-strand adductor magnus transfer technique. First, maintaining the distal insertion, a graft of approximately 14 cm to 18 cm is harvested from the adductor tendon and then passed through a subcutaneous tunnel between the distal vastus medialis obliquus and the superficial joint capsule. The graft is then looped at the medial patella so that the distal bundle runs back to the adductor tubercle.¹²⁵ With the knee at 30° of flexion to assure proper tension, the graft is secured at both the patella and near the adductor tubercle with suture anchors.¹²⁵ Hambridge and colleagues¹²⁶ compared a similar adductor magnus transfer with other pedicled techniques including bone-quadriceps tendon autograft and bone-patellar tendon allograft and found positive results for all 3 methods of reconstruction.

HEMI-PATELLA TENDON TRANSFER

In a similar technique to the adductor tendon transfer, the medial section of the patellar tendon is harvested from the TT and run from its proximal insertion at the medial patella to the medial femoral attachment via a subcutaneous tunnel. The free end of the graft is then secured with suture anchors or incomplete osseous sockets with the knee at 30° of flexion.¹²⁷

HAMSTRING GRAFT WITH ADDUCTOR TENDON AS A PULLEY

Several techniques opt to use a more dynamic model of MPFL reconstruction in which the adductor tendon or medial collateral ligament (MCL) is used as a pulley for the hamstring graft (Figure 6).^128,129 The site of the pulley approximates the normal attachment of the MPFL to the femur and so acts as an effective anatomic replica of the MPFL origin. A semitendinosus graft is harvested and is prepared with continuous sutures, and 2 tunnels to secure the graft are drilled into the patella. The graft is then run subcutaneously from the medial side of the patella to the adductor magnus tubercle into which an osteoperiosteal tunnel is drilled at its distal femoral insertion. The graft is looped through the adductor tunnel and secured with sutures. Proper knee kinematics was ensured by placing the knee at 30° of flexion as the ends of the tendon are secured to the patella.^114,130

HAMSTRING GRAFT WITH MCL AS A PULLEY

The MCL can also be used as a pulley rather than the adductor tendon. The semitendinosus graft is harvested and prepared and the patella drilled as it is in the previous technique. The MCL was fashioned into a pulley by making a slit in its posterior one-third. The semitendinosus graft is looped through this slit, and both ends of the graft are held in place with suture anchors on the surface of the patella.¹²⁹

ADDITIONAL PROCEDURAL COMBINATIONS

Depending on the needs of the individual patient, MPFL reconstruction, and other patellar stabilization techniques can also be combined with additional procedures. Arshi and colleagues⁸³ conducted a review of 6190 adolescents surgically treated for patellar instability and reported the most common additional procedures performed at the time of the stabilization. They found 43.7% of the population underwent lateral retinacular release, which while not effective as an isolated technique to treat patellar instability, has often been used in combination with MPFL reconstruction.^131-133 There is currently a lack of consensus regarding the success of adding a lateral release to the reconstruction. Some studies report no difference while others report a decrease in stability after lateral release.^90,134-136 While lateral retinacular release has been shown to decrease the force required to displace the patella, it can be surgically indicated in certain patients undergoing MPFL reconstruction.¹³¹ The authors advocate that if the lateral retinaculum is tight such that centralized patellar tracking is inhibited following the reconstruction, or if the patella cannot be pushed passively from a laterally tilted position to the neutral horizontal position, lateral retinacular lengthening should be performed to improve kinematics.¹³²

Continue to: Arshi and colleagues...

Arshi and colleagues⁸³ also reported a high rate of cartilage procedures, with chondroplasty performed in 31.1% and chondral fragment/loose body removal in 10.2%. These statistics suggest that a significant level of cartilage damage has occurred by the time of surgery.⁸³

COMPLICATIONS

As MPFL reconstruction techniques have only recently been popularized and developed, there are not many comprehensive studies evaluating the outcomes and complications associated with these procedures. However, in the current literature, there is a general consensus that patients usually experience positive short-term clinical outcomes and relatively low complication rates.^68,77 In one of the largest retrospective cohort studies of pediatric patients undergoing MPFL reconstruction, Parikh and colleagues¹¹⁴ reported both the type and rate of complications. They found complications occurred in 16.2% of patients, and the most common complications were recurrent patellar instability, patellar fractures, patellofemoral arthrosis, motion deficits, and stiffness with over half classified as avoidable. Most of these complications were due to technical errors with episodes of recurrent instability only reported in 4.5% of patients.¹¹⁴ In a comprehensive meta-analysis of MPFL reconstruction studies, Shah and colleagues¹³⁷ reported a complication rate of 26% in both pediatric and adult patients. The cohort was not stratified by age, yet complications were similar to those reported by Parikh and colleagues,¹¹⁴ including pain, loss of knee flexion, wound complications, and patellar fracture.¹³⁷

As indicated by the frequency of technical complications reported by Parikh and colleagues,¹¹⁴ extra caution should be taken in the operating room to minimize potential errors. In techniques that require drilling of femoral sockets, proper length for and placement of the graft is essential to reestablish proper kinematics. Studies have reported that placing the femoral socket too proximally can result in loss of ROM during flexion and increased compressive forces across the patella.¹³⁸ A graft that is too short can have similar negative outcomes, and a graft that is too long can result in recurrent instability. Positioning the graft while the knee is in 30° of flexion can help ensure the proper length and tension is achieved. Once the graft is in place, it is important to ensure the ROM and isometry before completing the fixation.⁷² It is also essential to be vigilant about potential violation of the physes and subsequent growth disturbances. To establish the safest angles for drilling the distal femoral epiphysis for graft placement, Nguyen and colleagues¹³⁹ conducted a study using high-resolution 3-dimensional images of cadaveric distal femoral epiphyses. By recording which tunnels disrupted the physis before reaching 20 mm of depth, the authors concluded that it is safest to drill distally and anteriorly at an angle between 15° and 20°.¹³⁹ This technique should minimize damage to the physis, notch, and distal femoral cartilage and decrease potential complications.¹³⁹

OUTCOMES

In general, the literature reports positive outcomes for MPFL reconstruction—in both studies that address a specific technique and all-encompassing studies. Outcomes are typically reported as Kujala and Tegner scores, results from clinical examinations, and rates of subsequence recurrences. Several recent studies have also evaluated the ability of MPFL reconstruction to restore proper kinematics. Edmonds and colleagues¹⁴⁰ evaluated the difference in patellofemoral joint reaction forces and load experienced by 3 groups of adolescents: a cohort treated with MPFL reconstruction, a cohort treated with soft-tissue realignment of the extensor mechanism (the Insall method), and controls. While both surgical techniques were able to restore medial constraints to the patella, the study showed that only the MPFL reconstruction cohort experienced joint reaction forces that were analogous to the control group. In comparison, the cohort that was treated with soft-tissue realignment alone experienced higher patellofemoral joint reaction forces and did not regain normal joint mechanics.¹⁴⁰ These results can be used to advocate for the further use of MPFL reconstruction as an effective anatomic replacement of the native ligament. Radiographic studies have similarly reported MPFL reconstruction as an effective means to restore anatomic normality. Fabricant and colleagues¹⁴¹ conducted a radiographic study in which patella alta was corrected to normal childhood ranges in patients who underwent MPFL reconstruction technique using a hamstring autograft. Lykissas and colleagues¹⁴² corroborated these results with another radiographic study that reported small but significant decreases in the Blackburne-Peel index and CD index following MPFL reconstruction in 25 adolescents. As correction of patella alta allows the patella to rest in a deeper, more secure position in the TG, these results indicate that effective early MPFL reconstruction can correct for patellar anatomic abnormalities that could be future risk factors.^143,144 Several studies have also reported outcomes addressing specific MPFL techniques; these are reported and discussed in this article.

OUTCOMES BY TECHNIQUE

HAMSTRING AUTOGRAFT

Reports on outcomes following MPFL reconstructions using hamstring autografts have been particularly promising. A cohort of 21 skeletally immature patients who underwent MPFL reconstruction was evaluated pre- and postoperatively with an average of a 2.8-year follow-up. The authors of the study reported no redislocation events and significant improvement in the Kujala scores, and patients were able to return to athletic activities safely.¹⁴⁵ Previous studies report similar positive increases in Kujala scores, subjective patient reports, and lack of subsequent redislocation for patients who underwent either semitendinosus or gracilis autograft MPFL reconstructions. One such study further documented an average patellar inclination angle decrease from 34.3° to 18.6° following MPFL reconstruction.¹⁴⁶ However, while the literature typically reports positive Kujala scores and subjective outcomes for the hamstring autograft procedure, a study arthroscopically evaluating patellar tracking immediately following surgery and then at 6 to 26 months follow-up found that patellar tracking correction was not maintained for all patients who underwent this type of MPFL reconstruction.¹⁴⁷

Continue to: QUADRICEPS TENDON TRANSFER OUTCOMES

Studies specifically evaluating the quadriceps tendon transfer technique for MPFL reconstruction in children are sparse, but authors have reported positive clinical outcomes and low complication rates in adults. After following 32 young adults who underwent this MPFL reconstruction technique for 3 years, Goyal¹⁰⁹ reported a significant increase in mean Kujala scores from 49.31 to 91.25 and no complications or redislocation. He argues this type of quadriceps graft has a high success rate because it is anatomically more similar to the MPFL than other grafts and does not require additional patellar fixation.^101,109 Similar positive Kujala scores and minimal complications have been reported in adult patient populations.¹⁴⁸ Abouelsoud and colleagues¹⁴⁹ conducted one of the few studies in skeletally immature patients and reported similarly positive results with no redislocations and significantly improved Kujala scores at a mean follow-up of 29.25 months in their 16-patient cohorts.

ADDUCTOR MAGNUS TENDON TRANSFER

After initially describing this technique in 14 adult patients, Avikainen and colleagues⁹⁶ followed this cohort and reported positive subjective results and only 1 redislocation. In a more recent study in which the adductor tendon transfer technique was compared with the quadriceps tendon transfer described above and the bone-patellar tendon allograft, Steiner and colleagues⁶⁹ reported similarly significant improvement in all cohorts in Lysholm, Kujala, and Tegner scores with no redislocations. Additionally, Malecki and colleagues¹⁵⁰ followed a cohort of 33 children with 39 knees diagnosed with recurrent patellar dislocation, who underwent MPFL reconstruction using the adductor magnus tendon. After evaluating this cohort functionally and radiographically, the authors reported improvements in Lysholm and Kujala scores, patellar tilt and congruence angles, and peak torque of the quadriceps muscle and flexor.¹⁵⁰ However, this cohort did report postoperative redislocations in 36.4% of patients (4 of 11).¹⁵⁰

HEMI-PATELLA TENDON TRANSFER

In 2012, in the first randomized controlled trial, Bitar and colleagues⁶⁷ compared the outcomes of patients who underwent MPFL reconstruction via the hemi-patellar tendon technique with those who were managed nonoperatively with immobilization and physiotherapy after first-time patellar dislocation. At 2-year follow-up, the surgical cohort presented positive results with a significantly higher mean Kujala score (88.9 to 70.8) and no redislocations or subluxations. In contrast, 35% of nonoperative cases presented with recurrences and subluxations over the 2-year period.⁶⁷

MCL OR ADDUCTOR TENDON AS A PULLEY

Studies have reported good postoperative results and low complication rates for these dynamic techniques.^128,129 In terms of kinematics, while hypermobility and patellar height were not fully corrected, improvements in patellar tilt and lateral shift were reported in a cohort of 6 patients with a minimum 4-year follow-up.¹²⁹ To further evaluate whether the more dynamic pulley reconstruction technique resulted in better outcomes, Gomes and colleagues¹²⁸ compared the subjective reports, clinical evaluations, and complication rates of patients who underwent MPFL reconstruction with a rigid adductor magnus fixation vs a semitendinosus tendon dynamic femoral fixation. One case in the rigid cohort experienced a subsequent subluxation, while patients in the semitendinosus group had better subjective reports and a higher rate of return to sport.¹²⁸ More recently, Kumahashi and colleagues¹⁵¹ specifically studied the outcomes of the MCL tendon as a pulley in 5 patients aged 14 to 15 years. They reported similar successful results as no patients experienced recurrence, and all patients exhibited improvement in radiographic measures of patellar tilt and congruence angle, lateral shift ratio, and both Kujala and Lysholm scores.¹⁵¹

While there has yet to be a randomized controlled trial comparing all of these different techniques, there is a general consensus in the literature that patients tend to perform better following MPFL reconstruction vs MPFL repair.

OTHER STABILIZATION PROCEDURES, INCLUDING DISTAL REALIGNMENT

Patients with additional underlying deficits and malalignment issues such as significant trochlear dysplasia, increased TT-TG distance, patella alta, increased Q angle, and/or positive J sign may require stabilization procedures beyond MPFL reconstruction.^152,153 TT osteotomies are often used to correct alignment issues in the adult patient population; however, these procedures are typically contraindicated in skeletally immature patients. Alternative realignment procedures for the pediatric population include both proximal and distal realignment, with proximal realignment performed primarily in children under the age of 12 years.¹⁵³ Many variations on these procedures exist, some of which are no longer regularly performed due to poor reported outcomes. In this article, we discuss several of the techniques, focusing primarily on those that have demonstrated higher success rates.

Continue to: GALEAZZI TECHNIQUE

One of the first and most famous soft-tissue techniques to address patellar instability was the semitendinosus tenodesis, published by Galeazzi¹⁵⁴ in 1922 (Figure 7). This technique stabilizes the patella without altering the TT. In the original technique, a portion of the semitendinosus tendon is harvested with its tibial insertion left intact. The free end of the tendon is then secured with sutures at the periosteal groove of the medial patella.^154,155 Fiume¹⁵⁶ modified this technique by adding a lateral release and medial retinacular reefing. The most recent addition to this procedure was introduced by Baker and colleagues,¹⁵⁷ in which a tunnel is drilled from the medial to the lateral border of the patella. Tension placed on the grafted tendon is used to reposition the patella medially and draw it downward. Preliminary literature on this modified procedure reported fair clinical results with success rates of approximately 75%.^155,158-160 A recent study evaluating both the clinical and radiographic outcomes of this technique also indicated that while clinical results were excellent in 62.5% of patients, this technique alone was unsuccessful in fully addressing patellar instability in patients with underlying anatomic abnormalities such as patellar alta.¹⁶¹ In light of these less than ideal reports, the authors no longer recommend this technique for patellofemoral instability cases.

ROUX-GOLDTHWAIT PROCEDURE

The Roux-Goldthwait procedure, first described by both Roux¹⁶² and Goldthwait¹⁶³ in 1888 and 1895 respectively, was later modified in 1985 to involve a lateral release, plication of the medial retinaculum, medial transfer of the lateral patellar tendon without advancement, and advancement of the vastus medialis (Figure 8).¹⁶⁴ More recently, Marsh and colleagues¹⁵² introduced an addition to aligning the extensor mechanism with the femoral shaft better. In this technique modification, the patellar tendon is split longitudinally, and its lateral half is detached and transferred distally beneath its medial half. The free end is then sutured to the periosteum on the medial side of the tibia.¹⁵² With a mean long-term follow-up of 6.2 years, Marsh and colleagues¹⁵² reported excellent results in 65%, good in 11%, and fair in 3% of the knees operated on with this modified technique. Of the patients in this cohort whose strength was evaluated, 80% had their strength returned to 90% of preoperative levels in the operated leg.¹⁵² While this study and others report improved outcomes, an increasing body of literature has found high rates of recurrence, patella infera, and other complications following the modified Roux-Goldthwait procedure.^36,165-171 Also, a study comparing MPFL reconstruction using adductus magnus transfer with the Roux-Goldthwait procedure reported that patients in the MPFL cohort reported less pain postoperatively.¹⁵⁰ In addition, whereas the Kujala and Lysholm scores, recurrence rates, patellofemoral angles, and apprehension test results did not demonstrate significant differences between these 2 groups, the MPFL group had significantly fewer abnormal congruence angles, better patellar medialization, and higher peak torque of the hamstring.¹⁵⁰

COMBINED MPFL AND MEDIAL PATELLOTIBIAL LIGAMENT RECONSTRUCTION

While the medial patellotibial ligament (MPTL) has not received much attention with regard to patellar stability, recent studies have indicated its role during higher degrees of both flexion and extension.¹⁷² The MPTL acts as a secondary restrictor ligament which helps release stress on the MPFL by decreasing the Q angle and further normalizing patellar kinematics.¹⁷³ Patients who present with hyperlaxity or knee hyperextension combined with extension subluxation and flexion instability could be indicated for this additional stabilizing procedure. Both Nietosvaara and colleagues⁸⁵ and Brown and Ahmad¹⁷⁴ have described a dual MPTL and MPFL reconstruction technique using a semitendinosus hamstring graft. More recently Hinckel and colleagues¹⁷² described a combined MPFL and MPTL reconstruction, using a graft from the quadriceps tendon to reconstruct the MPFL and one from the patellar tendon to reconstruct the MPTL. In this technique, once the respective grafts have been harvested, a femoral insertion for the graft recreating the MPFL is fluoroscopically established so that an anchor can be inserted distal to the femoral physeal growth plate. For the MPTL insertion, attachment to the tibia below the joint line and 2 cm medial to the patellar tendon is established fluoroscopically just above the physeal growth plate on the proximal epiphysis.^19,175 The MPTL graft is sutured first with the knee at 90° of flexion to establish tension similar to that of the patellar tendon.¹⁷⁶ Then, the knee is placed in 30° of flexion to fix the MPFL graft to the medial patella to prevent excessive lateral translation of the patella.

PATELLAR TENDON TRANSFER

Patellar tendon transfer with proximal realignment is a technique used in particularly young patients to address cases of patellofemoral instability involving concomitant bony or anatomic abnormalities. This procedure is effective for young children with substantial amounts of remaining growth as it better mimics native anatomy than other realignment procedures and does not require bony remodeling.^152-154 It is important to familiarize with surgical techniques to address malalignment issues in young patients as neglected alignment issues can lead to worsening of trochlear dysplasia and instability, which are very difficult to treat later on when patients are older.¹⁵³

The patellar tendon transfer technique (Figure 9), as described by Gordon and Schoenecker,¹⁷⁷ starts with an extensive lateral retinacular release. The patellar tendon is then released from its distal insertion at the TT so that it can be moved medially without moving it inferiorly. After confirming patellar tracking and alignment by flexing the knee from 0° to 90° with the graft in place, the patellar tendon graft is secured with multiple nonabsorbable horizontal sutures.¹⁷⁷ Of note, in skeletally mature patients, a TT osteotomy is used to accomplish the same goal. This osteotomy has been shown to improve both patellar height and TT-TG distance in skeletally mature patients, but is contraindicated in skeletally immature patients.^92,178

Continue to: Initial studies conducted on patellar tendon...

Initial studies conducted on patellar tendon transfer have positive outcomes.¹⁷⁹ At a mean follow-up of 5.1 years, patients reported a decrease in pain and increased the ROM and activity, and only 1 reported a postoperative redislocation.¹⁷⁹ In more recent studies, both Benoit and colleagues³⁶ and Garin and colleagues⁵⁸ reviewed cases of patellar instability treated with patellar tendon transfer to address concomitant patellar alignment and anatomic abnormalities. They reported good functional, clinical, and radiographic outcomes with 12.5% and 16% recurrence rates, respectively.^36,58 They also noted radiographic improvements in femoral sulcus angle, particularly in younger patients, which indicate this procedure is effective in addressing bony abnormalities that can result from neglected malalignment issues.^36,58,154

QUADRICEPSPLASTY

Quadricepsplasty is a lengthening and remodeling technique not frequently used in the pediatric population. The goal of this procedure in patients with significant amounts of growth remaining is to reposition the patella to ameliorate trochlear remodeling and prevent worsening symptoms and anatomic abnormalities.³⁶ A quadricepsplasty accomplishes this by de-rotating and/or lengthening the extensor mechanism and may or may not involve a concomitant MPFL reconstruction. This procedure is particularly effective in young patients who experience obligatory dislocation.^60,72 Several quadricepsplasty techniques have been described including Thompson, Curtis and Fisher, Judet, Stanisavljevic, and V-Y technique.^180-186 Most techniques initially involve sharp dissection of the vastus medialis and lateralis from the rectus femoral tendon. A tongue is then fashioned out of the rectus femoral tendon. Once the vastus medialis and lateralis are detached from the margins of the patella, the knee is extended, and the distal ends of the vasti are sutured to the tongue of the rectus tendon. Effective extension facilitates flexion to 90°.¹⁸⁴ The authors recommend a modification of this technique in which a Z lengthening of the quadriceps tendon is performed after the vastus lateralis is removed distally from the patella and the quadriceps tendon.

Several series and case reports evaluating quadricepsplasty in adult patients report positive outcomes with most patients achieving good or excellent flexion with minimal complications.^{183,185,187-189} Reports on quadricepsplasty used to treat conditions other than patellofemoral instability in children have reported similar positive outcomes.^190-192 As quadricepsplasty for patellar instability is relatively rare in pediatric patients, there is not much relevant literature. However, Kocon and colleagues¹⁹³ reported results of quadricepsplasty and quadricepsplasty combined with the modified Galeazzi procedure in 8 children (10 knees) with a mean follow-up of 3.25 years. Seventy percent of cases resulted in stabilization and correction of patellar position, and only 2 postoperative redislocations were noted.¹⁹³ Additionally, in a study evaluating 6 patients suffering from patellar instability, 2 of whom were obligate dislocators, quadricepsplasty resulted in patellar stability, satisfaction, and near normal gait patterns.¹⁹⁴

Figure 10 shows the surgical algorithm used for patellar instability characteristics.

CONCLUSION

Patellofemoral joint stability relies on a complex interplay of musculotendinous units, ligaments and the osteocartilaginous morphology of the patellofemoral joint. Patellar instability in pediatric patients is different from adults. Having an in-depth understanding of the remodeling potential, the insertion sites for the MPFL and its relationship to the physis are of utmost importance when planning surgery. Reducing and maintaining the patella within the patellofemoral joint early enough can allow for remodeling of the patella and/or the trochlea to provide for lasting stability. Appropriate surgical principles, such as tensioning, can help both prevent continued pain and minimize future complications.

ABSTRACT

Patellar instability in children and adolescents is a challenging subset to treat. Varied forms of instability, ranging from episodic dislocation to fixed dislocation, have been recognized. It is of utmost importance for the treating physician to recognize these different patterns of instability and their associated risk factors, as more complex patterns of instability would require more extensive surgical procedures. Medial patellofemoral ligament (MPFL) reconstruction, by itself, may not suffice or may not be appropriate for the more complex instability patterns. Appropriate and early treatment of such instability in children would allow for functional progression and possible remodeling of the trochlea. However, early treatment has the associated risk of growth disturbances when surgical procedures are performed around open physis or if adult-type bony procedures are performed in children. Recent knowledge about the relationship between trochlea, MPFL femoral attachment, and distal femoral physis could help to advance safe surgical care for these patients. This article reviews the pathophysiology, risk factors, and the existing classification systems for patellar instability in children and adolescents. It focuses on varied surgical techniques, which are unique to the pediatric population, and summarizes the outcomes of these surgical techniques.

Continue to: EPIDEMIOLOGY

EPIDEMIOLOGY

In a prospective 2-year study of Finnish children, the annual incidence rate of patellar instability was 43/100,000 pediatric population.¹ In patients 9 to 15 years of age, the incidence was approximately 1/1000.¹ In another study, patients at highest risk for a first-time patellar dislocation were females aged 10 to 17 years.² In a study in patients with traumatic hemarthrosis, 36% in the younger age group (10-14 years) and 28% in the older age group (15-18 years) had sustained patellar dislocation. In contrast, 22% in the younger age group and 40% in the older age group had sustained an anterior cruciate ligament tear.³

Approximately one-half of patients who dislocate their patella suffer from long-term complications.^4,5 These complications include recurrent instability, patellofemoral pain, osteochondral lesions, and eventual arthritis.^1,4,5 Young, active individuals are more prone to these issues.⁶ Also, 39% or more of patellar dislocation patients have an associated osteochondral fracture that might influence the management.¹ Thus, patellar instability in young patients is an area of concern.

DEVELOPMENTAL ANATOMY

At 4-week gestation, the patellofemoral joint is an ectodermal sac filled with mesenchyme of the somatic mesoderm.⁷ Mesenchymal condensations then appear at 4 to 5 weeks gestation, followed by chondrification of both the femur and patella.⁷ The joint space is present by 6 weeks, and the patellar and distal femoral condyles are present at 7 weeks gestation.⁷ By 8 weeks gestation, the basic knee anatomy resembles that of an adult with the chondroepiphysis forming the articular surfaces of the femur, tibia, and patella.⁷ By this time, the extensor mechanism is formed, and active joint motion has begun, facilitating the development of the trochlear sulcus.⁷ The secondary ossification center in the distal femoral epiphysis forms around 36 weeks gestation.⁸ Postnatally, both the patella and distal femur grow through endochondral ossification.^9,10

The patella is the largest sesamoid bone in the human body.¹¹ The patella begins as a dense consolidation of cells that differentiate as the quadriceps mechanisms develop.^12,13 The patellar anlage becomes distinguishable within the quadriceps tendon around 7.5-week gestation.¹² The morphology of the patella conforms to the distal femur.¹² The patella molds or re-models as the knee begins to move in response to mechanical stresses.⁷ The patella increases in relative size during the first 6 months of gestation, then enlarges proportionately to the rest of the bones.⁷ Ossification begins around 3 years of age for females and 4 to 5 years of age for males.^8,14 The ossification center may appear irregular as it rapidly expands.¹⁴ Ossification proceeds in a proximal to distal direction, thus giving a spurious estimation of patellar height on radiographs in children. The overall morphology of the cartilaginous patella during development is comparable to the final mature shape.¹⁴ Abnormal contact stresses on the articular surface of the patella during skeletal immaturity can lead to deformation.⁷

Ultrasonographic measurements in normal patients show that trochlear groove (TG) morphology is present early and becomes more radiographically apparent as distal femoral ossification is completed.¹⁵ Anatomic dissections of aborted fetuses have verified the morphology of the TG as it remains constant during growth and the groove morphology is the same for both fetuses and adults.¹⁶ An ultrasound study performed on patients aged 12 to 18 years showed the cartilaginous sulcus angle (CSA) remained constant throughout all age groups (146°).¹⁷ The CSA however, differed in patients who suffered a patellar dislocation (average, 164°; range, 154°-195°) compared with normal knees (average CSA, 145°; range, 131°-158°).^15,17,18 The osseous sulcus angle, on the other hand, appears flat at birth and the TG deepens with age. This increase in depth is more of a reflection of progressive ossification of a well-formed cartilaginous trochlea, rather than a true deepening of the sulcus.¹⁷ Thus, the axial radiographic view of the patella provides misleading information about the sulcus angle in children and should not be used to define trochlear morphology.

Continue to: MEDIAL PATELLOFEMORAL LIGAMENT ANATOMY

The medial patellofemoral ligament (MPFL) functions to limit the lateral translation of the patella.¹⁹ The attachment sites on the femur and patella for the MPFL have been studied in children.^20-23 Cadaveric dissections in specimens aged 2 to 11 years have noted the patellar attachment to be an average of 12 mm in length with the midpoint approximately 5 mm superior to the mid-pole of the patella.²² The patellar footprint of the MPFL insertion was a mean 41% of the entire patellar length.²²

It is important to be aware of the characteristic anatomy of the MPFL, as fixation points should mimic the anatomic insertion as best as possible while also avoiding violation of the nearby physis. The MPFL originates between the adductor tubercle and the medial femoral epicondyle just distal to the distal femoral physis and attaches to the superomedial aspect of the patella.^20-25 In relation to the physis in pediatric patients, the midpoint of MPFL insertion has been measured to be 4 mm to 9 mm distal to the femoral physis.^21,24,25 These measurements represent averages as cadaveric studies have reported that some part of MPFL femoral insertion extends proximal to the distal femoral physis.²¹ A recent report of physeal injury to the posterior distal femoral physis during MPFL reconstruction leading to femoral flexion deformity highlights the importance of physeal-respecting surgery.²⁶

TROCHLEA AND ANTERIOR DISTAL FEMORAL PHYSIS

The relationship between the proximal aspect of the trochlea and the anterior distal femoral physis has been recently studied in 175 knees with dysplastic trochlea.²⁷ Based on magnetic resonance imaging evaluation, the lateral aspect of the trochlea extended proximal to the anterior distal femoral physis in 13% of patients and was at the level of the anterior physis in another 13% of patients (Figure 1).²⁷ Hence, a cautious approach is recommended for any surgery to address trochlear dysplasia or trochlear bump in younger patients to prevent iatrogenic injury to anterior distal femoral physis and resultant genu recurvatum. The distance between the trochlea and the physis increased with increasing age.

LIMB ALIGNMENT

Physiologically, the quadriceps angle (Q angle) changes through the course of growth. As children begin standing and walking, they stand with their feet wider apart and in genu varum.²⁸ Physiologic genu varum can reach 15°.²⁸ This degree lessens during the first 1.5 to 2 years of life, transitioning to physiologic valgus of nearly 12° by 3 years of age.²⁸ Genu valgum, thereafter, gradually decreases to reach the adult value of around 7° to 8° by age 7 years.²⁸ Increased genu valgum is a risk factor for patellar instability. In skeletally immature patients, correction of genu valgum through guided growth may be desirable in patients undergoing patellar stabilization surgery (Figures 2A, 2B).²⁹

PATHOPHYSIOLOGY OF PEDIATRIC PATELLAR DISLOCATION

TROCHLEAR DYSPLASIA

Trochlear dysplasia is an abnormal shape and depth of the TG.³⁰ Up to 96% of patients with patellar dislocation have trochlear dysplasia.^30-33 In a study of patellar instability in children, at least 1 of the 3 signs of trochlear dysplasia (the crossing sign, supratrochlear bump, and double contour sign) was present on lateral radiographs.³⁴ In another study on the growth of trochlear dysplasia in children and adolescents, all grades of trochlear dysplasia were present at all ages (ie, the dysplasia was most likely present at birth and did not necessarily worsen with age and growth).³⁵ The linear dimensions of lateral and medial condylar height as well as trochlear bump increased with age but both the sulcus angle and shape of the trochlea did not change significantly.³⁵ Remodeling of a dysplastic trochlea can happen if the patella is stabilized and appropriately located at a younger age, preferably before 10 years of age.^36,37

Continue to: PATELLAR HEIGHT

The role of patellar height in patellar instability has been well established.³⁸ In patients with patella alta, the patella remains proximal to the TG during the greater arc of knee motion, which predisposes it to patellar instability. Calculation of patellar height in children could be challenging due to incomplete ossification, as well as asymmetric ossification of the patella and the tibial tubercle (TT). Since the patella ossifies from proximal to distal, most radiographic methods that measure the patellar height from the distal aspect of the patella provide a spurious elevation of the measurement.

The Caton-Deschamps (CD) method measures the length of the patellar articular surface and the distance from the inferior edge of the articular surface to the anterosuperior corner of the tibial plateau.³⁹ A ratio >1.3 signifies patella alta. The CD ratio has been verified as a simple and reliable index for measuring patellar height in children.⁴⁰ Two other methods have been described for determining patellar height in children.^41,42 Based on anteroposterior (AP) radiographs of the knee in full extension, Micheli and colleagues⁴¹ calculated the difference between the distance from the superior pole of the patella to the tibial plateau and the length of the patella. A positive difference signified patella alta. The Koshino method involves the ratio between a reference line from the midpoint of the patella to the midpoint of the proximal tibial physis and a second distance from the midpoint of the distal femoral physis to the midpoint of the proximal tibial physis on lateral knee radiographs.⁴² Normal values range from 0.99 to 1.20 with the knee in >30° flexion, in children 3 to 18 years of age.

HYPERLAXITY

In contrast to adults, children have increased levels of collagen III compared with collagen I, which is responsible for tissue elasticity.⁴³ Tissue elasticity leads to increased joint mobility, which is more common in children. Joint hypermobility or hyperlaxity has to be differentiated from symptomatic instability. The traditional Beighton score identifies individuals as having joint hypermobility with a score of 5/9 or higher in school-aged children.^44-46 Smits-Engelsman and colleagues⁴⁴ suggested using stricter criteria with scores of 7/9 or higher being indicative of hyperlaxity in school-aged children. A study of 1845 Swedish school children noted that females have a higher degree of joint laxity.⁴⁵ Maximal laxity was noted in females at 15 years of age.⁴⁵ Hyperlaxity has been demonstrated to be greater on the left side of the body⁴⁴ and can be part of generalized syndromes including Down’s syndrome, Marfan’s syndrome, or Ehlers-Danlos syndrome.

LIMB TORSION

Staheli and colleagues⁴⁷ described the normative values of a lower extremity rotational profile, including femoral anteversion and tibial torsion. Children normally have increased femoral anteversion, which decreases with growth. Miserable malalignment is a term used to denote increased femoral anteversion and increased external tibial torsion.^48,49 These rotational abnormalities can increase the Q angle and the lateral forces on the patella. Femoral anteversion or internal rotation of the femur of 30° significantly increases strain in all areas of the MPFL.⁴⁸ This increased strain may lead to MPFL failure and patellar instability.⁴⁸ Increased internal rotation of the femur also increases contact pressure on the lateral aspect of the patellofemoral joint.⁴⁸ Miserable malalignment frequently manifests following a pubertal growth spurt and may require femoral and tibial osteotomy.⁵⁰

SYNDROMIC ASSOCIATIONS

Several syndromes have patellar instability as a part of their manifestation. The more common syndromes include nail-patella syndrome, Kabuki syndrome, Down’s syndrome, and Rubinstein-Taybi syndrome.^51-54 Other syndromes less commonly associated with patellar instability include Turner syndrome, patella aplasia, or absent patella syndrome. Since many patients with syndromic patellar instability are functionally limited, they may not require an aggressive approach to treatment. When treating these patients, it is important to recognize the unique features of a specific syndrome, which may affect the anesthesia risk profile, management decisions, rehabilitation, and prognosis.

Continue to: MPFL TEAR PATTERN

The MPFL serves as an important constraint to the patella to prevent lateral dislocation, primarily during the first 20° to 30° of knee flexion.^55,56 Injury to the MPFL is noted in over 90% of patients who suffer a patellar dislocation.⁵⁷ The location of MPFL tears in pediatric patients is variably reported at the patellar attachment (10%-61%), femoral attachment (12%-73%), both (12%-35%) or mid-substance (2.5%-15%).^25,57 The most common tear patterns in pediatric patients are tears at the patellar attachment.^25,57 This tear pattern may be accompanied by an avulsion fracture of the medial rim of the patella, though this fracture, being extra-articular, seldom needs treatment.

CLASSIFICATION

While several authors have established extensive classification systems of patellar dislocation based on both clinical and radiographic presentation and reviews of the literature, a single classification system has not been recognized as the gold standard. In this section, in addition to presenting our preferred methods of classification, we will review some of the more recent and extensive classification systems for patellar dislocation and patellar instability.

Dejour and colleagues³¹ initially used both the presence of patellofemoral anatomic abnormalities and pain to define 3 types of patellar instability: major, objective, and potential patellar instability. Major patellar instability indicates that the patient has experienced more than 1 documented dislocation, objective instability involves one dislocation in addition to an associated anatomic abnormality, and potential patellar instability refers to cases in which the patient has radiographic abnormalities and patellar pain.³¹ Garin and colleagues⁵⁸ more simplistically divided patellar dislocation patients into 2 groups: major (permanent or habitual) dislocation of the patella and recurrent dislocation. Sillanpaa⁵⁹ stressed the distinction between first-time dislocation and recurrent dislocation specifically in the context of acute injuries. These classification systems were formulated with adults as the most relevant population; however, classifications targeted specifically to pediatric patients have recently been presented in the literature.

Historically, pediatric patella dislocations were simply categorized as traumatic or congenital.⁶⁰ In 2014, Chotel and colleagues⁶¹ focused on classifying patellar dislocation by extensively reviewing anatomic, biomechanical, pathophysiological, and clinical patterns seen most commonly in children. They included 5 categories: congenital dislocation, permanent dislocation, habitual dislocation during knee flexion, habitual dislocation during knee extension, and recurrent dislocation; however, they did not address traumatic dislocations.⁶¹ Congenital dislocation is a rare condition, typically presenting at birth, which produces a pattern of functional genu valgum.⁶² Permanent dislocation typically presents after the child has started walking, but before the age of 5 years.⁶¹ The 2 variations of habitual dislocation typically present between ages 5 and 8 years.⁶¹ The final category is the most common and typically occurs during pre-adolescence or adolescence as a result of an atraumatic or trivial traumatic event or sports injury.¹ Using more specific terminology, Hiemstra and colleagues⁶³ modeled a classification system based on the traumatic, unilateral, bankart lesion, surgery (TUBS)/atraumatic, multidirectional, bilateral, rehabilitation, inferior shift (AMBRI) for shoulder dislocation classifications. The patellar dislocation system is used to identify 2 distinct subsets of patients in the patellofemoral instability population. One subset is defined by the acronym WARPS (weak, atraumatic, risky anatomy, pain, and subluxation), the other is STAID (strong, traumatic, anatomy normal, instability, and dislocation).⁶⁴ Patients categorized by the WARPS acronym tend to experience atraumatic onsets of patellofemoral instability and demonstrate anatomic issues that increase this instability. These underlying anatomic issues include valgus alignment, ligamentous laxity, rotational abnormalities, shallow and short TG, and patella alta. On the other hand, STAID patients describe a traumatic dislocation event and do not have underlying anatomic abnormalities that predispose them to instability.⁶⁴

Taking into account these previous classifications, Frosch and colleagues⁶⁵ added specific pathologies including “instability,” “maltracking,” and “loss of patellar tracking,” in addition to both clinical and radiographic factors to define 5 types of patellar dislocation and their specific treatment recommendations.⁶⁵ Type 1 involves simple dislocation with neither maltracking nor instability and a low risk of redislocation.⁶⁵ Type 2 is defined as primary dislocation followed by subsequent high risk of dislocation and no maltracking.⁶⁵ Type 3 is divided into 5 subcategories of instability and maltracking issues involving soft tissue contracture, patella alta, pathological tibial tuberosity, and TG distance.⁶⁵ Type 4 is defined as the highly unstable “floating patella,” and type 5 involves patellar maltracking without instability ⁶⁵. In terms of treatment, conservative rehabilitation is recommended for type 1 whereas MPFL reconstruction tends to show positive outcomes for both types 2 and 3.^66-70

Continue to: Parikh and Lykissas recently published...

Parikh and Lykissas recently published a comprehensive classification system of 4 defined types of patellar dislocation in addition to voluntary patellar instability and syndromic patellar instability (Table).⁶⁰ The 4 types are Type 1, first-time patellar dislocation; Type 2, recurrent patellar instability; Type 3, dislocatable; and Type 4, dislocated. Type 2 is further subdivided into Type 2A, which presents with positive apprehension signs, and Type 2B, which involves instabilities related to anatomic abnormalities.⁶⁰ A distinction is also made between Type 3A or passive patellar dislocation and Type 3B habitual patellar dislocation.⁶⁰

The classification system proposed by Green and colleagues is more simplified with 3 main categories (Table) of pediatric patellar dislocation: traumatic (acute or recurrent), obligatory (either in flexion or extension), and fixed laterally.^71,72 The acute traumatic categorization refers to patients who experienced an initial dislocation event due to trauma whereas recurrent traumatic involves repeated patella dislocations following an initial incident. Studies report that between 60% to 70% of these acute traumatic dislocations occur as a result of a sports-related incident.^2,33,73 Obligatory dislocations occur with every episode of either knee flexion or extension, depending on the subtype. Obligatory patella dislocation in flexion typically cannot be manipulated or relocated into the trochlea while the knee is fixed but does reduce into the trochlea in full extension. Fixed lateral dislocations are rare, irreducible dislocations in which the patella stays dislocated laterally in flexion and extension. These dislocations often present with other congenital abnormalities. Each of these categories can be further specified as syndromic if the dislocation is associated with genetic or congenital conditions including skeletal dysplasia, Ehlers-Danlos syndrome, cerebral palsy, Marfan disease, nail-patella syndrome, Down syndrome, Rubenstein-Taybi syndrome, and Kabuki syndrome.^{51-54,61,74-76}

SURGICAL TECHNIQUES IN SKELETALLY IMMATURE PATIENTS

While nonsurgical, conservative treatment involving physical therapy and activity modification is recommended for most patients who experience first-time traumatic patellar dislocations, many patients experience complicating factors that indicate them for surgery. These factors include recurrent dislocation, risk factors for patellofemoral instability, underlying malalignment issues, and congenital deformities. When evaluating these factors, particularly patellofemoral instability, the authors recommend assessing osteochondral lesions, age, skeletal maturity, number of previous dislocations, family history, and anatomic risk factors.^2,5,77-79 Extra care should be taken when considering surgical treatment for skeletally immature patients at elevated risk for recurrent instability as the risk of cartilage damage in these cases is high.^80-82

Recently, there has been a reported increase in surgical treatment for patellar instability in the skeletally immature.⁸³ This finding may be attributed to heightened awareness of factors that indicate patients for surgical treatment and increased familiarity of surgeons with newer techniques.⁸³ Many surgical techniques have been described to address patellar instability involving both soft-tissue procedures and bony corrections.⁸⁴ In this article, we discuss the various surgical techniques for MPFL reconstruction, quadricepsplasty, and distal realignment. These procedures can be paired with any number of additional procedures including, but not limited to, lateral retinacular release or lengthening, chondroplasty, TT osteotomy (in skeletally mature patients), and removal of loose bodies.⁸³

There is a need for more comprehensive studies, particularly randomized controlled trials, to evaluate the outcomes for both surgical and nonsurgical treatments for first-time dislocations. In the current literature, only very recently have surgical treatments shown outcomes that are more positive. In 2009, Nietosvaara and colleagues⁸⁵ conducted a randomized controlled trial of nonoperative and operative treatment of primary acute patellar dislocation in both children and adolescents. After a long-term mean follow-up of 14 years, there was not a significant difference between the groups in recurrent dislocation and instability, subjective outcome, or activity scores.⁸⁵ In a subsequent review of 5 studies including 339 knees, Hing and colleagues⁸⁶ also found similar results in both the operative and nonoperative cohorts at risk of recurrent dislocations, Kujala scores, and reoperations. However, a recent systematic review comparing redislocation rates and clinical outcomes between surgical and conservative management of acute patellar dislocation reported more positive outcomes for the surgical cohort.⁸⁷ This review included 627 knees, 470 of which received conservative management, 157 of which received operative treatment. The conservative cohort was followed for an average of 3.9 years and had a 31% rate of recurrent dislocation while the surgical group was followed for a mean 4.7 years and experienced a 22% redislocation rate.⁸⁷ This study indicates that operative management for acute first-time dislocations may be the preferred treatment option.

Continue to: A potential reason some of these studies...

A potential reason some of these studies did not show any significant difference between the operative and nonoperative cohort could be that the surgical cohorts included a wide range of procedures including lateral releases and MPFL repairs. Recent publications have indicated that these techniques do not produce overall positive outcomes. While each surgical treatment plan is unique depending on the patient; recently, MPFL reconstruction has been shown to have better outcomes than both nonoperative management and simple medial repair and/or lateral
release.^67,88-90

MPFL RECONSTRUCTION

INDICATIONS/OVERVIEW

The MPFL is an important stabilizer for the knee that primarily resists lateral translation of the patella. Damage to the MPFL is very common in acute patellar dislocations with up to 90% of first-time dislocations resulting in injury to the MPFL.^91,92 Historically, simple medial and/or lateral MPFL repairs have not been shown to improve patellofemoral kinematics significantly and often result in recurrence.^90,93 To address this issue, during the past few decades, numerous MPFL reconstruction techniques have been developed to reconstruct a stronger ligament with the same kinematics as the anatomic MPFL.^{2,19,69,81,94-106} The ultimate goal of MPFL reconstruction is to reestablish the anatomic “checkrein” to guide the patella into the trochlea between 0° and 30° of knee flexion.^107,108 An essential secondary surgical goal in skeletally immature patients is to avoid damaging the distal femoral physis.

There are many variations in both the grafts used to replace the MPFL and the means by which to secure them. The ones discussed below include free semitendinosus or gracilis autografts or grafts constructed from a pedicled adductor, patellar, or quadriceps tendon.^69,105,109 While not used as frequently, allografts have also been used.¹¹⁰ Methods to secure these grafts in osseous tunnels include suture anchors or tenodesis screws. Incomplete osseous sockets or medial-sided bone tunnels have also been used as a method to decrease patellar fractures as they preserve the lateral patellar cortex.^111-114

DOUBLE-BUNDLE HAMSTRING AUTOGRAFT

The technique most often used by the author is a double-bundle hamstring autograft harvested from either the semitendinosus or the gracilis secured by short patellar and femoral sockets (Figure 3). After harvesting the hamstring graft from a posteromedial incision, an approximately 90-mm graft is prepared with Krackow stitches to secure 15 mm of the tendon in each socket.¹¹⁵ Lateral radiographs are used intraoperatively to ensure the guidewire for the femoral drill hole falls along the posterior cortex of the diaphysis of the femur while AP radiographs confirm placement distal to the physis. It is important to take both AP and lateral radiographs intraoperatively due to the concave curvature of the distal femoral physis. This unique anatomy can make a point that is located distally to the physis on the AP view appear on or proximal to it on the lateral cross reference view.^24,116 For the patellar socket, 2 short sockets are made in the superior half of the patella. Once the sockets have been drilled, the graft is adjusted so that the patella stays seated in the center of the trochlea between 20° and 30° of flexion. This anchoring is accomplished by securing the graft while the knee is kept at 30° of flexion. Proper tension is confirmed by ensuring that the graft does not allow lateral patella movement over one-fourth the width of the patella in extension while crepitation must not appear throughout the ROM.⁹²

QUADRICPETS TENDON TRANSFER

A combination of techniques by Steensen and colleagues,¹⁰⁵ Goyal,¹⁰⁹ Noyes and Albright,¹¹⁷ and Pinkowsky and Hennrikus¹¹⁸ describe an MPFL reconstruction in which the proximal end of a small medial portion of the quadriceps tendon is released and then attached to the medial epicondyle through a subcutaneous tunnel (Figure 4). This technique is particularly useful for cases in which the extra strength provided by the bone-quadriceps tendon is necessary to correct more severe dysplasia. Leaving the distal end of the quadriceps tendon intact at its patellar insertion, a graft of about 8 mm x 70 mm thickness is harvested from the tendon. The free distal end of the tendon is then run anatomically through the synovium and retinaculum to be either sutured to the medial intermuscular septum at the medial femoral epicondyle or fixed in femoral tunnel using interference screw.^105,109,118 The placement of the femoral fixation point is essential to ensure positive surgical outcomes. If the graft is secured too anteriorly, it may be too loose in extension and too tight in flexion, both of which can lead to postoperative pain, loss of normal kinematics, and overload of the medial patellofemoral cartilage.^119-121 Once the ideal placement of the femoral fixation point has been confirmed by intraoperative radiographs, the graft is secured with a small absorbable suture.^122,123 While this technique has good clinical results, the longitudinal scar that results from graft harvesting is cosmetically unappealing, and it is technically challenging to harvest a consistent strip of the quadriceps tendon. To address some of these concerns, Fink and colleagues¹²⁴ described a new harvesting technique that produces more consistent grafts and requires a smaller incision.

Continue to: ADDUCTOR MAGNUS TENDON TRANSFER

This technique is a double-bundle MPFL reconstruction that uses a pedicled graft of the distal adductor magnus tendon and suture anchors or incomplete osseous sockets to recreate the MPFL anatomically (Figure 5). Avikainen and colleagues⁹⁶ and Sillanpää and colleagues¹²⁵ described this procedure as a progression from the original single-strand adductor magnus transfer technique. First, maintaining the distal insertion, a graft of approximately 14 cm to 18 cm is harvested from the adductor tendon and then passed through a subcutaneous tunnel between the distal vastus medialis obliquus and the superficial joint capsule. The graft is then looped at the medial patella so that the distal bundle runs back to the adductor tubercle.¹²⁵ With the knee at 30° of flexion to assure proper tension, the graft is secured at both the patella and near the adductor tubercle with suture anchors.¹²⁵ Hambridge and colleagues¹²⁶ compared a similar adductor magnus transfer with other pedicled techniques including bone-quadriceps tendon autograft and bone-patellar tendon allograft and found positive results for all 3 methods of reconstruction.

HEMI-PATELLA TENDON TRANSFER

In a similar technique to the adductor tendon transfer, the medial section of the patellar tendon is harvested from the TT and run from its proximal insertion at the medial patella to the medial femoral attachment via a subcutaneous tunnel. The free end of the graft is then secured with suture anchors or incomplete osseous sockets with the knee at 30° of flexion.¹²⁷

HAMSTRING GRAFT WITH ADDUCTOR TENDON AS A PULLEY

Several techniques opt to use a more dynamic model of MPFL reconstruction in which the adductor tendon or medial collateral ligament (MCL) is used as a pulley for the hamstring graft (Figure 6).^128,129 The site of the pulley approximates the normal attachment of the MPFL to the femur and so acts as an effective anatomic replica of the MPFL origin. A semitendinosus graft is harvested and is prepared with continuous sutures, and 2 tunnels to secure the graft are drilled into the patella. The graft is then run subcutaneously from the medial side of the patella to the adductor magnus tubercle into which an osteoperiosteal tunnel is drilled at its distal femoral insertion. The graft is looped through the adductor tunnel and secured with sutures. Proper knee kinematics was ensured by placing the knee at 30° of flexion as the ends of the tendon are secured to the patella.^114,130

HAMSTRING GRAFT WITH MCL AS A PULLEY

The MCL can also be used as a pulley rather than the adductor tendon. The semitendinosus graft is harvested and prepared and the patella drilled as it is in the previous technique. The MCL was fashioned into a pulley by making a slit in its posterior one-third. The semitendinosus graft is looped through this slit, and both ends of the graft are held in place with suture anchors on the surface of the patella.¹²⁹

ADDITIONAL PROCEDURAL COMBINATIONS

Depending on the needs of the individual patient, MPFL reconstruction, and other patellar stabilization techniques can also be combined with additional procedures. Arshi and colleagues⁸³ conducted a review of 6190 adolescents surgically treated for patellar instability and reported the most common additional procedures performed at the time of the stabilization. They found 43.7% of the population underwent lateral retinacular release, which while not effective as an isolated technique to treat patellar instability, has often been used in combination with MPFL reconstruction.^131-133 There is currently a lack of consensus regarding the success of adding a lateral release to the reconstruction. Some studies report no difference while others report a decrease in stability after lateral release.^90,134-136 While lateral retinacular release has been shown to decrease the force required to displace the patella, it can be surgically indicated in certain patients undergoing MPFL reconstruction.¹³¹ The authors advocate that if the lateral retinaculum is tight such that centralized patellar tracking is inhibited following the reconstruction, or if the patella cannot be pushed passively from a laterally tilted position to the neutral horizontal position, lateral retinacular lengthening should be performed to improve kinematics.¹³²

Continue to: Arshi and colleagues...

Arshi and colleagues⁸³ also reported a high rate of cartilage procedures, with chondroplasty performed in 31.1% and chondral fragment/loose body removal in 10.2%. These statistics suggest that a significant level of cartilage damage has occurred by the time of surgery.⁸³

COMPLICATIONS

As MPFL reconstruction techniques have only recently been popularized and developed, there are not many comprehensive studies evaluating the outcomes and complications associated with these procedures. However, in the current literature, there is a general consensus that patients usually experience positive short-term clinical outcomes and relatively low complication rates.^68,77 In one of the largest retrospective cohort studies of pediatric patients undergoing MPFL reconstruction, Parikh and colleagues¹¹⁴ reported both the type and rate of complications. They found complications occurred in 16.2% of patients, and the most common complications were recurrent patellar instability, patellar fractures, patellofemoral arthrosis, motion deficits, and stiffness with over half classified as avoidable. Most of these complications were due to technical errors with episodes of recurrent instability only reported in 4.5% of patients.¹¹⁴ In a comprehensive meta-analysis of MPFL reconstruction studies, Shah and colleagues¹³⁷ reported a complication rate of 26% in both pediatric and adult patients. The cohort was not stratified by age, yet complications were similar to those reported by Parikh and colleagues,¹¹⁴ including pain, loss of knee flexion, wound complications, and patellar fracture.¹³⁷

As indicated by the frequency of technical complications reported by Parikh and colleagues,¹¹⁴ extra caution should be taken in the operating room to minimize potential errors. In techniques that require drilling of femoral sockets, proper length for and placement of the graft is essential to reestablish proper kinematics. Studies have reported that placing the femoral socket too proximally can result in loss of ROM during flexion and increased compressive forces across the patella.¹³⁸ A graft that is too short can have similar negative outcomes, and a graft that is too long can result in recurrent instability. Positioning the graft while the knee is in 30° of flexion can help ensure the proper length and tension is achieved. Once the graft is in place, it is important to ensure the ROM and isometry before completing the fixation.⁷² It is also essential to be vigilant about potential violation of the physes and subsequent growth disturbances. To establish the safest angles for drilling the distal femoral epiphysis for graft placement, Nguyen and colleagues¹³⁹ conducted a study using high-resolution 3-dimensional images of cadaveric distal femoral epiphyses. By recording which tunnels disrupted the physis before reaching 20 mm of depth, the authors concluded that it is safest to drill distally and anteriorly at an angle between 15° and 20°.¹³⁹ This technique should minimize damage to the physis, notch, and distal femoral cartilage and decrease potential complications.¹³⁹

OUTCOMES

In general, the literature reports positive outcomes for MPFL reconstruction—in both studies that address a specific technique and all-encompassing studies. Outcomes are typically reported as Kujala and Tegner scores, results from clinical examinations, and rates of subsequence recurrences. Several recent studies have also evaluated the ability of MPFL reconstruction to restore proper kinematics. Edmonds and colleagues¹⁴⁰ evaluated the difference in patellofemoral joint reaction forces and load experienced by 3 groups of adolescents: a cohort treated with MPFL reconstruction, a cohort treated with soft-tissue realignment of the extensor mechanism (the Insall method), and controls. While both surgical techniques were able to restore medial constraints to the patella, the study showed that only the MPFL reconstruction cohort experienced joint reaction forces that were analogous to the control group. In comparison, the cohort that was treated with soft-tissue realignment alone experienced higher patellofemoral joint reaction forces and did not regain normal joint mechanics.¹⁴⁰ These results can be used to advocate for the further use of MPFL reconstruction as an effective anatomic replacement of the native ligament. Radiographic studies have similarly reported MPFL reconstruction as an effective means to restore anatomic normality. Fabricant and colleagues¹⁴¹ conducted a radiographic study in which patella alta was corrected to normal childhood ranges in patients who underwent MPFL reconstruction technique using a hamstring autograft. Lykissas and colleagues¹⁴² corroborated these results with another radiographic study that reported small but significant decreases in the Blackburne-Peel index and CD index following MPFL reconstruction in 25 adolescents. As correction of patella alta allows the patella to rest in a deeper, more secure position in the TG, these results indicate that effective early MPFL reconstruction can correct for patellar anatomic abnormalities that could be future risk factors.^143,144 Several studies have also reported outcomes addressing specific MPFL techniques; these are reported and discussed in this article.

OUTCOMES BY TECHNIQUE

HAMSTRING AUTOGRAFT

Reports on outcomes following MPFL reconstructions using hamstring autografts have been particularly promising. A cohort of 21 skeletally immature patients who underwent MPFL reconstruction was evaluated pre- and postoperatively with an average of a 2.8-year follow-up. The authors of the study reported no redislocation events and significant improvement in the Kujala scores, and patients were able to return to athletic activities safely.¹⁴⁵ Previous studies report similar positive increases in Kujala scores, subjective patient reports, and lack of subsequent redislocation for patients who underwent either semitendinosus or gracilis autograft MPFL reconstructions. One such study further documented an average patellar inclination angle decrease from 34.3° to 18.6° following MPFL reconstruction.¹⁴⁶ However, while the literature typically reports positive Kujala scores and subjective outcomes for the hamstring autograft procedure, a study arthroscopically evaluating patellar tracking immediately following surgery and then at 6 to 26 months follow-up found that patellar tracking correction was not maintained for all patients who underwent this type of MPFL reconstruction.¹⁴⁷

Continue to: QUADRICEPS TENDON TRANSFER OUTCOMES

Studies specifically evaluating the quadriceps tendon transfer technique for MPFL reconstruction in children are sparse, but authors have reported positive clinical outcomes and low complication rates in adults. After following 32 young adults who underwent this MPFL reconstruction technique for 3 years, Goyal¹⁰⁹ reported a significant increase in mean Kujala scores from 49.31 to 91.25 and no complications or redislocation. He argues this type of quadriceps graft has a high success rate because it is anatomically more similar to the MPFL than other grafts and does not require additional patellar fixation.^101,109 Similar positive Kujala scores and minimal complications have been reported in adult patient populations.¹⁴⁸ Abouelsoud and colleagues¹⁴⁹ conducted one of the few studies in skeletally immature patients and reported similarly positive results with no redislocations and significantly improved Kujala scores at a mean follow-up of 29.25 months in their 16-patient cohorts.

ADDUCTOR MAGNUS TENDON TRANSFER

After initially describing this technique in 14 adult patients, Avikainen and colleagues⁹⁶ followed this cohort and reported positive subjective results and only 1 redislocation. In a more recent study in which the adductor tendon transfer technique was compared with the quadriceps tendon transfer described above and the bone-patellar tendon allograft, Steiner and colleagues⁶⁹ reported similarly significant improvement in all cohorts in Lysholm, Kujala, and Tegner scores with no redislocations. Additionally, Malecki and colleagues¹⁵⁰ followed a cohort of 33 children with 39 knees diagnosed with recurrent patellar dislocation, who underwent MPFL reconstruction using the adductor magnus tendon. After evaluating this cohort functionally and radiographically, the authors reported improvements in Lysholm and Kujala scores, patellar tilt and congruence angles, and peak torque of the quadriceps muscle and flexor.¹⁵⁰ However, this cohort did report postoperative redislocations in 36.4% of patients (4 of 11).¹⁵⁰

HEMI-PATELLA TENDON TRANSFER

In 2012, in the first randomized controlled trial, Bitar and colleagues⁶⁷ compared the outcomes of patients who underwent MPFL reconstruction via the hemi-patellar tendon technique with those who were managed nonoperatively with immobilization and physiotherapy after first-time patellar dislocation. At 2-year follow-up, the surgical cohort presented positive results with a significantly higher mean Kujala score (88.9 to 70.8) and no redislocations or subluxations. In contrast, 35% of nonoperative cases presented with recurrences and subluxations over the 2-year period.⁶⁷

MCL OR ADDUCTOR TENDON AS A PULLEY

Studies have reported good postoperative results and low complication rates for these dynamic techniques.^128,129 In terms of kinematics, while hypermobility and patellar height were not fully corrected, improvements in patellar tilt and lateral shift were reported in a cohort of 6 patients with a minimum 4-year follow-up.¹²⁹ To further evaluate whether the more dynamic pulley reconstruction technique resulted in better outcomes, Gomes and colleagues¹²⁸ compared the subjective reports, clinical evaluations, and complication rates of patients who underwent MPFL reconstruction with a rigid adductor magnus fixation vs a semitendinosus tendon dynamic femoral fixation. One case in the rigid cohort experienced a subsequent subluxation, while patients in the semitendinosus group had better subjective reports and a higher rate of return to sport.¹²⁸ More recently, Kumahashi and colleagues¹⁵¹ specifically studied the outcomes of the MCL tendon as a pulley in 5 patients aged 14 to 15 years. They reported similar successful results as no patients experienced recurrence, and all patients exhibited improvement in radiographic measures of patellar tilt and congruence angle, lateral shift ratio, and both Kujala and Lysholm scores.¹⁵¹

While there has yet to be a randomized controlled trial comparing all of these different techniques, there is a general consensus in the literature that patients tend to perform better following MPFL reconstruction vs MPFL repair.

OTHER STABILIZATION PROCEDURES, INCLUDING DISTAL REALIGNMENT

Patients with additional underlying deficits and malalignment issues such as significant trochlear dysplasia, increased TT-TG distance, patella alta, increased Q angle, and/or positive J sign may require stabilization procedures beyond MPFL reconstruction.^152,153 TT osteotomies are often used to correct alignment issues in the adult patient population; however, these procedures are typically contraindicated in skeletally immature patients. Alternative realignment procedures for the pediatric population include both proximal and distal realignment, with proximal realignment performed primarily in children under the age of 12 years.¹⁵³ Many variations on these procedures exist, some of which are no longer regularly performed due to poor reported outcomes. In this article, we discuss several of the techniques, focusing primarily on those that have demonstrated higher success rates.

Continue to: GALEAZZI TECHNIQUE

One of the first and most famous soft-tissue techniques to address patellar instability was the semitendinosus tenodesis, published by Galeazzi¹⁵⁴ in 1922 (Figure 7). This technique stabilizes the patella without altering the TT. In the original technique, a portion of the semitendinosus tendon is harvested with its tibial insertion left intact. The free end of the tendon is then secured with sutures at the periosteal groove of the medial patella.^154,155 Fiume¹⁵⁶ modified this technique by adding a lateral release and medial retinacular reefing. The most recent addition to this procedure was introduced by Baker and colleagues,¹⁵⁷ in which a tunnel is drilled from the medial to the lateral border of the patella. Tension placed on the grafted tendon is used to reposition the patella medially and draw it downward. Preliminary literature on this modified procedure reported fair clinical results with success rates of approximately 75%.^155,158-160 A recent study evaluating both the clinical and radiographic outcomes of this technique also indicated that while clinical results were excellent in 62.5% of patients, this technique alone was unsuccessful in fully addressing patellar instability in patients with underlying anatomic abnormalities such as patellar alta.¹⁶¹ In light of these less than ideal reports, the authors no longer recommend this technique for patellofemoral instability cases.

ROUX-GOLDTHWAIT PROCEDURE

The Roux-Goldthwait procedure, first described by both Roux¹⁶² and Goldthwait¹⁶³ in 1888 and 1895 respectively, was later modified in 1985 to involve a lateral release, plication of the medial retinaculum, medial transfer of the lateral patellar tendon without advancement, and advancement of the vastus medialis (Figure 8).¹⁶⁴ More recently, Marsh and colleagues¹⁵² introduced an addition to aligning the extensor mechanism with the femoral shaft better. In this technique modification, the patellar tendon is split longitudinally, and its lateral half is detached and transferred distally beneath its medial half. The free end is then sutured to the periosteum on the medial side of the tibia.¹⁵² With a mean long-term follow-up of 6.2 years, Marsh and colleagues¹⁵² reported excellent results in 65%, good in 11%, and fair in 3% of the knees operated on with this modified technique. Of the patients in this cohort whose strength was evaluated, 80% had their strength returned to 90% of preoperative levels in the operated leg.¹⁵² While this study and others report improved outcomes, an increasing body of literature has found high rates of recurrence, patella infera, and other complications following the modified Roux-Goldthwait procedure.^36,165-171 Also, a study comparing MPFL reconstruction using adductus magnus transfer with the Roux-Goldthwait procedure reported that patients in the MPFL cohort reported less pain postoperatively.¹⁵⁰ In addition, whereas the Kujala and Lysholm scores, recurrence rates, patellofemoral angles, and apprehension test results did not demonstrate significant differences between these 2 groups, the MPFL group had significantly fewer abnormal congruence angles, better patellar medialization, and higher peak torque of the hamstring.¹⁵⁰

COMBINED MPFL AND MEDIAL PATELLOTIBIAL LIGAMENT RECONSTRUCTION

While the medial patellotibial ligament (MPTL) has not received much attention with regard to patellar stability, recent studies have indicated its role during higher degrees of both flexion and extension.¹⁷² The MPTL acts as a secondary restrictor ligament which helps release stress on the MPFL by decreasing the Q angle and further normalizing patellar kinematics.¹⁷³ Patients who present with hyperlaxity or knee hyperextension combined with extension subluxation and flexion instability could be indicated for this additional stabilizing procedure. Both Nietosvaara and colleagues⁸⁵ and Brown and Ahmad¹⁷⁴ have described a dual MPTL and MPFL reconstruction technique using a semitendinosus hamstring graft. More recently Hinckel and colleagues¹⁷² described a combined MPFL and MPTL reconstruction, using a graft from the quadriceps tendon to reconstruct the MPFL and one from the patellar tendon to reconstruct the MPTL. In this technique, once the respective grafts have been harvested, a femoral insertion for the graft recreating the MPFL is fluoroscopically established so that an anchor can be inserted distal to the femoral physeal growth plate. For the MPTL insertion, attachment to the tibia below the joint line and 2 cm medial to the patellar tendon is established fluoroscopically just above the physeal growth plate on the proximal epiphysis.^19,175 The MPTL graft is sutured first with the knee at 90° of flexion to establish tension similar to that of the patellar tendon.¹⁷⁶ Then, the knee is placed in 30° of flexion to fix the MPFL graft to the medial patella to prevent excessive lateral translation of the patella.

PATELLAR TENDON TRANSFER

Patellar tendon transfer with proximal realignment is a technique used in particularly young patients to address cases of patellofemoral instability involving concomitant bony or anatomic abnormalities. This procedure is effective for young children with substantial amounts of remaining growth as it better mimics native anatomy than other realignment procedures and does not require bony remodeling.^152-154 It is important to familiarize with surgical techniques to address malalignment issues in young patients as neglected alignment issues can lead to worsening of trochlear dysplasia and instability, which are very difficult to treat later on when patients are older.¹⁵³

The patellar tendon transfer technique (Figure 9), as described by Gordon and Schoenecker,¹⁷⁷ starts with an extensive lateral retinacular release. The patellar tendon is then released from its distal insertion at the TT so that it can be moved medially without moving it inferiorly. After confirming patellar tracking and alignment by flexing the knee from 0° to 90° with the graft in place, the patellar tendon graft is secured with multiple nonabsorbable horizontal sutures.¹⁷⁷ Of note, in skeletally mature patients, a TT osteotomy is used to accomplish the same goal. This osteotomy has been shown to improve both patellar height and TT-TG distance in skeletally mature patients, but is contraindicated in skeletally immature patients.^92,178

Continue to: Initial studies conducted on patellar tendon...

Initial studies conducted on patellar tendon transfer have positive outcomes.¹⁷⁹ At a mean follow-up of 5.1 years, patients reported a decrease in pain and increased the ROM and activity, and only 1 reported a postoperative redislocation.¹⁷⁹ In more recent studies, both Benoit and colleagues³⁶ and Garin and colleagues⁵⁸ reviewed cases of patellar instability treated with patellar tendon transfer to address concomitant patellar alignment and anatomic abnormalities. They reported good functional, clinical, and radiographic outcomes with 12.5% and 16% recurrence rates, respectively.^36,58 They also noted radiographic improvements in femoral sulcus angle, particularly in younger patients, which indicate this procedure is effective in addressing bony abnormalities that can result from neglected malalignment issues.^36,58,154

QUADRICEPSPLASTY

Quadricepsplasty is a lengthening and remodeling technique not frequently used in the pediatric population. The goal of this procedure in patients with significant amounts of growth remaining is to reposition the patella to ameliorate trochlear remodeling and prevent worsening symptoms and anatomic abnormalities.³⁶ A quadricepsplasty accomplishes this by de-rotating and/or lengthening the extensor mechanism and may or may not involve a concomitant MPFL reconstruction. This procedure is particularly effective in young patients who experience obligatory dislocation.^60,72 Several quadricepsplasty techniques have been described including Thompson, Curtis and Fisher, Judet, Stanisavljevic, and V-Y technique.^180-186 Most techniques initially involve sharp dissection of the vastus medialis and lateralis from the rectus femoral tendon. A tongue is then fashioned out of the rectus femoral tendon. Once the vastus medialis and lateralis are detached from the margins of the patella, the knee is extended, and the distal ends of the vasti are sutured to the tongue of the rectus tendon. Effective extension facilitates flexion to 90°.¹⁸⁴ The authors recommend a modification of this technique in which a Z lengthening of the quadriceps tendon is performed after the vastus lateralis is removed distally from the patella and the quadriceps tendon.

Several series and case reports evaluating quadricepsplasty in adult patients report positive outcomes with most patients achieving good or excellent flexion with minimal complications.^{183,185,187-189} Reports on quadricepsplasty used to treat conditions other than patellofemoral instability in children have reported similar positive outcomes.^190-192 As quadricepsplasty for patellar instability is relatively rare in pediatric patients, there is not much relevant literature. However, Kocon and colleagues¹⁹³ reported results of quadricepsplasty and quadricepsplasty combined with the modified Galeazzi procedure in 8 children (10 knees) with a mean follow-up of 3.25 years. Seventy percent of cases resulted in stabilization and correction of patellar position, and only 2 postoperative redislocations were noted.¹⁹³ Additionally, in a study evaluating 6 patients suffering from patellar instability, 2 of whom were obligate dislocators, quadricepsplasty resulted in patellar stability, satisfaction, and near normal gait patterns.¹⁹⁴

Figure 10 shows the surgical algorithm used for patellar instability characteristics.

CONCLUSION

Patellofemoral joint stability relies on a complex interplay of musculotendinous units, ligaments and the osteocartilaginous morphology of the patellofemoral joint. Patellar instability in pediatric patients is different from adults. Having an in-depth understanding of the remodeling potential, the insertion sites for the MPFL and its relationship to the physis are of utmost importance when planning surgery. Reducing and maintaining the patella within the patellofemoral joint early enough can allow for remodeling of the patella and/or the trochlea to provide for lasting stability. Appropriate surgical principles, such as tensioning, can help both prevent continued pain and minimize future complications.