Clinical Review

BY DOUG BRUNK

FRONTLINE MEDICAL NEWS

As the spread of the Zika virus continues to garner attention in the national spotlight, two other mosquito-borne viral infections pose a potential threat to the United States: dengue fever and chikungunya.

At the annual meeting of the Pacific Dermatologic Association, Iris Z. Ahronowitz, MD, shared tips on how to spot and diagnose patients with these viral infections.

“You really need to use all the data at your disposal, including a thorough symptom history, a thorough exposure history, and of course, our most important tool in all of this: our eyes,” said Dr Ahronowitz, a dermatologist at the University of Southern California, Los Angeles. Reaching a diagnosis involves asking about epidemiologic exposure, symptoms, morphology, and performing confirmatory testing by polymerase chain reaction (PCR) and/or enzyme-linked immunosorbent assay (ELISA). “Unfortunately we are not getting these results very quickly,” she said. “Sometimes the turnaround time can be 3 weeks or longer.”

She discussed the case of a 32-year-old woman who had returned from travel to Central Mexico. Two days later, the patient developed fever, fatigue, and retro-orbital headache, as well as flushing macular erythema over the chest. Three days later, she developed a generalized morbilliform eruption. Her white blood cell count was 1.5 x 10⁹/L, platelet count was 37 x 10⁹/L, aspartate aminotransferase (AST) was 124 U/L, and alanine aminotransferase (ALT) was 87 U/L.

The differential diagnosis for morbilliform eruption plus fever in a returning traveler is extensive, Dr Ahronowitz said. It includes measles, chikungunya, West Nile virus, O’nyong-nyong virus, Mayaro virus, Sindbis virus, Ross river disease, Ebola/Marburg, dengue, and Zika. Bacterial/rickettsial possibilities include typhoid fever, typhus, and leptospirosis.

The patient was ultimately diagnosed with dengue virus, a mosquito-borne flavivirus. Five serotypes have been identified, the most recent in 2013. According to Dr Ahronowitz, dengue ranks as the most common febrile illness in travelers returning from the Caribbean, South America, and Southeast Asia. “There are up to 100 million cases every year, 40% of the world population is at risk, and an estimated 80% of people are asymptomatic carriers, which is facilitating the spread of this disease,” she said. The most common vector is Aedes aegypti, a daytime biting mosquito that is endemic to the tropics and subtropics. But a new vector is emerging, Aedes albopictus, which is common in temperate areas. “Both types of mosquitoes are in the United States, and they’re spreading rapidly,” she said. “This is probably due to a combination of climate change and international travel.”

Dengue classically presents with sudden onset of fever, headache, retro-orbital pain, and severe myalgia; 50% to 82% of cases develop a distinctive rash. “While most viruses have nonspecific lab abnormalities, one that can be very helpful to you with suspected dengue is thrombocytopenia,” she said. “The incubation period ranges from 3 to 14 days.”

Rashes associated with dengue are classically biphasic and sequential. The initial rash occurs within 24 to 48 hours of symptom onset and is often mistaken for sunburn, with a flushing erythema of the face, neck, and chest. Three to 5 days later, a subsequent rash develops that starts out as a generalized morbilliform eruption but becomes confluent with petechiae and islands of sparing. “It’s been described as ‘white islands in a sea of red,’” Dr Ahronowitz said.

A more severe form of the disease, dengue hemorrhagic fever, is characterized by extensive purpura and bleeding from mucosa, gastrointestinal tract, and injection sites. “The patients who get this have prior immunity to a different serotype,” she said. “This is thought to be due to a phenomenon called antibody-dependent enhancement, whereby the presence of preexisting antibodies facilitates entry of the virus and produces a more robust inflammatory response. Most of these patients, even the ones with severe dengue, recover fully. The most common long-term sequela we’re seeing is chronic fatigue.”

The diagnosis is made with viral PCR from serum less than 7 days from onset of symptoms, or immunoglobulin M (IgM)ELISA more than 4 days from onset of symptoms. The treatment is supportive care with fluid resuscitation and analgesia; there is no specific treatment. “Do not give nonsteroidal anti-­inflammatory drugs (NSAIDs) which can potentiate hemorrhage; give acetaminophen for pain and fevers,” she advised. “A tetravalent vaccine is now available for dengue. Prevention is so important because there is no treatment.”

Next, Dr Ahronowitz discussed the case of a 38-year-old man who returned from travel to Bangladesh. Two days after returning he developed fever to 104˚F, headache, and cervical lymphadenopathy. Three days after returning, he developed severe pain in the wrist, knees, and ankles, and a rash. “This rash was not specific; it was a morbilliform eruption primarily on the chest,” she said.

The patient was ultimately diagnosed with chikungunya, a single-strand RNA mosquito-borne virus with the same vectors as dengue. “This has been wreaking havoc across the Caribbean in the past few years,” Dr Ahronowitz said. “Chikungunya was first identified in the Americas in 2013, and there have been hundreds of thousands of cases in the Caribbean.” The first case acquired in the United States occurred in Florida in the summer of 2014. As of January 2016 there were 679 imported cases of the infection in the United States. “Fortunately, this most recent epidemic is slowing down a bit, but it’s important to be aware of,” she said.

Clinical presentation of chikungunya includes an incubation period of 3 to 7 days, acute onset of high fevers, chills, and myalgia. Nonspecific exanthem around 3 days occurs in 40% to 75% of cases, and symmetric polyarthralgias are common in the fingers, wrists, and ankles. Labs may reveal lymphopenia, acute kidney injury, and elevated AST and ALT levels. Acute symptoms resolve within 7 to 10 days.

Besides the rash, other cutaneous signs of the disease include aphthous-like ulcers and anogenital ulcers, particularly around the scrotum. Other patients may present with facial hyperpigmentation, also known as “brownie nose,” that appears with the rash. In babies, bullous lesions can occur. More than 20% of patients who acquire chikungunya still have severe joint pain 1 year after initial presentation. “This can be really debilitating,” she said. “A subset of patients will develop an inflammatory seronegative rheumatoid-like arthritis. It’s generally not a fatal condition except in the extremes of age and in people with a lot of comorbidities. Most people recover fully.”

As in dengue, clinicians can diagnose chikungunya by viral culture in the first 3 days of illness, and by reverse transcription PCR in the first 8 days of illness. On serology, IgM is positive by 5 days of symptom onset.

“If testing is not available locally, contact the Centers for Disease Control and Prevention,” Dr Ahronowitz said. “Treatment is supportive. Evaluate for and treat potential coinfections, including dengue, malaria, and bacterial infections. If dengue is in the differential diagnosis, avoid NSAIDs.” A new vaccine for chikungunya is currently in phase II trials.

BY DOUG BRUNK

FRONTLINE MEDICAL NEWS

As the spread of the Zika virus continues to garner attention in the national spotlight, two other mosquito-borne viral infections pose a potential threat to the United States: dengue fever and chikungunya.

At the annual meeting of the Pacific Dermatologic Association, Iris Z. Ahronowitz, MD, shared tips on how to spot and diagnose patients with these viral infections.

“You really need to use all the data at your disposal, including a thorough symptom history, a thorough exposure history, and of course, our most important tool in all of this: our eyes,” said Dr Ahronowitz, a dermatologist at the University of Southern California, Los Angeles. Reaching a diagnosis involves asking about epidemiologic exposure, symptoms, morphology, and performing confirmatory testing by polymerase chain reaction (PCR) and/or enzyme-linked immunosorbent assay (ELISA). “Unfortunately we are not getting these results very quickly,” she said. “Sometimes the turnaround time can be 3 weeks or longer.”

She discussed the case of a 32-year-old woman who had returned from travel to Central Mexico. Two days later, the patient developed fever, fatigue, and retro-orbital headache, as well as flushing macular erythema over the chest. Three days later, she developed a generalized morbilliform eruption. Her white blood cell count was 1.5 x 10⁹/L, platelet count was 37 x 10⁹/L, aspartate aminotransferase (AST) was 124 U/L, and alanine aminotransferase (ALT) was 87 U/L.

The differential diagnosis for morbilliform eruption plus fever in a returning traveler is extensive, Dr Ahronowitz said. It includes measles, chikungunya, West Nile virus, O’nyong-nyong virus, Mayaro virus, Sindbis virus, Ross river disease, Ebola/Marburg, dengue, and Zika. Bacterial/rickettsial possibilities include typhoid fever, typhus, and leptospirosis.

The patient was ultimately diagnosed with dengue virus, a mosquito-borne flavivirus. Five serotypes have been identified, the most recent in 2013. According to Dr Ahronowitz, dengue ranks as the most common febrile illness in travelers returning from the Caribbean, South America, and Southeast Asia. “There are up to 100 million cases every year, 40% of the world population is at risk, and an estimated 80% of people are asymptomatic carriers, which is facilitating the spread of this disease,” she said. The most common vector is Aedes aegypti, a daytime biting mosquito that is endemic to the tropics and subtropics. But a new vector is emerging, Aedes albopictus, which is common in temperate areas. “Both types of mosquitoes are in the United States, and they’re spreading rapidly,” she said. “This is probably due to a combination of climate change and international travel.”

Dengue classically presents with sudden onset of fever, headache, retro-orbital pain, and severe myalgia; 50% to 82% of cases develop a distinctive rash. “While most viruses have nonspecific lab abnormalities, one that can be very helpful to you with suspected dengue is thrombocytopenia,” she said. “The incubation period ranges from 3 to 14 days.”

Rashes associated with dengue are classically biphasic and sequential. The initial rash occurs within 24 to 48 hours of symptom onset and is often mistaken for sunburn, with a flushing erythema of the face, neck, and chest. Three to 5 days later, a subsequent rash develops that starts out as a generalized morbilliform eruption but becomes confluent with petechiae and islands of sparing. “It’s been described as ‘white islands in a sea of red,’” Dr Ahronowitz said.

A more severe form of the disease, dengue hemorrhagic fever, is characterized by extensive purpura and bleeding from mucosa, gastrointestinal tract, and injection sites. “The patients who get this have prior immunity to a different serotype,” she said. “This is thought to be due to a phenomenon called antibody-dependent enhancement, whereby the presence of preexisting antibodies facilitates entry of the virus and produces a more robust inflammatory response. Most of these patients, even the ones with severe dengue, recover fully. The most common long-term sequela we’re seeing is chronic fatigue.”

The diagnosis is made with viral PCR from serum less than 7 days from onset of symptoms, or immunoglobulin M (IgM)ELISA more than 4 days from onset of symptoms. The treatment is supportive care with fluid resuscitation and analgesia; there is no specific treatment. “Do not give nonsteroidal anti-­inflammatory drugs (NSAIDs) which can potentiate hemorrhage; give acetaminophen for pain and fevers,” she advised. “A tetravalent vaccine is now available for dengue. Prevention is so important because there is no treatment.”

Next, Dr Ahronowitz discussed the case of a 38-year-old man who returned from travel to Bangladesh. Two days after returning he developed fever to 104˚F, headache, and cervical lymphadenopathy. Three days after returning, he developed severe pain in the wrist, knees, and ankles, and a rash. “This rash was not specific; it was a morbilliform eruption primarily on the chest,” she said.

The patient was ultimately diagnosed with chikungunya, a single-strand RNA mosquito-borne virus with the same vectors as dengue. “This has been wreaking havoc across the Caribbean in the past few years,” Dr Ahronowitz said. “Chikungunya was first identified in the Americas in 2013, and there have been hundreds of thousands of cases in the Caribbean.” The first case acquired in the United States occurred in Florida in the summer of 2014. As of January 2016 there were 679 imported cases of the infection in the United States. “Fortunately, this most recent epidemic is slowing down a bit, but it’s important to be aware of,” she said.

Clinical presentation of chikungunya includes an incubation period of 3 to 7 days, acute onset of high fevers, chills, and myalgia. Nonspecific exanthem around 3 days occurs in 40% to 75% of cases, and symmetric polyarthralgias are common in the fingers, wrists, and ankles. Labs may reveal lymphopenia, acute kidney injury, and elevated AST and ALT levels. Acute symptoms resolve within 7 to 10 days.

Besides the rash, other cutaneous signs of the disease include aphthous-like ulcers and anogenital ulcers, particularly around the scrotum. Other patients may present with facial hyperpigmentation, also known as “brownie nose,” that appears with the rash. In babies, bullous lesions can occur. More than 20% of patients who acquire chikungunya still have severe joint pain 1 year after initial presentation. “This can be really debilitating,” she said. “A subset of patients will develop an inflammatory seronegative rheumatoid-like arthritis. It’s generally not a fatal condition except in the extremes of age and in people with a lot of comorbidities. Most people recover fully.”

As in dengue, clinicians can diagnose chikungunya by viral culture in the first 3 days of illness, and by reverse transcription PCR in the first 8 days of illness. On serology, IgM is positive by 5 days of symptom onset.

“If testing is not available locally, contact the Centers for Disease Control and Prevention,” Dr Ahronowitz said. “Treatment is supportive. Evaluate for and treat potential coinfections, including dengue, malaria, and bacterial infections. If dengue is in the differential diagnosis, avoid NSAIDs.” A new vaccine for chikungunya is currently in phase II trials.

BY DOUG BRUNK

FRONTLINE MEDICAL NEWS

As the spread of the Zika virus continues to garner attention in the national spotlight, two other mosquito-borne viral infections pose a potential threat to the United States: dengue fever and chikungunya.

At the annual meeting of the Pacific Dermatologic Association, Iris Z. Ahronowitz, MD, shared tips on how to spot and diagnose patients with these viral infections.

“You really need to use all the data at your disposal, including a thorough symptom history, a thorough exposure history, and of course, our most important tool in all of this: our eyes,” said Dr Ahronowitz, a dermatologist at the University of Southern California, Los Angeles. Reaching a diagnosis involves asking about epidemiologic exposure, symptoms, morphology, and performing confirmatory testing by polymerase chain reaction (PCR) and/or enzyme-linked immunosorbent assay (ELISA). “Unfortunately we are not getting these results very quickly,” she said. “Sometimes the turnaround time can be 3 weeks or longer.”

She discussed the case of a 32-year-old woman who had returned from travel to Central Mexico. Two days later, the patient developed fever, fatigue, and retro-orbital headache, as well as flushing macular erythema over the chest. Three days later, she developed a generalized morbilliform eruption. Her white blood cell count was 1.5 x 10⁹/L, platelet count was 37 x 10⁹/L, aspartate aminotransferase (AST) was 124 U/L, and alanine aminotransferase (ALT) was 87 U/L.

The differential diagnosis for morbilliform eruption plus fever in a returning traveler is extensive, Dr Ahronowitz said. It includes measles, chikungunya, West Nile virus, O’nyong-nyong virus, Mayaro virus, Sindbis virus, Ross river disease, Ebola/Marburg, dengue, and Zika. Bacterial/rickettsial possibilities include typhoid fever, typhus, and leptospirosis.

The patient was ultimately diagnosed with dengue virus, a mosquito-borne flavivirus. Five serotypes have been identified, the most recent in 2013. According to Dr Ahronowitz, dengue ranks as the most common febrile illness in travelers returning from the Caribbean, South America, and Southeast Asia. “There are up to 100 million cases every year, 40% of the world population is at risk, and an estimated 80% of people are asymptomatic carriers, which is facilitating the spread of this disease,” she said. The most common vector is Aedes aegypti, a daytime biting mosquito that is endemic to the tropics and subtropics. But a new vector is emerging, Aedes albopictus, which is common in temperate areas. “Both types of mosquitoes are in the United States, and they’re spreading rapidly,” she said. “This is probably due to a combination of climate change and international travel.”

Dengue classically presents with sudden onset of fever, headache, retro-orbital pain, and severe myalgia; 50% to 82% of cases develop a distinctive rash. “While most viruses have nonspecific lab abnormalities, one that can be very helpful to you with suspected dengue is thrombocytopenia,” she said. “The incubation period ranges from 3 to 14 days.”

Rashes associated with dengue are classically biphasic and sequential. The initial rash occurs within 24 to 48 hours of symptom onset and is often mistaken for sunburn, with a flushing erythema of the face, neck, and chest. Three to 5 days later, a subsequent rash develops that starts out as a generalized morbilliform eruption but becomes confluent with petechiae and islands of sparing. “It’s been described as ‘white islands in a sea of red,’” Dr Ahronowitz said.

A more severe form of the disease, dengue hemorrhagic fever, is characterized by extensive purpura and bleeding from mucosa, gastrointestinal tract, and injection sites. “The patients who get this have prior immunity to a different serotype,” she said. “This is thought to be due to a phenomenon called antibody-dependent enhancement, whereby the presence of preexisting antibodies facilitates entry of the virus and produces a more robust inflammatory response. Most of these patients, even the ones with severe dengue, recover fully. The most common long-term sequela we’re seeing is chronic fatigue.”

The diagnosis is made with viral PCR from serum less than 7 days from onset of symptoms, or immunoglobulin M (IgM)ELISA more than 4 days from onset of symptoms. The treatment is supportive care with fluid resuscitation and analgesia; there is no specific treatment. “Do not give nonsteroidal anti-­inflammatory drugs (NSAIDs) which can potentiate hemorrhage; give acetaminophen for pain and fevers,” she advised. “A tetravalent vaccine is now available for dengue. Prevention is so important because there is no treatment.”

Next, Dr Ahronowitz discussed the case of a 38-year-old man who returned from travel to Bangladesh. Two days after returning he developed fever to 104˚F, headache, and cervical lymphadenopathy. Three days after returning, he developed severe pain in the wrist, knees, and ankles, and a rash. “This rash was not specific; it was a morbilliform eruption primarily on the chest,” she said.

The patient was ultimately diagnosed with chikungunya, a single-strand RNA mosquito-borne virus with the same vectors as dengue. “This has been wreaking havoc across the Caribbean in the past few years,” Dr Ahronowitz said. “Chikungunya was first identified in the Americas in 2013, and there have been hundreds of thousands of cases in the Caribbean.” The first case acquired in the United States occurred in Florida in the summer of 2014. As of January 2016 there were 679 imported cases of the infection in the United States. “Fortunately, this most recent epidemic is slowing down a bit, but it’s important to be aware of,” she said.

Clinical presentation of chikungunya includes an incubation period of 3 to 7 days, acute onset of high fevers, chills, and myalgia. Nonspecific exanthem around 3 days occurs in 40% to 75% of cases, and symmetric polyarthralgias are common in the fingers, wrists, and ankles. Labs may reveal lymphopenia, acute kidney injury, and elevated AST and ALT levels. Acute symptoms resolve within 7 to 10 days.

Besides the rash, other cutaneous signs of the disease include aphthous-like ulcers and anogenital ulcers, particularly around the scrotum. Other patients may present with facial hyperpigmentation, also known as “brownie nose,” that appears with the rash. In babies, bullous lesions can occur. More than 20% of patients who acquire chikungunya still have severe joint pain 1 year after initial presentation. “This can be really debilitating,” she said. “A subset of patients will develop an inflammatory seronegative rheumatoid-like arthritis. It’s generally not a fatal condition except in the extremes of age and in people with a lot of comorbidities. Most people recover fully.”

As in dengue, clinicians can diagnose chikungunya by viral culture in the first 3 days of illness, and by reverse transcription PCR in the first 8 days of illness. On serology, IgM is positive by 5 days of symptom onset.

“If testing is not available locally, contact the Centers for Disease Control and Prevention,” Dr Ahronowitz said. “Treatment is supportive. Evaluate for and treat potential coinfections, including dengue, malaria, and bacterial infections. If dengue is in the differential diagnosis, avoid NSAIDs.” A new vaccine for chikungunya is currently in phase II trials.

An increasingly number of patients with symptomatic isolated medial unicompartmental knee osteoarthritis (OA) are too young and too functionally active to be ideal candidates for total knee arthroplasty (TKA). Isolated medial compartment OA occurs in 10% to 29.5% of all cases, whereas the isolated lateral variant is less common, with a reported incidence of 1% to 7%.^1,2 In 1961, Jackson and Waugh³ introduced the high tibial osteotomy (HTO) as a surgical treatment for single-compartment OA. This procedure is designed to increase the life span of articular cartilage by unloading and redistributing the mechanical forces over the nonaffected compartment. Unicompartmental knee arthroplasty (UKA) was introduced in the 1970s as an alternative to TKA or HTO for single-compartment OA.

Since the introduction of these methods, there has been debate about which patients are appropriate candidates for each procedure. Improved surgical techniques and implant designs have led surgeons to reexamine the selection criteria and contraindications for these procedures. Furthermore, given the increasing popularity and use of UKA, the question arises as to whether HTO still has a role in clinical practice in the surgical treatment of medial OA of the knee.

To clarify current ambiguities, we review the modern indications, subjective outcome scores, and survivorship results of UKA and HTO in the treatment of isolated medial compartment degeneration of the knee. In addition, in a thorough review of the literature, we evaluate global trends in the use of both methods.

High Tibial Osteotomy for Medial Compartment OA

Indications

Before the introduction of TKA and UKA for single-compartment OA, surgical management consisted of HTO. When the mechanical axis is slightly overcorrected, the medial compartment is decompressed, ensuring tissue viability and delaying progressive compartment degeneration.

Traditionally, HTO is indicated for young (age <60 years), normal-weight, active patients with radiographic single-compartment OA.⁶ The knee should be stable and have good range of motion (ROM; flexion >120°), and pain should be localized to the tibiofemoral joint line.

Over the past few decades, numerous authors have reported similar inclusion criteria, clarifying their definition. This definition should be further refined in order to optimize survivorship and clinical outcomes.

Confirming age as an inclusion criterion for HTO, Trieb and colleagues⁷ found that the risk of failure was significantly (P = .046) higher for HTO patients older than 65 years than for those younger than 65 years (relative risk, 1.5). This finding agrees with findings of other studies, which suggests that, in particular, young patients benefit from HTO.^8-11

Moreover, there is a clear relation between HTO survival and obesity. In a study of 159 CWHTOs, Akizuki and colleagues¹² reported that preoperative body mass index (BMI) higher than 27.5 kg/m² was a significant risk factor for early failure. Using BMI higher than 30 kg/m² as a threshold, Howells and colleagues⁹ found significantly inferior Knee Society Score (KSS) and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) results for the obese group 5 years after HTO.

Radiographic evidence of severe preoperative compartment degeneration has been associated with early conversion to TKA. Flecher and colleagues¹¹ and van Raaij and colleagues¹³ both concluded the best long-term survival grades are achieved in HTO patients with mild compartment OA (Ahlbäck^14 grade I). The question then becomes whether these patients should be treated nonoperatively instead.^15,16The literature supports strict adherence to inclusion criteria in the selection of a potential HTO candidate. Age, BMI, and the preoperative state of OA should be taken into account in order to optimize clinical outcome and survivorship results in patients about to undergo HTO.

Outcomes

Multiple authors have described or compared the midterm or long-term results of the various surgical HTO techniques. Howells and colleagues⁹ noted overall survival rates of 87% (5 years after CWHTO) and 79% (10 years after CWHTO). Over the 10-year postoperative period, there was significant deterioration in clinical outcome scores and survivorship. Others authors have had similar findings.^17-19 van Raaij and colleagues¹³ found that the 10-year probability of survival after CWHTO was 75%. In 455 patients who underwent lateral CWHTO, Hui and colleagues⁸ found that 5-year probability of survival was 95%, 10-year probability was 79%, and 15-year probability was 56%. Niinimäki and colleagues¹⁰ used the Finnish Arthroplasty Register to report HTO survivorship at a national level. Using conversion to TKA as a cutoff, they noted 5-year survivorship of 89% and 10-year survivorship of 73%. To our knowledge, 2 groups, both in Japan, have reported substantially higher 15-year survival rates: 90%¹² and 93%.²⁰ The authors acknowledged that their results were significantly better than in other countries and that Japanese lifestyle, culture, and body habitus therefore require further investigation. At this time, it is not possible to compare their results with Western results.

In an attempt to compare the different survival rates of the various HTO techniques, Schallberger and colleagues²¹ conducted a retrospective study of OWHTOs and CWHTOs. At median follow-up of 16.5 years, comparative survival rates showed a trend of deterioration. Although data were limited, there were no significant differences in survival or functional outcome between the 2 techniques. In a recent randomized clinical trial, Duivenvoorden and colleagues⁵ compared these techniques’ midterm results (mean follow-up, 6 years). Clinical outcomes were not significantly different. There were more complications in the OWHTO group and more conversions to TKA in the CWHTO group. Considering these results, the authors suggested OWHTO without autologous bone graft is the best HTO treatment strategy for medial gonarthritis with varus malalignment of <12°.

The HTO results noted in these studies show a similar deteriorating trend; expected 10-year survivorship is 75%. Although modern implants and surgical techniques are being used, evidence supporting use of one surgical HTO method over another is lacking.

UKA for Medial Compartment OA

Indications

Since it was first introduced in the 1970s, use of UKA for single-compartment OA has been a subject of debate. The high failure rates reported at the time raised skepticism about the new treatment.²² Kozinn and Scott²³ defined classic indications and contraindications. Indications included isolated medial or lateral compartment OA or osteonecrosis of the knee, age over 60 years, and weight under 82 kg. In addition, the angular deformity of the affected lower extremity had to be <15° and passively correctable to neutral at time of surgery. Last, the flexion contracture had to be <5°, and ideal ROM was 90°. Contraindications included high activity, age under 60 years, and inflammatory arthritis. Strict adherence led to improved implant survival and lower revision rates. Because of improved surgical techniques, modern implant designs, and accumulating experience with the procedure, the surgical indications for UKA have expanded. Exact thresholds for UKA inclusion, however, remain unclear.

The modern literature is overturning the traditional idea that UKA is not indicated for patients under age 60 years.²³ Using KSS, Thompson and colleagues²⁴ found that younger patients did better than older patients 2 years after UKA using various types of implants. Analyzing survivorship results, Heyse and colleagues²⁵ concluded that UKA can be successful in patients under age 60 years and reported a 15-year survivorship rate of 85.6% and excellent outcome scores. Other authors have had similar findings.^26-28

Evaluating the influence of weight, Thompson and colleagues²⁴ found obese patients did not have a higher revision rate but did have slower progression of improvement 2 years after UKA. Cavaignac and colleagues²⁹ concluded that, at minimum follow-up of 7 years (range, 7-22 years), weight did not influence UKA survivorship. Other authors^30-33 have found no significant influence of BMI on survival.

Reports on preoperative radiographic parameters that can potentially influence UKA results are limited. In 113 medial UKAs studied by Niinimäki and colleagues,³⁴ mild medial compartment degeneration, seen on preoperative radiographs, was associated with significantly higher failure rates. The authors concluded that other treatment options should be favored in the absence of severe isolated compartment OA.

Although the classic indications defined by Kozinn and Scott²³ have yielded good to excellent UKA results, improvements in implants and surgical techniques^35-38 have extended the criteria. The modern literature demonstrates that age and BMI should not be used as criteria for excluding UKA candidates. Radiographically, there should be significant isolated compartment degeneration in order to optimize patient-reported outcome and survivorship.

Outcomes

Improved implant designs and modern minimally invasive techniques have effected a change in outcome results and a renewed interest in implants. Over the past decade, multiple authors have described the various modern UKA implants and their survivorship. Reports published since UKA was introduced in the 1970s show a continual increase in implant survival. Koskinen and colleagues,³⁹ using Finnish Arthroplasty Register data on 1819 UKAs performed between 1985 and 2003, found 10-year survival rates of 81% for Oxford implants (Zimmer Biomet), 79% for Miller-Galante II (Zimmer Biomet), 78% for Duracon (Howmedica), and 53% for PCA unicompartmental knee (Howmedica). Heyse and colleagues²⁵ reported 10- and 15-year survivorship data (93.5% and 86.3%, respectively) for 223 patients under age 60 years at the time of their index surgery (Genesis Unicondylar implant, Smith & Nephew), performed between 1993 and 2005. KSS was good to excellent. Similar numbers in cohorts under age 60 years were reported by Schai and colleagues²⁶ using the PFC system (Johnson & Johnson) and by Price and colleagues²⁷ using the medial Oxford UKA. Both groups reported excellent survivorship rates: 93% at 2- to 6-year follow-up and 91% at 10-year follow-up. The outcome in older patients seems satisfactory as well. In another multicenter report, by Price and colleagues,⁴⁰ medial Oxford UKAs had a 15-year survival rate of 93%. Berger and colleagues⁴¹ reported similar numbers for the Miller-Galante prosthesis. Survival rates were 98% (10 years) and 95.7% (13 years), and 92% of patients had good to excellent Hospital for Special Surgery knee scores.

Although various modern implants have had good to excellent results, the historical question of what type of UKA to use (mobile or fixed-bearing) remains unanswered. To try to address it, Peersman and colleagues⁴² performed a systematic review of 44 papers (9463 knees). The 2 implant types had comparable revision rates. Another recent retrospective study tried to determine what is crucial for implant survival: implant design or surgeon experience.⁴³ The authors concluded that prosthetic component positioning is key. Other authors have reported high-volume centers are crucial for satisfactory UKA results and lower revision rates.^44-46

Results of these studies indicate that, where UKAs are being performed in volume, 10-year survivorship rates higher than 90% and good to excellent outcomes can be expected.

UKA vs HTO

Cohort studies that have directly compared the 2 treatment modalities are scarce, and most have been retrospective. In a prospective study, Stukenborg-Colsman and colleagues⁴⁷ randomized patients with medial compartment OA to undergo either CWHTO (32 patients) with a technique reported by Coventry⁴⁸ or UKA (28 patients) with the unicondylar knee sliding prosthesis, Tübingen pattern (Aesculap), between 1988 and 1991. Patients were assessed 2.5, 4.5, and 7.5 years after surgery. More postoperative complications were noted in the HTO group. At 7- to 10-year follow-up, 71% of the HTO group and 65% of the UKA group had excellent KSS. Mean ROM was 103° after UKA (range, 35°-140°) and 117° after HTO (range, 85°-135°) during the same assessment. Although differences were not significant, Kaplan-Meier survival analysis was 60% for HTO and 77% for UKA at 10 years. Results were not promising for the implants used, compared with other implants, but the authors concluded that, because of improvements in implant designs and image-guided techniques, better long-term success can be expected with UKA than with HTO.

In another prospective study, Börjesson and colleagues⁴⁹ evaluated pain during walking, ROM, British Orthopaedic Association (BOA) scores, and gait variables at 1- and 5-year follow-up. Patients with moderate medial OA (Ahlbäck¹⁴ grade I-III) were randomly selected to undergo CWHTO or UKA (Brigham, DePuy). There were no significant differences in BOA scores, ROM, or pain during walking between the 2 groups at 3 months, 1 year, and 5 years after surgery. Gait analysis showed a significant difference in favor of UKA only at 3 months after surgery. At 1- and 5-year follow-up, no significant differences were noted.

To clarify current ambiguities, Fu and colleagues⁵⁰ performed a systematic review of all (11) comparative studies. These studies had a total of 5840 (5081 UKA, 759 HTO) patients. Although ROM was significantly better for the HTO group than the UKA group, the UKA group had significantly better functional results. Walking after surgery was significantly faster for the UKA group. The authors suggested the difference might be attributed to the different postoperative regimens—HTO patients wore a whole-leg plaster cast for 6 weeks, and UKA patients were allowed immediate postoperative weight-bearing. Regarding rates of survival and complications, pooled data showed no significant differences. Despite these results, the authors acknowledged the limitation of available randomized clinical trials and the multiple techniques and implants used. We share their assertion that larger prospective controlled trials are needed. These are crucial to getting a definitive answer regarding which of the 2 treatment strategies should be used for isolated compartment OA.

Current Trends in Use of UKA and HTO

Evaluation of national registries and recent reports showed a global shift in use of both HTO and UKA. Despite the lack of national HTO registries, a few reports have described use of TKA, UKA, and HTO in Western populations over the past 2 decades. Using 1998-2007 data from the Swedish Knee Arthroplasty Register, W-Dahl and colleagues⁵¹ found a 3-fold increase in UKA use, whereas HTO use was halved over the same period. Niinimäki and colleagues⁵² reported similar findings with the Finnish National Hospital Discharge Register. They noted a steady 6.8% annual decrease in osteotomies, whereas UKA use increased sharply after the Oxford UKA was introduced (Phase 3; Biomet). These findings are consistent with several reports from North America. In their epidemiologic analysis covering the period 1985-1990, Wright and colleagues⁵³ found an 11% to 14% annual decrease in osteotomies among the elderly, compared with an annual decrease of only 3% to 4% among patients younger than 65 years. Nwachukwu and colleagues⁵⁴ recently compared UKA and HTO practice patterns between 2007 and 2011, using data from a large US private payer insurance database. They noted an annual growth rate of 4.7% in UKA use, compared with an annual 3.9% decrease in HTO use. Furthermore, based on their subgroup analysis, they speculated there was a demographic shift toward UKA, as opposed to TKA, particularly in older women. Bolognesi and colleagues⁵⁵ investigated further. Evaluating all Medicare beneficiaries who underwent knee arthroplasty in the United States between 2000 and 2009, they noted a 1.7-fold increase in TKA use and a 6.2-fold increase in UKA use. As there were no substantial changes in patient characteristics over that period, the authors hypothesized that a possible broadening of inclusion criteria may have led to the increased use of UKA.

There is a possible multifactorial explanation for the current global shift in favor of UKA. First, UKA was once a technically demanding procedure, but improved surgical techniques, image guidance, and robot assistance⁵⁶ have made it relatively less difficult. Second, UKA surgery is associated with lower reported perioperative morbidities.⁵⁷ We think these factors have contributed to the global trend of less HTO use and more UKA use in the treatment of unicompartmental OA.

Conclusion

The modern literature suggests the inclusion criteria for HTO have been well investigated and defined; the UKA criteria remain a matter of debate but seem to be expanding. Long-term survival results seem to favor UKA, though patient satisfaction with both procedures is good to excellent. The broadening range of inclusion criteria and consistent reports of durable outcomes, coupled with excellent patient satisfaction, likely explain the shift toward UKA in the treatment of isolated compartment degeneration.

Am J Orthop. 2016;45(6):E355-E361. Copyright Frontline Medical Communications Inc. 2016. All rights reserved.

An increasingly number of patients with symptomatic isolated medial unicompartmental knee osteoarthritis (OA) are too young and too functionally active to be ideal candidates for total knee arthroplasty (TKA). Isolated medial compartment OA occurs in 10% to 29.5% of all cases, whereas the isolated lateral variant is less common, with a reported incidence of 1% to 7%.^1,2 In 1961, Jackson and Waugh³ introduced the high tibial osteotomy (HTO) as a surgical treatment for single-compartment OA. This procedure is designed to increase the life span of articular cartilage by unloading and redistributing the mechanical forces over the nonaffected compartment. Unicompartmental knee arthroplasty (UKA) was introduced in the 1970s as an alternative to TKA or HTO for single-compartment OA.

Since the introduction of these methods, there has been debate about which patients are appropriate candidates for each procedure. Improved surgical techniques and implant designs have led surgeons to reexamine the selection criteria and contraindications for these procedures. Furthermore, given the increasing popularity and use of UKA, the question arises as to whether HTO still has a role in clinical practice in the surgical treatment of medial OA of the knee.

To clarify current ambiguities, we review the modern indications, subjective outcome scores, and survivorship results of UKA and HTO in the treatment of isolated medial compartment degeneration of the knee. In addition, in a thorough review of the literature, we evaluate global trends in the use of both methods.

High Tibial Osteotomy for Medial Compartment OA

Indications

Before the introduction of TKA and UKA for single-compartment OA, surgical management consisted of HTO. When the mechanical axis is slightly overcorrected, the medial compartment is decompressed, ensuring tissue viability and delaying progressive compartment degeneration.

Traditionally, HTO is indicated for young (age <60 years), normal-weight, active patients with radiographic single-compartment OA.⁶ The knee should be stable and have good range of motion (ROM; flexion >120°), and pain should be localized to the tibiofemoral joint line.

Over the past few decades, numerous authors have reported similar inclusion criteria, clarifying their definition. This definition should be further refined in order to optimize survivorship and clinical outcomes.

Confirming age as an inclusion criterion for HTO, Trieb and colleagues⁷ found that the risk of failure was significantly (P = .046) higher for HTO patients older than 65 years than for those younger than 65 years (relative risk, 1.5). This finding agrees with findings of other studies, which suggests that, in particular, young patients benefit from HTO.^8-11

Moreover, there is a clear relation between HTO survival and obesity. In a study of 159 CWHTOs, Akizuki and colleagues¹² reported that preoperative body mass index (BMI) higher than 27.5 kg/m² was a significant risk factor for early failure. Using BMI higher than 30 kg/m² as a threshold, Howells and colleagues⁹ found significantly inferior Knee Society Score (KSS) and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) results for the obese group 5 years after HTO.

Radiographic evidence of severe preoperative compartment degeneration has been associated with early conversion to TKA. Flecher and colleagues¹¹ and van Raaij and colleagues¹³ both concluded the best long-term survival grades are achieved in HTO patients with mild compartment OA (Ahlbäck^14 grade I). The question then becomes whether these patients should be treated nonoperatively instead.^15,16The literature supports strict adherence to inclusion criteria in the selection of a potential HTO candidate. Age, BMI, and the preoperative state of OA should be taken into account in order to optimize clinical outcome and survivorship results in patients about to undergo HTO.

Outcomes

Multiple authors have described or compared the midterm or long-term results of the various surgical HTO techniques. Howells and colleagues⁹ noted overall survival rates of 87% (5 years after CWHTO) and 79% (10 years after CWHTO). Over the 10-year postoperative period, there was significant deterioration in clinical outcome scores and survivorship. Others authors have had similar findings.^17-19 van Raaij and colleagues¹³ found that the 10-year probability of survival after CWHTO was 75%. In 455 patients who underwent lateral CWHTO, Hui and colleagues⁸ found that 5-year probability of survival was 95%, 10-year probability was 79%, and 15-year probability was 56%. Niinimäki and colleagues¹⁰ used the Finnish Arthroplasty Register to report HTO survivorship at a national level. Using conversion to TKA as a cutoff, they noted 5-year survivorship of 89% and 10-year survivorship of 73%. To our knowledge, 2 groups, both in Japan, have reported substantially higher 15-year survival rates: 90%¹² and 93%.²⁰ The authors acknowledged that their results were significantly better than in other countries and that Japanese lifestyle, culture, and body habitus therefore require further investigation. At this time, it is not possible to compare their results with Western results.

In an attempt to compare the different survival rates of the various HTO techniques, Schallberger and colleagues²¹ conducted a retrospective study of OWHTOs and CWHTOs. At median follow-up of 16.5 years, comparative survival rates showed a trend of deterioration. Although data were limited, there were no significant differences in survival or functional outcome between the 2 techniques. In a recent randomized clinical trial, Duivenvoorden and colleagues⁵ compared these techniques’ midterm results (mean follow-up, 6 years). Clinical outcomes were not significantly different. There were more complications in the OWHTO group and more conversions to TKA in the CWHTO group. Considering these results, the authors suggested OWHTO without autologous bone graft is the best HTO treatment strategy for medial gonarthritis with varus malalignment of <12°.

The HTO results noted in these studies show a similar deteriorating trend; expected 10-year survivorship is 75%. Although modern implants and surgical techniques are being used, evidence supporting use of one surgical HTO method over another is lacking.

UKA for Medial Compartment OA

Indications

Since it was first introduced in the 1970s, use of UKA for single-compartment OA has been a subject of debate. The high failure rates reported at the time raised skepticism about the new treatment.²² Kozinn and Scott²³ defined classic indications and contraindications. Indications included isolated medial or lateral compartment OA or osteonecrosis of the knee, age over 60 years, and weight under 82 kg. In addition, the angular deformity of the affected lower extremity had to be <15° and passively correctable to neutral at time of surgery. Last, the flexion contracture had to be <5°, and ideal ROM was 90°. Contraindications included high activity, age under 60 years, and inflammatory arthritis. Strict adherence led to improved implant survival and lower revision rates. Because of improved surgical techniques, modern implant designs, and accumulating experience with the procedure, the surgical indications for UKA have expanded. Exact thresholds for UKA inclusion, however, remain unclear.

The modern literature is overturning the traditional idea that UKA is not indicated for patients under age 60 years.²³ Using KSS, Thompson and colleagues²⁴ found that younger patients did better than older patients 2 years after UKA using various types of implants. Analyzing survivorship results, Heyse and colleagues²⁵ concluded that UKA can be successful in patients under age 60 years and reported a 15-year survivorship rate of 85.6% and excellent outcome scores. Other authors have had similar findings.^26-28

Evaluating the influence of weight, Thompson and colleagues²⁴ found obese patients did not have a higher revision rate but did have slower progression of improvement 2 years after UKA. Cavaignac and colleagues²⁹ concluded that, at minimum follow-up of 7 years (range, 7-22 years), weight did not influence UKA survivorship. Other authors^30-33 have found no significant influence of BMI on survival.

Reports on preoperative radiographic parameters that can potentially influence UKA results are limited. In 113 medial UKAs studied by Niinimäki and colleagues,³⁴ mild medial compartment degeneration, seen on preoperative radiographs, was associated with significantly higher failure rates. The authors concluded that other treatment options should be favored in the absence of severe isolated compartment OA.

Although the classic indications defined by Kozinn and Scott²³ have yielded good to excellent UKA results, improvements in implants and surgical techniques^35-38 have extended the criteria. The modern literature demonstrates that age and BMI should not be used as criteria for excluding UKA candidates. Radiographically, there should be significant isolated compartment degeneration in order to optimize patient-reported outcome and survivorship.

Outcomes

Improved implant designs and modern minimally invasive techniques have effected a change in outcome results and a renewed interest in implants. Over the past decade, multiple authors have described the various modern UKA implants and their survivorship. Reports published since UKA was introduced in the 1970s show a continual increase in implant survival. Koskinen and colleagues,³⁹ using Finnish Arthroplasty Register data on 1819 UKAs performed between 1985 and 2003, found 10-year survival rates of 81% for Oxford implants (Zimmer Biomet), 79% for Miller-Galante II (Zimmer Biomet), 78% for Duracon (Howmedica), and 53% for PCA unicompartmental knee (Howmedica). Heyse and colleagues²⁵ reported 10- and 15-year survivorship data (93.5% and 86.3%, respectively) for 223 patients under age 60 years at the time of their index surgery (Genesis Unicondylar implant, Smith & Nephew), performed between 1993 and 2005. KSS was good to excellent. Similar numbers in cohorts under age 60 years were reported by Schai and colleagues²⁶ using the PFC system (Johnson & Johnson) and by Price and colleagues²⁷ using the medial Oxford UKA. Both groups reported excellent survivorship rates: 93% at 2- to 6-year follow-up and 91% at 10-year follow-up. The outcome in older patients seems satisfactory as well. In another multicenter report, by Price and colleagues,⁴⁰ medial Oxford UKAs had a 15-year survival rate of 93%. Berger and colleagues⁴¹ reported similar numbers for the Miller-Galante prosthesis. Survival rates were 98% (10 years) and 95.7% (13 years), and 92% of patients had good to excellent Hospital for Special Surgery knee scores.

Although various modern implants have had good to excellent results, the historical question of what type of UKA to use (mobile or fixed-bearing) remains unanswered. To try to address it, Peersman and colleagues⁴² performed a systematic review of 44 papers (9463 knees). The 2 implant types had comparable revision rates. Another recent retrospective study tried to determine what is crucial for implant survival: implant design or surgeon experience.⁴³ The authors concluded that prosthetic component positioning is key. Other authors have reported high-volume centers are crucial for satisfactory UKA results and lower revision rates.^44-46

Results of these studies indicate that, where UKAs are being performed in volume, 10-year survivorship rates higher than 90% and good to excellent outcomes can be expected.

UKA vs HTO

Cohort studies that have directly compared the 2 treatment modalities are scarce, and most have been retrospective. In a prospective study, Stukenborg-Colsman and colleagues⁴⁷ randomized patients with medial compartment OA to undergo either CWHTO (32 patients) with a technique reported by Coventry⁴⁸ or UKA (28 patients) with the unicondylar knee sliding prosthesis, Tübingen pattern (Aesculap), between 1988 and 1991. Patients were assessed 2.5, 4.5, and 7.5 years after surgery. More postoperative complications were noted in the HTO group. At 7- to 10-year follow-up, 71% of the HTO group and 65% of the UKA group had excellent KSS. Mean ROM was 103° after UKA (range, 35°-140°) and 117° after HTO (range, 85°-135°) during the same assessment. Although differences were not significant, Kaplan-Meier survival analysis was 60% for HTO and 77% for UKA at 10 years. Results were not promising for the implants used, compared with other implants, but the authors concluded that, because of improvements in implant designs and image-guided techniques, better long-term success can be expected with UKA than with HTO.

In another prospective study, Börjesson and colleagues⁴⁹ evaluated pain during walking, ROM, British Orthopaedic Association (BOA) scores, and gait variables at 1- and 5-year follow-up. Patients with moderate medial OA (Ahlbäck¹⁴ grade I-III) were randomly selected to undergo CWHTO or UKA (Brigham, DePuy). There were no significant differences in BOA scores, ROM, or pain during walking between the 2 groups at 3 months, 1 year, and 5 years after surgery. Gait analysis showed a significant difference in favor of UKA only at 3 months after surgery. At 1- and 5-year follow-up, no significant differences were noted.

To clarify current ambiguities, Fu and colleagues⁵⁰ performed a systematic review of all (11) comparative studies. These studies had a total of 5840 (5081 UKA, 759 HTO) patients. Although ROM was significantly better for the HTO group than the UKA group, the UKA group had significantly better functional results. Walking after surgery was significantly faster for the UKA group. The authors suggested the difference might be attributed to the different postoperative regimens—HTO patients wore a whole-leg plaster cast for 6 weeks, and UKA patients were allowed immediate postoperative weight-bearing. Regarding rates of survival and complications, pooled data showed no significant differences. Despite these results, the authors acknowledged the limitation of available randomized clinical trials and the multiple techniques and implants used. We share their assertion that larger prospective controlled trials are needed. These are crucial to getting a definitive answer regarding which of the 2 treatment strategies should be used for isolated compartment OA.

Current Trends in Use of UKA and HTO

Evaluation of national registries and recent reports showed a global shift in use of both HTO and UKA. Despite the lack of national HTO registries, a few reports have described use of TKA, UKA, and HTO in Western populations over the past 2 decades. Using 1998-2007 data from the Swedish Knee Arthroplasty Register, W-Dahl and colleagues⁵¹ found a 3-fold increase in UKA use, whereas HTO use was halved over the same period. Niinimäki and colleagues⁵² reported similar findings with the Finnish National Hospital Discharge Register. They noted a steady 6.8% annual decrease in osteotomies, whereas UKA use increased sharply after the Oxford UKA was introduced (Phase 3; Biomet). These findings are consistent with several reports from North America. In their epidemiologic analysis covering the period 1985-1990, Wright and colleagues⁵³ found an 11% to 14% annual decrease in osteotomies among the elderly, compared with an annual decrease of only 3% to 4% among patients younger than 65 years. Nwachukwu and colleagues⁵⁴ recently compared UKA and HTO practice patterns between 2007 and 2011, using data from a large US private payer insurance database. They noted an annual growth rate of 4.7% in UKA use, compared with an annual 3.9% decrease in HTO use. Furthermore, based on their subgroup analysis, they speculated there was a demographic shift toward UKA, as opposed to TKA, particularly in older women. Bolognesi and colleagues⁵⁵ investigated further. Evaluating all Medicare beneficiaries who underwent knee arthroplasty in the United States between 2000 and 2009, they noted a 1.7-fold increase in TKA use and a 6.2-fold increase in UKA use. As there were no substantial changes in patient characteristics over that period, the authors hypothesized that a possible broadening of inclusion criteria may have led to the increased use of UKA.

There is a possible multifactorial explanation for the current global shift in favor of UKA. First, UKA was once a technically demanding procedure, but improved surgical techniques, image guidance, and robot assistance⁵⁶ have made it relatively less difficult. Second, UKA surgery is associated with lower reported perioperative morbidities.⁵⁷ We think these factors have contributed to the global trend of less HTO use and more UKA use in the treatment of unicompartmental OA.

Conclusion

The modern literature suggests the inclusion criteria for HTO have been well investigated and defined; the UKA criteria remain a matter of debate but seem to be expanding. Long-term survival results seem to favor UKA, though patient satisfaction with both procedures is good to excellent. The broadening range of inclusion criteria and consistent reports of durable outcomes, coupled with excellent patient satisfaction, likely explain the shift toward UKA in the treatment of isolated compartment degeneration.

Am J Orthop. 2016;45(6):E355-E361. Copyright Frontline Medical Communications Inc. 2016. All rights reserved.

An increasingly number of patients with symptomatic isolated medial unicompartmental knee osteoarthritis (OA) are too young and too functionally active to be ideal candidates for total knee arthroplasty (TKA). Isolated medial compartment OA occurs in 10% to 29.5% of all cases, whereas the isolated lateral variant is less common, with a reported incidence of 1% to 7%.^1,2 In 1961, Jackson and Waugh³ introduced the high tibial osteotomy (HTO) as a surgical treatment for single-compartment OA. This procedure is designed to increase the life span of articular cartilage by unloading and redistributing the mechanical forces over the nonaffected compartment. Unicompartmental knee arthroplasty (UKA) was introduced in the 1970s as an alternative to TKA or HTO for single-compartment OA.

Since the introduction of these methods, there has been debate about which patients are appropriate candidates for each procedure. Improved surgical techniques and implant designs have led surgeons to reexamine the selection criteria and contraindications for these procedures. Furthermore, given the increasing popularity and use of UKA, the question arises as to whether HTO still has a role in clinical practice in the surgical treatment of medial OA of the knee.

To clarify current ambiguities, we review the modern indications, subjective outcome scores, and survivorship results of UKA and HTO in the treatment of isolated medial compartment degeneration of the knee. In addition, in a thorough review of the literature, we evaluate global trends in the use of both methods.

High Tibial Osteotomy for Medial Compartment OA

Indications

Before the introduction of TKA and UKA for single-compartment OA, surgical management consisted of HTO. When the mechanical axis is slightly overcorrected, the medial compartment is decompressed, ensuring tissue viability and delaying progressive compartment degeneration.

Traditionally, HTO is indicated for young (age <60 years), normal-weight, active patients with radiographic single-compartment OA.⁶ The knee should be stable and have good range of motion (ROM; flexion >120°), and pain should be localized to the tibiofemoral joint line.

Over the past few decades, numerous authors have reported similar inclusion criteria, clarifying their definition. This definition should be further refined in order to optimize survivorship and clinical outcomes.

Confirming age as an inclusion criterion for HTO, Trieb and colleagues⁷ found that the risk of failure was significantly (P = .046) higher for HTO patients older than 65 years than for those younger than 65 years (relative risk, 1.5). This finding agrees with findings of other studies, which suggests that, in particular, young patients benefit from HTO.^8-11

Moreover, there is a clear relation between HTO survival and obesity. In a study of 159 CWHTOs, Akizuki and colleagues¹² reported that preoperative body mass index (BMI) higher than 27.5 kg/m² was a significant risk factor for early failure. Using BMI higher than 30 kg/m² as a threshold, Howells and colleagues⁹ found significantly inferior Knee Society Score (KSS) and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) results for the obese group 5 years after HTO.

Radiographic evidence of severe preoperative compartment degeneration has been associated with early conversion to TKA. Flecher and colleagues¹¹ and van Raaij and colleagues¹³ both concluded the best long-term survival grades are achieved in HTO patients with mild compartment OA (Ahlbäck^14 grade I). The question then becomes whether these patients should be treated nonoperatively instead.^15,16The literature supports strict adherence to inclusion criteria in the selection of a potential HTO candidate. Age, BMI, and the preoperative state of OA should be taken into account in order to optimize clinical outcome and survivorship results in patients about to undergo HTO.

Outcomes

Multiple authors have described or compared the midterm or long-term results of the various surgical HTO techniques. Howells and colleagues⁹ noted overall survival rates of 87% (5 years after CWHTO) and 79% (10 years after CWHTO). Over the 10-year postoperative period, there was significant deterioration in clinical outcome scores and survivorship. Others authors have had similar findings.^17-19 van Raaij and colleagues¹³ found that the 10-year probability of survival after CWHTO was 75%. In 455 patients who underwent lateral CWHTO, Hui and colleagues⁸ found that 5-year probability of survival was 95%, 10-year probability was 79%, and 15-year probability was 56%. Niinimäki and colleagues¹⁰ used the Finnish Arthroplasty Register to report HTO survivorship at a national level. Using conversion to TKA as a cutoff, they noted 5-year survivorship of 89% and 10-year survivorship of 73%. To our knowledge, 2 groups, both in Japan, have reported substantially higher 15-year survival rates: 90%¹² and 93%.²⁰ The authors acknowledged that their results were significantly better than in other countries and that Japanese lifestyle, culture, and body habitus therefore require further investigation. At this time, it is not possible to compare their results with Western results.

In an attempt to compare the different survival rates of the various HTO techniques, Schallberger and colleagues²¹ conducted a retrospective study of OWHTOs and CWHTOs. At median follow-up of 16.5 years, comparative survival rates showed a trend of deterioration. Although data were limited, there were no significant differences in survival or functional outcome between the 2 techniques. In a recent randomized clinical trial, Duivenvoorden and colleagues⁵ compared these techniques’ midterm results (mean follow-up, 6 years). Clinical outcomes were not significantly different. There were more complications in the OWHTO group and more conversions to TKA in the CWHTO group. Considering these results, the authors suggested OWHTO without autologous bone graft is the best HTO treatment strategy for medial gonarthritis with varus malalignment of <12°.

The HTO results noted in these studies show a similar deteriorating trend; expected 10-year survivorship is 75%. Although modern implants and surgical techniques are being used, evidence supporting use of one surgical HTO method over another is lacking.

UKA for Medial Compartment OA

Indications

Since it was first introduced in the 1970s, use of UKA for single-compartment OA has been a subject of debate. The high failure rates reported at the time raised skepticism about the new treatment.²² Kozinn and Scott²³ defined classic indications and contraindications. Indications included isolated medial or lateral compartment OA or osteonecrosis of the knee, age over 60 years, and weight under 82 kg. In addition, the angular deformity of the affected lower extremity had to be <15° and passively correctable to neutral at time of surgery. Last, the flexion contracture had to be <5°, and ideal ROM was 90°. Contraindications included high activity, age under 60 years, and inflammatory arthritis. Strict adherence led to improved implant survival and lower revision rates. Because of improved surgical techniques, modern implant designs, and accumulating experience with the procedure, the surgical indications for UKA have expanded. Exact thresholds for UKA inclusion, however, remain unclear.

The modern literature is overturning the traditional idea that UKA is not indicated for patients under age 60 years.²³ Using KSS, Thompson and colleagues²⁴ found that younger patients did better than older patients 2 years after UKA using various types of implants. Analyzing survivorship results, Heyse and colleagues²⁵ concluded that UKA can be successful in patients under age 60 years and reported a 15-year survivorship rate of 85.6% and excellent outcome scores. Other authors have had similar findings.^26-28

Evaluating the influence of weight, Thompson and colleagues²⁴ found obese patients did not have a higher revision rate but did have slower progression of improvement 2 years after UKA. Cavaignac and colleagues²⁹ concluded that, at minimum follow-up of 7 years (range, 7-22 years), weight did not influence UKA survivorship. Other authors^30-33 have found no significant influence of BMI on survival.

Reports on preoperative radiographic parameters that can potentially influence UKA results are limited. In 113 medial UKAs studied by Niinimäki and colleagues,³⁴ mild medial compartment degeneration, seen on preoperative radiographs, was associated with significantly higher failure rates. The authors concluded that other treatment options should be favored in the absence of severe isolated compartment OA.

Although the classic indications defined by Kozinn and Scott²³ have yielded good to excellent UKA results, improvements in implants and surgical techniques^35-38 have extended the criteria. The modern literature demonstrates that age and BMI should not be used as criteria for excluding UKA candidates. Radiographically, there should be significant isolated compartment degeneration in order to optimize patient-reported outcome and survivorship.

Outcomes

Improved implant designs and modern minimally invasive techniques have effected a change in outcome results and a renewed interest in implants. Over the past decade, multiple authors have described the various modern UKA implants and their survivorship. Reports published since UKA was introduced in the 1970s show a continual increase in implant survival. Koskinen and colleagues,³⁹ using Finnish Arthroplasty Register data on 1819 UKAs performed between 1985 and 2003, found 10-year survival rates of 81% for Oxford implants (Zimmer Biomet), 79% for Miller-Galante II (Zimmer Biomet), 78% for Duracon (Howmedica), and 53% for PCA unicompartmental knee (Howmedica). Heyse and colleagues²⁵ reported 10- and 15-year survivorship data (93.5% and 86.3%, respectively) for 223 patients under age 60 years at the time of their index surgery (Genesis Unicondylar implant, Smith & Nephew), performed between 1993 and 2005. KSS was good to excellent. Similar numbers in cohorts under age 60 years were reported by Schai and colleagues²⁶ using the PFC system (Johnson & Johnson) and by Price and colleagues²⁷ using the medial Oxford UKA. Both groups reported excellent survivorship rates: 93% at 2- to 6-year follow-up and 91% at 10-year follow-up. The outcome in older patients seems satisfactory as well. In another multicenter report, by Price and colleagues,⁴⁰ medial Oxford UKAs had a 15-year survival rate of 93%. Berger and colleagues⁴¹ reported similar numbers for the Miller-Galante prosthesis. Survival rates were 98% (10 years) and 95.7% (13 years), and 92% of patients had good to excellent Hospital for Special Surgery knee scores.

Although various modern implants have had good to excellent results, the historical question of what type of UKA to use (mobile or fixed-bearing) remains unanswered. To try to address it, Peersman and colleagues⁴² performed a systematic review of 44 papers (9463 knees). The 2 implant types had comparable revision rates. Another recent retrospective study tried to determine what is crucial for implant survival: implant design or surgeon experience.⁴³ The authors concluded that prosthetic component positioning is key. Other authors have reported high-volume centers are crucial for satisfactory UKA results and lower revision rates.^44-46

Results of these studies indicate that, where UKAs are being performed in volume, 10-year survivorship rates higher than 90% and good to excellent outcomes can be expected.

UKA vs HTO

Cohort studies that have directly compared the 2 treatment modalities are scarce, and most have been retrospective. In a prospective study, Stukenborg-Colsman and colleagues⁴⁷ randomized patients with medial compartment OA to undergo either CWHTO (32 patients) with a technique reported by Coventry⁴⁸ or UKA (28 patients) with the unicondylar knee sliding prosthesis, Tübingen pattern (Aesculap), between 1988 and 1991. Patients were assessed 2.5, 4.5, and 7.5 years after surgery. More postoperative complications were noted in the HTO group. At 7- to 10-year follow-up, 71% of the HTO group and 65% of the UKA group had excellent KSS. Mean ROM was 103° after UKA (range, 35°-140°) and 117° after HTO (range, 85°-135°) during the same assessment. Although differences were not significant, Kaplan-Meier survival analysis was 60% for HTO and 77% for UKA at 10 years. Results were not promising for the implants used, compared with other implants, but the authors concluded that, because of improvements in implant designs and image-guided techniques, better long-term success can be expected with UKA than with HTO.

In another prospective study, Börjesson and colleagues⁴⁹ evaluated pain during walking, ROM, British Orthopaedic Association (BOA) scores, and gait variables at 1- and 5-year follow-up. Patients with moderate medial OA (Ahlbäck¹⁴ grade I-III) were randomly selected to undergo CWHTO or UKA (Brigham, DePuy). There were no significant differences in BOA scores, ROM, or pain during walking between the 2 groups at 3 months, 1 year, and 5 years after surgery. Gait analysis showed a significant difference in favor of UKA only at 3 months after surgery. At 1- and 5-year follow-up, no significant differences were noted.

To clarify current ambiguities, Fu and colleagues⁵⁰ performed a systematic review of all (11) comparative studies. These studies had a total of 5840 (5081 UKA, 759 HTO) patients. Although ROM was significantly better for the HTO group than the UKA group, the UKA group had significantly better functional results. Walking after surgery was significantly faster for the UKA group. The authors suggested the difference might be attributed to the different postoperative regimens—HTO patients wore a whole-leg plaster cast for 6 weeks, and UKA patients were allowed immediate postoperative weight-bearing. Regarding rates of survival and complications, pooled data showed no significant differences. Despite these results, the authors acknowledged the limitation of available randomized clinical trials and the multiple techniques and implants used. We share their assertion that larger prospective controlled trials are needed. These are crucial to getting a definitive answer regarding which of the 2 treatment strategies should be used for isolated compartment OA.

Current Trends in Use of UKA and HTO

Evaluation of national registries and recent reports showed a global shift in use of both HTO and UKA. Despite the lack of national HTO registries, a few reports have described use of TKA, UKA, and HTO in Western populations over the past 2 decades. Using 1998-2007 data from the Swedish Knee Arthroplasty Register, W-Dahl and colleagues⁵¹ found a 3-fold increase in UKA use, whereas HTO use was halved over the same period. Niinimäki and colleagues⁵² reported similar findings with the Finnish National Hospital Discharge Register. They noted a steady 6.8% annual decrease in osteotomies, whereas UKA use increased sharply after the Oxford UKA was introduced (Phase 3; Biomet). These findings are consistent with several reports from North America. In their epidemiologic analysis covering the period 1985-1990, Wright and colleagues⁵³ found an 11% to 14% annual decrease in osteotomies among the elderly, compared with an annual decrease of only 3% to 4% among patients younger than 65 years. Nwachukwu and colleagues⁵⁴ recently compared UKA and HTO practice patterns between 2007 and 2011, using data from a large US private payer insurance database. They noted an annual growth rate of 4.7% in UKA use, compared with an annual 3.9% decrease in HTO use. Furthermore, based on their subgroup analysis, they speculated there was a demographic shift toward UKA, as opposed to TKA, particularly in older women. Bolognesi and colleagues⁵⁵ investigated further. Evaluating all Medicare beneficiaries who underwent knee arthroplasty in the United States between 2000 and 2009, they noted a 1.7-fold increase in TKA use and a 6.2-fold increase in UKA use. As there were no substantial changes in patient characteristics over that period, the authors hypothesized that a possible broadening of inclusion criteria may have led to the increased use of UKA.

There is a possible multifactorial explanation for the current global shift in favor of UKA. First, UKA was once a technically demanding procedure, but improved surgical techniques, image guidance, and robot assistance⁵⁶ have made it relatively less difficult. Second, UKA surgery is associated with lower reported perioperative morbidities.⁵⁷ We think these factors have contributed to the global trend of less HTO use and more UKA use in the treatment of unicompartmental OA.

Conclusion

The modern literature suggests the inclusion criteria for HTO have been well investigated and defined; the UKA criteria remain a matter of debate but seem to be expanding. Long-term survival results seem to favor UKA, though patient satisfaction with both procedures is good to excellent. The broadening range of inclusion criteria and consistent reports of durable outcomes, coupled with excellent patient satisfaction, likely explain the shift toward UKA in the treatment of isolated compartment degeneration.

Am J Orthop. 2016;45(6):E355-E361. Copyright Frontline Medical Communications Inc. 2016. All rights reserved.

From the Department of Neurootology, National Hospital of Neurology and Neurosurgery, London (Dr. Tsang, Miss Anwer) and the Ear Institute, University College London, and Guy’s and St Thomas’ NHS Foundation Trust, London, UK (Dr. Murdin).

Abstract

• Objective: To review the clinical manifestations, diagnosis, and management of vestibular migraine (VM).
• Methods: Review of the literature.
• Results: Apart from headache, other symptoms of VM include unsteadiness, imbalance, and spontaneous as well as visual vertigo. Acute vestibular symptoms that qualify for VM must be of at least moderate or severe intensity which lasts within a time window of 5 minutes to 72 hours. The interindividual temporal association of headache and vertigo is highly variable in VM patients  Grossly normal peripheral vestibular function and audiometry both during and between attacks distinguishes VM from its mimics. Treatment options for VM are mainly based on expert opinion and include lifestyle modifications, acute and prophylactic migraine pharmacotherapy, and vestibular rehabilitation therapy.
• Conclusion: Despite a lack of diagnostic biomarkers for VM, a meticulous workup is important to exclude alternative mimics. More longitudinal and treatment studies are required to help elucidate the prognosis and optimal management of this condition.

The coexistence of migraine and vestibular symptoms has been mentioned in the headache literature for many years [1–3]. It was first addressed by Kayan and Hood in 1984, who found that dizziness and vertigo occurred in 54% of migraine patients compared with 30% of patients with tension-type headache [1]. The frequent coexistence of migraine and vertigo led researchers to hypothesize that their co-occurence could be due to more than mere chance. As per Lempert and Neuhauser’s evaluation, there is a lifetime prevalence of 16% for migraine and 7% for vertigo, with a 1.1 % chance of vertigo and migraine occurring together by chance alone [4]. In a study looking at the point prevalence of vertigo or dizziness among those presenting for a routine appointment at a headache center, an astounding 72.8% of those with severe headaches had vestibular symptoms [5].

Most epidemiologic studies of what we call vestibular migraine (VM) were based on presentations to specialist clinics and were performed in an era during which no established diagnostic criteria existed. Despite this, most neurootologists would consider VM to be one of the most common causes of spontaneous recurrent vertigo [6]. Neuhauser et al reported that VM was diagnosed in 7% of a group of 200 specialist clinic patients with dizziness and 9% of a group of 200 clinic patients who had migraine [2]. In a population-based study in Germany, the lifetime prevalence of VM according to the Neuhauser criteria was estimated to be 0.98% and the 12-month prevalence 0.89% [7]. The condition has a 3:1 female predilection [8].

VM has only recently been recognised as a separate migraine entity by the International Headache Society (IHS), appearing in the appendix of their International Classification of Headache Disorders (ICHD)–3 beta. The previous ICHD recognised vertigo as a migrainous symptom only within the framework of basilar migraine.  The nomenclature used in the literature to describe this entity has been inconsistent and therefore confusing, including terms such as migraine-associated vertigo [9], migraine-related dizziness [3] or vertigo [10],migrainous vertigo [2], benign recurrent vertigo [11], and migraine-related vestibulopathy [12]. For the most part, these terms refer to the co-experience of migraine and vertigo or dizziness, with only a few terms having a more specific meaning of how the 2 symptoms relate temporally. Neuhauser and colleagues developed criteria in 2001 to classify migraineurs for whom vestibular symptoms are an integral part of migraine symptomatology, using the term migrainous vertigo [2]. Others preferred the terms migraine-associated dizziness or migraine-related dizziness [3] over migrainous vertigo because they felt the symptoms of vestibular dysfunction related to migraine are varied and may include gait instability and spatial disorientation but not necessarily with vertigo. To best avoid confounding nonvestibular dizziness or motion sickness associated with migraine, VM has been the preferred term because it emphasises the particular vestibular manifestation of migraine.

The lack of a universally accepted definition for this complex entity has contributed to delayed diagnosis and and treatment for those with this disorder. In this article, we will review the clinical manifestation, diagnosis and management of VM, with a focus on assisting in the differentiation between other potential diagnoses.

Pathophysiology of VM

A clear pathophysiology of VM has not been elucidated. Although predominantly a sporadic disease, there have been reported cases of familial occurrence with an auto-somal dominant inheritance [11,13]. Bahmad and colleagues mapped the first locus for familial VM to 5q35 within a 4-generation family [13]. On the contrary, a larger study conducted by Lee et al found VM to be to genetically heterogeneous with a subset linking to chromosome 22q12 [14]. Genetic defects of voltage-gated calcium channels are identified as causal factors for familial hemiplegic migraine and episodic ataxia type 2. Both these disease entities present with vertigo and migraine headaches suggesting a defective gene within the same chromosomal region could indicate a direct genetic link to VM. However, no such gene has been identified.

General consensus is that the action of spreading cortical depression as it reaches the somatosensory cortex in the posterior insula and temporoparietal junction elucidates migraine aura in patients with short attacks. However, due to the heterogeneity of VM, canal paresis and complex conditional nystagmus during acute stages are not explained through cortical spreading. Eggers et al suggests that vertigo symptoms occur as ictal sensation rather than the spreading of sensory or motor cortical depression [15]. However, due to discrepancies within the literature it is apparent that further research needs to be conducted to fully understand the pathophysiology of VM.

Clinical Manifestations of VM

Symptoms

As many as 80% to 90% of patients with VM report unsteadiness or balance problems, of which 50% to 60% typically report episodic spontaneous vertigo [16], either internal vertigo (a false sensation of self-motion) or external vertigo (a false sensation that the visual surround is spinning or flowing) [17]. The duration of episodes is highly variable, whereby approximately 30% of patients have episodes lasting minutes, 30% have attacks lasting hours, 30% have attacks over several days, while the remaining 10% have attacks lasting seconds only [18]. It may be difficult to distinguish if vestibular symptoms lasting seconds are related to their head motion intolerance, also known as head motion–induced vertigo [17], which is another frequent symptom in VM. Head motion–induced vertigo bears many similarities to motion sickness.

The interindividual temporal association of headache and vertigo is highly variable in VM patients and is a reason many patients find this diagnostic construct difficult to accept. Approximately 30% of adult patients eventually diagnosed with VM initially present without headaches [8]. Vertigo is only regularly associated with headache in 25% to 50% of VM patients [2,7]. A minority of patients report headache and vertigo never occurring together [2]. A temporal pattern, presenting as aura, occurs only in approximately 10% of cases [19]; therefore, vestibular episodes of VM should not be regarded as migraine auras [18]. Patients typically have migraine manifesting earlier in life with the vestibular symptoms following [13,20], whereby the mean age at onset of migraine and diagnosis of VM are approximately 22 and 35 years, respectively [2]. Consistently across studies that measure quality of life scores, VM patients report higher subjective levels of disability compared to patients with other vestibular illnesses, despite having less objective abnormalities [21]. Approximately 85% of VM patients experienced vestibular symptoms for at least 1 year before consulting neurootology services [21]. It could be argued that hypersensitivity of percept to vestibular symptoms reflect the general finding of augmented perceptions to various external stimuli underlying migraine [22,23].

Another prominent feature of VM is that patients report a syndrome of visually-induced dizziness termed visual vertigo (VV). This is a heterogeneous syndrome with strabismic, peripheral, and/or central vestibular aetiologies [24]. Patients with VV complain of discomfort, postural destabilisation, dizziness, imbalance and spatial disorientation in challenging visual environments. Examples of such environments include walking down supermarket aisles, observing moving objects (eg, disco lights, people walking, moving traffic) or moving surroundings during travelling, and the movement of the eyes in general [24–26]. Most patients report more than one visual trigger [24]. Visual vertigo can often be difficult to distinguish from oscillopsia in patients with bilateral vestibular failure. What is most surprising is that patients with VV have a similar handicap level yet report much more vestibular symptoms compared with patients with bilateral vestibular failure [25]. Postural reactions triggered by external visual motion are destabilising with respect to the earth-vertical and are normally suppressed by central re-weighting of sensory postural cues [24]. Surprisingly, premorbid levels of anxiety and childhood motion sickness do not appear to have a correlation with VV [25]. Even in normal subjects, certain complex visual stimuli can induce transient motion sickness–like symptoms, as shown in experimental visually induced self-vection [27]. The Situational Characteristics Questionnaire (SVQ) is a 19-question, symptom-based questionnaire that has been shown to be useful in quantifying features of VV and may be useful in gauging improvement following physical therapies [25,26].

Early in the disease course, hearing loss should prompt an alternative diagnosis. However, late onset cochlear symptoms have been reported in VM. A study found that after 9 years of follow-up, the number of patients with cochlear symptoms more than doubled [28].

Clinical Examination Findings

The importance of the clinical examination is to rule out peripheral vestibular dysfunction and perform positional testing to look for benign paroxysmal positional vertigo (BPPV) or central positional nystagmus. Nonetheless, positional nystagmus has been reported in up to 28% of cases, including definite central-type positional nystagmus reported in as many as 18% [28].

Audiometric Findings and Auditory Brainstem Responses

Normal audiometry both during and between attacks is one of the key clinical features that distinguishes VM from Meniere’s disease [29]. Auditory brainstem response (ABR) results are typically normal in about 65% of patients [29]. Abnormal ABR results are typically nonspecific, such as mild elongation of wave I, III and V latencies and less commonly, prolongation of the inter-peak latencies.

Findings on Vestibular Function Testing

Whilst there are some reported abnormalities in vestibular function testing in VM patients, such findings need to be interpreted with caution due to the small number of subjects, as well as the variation in case definition and cut-off values. Most importantly, very few papers studied patients in the acute phase, and in some studies it was not even specified. The majority of studies report that VM patients interictally have grossly normal peripheral vestibular function with occasional minor irregularities. Profound interictal abnormalities such as complete canal paresis are usually indicative of other diagnoses. In between acute attacks, patients with VM typically have normal gaze, saccadic parameters, ocular pursuit gains and optokinetic nystagmus (OKN) gains on electronystagmography (ENG) or videonystagmography (VNG) [3]. A minority had a low amplitude (< 4 degrees per second) persistent positional nystagmus. On rotation testing of the vestibo-ocular reflex there is reduction of the mean gains compared to headache-free controls. Most reports in the literature do support that the majority of VM patients have grossly normal bithermal caloric testing, although abnormalities including higher slow phase velocities and canal paresis (usually partial) are reported [29–31]. The observation that the artificial vestibular stimulation caused by the caloric test was followed by a migraine attack within 24 hours in 49% of patients with migraine is very interesting [30], and it remains to be tested whether this phenomenon has the potential to be of assistance in the diagnosis of VM. Both VM patients and migraineurs without vertigo have similar subtle cVEMP (Cervical vestibular-evoked myogenic potentials) abnormalities, namely decreased global amplitude and absence of habituation [31]. On computerized dynamic posturography (CDP), a test of sway, VM patients typically demonstrate a surface-dependent pattern based on their SOT analysis [3], suggesting that VM patients may have a substantial vestibulo-spinal abnormality leading to difficulties integrating multiple conflicting sensory inputs [32].

Diagnostic Criteria

Separating VM into 2 diagnostic entities seems particularly useful: definite VM and the more sensitive but less specific category of probable VM. The sensitivity and specificity of the proposed criteria still need to be determined. Although some authors criticize the probable diagnostic entity for its heterogeneity, about 50% of patients initially diagnosed with probable VM ultimately progress to definite VM [12,33]. Definite vestibular migraine appears in the ICHD-3 beta but only in the appendix section for “new disorders that need further research for validation.” However, probable VM will not be included until further evidence of its utility has been accumulated.

The diagnosis is particularly challenging when headache is not a regular accompaniment of the vertiginous attacks. A patient diary may help link migrainous and vertigo symptoms. When headache is not a prominent feature of the attacks, the clinician will have to put migrainous triggers or symptoms such as photophobia or scintillating scotomas in the context of vertigo symptoms to aid with the diagnosis. One needs to be pedantic about differentiating the qualifying symptom of phonophobia, which is defined as a sound-induced discomfort that is often transient and bilateral from the uncomfortable distorted loud sound perception, which occurs with a recruiting sensorineural hearing loss, and is often persistent and unilateral [18]. Response to migraine treatment is not sufficiently specific to be included in the diagnostic criteria. High placebo response rates from migraine trials [34] suggest that placebo effects can likewise be expected in the treatment of VM. Despite these challenges, acceptance of the diagnostic entity of VM seems to be gaining momentum. In a follow-up study over 9 years, the diagnosis remained consistent in 85% of patients [33].

Benign Paroxysmal Vertigo of Childhood and Vestibular Migraine in Children

VM can present at any age, however, the ICHD specifically recognises an early vertiginous entity regarded as a precursor syndrome of migraine in otherwise healthy children called benign paroxysmal vertigo of childhood. This diagnosis requires 5 episodes of severe vertigo, occurring without warning and resolving spontaneously after minutes to hours [35]. In between episodes, neurological examination, audiometry, vestibular functions and EEG must be normal. A unilateral throbbing headache may occur during attacks but it is not a mandatory criterion. It is unclear whether these two conditions in children are the same entity, however it is important to note that the classification of VM does not involve any age limit [18].

Basilar-type Migraine

The term basilar migraine should be restricted to patients who fulfill the ICHD diagnostic criteria [35] given it is a clinically distinct entity from VM. Less than 10% of VM patients further fulfill the ICHD criteria for basilar migraine [2,18]. More than 60% of basilar-type migraine patients have vertigo and there are many overlapping clinical manifestations with VM. This diagnosis requires at least 2 symptoms from aura in the posterior circulation territory, whereas most patients with VM have vestibular symptoms only [35]. Moreover, in basilar migraine the duration of vertigo should correspond to the length of an aura, that is, between 5 and 60 minutes [35]. Further studies are required to further elucidate and delineate these 2 conditions.

Other Important Diagnostic Considerations

Meniere’s Disease

An important differential diagnosis of VM is the early presentation of Meniere’s disease (MD). Although fluctuating hearing loss, aural fullness and episodic vertigo are important symptoms in the recent updated diagnostic criteria for definite MD [36,37], these symptoms have been reported in patients with migraine [38]. Moreover, minor abnormalities in cVEMPs and arguably in caloric testing can be found in VM patients, as previously mentioned. Predominantly, the distinction can be made considering that a more sustained, albeit occasionally fluctuating, hearing loss would occur in MD, which can progress to severe hearing loss within a few years. However, the diagnosis can be difficult considering that audiometric and vestibular function abnormalities as well as the typical cochlear symptoms are often absent in the early stages of the MD. Nonetheless, preclinical labelling of patients with episodic vertigo without hearing loss as “vestibular MD” is unhelpful as this population may be overrepresented by actual migraineurs. Studies of patients with so-called benign recurrent vertigo or recurrent vestibulopathy are likely to be heterogeneous entities, with perhaps cases later evolving into VM or MD.

Coexisting migraine and MD is often challenging both in terms of diagnosis and management. Many studies have shown an increased prevalence of migraine in MD patients compared to controls [39,40], an asso-ciation suggested by Prosper Ménière himself in 1861 [41]. A study by Radtke et al found that the lifetime prevalence of migraine with and without aura was over 2 times higher in definite MD patients of both sexes compared to age-matched controls (56% versus 25%) [39]. Interestingly, 45% of the patients with MD always experienced at least 1 migrainous symptom (migrainous headache, photophobia, aura symptoms) with their Meniere attacks [39]. This may be at least partly due to the triggering effect of vestibular symptoms on migraineurs [30]. Migraine may even influence the disease course of MD as indicated by a retrospective case control study which found that definite MD patients who have concomitant ICHD criteria for migraine [35] had a significantly earlier onset of MD symptoms (mean age, 37.2 versus 49.3 years) and a much greater susceptibility to simultaneous bilateral, but not sequential, hearing loss as compared to MD patients without migraine (56% versus 4%) [42]. There were no significant differences in the severity of hearing loss between the 2 groups even when controlling for time to evaluation [42]. A family history of episodic vertigo was seen in 39% of MD patients with migraine, which is significantly higher than the 2% seen in MD patients, suggesting a possible genetic basis for this association [42]. The nature of the association between migraine and MD is not well elucidated, however, some authors propose that migraine leads to isolated microvascular ischaemic damage of the inner ear, presumably through small arterial vasospasm [40,42].

In summary, when the criteria for MD are met together with documented audiometric abnormalities, MD should be diagnosed, even if migraine symptoms occur during the vestibular attacks [18]. Only patients who experience 2 different types of attacks, one fulfilling the criteria for VM and the other for MD, should be labelled as Meniere’s disease/migraine overlap syndrome. It is hoped that future revisions of diagnostic criteria will include this overlap entity.

Migraine and Benign Paroxysmal Positional Vertigo

VM patients can experience brief positional dizziness and therefore VM may mimic BPPV. It is therefore important to perform positional testing to look for nystagmus typical for BPPV. Certainly the positional characteristics are distinct from BPPV with regard to the duration of attacks (often as long as the head position is maintained in VM rather than seconds in BPPV). BPPV may also produce attacks of vertigo that can act as triggers for migraine headaches. In these patients, treatment of the BPPV will reduce headache frequency [30].

Transient Ischemic Attacks

Transient ischemic attack (TIA) is a cerebrovascular disease with temporary neurological symptoms [43] and is differentiated from VM mainly from the characteristics of reported symptoms. Being a vascular phenomenon, one would expect TIA symptoms to have a sudden onset, with a brief duration of symptoms (typically short minutes), followed by a rapid improvement to baseline, as well as correspond to a vascular territory. The other important message is that stereotyped, frequently recurrent symptoms are less likely to be TIAs, with the exception of capsular warning syndrome [44] and limb shaking TIAs [43] described elsewhere.

Migraine and Motion Sickness

In an individual patient it may be difficult to differentiate between motion sickness and acute attacks of VM induced by motion stimuli. The distinction may be helped by observing nausea and dizziness improving after cessation of motion which points more towards motion sickness, as oppose to the persistent vertigo after the motion stimulus has ended, thus pointing more towards VM.

Episodic Ataxia Type 2

Of the various episodic ataxias, episodic ataxia type 2 would be the most important subtype in the differential diagnosis of VM given it presents with episodic vertigo and is the most frequently occurring subtype. It is a rare autosomal dominant inherited neurological disorder resulting from mutations of the calcium channel gene CACNA1A [45]. The clinical manifestations include recurrent disabling attacks of imbalance, vertigo and ataxia, which can be provoked by physical exertion or emotional stress. Patients may have downbeat nystagmus interictally. A slow progression of cerebellar signs accompanied by atrophy of midline cerebellar structures and a response to acetazolamide or 4-aminopyridine can help distinguish it from VM.

Migraine, Dizziness, and Comorbid Psychiatric Disorders

Particularly in patients with protracted symptoms, it is difficult to tease out the difference between the symptoms of migraine and dizziness from the symptoms of certain psychiatric disorders given their bidirectional associations. Migraine is a risk factor for first-onset major depression [46] and panic disorder [47]. Patients with VM have very high rates (30%–65%) of coexisting psychiatric illness, especially anxiety and depression, with frequencies higher than that associated with other migraine or vestibular disorders [48,49]. Vestibular migraine patients who have a positive history of psychiatric disorders have a comparatively higher risk of developing somatoform dizziness [48]. The unpredictability of recurrent vestibular symptoms could be a factor leading to elevated distress in VM patients. It is not uncommon to see a premature diagnosis of psychogenic dizziness to be given to patients without objective abnormalities. On the contrary, a diagnosis of psychogenic dizziness can rarely be made with certainty due to multiple reasons. Disabling vertigo leading to physical symptoms and avoidance of social activities can easily be misconstrued to have panic disorder with or without agoraphobia. Moreover, dizziness is the second most common symptom of a panic attack after palpitations [50].

Unfortunately, there are no objective tests that can reliably discriminate vestibular syndromes from psychiatric syndromes in patients with dizziness. The SVQ is not specific enough to differentiate symptoms of VV from the space and motion discomfort symptoms often found in agoraphobic patients [25]. Experimentally, agoraphobia patients may have a more surface-dependent strategy rather than a visual-dependent strategy on CDP [51]. It is unclear whether the vestibular system is causally linked to emotion processing pathways.

Chronic Subjective Dizziness

Chronic subjective dizziness is an entity characterised by chronic unsteadiness or nonvertiginous dizziness accompanied by hypersensitivity to motion stimuli and poor tolerance for complex visual stimuli lasting for 3 months or more without objective abnormalities [52]. These vestibular symptoms are often difficult to distinguish from symptoms of VM. This condition is thought to be a spatial sensory analog of allodynia experienced by some chronic migraine headache sufferers [8].

Dizziness Due to Side Effects of Migraine Prophylactic Medications

Dizziness is often listed as a side effect in the product information of various medications including those used for migraine prophylaxis. It is important to take an accurate history of the suspected offending drug in terms of its temporal relationship to vestibular symptoms. Tricyclic antidepressants (TCAs) can cause drowsiness, lightheadedness, fatigue and blurred vision [53]. Beta-blockers can cause orthostatic hypotension [53]. All the above effects could be confused with vestibular symptoms.

Treatment of Vestibular Migraine

Current treatment options for VM are mainly limited to expert opinion rather than inferred from randomized controlled trials (RCTs) [54]. Below we have offered our consensus on how VM should be managed, with concepts based on the guidelines of treatment for typical migraine [55]. Avoidance of migraine triggers should always be the first avenue of treatment. In addition, any vestibular disorder that is triggering migraine attacks should be identified and treated in its own right. Pharmacotherapy can be abortive for acute episodes and prophylactic.

Lifestyle Advice

The key first task in management is the correct diagnosis and educating the patient about the condition. A thorough explanation of the migraine origin of the attacks can address patients fear and expectations. Nonpharmaceutical approaches in the treatment of VM should not be neglected, even though only a very small proportion of patients may derive a benefit. Advice on dietary manipulation is routinely given; however, its efficacy in VM is questionable. Dietary advice includes healthy eating at regular intervals to prevent skipped meals as well as avoidance of excess caffeine and rich foods. A retrospective study found that lifestyle intervention alone resulted in 13 of 81 patients experiencing significant relief from vestibular symptoms with migraine. The remaining cohort of patients required a multifaceted approach including pharmacotherapy to achieve similar benefit [56].

Acute Abortive Treatments

Oral antiemetics are commonly prescribed for motion sickness and acute migraine, however there is no evidence supporting their effectiveness in VM (Table 2). Patients should be counselled about avoiding overuse of antiemetics given their risk of causing extrapyramidal side effects [53].

Simple analgesics, such as paracetamol and nonsteroidal anti-inflammatory drugs (NSAIDs), have been found to be helpful in acute VM attacks in observational studies. Bikhazi performed a survey of patients presenting to a headache clinic with vestibular symptoms and found that simple analgesics were valued by patients as effective symptomatic treatment, but were not considered as effective as triptans [59]. Doses of simple analgesics are listed in Table 2. Soluble formulations are preferable due to faster absorption and speed of onset. Opioids should be avoided in acute attacks of VM given the risk of developing opioid overuse headache [55].

Migraine Prophylaxis in Vestibular Migraine

TCAs remain a popular choice of migraine prophylaxis amongst neurootologists because of its additional effects on comorbid affective symptoms. We recommend that the starting dose of either amitriptyline or nortriptyline should be between 5 to 10 mg daily at night, slowly uptitrated to response over several weeks up to a maximum of 100 mg at night. Interval electrocardiography should be performed to monitor for prolongation of the QTc interval. A retrospective chart review found 46% of VM patients (by Neuhauser criteria) reported a reduction in dizziness after nortriptyline administration up to 75 mg daily [62]. However, the current evidence is limited to observational studies [59,62–64].

The evidence for beta-blockers is limited in VM but anecdotally has been useful for patients with frequent episodic migraine [59,63,64]. Recommended starting and maintenance doses are listed in Table 3. Furthermore, propranolol can be used in patients with depression [65,66]. Heart rate and electrocardiography should be monitored during dose escalation. Beta-blockers should be avoided in asthmatics. Commonly reported adverse events include cold, extremities reduced exercise tolerance and dizziness [53].

Flunarizine, a calcium channel blocker widely used in migraine [67,68] and vestibular conditions [69], was recently studied in a RCT of 12 weeks' duration for prophylaxis of migrainous vertigo (Neuhauser criteria) in 48 patients [70]. Although flunarizine 10 mg daily did not result in improved headache frequency and severity compared to the control arm, there was a significant improvement in vertigo severity. The most commonly reported side effects of flunarizine are weight gain and somnolence, both of which are minimal or infrequent. Verapamil is another calcium channel blocker that may be helpful but has major limiting adverse effects are bradycardia, constipation and peripheral edema [53].

Pizotifen, a serotonin antagonist, is one of the most well tolerated prophylaxis agents from our experience, however some patients do not adhere to treatment due to drowsiness or weight gain, as evidenced in retrospective case studies [64].

Topiramate with an average daily dose of 100 mg has reported positive results in a prospective observational study of ten patients with VM with auditory symptoms [71]. Nine of 10 patients reported no symptoms after follow-up period of up to sixteen months. The recommended dose is listed in Table 3. Common side effects include distal paresthesias, reduced ability to concentrate and drowsiness [53]. Sodium valproate has been anecdotally effective [59] and is usually well tolerated especially when starting at a low dose of 200 mg at night, slowly titrated to 1200 mg in 2 divided doses. Liver function and full blood evaluation should be monitored on a periodic basis [53].

Third-line medications have only been used anecdotally and should be reserved for extenuating cases (Table 3).

Vestibular Rehabilitation

Vestibular rehabilitation therapy (VRT) has been shown to alleviate significantly ongoing balance and dizziness symptoms in patients with various vestibular disorders [73,74] and improving confidence with balance in elderly patients [75,76]. However, the value of VRT is not as well established in VM. Anecdotally, patients with VM report persistent significant symptoms at the end of a standard VRT period, in contrast to other nonmigrainous patients who appear to be accomplishing their treatment goals faster. However, recent studies [21,73,77] are suggesting that customised VRT may play a useful role in VM, especially since it appears to target issues of anxiety, visual dependence or loss of confidence in balance. Small retrospective case series found that VRT reduced disability scores, and gait and balance function in over 85% of patients with migraine and vestibular symptoms [73,76,77]. An Australian VRT study (21) has recently assessed the efficacy of a 9-week customised VRT in 20 patients with VM compared to 16 patients with vestibular symptoms but without migraine. The customized VRT program consisted of habituation, gaze stability, static tilt, balance and gait exercises. A pictorial exercise instruction sheet for home use would describe these exercises of approximately 15 minutes duration consisting of 4 to 6 exercises to be performed 3 times a day, every day for 9 weeks. Interestingly, both groups benefitted equally from VRT. Compliance with VRT was comparable between the two groups. Commonly reported reasons for non-attendance in VM patients included a recent acute attack of VM, anxiety related to using public transport, and commitment issues related to occupation. This study also suggested that VM patients required more customized and intensive therapy as 15% of VM patients required additional appointments outside the study timeline.

Given that visual dependency has been shown to be reduced with short-term graded optokinetic stimulation exposure in healthy subjects [78], there has been interest using this intervention in conjunction with customized VRT to promote desensitization to visual stimuli as a treatment for VM patients with VV. Most promisingly is the finding that a subgroup of patients with a history of migraine improved significantly more than other vestibular patients with respect to VV symptoms.

There has been controversy surrounding whether patients should avoid medications when undergoing VRT. The protagonists of this view suggest that medications that affect the central nervous system (CNS) may modulate the rate of central compensation. In the aforementioned study by Vitkovic and colleagues [21], the same degree of improvement was seen in the VM group regardless of medication regimen. A study by Whitney and colleagues [73] found that migraine related vestibulopathy patients taking prophylaxis demonstrated better subjective and objective balance scores at baseline and after therapy. Further research is required to clarify the role of CNS-acting medication and their administration around VRT sessions.

Physical therapists dealing with VM patients may face additional challenges in encouraging exercise compliance and providing emotional support. Although more time consuming for the therapist, this is important in the face of high rates of comorbid affective disorders and head motion intolerance. Supervised VRT is believed to implicitly improve psychological status through increasing confidence, providing reassurance, and emphasizing positive effects of VRT, particularly when the patient feels their symptoms have been made worse by it.

Cognitive Behavioral Therapy

Cognitive behavioral therapy (CBT) has been shown to be helpful as part of the holistic treatment of various disorders including post-concussive syndrome and depression in neurology patients [79,80]. Among patients suffering from dizziness, a small study comparing explicit CBT combined with VRT versus waiting-list controls demonstrated improvements in patients’ coping ability, function, symptoms, and care satisfaction [81]. However, to our knowledge there are no studies directly evaluating the benefits of CBT specifically in VM patients. Despite this, it is our practice to request CBT for VM patients who report disabling anxiety or depressive symptoms.

Prognosis

Although migraine in general can improve in later life, this is less certain with VM given the lack of good quality longitudinal studies. Recently Radtke and colleagues published their long-term (median, 9 years) follow-up study of 61 definite VM cases (28). They found that 87% of patients had recurrent vertigo at follow-up. The frequency of vertigo was reduced in 56%, increased in 29%, and unchanged in 16% of patients. The impact of vertigo was graded as severe in 21%, moderate in 43%, and mild in 36% of patients. However, they found that concomitant cochlear symptoms with vertigo had increased from 15% at study inception to 49% at follow-up and secondly, 18% of patients had developed mild bilateral low-frequency sensorineural hearing loss. Therefore, one major criticism of the study is whether some of the patients had MD as their eventual diagnosis rather than definite VM. On the contrary, the authors conclude that these changes represent new vestibulo-cochlear dysfunction as a result of VM disease progression. Due to these reasons, the prognosis of VM patients is unclear. It is our practice to ensure patients do receive delayed follow-up to allow consideration of other neurotological diagnoses.

Conclusion

Given the large heterogeneity in presentation and objective testing, VM as a diagnostic construct has remained quite controversial, though increasingly more accepted. The more we study this common vestibular condition, the more we are realising that the complex relationship between migraine and dizziness extend beyond VM to encompass other vestibular disorders such as MD and anxiety. The lack of a physiological biomarker contributes to its diagnostic difficulties, but a meticulous workup is important to exclude alternative vestibular diagnoses. More longitudinal studies and RCTs are required to help both understand the prognosis and management of VM patients.

Corresponding author: Benjamin K-T Tsang, MBBS, FRACP, The Prince Charles Hospital, Rode Road, Chermside, Queensland 4032, Australia, [email protected].

Financial disclosures: None.

From the Department of Neurootology, National Hospital of Neurology and Neurosurgery, London (Dr. Tsang, Miss Anwer) and the Ear Institute, University College London, and Guy’s and St Thomas’ NHS Foundation Trust, London, UK (Dr. Murdin).

Abstract

• Objective: To review the clinical manifestations, diagnosis, and management of vestibular migraine (VM).
• Methods: Review of the literature.
• Results: Apart from headache, other symptoms of VM include unsteadiness, imbalance, and spontaneous as well as visual vertigo. Acute vestibular symptoms that qualify for VM must be of at least moderate or severe intensity which lasts within a time window of 5 minutes to 72 hours. The interindividual temporal association of headache and vertigo is highly variable in VM patients  Grossly normal peripheral vestibular function and audiometry both during and between attacks distinguishes VM from its mimics. Treatment options for VM are mainly based on expert opinion and include lifestyle modifications, acute and prophylactic migraine pharmacotherapy, and vestibular rehabilitation therapy.
• Conclusion: Despite a lack of diagnostic biomarkers for VM, a meticulous workup is important to exclude alternative mimics. More longitudinal and treatment studies are required to help elucidate the prognosis and optimal management of this condition.

The coexistence of migraine and vestibular symptoms has been mentioned in the headache literature for many years [1–3]. It was first addressed by Kayan and Hood in 1984, who found that dizziness and vertigo occurred in 54% of migraine patients compared with 30% of patients with tension-type headache [1]. The frequent coexistence of migraine and vertigo led researchers to hypothesize that their co-occurence could be due to more than mere chance. As per Lempert and Neuhauser’s evaluation, there is a lifetime prevalence of 16% for migraine and 7% for vertigo, with a 1.1 % chance of vertigo and migraine occurring together by chance alone [4]. In a study looking at the point prevalence of vertigo or dizziness among those presenting for a routine appointment at a headache center, an astounding 72.8% of those with severe headaches had vestibular symptoms [5].

Most epidemiologic studies of what we call vestibular migraine (VM) were based on presentations to specialist clinics and were performed in an era during which no established diagnostic criteria existed. Despite this, most neurootologists would consider VM to be one of the most common causes of spontaneous recurrent vertigo [6]. Neuhauser et al reported that VM was diagnosed in 7% of a group of 200 specialist clinic patients with dizziness and 9% of a group of 200 clinic patients who had migraine [2]. In a population-based study in Germany, the lifetime prevalence of VM according to the Neuhauser criteria was estimated to be 0.98% and the 12-month prevalence 0.89% [7]. The condition has a 3:1 female predilection [8].

VM has only recently been recognised as a separate migraine entity by the International Headache Society (IHS), appearing in the appendix of their International Classification of Headache Disorders (ICHD)–3 beta. The previous ICHD recognised vertigo as a migrainous symptom only within the framework of basilar migraine.  The nomenclature used in the literature to describe this entity has been inconsistent and therefore confusing, including terms such as migraine-associated vertigo [9], migraine-related dizziness [3] or vertigo [10],migrainous vertigo [2], benign recurrent vertigo [11], and migraine-related vestibulopathy [12]. For the most part, these terms refer to the co-experience of migraine and vertigo or dizziness, with only a few terms having a more specific meaning of how the 2 symptoms relate temporally. Neuhauser and colleagues developed criteria in 2001 to classify migraineurs for whom vestibular symptoms are an integral part of migraine symptomatology, using the term migrainous vertigo [2]. Others preferred the terms migraine-associated dizziness or migraine-related dizziness [3] over migrainous vertigo because they felt the symptoms of vestibular dysfunction related to migraine are varied and may include gait instability and spatial disorientation but not necessarily with vertigo. To best avoid confounding nonvestibular dizziness or motion sickness associated with migraine, VM has been the preferred term because it emphasises the particular vestibular manifestation of migraine.

The lack of a universally accepted definition for this complex entity has contributed to delayed diagnosis and and treatment for those with this disorder. In this article, we will review the clinical manifestation, diagnosis and management of VM, with a focus on assisting in the differentiation between other potential diagnoses.

Pathophysiology of VM

A clear pathophysiology of VM has not been elucidated. Although predominantly a sporadic disease, there have been reported cases of familial occurrence with an auto-somal dominant inheritance [11,13]. Bahmad and colleagues mapped the first locus for familial VM to 5q35 within a 4-generation family [13]. On the contrary, a larger study conducted by Lee et al found VM to be to genetically heterogeneous with a subset linking to chromosome 22q12 [14]. Genetic defects of voltage-gated calcium channels are identified as causal factors for familial hemiplegic migraine and episodic ataxia type 2. Both these disease entities present with vertigo and migraine headaches suggesting a defective gene within the same chromosomal region could indicate a direct genetic link to VM. However, no such gene has been identified.

General consensus is that the action of spreading cortical depression as it reaches the somatosensory cortex in the posterior insula and temporoparietal junction elucidates migraine aura in patients with short attacks. However, due to the heterogeneity of VM, canal paresis and complex conditional nystagmus during acute stages are not explained through cortical spreading. Eggers et al suggests that vertigo symptoms occur as ictal sensation rather than the spreading of sensory or motor cortical depression [15]. However, due to discrepancies within the literature it is apparent that further research needs to be conducted to fully understand the pathophysiology of VM.

Clinical Manifestations of VM

Symptoms

As many as 80% to 90% of patients with VM report unsteadiness or balance problems, of which 50% to 60% typically report episodic spontaneous vertigo [16], either internal vertigo (a false sensation of self-motion) or external vertigo (a false sensation that the visual surround is spinning or flowing) [17]. The duration of episodes is highly variable, whereby approximately 30% of patients have episodes lasting minutes, 30% have attacks lasting hours, 30% have attacks over several days, while the remaining 10% have attacks lasting seconds only [18]. It may be difficult to distinguish if vestibular symptoms lasting seconds are related to their head motion intolerance, also known as head motion–induced vertigo [17], which is another frequent symptom in VM. Head motion–induced vertigo bears many similarities to motion sickness.

The interindividual temporal association of headache and vertigo is highly variable in VM patients and is a reason many patients find this diagnostic construct difficult to accept. Approximately 30% of adult patients eventually diagnosed with VM initially present without headaches [8]. Vertigo is only regularly associated with headache in 25% to 50% of VM patients [2,7]. A minority of patients report headache and vertigo never occurring together [2]. A temporal pattern, presenting as aura, occurs only in approximately 10% of cases [19]; therefore, vestibular episodes of VM should not be regarded as migraine auras [18]. Patients typically have migraine manifesting earlier in life with the vestibular symptoms following [13,20], whereby the mean age at onset of migraine and diagnosis of VM are approximately 22 and 35 years, respectively [2]. Consistently across studies that measure quality of life scores, VM patients report higher subjective levels of disability compared to patients with other vestibular illnesses, despite having less objective abnormalities [21]. Approximately 85% of VM patients experienced vestibular symptoms for at least 1 year before consulting neurootology services [21]. It could be argued that hypersensitivity of percept to vestibular symptoms reflect the general finding of augmented perceptions to various external stimuli underlying migraine [22,23].

Another prominent feature of VM is that patients report a syndrome of visually-induced dizziness termed visual vertigo (VV). This is a heterogeneous syndrome with strabismic, peripheral, and/or central vestibular aetiologies [24]. Patients with VV complain of discomfort, postural destabilisation, dizziness, imbalance and spatial disorientation in challenging visual environments. Examples of such environments include walking down supermarket aisles, observing moving objects (eg, disco lights, people walking, moving traffic) or moving surroundings during travelling, and the movement of the eyes in general [24–26]. Most patients report more than one visual trigger [24]. Visual vertigo can often be difficult to distinguish from oscillopsia in patients with bilateral vestibular failure. What is most surprising is that patients with VV have a similar handicap level yet report much more vestibular symptoms compared with patients with bilateral vestibular failure [25]. Postural reactions triggered by external visual motion are destabilising with respect to the earth-vertical and are normally suppressed by central re-weighting of sensory postural cues [24]. Surprisingly, premorbid levels of anxiety and childhood motion sickness do not appear to have a correlation with VV [25]. Even in normal subjects, certain complex visual stimuli can induce transient motion sickness–like symptoms, as shown in experimental visually induced self-vection [27]. The Situational Characteristics Questionnaire (SVQ) is a 19-question, symptom-based questionnaire that has been shown to be useful in quantifying features of VV and may be useful in gauging improvement following physical therapies [25,26].

Early in the disease course, hearing loss should prompt an alternative diagnosis. However, late onset cochlear symptoms have been reported in VM. A study found that after 9 years of follow-up, the number of patients with cochlear symptoms more than doubled [28].

Clinical Examination Findings

The importance of the clinical examination is to rule out peripheral vestibular dysfunction and perform positional testing to look for benign paroxysmal positional vertigo (BPPV) or central positional nystagmus. Nonetheless, positional nystagmus has been reported in up to 28% of cases, including definite central-type positional nystagmus reported in as many as 18% [28].

Audiometric Findings and Auditory Brainstem Responses

Normal audiometry both during and between attacks is one of the key clinical features that distinguishes VM from Meniere’s disease [29]. Auditory brainstem response (ABR) results are typically normal in about 65% of patients [29]. Abnormal ABR results are typically nonspecific, such as mild elongation of wave I, III and V latencies and less commonly, prolongation of the inter-peak latencies.

Findings on Vestibular Function Testing

Whilst there are some reported abnormalities in vestibular function testing in VM patients, such findings need to be interpreted with caution due to the small number of subjects, as well as the variation in case definition and cut-off values. Most importantly, very few papers studied patients in the acute phase, and in some studies it was not even specified. The majority of studies report that VM patients interictally have grossly normal peripheral vestibular function with occasional minor irregularities. Profound interictal abnormalities such as complete canal paresis are usually indicative of other diagnoses. In between acute attacks, patients with VM typically have normal gaze, saccadic parameters, ocular pursuit gains and optokinetic nystagmus (OKN) gains on electronystagmography (ENG) or videonystagmography (VNG) [3]. A minority had a low amplitude (< 4 degrees per second) persistent positional nystagmus. On rotation testing of the vestibo-ocular reflex there is reduction of the mean gains compared to headache-free controls. Most reports in the literature do support that the majority of VM patients have grossly normal bithermal caloric testing, although abnormalities including higher slow phase velocities and canal paresis (usually partial) are reported [29–31]. The observation that the artificial vestibular stimulation caused by the caloric test was followed by a migraine attack within 24 hours in 49% of patients with migraine is very interesting [30], and it remains to be tested whether this phenomenon has the potential to be of assistance in the diagnosis of VM. Both VM patients and migraineurs without vertigo have similar subtle cVEMP (Cervical vestibular-evoked myogenic potentials) abnormalities, namely decreased global amplitude and absence of habituation [31]. On computerized dynamic posturography (CDP), a test of sway, VM patients typically demonstrate a surface-dependent pattern based on their SOT analysis [3], suggesting that VM patients may have a substantial vestibulo-spinal abnormality leading to difficulties integrating multiple conflicting sensory inputs [32].

Diagnostic Criteria

Separating VM into 2 diagnostic entities seems particularly useful: definite VM and the more sensitive but less specific category of probable VM. The sensitivity and specificity of the proposed criteria still need to be determined. Although some authors criticize the probable diagnostic entity for its heterogeneity, about 50% of patients initially diagnosed with probable VM ultimately progress to definite VM [12,33]. Definite vestibular migraine appears in the ICHD-3 beta but only in the appendix section for “new disorders that need further research for validation.” However, probable VM will not be included until further evidence of its utility has been accumulated.

The diagnosis is particularly challenging when headache is not a regular accompaniment of the vertiginous attacks. A patient diary may help link migrainous and vertigo symptoms. When headache is not a prominent feature of the attacks, the clinician will have to put migrainous triggers or symptoms such as photophobia or scintillating scotomas in the context of vertigo symptoms to aid with the diagnosis. One needs to be pedantic about differentiating the qualifying symptom of phonophobia, which is defined as a sound-induced discomfort that is often transient and bilateral from the uncomfortable distorted loud sound perception, which occurs with a recruiting sensorineural hearing loss, and is often persistent and unilateral [18]. Response to migraine treatment is not sufficiently specific to be included in the diagnostic criteria. High placebo response rates from migraine trials [34] suggest that placebo effects can likewise be expected in the treatment of VM. Despite these challenges, acceptance of the diagnostic entity of VM seems to be gaining momentum. In a follow-up study over 9 years, the diagnosis remained consistent in 85% of patients [33].

Benign Paroxysmal Vertigo of Childhood and Vestibular Migraine in Children

VM can present at any age, however, the ICHD specifically recognises an early vertiginous entity regarded as a precursor syndrome of migraine in otherwise healthy children called benign paroxysmal vertigo of childhood. This diagnosis requires 5 episodes of severe vertigo, occurring without warning and resolving spontaneously after minutes to hours [35]. In between episodes, neurological examination, audiometry, vestibular functions and EEG must be normal. A unilateral throbbing headache may occur during attacks but it is not a mandatory criterion. It is unclear whether these two conditions in children are the same entity, however it is important to note that the classification of VM does not involve any age limit [18].

Basilar-type Migraine

The term basilar migraine should be restricted to patients who fulfill the ICHD diagnostic criteria [35] given it is a clinically distinct entity from VM. Less than 10% of VM patients further fulfill the ICHD criteria for basilar migraine [2,18]. More than 60% of basilar-type migraine patients have vertigo and there are many overlapping clinical manifestations with VM. This diagnosis requires at least 2 symptoms from aura in the posterior circulation territory, whereas most patients with VM have vestibular symptoms only [35]. Moreover, in basilar migraine the duration of vertigo should correspond to the length of an aura, that is, between 5 and 60 minutes [35]. Further studies are required to further elucidate and delineate these 2 conditions.

Other Important Diagnostic Considerations

Meniere’s Disease

An important differential diagnosis of VM is the early presentation of Meniere’s disease (MD). Although fluctuating hearing loss, aural fullness and episodic vertigo are important symptoms in the recent updated diagnostic criteria for definite MD [36,37], these symptoms have been reported in patients with migraine [38]. Moreover, minor abnormalities in cVEMPs and arguably in caloric testing can be found in VM patients, as previously mentioned. Predominantly, the distinction can be made considering that a more sustained, albeit occasionally fluctuating, hearing loss would occur in MD, which can progress to severe hearing loss within a few years. However, the diagnosis can be difficult considering that audiometric and vestibular function abnormalities as well as the typical cochlear symptoms are often absent in the early stages of the MD. Nonetheless, preclinical labelling of patients with episodic vertigo without hearing loss as “vestibular MD” is unhelpful as this population may be overrepresented by actual migraineurs. Studies of patients with so-called benign recurrent vertigo or recurrent vestibulopathy are likely to be heterogeneous entities, with perhaps cases later evolving into VM or MD.

Coexisting migraine and MD is often challenging both in terms of diagnosis and management. Many studies have shown an increased prevalence of migraine in MD patients compared to controls [39,40], an asso-ciation suggested by Prosper Ménière himself in 1861 [41]. A study by Radtke et al found that the lifetime prevalence of migraine with and without aura was over 2 times higher in definite MD patients of both sexes compared to age-matched controls (56% versus 25%) [39]. Interestingly, 45% of the patients with MD always experienced at least 1 migrainous symptom (migrainous headache, photophobia, aura symptoms) with their Meniere attacks [39]. This may be at least partly due to the triggering effect of vestibular symptoms on migraineurs [30]. Migraine may even influence the disease course of MD as indicated by a retrospective case control study which found that definite MD patients who have concomitant ICHD criteria for migraine [35] had a significantly earlier onset of MD symptoms (mean age, 37.2 versus 49.3 years) and a much greater susceptibility to simultaneous bilateral, but not sequential, hearing loss as compared to MD patients without migraine (56% versus 4%) [42]. There were no significant differences in the severity of hearing loss between the 2 groups even when controlling for time to evaluation [42]. A family history of episodic vertigo was seen in 39% of MD patients with migraine, which is significantly higher than the 2% seen in MD patients, suggesting a possible genetic basis for this association [42]. The nature of the association between migraine and MD is not well elucidated, however, some authors propose that migraine leads to isolated microvascular ischaemic damage of the inner ear, presumably through small arterial vasospasm [40,42].

In summary, when the criteria for MD are met together with documented audiometric abnormalities, MD should be diagnosed, even if migraine symptoms occur during the vestibular attacks [18]. Only patients who experience 2 different types of attacks, one fulfilling the criteria for VM and the other for MD, should be labelled as Meniere’s disease/migraine overlap syndrome. It is hoped that future revisions of diagnostic criteria will include this overlap entity.

Migraine and Benign Paroxysmal Positional Vertigo

VM patients can experience brief positional dizziness and therefore VM may mimic BPPV. It is therefore important to perform positional testing to look for nystagmus typical for BPPV. Certainly the positional characteristics are distinct from BPPV with regard to the duration of attacks (often as long as the head position is maintained in VM rather than seconds in BPPV). BPPV may also produce attacks of vertigo that can act as triggers for migraine headaches. In these patients, treatment of the BPPV will reduce headache frequency [30].

Transient Ischemic Attacks

Transient ischemic attack (TIA) is a cerebrovascular disease with temporary neurological symptoms [43] and is differentiated from VM mainly from the characteristics of reported symptoms. Being a vascular phenomenon, one would expect TIA symptoms to have a sudden onset, with a brief duration of symptoms (typically short minutes), followed by a rapid improvement to baseline, as well as correspond to a vascular territory. The other important message is that stereotyped, frequently recurrent symptoms are less likely to be TIAs, with the exception of capsular warning syndrome [44] and limb shaking TIAs [43] described elsewhere.

Migraine and Motion Sickness

In an individual patient it may be difficult to differentiate between motion sickness and acute attacks of VM induced by motion stimuli. The distinction may be helped by observing nausea and dizziness improving after cessation of motion which points more towards motion sickness, as oppose to the persistent vertigo after the motion stimulus has ended, thus pointing more towards VM.

Episodic Ataxia Type 2

Of the various episodic ataxias, episodic ataxia type 2 would be the most important subtype in the differential diagnosis of VM given it presents with episodic vertigo and is the most frequently occurring subtype. It is a rare autosomal dominant inherited neurological disorder resulting from mutations of the calcium channel gene CACNA1A [45]. The clinical manifestations include recurrent disabling attacks of imbalance, vertigo and ataxia, which can be provoked by physical exertion or emotional stress. Patients may have downbeat nystagmus interictally. A slow progression of cerebellar signs accompanied by atrophy of midline cerebellar structures and a response to acetazolamide or 4-aminopyridine can help distinguish it from VM.

Migraine, Dizziness, and Comorbid Psychiatric Disorders

Particularly in patients with protracted symptoms, it is difficult to tease out the difference between the symptoms of migraine and dizziness from the symptoms of certain psychiatric disorders given their bidirectional associations. Migraine is a risk factor for first-onset major depression [46] and panic disorder [47]. Patients with VM have very high rates (30%–65%) of coexisting psychiatric illness, especially anxiety and depression, with frequencies higher than that associated with other migraine or vestibular disorders [48,49]. Vestibular migraine patients who have a positive history of psychiatric disorders have a comparatively higher risk of developing somatoform dizziness [48]. The unpredictability of recurrent vestibular symptoms could be a factor leading to elevated distress in VM patients. It is not uncommon to see a premature diagnosis of psychogenic dizziness to be given to patients without objective abnormalities. On the contrary, a diagnosis of psychogenic dizziness can rarely be made with certainty due to multiple reasons. Disabling vertigo leading to physical symptoms and avoidance of social activities can easily be misconstrued to have panic disorder with or without agoraphobia. Moreover, dizziness is the second most common symptom of a panic attack after palpitations [50].

Unfortunately, there are no objective tests that can reliably discriminate vestibular syndromes from psychiatric syndromes in patients with dizziness. The SVQ is not specific enough to differentiate symptoms of VV from the space and motion discomfort symptoms often found in agoraphobic patients [25]. Experimentally, agoraphobia patients may have a more surface-dependent strategy rather than a visual-dependent strategy on CDP [51]. It is unclear whether the vestibular system is causally linked to emotion processing pathways.

Chronic Subjective Dizziness

Chronic subjective dizziness is an entity characterised by chronic unsteadiness or nonvertiginous dizziness accompanied by hypersensitivity to motion stimuli and poor tolerance for complex visual stimuli lasting for 3 months or more without objective abnormalities [52]. These vestibular symptoms are often difficult to distinguish from symptoms of VM. This condition is thought to be a spatial sensory analog of allodynia experienced by some chronic migraine headache sufferers [8].

Dizziness Due to Side Effects of Migraine Prophylactic Medications

Dizziness is often listed as a side effect in the product information of various medications including those used for migraine prophylaxis. It is important to take an accurate history of the suspected offending drug in terms of its temporal relationship to vestibular symptoms. Tricyclic antidepressants (TCAs) can cause drowsiness, lightheadedness, fatigue and blurred vision [53]. Beta-blockers can cause orthostatic hypotension [53]. All the above effects could be confused with vestibular symptoms.

Treatment of Vestibular Migraine

Current treatment options for VM are mainly limited to expert opinion rather than inferred from randomized controlled trials (RCTs) [54]. Below we have offered our consensus on how VM should be managed, with concepts based on the guidelines of treatment for typical migraine [55]. Avoidance of migraine triggers should always be the first avenue of treatment. In addition, any vestibular disorder that is triggering migraine attacks should be identified and treated in its own right. Pharmacotherapy can be abortive for acute episodes and prophylactic.

Lifestyle Advice

The key first task in management is the correct diagnosis and educating the patient about the condition. A thorough explanation of the migraine origin of the attacks can address patients fear and expectations. Nonpharmaceutical approaches in the treatment of VM should not be neglected, even though only a very small proportion of patients may derive a benefit. Advice on dietary manipulation is routinely given; however, its efficacy in VM is questionable. Dietary advice includes healthy eating at regular intervals to prevent skipped meals as well as avoidance of excess caffeine and rich foods. A retrospective study found that lifestyle intervention alone resulted in 13 of 81 patients experiencing significant relief from vestibular symptoms with migraine. The remaining cohort of patients required a multifaceted approach including pharmacotherapy to achieve similar benefit [56].

Acute Abortive Treatments

Oral antiemetics are commonly prescribed for motion sickness and acute migraine, however there is no evidence supporting their effectiveness in VM (Table 2). Patients should be counselled about avoiding overuse of antiemetics given their risk of causing extrapyramidal side effects [53].

Simple analgesics, such as paracetamol and nonsteroidal anti-inflammatory drugs (NSAIDs), have been found to be helpful in acute VM attacks in observational studies. Bikhazi performed a survey of patients presenting to a headache clinic with vestibular symptoms and found that simple analgesics were valued by patients as effective symptomatic treatment, but were not considered as effective as triptans [59]. Doses of simple analgesics are listed in Table 2. Soluble formulations are preferable due to faster absorption and speed of onset. Opioids should be avoided in acute attacks of VM given the risk of developing opioid overuse headache [55].

Migraine Prophylaxis in Vestibular Migraine

TCAs remain a popular choice of migraine prophylaxis amongst neurootologists because of its additional effects on comorbid affective symptoms. We recommend that the starting dose of either amitriptyline or nortriptyline should be between 5 to 10 mg daily at night, slowly uptitrated to response over several weeks up to a maximum of 100 mg at night. Interval electrocardiography should be performed to monitor for prolongation of the QTc interval. A retrospective chart review found 46% of VM patients (by Neuhauser criteria) reported a reduction in dizziness after nortriptyline administration up to 75 mg daily [62]. However, the current evidence is limited to observational studies [59,62–64].

The evidence for beta-blockers is limited in VM but anecdotally has been useful for patients with frequent episodic migraine [59,63,64]. Recommended starting and maintenance doses are listed in Table 3. Furthermore, propranolol can be used in patients with depression [65,66]. Heart rate and electrocardiography should be monitored during dose escalation. Beta-blockers should be avoided in asthmatics. Commonly reported adverse events include cold, extremities reduced exercise tolerance and dizziness [53].

Flunarizine, a calcium channel blocker widely used in migraine [67,68] and vestibular conditions [69], was recently studied in a RCT of 12 weeks' duration for prophylaxis of migrainous vertigo (Neuhauser criteria) in 48 patients [70]. Although flunarizine 10 mg daily did not result in improved headache frequency and severity compared to the control arm, there was a significant improvement in vertigo severity. The most commonly reported side effects of flunarizine are weight gain and somnolence, both of which are minimal or infrequent. Verapamil is another calcium channel blocker that may be helpful but has major limiting adverse effects are bradycardia, constipation and peripheral edema [53].

Pizotifen, a serotonin antagonist, is one of the most well tolerated prophylaxis agents from our experience, however some patients do not adhere to treatment due to drowsiness or weight gain, as evidenced in retrospective case studies [64].

Topiramate with an average daily dose of 100 mg has reported positive results in a prospective observational study of ten patients with VM with auditory symptoms [71]. Nine of 10 patients reported no symptoms after follow-up period of up to sixteen months. The recommended dose is listed in Table 3. Common side effects include distal paresthesias, reduced ability to concentrate and drowsiness [53]. Sodium valproate has been anecdotally effective [59] and is usually well tolerated especially when starting at a low dose of 200 mg at night, slowly titrated to 1200 mg in 2 divided doses. Liver function and full blood evaluation should be monitored on a periodic basis [53].

Third-line medications have only been used anecdotally and should be reserved for extenuating cases (Table 3).

Vestibular Rehabilitation

Vestibular rehabilitation therapy (VRT) has been shown to alleviate significantly ongoing balance and dizziness symptoms in patients with various vestibular disorders [73,74] and improving confidence with balance in elderly patients [75,76]. However, the value of VRT is not as well established in VM. Anecdotally, patients with VM report persistent significant symptoms at the end of a standard VRT period, in contrast to other nonmigrainous patients who appear to be accomplishing their treatment goals faster. However, recent studies [21,73,77] are suggesting that customised VRT may play a useful role in VM, especially since it appears to target issues of anxiety, visual dependence or loss of confidence in balance. Small retrospective case series found that VRT reduced disability scores, and gait and balance function in over 85% of patients with migraine and vestibular symptoms [73,76,77]. An Australian VRT study (21) has recently assessed the efficacy of a 9-week customised VRT in 20 patients with VM compared to 16 patients with vestibular symptoms but without migraine. The customized VRT program consisted of habituation, gaze stability, static tilt, balance and gait exercises. A pictorial exercise instruction sheet for home use would describe these exercises of approximately 15 minutes duration consisting of 4 to 6 exercises to be performed 3 times a day, every day for 9 weeks. Interestingly, both groups benefitted equally from VRT. Compliance with VRT was comparable between the two groups. Commonly reported reasons for non-attendance in VM patients included a recent acute attack of VM, anxiety related to using public transport, and commitment issues related to occupation. This study also suggested that VM patients required more customized and intensive therapy as 15% of VM patients required additional appointments outside the study timeline.

Given that visual dependency has been shown to be reduced with short-term graded optokinetic stimulation exposure in healthy subjects [78], there has been interest using this intervention in conjunction with customized VRT to promote desensitization to visual stimuli as a treatment for VM patients with VV. Most promisingly is the finding that a subgroup of patients with a history of migraine improved significantly more than other vestibular patients with respect to VV symptoms.

There has been controversy surrounding whether patients should avoid medications when undergoing VRT. The protagonists of this view suggest that medications that affect the central nervous system (CNS) may modulate the rate of central compensation. In the aforementioned study by Vitkovic and colleagues [21], the same degree of improvement was seen in the VM group regardless of medication regimen. A study by Whitney and colleagues [73] found that migraine related vestibulopathy patients taking prophylaxis demonstrated better subjective and objective balance scores at baseline and after therapy. Further research is required to clarify the role of CNS-acting medication and their administration around VRT sessions.

Physical therapists dealing with VM patients may face additional challenges in encouraging exercise compliance and providing emotional support. Although more time consuming for the therapist, this is important in the face of high rates of comorbid affective disorders and head motion intolerance. Supervised VRT is believed to implicitly improve psychological status through increasing confidence, providing reassurance, and emphasizing positive effects of VRT, particularly when the patient feels their symptoms have been made worse by it.

Cognitive Behavioral Therapy

Cognitive behavioral therapy (CBT) has been shown to be helpful as part of the holistic treatment of various disorders including post-concussive syndrome and depression in neurology patients [79,80]. Among patients suffering from dizziness, a small study comparing explicit CBT combined with VRT versus waiting-list controls demonstrated improvements in patients’ coping ability, function, symptoms, and care satisfaction [81]. However, to our knowledge there are no studies directly evaluating the benefits of CBT specifically in VM patients. Despite this, it is our practice to request CBT for VM patients who report disabling anxiety or depressive symptoms.

Prognosis

Although migraine in general can improve in later life, this is less certain with VM given the lack of good quality longitudinal studies. Recently Radtke and colleagues published their long-term (median, 9 years) follow-up study of 61 definite VM cases (28). They found that 87% of patients had recurrent vertigo at follow-up. The frequency of vertigo was reduced in 56%, increased in 29%, and unchanged in 16% of patients. The impact of vertigo was graded as severe in 21%, moderate in 43%, and mild in 36% of patients. However, they found that concomitant cochlear symptoms with vertigo had increased from 15% at study inception to 49% at follow-up and secondly, 18% of patients had developed mild bilateral low-frequency sensorineural hearing loss. Therefore, one major criticism of the study is whether some of the patients had MD as their eventual diagnosis rather than definite VM. On the contrary, the authors conclude that these changes represent new vestibulo-cochlear dysfunction as a result of VM disease progression. Due to these reasons, the prognosis of VM patients is unclear. It is our practice to ensure patients do receive delayed follow-up to allow consideration of other neurotological diagnoses.

Conclusion

Given the large heterogeneity in presentation and objective testing, VM as a diagnostic construct has remained quite controversial, though increasingly more accepted. The more we study this common vestibular condition, the more we are realising that the complex relationship between migraine and dizziness extend beyond VM to encompass other vestibular disorders such as MD and anxiety. The lack of a physiological biomarker contributes to its diagnostic difficulties, but a meticulous workup is important to exclude alternative vestibular diagnoses. More longitudinal studies and RCTs are required to help both understand the prognosis and management of VM patients.

Corresponding author: Benjamin K-T Tsang, MBBS, FRACP, The Prince Charles Hospital, Rode Road, Chermside, Queensland 4032, Australia, [email protected].

Financial disclosures: None.

From the Department of Neurootology, National Hospital of Neurology and Neurosurgery, London (Dr. Tsang, Miss Anwer) and the Ear Institute, University College London, and Guy’s and St Thomas’ NHS Foundation Trust, London, UK (Dr. Murdin).

Abstract

• Objective: To review the clinical manifestations, diagnosis, and management of vestibular migraine (VM).
• Methods: Review of the literature.
• Results: Apart from headache, other symptoms of VM include unsteadiness, imbalance, and spontaneous as well as visual vertigo. Acute vestibular symptoms that qualify for VM must be of at least moderate or severe intensity which lasts within a time window of 5 minutes to 72 hours. The interindividual temporal association of headache and vertigo is highly variable in VM patients  Grossly normal peripheral vestibular function and audiometry both during and between attacks distinguishes VM from its mimics. Treatment options for VM are mainly based on expert opinion and include lifestyle modifications, acute and prophylactic migraine pharmacotherapy, and vestibular rehabilitation therapy.
• Conclusion: Despite a lack of diagnostic biomarkers for VM, a meticulous workup is important to exclude alternative mimics. More longitudinal and treatment studies are required to help elucidate the prognosis and optimal management of this condition.

The coexistence of migraine and vestibular symptoms has been mentioned in the headache literature for many years [1–3]. It was first addressed by Kayan and Hood in 1984, who found that dizziness and vertigo occurred in 54% of migraine patients compared with 30% of patients with tension-type headache [1]. The frequent coexistence of migraine and vertigo led researchers to hypothesize that their co-occurence could be due to more than mere chance. As per Lempert and Neuhauser’s evaluation, there is a lifetime prevalence of 16% for migraine and 7% for vertigo, with a 1.1 % chance of vertigo and migraine occurring together by chance alone [4]. In a study looking at the point prevalence of vertigo or dizziness among those presenting for a routine appointment at a headache center, an astounding 72.8% of those with severe headaches had vestibular symptoms [5].

Most epidemiologic studies of what we call vestibular migraine (VM) were based on presentations to specialist clinics and were performed in an era during which no established diagnostic criteria existed. Despite this, most neurootologists would consider VM to be one of the most common causes of spontaneous recurrent vertigo [6]. Neuhauser et al reported that VM was diagnosed in 7% of a group of 200 specialist clinic patients with dizziness and 9% of a group of 200 clinic patients who had migraine [2]. In a population-based study in Germany, the lifetime prevalence of VM according to the Neuhauser criteria was estimated to be 0.98% and the 12-month prevalence 0.89% [7]. The condition has a 3:1 female predilection [8].

VM has only recently been recognised as a separate migraine entity by the International Headache Society (IHS), appearing in the appendix of their International Classification of Headache Disorders (ICHD)–3 beta. The previous ICHD recognised vertigo as a migrainous symptom only within the framework of basilar migraine.  The nomenclature used in the literature to describe this entity has been inconsistent and therefore confusing, including terms such as migraine-associated vertigo [9], migraine-related dizziness [3] or vertigo [10],migrainous vertigo [2], benign recurrent vertigo [11], and migraine-related vestibulopathy [12]. For the most part, these terms refer to the co-experience of migraine and vertigo or dizziness, with only a few terms having a more specific meaning of how the 2 symptoms relate temporally. Neuhauser and colleagues developed criteria in 2001 to classify migraineurs for whom vestibular symptoms are an integral part of migraine symptomatology, using the term migrainous vertigo [2]. Others preferred the terms migraine-associated dizziness or migraine-related dizziness [3] over migrainous vertigo because they felt the symptoms of vestibular dysfunction related to migraine are varied and may include gait instability and spatial disorientation but not necessarily with vertigo. To best avoid confounding nonvestibular dizziness or motion sickness associated with migraine, VM has been the preferred term because it emphasises the particular vestibular manifestation of migraine.

The lack of a universally accepted definition for this complex entity has contributed to delayed diagnosis and and treatment for those with this disorder. In this article, we will review the clinical manifestation, diagnosis and management of VM, with a focus on assisting in the differentiation between other potential diagnoses.

Pathophysiology of VM

A clear pathophysiology of VM has not been elucidated. Although predominantly a sporadic disease, there have been reported cases of familial occurrence with an auto-somal dominant inheritance [11,13]. Bahmad and colleagues mapped the first locus for familial VM to 5q35 within a 4-generation family [13]. On the contrary, a larger study conducted by Lee et al found VM to be to genetically heterogeneous with a subset linking to chromosome 22q12 [14]. Genetic defects of voltage-gated calcium channels are identified as causal factors for familial hemiplegic migraine and episodic ataxia type 2. Both these disease entities present with vertigo and migraine headaches suggesting a defective gene within the same chromosomal region could indicate a direct genetic link to VM. However, no such gene has been identified.

General consensus is that the action of spreading cortical depression as it reaches the somatosensory cortex in the posterior insula and temporoparietal junction elucidates migraine aura in patients with short attacks. However, due to the heterogeneity of VM, canal paresis and complex conditional nystagmus during acute stages are not explained through cortical spreading. Eggers et al suggests that vertigo symptoms occur as ictal sensation rather than the spreading of sensory or motor cortical depression [15]. However, due to discrepancies within the literature it is apparent that further research needs to be conducted to fully understand the pathophysiology of VM.

Clinical Manifestations of VM

Symptoms

As many as 80% to 90% of patients with VM report unsteadiness or balance problems, of which 50% to 60% typically report episodic spontaneous vertigo [16], either internal vertigo (a false sensation of self-motion) or external vertigo (a false sensation that the visual surround is spinning or flowing) [17]. The duration of episodes is highly variable, whereby approximately 30% of patients have episodes lasting minutes, 30% have attacks lasting hours, 30% have attacks over several days, while the remaining 10% have attacks lasting seconds only [18]. It may be difficult to distinguish if vestibular symptoms lasting seconds are related to their head motion intolerance, also known as head motion–induced vertigo [17], which is another frequent symptom in VM. Head motion–induced vertigo bears many similarities to motion sickness.

The interindividual temporal association of headache and vertigo is highly variable in VM patients and is a reason many patients find this diagnostic construct difficult to accept. Approximately 30% of adult patients eventually diagnosed with VM initially present without headaches [8]. Vertigo is only regularly associated with headache in 25% to 50% of VM patients [2,7]. A minority of patients report headache and vertigo never occurring together [2]. A temporal pattern, presenting as aura, occurs only in approximately 10% of cases [19]; therefore, vestibular episodes of VM should not be regarded as migraine auras [18]. Patients typically have migraine manifesting earlier in life with the vestibular symptoms following [13,20], whereby the mean age at onset of migraine and diagnosis of VM are approximately 22 and 35 years, respectively [2]. Consistently across studies that measure quality of life scores, VM patients report higher subjective levels of disability compared to patients with other vestibular illnesses, despite having less objective abnormalities [21]. Approximately 85% of VM patients experienced vestibular symptoms for at least 1 year before consulting neurootology services [21]. It could be argued that hypersensitivity of percept to vestibular symptoms reflect the general finding of augmented perceptions to various external stimuli underlying migraine [22,23].

Another prominent feature of VM is that patients report a syndrome of visually-induced dizziness termed visual vertigo (VV). This is a heterogeneous syndrome with strabismic, peripheral, and/or central vestibular aetiologies [24]. Patients with VV complain of discomfort, postural destabilisation, dizziness, imbalance and spatial disorientation in challenging visual environments. Examples of such environments include walking down supermarket aisles, observing moving objects (eg, disco lights, people walking, moving traffic) or moving surroundings during travelling, and the movement of the eyes in general [24–26]. Most patients report more than one visual trigger [24]. Visual vertigo can often be difficult to distinguish from oscillopsia in patients with bilateral vestibular failure. What is most surprising is that patients with VV have a similar handicap level yet report much more vestibular symptoms compared with patients with bilateral vestibular failure [25]. Postural reactions triggered by external visual motion are destabilising with respect to the earth-vertical and are normally suppressed by central re-weighting of sensory postural cues [24]. Surprisingly, premorbid levels of anxiety and childhood motion sickness do not appear to have a correlation with VV [25]. Even in normal subjects, certain complex visual stimuli can induce transient motion sickness–like symptoms, as shown in experimental visually induced self-vection [27]. The Situational Characteristics Questionnaire (SVQ) is a 19-question, symptom-based questionnaire that has been shown to be useful in quantifying features of VV and may be useful in gauging improvement following physical therapies [25,26].

Early in the disease course, hearing loss should prompt an alternative diagnosis. However, late onset cochlear symptoms have been reported in VM. A study found that after 9 years of follow-up, the number of patients with cochlear symptoms more than doubled [28].

Clinical Examination Findings

The importance of the clinical examination is to rule out peripheral vestibular dysfunction and perform positional testing to look for benign paroxysmal positional vertigo (BPPV) or central positional nystagmus. Nonetheless, positional nystagmus has been reported in up to 28% of cases, including definite central-type positional nystagmus reported in as many as 18% [28].

Audiometric Findings and Auditory Brainstem Responses

Normal audiometry both during and between attacks is one of the key clinical features that distinguishes VM from Meniere’s disease [29]. Auditory brainstem response (ABR) results are typically normal in about 65% of patients [29]. Abnormal ABR results are typically nonspecific, such as mild elongation of wave I, III and V latencies and less commonly, prolongation of the inter-peak latencies.

Findings on Vestibular Function Testing

Whilst there are some reported abnormalities in vestibular function testing in VM patients, such findings need to be interpreted with caution due to the small number of subjects, as well as the variation in case definition and cut-off values. Most importantly, very few papers studied patients in the acute phase, and in some studies it was not even specified. The majority of studies report that VM patients interictally have grossly normal peripheral vestibular function with occasional minor irregularities. Profound interictal abnormalities such as complete canal paresis are usually indicative of other diagnoses. In between acute attacks, patients with VM typically have normal gaze, saccadic parameters, ocular pursuit gains and optokinetic nystagmus (OKN) gains on electronystagmography (ENG) or videonystagmography (VNG) [3]. A minority had a low amplitude (< 4 degrees per second) persistent positional nystagmus. On rotation testing of the vestibo-ocular reflex there is reduction of the mean gains compared to headache-free controls. Most reports in the literature do support that the majority of VM patients have grossly normal bithermal caloric testing, although abnormalities including higher slow phase velocities and canal paresis (usually partial) are reported [29–31]. The observation that the artificial vestibular stimulation caused by the caloric test was followed by a migraine attack within 24 hours in 49% of patients with migraine is very interesting [30], and it remains to be tested whether this phenomenon has the potential to be of assistance in the diagnosis of VM. Both VM patients and migraineurs without vertigo have similar subtle cVEMP (Cervical vestibular-evoked myogenic potentials) abnormalities, namely decreased global amplitude and absence of habituation [31]. On computerized dynamic posturography (CDP), a test of sway, VM patients typically demonstrate a surface-dependent pattern based on their SOT analysis [3], suggesting that VM patients may have a substantial vestibulo-spinal abnormality leading to difficulties integrating multiple conflicting sensory inputs [32].

Diagnostic Criteria

Separating VM into 2 diagnostic entities seems particularly useful: definite VM and the more sensitive but less specific category of probable VM. The sensitivity and specificity of the proposed criteria still need to be determined. Although some authors criticize the probable diagnostic entity for its heterogeneity, about 50% of patients initially diagnosed with probable VM ultimately progress to definite VM [12,33]. Definite vestibular migraine appears in the ICHD-3 beta but only in the appendix section for “new disorders that need further research for validation.” However, probable VM will not be included until further evidence of its utility has been accumulated.

The diagnosis is particularly challenging when headache is not a regular accompaniment of the vertiginous attacks. A patient diary may help link migrainous and vertigo symptoms. When headache is not a prominent feature of the attacks, the clinician will have to put migrainous triggers or symptoms such as photophobia or scintillating scotomas in the context of vertigo symptoms to aid with the diagnosis. One needs to be pedantic about differentiating the qualifying symptom of phonophobia, which is defined as a sound-induced discomfort that is often transient and bilateral from the uncomfortable distorted loud sound perception, which occurs with a recruiting sensorineural hearing loss, and is often persistent and unilateral [18]. Response to migraine treatment is not sufficiently specific to be included in the diagnostic criteria. High placebo response rates from migraine trials [34] suggest that placebo effects can likewise be expected in the treatment of VM. Despite these challenges, acceptance of the diagnostic entity of VM seems to be gaining momentum. In a follow-up study over 9 years, the diagnosis remained consistent in 85% of patients [33].

Benign Paroxysmal Vertigo of Childhood and Vestibular Migraine in Children

VM can present at any age, however, the ICHD specifically recognises an early vertiginous entity regarded as a precursor syndrome of migraine in otherwise healthy children called benign paroxysmal vertigo of childhood. This diagnosis requires 5 episodes of severe vertigo, occurring without warning and resolving spontaneously after minutes to hours [35]. In between episodes, neurological examination, audiometry, vestibular functions and EEG must be normal. A unilateral throbbing headache may occur during attacks but it is not a mandatory criterion. It is unclear whether these two conditions in children are the same entity, however it is important to note that the classification of VM does not involve any age limit [18].

Basilar-type Migraine

The term basilar migraine should be restricted to patients who fulfill the ICHD diagnostic criteria [35] given it is a clinically distinct entity from VM. Less than 10% of VM patients further fulfill the ICHD criteria for basilar migraine [2,18]. More than 60% of basilar-type migraine patients have vertigo and there are many overlapping clinical manifestations with VM. This diagnosis requires at least 2 symptoms from aura in the posterior circulation territory, whereas most patients with VM have vestibular symptoms only [35]. Moreover, in basilar migraine the duration of vertigo should correspond to the length of an aura, that is, between 5 and 60 minutes [35]. Further studies are required to further elucidate and delineate these 2 conditions.

Other Important Diagnostic Considerations

Meniere’s Disease

An important differential diagnosis of VM is the early presentation of Meniere’s disease (MD). Although fluctuating hearing loss, aural fullness and episodic vertigo are important symptoms in the recent updated diagnostic criteria for definite MD [36,37], these symptoms have been reported in patients with migraine [38]. Moreover, minor abnormalities in cVEMPs and arguably in caloric testing can be found in VM patients, as previously mentioned. Predominantly, the distinction can be made considering that a more sustained, albeit occasionally fluctuating, hearing loss would occur in MD, which can progress to severe hearing loss within a few years. However, the diagnosis can be difficult considering that audiometric and vestibular function abnormalities as well as the typical cochlear symptoms are often absent in the early stages of the MD. Nonetheless, preclinical labelling of patients with episodic vertigo without hearing loss as “vestibular MD” is unhelpful as this population may be overrepresented by actual migraineurs. Studies of patients with so-called benign recurrent vertigo or recurrent vestibulopathy are likely to be heterogeneous entities, with perhaps cases later evolving into VM or MD.

Coexisting migraine and MD is often challenging both in terms of diagnosis and management. Many studies have shown an increased prevalence of migraine in MD patients compared to controls [39,40], an asso-ciation suggested by Prosper Ménière himself in 1861 [41]. A study by Radtke et al found that the lifetime prevalence of migraine with and without aura was over 2 times higher in definite MD patients of both sexes compared to age-matched controls (56% versus 25%) [39]. Interestingly, 45% of the patients with MD always experienced at least 1 migrainous symptom (migrainous headache, photophobia, aura symptoms) with their Meniere attacks [39]. This may be at least partly due to the triggering effect of vestibular symptoms on migraineurs [30]. Migraine may even influence the disease course of MD as indicated by a retrospective case control study which found that definite MD patients who have concomitant ICHD criteria for migraine [35] had a significantly earlier onset of MD symptoms (mean age, 37.2 versus 49.3 years) and a much greater susceptibility to simultaneous bilateral, but not sequential, hearing loss as compared to MD patients without migraine (56% versus 4%) [42]. There were no significant differences in the severity of hearing loss between the 2 groups even when controlling for time to evaluation [42]. A family history of episodic vertigo was seen in 39% of MD patients with migraine, which is significantly higher than the 2% seen in MD patients, suggesting a possible genetic basis for this association [42]. The nature of the association between migraine and MD is not well elucidated, however, some authors propose that migraine leads to isolated microvascular ischaemic damage of the inner ear, presumably through small arterial vasospasm [40,42].

In summary, when the criteria for MD are met together with documented audiometric abnormalities, MD should be diagnosed, even if migraine symptoms occur during the vestibular attacks [18]. Only patients who experience 2 different types of attacks, one fulfilling the criteria for VM and the other for MD, should be labelled as Meniere’s disease/migraine overlap syndrome. It is hoped that future revisions of diagnostic criteria will include this overlap entity.

Migraine and Benign Paroxysmal Positional Vertigo

VM patients can experience brief positional dizziness and therefore VM may mimic BPPV. It is therefore important to perform positional testing to look for nystagmus typical for BPPV. Certainly the positional characteristics are distinct from BPPV with regard to the duration of attacks (often as long as the head position is maintained in VM rather than seconds in BPPV). BPPV may also produce attacks of vertigo that can act as triggers for migraine headaches. In these patients, treatment of the BPPV will reduce headache frequency [30].

Transient Ischemic Attacks

Transient ischemic attack (TIA) is a cerebrovascular disease with temporary neurological symptoms [43] and is differentiated from VM mainly from the characteristics of reported symptoms. Being a vascular phenomenon, one would expect TIA symptoms to have a sudden onset, with a brief duration of symptoms (typically short minutes), followed by a rapid improvement to baseline, as well as correspond to a vascular territory. The other important message is that stereotyped, frequently recurrent symptoms are less likely to be TIAs, with the exception of capsular warning syndrome [44] and limb shaking TIAs [43] described elsewhere.

Migraine and Motion Sickness

In an individual patient it may be difficult to differentiate between motion sickness and acute attacks of VM induced by motion stimuli. The distinction may be helped by observing nausea and dizziness improving after cessation of motion which points more towards motion sickness, as oppose to the persistent vertigo after the motion stimulus has ended, thus pointing more towards VM.

Episodic Ataxia Type 2

Of the various episodic ataxias, episodic ataxia type 2 would be the most important subtype in the differential diagnosis of VM given it presents with episodic vertigo and is the most frequently occurring subtype. It is a rare autosomal dominant inherited neurological disorder resulting from mutations of the calcium channel gene CACNA1A [45]. The clinical manifestations include recurrent disabling attacks of imbalance, vertigo and ataxia, which can be provoked by physical exertion or emotional stress. Patients may have downbeat nystagmus interictally. A slow progression of cerebellar signs accompanied by atrophy of midline cerebellar structures and a response to acetazolamide or 4-aminopyridine can help distinguish it from VM.

Migraine, Dizziness, and Comorbid Psychiatric Disorders

Particularly in patients with protracted symptoms, it is difficult to tease out the difference between the symptoms of migraine and dizziness from the symptoms of certain psychiatric disorders given their bidirectional associations. Migraine is a risk factor for first-onset major depression [46] and panic disorder [47]. Patients with VM have very high rates (30%–65%) of coexisting psychiatric illness, especially anxiety and depression, with frequencies higher than that associated with other migraine or vestibular disorders [48,49]. Vestibular migraine patients who have a positive history of psychiatric disorders have a comparatively higher risk of developing somatoform dizziness [48]. The unpredictability of recurrent vestibular symptoms could be a factor leading to elevated distress in VM patients. It is not uncommon to see a premature diagnosis of psychogenic dizziness to be given to patients without objective abnormalities. On the contrary, a diagnosis of psychogenic dizziness can rarely be made with certainty due to multiple reasons. Disabling vertigo leading to physical symptoms and avoidance of social activities can easily be misconstrued to have panic disorder with or without agoraphobia. Moreover, dizziness is the second most common symptom of a panic attack after palpitations [50].

Unfortunately, there are no objective tests that can reliably discriminate vestibular syndromes from psychiatric syndromes in patients with dizziness. The SVQ is not specific enough to differentiate symptoms of VV from the space and motion discomfort symptoms often found in agoraphobic patients [25]. Experimentally, agoraphobia patients may have a more surface-dependent strategy rather than a visual-dependent strategy on CDP [51]. It is unclear whether the vestibular system is causally linked to emotion processing pathways.

Chronic Subjective Dizziness

Chronic subjective dizziness is an entity characterised by chronic unsteadiness or nonvertiginous dizziness accompanied by hypersensitivity to motion stimuli and poor tolerance for complex visual stimuli lasting for 3 months or more without objective abnormalities [52]. These vestibular symptoms are often difficult to distinguish from symptoms of VM. This condition is thought to be a spatial sensory analog of allodynia experienced by some chronic migraine headache sufferers [8].

Dizziness Due to Side Effects of Migraine Prophylactic Medications

Dizziness is often listed as a side effect in the product information of various medications including those used for migraine prophylaxis. It is important to take an accurate history of the suspected offending drug in terms of its temporal relationship to vestibular symptoms. Tricyclic antidepressants (TCAs) can cause drowsiness, lightheadedness, fatigue and blurred vision [53]. Beta-blockers can cause orthostatic hypotension [53]. All the above effects could be confused with vestibular symptoms.

Treatment of Vestibular Migraine

Current treatment options for VM are mainly limited to expert opinion rather than inferred from randomized controlled trials (RCTs) [54]. Below we have offered our consensus on how VM should be managed, with concepts based on the guidelines of treatment for typical migraine [55]. Avoidance of migraine triggers should always be the first avenue of treatment. In addition, any vestibular disorder that is triggering migraine attacks should be identified and treated in its own right. Pharmacotherapy can be abortive for acute episodes and prophylactic.

Lifestyle Advice

The key first task in management is the correct diagnosis and educating the patient about the condition. A thorough explanation of the migraine origin of the attacks can address patients fear and expectations. Nonpharmaceutical approaches in the treatment of VM should not be neglected, even though only a very small proportion of patients may derive a benefit. Advice on dietary manipulation is routinely given; however, its efficacy in VM is questionable. Dietary advice includes healthy eating at regular intervals to prevent skipped meals as well as avoidance of excess caffeine and rich foods. A retrospective study found that lifestyle intervention alone resulted in 13 of 81 patients experiencing significant relief from vestibular symptoms with migraine. The remaining cohort of patients required a multifaceted approach including pharmacotherapy to achieve similar benefit [56].

Acute Abortive Treatments

Oral antiemetics are commonly prescribed for motion sickness and acute migraine, however there is no evidence supporting their effectiveness in VM (Table 2). Patients should be counselled about avoiding overuse of antiemetics given their risk of causing extrapyramidal side effects [53].

Simple analgesics, such as paracetamol and nonsteroidal anti-inflammatory drugs (NSAIDs), have been found to be helpful in acute VM attacks in observational studies. Bikhazi performed a survey of patients presenting to a headache clinic with vestibular symptoms and found that simple analgesics were valued by patients as effective symptomatic treatment, but were not considered as effective as triptans [59]. Doses of simple analgesics are listed in Table 2. Soluble formulations are preferable due to faster absorption and speed of onset. Opioids should be avoided in acute attacks of VM given the risk of developing opioid overuse headache [55].

Migraine Prophylaxis in Vestibular Migraine

TCAs remain a popular choice of migraine prophylaxis amongst neurootologists because of its additional effects on comorbid affective symptoms. We recommend that the starting dose of either amitriptyline or nortriptyline should be between 5 to 10 mg daily at night, slowly uptitrated to response over several weeks up to a maximum of 100 mg at night. Interval electrocardiography should be performed to monitor for prolongation of the QTc interval. A retrospective chart review found 46% of VM patients (by Neuhauser criteria) reported a reduction in dizziness after nortriptyline administration up to 75 mg daily [62]. However, the current evidence is limited to observational studies [59,62–64].

The evidence for beta-blockers is limited in VM but anecdotally has been useful for patients with frequent episodic migraine [59,63,64]. Recommended starting and maintenance doses are listed in Table 3. Furthermore, propranolol can be used in patients with depression [65,66]. Heart rate and electrocardiography should be monitored during dose escalation. Beta-blockers should be avoided in asthmatics. Commonly reported adverse events include cold, extremities reduced exercise tolerance and dizziness [53].

Flunarizine, a calcium channel blocker widely used in migraine [67,68] and vestibular conditions [69], was recently studied in a RCT of 12 weeks' duration for prophylaxis of migrainous vertigo (Neuhauser criteria) in 48 patients [70]. Although flunarizine 10 mg daily did not result in improved headache frequency and severity compared to the control arm, there was a significant improvement in vertigo severity. The most commonly reported side effects of flunarizine are weight gain and somnolence, both of which are minimal or infrequent. Verapamil is another calcium channel blocker that may be helpful but has major limiting adverse effects are bradycardia, constipation and peripheral edema [53].

Pizotifen, a serotonin antagonist, is one of the most well tolerated prophylaxis agents from our experience, however some patients do not adhere to treatment due to drowsiness or weight gain, as evidenced in retrospective case studies [64].

Topiramate with an average daily dose of 100 mg has reported positive results in a prospective observational study of ten patients with VM with auditory symptoms [71]. Nine of 10 patients reported no symptoms after follow-up period of up to sixteen months. The recommended dose is listed in Table 3. Common side effects include distal paresthesias, reduced ability to concentrate and drowsiness [53]. Sodium valproate has been anecdotally effective [59] and is usually well tolerated especially when starting at a low dose of 200 mg at night, slowly titrated to 1200 mg in 2 divided doses. Liver function and full blood evaluation should be monitored on a periodic basis [53].

Third-line medications have only been used anecdotally and should be reserved for extenuating cases (Table 3).

Vestibular Rehabilitation

Vestibular rehabilitation therapy (VRT) has been shown to alleviate significantly ongoing balance and dizziness symptoms in patients with various vestibular disorders [73,74] and improving confidence with balance in elderly patients [75,76]. However, the value of VRT is not as well established in VM. Anecdotally, patients with VM report persistent significant symptoms at the end of a standard VRT period, in contrast to other nonmigrainous patients who appear to be accomplishing their treatment goals faster. However, recent studies [21,73,77] are suggesting that customised VRT may play a useful role in VM, especially since it appears to target issues of anxiety, visual dependence or loss of confidence in balance. Small retrospective case series found that VRT reduced disability scores, and gait and balance function in over 85% of patients with migraine and vestibular symptoms [73,76,77]. An Australian VRT study (21) has recently assessed the efficacy of a 9-week customised VRT in 20 patients with VM compared to 16 patients with vestibular symptoms but without migraine. The customized VRT program consisted of habituation, gaze stability, static tilt, balance and gait exercises. A pictorial exercise instruction sheet for home use would describe these exercises of approximately 15 minutes duration consisting of 4 to 6 exercises to be performed 3 times a day, every day for 9 weeks. Interestingly, both groups benefitted equally from VRT. Compliance with VRT was comparable between the two groups. Commonly reported reasons for non-attendance in VM patients included a recent acute attack of VM, anxiety related to using public transport, and commitment issues related to occupation. This study also suggested that VM patients required more customized and intensive therapy as 15% of VM patients required additional appointments outside the study timeline.

Given that visual dependency has been shown to be reduced with short-term graded optokinetic stimulation exposure in healthy subjects [78], there has been interest using this intervention in conjunction with customized VRT to promote desensitization to visual stimuli as a treatment for VM patients with VV. Most promisingly is the finding that a subgroup of patients with a history of migraine improved significantly more than other vestibular patients with respect to VV symptoms.

There has been controversy surrounding whether patients should avoid medications when undergoing VRT. The protagonists of this view suggest that medications that affect the central nervous system (CNS) may modulate the rate of central compensation. In the aforementioned study by Vitkovic and colleagues [21], the same degree of improvement was seen in the VM group regardless of medication regimen. A study by Whitney and colleagues [73] found that migraine related vestibulopathy patients taking prophylaxis demonstrated better subjective and objective balance scores at baseline and after therapy. Further research is required to clarify the role of CNS-acting medication and their administration around VRT sessions.

Physical therapists dealing with VM patients may face additional challenges in encouraging exercise compliance and providing emotional support. Although more time consuming for the therapist, this is important in the face of high rates of comorbid affective disorders and head motion intolerance. Supervised VRT is believed to implicitly improve psychological status through increasing confidence, providing reassurance, and emphasizing positive effects of VRT, particularly when the patient feels their symptoms have been made worse by it.

Cognitive Behavioral Therapy

Cognitive behavioral therapy (CBT) has been shown to be helpful as part of the holistic treatment of various disorders including post-concussive syndrome and depression in neurology patients [79,80]. Among patients suffering from dizziness, a small study comparing explicit CBT combined with VRT versus waiting-list controls demonstrated improvements in patients’ coping ability, function, symptoms, and care satisfaction [81]. However, to our knowledge there are no studies directly evaluating the benefits of CBT specifically in VM patients. Despite this, it is our practice to request CBT for VM patients who report disabling anxiety or depressive symptoms.

Prognosis

Although migraine in general can improve in later life, this is less certain with VM given the lack of good quality longitudinal studies. Recently Radtke and colleagues published their long-term (median, 9 years) follow-up study of 61 definite VM cases (28). They found that 87% of patients had recurrent vertigo at follow-up. The frequency of vertigo was reduced in 56%, increased in 29%, and unchanged in 16% of patients. The impact of vertigo was graded as severe in 21%, moderate in 43%, and mild in 36% of patients. However, they found that concomitant cochlear symptoms with vertigo had increased from 15% at study inception to 49% at follow-up and secondly, 18% of patients had developed mild bilateral low-frequency sensorineural hearing loss. Therefore, one major criticism of the study is whether some of the patients had MD as their eventual diagnosis rather than definite VM. On the contrary, the authors conclude that these changes represent new vestibulo-cochlear dysfunction as a result of VM disease progression. Due to these reasons, the prognosis of VM patients is unclear. It is our practice to ensure patients do receive delayed follow-up to allow consideration of other neurotological diagnoses.

Conclusion

Given the large heterogeneity in presentation and objective testing, VM as a diagnostic construct has remained quite controversial, though increasingly more accepted. The more we study this common vestibular condition, the more we are realising that the complex relationship between migraine and dizziness extend beyond VM to encompass other vestibular disorders such as MD and anxiety. The lack of a physiological biomarker contributes to its diagnostic difficulties, but a meticulous workup is important to exclude alternative vestibular diagnoses. More longitudinal studies and RCTs are required to help both understand the prognosis and management of VM patients.

Corresponding author: Benjamin K-T Tsang, MBBS, FRACP, The Prince Charles Hospital, Rode Road, Chermside, Queensland 4032, Australia, [email protected].

Financial disclosures: None.

Each year approximately 60,000 women are diagnosed with endometrial cancer. The majority of the identified tumors will be low grade—cancer found at an early stage that may be treated with surgery alone. Unfortunately, however, too many of the 60,000 patients will have poor prognostic features, such as serous or clear cell histology (high-grade cancer), lymphovascular space invasion, or positive lymph node status.

Advances in technology and the state of science have come a long way since the dichotomy of Type I (endometrioid) and Type II (serous and clear cell) tumors were described by Dr. J. Bokhman in the early 1980s.¹ Our previous Update from several years ago stressed the importance of further understanding of the molecular rationale of high-risk, Type II tumors.² To review, The Cancer Genome Atlas project (TCGA) performed a genomic and proteomic characterization in 373 endometrial carcinomas demonstrating the traditional p53 mutations of serous tumors and PTEN or KRAS genes of endometrioid tumors.³ Most interestingly, they identified numerous other mutations and proposed 4 new genomic categories:

1. polymerase (DNA-directed) epsilon catalytic subunit (POLE) ultramutated
2. microsatellite instability (MSI) hypermutated
3. somatic copy number alterations high (serous tumors)
4. somatic copy number alterations low (endometrioid cancer).

In 2016, we are now understanding the molecular basis of disease and how it affects survival; these 4 categories have different survival. But why? Perhaps the answer lies within the endogenous immune system. Tumor-infiltrating lymphocytes are associated with improved survival in multiple types of cancer, including endometrial. Whether these lymphocytes are regulatory or cytotoxic T-cells convolutes the matter further.⁴ To understand these intricacies we need to further categorize how a tumor’s genetic mutations affect antigen exposure to the immune system, quantitate the clinical impact of the findings, and selectively target patients with novel therapeutics.

In this Update, we look at data on POLE mutations, exploring 2 studies that help us to better understand why these types of mutations have uniquely positive prognostic implications (when they logically should not have good survival rates). In addition, we discuss 2 studies that examined mismatch repair defects, in endometrial cancer specifically, and the programmed death (PD)-1 pathway in both endometrial and other cancer types. Are these molecular entities of tumors associated with better or worse prognosis, and why?

Molecular profiling: Prognostic implications of POLE mutations

Church DN, Stelloo E, Nout RA, et al. Prognostic significance of POLE proofreading mutations in endometrial cancer. J Natl Cancer Inst. 2014;107(1):402.

van Gool IC, Eggink FA, Freeman-Mills L, et al. POLE Proofreading mutations elicit an antitumor immune response in endometrial cancer. Clin Cancer Res. 2015;21(14):3347 - 3355.

The TCGA identified a subgroup of endometrial carcinomas with mutations of the DNA polymerase POLE. These mutants have a high rate of proofreading error and frequent base pair substitutions. This POLE subgroup (6% to 12% of endometrial tumors) is associated with endometrioid histology and high-grade tumors. Patients with these tumors would be expected to have an aggressive course with poor survival, but often these patients survive without a recurrence. We need more understanding of why. 

POLE mutations and prognosis

In a secondary analysis by Church and colleagues of the PORTEC-1 and -2 studies (2 large, randomized controlled trials evaluating postoperative external beam radiation therapy [EBRT] or vaginal brachytherapy), tumors were tested for mutations in POLE (POLE-mutant and POLE wild-type). POLE mutations were detected in 6.1% of tumors overall. Despite their high grade, POLE-mutant tumors resulted in fewer recurrences (6.2% vs 14.1%) and fewer deaths (2.3% vs 9.7%) than POLE wild-type tumors. In grade 3 tumors, 0 of 15 POLE-mutant tumors recurred.

These results indicate that, even with having poor prognostic features, endometrial cancers with mutations in POLE have an excellent prognosis.⁵

POLE mutations and the immune response

To explain the discrepancy in the results by Church and colleagues, van Gool and colleagues analyzed endometrial cancer specimens from PORTEC-1, -2, and the TCGA studies. Endometrial cancers were categorized as POLE-mutants, POLE wild-type, or microsatellite stable (MSS) tumors. They found that POLE-mutant endometrial cancers have an increased lymphocytic infiltrate (present in 22 of 47 POLE-mutant specimens) as compared with POLE wild-type or MSS tumors. 

Also, POLE-mutants had an increased density of cytotoxic T-cells (CD8+) at the tumor center and margin that significantly exceeded that of POLE wild-type or MSS tumors. The proportion of tumors with CD8+ cells exceeding the median were also higher in POLE-mutant (60%) compared with POLE wild-type (31.3%) and MSS (7.2%) tumors. Markers LAG3, TIM-3, TIGI, as well as T-cell inhibitors PD1 and CTLA-4, confirmed evidence of T-cell exhaustion--all of which correlated with CD8 expression. 

These findings suggest that POLE mutations lead to hundreds of thousands of DNA fragments stimulating the immune system through prolonged antigenic exposure.⁶ This immune response is so powerful that even these tumors with poor prognostic features will have excellent clinical outcomes.

Mismatch repair and immunology: Targeted therapy for targeted patients

McMeekin DS, Tritchler DL, Cohn DE, et al. Clinicopathologic significance of mismatch repair defects in endometrial cancer: an NRG oncology/gynecologic oncology group study. J Clin Oncol. 2016;34(25):3062-3068.

Le DT, Uram JN, Wang H, et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med. 2015;372(26):2509-2520.

The most frequent genetic mutation in endometrial cancer is mismatch repair (MMR) deficiency. Loss of this pathway leads to a failure of repairing replication errors and gives rise to small repeated sequences of DNA, known as MSI. Germline mutations in MMR (Lynch syndrome) occur in only 3% to 5% of endometrial cancers. Somatic mutations in MMR give rise to 10% to 20% of colorectal cancers and upwards of 20% to 40% of endometrial cancers.

Given this high frequency, universal screening utilizing immunohistochemistry of proteins MLH1, MSH2, MSH6, and PMS2 has become the standard of care in tumors to identify MMR deficiency. MMR-deficient endometrial tumors are associated with higher grade and lymphovascular space invasion. The actual clinical prognosis of these tumors, however, has not been well described.⁷ McMeekin and colleagues set out to examine prognosis.

Details of the study by McMeekin and colleagues
In the collaborative study, researchers assessed 1,024 tumors for MMR and categorized them into 1 of 4 groups: normal(62.4%), epigenetic MMR-defective (25.78%),MMR-probable mutation (9.67%), or MSI-low (2.15%). The researchers found that the pathologic features were associatedwith MMR status. For instance, MMR-defective tumors were more likely thanMMR-normal tumors to be Grade 2 (50% vs 40.7%, respectively). Lymphovascular space invasion also occurred more frequently in MMR-defective than in MMR-normal tumors (32.7% vs 17.13%, respectively). Approximately 22% of patients with MMR-defective tumors had stage III or IV disease, while only 13% to 14% of the other groups presented with such advanced stage.

On univariate analysis, an MMR-defective tumor was associated with worsened progression-free survival (hazard ratio [HR], 1.37). On subsequent multivariate analysis, no difference in survival in MMR-defective vs MMR-normal tumors was found. The authors concluded that MMR status is predictive of response to adjuvant therapy.

An intriguing biologic explanation of how MMR status affects response to adjuvant therapy is that MMR-defective tumors contain lymphocytic infiltrates, consistent with an increased immunologic response.⁸ Similar to the previously discussed POLE mutations, MMR-defective tumors have a tremendous increase in somatic mutations that are on the order of 10 to 100 times that of MMR-proficient tumors. These MMR-defective tumors likely give rise to increased antigen exposure to the immune system.

These immune infiltrates will show signs of exhaustion and upregulate negative feedback systems, which is the point at which the PD-1 pathway becomes critically important. The PD-1 receptor is expressed predominately on T-cells and its ligands regulate the immune system by inhibition of self-reactive T-cells.⁹

MMR deficiency and anti-programmed death receptor 1

The study by McMeekin and colleagues shows MMR-defective tumors have poor prognostic features but the same survival as those with MMR proficiency or good prognostic features. Why is this the case? A recent study by Le and colleagues analyzed this question.  

Details of the study by Le and colleagues
The investigators performed a phase 2 trial evaluating pembrolizumab (10 mg/kg IV every 14 days), an anti-PD 1 immune checkpoint inhibitor in patients with tumors demonstrating MMR-deficiency. The 3 cohorts included: MMR-defective colorectal cancer (n = 10), MMR-proficient colorectal cancer (n = 18), and MMR-defective noncolorectal cancer (n = 7, including 2 endometrial cancers). Objective response rates were 40%, 0%, and 71% for each group, respectively. 

MMR-defective tumors had a striking HR of disease progression or death of 0.04 (95% confidence interval, 0.01-0.21; P<.001). Genomic analysis was performed and identified 578 potential mutation- associated neoantigens in the MMR-defective groups (compared with only 21 in the MMR-proficient tumors). These findings promote the concept of a mutation-associated antigen component to the endogenous immune response.¹⁰

Conclusion

The above-stated mutations of mismatch repair and POLE are changing our perspective of endometrial cancer and shedding light on the complexities of tumor biology. As future research increasingly incorporates genomic profiling, we anticipate clinical trials may build evidence that adjuvant therapy will be directed by molecular staging, as opposed to traditional surgical or even histologic staging, as these mutations are the root cause of the tumor phenotype.

Key for readers to take away from this Update is that genomic profiling and enrollment in clinical trials is critical to understanding the implications of these mutations and how to best treat our patients. In addition, we should encourage our patients with endometrial cancer to see genetic counselors and have appropriate screening of MMR-deficiency. This will continue to advance our understanding as well as to provide patients with valuable information regarding their diagnosis.

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.

Each year approximately 60,000 women are diagnosed with endometrial cancer. The majority of the identified tumors will be low grade—cancer found at an early stage that may be treated with surgery alone. Unfortunately, however, too many of the 60,000 patients will have poor prognostic features, such as serous or clear cell histology (high-grade cancer), lymphovascular space invasion, or positive lymph node status.

Advances in technology and the state of science have come a long way since the dichotomy of Type I (endometrioid) and Type II (serous and clear cell) tumors were described by Dr. J. Bokhman in the early 1980s.¹ Our previous Update from several years ago stressed the importance of further understanding of the molecular rationale of high-risk, Type II tumors.² To review, The Cancer Genome Atlas project (TCGA) performed a genomic and proteomic characterization in 373 endometrial carcinomas demonstrating the traditional p53 mutations of serous tumors and PTEN or KRAS genes of endometrioid tumors.³ Most interestingly, they identified numerous other mutations and proposed 4 new genomic categories:

1. polymerase (DNA-directed) epsilon catalytic subunit (POLE) ultramutated
2. microsatellite instability (MSI) hypermutated
3. somatic copy number alterations high (serous tumors)
4. somatic copy number alterations low (endometrioid cancer).

In 2016, we are now understanding the molecular basis of disease and how it affects survival; these 4 categories have different survival. But why? Perhaps the answer lies within the endogenous immune system. Tumor-infiltrating lymphocytes are associated with improved survival in multiple types of cancer, including endometrial. Whether these lymphocytes are regulatory or cytotoxic T-cells convolutes the matter further.⁴ To understand these intricacies we need to further categorize how a tumor’s genetic mutations affect antigen exposure to the immune system, quantitate the clinical impact of the findings, and selectively target patients with novel therapeutics.

In this Update, we look at data on POLE mutations, exploring 2 studies that help us to better understand why these types of mutations have uniquely positive prognostic implications (when they logically should not have good survival rates). In addition, we discuss 2 studies that examined mismatch repair defects, in endometrial cancer specifically, and the programmed death (PD)-1 pathway in both endometrial and other cancer types. Are these molecular entities of tumors associated with better or worse prognosis, and why?

Molecular profiling: Prognostic implications of POLE mutations

Church DN, Stelloo E, Nout RA, et al. Prognostic significance of POLE proofreading mutations in endometrial cancer. J Natl Cancer Inst. 2014;107(1):402.

van Gool IC, Eggink FA, Freeman-Mills L, et al. POLE Proofreading mutations elicit an antitumor immune response in endometrial cancer. Clin Cancer Res. 2015;21(14):3347 - 3355.

The TCGA identified a subgroup of endometrial carcinomas with mutations of the DNA polymerase POLE. These mutants have a high rate of proofreading error and frequent base pair substitutions. This POLE subgroup (6% to 12% of endometrial tumors) is associated with endometrioid histology and high-grade tumors. Patients with these tumors would be expected to have an aggressive course with poor survival, but often these patients survive without a recurrence. We need more understanding of why. 

POLE mutations and prognosis

In a secondary analysis by Church and colleagues of the PORTEC-1 and -2 studies (2 large, randomized controlled trials evaluating postoperative external beam radiation therapy [EBRT] or vaginal brachytherapy), tumors were tested for mutations in POLE (POLE-mutant and POLE wild-type). POLE mutations were detected in 6.1% of tumors overall. Despite their high grade, POLE-mutant tumors resulted in fewer recurrences (6.2% vs 14.1%) and fewer deaths (2.3% vs 9.7%) than POLE wild-type tumors. In grade 3 tumors, 0 of 15 POLE-mutant tumors recurred.

These results indicate that, even with having poor prognostic features, endometrial cancers with mutations in POLE have an excellent prognosis.⁵

POLE mutations and the immune response

To explain the discrepancy in the results by Church and colleagues, van Gool and colleagues analyzed endometrial cancer specimens from PORTEC-1, -2, and the TCGA studies. Endometrial cancers were categorized as POLE-mutants, POLE wild-type, or microsatellite stable (MSS) tumors. They found that POLE-mutant endometrial cancers have an increased lymphocytic infiltrate (present in 22 of 47 POLE-mutant specimens) as compared with POLE wild-type or MSS tumors. 

Also, POLE-mutants had an increased density of cytotoxic T-cells (CD8+) at the tumor center and margin that significantly exceeded that of POLE wild-type or MSS tumors. The proportion of tumors with CD8+ cells exceeding the median were also higher in POLE-mutant (60%) compared with POLE wild-type (31.3%) and MSS (7.2%) tumors. Markers LAG3, TIM-3, TIGI, as well as T-cell inhibitors PD1 and CTLA-4, confirmed evidence of T-cell exhaustion--all of which correlated with CD8 expression. 

These findings suggest that POLE mutations lead to hundreds of thousands of DNA fragments stimulating the immune system through prolonged antigenic exposure.⁶ This immune response is so powerful that even these tumors with poor prognostic features will have excellent clinical outcomes.

Mismatch repair and immunology: Targeted therapy for targeted patients

McMeekin DS, Tritchler DL, Cohn DE, et al. Clinicopathologic significance of mismatch repair defects in endometrial cancer: an NRG oncology/gynecologic oncology group study. J Clin Oncol. 2016;34(25):3062-3068.

Le DT, Uram JN, Wang H, et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med. 2015;372(26):2509-2520.

The most frequent genetic mutation in endometrial cancer is mismatch repair (MMR) deficiency. Loss of this pathway leads to a failure of repairing replication errors and gives rise to small repeated sequences of DNA, known as MSI. Germline mutations in MMR (Lynch syndrome) occur in only 3% to 5% of endometrial cancers. Somatic mutations in MMR give rise to 10% to 20% of colorectal cancers and upwards of 20% to 40% of endometrial cancers.

Given this high frequency, universal screening utilizing immunohistochemistry of proteins MLH1, MSH2, MSH6, and PMS2 has become the standard of care in tumors to identify MMR deficiency. MMR-deficient endometrial tumors are associated with higher grade and lymphovascular space invasion. The actual clinical prognosis of these tumors, however, has not been well described.⁷ McMeekin and colleagues set out to examine prognosis.

Details of the study by McMeekin and colleagues
In the collaborative study, researchers assessed 1,024 tumors for MMR and categorized them into 1 of 4 groups: normal(62.4%), epigenetic MMR-defective (25.78%),MMR-probable mutation (9.67%), or MSI-low (2.15%). The researchers found that the pathologic features were associatedwith MMR status. For instance, MMR-defective tumors were more likely thanMMR-normal tumors to be Grade 2 (50% vs 40.7%, respectively). Lymphovascular space invasion also occurred more frequently in MMR-defective than in MMR-normal tumors (32.7% vs 17.13%, respectively). Approximately 22% of patients with MMR-defective tumors had stage III or IV disease, while only 13% to 14% of the other groups presented with such advanced stage.

On univariate analysis, an MMR-defective tumor was associated with worsened progression-free survival (hazard ratio [HR], 1.37). On subsequent multivariate analysis, no difference in survival in MMR-defective vs MMR-normal tumors was found. The authors concluded that MMR status is predictive of response to adjuvant therapy.

An intriguing biologic explanation of how MMR status affects response to adjuvant therapy is that MMR-defective tumors contain lymphocytic infiltrates, consistent with an increased immunologic response.⁸ Similar to the previously discussed POLE mutations, MMR-defective tumors have a tremendous increase in somatic mutations that are on the order of 10 to 100 times that of MMR-proficient tumors. These MMR-defective tumors likely give rise to increased antigen exposure to the immune system.

These immune infiltrates will show signs of exhaustion and upregulate negative feedback systems, which is the point at which the PD-1 pathway becomes critically important. The PD-1 receptor is expressed predominately on T-cells and its ligands regulate the immune system by inhibition of self-reactive T-cells.⁹

MMR deficiency and anti-programmed death receptor 1

The study by McMeekin and colleagues shows MMR-defective tumors have poor prognostic features but the same survival as those with MMR proficiency or good prognostic features. Why is this the case? A recent study by Le and colleagues analyzed this question.  

Details of the study by Le and colleagues
The investigators performed a phase 2 trial evaluating pembrolizumab (10 mg/kg IV every 14 days), an anti-PD 1 immune checkpoint inhibitor in patients with tumors demonstrating MMR-deficiency. The 3 cohorts included: MMR-defective colorectal cancer (n = 10), MMR-proficient colorectal cancer (n = 18), and MMR-defective noncolorectal cancer (n = 7, including 2 endometrial cancers). Objective response rates were 40%, 0%, and 71% for each group, respectively. 

MMR-defective tumors had a striking HR of disease progression or death of 0.04 (95% confidence interval, 0.01-0.21; P<.001). Genomic analysis was performed and identified 578 potential mutation- associated neoantigens in the MMR-defective groups (compared with only 21 in the MMR-proficient tumors). These findings promote the concept of a mutation-associated antigen component to the endogenous immune response.¹⁰

Conclusion

The above-stated mutations of mismatch repair and POLE are changing our perspective of endometrial cancer and shedding light on the complexities of tumor biology. As future research increasingly incorporates genomic profiling, we anticipate clinical trials may build evidence that adjuvant therapy will be directed by molecular staging, as opposed to traditional surgical or even histologic staging, as these mutations are the root cause of the tumor phenotype.

Key for readers to take away from this Update is that genomic profiling and enrollment in clinical trials is critical to understanding the implications of these mutations and how to best treat our patients. In addition, we should encourage our patients with endometrial cancer to see genetic counselors and have appropriate screening of MMR-deficiency. This will continue to advance our understanding as well as to provide patients with valuable information regarding their diagnosis.

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.

Each year approximately 60,000 women are diagnosed with endometrial cancer. The majority of the identified tumors will be low grade—cancer found at an early stage that may be treated with surgery alone. Unfortunately, however, too many of the 60,000 patients will have poor prognostic features, such as serous or clear cell histology (high-grade cancer), lymphovascular space invasion, or positive lymph node status.

Advances in technology and the state of science have come a long way since the dichotomy of Type I (endometrioid) and Type II (serous and clear cell) tumors were described by Dr. J. Bokhman in the early 1980s.¹ Our previous Update from several years ago stressed the importance of further understanding of the molecular rationale of high-risk, Type II tumors.² To review, The Cancer Genome Atlas project (TCGA) performed a genomic and proteomic characterization in 373 endometrial carcinomas demonstrating the traditional p53 mutations of serous tumors and PTEN or KRAS genes of endometrioid tumors.³ Most interestingly, they identified numerous other mutations and proposed 4 new genomic categories:

1. polymerase (DNA-directed) epsilon catalytic subunit (POLE) ultramutated
2. microsatellite instability (MSI) hypermutated
3. somatic copy number alterations high (serous tumors)
4. somatic copy number alterations low (endometrioid cancer).

In 2016, we are now understanding the molecular basis of disease and how it affects survival; these 4 categories have different survival. But why? Perhaps the answer lies within the endogenous immune system. Tumor-infiltrating lymphocytes are associated with improved survival in multiple types of cancer, including endometrial. Whether these lymphocytes are regulatory or cytotoxic T-cells convolutes the matter further.⁴ To understand these intricacies we need to further categorize how a tumor’s genetic mutations affect antigen exposure to the immune system, quantitate the clinical impact of the findings, and selectively target patients with novel therapeutics.

In this Update, we look at data on POLE mutations, exploring 2 studies that help us to better understand why these types of mutations have uniquely positive prognostic implications (when they logically should not have good survival rates). In addition, we discuss 2 studies that examined mismatch repair defects, in endometrial cancer specifically, and the programmed death (PD)-1 pathway in both endometrial and other cancer types. Are these molecular entities of tumors associated with better or worse prognosis, and why?

Molecular profiling: Prognostic implications of POLE mutations

Church DN, Stelloo E, Nout RA, et al. Prognostic significance of POLE proofreading mutations in endometrial cancer. J Natl Cancer Inst. 2014;107(1):402.

van Gool IC, Eggink FA, Freeman-Mills L, et al. POLE Proofreading mutations elicit an antitumor immune response in endometrial cancer. Clin Cancer Res. 2015;21(14):3347 - 3355.

The TCGA identified a subgroup of endometrial carcinomas with mutations of the DNA polymerase POLE. These mutants have a high rate of proofreading error and frequent base pair substitutions. This POLE subgroup (6% to 12% of endometrial tumors) is associated with endometrioid histology and high-grade tumors. Patients with these tumors would be expected to have an aggressive course with poor survival, but often these patients survive without a recurrence. We need more understanding of why. 

POLE mutations and prognosis

In a secondary analysis by Church and colleagues of the PORTEC-1 and -2 studies (2 large, randomized controlled trials evaluating postoperative external beam radiation therapy [EBRT] or vaginal brachytherapy), tumors were tested for mutations in POLE (POLE-mutant and POLE wild-type). POLE mutations were detected in 6.1% of tumors overall. Despite their high grade, POLE-mutant tumors resulted in fewer recurrences (6.2% vs 14.1%) and fewer deaths (2.3% vs 9.7%) than POLE wild-type tumors. In grade 3 tumors, 0 of 15 POLE-mutant tumors recurred.

These results indicate that, even with having poor prognostic features, endometrial cancers with mutations in POLE have an excellent prognosis.⁵

POLE mutations and the immune response

To explain the discrepancy in the results by Church and colleagues, van Gool and colleagues analyzed endometrial cancer specimens from PORTEC-1, -2, and the TCGA studies. Endometrial cancers were categorized as POLE-mutants, POLE wild-type, or microsatellite stable (MSS) tumors. They found that POLE-mutant endometrial cancers have an increased lymphocytic infiltrate (present in 22 of 47 POLE-mutant specimens) as compared with POLE wild-type or MSS tumors. 

Also, POLE-mutants had an increased density of cytotoxic T-cells (CD8+) at the tumor center and margin that significantly exceeded that of POLE wild-type or MSS tumors. The proportion of tumors with CD8+ cells exceeding the median were also higher in POLE-mutant (60%) compared with POLE wild-type (31.3%) and MSS (7.2%) tumors. Markers LAG3, TIM-3, TIGI, as well as T-cell inhibitors PD1 and CTLA-4, confirmed evidence of T-cell exhaustion--all of which correlated with CD8 expression. 

These findings suggest that POLE mutations lead to hundreds of thousands of DNA fragments stimulating the immune system through prolonged antigenic exposure.⁶ This immune response is so powerful that even these tumors with poor prognostic features will have excellent clinical outcomes.

Mismatch repair and immunology: Targeted therapy for targeted patients

McMeekin DS, Tritchler DL, Cohn DE, et al. Clinicopathologic significance of mismatch repair defects in endometrial cancer: an NRG oncology/gynecologic oncology group study. J Clin Oncol. 2016;34(25):3062-3068.

Le DT, Uram JN, Wang H, et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med. 2015;372(26):2509-2520.

The most frequent genetic mutation in endometrial cancer is mismatch repair (MMR) deficiency. Loss of this pathway leads to a failure of repairing replication errors and gives rise to small repeated sequences of DNA, known as MSI. Germline mutations in MMR (Lynch syndrome) occur in only 3% to 5% of endometrial cancers. Somatic mutations in MMR give rise to 10% to 20% of colorectal cancers and upwards of 20% to 40% of endometrial cancers.

Given this high frequency, universal screening utilizing immunohistochemistry of proteins MLH1, MSH2, MSH6, and PMS2 has become the standard of care in tumors to identify MMR deficiency. MMR-deficient endometrial tumors are associated with higher grade and lymphovascular space invasion. The actual clinical prognosis of these tumors, however, has not been well described.⁷ McMeekin and colleagues set out to examine prognosis.

Details of the study by McMeekin and colleagues
In the collaborative study, researchers assessed 1,024 tumors for MMR and categorized them into 1 of 4 groups: normal(62.4%), epigenetic MMR-defective (25.78%),MMR-probable mutation (9.67%), or MSI-low (2.15%). The researchers found that the pathologic features were associatedwith MMR status. For instance, MMR-defective tumors were more likely thanMMR-normal tumors to be Grade 2 (50% vs 40.7%, respectively). Lymphovascular space invasion also occurred more frequently in MMR-defective than in MMR-normal tumors (32.7% vs 17.13%, respectively). Approximately 22% of patients with MMR-defective tumors had stage III or IV disease, while only 13% to 14% of the other groups presented with such advanced stage.

On univariate analysis, an MMR-defective tumor was associated with worsened progression-free survival (hazard ratio [HR], 1.37). On subsequent multivariate analysis, no difference in survival in MMR-defective vs MMR-normal tumors was found. The authors concluded that MMR status is predictive of response to adjuvant therapy.

An intriguing biologic explanation of how MMR status affects response to adjuvant therapy is that MMR-defective tumors contain lymphocytic infiltrates, consistent with an increased immunologic response.⁸ Similar to the previously discussed POLE mutations, MMR-defective tumors have a tremendous increase in somatic mutations that are on the order of 10 to 100 times that of MMR-proficient tumors. These MMR-defective tumors likely give rise to increased antigen exposure to the immune system.

These immune infiltrates will show signs of exhaustion and upregulate negative feedback systems, which is the point at which the PD-1 pathway becomes critically important. The PD-1 receptor is expressed predominately on T-cells and its ligands regulate the immune system by inhibition of self-reactive T-cells.⁹

MMR deficiency and anti-programmed death receptor 1

The study by McMeekin and colleagues shows MMR-defective tumors have poor prognostic features but the same survival as those with MMR proficiency or good prognostic features. Why is this the case? A recent study by Le and colleagues analyzed this question.  

Details of the study by Le and colleagues
The investigators performed a phase 2 trial evaluating pembrolizumab (10 mg/kg IV every 14 days), an anti-PD 1 immune checkpoint inhibitor in patients with tumors demonstrating MMR-deficiency. The 3 cohorts included: MMR-defective colorectal cancer (n = 10), MMR-proficient colorectal cancer (n = 18), and MMR-defective noncolorectal cancer (n = 7, including 2 endometrial cancers). Objective response rates were 40%, 0%, and 71% for each group, respectively. 

MMR-defective tumors had a striking HR of disease progression or death of 0.04 (95% confidence interval, 0.01-0.21; P<.001). Genomic analysis was performed and identified 578 potential mutation- associated neoantigens in the MMR-defective groups (compared with only 21 in the MMR-proficient tumors). These findings promote the concept of a mutation-associated antigen component to the endogenous immune response.¹⁰

Conclusion

The above-stated mutations of mismatch repair and POLE are changing our perspective of endometrial cancer and shedding light on the complexities of tumor biology. As future research increasingly incorporates genomic profiling, we anticipate clinical trials may build evidence that adjuvant therapy will be directed by molecular staging, as opposed to traditional surgical or even histologic staging, as these mutations are the root cause of the tumor phenotype.

Key for readers to take away from this Update is that genomic profiling and enrollment in clinical trials is critical to understanding the implications of these mutations and how to best treat our patients. In addition, we should encourage our patients with endometrial cancer to see genetic counselors and have appropriate screening of MMR-deficiency. This will continue to advance our understanding as well as to provide patients with valuable information regarding their diagnosis.

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.

Epilepsy is a common and complex neurologic condition marked by recurrent seizures. It has been diagnosed in more than 87,000 veterans enrolled in the VA health care system, 16% of whom have comorbid traumatic brain injury (TBI), and nearly 25% also have posttraumatic stress disorder (PTSD).¹ These comorbidities were even more common in Operation Enduring Freedom (OEF), Operation Iraqi Freedom (OIF), and Operation New Dawn (OND) veterans: TBI in 52.6% and PTSD in 70.4%. With 25 drugs for seizures and 2 approved devices, treatment of epilepsy can prove challenging to providers whose goal is to balance seizure control and adverse effects (AEs).

Despite the therapeutic armamentarium, about one-third of people with epilepsy have poorly controlled seizures, and an untold number may experience delays in referral to higher levels of epilepsy care or undergo troubling antiepileptic medication AEs and comorbid psychiatric disorders that have profound impacts on quality of life (QOL).

Quality generally has been defined as “providing the right care to the right patient at the right time and in the right way to achieve the best possible results.”² Much work has been done over the past 2 decades to identify “the right care” for epilepsy patients.³

The American Academy of Neurology (AAN) has developed evidence-based, clinically focused guidelines on numerous topics, including antiepileptic drugs and women’s health, and has developed quality measure sets.^4,5 More broadly, the Institute of Medicine (IOM) proposed 13 recommendations, including improving quality of care, establishing epilepsy centers and an epilepsy care network, educating health professionals about epilepsy, and providing education for people with epilepsy and their families.⁶

Within the VA, health care for veterans with epilepsy is changing in part by the Epilepsy Centers of Excellence (ECoC), established by federal law. The ECoE’s primary missions are to improve quality of and access to epilepsy specialty care to improve the health and well-being of veteran patients with epilepsy and other seizure disorders through integration of clinical care, outreach, research, and education to VA providers and patients.⁷

The goal of this article is to outline the key elements of quality epilepsy care and make recommendations for providing quality care in the VA health care system.

Diagnosis and Seizure Types

Quality care for veterans with epilepsy begins with the provider reviewing pertinent history and establishing the clinical characteristics of the patient’s seizures and epilepsy. The provider should ask about the first signs of the seizure or warning (aura), the seizure (ictal period), and the period after the seizure (postictal period). Seizure histories from the patient and observers are critical.

The first step is to define whether the patient’s seizures are generalized, that is, start all over the brain at once, or focal, starting in one area of the brain. The patient’s initial sensation at the onset of a seizure (aura) may help localize onset and define focal seizures. For example, déjà vu sensations often point to seizure onset in the mesial temporal lobe and hippocampus. Focal seizures can spread and cause cognitive dysfunction, including aphasia and amnesia, or evolve into a generalized convulsion (tonic-clonic seizure). Many patients present with a generalized tonic-clonic seizure and have had brief focal seizures that were not considered seizures by the patient or by other providers. This seizure type should be clarified by asking specifically about paroxysmal symptoms. For example, brief periods of confusion that are episodic may be focal seizures. In general, focal seizures are stereotyped and may have a feature that helps in establishing the diagnosis. Many temporal lobe seizures are associated with lip smacking behaviors (oral buccal automatisms).

Tonic-clonic seizures may begin without an aura and are generalized from onset. Patients with this type of seizure may have electroencephalogram (EEG) findings that define a generalized abnormality, which consist of frontocentral spike and wave discharges in the EEG. In the VA population, the first generalized tonic-clonic seizure may occur while in the military. Some of these patients have juvenile myoclonic epilepsy, and a history of brief jerks on waking (myoclonus) may have been occurring but not recognized as seizures. The treatment of seizures, in part, depends on whether they begin focally or are generalized at onset.

Often people with epilepsy have multiple seizure types. The types of seizures should be documented and, if possible, corroborated by a witness. Epileptic seizures tend to be stereotyped and of relatively brief duration, usually < 2 minutes. The period after a seizure may be followed by a more prolonged period of neurologic dysfunction that includes confusion and fatigue. These symptoms may be the only indication that the patient has had a seizure.

At each clinic visit, the characteristics of the patient’s seizures should be reviewed and the frequency of seizures documented. A calendar to track seizure frequency is helpful to understand precipitating factors and response to treatment.

The health care provider (HCP) should look for the cause of a patient’s epilepsy. It is important to ask the patient about family history, age of first seizure, occurrence of febrile seizures, developmental history, past history of meningitis or encephalitis, history of childhood seizures or spells, and history of brain lesions, including tumors, strokes, or TBI. Most patients with epilepsy do not have a clear cause for their epilepsy, but the cause may be clarified with EEG and magnetic resonance imaging (MRI) testing.

EEG and Brain Imaging

All patients with epilepsy should be evaluated with an EEG, and for those with focal epilepsy or undefined epilepsy, with an imaging study of the brain, preferably an MRI. These results should be reviewed at each visit. The EEG may show focal features that are related to neurophysiologic dysfunction, such as slowing that is not definitely epileptiform in character, or show focal spike or sharp waves that are epileptiform in character. Generalized abnormalities may include generalized slowing that is not an epileptiform feature or frontocentral spike wave patterns that are epileptiform in character. The EEG cannot rule out epilepsy, but can rule in the likelihood of epilepsy when definite epileptiform features are present.

Brain imaging can define many conditions that can cause focal epilepsy, and an MRI is more sensitive for defining a number of these conditions (cavernous angiomas, hippocampal sclerosis, developmental migration disorders, and low-grade neoplasms). Significant trauma with signal abnormalities to suggest prior bleeding predispose to epilepsy. When patients are refractory to medical therapy and have imaging findings concordant with EEG onset of seizures, then surgery can be a better treatment.

Adverse Effects

Broad-spectrum drug treatments are efficacious for either generalized or focal seizures, whereas narrow-spectrum treatments are most efficacious for focal seizures (Table 1). The choice of a seizure medication is based on the patient’s seizure type(s) and other comorbid conditions.⁷ For example, a patient with epilepsy and migraines may do better with a seizure medication that also is used for migraine prophylaxis (valproate or topiramate). In general, seizure control is unlikely to be achieved if patients fail the first 2 medications tried.⁸ Treating with > 1 medication may improve seizure control but may increase AEs. A review of current seizure medications and their AEs can be found on the ECoE website (http://www.epilepsy.va.gov/Provider_Education.asp).

In VA cooperative studies that evaluated seizure medications, the most common reason for discontinuing a drug was the combination of ineffectiveness and AEs.^9-11 Addressing AEs is a quality measure for the care of patients with epilepsy. Adverse effects may be dose dependent or idiosyncratic (rashes). Drug levels may help in determining dose-dependent AEs; for example, diplopia with carbamazepine levels above 10 μg/mL. Each patient may have susceptibility to medication AEs that do not exactly match therapeutic levels. When patients have AEs, a reduction in dose or trial of an alternative medication is advised.

Uncontrollable Epilepsy

About one-third of people with epilepsy have uncontrolled seizures, known as medically intractable epilepsy, which may be identified early in their clinical course by failure of the first 2 tolerated medications.⁸ Patients should be referred to an epilepsy center so their epilepsy can be defined by video EEG monitoring to capture seizures. Unfortunately, in the VA system, this route is often delayed, and patients may not be diagnosed appropriately for years.¹² Some of these patients may be considered treatment failures because the right medications were not tried (eg, generalized epilepsy that is treated with narrow-spectrum seizure medications). Juvenile myoclonic epilepsy often may not be controlled by phenytoin or carbamazepine, but valproate, lamotrigine, levetiracetam, and zonisamide may be more effective.

Other patients may not have epilepsy but have psychogenic nonepileptic seizures (PNES). These behavioral seizures do not have an EEG epileptiform correlate. About 25% of patients who undergo prolonged video EEG monitoring have PNES, and seizure medications do not treat these events.¹² A smaller percentage of patients have both epileptic and nonepileptic seizures (5%-15%). Psychogenic nonepileptic seizures often occur within the context of traumatic exposure(s) or previous physical or sexual abuse.

In the VA population, PNES is more often associated with PTSD or head trauma history than in patients with epilepsy.^13,14 To confirm the diagnosis of PNES, video-EEG capture of the patient’s seizures is required. Because of the increased number of combat veterans with TBI and PTSD, the diagnosis of epilepsy may be difficult without video-EEG monitoring. Management consists of addressing the underlying conversion disorder and recognition and treatment of comorbidities, such as mood, anxiety, personality, or PTSD. Recently, cognitive behavioral-informed psychotherapy (CB-ip) has been shown to be effective in patients with PNES and is available through the VA national telemental health center and at some ECoE sites.¹⁵

If a patient with uncontrolled epilepsy has focal seizures, surgical therapy is more likely to result in seizure control than will medical therapy.^16,17 This is especially true when other testing, including MRI, positron emission tomography, and neuropsychiatric evaluation, point to a concordance of localization. These patients should be evaluated in a center that can provide surgical therapy and if necessary also record seizures with invasive techniques using electrodes placed directly over the cortex or into the brain to sample deeper structures like the hippocampus or amygdala. Patients who are refractory should be considered for reevaluation every 2 years by a comprehensive epilepsy center.

Unfortunately, some patients have seizures that begin in eloquent cortex, which if removed, leads to undesirable neurologic loss or multifocal seizure onset. In these patients, seizure frequency can be reduced by vagus nerve stimulation or intracranial responsive neurostimulation.^18,19

Safety

Epilepsy has inherent risks for injury. Patients and their families often need to be informed about risks and risky behaviors to avoid. A frank discussion about safety is prudent. What to do for the patient during a seizure should be addressed. For convulsive seizures: Protect the patient from injury by placing something soft between the patient’s head and the floor, keep the patient on his or her side; do not restrain the patient or put anything in the mouth; stay calm and time the seizure; as the patient gains consciousness, talk to the patient and be reassuring. For nonconvulsive seizures: Stay with the patient; time the seizure; gently guide the patient away from dangerous situations like streets or stairs; stay with the patient until he or she is back to normal, and reassure the patient.

Driving

People with epilepsy identify driving as one of their major concerns; therefore, it is important for HCPs to properly counsel patients with seizure disorders and their families about driving (Figure).²⁰ In general people with controlled seizures are permitted to drive in every state in the U.S., but people with uncontrolled seizures are restricted from licensure. Despite the desire and necessity to drive for many individuals with epilepsy, seizures while driving pose risks for crashes, which may result in property damage, injuries, and death.²¹ Factors, such as duration of seizure freedom, help predict the risk for crashes. The legal rules for determining control and administering restrictions are a complex mix of federal and state laws, regulations, and local practices, which vary widely across the country.^21,22 The standards also change over time; updated information is available from local state authorities and on good informational sites, such as those of the Epilepsy Foundation.

The key standard for determining accident risks is the seizure free interval, which is the duration of time a person with epilepsy has been seizure-free.^21-23 In the U.S., the accepted period for seizure freedom varies from about 3 months to 12 months, depending on individual state rules.²⁴

California, Delaware, Nevada, New Jersey, Oregon, and Pennsylvania require mandatory reporting. Generally physician groups in the U.S. and elsewhere oppose such mandatory reporting, because of the concern that their patients will not report their seizures, and thus may not receive appropriate treatment. Indeed, patients with epilepsy often do not tell physicians about their seizures, fearing loss of driving privileges and other social consequences.^21,23 Providers should make an effort to determine seizure frequency and whether the patient is being truthful. This information then provides a background for the provider to discuss driving issues.

Injury

People with epilepsy are susceptible to injury during a seizure and need to be counseled regarding safety, particularly when seizures are not well controlled. Hazardous situations include being near stoves or cooking, bathing alone, swimming alone, working at heights without a safety harness, and using power tools.²⁶

Sudden Unexplained Death

Patients with recurrent seizures have an increased risk for accidental fatality and for sudden unexplained death in epilepsy (SUDEP), which accounts for up to 17% of all deaths in people with epilepsy. The risk for sudden death from recurrent seizures increases 2.3 times compared with the risk in the general population.²⁵ A SUDEP is an unexpected death in a person who has epilepsy with no other obvious cause of death.²⁶ Because increased seizure frequency, the presence of tonic-clonic seizures, and other accidental risks of seizures are associated with SUDEP, the subject should be discussed with patients and their families, to encourage adherence to treatment. Epileptologists also discuss these risks with patients and their families when surgical interventions are being considered. The potential risks for injury or SUDEP may offset the surgical risks when pursuing a potentially curative epilepsy procedure.

Women of Childbearing Age

In January 2015, the ECoE started a women veterans epilepsy workgroup with the goal of improving clinical care within the VAHCS to provide education to patients, family members, and VA health care providers about the care of women with epilepsy.

Providers need to be aware that seizure medications that induce certain hepatic enzymes can lead to hormonal contraceptive failure (Table 2).²⁷ Preconception folic acid supplementation (with at least 0.4 mg) should be considered, because it may reduce the risk of major congenital malformations.²⁸ The goal of epilepsy management prior to conception is to maximize seizure control with the optimal seizure medication to avoid the need to make changes during the pregnancy.

During pregnancy, the volume of distribution increases and seizure medication metabolism may change requiring dose adjustment. The best predictor of seizure frequency during pregnancy is a woman’s epilepsy pattern prior to conception. Seizure freedom for 9 months prior to conception is associated with a 84% to 92% likelihood of seizure freedom throughout the pregnancy.²⁹

International seizure medication pregnancy registries have provided valuable information regarding the risk of major congenital malformation (MCM) of development, which seems to be a consequence of seizure medication therapy and not epilepsy itself. The risk of MCM associated with seizure medication therapy is about 4% to 5% compared with 1.5% to 3% in the general population.^30,31 A seizure medication table that supplements the existing VA ECoE information specifically addresses women’s issues with the recognition that recent revisions to the teratogenicity classification have been made by the FDA (Table 2).³² If possible, valproate should be avoided during pregnancy due to its higher rate of MCM and impact on neurocognitive function.³³ Obstetrical input is essential in arranging routine prenatal fetal testing. Although women with epilepsy do not have a substantially increased risk of undergoing a cesarean section, delivery in a hospital obstetric unit is advised.

Postpartum women veterans with epilepsy should be encouraged to breast feed since the potential benefits seem to outweigh any established risk of seizure medication exposure to the infant. No relative impact on cognition was found in breastfed infants exposed to a variety of seizure medications.³⁴ Following delivery, vigilance is needed to monitor for sleep deprivation, postpartum depression, and the safe care of the infant.³⁵ Care of women with epilepsy does not end with pregnancy planning, additional important topics include psychiatric comorbidities, catamenial epilepsy, and bone health, which are unique to women veterans with epilepsy.

Identifying Psychiatric Conditions

People with epilepsy have a number of psychiatric comorbidities. Suicide and suicide attempts are 6 to 25 times more common in patients with temporal lobe epilepsy compared with those in the general population.^36-38 Although the FDA identified all seizure medications as potential contributors to suicide risk, a recent longitudinal study of suicidal ideation and attempt found that those who received seizure medications were more likely to have suicidal ideation and attempt than those who did not received seizure medications, suggesting that medication may relate to baseline depression or suicidal ideation.³⁹ When seeing patients with epilepsy, screening for suicidal ideation is good practice.

Depression and anxiety disorders are the most common psychiatric comorbidities in people with epilepsy.^40,41 About half of people with epilepsy have symptoms of depression, and 40% have anxiety.⁴² Depression often precedes the diagnosis of epilepsy, and anxiety often is present and related to the fear of having seizures and of social embarrassment.⁴³ People with epilepsy may not self-report these symptoms if not asked directly. Identification of comorbid depression and anxiety should lead to appropriate treatment. The CB-ip being used for PNES also is being used for treatment of epilepsy and its comorbidities.⁴⁴

Mild traumatic brain injury (mTBI) has a small increased risk of epilepsy.⁴⁵ Veterans with mTBI that occurs in the context of blasts are set up for the development of PTSD. These veterans may have other mild cognitive symptoms that can be confused with seizures. Furthermore, mTBI and PNES often occur together, more so than do mTBI and epileptic seizures.¹⁴ Video-EEG monitoring may be warranted for these patients.

Education and Self-Management

The IOM report on epilepsy identified patient and family education as essential for better epilepsy care.⁶ Providers should help educate patients about their epilepsy and refer them to resources available online (Table 3). A continuing exchange about their condition and treatment with seizure medications should occur with each visit. People with epilepsy should also receive guidance regarding how to manage their epilepsy and day-to-day issues. Referring, patients to social workers, psychologists, vocational rehabilitation services, and support groups can enhance a patient’s QOL.^3,6 The stigma of epilepsy is another burden that can be diminished by attending support groups. Recently, being a part of an online patient community of veterans was found to improve self-management.⁴⁶

Conclusion

People with epilepsy have many issues that are unique to the condition and, in part, are related to the unpredictable occurrence of seizures and loss of function. Ideally, seizure control provides a normal lifestyle; however, some mood and anxiety comorbidities may persist despite seizure control. Care in the VA system includes access to 16 sites that have programs dedicated to treating veterans with epilepsy and many more consortium sites that interact with the ECoE to provide high-quality patient care (http:\\www.epilepsy.va.gov). The ECoE also provides a readily available resource to optimally manage veterans with epilepsy. Attention to the issues addressed in this article will promote quality care for veterans with epilepsy.

Epilepsy is a common and complex neurologic condition marked by recurrent seizures. It has been diagnosed in more than 87,000 veterans enrolled in the VA health care system, 16% of whom have comorbid traumatic brain injury (TBI), and nearly 25% also have posttraumatic stress disorder (PTSD).¹ These comorbidities were even more common in Operation Enduring Freedom (OEF), Operation Iraqi Freedom (OIF), and Operation New Dawn (OND) veterans: TBI in 52.6% and PTSD in 70.4%. With 25 drugs for seizures and 2 approved devices, treatment of epilepsy can prove challenging to providers whose goal is to balance seizure control and adverse effects (AEs).

Despite the therapeutic armamentarium, about one-third of people with epilepsy have poorly controlled seizures, and an untold number may experience delays in referral to higher levels of epilepsy care or undergo troubling antiepileptic medication AEs and comorbid psychiatric disorders that have profound impacts on quality of life (QOL).

Quality generally has been defined as “providing the right care to the right patient at the right time and in the right way to achieve the best possible results.”² Much work has been done over the past 2 decades to identify “the right care” for epilepsy patients.³

The American Academy of Neurology (AAN) has developed evidence-based, clinically focused guidelines on numerous topics, including antiepileptic drugs and women’s health, and has developed quality measure sets.^4,5 More broadly, the Institute of Medicine (IOM) proposed 13 recommendations, including improving quality of care, establishing epilepsy centers and an epilepsy care network, educating health professionals about epilepsy, and providing education for people with epilepsy and their families.⁶

Within the VA, health care for veterans with epilepsy is changing in part by the Epilepsy Centers of Excellence (ECoC), established by federal law. The ECoE’s primary missions are to improve quality of and access to epilepsy specialty care to improve the health and well-being of veteran patients with epilepsy and other seizure disorders through integration of clinical care, outreach, research, and education to VA providers and patients.⁷

The goal of this article is to outline the key elements of quality epilepsy care and make recommendations for providing quality care in the VA health care system.

Diagnosis and Seizure Types

Quality care for veterans with epilepsy begins with the provider reviewing pertinent history and establishing the clinical characteristics of the patient’s seizures and epilepsy. The provider should ask about the first signs of the seizure or warning (aura), the seizure (ictal period), and the period after the seizure (postictal period). Seizure histories from the patient and observers are critical.

The first step is to define whether the patient’s seizures are generalized, that is, start all over the brain at once, or focal, starting in one area of the brain. The patient’s initial sensation at the onset of a seizure (aura) may help localize onset and define focal seizures. For example, déjà vu sensations often point to seizure onset in the mesial temporal lobe and hippocampus. Focal seizures can spread and cause cognitive dysfunction, including aphasia and amnesia, or evolve into a generalized convulsion (tonic-clonic seizure). Many patients present with a generalized tonic-clonic seizure and have had brief focal seizures that were not considered seizures by the patient or by other providers. This seizure type should be clarified by asking specifically about paroxysmal symptoms. For example, brief periods of confusion that are episodic may be focal seizures. In general, focal seizures are stereotyped and may have a feature that helps in establishing the diagnosis. Many temporal lobe seizures are associated with lip smacking behaviors (oral buccal automatisms).

Tonic-clonic seizures may begin without an aura and are generalized from onset. Patients with this type of seizure may have electroencephalogram (EEG) findings that define a generalized abnormality, which consist of frontocentral spike and wave discharges in the EEG. In the VA population, the first generalized tonic-clonic seizure may occur while in the military. Some of these patients have juvenile myoclonic epilepsy, and a history of brief jerks on waking (myoclonus) may have been occurring but not recognized as seizures. The treatment of seizures, in part, depends on whether they begin focally or are generalized at onset.

Often people with epilepsy have multiple seizure types. The types of seizures should be documented and, if possible, corroborated by a witness. Epileptic seizures tend to be stereotyped and of relatively brief duration, usually < 2 minutes. The period after a seizure may be followed by a more prolonged period of neurologic dysfunction that includes confusion and fatigue. These symptoms may be the only indication that the patient has had a seizure.

At each clinic visit, the characteristics of the patient’s seizures should be reviewed and the frequency of seizures documented. A calendar to track seizure frequency is helpful to understand precipitating factors and response to treatment.

The health care provider (HCP) should look for the cause of a patient’s epilepsy. It is important to ask the patient about family history, age of first seizure, occurrence of febrile seizures, developmental history, past history of meningitis or encephalitis, history of childhood seizures or spells, and history of brain lesions, including tumors, strokes, or TBI. Most patients with epilepsy do not have a clear cause for their epilepsy, but the cause may be clarified with EEG and magnetic resonance imaging (MRI) testing.

EEG and Brain Imaging

All patients with epilepsy should be evaluated with an EEG, and for those with focal epilepsy or undefined epilepsy, with an imaging study of the brain, preferably an MRI. These results should be reviewed at each visit. The EEG may show focal features that are related to neurophysiologic dysfunction, such as slowing that is not definitely epileptiform in character, or show focal spike or sharp waves that are epileptiform in character. Generalized abnormalities may include generalized slowing that is not an epileptiform feature or frontocentral spike wave patterns that are epileptiform in character. The EEG cannot rule out epilepsy, but can rule in the likelihood of epilepsy when definite epileptiform features are present.

Brain imaging can define many conditions that can cause focal epilepsy, and an MRI is more sensitive for defining a number of these conditions (cavernous angiomas, hippocampal sclerosis, developmental migration disorders, and low-grade neoplasms). Significant trauma with signal abnormalities to suggest prior bleeding predispose to epilepsy. When patients are refractory to medical therapy and have imaging findings concordant with EEG onset of seizures, then surgery can be a better treatment.

Adverse Effects

Broad-spectrum drug treatments are efficacious for either generalized or focal seizures, whereas narrow-spectrum treatments are most efficacious for focal seizures (Table 1). The choice of a seizure medication is based on the patient’s seizure type(s) and other comorbid conditions.⁷ For example, a patient with epilepsy and migraines may do better with a seizure medication that also is used for migraine prophylaxis (valproate or topiramate). In general, seizure control is unlikely to be achieved if patients fail the first 2 medications tried.⁸ Treating with > 1 medication may improve seizure control but may increase AEs. A review of current seizure medications and their AEs can be found on the ECoE website (http://www.epilepsy.va.gov/Provider_Education.asp).

In VA cooperative studies that evaluated seizure medications, the most common reason for discontinuing a drug was the combination of ineffectiveness and AEs.^9-11 Addressing AEs is a quality measure for the care of patients with epilepsy. Adverse effects may be dose dependent or idiosyncratic (rashes). Drug levels may help in determining dose-dependent AEs; for example, diplopia with carbamazepine levels above 10 μg/mL. Each patient may have susceptibility to medication AEs that do not exactly match therapeutic levels. When patients have AEs, a reduction in dose or trial of an alternative medication is advised.

Uncontrollable Epilepsy

About one-third of people with epilepsy have uncontrolled seizures, known as medically intractable epilepsy, which may be identified early in their clinical course by failure of the first 2 tolerated medications.⁸ Patients should be referred to an epilepsy center so their epilepsy can be defined by video EEG monitoring to capture seizures. Unfortunately, in the VA system, this route is often delayed, and patients may not be diagnosed appropriately for years.¹² Some of these patients may be considered treatment failures because the right medications were not tried (eg, generalized epilepsy that is treated with narrow-spectrum seizure medications). Juvenile myoclonic epilepsy often may not be controlled by phenytoin or carbamazepine, but valproate, lamotrigine, levetiracetam, and zonisamide may be more effective.

Other patients may not have epilepsy but have psychogenic nonepileptic seizures (PNES). These behavioral seizures do not have an EEG epileptiform correlate. About 25% of patients who undergo prolonged video EEG monitoring have PNES, and seizure medications do not treat these events.¹² A smaller percentage of patients have both epileptic and nonepileptic seizures (5%-15%). Psychogenic nonepileptic seizures often occur within the context of traumatic exposure(s) or previous physical or sexual abuse.

In the VA population, PNES is more often associated with PTSD or head trauma history than in patients with epilepsy.^13,14 To confirm the diagnosis of PNES, video-EEG capture of the patient’s seizures is required. Because of the increased number of combat veterans with TBI and PTSD, the diagnosis of epilepsy may be difficult without video-EEG monitoring. Management consists of addressing the underlying conversion disorder and recognition and treatment of comorbidities, such as mood, anxiety, personality, or PTSD. Recently, cognitive behavioral-informed psychotherapy (CB-ip) has been shown to be effective in patients with PNES and is available through the VA national telemental health center and at some ECoE sites.¹⁵

If a patient with uncontrolled epilepsy has focal seizures, surgical therapy is more likely to result in seizure control than will medical therapy.^16,17 This is especially true when other testing, including MRI, positron emission tomography, and neuropsychiatric evaluation, point to a concordance of localization. These patients should be evaluated in a center that can provide surgical therapy and if necessary also record seizures with invasive techniques using electrodes placed directly over the cortex or into the brain to sample deeper structures like the hippocampus or amygdala. Patients who are refractory should be considered for reevaluation every 2 years by a comprehensive epilepsy center.

Unfortunately, some patients have seizures that begin in eloquent cortex, which if removed, leads to undesirable neurologic loss or multifocal seizure onset. In these patients, seizure frequency can be reduced by vagus nerve stimulation or intracranial responsive neurostimulation.^18,19

Safety

Epilepsy has inherent risks for injury. Patients and their families often need to be informed about risks and risky behaviors to avoid. A frank discussion about safety is prudent. What to do for the patient during a seizure should be addressed. For convulsive seizures: Protect the patient from injury by placing something soft between the patient’s head and the floor, keep the patient on his or her side; do not restrain the patient or put anything in the mouth; stay calm and time the seizure; as the patient gains consciousness, talk to the patient and be reassuring. For nonconvulsive seizures: Stay with the patient; time the seizure; gently guide the patient away from dangerous situations like streets or stairs; stay with the patient until he or she is back to normal, and reassure the patient.

Driving

People with epilepsy identify driving as one of their major concerns; therefore, it is important for HCPs to properly counsel patients with seizure disorders and their families about driving (Figure).²⁰ In general people with controlled seizures are permitted to drive in every state in the U.S., but people with uncontrolled seizures are restricted from licensure. Despite the desire and necessity to drive for many individuals with epilepsy, seizures while driving pose risks for crashes, which may result in property damage, injuries, and death.²¹ Factors, such as duration of seizure freedom, help predict the risk for crashes. The legal rules for determining control and administering restrictions are a complex mix of federal and state laws, regulations, and local practices, which vary widely across the country.^21,22 The standards also change over time; updated information is available from local state authorities and on good informational sites, such as those of the Epilepsy Foundation.

The key standard for determining accident risks is the seizure free interval, which is the duration of time a person with epilepsy has been seizure-free.^21-23 In the U.S., the accepted period for seizure freedom varies from about 3 months to 12 months, depending on individual state rules.²⁴

California, Delaware, Nevada, New Jersey, Oregon, and Pennsylvania require mandatory reporting. Generally physician groups in the U.S. and elsewhere oppose such mandatory reporting, because of the concern that their patients will not report their seizures, and thus may not receive appropriate treatment. Indeed, patients with epilepsy often do not tell physicians about their seizures, fearing loss of driving privileges and other social consequences.^21,23 Providers should make an effort to determine seizure frequency and whether the patient is being truthful. This information then provides a background for the provider to discuss driving issues.

Injury

People with epilepsy are susceptible to injury during a seizure and need to be counseled regarding safety, particularly when seizures are not well controlled. Hazardous situations include being near stoves or cooking, bathing alone, swimming alone, working at heights without a safety harness, and using power tools.²⁶

Sudden Unexplained Death

Patients with recurrent seizures have an increased risk for accidental fatality and for sudden unexplained death in epilepsy (SUDEP), which accounts for up to 17% of all deaths in people with epilepsy. The risk for sudden death from recurrent seizures increases 2.3 times compared with the risk in the general population.²⁵ A SUDEP is an unexpected death in a person who has epilepsy with no other obvious cause of death.²⁶ Because increased seizure frequency, the presence of tonic-clonic seizures, and other accidental risks of seizures are associated with SUDEP, the subject should be discussed with patients and their families, to encourage adherence to treatment. Epileptologists also discuss these risks with patients and their families when surgical interventions are being considered. The potential risks for injury or SUDEP may offset the surgical risks when pursuing a potentially curative epilepsy procedure.

Women of Childbearing Age

In January 2015, the ECoE started a women veterans epilepsy workgroup with the goal of improving clinical care within the VAHCS to provide education to patients, family members, and VA health care providers about the care of women with epilepsy.

Providers need to be aware that seizure medications that induce certain hepatic enzymes can lead to hormonal contraceptive failure (Table 2).²⁷ Preconception folic acid supplementation (with at least 0.4 mg) should be considered, because it may reduce the risk of major congenital malformations.²⁸ The goal of epilepsy management prior to conception is to maximize seizure control with the optimal seizure medication to avoid the need to make changes during the pregnancy.

During pregnancy, the volume of distribution increases and seizure medication metabolism may change requiring dose adjustment. The best predictor of seizure frequency during pregnancy is a woman’s epilepsy pattern prior to conception. Seizure freedom for 9 months prior to conception is associated with a 84% to 92% likelihood of seizure freedom throughout the pregnancy.²⁹

International seizure medication pregnancy registries have provided valuable information regarding the risk of major congenital malformation (MCM) of development, which seems to be a consequence of seizure medication therapy and not epilepsy itself. The risk of MCM associated with seizure medication therapy is about 4% to 5% compared with 1.5% to 3% in the general population.^30,31 A seizure medication table that supplements the existing VA ECoE information specifically addresses women’s issues with the recognition that recent revisions to the teratogenicity classification have been made by the FDA (Table 2).³² If possible, valproate should be avoided during pregnancy due to its higher rate of MCM and impact on neurocognitive function.³³ Obstetrical input is essential in arranging routine prenatal fetal testing. Although women with epilepsy do not have a substantially increased risk of undergoing a cesarean section, delivery in a hospital obstetric unit is advised.

Postpartum women veterans with epilepsy should be encouraged to breast feed since the potential benefits seem to outweigh any established risk of seizure medication exposure to the infant. No relative impact on cognition was found in breastfed infants exposed to a variety of seizure medications.³⁴ Following delivery, vigilance is needed to monitor for sleep deprivation, postpartum depression, and the safe care of the infant.³⁵ Care of women with epilepsy does not end with pregnancy planning, additional important topics include psychiatric comorbidities, catamenial epilepsy, and bone health, which are unique to women veterans with epilepsy.

Identifying Psychiatric Conditions

People with epilepsy have a number of psychiatric comorbidities. Suicide and suicide attempts are 6 to 25 times more common in patients with temporal lobe epilepsy compared with those in the general population.^36-38 Although the FDA identified all seizure medications as potential contributors to suicide risk, a recent longitudinal study of suicidal ideation and attempt found that those who received seizure medications were more likely to have suicidal ideation and attempt than those who did not received seizure medications, suggesting that medication may relate to baseline depression or suicidal ideation.³⁹ When seeing patients with epilepsy, screening for suicidal ideation is good practice.

Depression and anxiety disorders are the most common psychiatric comorbidities in people with epilepsy.^40,41 About half of people with epilepsy have symptoms of depression, and 40% have anxiety.⁴² Depression often precedes the diagnosis of epilepsy, and anxiety often is present and related to the fear of having seizures and of social embarrassment.⁴³ People with epilepsy may not self-report these symptoms if not asked directly. Identification of comorbid depression and anxiety should lead to appropriate treatment. The CB-ip being used for PNES also is being used for treatment of epilepsy and its comorbidities.⁴⁴

Mild traumatic brain injury (mTBI) has a small increased risk of epilepsy.⁴⁵ Veterans with mTBI that occurs in the context of blasts are set up for the development of PTSD. These veterans may have other mild cognitive symptoms that can be confused with seizures. Furthermore, mTBI and PNES often occur together, more so than do mTBI and epileptic seizures.¹⁴ Video-EEG monitoring may be warranted for these patients.

Education and Self-Management

The IOM report on epilepsy identified patient and family education as essential for better epilepsy care.⁶ Providers should help educate patients about their epilepsy and refer them to resources available online (Table 3). A continuing exchange about their condition and treatment with seizure medications should occur with each visit. People with epilepsy should also receive guidance regarding how to manage their epilepsy and day-to-day issues. Referring, patients to social workers, psychologists, vocational rehabilitation services, and support groups can enhance a patient’s QOL.^3,6 The stigma of epilepsy is another burden that can be diminished by attending support groups. Recently, being a part of an online patient community of veterans was found to improve self-management.⁴⁶

Conclusion

People with epilepsy have many issues that are unique to the condition and, in part, are related to the unpredictable occurrence of seizures and loss of function. Ideally, seizure control provides a normal lifestyle; however, some mood and anxiety comorbidities may persist despite seizure control. Care in the VA system includes access to 16 sites that have programs dedicated to treating veterans with epilepsy and many more consortium sites that interact with the ECoE to provide high-quality patient care (http:\\www.epilepsy.va.gov). The ECoE also provides a readily available resource to optimally manage veterans with epilepsy. Attention to the issues addressed in this article will promote quality care for veterans with epilepsy.

Epilepsy is a common and complex neurologic condition marked by recurrent seizures. It has been diagnosed in more than 87,000 veterans enrolled in the VA health care system, 16% of whom have comorbid traumatic brain injury (TBI), and nearly 25% also have posttraumatic stress disorder (PTSD).¹ These comorbidities were even more common in Operation Enduring Freedom (OEF), Operation Iraqi Freedom (OIF), and Operation New Dawn (OND) veterans: TBI in 52.6% and PTSD in 70.4%. With 25 drugs for seizures and 2 approved devices, treatment of epilepsy can prove challenging to providers whose goal is to balance seizure control and adverse effects (AEs).

Despite the therapeutic armamentarium, about one-third of people with epilepsy have poorly controlled seizures, and an untold number may experience delays in referral to higher levels of epilepsy care or undergo troubling antiepileptic medication AEs and comorbid psychiatric disorders that have profound impacts on quality of life (QOL).

Quality generally has been defined as “providing the right care to the right patient at the right time and in the right way to achieve the best possible results.”² Much work has been done over the past 2 decades to identify “the right care” for epilepsy patients.³

The American Academy of Neurology (AAN) has developed evidence-based, clinically focused guidelines on numerous topics, including antiepileptic drugs and women’s health, and has developed quality measure sets.^4,5 More broadly, the Institute of Medicine (IOM) proposed 13 recommendations, including improving quality of care, establishing epilepsy centers and an epilepsy care network, educating health professionals about epilepsy, and providing education for people with epilepsy and their families.⁶

Within the VA, health care for veterans with epilepsy is changing in part by the Epilepsy Centers of Excellence (ECoC), established by federal law. The ECoE’s primary missions are to improve quality of and access to epilepsy specialty care to improve the health and well-being of veteran patients with epilepsy and other seizure disorders through integration of clinical care, outreach, research, and education to VA providers and patients.⁷

The goal of this article is to outline the key elements of quality epilepsy care and make recommendations for providing quality care in the VA health care system.

Diagnosis and Seizure Types

Quality care for veterans with epilepsy begins with the provider reviewing pertinent history and establishing the clinical characteristics of the patient’s seizures and epilepsy. The provider should ask about the first signs of the seizure or warning (aura), the seizure (ictal period), and the period after the seizure (postictal period). Seizure histories from the patient and observers are critical.

The first step is to define whether the patient’s seizures are generalized, that is, start all over the brain at once, or focal, starting in one area of the brain. The patient’s initial sensation at the onset of a seizure (aura) may help localize onset and define focal seizures. For example, déjà vu sensations often point to seizure onset in the mesial temporal lobe and hippocampus. Focal seizures can spread and cause cognitive dysfunction, including aphasia and amnesia, or evolve into a generalized convulsion (tonic-clonic seizure). Many patients present with a generalized tonic-clonic seizure and have had brief focal seizures that were not considered seizures by the patient or by other providers. This seizure type should be clarified by asking specifically about paroxysmal symptoms. For example, brief periods of confusion that are episodic may be focal seizures. In general, focal seizures are stereotyped and may have a feature that helps in establishing the diagnosis. Many temporal lobe seizures are associated with lip smacking behaviors (oral buccal automatisms).

Tonic-clonic seizures may begin without an aura and are generalized from onset. Patients with this type of seizure may have electroencephalogram (EEG) findings that define a generalized abnormality, which consist of frontocentral spike and wave discharges in the EEG. In the VA population, the first generalized tonic-clonic seizure may occur while in the military. Some of these patients have juvenile myoclonic epilepsy, and a history of brief jerks on waking (myoclonus) may have been occurring but not recognized as seizures. The treatment of seizures, in part, depends on whether they begin focally or are generalized at onset.

Often people with epilepsy have multiple seizure types. The types of seizures should be documented and, if possible, corroborated by a witness. Epileptic seizures tend to be stereotyped and of relatively brief duration, usually < 2 minutes. The period after a seizure may be followed by a more prolonged period of neurologic dysfunction that includes confusion and fatigue. These symptoms may be the only indication that the patient has had a seizure.

At each clinic visit, the characteristics of the patient’s seizures should be reviewed and the frequency of seizures documented. A calendar to track seizure frequency is helpful to understand precipitating factors and response to treatment.

The health care provider (HCP) should look for the cause of a patient’s epilepsy. It is important to ask the patient about family history, age of first seizure, occurrence of febrile seizures, developmental history, past history of meningitis or encephalitis, history of childhood seizures or spells, and history of brain lesions, including tumors, strokes, or TBI. Most patients with epilepsy do not have a clear cause for their epilepsy, but the cause may be clarified with EEG and magnetic resonance imaging (MRI) testing.

EEG and Brain Imaging

All patients with epilepsy should be evaluated with an EEG, and for those with focal epilepsy or undefined epilepsy, with an imaging study of the brain, preferably an MRI. These results should be reviewed at each visit. The EEG may show focal features that are related to neurophysiologic dysfunction, such as slowing that is not definitely epileptiform in character, or show focal spike or sharp waves that are epileptiform in character. Generalized abnormalities may include generalized slowing that is not an epileptiform feature or frontocentral spike wave patterns that are epileptiform in character. The EEG cannot rule out epilepsy, but can rule in the likelihood of epilepsy when definite epileptiform features are present.

Brain imaging can define many conditions that can cause focal epilepsy, and an MRI is more sensitive for defining a number of these conditions (cavernous angiomas, hippocampal sclerosis, developmental migration disorders, and low-grade neoplasms). Significant trauma with signal abnormalities to suggest prior bleeding predispose to epilepsy. When patients are refractory to medical therapy and have imaging findings concordant with EEG onset of seizures, then surgery can be a better treatment.

Adverse Effects

Broad-spectrum drug treatments are efficacious for either generalized or focal seizures, whereas narrow-spectrum treatments are most efficacious for focal seizures (Table 1). The choice of a seizure medication is based on the patient’s seizure type(s) and other comorbid conditions.⁷ For example, a patient with epilepsy and migraines may do better with a seizure medication that also is used for migraine prophylaxis (valproate or topiramate). In general, seizure control is unlikely to be achieved if patients fail the first 2 medications tried.⁸ Treating with > 1 medication may improve seizure control but may increase AEs. A review of current seizure medications and their AEs can be found on the ECoE website (http://www.epilepsy.va.gov/Provider_Education.asp).

In VA cooperative studies that evaluated seizure medications, the most common reason for discontinuing a drug was the combination of ineffectiveness and AEs.^9-11 Addressing AEs is a quality measure for the care of patients with epilepsy. Adverse effects may be dose dependent or idiosyncratic (rashes). Drug levels may help in determining dose-dependent AEs; for example, diplopia with carbamazepine levels above 10 μg/mL. Each patient may have susceptibility to medication AEs that do not exactly match therapeutic levels. When patients have AEs, a reduction in dose or trial of an alternative medication is advised.

Uncontrollable Epilepsy

About one-third of people with epilepsy have uncontrolled seizures, known as medically intractable epilepsy, which may be identified early in their clinical course by failure of the first 2 tolerated medications.⁸ Patients should be referred to an epilepsy center so their epilepsy can be defined by video EEG monitoring to capture seizures. Unfortunately, in the VA system, this route is often delayed, and patients may not be diagnosed appropriately for years.¹² Some of these patients may be considered treatment failures because the right medications were not tried (eg, generalized epilepsy that is treated with narrow-spectrum seizure medications). Juvenile myoclonic epilepsy often may not be controlled by phenytoin or carbamazepine, but valproate, lamotrigine, levetiracetam, and zonisamide may be more effective.

Other patients may not have epilepsy but have psychogenic nonepileptic seizures (PNES). These behavioral seizures do not have an EEG epileptiform correlate. About 25% of patients who undergo prolonged video EEG monitoring have PNES, and seizure medications do not treat these events.¹² A smaller percentage of patients have both epileptic and nonepileptic seizures (5%-15%). Psychogenic nonepileptic seizures often occur within the context of traumatic exposure(s) or previous physical or sexual abuse.

In the VA population, PNES is more often associated with PTSD or head trauma history than in patients with epilepsy.^13,14 To confirm the diagnosis of PNES, video-EEG capture of the patient’s seizures is required. Because of the increased number of combat veterans with TBI and PTSD, the diagnosis of epilepsy may be difficult without video-EEG monitoring. Management consists of addressing the underlying conversion disorder and recognition and treatment of comorbidities, such as mood, anxiety, personality, or PTSD. Recently, cognitive behavioral-informed psychotherapy (CB-ip) has been shown to be effective in patients with PNES and is available through the VA national telemental health center and at some ECoE sites.¹⁵

If a patient with uncontrolled epilepsy has focal seizures, surgical therapy is more likely to result in seizure control than will medical therapy.^16,17 This is especially true when other testing, including MRI, positron emission tomography, and neuropsychiatric evaluation, point to a concordance of localization. These patients should be evaluated in a center that can provide surgical therapy and if necessary also record seizures with invasive techniques using electrodes placed directly over the cortex or into the brain to sample deeper structures like the hippocampus or amygdala. Patients who are refractory should be considered for reevaluation every 2 years by a comprehensive epilepsy center.

Unfortunately, some patients have seizures that begin in eloquent cortex, which if removed, leads to undesirable neurologic loss or multifocal seizure onset. In these patients, seizure frequency can be reduced by vagus nerve stimulation or intracranial responsive neurostimulation.^18,19

Safety

Epilepsy has inherent risks for injury. Patients and their families often need to be informed about risks and risky behaviors to avoid. A frank discussion about safety is prudent. What to do for the patient during a seizure should be addressed. For convulsive seizures: Protect the patient from injury by placing something soft between the patient’s head and the floor, keep the patient on his or her side; do not restrain the patient or put anything in the mouth; stay calm and time the seizure; as the patient gains consciousness, talk to the patient and be reassuring. For nonconvulsive seizures: Stay with the patient; time the seizure; gently guide the patient away from dangerous situations like streets or stairs; stay with the patient until he or she is back to normal, and reassure the patient.

Driving

People with epilepsy identify driving as one of their major concerns; therefore, it is important for HCPs to properly counsel patients with seizure disorders and their families about driving (Figure).²⁰ In general people with controlled seizures are permitted to drive in every state in the U.S., but people with uncontrolled seizures are restricted from licensure. Despite the desire and necessity to drive for many individuals with epilepsy, seizures while driving pose risks for crashes, which may result in property damage, injuries, and death.²¹ Factors, such as duration of seizure freedom, help predict the risk for crashes. The legal rules for determining control and administering restrictions are a complex mix of federal and state laws, regulations, and local practices, which vary widely across the country.^21,22 The standards also change over time; updated information is available from local state authorities and on good informational sites, such as those of the Epilepsy Foundation.

The key standard for determining accident risks is the seizure free interval, which is the duration of time a person with epilepsy has been seizure-free.^21-23 In the U.S., the accepted period for seizure freedom varies from about 3 months to 12 months, depending on individual state rules.²⁴

California, Delaware, Nevada, New Jersey, Oregon, and Pennsylvania require mandatory reporting. Generally physician groups in the U.S. and elsewhere oppose such mandatory reporting, because of the concern that their patients will not report their seizures, and thus may not receive appropriate treatment. Indeed, patients with epilepsy often do not tell physicians about their seizures, fearing loss of driving privileges and other social consequences.^21,23 Providers should make an effort to determine seizure frequency and whether the patient is being truthful. This information then provides a background for the provider to discuss driving issues.

Injury

People with epilepsy are susceptible to injury during a seizure and need to be counseled regarding safety, particularly when seizures are not well controlled. Hazardous situations include being near stoves or cooking, bathing alone, swimming alone, working at heights without a safety harness, and using power tools.²⁶

Sudden Unexplained Death

Patients with recurrent seizures have an increased risk for accidental fatality and for sudden unexplained death in epilepsy (SUDEP), which accounts for up to 17% of all deaths in people with epilepsy. The risk for sudden death from recurrent seizures increases 2.3 times compared with the risk in the general population.²⁵ A SUDEP is an unexpected death in a person who has epilepsy with no other obvious cause of death.²⁶ Because increased seizure frequency, the presence of tonic-clonic seizures, and other accidental risks of seizures are associated with SUDEP, the subject should be discussed with patients and their families, to encourage adherence to treatment. Epileptologists also discuss these risks with patients and their families when surgical interventions are being considered. The potential risks for injury or SUDEP may offset the surgical risks when pursuing a potentially curative epilepsy procedure.

Women of Childbearing Age

In January 2015, the ECoE started a women veterans epilepsy workgroup with the goal of improving clinical care within the VAHCS to provide education to patients, family members, and VA health care providers about the care of women with epilepsy.

Providers need to be aware that seizure medications that induce certain hepatic enzymes can lead to hormonal contraceptive failure (Table 2).²⁷ Preconception folic acid supplementation (with at least 0.4 mg) should be considered, because it may reduce the risk of major congenital malformations.²⁸ The goal of epilepsy management prior to conception is to maximize seizure control with the optimal seizure medication to avoid the need to make changes during the pregnancy.

During pregnancy, the volume of distribution increases and seizure medication metabolism may change requiring dose adjustment. The best predictor of seizure frequency during pregnancy is a woman’s epilepsy pattern prior to conception. Seizure freedom for 9 months prior to conception is associated with a 84% to 92% likelihood of seizure freedom throughout the pregnancy.²⁹

International seizure medication pregnancy registries have provided valuable information regarding the risk of major congenital malformation (MCM) of development, which seems to be a consequence of seizure medication therapy and not epilepsy itself. The risk of MCM associated with seizure medication therapy is about 4% to 5% compared with 1.5% to 3% in the general population.^30,31 A seizure medication table that supplements the existing VA ECoE information specifically addresses women’s issues with the recognition that recent revisions to the teratogenicity classification have been made by the FDA (Table 2).³² If possible, valproate should be avoided during pregnancy due to its higher rate of MCM and impact on neurocognitive function.³³ Obstetrical input is essential in arranging routine prenatal fetal testing. Although women with epilepsy do not have a substantially increased risk of undergoing a cesarean section, delivery in a hospital obstetric unit is advised.

Postpartum women veterans with epilepsy should be encouraged to breast feed since the potential benefits seem to outweigh any established risk of seizure medication exposure to the infant. No relative impact on cognition was found in breastfed infants exposed to a variety of seizure medications.³⁴ Following delivery, vigilance is needed to monitor for sleep deprivation, postpartum depression, and the safe care of the infant.³⁵ Care of women with epilepsy does not end with pregnancy planning, additional important topics include psychiatric comorbidities, catamenial epilepsy, and bone health, which are unique to women veterans with epilepsy.

Identifying Psychiatric Conditions

People with epilepsy have a number of psychiatric comorbidities. Suicide and suicide attempts are 6 to 25 times more common in patients with temporal lobe epilepsy compared with those in the general population.^36-38 Although the FDA identified all seizure medications as potential contributors to suicide risk, a recent longitudinal study of suicidal ideation and attempt found that those who received seizure medications were more likely to have suicidal ideation and attempt than those who did not received seizure medications, suggesting that medication may relate to baseline depression or suicidal ideation.³⁹ When seeing patients with epilepsy, screening for suicidal ideation is good practice.

Depression and anxiety disorders are the most common psychiatric comorbidities in people with epilepsy.^40,41 About half of people with epilepsy have symptoms of depression, and 40% have anxiety.⁴² Depression often precedes the diagnosis of epilepsy, and anxiety often is present and related to the fear of having seizures and of social embarrassment.⁴³ People with epilepsy may not self-report these symptoms if not asked directly. Identification of comorbid depression and anxiety should lead to appropriate treatment. The CB-ip being used for PNES also is being used for treatment of epilepsy and its comorbidities.⁴⁴

Mild traumatic brain injury (mTBI) has a small increased risk of epilepsy.⁴⁵ Veterans with mTBI that occurs in the context of blasts are set up for the development of PTSD. These veterans may have other mild cognitive symptoms that can be confused with seizures. Furthermore, mTBI and PNES often occur together, more so than do mTBI and epileptic seizures.¹⁴ Video-EEG monitoring may be warranted for these patients.

Education and Self-Management

The IOM report on epilepsy identified patient and family education as essential for better epilepsy care.⁶ Providers should help educate patients about their epilepsy and refer them to resources available online (Table 3). A continuing exchange about their condition and treatment with seizure medications should occur with each visit. People with epilepsy should also receive guidance regarding how to manage their epilepsy and day-to-day issues. Referring, patients to social workers, psychologists, vocational rehabilitation services, and support groups can enhance a patient’s QOL.^3,6 The stigma of epilepsy is another burden that can be diminished by attending support groups. Recently, being a part of an online patient community of veterans was found to improve self-management.⁴⁶

Conclusion

People with epilepsy have many issues that are unique to the condition and, in part, are related to the unpredictable occurrence of seizures and loss of function. Ideally, seizure control provides a normal lifestyle; however, some mood and anxiety comorbidities may persist despite seizure control. Care in the VA system includes access to 16 sites that have programs dedicated to treating veterans with epilepsy and many more consortium sites that interact with the ECoE to provide high-quality patient care (http:\\www.epilepsy.va.gov). The ECoE also provides a readily available resource to optimally manage veterans with epilepsy. Attention to the issues addressed in this article will promote quality care for veterans with epilepsy.

From the Division of Infectious Diseases, School of Medicine, University of Louisville, Louisville, KY.

Abstract

• Objective: To summarize the published literature on cardiac complications in patients with community-acquired pneumonia (CAP) as well as provide a historical context for the topic; and to provide recommendations concerning preventing and anticipating cardiac complications in patients with CAP.
• Methods: Literature review.
• Results: CAP patients are at increased risk for arrhythmias (~5%), myocardial infarction (~5%), and congestive heart failure (~14%). Oxygenation, the level of heart conditioning, local (pulmonary) and systemic (cytokines) inflammation, and medication all contribute to the pathophysiology of cardiac complications in CAP patients. A high Pneumonia Severity Index (PSI) can be used to screen for risk of cardiac complications in CAP patients; however, a new but less studied clinical rule developed to risk stratify patient hospitalized for CAP was shown to outperform the PSI. A troponin test and ECG should be obtained in all patients admitted for CAP while a cardiac echocardiogram may be reserved for higher-risk patients.
• Conclusions: Cardiac complications, including arrhythmias, myocardial infarctions, and congestive heart failure, are a significant burden among patients hospitalized for CAP. Influenza and pneumococcal vaccination should be emphasized among appropriate patients. Preliminary data suggest that those with CAP may be helped if they are already on aspirin or a statin. Early recognition of cardiac complications and treatment may improve clinical outcomes for patients with CAP.

Community-acquired pneumonia (CAP) is a common condition in the United States and a leading cause of morbidity and mortality [1,2], with medical costs exceeding $10 billion in 2011 [3]. The mortality rate is much higher for those aged 65 years and older [4]. Men have a higher death rate than women (18.6 vs. 13.9 per 100,000 population), and death rate varies based on ethnicity, with mortality rates for American Indian/Alaska natives at 19.2, blacks at 17.1, whites at 15.9, Asian/Pacific Islanders at 15.0, and Hispanics at 13.1 (all rates per 100,000) [2]. CAP causes considerable worldwide mortality, with differences in mortality varying according to world region [5].

Cardiovascular complications and death from other comorbidities cause a substantial proportion of CAP-associated mortality. In Mortensen et al’s study, among patients with CAP who died, at least one third had a cardiac complication, and 13% had a cardiac-related cause of death [6]. One study showed that hospitalized patients with CAP complicated by heart disease were 30% more likely to die than patients hospitalized with CAP alone [7]. In this article, we discuss the burden of cardiac complications in adults with CAP, including underlying pathophysiological processes and strategies to prevent their occurence.

Pathophysiological Processes of Heart Disease Caused by CAP

The pathophysiology of cardiac complications as a result of CAP is made up of several hypotheses, including (1) declining oxygen provision by the lungs in the face of increasing demand by the heart, (2) a lack of reserve for stress because of cardiac comorbidities and (3) localized (pulmonary) inflammation leading to systemic (including cardiac) complications by the release of cytokines or other chemicals. Any of these may result in cardiac complications occurring before, during, or after a patient has been hospitalized for CAP. Antimicrobial treatment, specifically azithromycin, has also been implicated in myocardial adverse effects. Although azithromycin is most noted for causing QT prolongation, it was associated with myocardial infarction (MI) in a study of 73,690 patients with pneumonia [8]. A higher proportion of those who received azithromycin had an MI compared to those who did not (5.1% vs 4.4%; OR 1.17; 95% CI, 1.08–1.25), but there was no statistical difference in cardiac arrhythmias, and the 90-day mortality was actually better in the azithromycin group (17.4% vs 22.3%; odds ratio [OR], 0.73; 95% CI, 0.70–0.76).

Systemic inflammation is the result of several molecules, such as cytokines, chemokines and reactive oxidant species. Reactive oxidant species may determine oxidation of proteins, lipids and DNA, which leads to cell death. The hypothesis also purports that they also cause destabilization of atherosclerotic plaques leading to MIs. Other reactions as a result of inflammation lead to arrhythmias with or without compromised cardiac function, causing congestive heart failure (CHF). For this reason, some authors have approached the pathophysiology of cardiac complications by considering them to be either plaque-related or plaque-unrelated events [9].

A few studies have linked specific inflammatory molecules to cardiac toxicity. NOX2 is chemically unstable and may provoke cellular damage, thus maintaining a certain redox balance is crucial for cardiomyocyte health. In 248 patients with CAP, an elevated troponin T was present in 135 patients and among those, NOX2 correlated with the troponin T values (OR 1.13, 95% CI 1.08–1.17; P < 0.001) [10]. Both disrupting the equilibrium of the redox balance by upregulating NOX2, and finding NOX2 to be associated with troponin T suggest that oxidative stress is implicated in damage to the myocardium during CAP. In another study of 432 patients with CAP, 41 developed atrial fibrillation within 24 to 72 hours of admission and showed higher blood levels of NOX2 than those who had CAP without atrial fibrillation [11]. Oxidative stress has been shown to cause hypertrophy, dysfunction, apoptotic cell death, and fibrosis in the myocardium [12].

There is likely a high level of variability in how individual patients respond to a predisposing factor for a cardiac complication. For example, one patient may tolerate a mild hypoxia while another is sensitive. The association of inflammatory markers with the presence of cardiac markers, however, would support that once there are systemic reactions, the complications increase. Macrolides, however, were not found to contribute to long-term mortality due to cardiac complications.

Cardiac Complications of CAP

After the H₁N₁ influenza outbreak of 1918, it was noted that all-cause mortality increased during the outbreak as did influenza-related deaths. This prompted inquiry as to whether there was an actual association between the outbreak and increased overall mortality, or whether the 2 occurrences were simply coincidental [14]. Near that time, arrhythmias in CAP patients were studied. T-wave changes were found to be associated with CAP [15]. Among 92 patients studied, 449 electrocardiograms (ECGs) were reviewed. T-wave changes were the most common ECG changes. They were found in 5 of 10 of the patients who died, and in 35 of the 82 patients who lived. Twelve living patients had persistent ECG changes, and although they were all thought to have had underlying myocardial disease, 2 of them certainly did as they each had an acute MI (and the ECG was included as a figure for one of them).

A study in the 1980s that reported 3 of 38 CAP patients with CHF interrupted the paucity of data at the time that showed that having a cardiac complication during CAP was a known entity [16]. By the end of the 20th century, Meier et al noted that among case patients who had an MI, an acute respiratory tract infection preceded the MI in 2.8% while in only 0.9% of control patients [17]. They also noted that patients who had an acute respiratory tract infection were 2.7 times more likely to have an MI in the following 10 days than control patients.

Further study by Musher et al revealed that MI was associated with pneumococcal pneumonia in 12 (7%) of 170 veteran patients [18]. An MI was defined on the basis of ECG abnormalities (Q waves or ST segment elevation or depression) with troponin I levels ≥ 0.5 ng/mL. They also evaluated arrhythmias and CHF. They included atrial fibrillation or flutter and ventricular tachycardia while excluding terminal arrhythmias. An arrhythmia was found in 8 (5%) patients. CHF was based on Framingham criteria (Table 1) [19]. New or worsening CHF was determined by comparing physical findings, laboratory values, chest radiograph, and echocardiogram reports in medical records. CHF was found in 13 (19%) patients. Ramirez et al found that MI was associated with CAP in 29 (5.8%) of 500 similar veteran patients [20].

Corrales-Medina et al reported cardiac complications in CAP patients in the Pneumonia Patient Outcomes Team cohort study [21]. They defined MI as the presence of 2 of 3 criteria: ECG abnormalities, elevated cardiac enzymes, and chest pain. They found 43 (3.2%) of 1343 patients with an MI. Arrhythmias included atrial fibrillation or flutter, multifocal atrial tachycardia, supraventricular tachycardia, ventricular tachycardia (≥ 3 beat run) or ventricular fibrillation. With the more inclusive list, they found a greater proportion, 137 (10%) patients affected. They defined CHF with physical examination findings plus a radiographic abnormality, and found 279 (21%) patients affected. A meta-analysis of 17 studies had pooled incidences for an MI of 5.3%, an arrhythmia of 4.7% and CHF of 14.1% [22].

In summary, the most prominent cardiac complications in patients with CAP have been found to be CHF, MI, and arrhythmia.

Timing of Cardiac Complications in Relation to CAP

While a patient is still in the community, cardiac complications may occur with the onset of CAP, or afterwards. For these patients, the primary goal is to identify the complication and manage it as soon as the patient is admitted for CAP, rather than allowing the complications to worsen only to be recognized later. Cardiac complications are rare in outpatients overall. A study of 944 outpatients found heart failure in 1.4%, arrhythmias in 1.0% and MI in 0.1% [21].

For patients who are admitted with CAP but who do not have a cardiac complication, the goals are either to prevent any complication or to recognize and manage a complication early. This also applies to patients who have been discharged after an admission for CAP. Cardiac complications have been recorded shortly after (within 30 days), and late (up to 1 year) after discharge. A study of over 50,000 veterans who were admitted for CAP were followed for any cardiovascular complication in the next 90 days. Approximately 7500 veterans were found to have a cardiac complication, including (in order of highest to lowest frequency) CHF, arrhythmia, MI, stroke and angina [23]. More than 75% of the complications were found on the day of hospitalization, but events were still measured at 30 days and 90 days.

Two other studies sought to determine an association between CAP and cardiac complications differently; not by following CAP patients prospectively for complications but by retrospectively evaluating patients for a respiratory infection among those who were admitted for a cardiovascular complication (MI or stroke). A study of over 35,000 first-time admissions for either an MI or a stroke were evaluated for a respiratory infection within the previous 90 days [24]. The incidence rates were statistically significant for every time period up to 90 days. The preceding 3 days was the time period with the highest frequency for a respiratory infection preceding an event. When the event was an MI, the incident rate was 4.95 (95% CI, 4.43–5.53). A similar study of over 20,000 first-time admissions for either an MI or stroke were evaluated for a preceding primary care visit for a respiratory infection [25]. An infection preceded 2.9% of patients with an MI and 2.8% of patients with a stroke. Statistical significance was found for the group of patients who had a respiratory infection within 7 days preceding an MI (OR 2.10 [95% CI 1.38–3.21]) or preceding a stroke (OR 1.92 [95% CI 1.24–2.97]). In fact, every time period analyzed for both complications (MI and stroke) was significant up to 1 year. Because the timing of a cardiac complication varies and can occur up to 90 days or even a year after acute infection, physicians should maintain vigilance in suspecting and screening for them.

Predictors of Cardiac Complications During CAP

Recently, Cangemi et al reviewed mortality in 301 patients admitted for CAP 6 to 60 months after they were discharged [26]. Mortality was compared between patients who experienced a cardiac complication—atrial fibrillation or an ST- or non-ST-elevation MI—during their admission and those who did not. A total of 55 (18%) patients had a cardiac complication while hospitalized. During the follow-up, 90 (30%) of the 301 patients died. Death occurred in more patients who had had a cardiac complication while hospitalized than in those who did not (32% vs 13%; P < 0.001). The study also showed that age and the pneumonia severity index (PSI) predicted death in addition to intra-hospital complication. A Cox regression analysis showed that intrahospital cardiac complications (hazard ratio [HR] 1.76 [95% CI 1.10–2.82]; P = 0.019), age (HR 1.05 [95% CI 1.03–1.08]; P < 0.001) and the PSI (HR 1.01 [95% CI 1.00–1.02] P = 0.012) independently predicted death after adjusting for possible confounders [26].

The PSI score was published in 1997, and it instructed that patients with a risk class of I or II (low risk) should be managed as outpatients. Data eventually showed that there is a portion of the population with a risk class of I or II whose hospital admission is justified [4]. Among the reasons found was “comorbidity,” including MI and other cardiac complications. The PSI prediction rule was found to be useful in novel ways, and being associated with a risk of MI in patients with CAP was one of them. The propensity-adjusted association between the PSI score and MI was significant (P < 0.05) in an observational study of the CAP Organization (CAPO) [20]. Knowing that a PSI of 80 is in the middle of risk class III (71–90), it was noted that below 80 the risk for MI was zero to 2.5%, while above 80 the risk rose from 2.5% to 12.5%. A later study using the same statistical method showed a correlation between the PSI score and cardiac complications (MI, arrhythmias and CHF) with a P value of < 0.01 [21]. Determining the probability for the combination of complications, rather than just an MI, yielded an unsurprisingly higher range of risk for the PSI below 80, which was zero to 17.5%, while risk for a PSI above 80 was 17.5% to 80%.

In a study to determine risk factors for cardiac complications among 3068 patients with CAP, Griffin et al applied a purposeful selection algorithm to a list of factors with reasonable potential to be associated with the 376 patients who actually had a cardiac complication [27]. After multivariate logistic regression analysis, hyperlipidemia, an infection with Staphlococcus aureus or Klebsiella pneumoniae, and the PSI were found to be statistically significant. In contrast, statin therapy was associated with a lower risk of an event.

In 2014, a validated score similar to the PSI and using the same database was derived to predict short-term risk for cardiac events in hospitalized patients with CAP [28]. It attributes points for age, 3 preexisting conditions, 2 vital signs and 7 radiological and laboratory values, with a point scoring system that defines 4 risk stratification classes. In the derivation cohort, the incidence of cardiac complications across the risk classes increased linearly (3%, 18%, 35%, and 72%, respectively). The score was validated in the original publication with a separate database but has not been evaluated since. The score outperformed the PSI score in predicting cardiac complications in the validation cohort (proportion of patients correctly reclassified by the new score, 44%). Potentially, the rule could help identify high-risk patients upon admission and could assist clinicians in their decision making.

Strategies to Prevent Cardiac Complications During CAP

It is now well established that there is a heavy burden of long-lasting cardiac complications among patients with CAP; therefore, preventing CAP should be a priority. This can be accomplished by counseling patients to refrain from alcohol and smoking and by administering influenza (Table 2) and pneumococcal vaccines (Figure 2). Since the 7-valent protein-polysaccharide conjugate pneumococcal vaccine (PCV-7) was released for children in 2000, there have been fewer hospitalizations in the United States [27] and improved outcomes globally; for instance, fewer hospitalizations among children < 14 years of age in Uruguay [29], and decreased invasive pneumococcal disease among children < 5 years of age in Taiwan [30]. Furthermore, a decrease in invasive pneumococcal disease by 18% in persons aged > 65 years in the US and Canada decreased with the introduction of PCV-7 to children. Although this showed a beneficial indirect effect (herd immunity) in unvaccinated populations [31,32], there have been no randomized controlled trials in adults demonstrating a decrease in pneumococcal pneumonia or invasive pneumococcal disease which were vaccinated with PCV-13. The Food and Drug Administration approved PCV-13 for children in 2010 and for adults in 2012. Although it included fewer serotypes, it did include serotype 6A, which has a high pathogenicity and is not in 23-valent pneumococcal polysaccharide vaccine (PPSV-23). The criteria for vaccinating adults for pneumococcal infection were recently published [33]. A study of patients with invasive pneumococcal disease, which also determined pneumococcal serotypes, included 5 patients who had CAP as well [34]. Those patients had serotypes 6A, 7C, 14, and 23F (2 patients). The patient who had serotype 14 (higher pathogenicity) died and the other 4 lived. Serotypes 14 and 23F are in both vaccines while serotype 7C is in neither. Vaccination status was not provided in the study. At this time, there is evidence to support vaccinating patients for both S. pneumoniae and influenza virus.

Two methods used to prevent cardiac complications in general have been administration of aspirin and statins. The anticlotting properties of aspirin help to maintain blood flow in arteries narrowed by atherosclerosis. A meta-analysis of 10 randomized controlled trials found a statistically significant association between aspirin and a benefit on nonfatal myocardial infarctions/coronary events [35]. The associations were found with doses of 100 mg or less daily, and benefits were seen within 1 to 5 years. Statins have also been found to reduce all-cause mortality, cardiac-related mortality, and myocardial infarction [36]. A statin may stabilize coronary artery plaques that otherwise may rupture and cause myocardial ischemia or an infarct. But statins have also been found to be associated with a decreased risk of CAP. A comprehensive systematic review and meta-analysis found a decreased risk of CAP (OR 0.84; 95% CI, 0.74– 0.95) and decreased short-term mortality in patients with CAP (OR 0.68; 95% CI, 0.56–0.78) as a result of statin therapy [37]. The studies included any of 8 available statins. A prospective observational study found that patients who had been on a statin prior to being admitted for CAP had lower mortality, a lower incidence of complicated pneumonia and a lower C-reactive protein [38]. The lower C-reactive protein identifies decreased inflammation, which translates into improved endothelial function, modulated antioxidant effects, and a reduction in pro-inflammatory cytokines, hence its association with less severe CAP. Further study may reveal that a certain patient population should receive a statin to prevent CAP and improve outcomes. Overall, data support taking aspirin to prevent cardiac events regardless of CAP; further investigation of the benefits of statins to prevent cardiac complications in CAP patients is needed.

Clinical Applications

There are several implications of knowing the relationship between cardiac complications and CAP. First, physicians can better inform their patients about risks once they have been diagnosed with pneumonia. Second, physicians may be more likely to recognize a complication early and provide appropriate intervention. Third, physicians can risk stratify patients using the prediction score for cardiac complications in CAP patients [28]. In 1931 Master et al found that some patients with CAP also had PR interval or T-wave changes present for about 3 days, so they recommended obtaining an ECG to determine when a patient might be able to be discharged or declared “cured” [39]. Now, we are similarly recommending obtaining an ECG in CAP patients, but upon admission, in order to identify those who may get ischemic changes, arrhythmias or QTc prolongations. Pro-brain natriuretic peptide and troponins may be obtained independently of ECG results, and a cardiac echocardiogram may be reserved for those with a high risk of complications [40]. Finally, we recommend screening all patients for need for influenza and pneumococcal vaccines and administering according to the Advisory Committee on Immunization Practices of the Centers for Disease and Prevention [33].

Research Implications

The fact that cardiac complications in CAP patients is a well-defined entity with a significant degree of morbidity and mortality should prompt attentiona and resources to be directed to this area. The prediction score created specifically for this subpopulation of patients [28] can improve research by allowing adequate risk stratification to efficiently design and execute studies. Studies may be designed with fewer patients required to be enrolled while maintaining statistical power by limiting subject inclusion criteria to certain risk classes. Specific areas of future investigation should include the mechanisms of pathophysiology, which are not completely understood, and other complications, such as pulmonary edema, infectious endocarditis and pericarditis. Finally, cost has not been studied in this area or the potential savings of recognizing and preventing cardiac complications.

Summary

Cardiac complications, including arrhythmias, MI, and CHF are a significant burden among patients hospitalized for CAP. Influenza and pneumococcal vaccination should be emphasized among appropriate patients. The cardiac complication prediction score may be used to screen patients once admitted. A troponin and ECG should be obtained in all patients admitted for CAP while a cardiac echocardiogram may be reserved in higher-risk patients. Future research may be directed towards the subjects of pathophysiology other complications and cost.

Acknowledgment: We appreciate the critical review by Jessica Lynn Petrey, MSLS, Clinical Librarian, Kornhauser Health Sciences Library, University of Louisville, Louisville, KY.

Corresponding author: Dr. Forest Arnold, 501 E. Broadway, Suite 140 B, Louisville, KY 40202, [email protected]

Financial disclosures: None.

From the Division of Infectious Diseases, School of Medicine, University of Louisville, Louisville, KY.

Abstract

• Objective: To summarize the published literature on cardiac complications in patients with community-acquired pneumonia (CAP) as well as provide a historical context for the topic; and to provide recommendations concerning preventing and anticipating cardiac complications in patients with CAP.
• Methods: Literature review.
• Results: CAP patients are at increased risk for arrhythmias (~5%), myocardial infarction (~5%), and congestive heart failure (~14%). Oxygenation, the level of heart conditioning, local (pulmonary) and systemic (cytokines) inflammation, and medication all contribute to the pathophysiology of cardiac complications in CAP patients. A high Pneumonia Severity Index (PSI) can be used to screen for risk of cardiac complications in CAP patients; however, a new but less studied clinical rule developed to risk stratify patient hospitalized for CAP was shown to outperform the PSI. A troponin test and ECG should be obtained in all patients admitted for CAP while a cardiac echocardiogram may be reserved for higher-risk patients.
• Conclusions: Cardiac complications, including arrhythmias, myocardial infarctions, and congestive heart failure, are a significant burden among patients hospitalized for CAP. Influenza and pneumococcal vaccination should be emphasized among appropriate patients. Preliminary data suggest that those with CAP may be helped if they are already on aspirin or a statin. Early recognition of cardiac complications and treatment may improve clinical outcomes for patients with CAP.

Community-acquired pneumonia (CAP) is a common condition in the United States and a leading cause of morbidity and mortality [1,2], with medical costs exceeding $10 billion in 2011 [3]. The mortality rate is much higher for those aged 65 years and older [4]. Men have a higher death rate than women (18.6 vs. 13.9 per 100,000 population), and death rate varies based on ethnicity, with mortality rates for American Indian/Alaska natives at 19.2, blacks at 17.1, whites at 15.9, Asian/Pacific Islanders at 15.0, and Hispanics at 13.1 (all rates per 100,000) [2]. CAP causes considerable worldwide mortality, with differences in mortality varying according to world region [5].

Cardiovascular complications and death from other comorbidities cause a substantial proportion of CAP-associated mortality. In Mortensen et al’s study, among patients with CAP who died, at least one third had a cardiac complication, and 13% had a cardiac-related cause of death [6]. One study showed that hospitalized patients with CAP complicated by heart disease were 30% more likely to die than patients hospitalized with CAP alone [7]. In this article, we discuss the burden of cardiac complications in adults with CAP, including underlying pathophysiological processes and strategies to prevent their occurence.

Pathophysiological Processes of Heart Disease Caused by CAP

The pathophysiology of cardiac complications as a result of CAP is made up of several hypotheses, including (1) declining oxygen provision by the lungs in the face of increasing demand by the heart, (2) a lack of reserve for stress because of cardiac comorbidities and (3) localized (pulmonary) inflammation leading to systemic (including cardiac) complications by the release of cytokines or other chemicals. Any of these may result in cardiac complications occurring before, during, or after a patient has been hospitalized for CAP. Antimicrobial treatment, specifically azithromycin, has also been implicated in myocardial adverse effects. Although azithromycin is most noted for causing QT prolongation, it was associated with myocardial infarction (MI) in a study of 73,690 patients with pneumonia [8]. A higher proportion of those who received azithromycin had an MI compared to those who did not (5.1% vs 4.4%; OR 1.17; 95% CI, 1.08–1.25), but there was no statistical difference in cardiac arrhythmias, and the 90-day mortality was actually better in the azithromycin group (17.4% vs 22.3%; odds ratio [OR], 0.73; 95% CI, 0.70–0.76).

Systemic inflammation is the result of several molecules, such as cytokines, chemokines and reactive oxidant species. Reactive oxidant species may determine oxidation of proteins, lipids and DNA, which leads to cell death. The hypothesis also purports that they also cause destabilization of atherosclerotic plaques leading to MIs. Other reactions as a result of inflammation lead to arrhythmias with or without compromised cardiac function, causing congestive heart failure (CHF). For this reason, some authors have approached the pathophysiology of cardiac complications by considering them to be either plaque-related or plaque-unrelated events [9].

A few studies have linked specific inflammatory molecules to cardiac toxicity. NOX2 is chemically unstable and may provoke cellular damage, thus maintaining a certain redox balance is crucial for cardiomyocyte health. In 248 patients with CAP, an elevated troponin T was present in 135 patients and among those, NOX2 correlated with the troponin T values (OR 1.13, 95% CI 1.08–1.17; P < 0.001) [10]. Both disrupting the equilibrium of the redox balance by upregulating NOX2, and finding NOX2 to be associated with troponin T suggest that oxidative stress is implicated in damage to the myocardium during CAP. In another study of 432 patients with CAP, 41 developed atrial fibrillation within 24 to 72 hours of admission and showed higher blood levels of NOX2 than those who had CAP without atrial fibrillation [11]. Oxidative stress has been shown to cause hypertrophy, dysfunction, apoptotic cell death, and fibrosis in the myocardium [12].

There is likely a high level of variability in how individual patients respond to a predisposing factor for a cardiac complication. For example, one patient may tolerate a mild hypoxia while another is sensitive. The association of inflammatory markers with the presence of cardiac markers, however, would support that once there are systemic reactions, the complications increase. Macrolides, however, were not found to contribute to long-term mortality due to cardiac complications.

Cardiac Complications of CAP

After the H₁N₁ influenza outbreak of 1918, it was noted that all-cause mortality increased during the outbreak as did influenza-related deaths. This prompted inquiry as to whether there was an actual association between the outbreak and increased overall mortality, or whether the 2 occurrences were simply coincidental [14]. Near that time, arrhythmias in CAP patients were studied. T-wave changes were found to be associated with CAP [15]. Among 92 patients studied, 449 electrocardiograms (ECGs) were reviewed. T-wave changes were the most common ECG changes. They were found in 5 of 10 of the patients who died, and in 35 of the 82 patients who lived. Twelve living patients had persistent ECG changes, and although they were all thought to have had underlying myocardial disease, 2 of them certainly did as they each had an acute MI (and the ECG was included as a figure for one of them).

A study in the 1980s that reported 3 of 38 CAP patients with CHF interrupted the paucity of data at the time that showed that having a cardiac complication during CAP was a known entity [16]. By the end of the 20th century, Meier et al noted that among case patients who had an MI, an acute respiratory tract infection preceded the MI in 2.8% while in only 0.9% of control patients [17]. They also noted that patients who had an acute respiratory tract infection were 2.7 times more likely to have an MI in the following 10 days than control patients.

Further study by Musher et al revealed that MI was associated with pneumococcal pneumonia in 12 (7%) of 170 veteran patients [18]. An MI was defined on the basis of ECG abnormalities (Q waves or ST segment elevation or depression) with troponin I levels ≥ 0.5 ng/mL. They also evaluated arrhythmias and CHF. They included atrial fibrillation or flutter and ventricular tachycardia while excluding terminal arrhythmias. An arrhythmia was found in 8 (5%) patients. CHF was based on Framingham criteria (Table 1) [19]. New or worsening CHF was determined by comparing physical findings, laboratory values, chest radiograph, and echocardiogram reports in medical records. CHF was found in 13 (19%) patients. Ramirez et al found that MI was associated with CAP in 29 (5.8%) of 500 similar veteran patients [20].

Corrales-Medina et al reported cardiac complications in CAP patients in the Pneumonia Patient Outcomes Team cohort study [21]. They defined MI as the presence of 2 of 3 criteria: ECG abnormalities, elevated cardiac enzymes, and chest pain. They found 43 (3.2%) of 1343 patients with an MI. Arrhythmias included atrial fibrillation or flutter, multifocal atrial tachycardia, supraventricular tachycardia, ventricular tachycardia (≥ 3 beat run) or ventricular fibrillation. With the more inclusive list, they found a greater proportion, 137 (10%) patients affected. They defined CHF with physical examination findings plus a radiographic abnormality, and found 279 (21%) patients affected. A meta-analysis of 17 studies had pooled incidences for an MI of 5.3%, an arrhythmia of 4.7% and CHF of 14.1% [22].

In summary, the most prominent cardiac complications in patients with CAP have been found to be CHF, MI, and arrhythmia.

Timing of Cardiac Complications in Relation to CAP

While a patient is still in the community, cardiac complications may occur with the onset of CAP, or afterwards. For these patients, the primary goal is to identify the complication and manage it as soon as the patient is admitted for CAP, rather than allowing the complications to worsen only to be recognized later. Cardiac complications are rare in outpatients overall. A study of 944 outpatients found heart failure in 1.4%, arrhythmias in 1.0% and MI in 0.1% [21].

For patients who are admitted with CAP but who do not have a cardiac complication, the goals are either to prevent any complication or to recognize and manage a complication early. This also applies to patients who have been discharged after an admission for CAP. Cardiac complications have been recorded shortly after (within 30 days), and late (up to 1 year) after discharge. A study of over 50,000 veterans who were admitted for CAP were followed for any cardiovascular complication in the next 90 days. Approximately 7500 veterans were found to have a cardiac complication, including (in order of highest to lowest frequency) CHF, arrhythmia, MI, stroke and angina [23]. More than 75% of the complications were found on the day of hospitalization, but events were still measured at 30 days and 90 days.

Two other studies sought to determine an association between CAP and cardiac complications differently; not by following CAP patients prospectively for complications but by retrospectively evaluating patients for a respiratory infection among those who were admitted for a cardiovascular complication (MI or stroke). A study of over 35,000 first-time admissions for either an MI or a stroke were evaluated for a respiratory infection within the previous 90 days [24]. The incidence rates were statistically significant for every time period up to 90 days. The preceding 3 days was the time period with the highest frequency for a respiratory infection preceding an event. When the event was an MI, the incident rate was 4.95 (95% CI, 4.43–5.53). A similar study of over 20,000 first-time admissions for either an MI or stroke were evaluated for a preceding primary care visit for a respiratory infection [25]. An infection preceded 2.9% of patients with an MI and 2.8% of patients with a stroke. Statistical significance was found for the group of patients who had a respiratory infection within 7 days preceding an MI (OR 2.10 [95% CI 1.38–3.21]) or preceding a stroke (OR 1.92 [95% CI 1.24–2.97]). In fact, every time period analyzed for both complications (MI and stroke) was significant up to 1 year. Because the timing of a cardiac complication varies and can occur up to 90 days or even a year after acute infection, physicians should maintain vigilance in suspecting and screening for them.

Predictors of Cardiac Complications During CAP

Recently, Cangemi et al reviewed mortality in 301 patients admitted for CAP 6 to 60 months after they were discharged [26]. Mortality was compared between patients who experienced a cardiac complication—atrial fibrillation or an ST- or non-ST-elevation MI—during their admission and those who did not. A total of 55 (18%) patients had a cardiac complication while hospitalized. During the follow-up, 90 (30%) of the 301 patients died. Death occurred in more patients who had had a cardiac complication while hospitalized than in those who did not (32% vs 13%; P < 0.001). The study also showed that age and the pneumonia severity index (PSI) predicted death in addition to intra-hospital complication. A Cox regression analysis showed that intrahospital cardiac complications (hazard ratio [HR] 1.76 [95% CI 1.10–2.82]; P = 0.019), age (HR 1.05 [95% CI 1.03–1.08]; P < 0.001) and the PSI (HR 1.01 [95% CI 1.00–1.02] P = 0.012) independently predicted death after adjusting for possible confounders [26].

The PSI score was published in 1997, and it instructed that patients with a risk class of I or II (low risk) should be managed as outpatients. Data eventually showed that there is a portion of the population with a risk class of I or II whose hospital admission is justified [4]. Among the reasons found was “comorbidity,” including MI and other cardiac complications. The PSI prediction rule was found to be useful in novel ways, and being associated with a risk of MI in patients with CAP was one of them. The propensity-adjusted association between the PSI score and MI was significant (P < 0.05) in an observational study of the CAP Organization (CAPO) [20]. Knowing that a PSI of 80 is in the middle of risk class III (71–90), it was noted that below 80 the risk for MI was zero to 2.5%, while above 80 the risk rose from 2.5% to 12.5%. A later study using the same statistical method showed a correlation between the PSI score and cardiac complications (MI, arrhythmias and CHF) with a P value of < 0.01 [21]. Determining the probability for the combination of complications, rather than just an MI, yielded an unsurprisingly higher range of risk for the PSI below 80, which was zero to 17.5%, while risk for a PSI above 80 was 17.5% to 80%.

In a study to determine risk factors for cardiac complications among 3068 patients with CAP, Griffin et al applied a purposeful selection algorithm to a list of factors with reasonable potential to be associated with the 376 patients who actually had a cardiac complication [27]. After multivariate logistic regression analysis, hyperlipidemia, an infection with Staphlococcus aureus or Klebsiella pneumoniae, and the PSI were found to be statistically significant. In contrast, statin therapy was associated with a lower risk of an event.

In 2014, a validated score similar to the PSI and using the same database was derived to predict short-term risk for cardiac events in hospitalized patients with CAP [28]. It attributes points for age, 3 preexisting conditions, 2 vital signs and 7 radiological and laboratory values, with a point scoring system that defines 4 risk stratification classes. In the derivation cohort, the incidence of cardiac complications across the risk classes increased linearly (3%, 18%, 35%, and 72%, respectively). The score was validated in the original publication with a separate database but has not been evaluated since. The score outperformed the PSI score in predicting cardiac complications in the validation cohort (proportion of patients correctly reclassified by the new score, 44%). Potentially, the rule could help identify high-risk patients upon admission and could assist clinicians in their decision making.

Strategies to Prevent Cardiac Complications During CAP

It is now well established that there is a heavy burden of long-lasting cardiac complications among patients with CAP; therefore, preventing CAP should be a priority. This can be accomplished by counseling patients to refrain from alcohol and smoking and by administering influenza (Table 2) and pneumococcal vaccines (Figure 2). Since the 7-valent protein-polysaccharide conjugate pneumococcal vaccine (PCV-7) was released for children in 2000, there have been fewer hospitalizations in the United States [27] and improved outcomes globally; for instance, fewer hospitalizations among children < 14 years of age in Uruguay [29], and decreased invasive pneumococcal disease among children < 5 years of age in Taiwan [30]. Furthermore, a decrease in invasive pneumococcal disease by 18% in persons aged > 65 years in the US and Canada decreased with the introduction of PCV-7 to children. Although this showed a beneficial indirect effect (herd immunity) in unvaccinated populations [31,32], there have been no randomized controlled trials in adults demonstrating a decrease in pneumococcal pneumonia or invasive pneumococcal disease which were vaccinated with PCV-13. The Food and Drug Administration approved PCV-13 for children in 2010 and for adults in 2012. Although it included fewer serotypes, it did include serotype 6A, which has a high pathogenicity and is not in 23-valent pneumococcal polysaccharide vaccine (PPSV-23). The criteria for vaccinating adults for pneumococcal infection were recently published [33]. A study of patients with invasive pneumococcal disease, which also determined pneumococcal serotypes, included 5 patients who had CAP as well [34]. Those patients had serotypes 6A, 7C, 14, and 23F (2 patients). The patient who had serotype 14 (higher pathogenicity) died and the other 4 lived. Serotypes 14 and 23F are in both vaccines while serotype 7C is in neither. Vaccination status was not provided in the study. At this time, there is evidence to support vaccinating patients for both S. pneumoniae and influenza virus.

Two methods used to prevent cardiac complications in general have been administration of aspirin and statins. The anticlotting properties of aspirin help to maintain blood flow in arteries narrowed by atherosclerosis. A meta-analysis of 10 randomized controlled trials found a statistically significant association between aspirin and a benefit on nonfatal myocardial infarctions/coronary events [35]. The associations were found with doses of 100 mg or less daily, and benefits were seen within 1 to 5 years. Statins have also been found to reduce all-cause mortality, cardiac-related mortality, and myocardial infarction [36]. A statin may stabilize coronary artery plaques that otherwise may rupture and cause myocardial ischemia or an infarct. But statins have also been found to be associated with a decreased risk of CAP. A comprehensive systematic review and meta-analysis found a decreased risk of CAP (OR 0.84; 95% CI, 0.74– 0.95) and decreased short-term mortality in patients with CAP (OR 0.68; 95% CI, 0.56–0.78) as a result of statin therapy [37]. The studies included any of 8 available statins. A prospective observational study found that patients who had been on a statin prior to being admitted for CAP had lower mortality, a lower incidence of complicated pneumonia and a lower C-reactive protein [38]. The lower C-reactive protein identifies decreased inflammation, which translates into improved endothelial function, modulated antioxidant effects, and a reduction in pro-inflammatory cytokines, hence its association with less severe CAP. Further study may reveal that a certain patient population should receive a statin to prevent CAP and improve outcomes. Overall, data support taking aspirin to prevent cardiac events regardless of CAP; further investigation of the benefits of statins to prevent cardiac complications in CAP patients is needed.

Clinical Applications

There are several implications of knowing the relationship between cardiac complications and CAP. First, physicians can better inform their patients about risks once they have been diagnosed with pneumonia. Second, physicians may be more likely to recognize a complication early and provide appropriate intervention. Third, physicians can risk stratify patients using the prediction score for cardiac complications in CAP patients [28]. In 1931 Master et al found that some patients with CAP also had PR interval or T-wave changes present for about 3 days, so they recommended obtaining an ECG to determine when a patient might be able to be discharged or declared “cured” [39]. Now, we are similarly recommending obtaining an ECG in CAP patients, but upon admission, in order to identify those who may get ischemic changes, arrhythmias or QTc prolongations. Pro-brain natriuretic peptide and troponins may be obtained independently of ECG results, and a cardiac echocardiogram may be reserved for those with a high risk of complications [40]. Finally, we recommend screening all patients for need for influenza and pneumococcal vaccines and administering according to the Advisory Committee on Immunization Practices of the Centers for Disease and Prevention [33].

Research Implications

The fact that cardiac complications in CAP patients is a well-defined entity with a significant degree of morbidity and mortality should prompt attentiona and resources to be directed to this area. The prediction score created specifically for this subpopulation of patients [28] can improve research by allowing adequate risk stratification to efficiently design and execute studies. Studies may be designed with fewer patients required to be enrolled while maintaining statistical power by limiting subject inclusion criteria to certain risk classes. Specific areas of future investigation should include the mechanisms of pathophysiology, which are not completely understood, and other complications, such as pulmonary edema, infectious endocarditis and pericarditis. Finally, cost has not been studied in this area or the potential savings of recognizing and preventing cardiac complications.

Summary

Cardiac complications, including arrhythmias, MI, and CHF are a significant burden among patients hospitalized for CAP. Influenza and pneumococcal vaccination should be emphasized among appropriate patients. The cardiac complication prediction score may be used to screen patients once admitted. A troponin and ECG should be obtained in all patients admitted for CAP while a cardiac echocardiogram may be reserved in higher-risk patients. Future research may be directed towards the subjects of pathophysiology other complications and cost.

Acknowledgment: We appreciate the critical review by Jessica Lynn Petrey, MSLS, Clinical Librarian, Kornhauser Health Sciences Library, University of Louisville, Louisville, KY.

Corresponding author: Dr. Forest Arnold, 501 E. Broadway, Suite 140 B, Louisville, KY 40202, [email protected]

Financial disclosures: None.

From the Division of Infectious Diseases, School of Medicine, University of Louisville, Louisville, KY.

Abstract

• Objective: To summarize the published literature on cardiac complications in patients with community-acquired pneumonia (CAP) as well as provide a historical context for the topic; and to provide recommendations concerning preventing and anticipating cardiac complications in patients with CAP.
• Methods: Literature review.
• Results: CAP patients are at increased risk for arrhythmias (~5%), myocardial infarction (~5%), and congestive heart failure (~14%). Oxygenation, the level of heart conditioning, local (pulmonary) and systemic (cytokines) inflammation, and medication all contribute to the pathophysiology of cardiac complications in CAP patients. A high Pneumonia Severity Index (PSI) can be used to screen for risk of cardiac complications in CAP patients; however, a new but less studied clinical rule developed to risk stratify patient hospitalized for CAP was shown to outperform the PSI. A troponin test and ECG should be obtained in all patients admitted for CAP while a cardiac echocardiogram may be reserved for higher-risk patients.
• Conclusions: Cardiac complications, including arrhythmias, myocardial infarctions, and congestive heart failure, are a significant burden among patients hospitalized for CAP. Influenza and pneumococcal vaccination should be emphasized among appropriate patients. Preliminary data suggest that those with CAP may be helped if they are already on aspirin or a statin. Early recognition of cardiac complications and treatment may improve clinical outcomes for patients with CAP.

Community-acquired pneumonia (CAP) is a common condition in the United States and a leading cause of morbidity and mortality [1,2], with medical costs exceeding $10 billion in 2011 [3]. The mortality rate is much higher for those aged 65 years and older [4]. Men have a higher death rate than women (18.6 vs. 13.9 per 100,000 population), and death rate varies based on ethnicity, with mortality rates for American Indian/Alaska natives at 19.2, blacks at 17.1, whites at 15.9, Asian/Pacific Islanders at 15.0, and Hispanics at 13.1 (all rates per 100,000) [2]. CAP causes considerable worldwide mortality, with differences in mortality varying according to world region [5].

Cardiovascular complications and death from other comorbidities cause a substantial proportion of CAP-associated mortality. In Mortensen et al’s study, among patients with CAP who died, at least one third had a cardiac complication, and 13% had a cardiac-related cause of death [6]. One study showed that hospitalized patients with CAP complicated by heart disease were 30% more likely to die than patients hospitalized with CAP alone [7]. In this article, we discuss the burden of cardiac complications in adults with CAP, including underlying pathophysiological processes and strategies to prevent their occurence.

Pathophysiological Processes of Heart Disease Caused by CAP

The pathophysiology of cardiac complications as a result of CAP is made up of several hypotheses, including (1) declining oxygen provision by the lungs in the face of increasing demand by the heart, (2) a lack of reserve for stress because of cardiac comorbidities and (3) localized (pulmonary) inflammation leading to systemic (including cardiac) complications by the release of cytokines or other chemicals. Any of these may result in cardiac complications occurring before, during, or after a patient has been hospitalized for CAP. Antimicrobial treatment, specifically azithromycin, has also been implicated in myocardial adverse effects. Although azithromycin is most noted for causing QT prolongation, it was associated with myocardial infarction (MI) in a study of 73,690 patients with pneumonia [8]. A higher proportion of those who received azithromycin had an MI compared to those who did not (5.1% vs 4.4%; OR 1.17; 95% CI, 1.08–1.25), but there was no statistical difference in cardiac arrhythmias, and the 90-day mortality was actually better in the azithromycin group (17.4% vs 22.3%; odds ratio [OR], 0.73; 95% CI, 0.70–0.76).

Systemic inflammation is the result of several molecules, such as cytokines, chemokines and reactive oxidant species. Reactive oxidant species may determine oxidation of proteins, lipids and DNA, which leads to cell death. The hypothesis also purports that they also cause destabilization of atherosclerotic plaques leading to MIs. Other reactions as a result of inflammation lead to arrhythmias with or without compromised cardiac function, causing congestive heart failure (CHF). For this reason, some authors have approached the pathophysiology of cardiac complications by considering them to be either plaque-related or plaque-unrelated events [9].

A few studies have linked specific inflammatory molecules to cardiac toxicity. NOX2 is chemically unstable and may provoke cellular damage, thus maintaining a certain redox balance is crucial for cardiomyocyte health. In 248 patients with CAP, an elevated troponin T was present in 135 patients and among those, NOX2 correlated with the troponin T values (OR 1.13, 95% CI 1.08–1.17; P < 0.001) [10]. Both disrupting the equilibrium of the redox balance by upregulating NOX2, and finding NOX2 to be associated with troponin T suggest that oxidative stress is implicated in damage to the myocardium during CAP. In another study of 432 patients with CAP, 41 developed atrial fibrillation within 24 to 72 hours of admission and showed higher blood levels of NOX2 than those who had CAP without atrial fibrillation [11]. Oxidative stress has been shown to cause hypertrophy, dysfunction, apoptotic cell death, and fibrosis in the myocardium [12].

There is likely a high level of variability in how individual patients respond to a predisposing factor for a cardiac complication. For example, one patient may tolerate a mild hypoxia while another is sensitive. The association of inflammatory markers with the presence of cardiac markers, however, would support that once there are systemic reactions, the complications increase. Macrolides, however, were not found to contribute to long-term mortality due to cardiac complications.

Cardiac Complications of CAP

After the H₁N₁ influenza outbreak of 1918, it was noted that all-cause mortality increased during the outbreak as did influenza-related deaths. This prompted inquiry as to whether there was an actual association between the outbreak and increased overall mortality, or whether the 2 occurrences were simply coincidental [14]. Near that time, arrhythmias in CAP patients were studied. T-wave changes were found to be associated with CAP [15]. Among 92 patients studied, 449 electrocardiograms (ECGs) were reviewed. T-wave changes were the most common ECG changes. They were found in 5 of 10 of the patients who died, and in 35 of the 82 patients who lived. Twelve living patients had persistent ECG changes, and although they were all thought to have had underlying myocardial disease, 2 of them certainly did as they each had an acute MI (and the ECG was included as a figure for one of them).

A study in the 1980s that reported 3 of 38 CAP patients with CHF interrupted the paucity of data at the time that showed that having a cardiac complication during CAP was a known entity [16]. By the end of the 20th century, Meier et al noted that among case patients who had an MI, an acute respiratory tract infection preceded the MI in 2.8% while in only 0.9% of control patients [17]. They also noted that patients who had an acute respiratory tract infection were 2.7 times more likely to have an MI in the following 10 days than control patients.

Further study by Musher et al revealed that MI was associated with pneumococcal pneumonia in 12 (7%) of 170 veteran patients [18]. An MI was defined on the basis of ECG abnormalities (Q waves or ST segment elevation or depression) with troponin I levels ≥ 0.5 ng/mL. They also evaluated arrhythmias and CHF. They included atrial fibrillation or flutter and ventricular tachycardia while excluding terminal arrhythmias. An arrhythmia was found in 8 (5%) patients. CHF was based on Framingham criteria (Table 1) [19]. New or worsening CHF was determined by comparing physical findings, laboratory values, chest radiograph, and echocardiogram reports in medical records. CHF was found in 13 (19%) patients. Ramirez et al found that MI was associated with CAP in 29 (5.8%) of 500 similar veteran patients [20].

Corrales-Medina et al reported cardiac complications in CAP patients in the Pneumonia Patient Outcomes Team cohort study [21]. They defined MI as the presence of 2 of 3 criteria: ECG abnormalities, elevated cardiac enzymes, and chest pain. They found 43 (3.2%) of 1343 patients with an MI. Arrhythmias included atrial fibrillation or flutter, multifocal atrial tachycardia, supraventricular tachycardia, ventricular tachycardia (≥ 3 beat run) or ventricular fibrillation. With the more inclusive list, they found a greater proportion, 137 (10%) patients affected. They defined CHF with physical examination findings plus a radiographic abnormality, and found 279 (21%) patients affected. A meta-analysis of 17 studies had pooled incidences for an MI of 5.3%, an arrhythmia of 4.7% and CHF of 14.1% [22].

In summary, the most prominent cardiac complications in patients with CAP have been found to be CHF, MI, and arrhythmia.

Timing of Cardiac Complications in Relation to CAP

While a patient is still in the community, cardiac complications may occur with the onset of CAP, or afterwards. For these patients, the primary goal is to identify the complication and manage it as soon as the patient is admitted for CAP, rather than allowing the complications to worsen only to be recognized later. Cardiac complications are rare in outpatients overall. A study of 944 outpatients found heart failure in 1.4%, arrhythmias in 1.0% and MI in 0.1% [21].

For patients who are admitted with CAP but who do not have a cardiac complication, the goals are either to prevent any complication or to recognize and manage a complication early. This also applies to patients who have been discharged after an admission for CAP. Cardiac complications have been recorded shortly after (within 30 days), and late (up to 1 year) after discharge. A study of over 50,000 veterans who were admitted for CAP were followed for any cardiovascular complication in the next 90 days. Approximately 7500 veterans were found to have a cardiac complication, including (in order of highest to lowest frequency) CHF, arrhythmia, MI, stroke and angina [23]. More than 75% of the complications were found on the day of hospitalization, but events were still measured at 30 days and 90 days.

Two other studies sought to determine an association between CAP and cardiac complications differently; not by following CAP patients prospectively for complications but by retrospectively evaluating patients for a respiratory infection among those who were admitted for a cardiovascular complication (MI or stroke). A study of over 35,000 first-time admissions for either an MI or a stroke were evaluated for a respiratory infection within the previous 90 days [24]. The incidence rates were statistically significant for every time period up to 90 days. The preceding 3 days was the time period with the highest frequency for a respiratory infection preceding an event. When the event was an MI, the incident rate was 4.95 (95% CI, 4.43–5.53). A similar study of over 20,000 first-time admissions for either an MI or stroke were evaluated for a preceding primary care visit for a respiratory infection [25]. An infection preceded 2.9% of patients with an MI and 2.8% of patients with a stroke. Statistical significance was found for the group of patients who had a respiratory infection within 7 days preceding an MI (OR 2.10 [95% CI 1.38–3.21]) or preceding a stroke (OR 1.92 [95% CI 1.24–2.97]). In fact, every time period analyzed for both complications (MI and stroke) was significant up to 1 year. Because the timing of a cardiac complication varies and can occur up to 90 days or even a year after acute infection, physicians should maintain vigilance in suspecting and screening for them.

Predictors of Cardiac Complications During CAP

Recently, Cangemi et al reviewed mortality in 301 patients admitted for CAP 6 to 60 months after they were discharged [26]. Mortality was compared between patients who experienced a cardiac complication—atrial fibrillation or an ST- or non-ST-elevation MI—during their admission and those who did not. A total of 55 (18%) patients had a cardiac complication while hospitalized. During the follow-up, 90 (30%) of the 301 patients died. Death occurred in more patients who had had a cardiac complication while hospitalized than in those who did not (32% vs 13%; P < 0.001). The study also showed that age and the pneumonia severity index (PSI) predicted death in addition to intra-hospital complication. A Cox regression analysis showed that intrahospital cardiac complications (hazard ratio [HR] 1.76 [95% CI 1.10–2.82]; P = 0.019), age (HR 1.05 [95% CI 1.03–1.08]; P < 0.001) and the PSI (HR 1.01 [95% CI 1.00–1.02] P = 0.012) independently predicted death after adjusting for possible confounders [26].

The PSI score was published in 1997, and it instructed that patients with a risk class of I or II (low risk) should be managed as outpatients. Data eventually showed that there is a portion of the population with a risk class of I or II whose hospital admission is justified [4]. Among the reasons found was “comorbidity,” including MI and other cardiac complications. The PSI prediction rule was found to be useful in novel ways, and being associated with a risk of MI in patients with CAP was one of them. The propensity-adjusted association between the PSI score and MI was significant (P < 0.05) in an observational study of the CAP Organization (CAPO) [20]. Knowing that a PSI of 80 is in the middle of risk class III (71–90), it was noted that below 80 the risk for MI was zero to 2.5%, while above 80 the risk rose from 2.5% to 12.5%. A later study using the same statistical method showed a correlation between the PSI score and cardiac complications (MI, arrhythmias and CHF) with a P value of < 0.01 [21]. Determining the probability for the combination of complications, rather than just an MI, yielded an unsurprisingly higher range of risk for the PSI below 80, which was zero to 17.5%, while risk for a PSI above 80 was 17.5% to 80%.

In a study to determine risk factors for cardiac complications among 3068 patients with CAP, Griffin et al applied a purposeful selection algorithm to a list of factors with reasonable potential to be associated with the 376 patients who actually had a cardiac complication [27]. After multivariate logistic regression analysis, hyperlipidemia, an infection with Staphlococcus aureus or Klebsiella pneumoniae, and the PSI were found to be statistically significant. In contrast, statin therapy was associated with a lower risk of an event.

In 2014, a validated score similar to the PSI and using the same database was derived to predict short-term risk for cardiac events in hospitalized patients with CAP [28]. It attributes points for age, 3 preexisting conditions, 2 vital signs and 7 radiological and laboratory values, with a point scoring system that defines 4 risk stratification classes. In the derivation cohort, the incidence of cardiac complications across the risk classes increased linearly (3%, 18%, 35%, and 72%, respectively). The score was validated in the original publication with a separate database but has not been evaluated since. The score outperformed the PSI score in predicting cardiac complications in the validation cohort (proportion of patients correctly reclassified by the new score, 44%). Potentially, the rule could help identify high-risk patients upon admission and could assist clinicians in their decision making.

Strategies to Prevent Cardiac Complications During CAP

It is now well established that there is a heavy burden of long-lasting cardiac complications among patients with CAP; therefore, preventing CAP should be a priority. This can be accomplished by counseling patients to refrain from alcohol and smoking and by administering influenza (Table 2) and pneumococcal vaccines (Figure 2). Since the 7-valent protein-polysaccharide conjugate pneumococcal vaccine (PCV-7) was released for children in 2000, there have been fewer hospitalizations in the United States [27] and improved outcomes globally; for instance, fewer hospitalizations among children < 14 years of age in Uruguay [29], and decreased invasive pneumococcal disease among children < 5 years of age in Taiwan [30]. Furthermore, a decrease in invasive pneumococcal disease by 18% in persons aged > 65 years in the US and Canada decreased with the introduction of PCV-7 to children. Although this showed a beneficial indirect effect (herd immunity) in unvaccinated populations [31,32], there have been no randomized controlled trials in adults demonstrating a decrease in pneumococcal pneumonia or invasive pneumococcal disease which were vaccinated with PCV-13. The Food and Drug Administration approved PCV-13 for children in 2010 and for adults in 2012. Although it included fewer serotypes, it did include serotype 6A, which has a high pathogenicity and is not in 23-valent pneumococcal polysaccharide vaccine (PPSV-23). The criteria for vaccinating adults for pneumococcal infection were recently published [33]. A study of patients with invasive pneumococcal disease, which also determined pneumococcal serotypes, included 5 patients who had CAP as well [34]. Those patients had serotypes 6A, 7C, 14, and 23F (2 patients). The patient who had serotype 14 (higher pathogenicity) died and the other 4 lived. Serotypes 14 and 23F are in both vaccines while serotype 7C is in neither. Vaccination status was not provided in the study. At this time, there is evidence to support vaccinating patients for both S. pneumoniae and influenza virus.

Two methods used to prevent cardiac complications in general have been administration of aspirin and statins. The anticlotting properties of aspirin help to maintain blood flow in arteries narrowed by atherosclerosis. A meta-analysis of 10 randomized controlled trials found a statistically significant association between aspirin and a benefit on nonfatal myocardial infarctions/coronary events [35]. The associations were found with doses of 100 mg or less daily, and benefits were seen within 1 to 5 years. Statins have also been found to reduce all-cause mortality, cardiac-related mortality, and myocardial infarction [36]. A statin may stabilize coronary artery plaques that otherwise may rupture and cause myocardial ischemia or an infarct. But statins have also been found to be associated with a decreased risk of CAP. A comprehensive systematic review and meta-analysis found a decreased risk of CAP (OR 0.84; 95% CI, 0.74– 0.95) and decreased short-term mortality in patients with CAP (OR 0.68; 95% CI, 0.56–0.78) as a result of statin therapy [37]. The studies included any of 8 available statins. A prospective observational study found that patients who had been on a statin prior to being admitted for CAP had lower mortality, a lower incidence of complicated pneumonia and a lower C-reactive protein [38]. The lower C-reactive protein identifies decreased inflammation, which translates into improved endothelial function, modulated antioxidant effects, and a reduction in pro-inflammatory cytokines, hence its association with less severe CAP. Further study may reveal that a certain patient population should receive a statin to prevent CAP and improve outcomes. Overall, data support taking aspirin to prevent cardiac events regardless of CAP; further investigation of the benefits of statins to prevent cardiac complications in CAP patients is needed.

Clinical Applications

There are several implications of knowing the relationship between cardiac complications and CAP. First, physicians can better inform their patients about risks once they have been diagnosed with pneumonia. Second, physicians may be more likely to recognize a complication early and provide appropriate intervention. Third, physicians can risk stratify patients using the prediction score for cardiac complications in CAP patients [28]. In 1931 Master et al found that some patients with CAP also had PR interval or T-wave changes present for about 3 days, so they recommended obtaining an ECG to determine when a patient might be able to be discharged or declared “cured” [39]. Now, we are similarly recommending obtaining an ECG in CAP patients, but upon admission, in order to identify those who may get ischemic changes, arrhythmias or QTc prolongations. Pro-brain natriuretic peptide and troponins may be obtained independently of ECG results, and a cardiac echocardiogram may be reserved for those with a high risk of complications [40]. Finally, we recommend screening all patients for need for influenza and pneumococcal vaccines and administering according to the Advisory Committee on Immunization Practices of the Centers for Disease and Prevention [33].

Research Implications

The fact that cardiac complications in CAP patients is a well-defined entity with a significant degree of morbidity and mortality should prompt attentiona and resources to be directed to this area. The prediction score created specifically for this subpopulation of patients [28] can improve research by allowing adequate risk stratification to efficiently design and execute studies. Studies may be designed with fewer patients required to be enrolled while maintaining statistical power by limiting subject inclusion criteria to certain risk classes. Specific areas of future investigation should include the mechanisms of pathophysiology, which are not completely understood, and other complications, such as pulmonary edema, infectious endocarditis and pericarditis. Finally, cost has not been studied in this area or the potential savings of recognizing and preventing cardiac complications.

Summary

Cardiac complications, including arrhythmias, MI, and CHF are a significant burden among patients hospitalized for CAP. Influenza and pneumococcal vaccination should be emphasized among appropriate patients. The cardiac complication prediction score may be used to screen patients once admitted. A troponin and ECG should be obtained in all patients admitted for CAP while a cardiac echocardiogram may be reserved in higher-risk patients. Future research may be directed towards the subjects of pathophysiology other complications and cost.

Acknowledgment: We appreciate the critical review by Jessica Lynn Petrey, MSLS, Clinical Librarian, Kornhauser Health Sciences Library, University of Louisville, Louisville, KY.

Corresponding author: Dr. Forest Arnold, 501 E. Broadway, Suite 140 B, Louisville, KY 40202, [email protected]

Financial disclosures: None.

American football has the highest injury rate of any team sport in the United States at the high school, collegiate, and professional levels.^1-3 Muscle strains and contusions constitute a large proportion of football injuries. For example, at the high school level, muscle strains comprise 12% to 24% of all injuries;² at the collegiate level, they account for approximately 20% of all practice injuries, with nearly half of all strains occurring within the thigh.^1,4 Among a single National Football League (NFL) team, Feeley and colleagues⁵ reported that muscle strains accounted for 46% of practice and 22% of preseason game injuries. The hamstrings, followed by the quadriceps, are the most commonly strained muscle groups among both professional and amateur athletes,^5,6 with hamstring and quadriceps injuries making up approximately 13% of all injuries among NFL players.⁷ Given the relatively large surface area and muscle volume of the anterior and posterior thigh, as well as the activities and maneuvers necessitated by the various football positions, it is not surprising that the thigh is frequently involved in football-related injuries.

The purpose of this review is to describe the clinical manifestations of thigh-related soft-tissue injuries seen in football players. Two of these conditions—muscle strains and contusions—are relatively common, while a third condition—the Morel-Lavallée lesion—is a rare, yet relevant injury that warrants discussion.

Quadriceps Contusion

Pathophysiology

Contusion to the quadriceps muscle is a common injury in contact sports generally resulting from a direct blow from a helmet, knee, or shoulder.⁸ Bleeding within the musculature causes swelling, pain, stiffness, and limitation of quadriceps excursion, ultimately resulting in loss of knee flexion and an inability to run or squat. The injury is typically confined to a single quadriceps muscle.⁸ The use of thigh padding, though helpful, does not completely eliminate the risk of this injury.

History and Physical Examination

Immediately after injury, the athlete may complain only of thigh pain. However, swelling, pain, and diminished range of knee motion may develop within the first 24 hours depending on the severity of injury and how quickly treatment is instituted.⁸ Jackson and Feagin⁹ developed an injury grading system for quadriceps contusions based on the limitation of knee flexion observed (Table 1).

Imaging

A quadriceps contusion is a clinical diagnosis based on a typical history and physical examination; therefore, advanced imaging usually does not need to be obtained except to gauge the severity of injury, to rule out concurrent injuries (ie, tendon rupture), and to identify the presence of a hematoma that may necessitate aspiration. Plain radiographs are typically unremarkable in the acute setting. Appearance on magnetic resonance imaging (MRI) varies by injury severity, with increased signal throughout the affected muscle belly and a diffuse, feathery appearance centered at the point of impact on short TI inversion recovery (STIR) and T2-weighted images reflecting edema and possibly hematoma (Figures 1A-1C).^8,11

Treatment

Treatment of a quadriceps contusion is nonoperative and consists of a 3-phase recovery.¹⁰ The first phase lasts approximately 2 days and consists of rest, ice, compression, and elevation (RICE) to limit hemorrhage. The knee should be rested in a flexed position to maintain quadriceps muscle fiber length in order to promote muscle compression and limit knee stiffness. For severe contusions in which there is a question of an acute thigh compartment syndrome, compression should be avoided with appropriate treatment based on typical symptoms and intra-compartmental pressure measurement.¹² Nonsteroidal anti-inflammatory drugs (NSAIDs) may be administered to diminish pain as well as the risk of myositis ossificans. While there is no data on the efficacy of NSAIDs in preventing myositis ossificans following quadriceps contusions, both COX-2 selective (ie, celecoxib) and nonselective (ie, naproxen, indomethacin) COX inhibitors have been demonstrated to significantly reduce the incidence of heterotopic ossification following hip surgery—a condition occurring from a similar pathophysiologic process as myositis ossificans.^13-17 However, this class of drugs should not be given any sooner than 48 to 72 hours after injury to decrease further bleeding risk, given its inhibitory effect on platelet function.¹⁸ Narcotic pain medications are rarely required.

The second phase focuses on restoring active and passive knee and hip flexion and begins when permitted by pain.⁸ Icing, pain control, and physical therapy modalities are also continued in order to reduce pain and swelling as knee motion is progressed. The third phase begins once full range of knee and hip motion is restored and consists of quadriceps strengthening and functional rehabilitation of the lower extremity.^8,19 Return to athletic activities and eventually competition should take place when a full, painless range of motion is restored and strength returns to baseline. Isokinetic strength testing may be utilized to more accurately assess strength and endurance. Noncontact, position-specific drills are incorporated as clinical improvement allows. A full recovery should be expected within 4 weeks of injury, with faster resolution and return to play seen in less severe contusions depending on the athlete’s position.⁸ Continued quadriceps stretching is recommended to prevent recurrence once the athlete returns to play. A protective hard shell may also be utilized both during rehabilitation as well as once the athlete returns to play in order to protect the thigh from reinjury, which may increase the risk of myositis ossificans.⁸

Complications

A prolonged recovery or persistent symptoms should alert the treating physician to the possibility of complications, including myositis ossificans.^8,20 Myositis ossificans typically results from moderate to severe contusions, which may present initially as a painful, indurated mass that later becomes quite firm. This mass may be seen on plain radiographs as early as 2 to 4 weeks following injury if the athlete complains of persistent pain or a palpable thigh mass (Figure 2).⁹

Mani-Babu and colleagues²³ reported a case of a 14-year-old male football player who sustained a quadriceps contusion after a direct blow from an opponent’s helmet to the lateral thigh. Persistent pain and limitation of motion at 2 months follow-up prompted imaging studies that demonstrated myositis ossificans. The patient was treated with intravenous pamidronate (a bisphosphonate) twice over a 3-month period and demonstrated a full recovery within 5 months.

Acute compartment syndrome of the thigh has also been reported following severe quadriceps contusions, with the majority occurring in the anterior compartment.^12,24-28 When injury from blunt trauma extends into and disrupts the muscular layer adjacent to the femur, vascular disruption can cause hematoma formation, muscle edema, and significant swelling, thereby increasing intracompartmental pressure. The relatively large volume of the anterior thigh compartment and lack of a rigid deep fascial envelope may be protective from the development of compartment syndrome compared to other sites.²⁸ It can be difficult to distinguish a severe contusion from a compartment syndrome, as both can occur from the same mechanism and have similar presenting signs and symptoms. Signs of a compartment syndrome include pain out of proportion to the injury that is aggravated by passive stretch of the quadriceps muscles, an increasingly firm muscle compartment to palpation, and neurovascular deficits.²⁹ Both acute compartment syndrome and a severe contusion may present with significant pain, inability to bear weight, tense swelling, tenderness to palpation, and pain with passive knee flexion.²⁴ While the successful conservative treatment of athletes with acute compartment syndrome of the thigh has been reported, it is important to closely monitor the patient’s condition and consider intracompartmental pressure monitoring if the patient’s clinical condition deteriorates.¹² An acute fasciotomy should be strongly considered when intracompartmental pressures are within 30 mm Hg of diastolic pressure.^24-27 Fortunately, it is highly uncommon for thigh compartment pressure to rise to this level. Percutaneous compartment decompression using liposuction equipment or a large cannula has been described to decrease intracompartmental pressure, potentially expediting recovery and minimizing morbidity.¹⁸ Interestingly, reports of fasciotomies for acute thigh compartment syndrome following closed athletic injuries have not described necrotic or non-contractile muscle typical of an acute compartment syndrome, calling into question the need for fasciotomy following closed blunt athletic trauma to the thigh.¹⁸

Quadriceps Strain

Pathophysiology

Acute quadriceps strains occur during sudden forceful eccentric contraction of the extensor mechanism. Occasionally, in the absence of a clear mechanism, these injuries mistakenly appear as a contusion resulting from a direct blow to the thigh.^30,31 The rectus femoris is the most frequently strained quadriceps muscle due, in part, to its superficial location and predominance of type II muscle fibers, which are more likely to be strained.^11,32 Although classically described as occurring along the distal portion of the rectus femoris at the musculotendinous junction, quadriceps strains most commonly occur at the mid to proximal aspect of the rectus femoris.^30,33 The quadriceps muscle complex crosses 2 joints and, as a result, is more predisposed to eccentric injury than mono-articular muscles.³⁴ We have had a subset of complete myotendinous tears of the rectus femoris that occur in the plant leg of placekickers that result in significant disability.

Risk Factors

Quadriceps and thigh injuries comprise approximately 4.5% of injuries among NFL players.⁷ Several risk factors for quadriceps strains have been described. In a study of Australian Rules football players, Orchard³⁵ demonstrated that for all muscle strains, the strongest risk factor was a recent history of the same injury, with the next strongest risk factor being a past history of the same injury. Increasing age was found to be a risk factor for hamstring strains but not quadriceps strains. Muscle fatigue may also contribute to injury susceptibility.³⁶

History and Physical Examination

Injuries typically occur during kicking, jumping, or a sudden change in direction while running.³⁰ Athletes may localize pain anywhere along the quadriceps muscle, although strains most commonly occur at the proximal to mid portion of the rectus femoris.^30,33 The grading system for quadriceps strains described by Kary³⁰ is based on level of pain, quadriceps strength, and the presence or absence of a palpable defect (Table 2).

The athlete typically walks with an antalgic gait. Visible swelling and/or ecchymosis may be present depending on when the athlete is seen, as ecchymosis may develop within the first 24 hours of injury. The examiner should palpate along the entire length of the injured muscle. High-grade strains or complete tears may present with a bulge or defect in the muscle belly, but in most cases no defect will be palpable. There may be loss of knee flexion similar to a quadriceps contusion. Strength testing should be performed in both the sitting and prone position with the hip both flexed and extended to assess resisted knee extension strength.³⁰ Loss of strength is proportional to the degree of injury.

Imaging

While most quadriceps strains are adequately diagnosed clinically without the need for imaging studies, ultrasound or MRI can be used to evaluate for partial or complete rupture.^30,33 In milder cases, MRI usually demonstrates interstitial edema and hemorrhage with a feathery appearance on STIR and T2-weighted imaging (Figures 3A-3C).¹¹

Treatment

Acute treatment of quadriceps strains focuses on minimizing bleeding using the principles of RICE treatment.³⁷ NSAIDs may be used immediately to assist with pain control.³⁰ COX-2-specific NSAIDs are preferred due to their lack of any inhibitory effect on platelet function in order to reduce the risk of further bleeding within the muscle compartment. For the first 24 to 72 hours following injury, the quadriceps should be maintained relatively immobilized to prevent further injury.³⁸ High-grade injuries might necessitate crutches for ambulatory assistance.

Depending on injury severity, the active phase of treatment usually begins within 5 days of injury and consists of stretching and knee/hip range of motion. An active warm-up should precede rehabilitation exercises to activate neural pathways within the muscle and improve muscle elasticity.³⁸ Ballistic stretching should be avoided to prevent additional injury to the muscle fibers. Strengthening should proceed when the athlete recovers a pain-free range of motion. When isometric exercises can be completed at increasing degrees of knee flexion, isotonic exercises may be implemented into the rehabilitation program.³⁰ Return to football can be considered when the athlete has recovered knee and hip range of motion, is pain-free, and has near-normal strength compared to the contralateral side. The athlete should also perform satisfactorily in simulated position-specific activities in a noncontact fashion prior to return to full competition.³⁰

Hamstring Strain

Pathophysiology

Hamstring strains are the most common noncontact injuries in football resulting from excessive muscle stretching during eccentric contraction generally occurring at the musculotendinous junction.^5,39 Because the hamstrings cross both the hip and knee, simultaneous hip flexion and knee extension results in maximal lengthening, making them most vulnerable to injury at the terminal swing phase of gait just prior to heel strike.^39-42 The long head of the biceps femoris undergoes the greatest stretch, reaching 110% of resting length during terminal swing phase and is the most commonly injured hamstring muscle.^43,44 Injury occurs when the force of eccentric contraction, and resulting muscle strain, exceeds the mechanical limits of the tissue.^42,45 It remains to be shown whether hamstring strains occur as a result of accumulated microscopic muscle damage or secondary to a single event that exceeds the mechanical limits of the muscle.⁴²

Epidemiology and Risk Factors

The majority of hamstring strains are sustained during noncontact activities, with most athletes citing sprinting as the activity at the time of injury.³ Approximately 93% of injuries occur during noncontact activities among defensive backs and wide receivers.³ Hamstring strains are the second-most common injury among NFL players, comprising approximately 9% of all injuries,^5,7 with 16% to 31% of these injuries associated with recurrence.^3,5,35,46 Using the NFL’s Injury Surveillance System, Elliott and colleagues³ reported 1716 hamstring strains over a 10-year period (1989-1998). Fifty-one percent of hamstring strains occurred during the 7-week preseason, with a greater than 4-fold increased injury rate noted during the preseason compared to the 16-week regular season. An increased incidence in the preseason is partially attributable to relative deconditioning over the offseason. Defensive backs, wide receivers, and special teams players accounted for the majority of injured players, suggesting that speed position players and those who must “backpedal” (run backwards) are at an increased risk for injury.

Several risk factors for hamstring strain have been described, including prior injury, older age, quadriceps-hamstring strength imbalances, limited hip and knee flexibility, and fatigue.^39,42,47 Inadequate rehabilitation and premature return to competition are also likely important factors predisposing to recurrent injury.^39,48

History and Physical Examination

The majority of hamstring strains occur in the acute setting when the player experiences the sudden onset of pain in the posterior thigh during strenuous exercise, most commonly while sprinting.³⁹ The injury typically occurs in the early or late stage of practice or competition due, in part, to inadequate warm-up or fatigue. The athlete may describe an audible pop and an inability to continue play, depending on injury severity.

Physical examination may demonstrate palpable induration and tenderness immediately or shortly after injury. In the setting of severe strains, there can be significant thigh swelling and ecchymosis, and in complete ruptures, a palpable defect.³⁹ The affected muscle should be palpated along its entire length, and is best performed prone with the knee flexed to 90° as well as with the knee partially extended to place it under mild tension. Injury severity can be assessed by determining the restriction of passive knee extension while the athlete is lying supine with the hip flexed to 90°. The severity of hamstring strains varies from minor damage of a few myofibers without loss of structural integrity to complete muscle rupture.

Imaging

Similar to other muscle strains, hamstring strains are a clinical diagnosis and generally do not necessitate advanced imaging studies except to assess the degree of damage (ie, partial vs complete rupture) and to rule out other injuries, especially if the athlete fails to respond to treatment. Plain radiographs in acute cases are usually unremarkable. However, more severe injuries may go on to develop myositis ossificans similar to quadriceps soft tissue injuries (Figure 5).

Figures 6A, 6B).

Treatment

Most hamstring strains respond to conservative treatment, with operative intervention rarely indicated except for proximal or distal tendon avulsions.³⁹ Like other muscle strains, initial management consists of RICE. COX-2-selective NSAIDs are preferred initially following injury. During a brief period of immobilization, the leg should be extended as much as tolerated to maximize muscle length, limit hematoma formation, and reduce the risk of contracture.³⁹ Controlled mobilization should begin as soon as tolerated by the athlete.³⁹ Isometric exercises and a stretching program should be started early in the rehabilitation period, with isotonic exercises added as motion and pain improve. Active stretching should be initiated and progressed to passive, static stretching as guided by pain.

The late phase of rehabilitation and long-term conditioning protocols should incorporate eccentric training once the athlete is pain-free, performing isotonic and isokinetic exercises. Eccentric exercises best strengthen the hamstrings at their most susceptible point, prepares the athlete for functional activities, and minimizes the risk of reinjury,^3,50,51 Elliot and colleagues³ reported an order of magnitude decrease in hamstring injuries in high-risk athletes with identifiable hamstring muscle weakness after implementing an eccentric strengthening program and progressive sprint training. Similarly, in a large cohort of elite soccer players, correction of strength deficits in players with prior hamstring injuries led to similar rates of injury compared to athletes without strength deficits or prior injury.⁵² Those athletes with persistent weakness who did not undergo rehabilitation had significantly higher rates of reinjury.

Various injections containing local anesthetics, corticosteroids, platelet-rich plasma (PRP), and other substances have been administered to football players following acute muscle strains in an effort to alleviate pain and safely return the athlete to competition. Some practitioners have been reluctant to administer injections (especially those containing corticosteroids) due to a potentially increased risk of tendinopathy or rupture.³¹ Drakos and colleagues⁵³ reported their outcomes following muscle and ligament strains treated with combined corticosteroid and local anesthetic injections on one NFL team. While quadriceps and hamstring strains were associated with the most missed games among all muscle strains, these injections resulted in no adverse events or progression of injury severity. Similarly, Levine and colleagues ⁵¹ administered intramuscular corticosteroid injections to 58 NFL players with high-grade hamstring injuries that had a palpable defect within the muscle belly. They reported no complications or strength deficits at final examination. In a case-control study, Rettig and colleagues⁴⁶ administered PRP injections under ultrasound guidance in 5 NFL players with hamstring injuries. Compared to players treated with a focused rehabilitation program only, there were no significant differences in recovery or return to play.

The decision to return to play should be based on a clinical assessment considering pain, strength, motion, and flexibility. Player position should also be considered. Return-to-play guidelines describing the appropriate progression through rehabilitation and return to sport have been described and can be used as a template for the rehabilitation of football players.⁵⁴ It should be noted that primary hamstring strains are associated with decreased athletic performance and an increased risk of more severe reinjury after return to sport.^55,56

Morel-Lavallée Lesion

Pathophysiology

Morel-Lavallée lesions (MLLs) are uncommon football injuries, but often occur in the thigh.^57,58 An MLL is a posttraumatic soft tissue injury in which deforming forces of pressure and shear cause a closed, soft tissue degloving injury; in this injury, the skin and subcutaneous tissues are separated from the underlying fascia, disrupting perforating blood vessels. The resulting space between the fascia and subcutaneous tissue fills with blood, lymphatics, and necrotic fat, resulting in a hematoma/seroma that can be a nidus for bacterial infection.⁵⁸ The most common anatomic regions are the anterior distal thigh and lateral hip. Both of these areas are commonly involved in both direct contact and shear forces following a fall to the ground.

History and Physical Examination

Athletes with MLLs typically present with the insidious onset of a fluid collection within the thigh following a fall to the ground, usually while sliding or diving on the playing surface.^57,58 The fluid collection can be associated with thigh tightness and may extend distally into the suprapatellar region or proximally over the greater trochanter. Thigh swelling, ecchymosis, and palpable fluctuance are seen in most cases. Progressive increases in pain and thigh swelling may be seen in severe injuries, but thigh compartments generally remain soft and nontender. Signs and symptoms of an MLL do not typically manifest immediately following the athletic event. Tejwani and colleagues⁵⁸ reported a case series of MLLs of the knee in 27 NFL players from a single team over a 14-year period, with an average of 3 days between injury and evaluation by the medical staff. The mechanism of injury was a shearing blow from the knee striking the playing surface in 81% of cases and direct contact to the knee from another player in 19% of cases; all cases occurred in game situations. No affected players were wearing kneepads at the time of injury.

Imaging

Plain radiography may reveal a noncalcified soft tissue mass over the involved area and is not usually helpful except to rule out an underlying fracture. The appearance of an MLL on ultrasound is nonspecific and variable, often described as anechoic, hypoechoic, or hyperechoic depending on the presence of hemolymphatic fluid sedimentation and varying amounts of internal fat debris. MRI is the imaging modality of choice and typically shows a well-defined oval or fusiform, fluid-filled mass with tapering margins blending with adjacent fascial planes.

Treatment

Similar to quadriceps contusions, treatment goals for MLLs are evacuation of the fluid collection, prevention of fluid recurrence, a full range of active knee flexion, and prompt return to play.^57,58 Initial treatment for smaller lesions consists of cryotherapy, compression wrapping of the involved area, and immediate active and passive range of motion of the hip and knee. While MLLs were traditionally treated with serial open debridements, less invasive approaches—including elastic compression, aspiration, percutaneous irrigation with debridement and suction drainage, or liposuction and drainage followed by suction therapy—have been recently described.^57,58,60,61 Less invasive approaches aim to minimize soft tissue dissection and disruption of the vascular supply while accelerating rehabilitation. The presence of a surrounding capsule on MRI makes conservative or minimally invasive approaches less likely to be successful and may necessitate an open procedure.⁶² Antibiotics should be used preoperatively due to the presence of a dead space containing necrotic debris that makes infection a potential complication. While elite contact athletes can expect to return to competition long before complete resolution of an MLL, there is a risk of further delamination and lesion expansion due to re-injury prior to compete healing.

Tejwani and colleagues⁵⁸ performed aspiration at the area of palpable fluctuance in the thigh or suprapatellar region using a 14-gauge needle in those athletes who failed to improve with conservative treatments alone. Mean time to resolution of the fluid collection was 16 days following aspiration. Fifty-two percent of the athletes were successfully treated with cryotherapy, compression, and motion exercises alone; 48% were treated with at least one aspiration, with a mean of 2.7 aspirations per knee. In 11% of cases that failed to resolve after multiple aspirations, doxycycline sclerodesis was performed immediately following an aspiration. Patients treated with sclerodesis had no return of the fluid collection and returned to play the following day.

Matava and colleagues⁵⁷ described the case of an NFL player who sustained a closed MLL of the lateral hip while diving onto an artificial turf surface attempting to catch a pass. Despite immediate thigh pain and swelling, he was able to continue play. Immediately following the game, the player was examined and had a tense thigh with ecchymosis extending into the trochanteric region. Aspiration of the fluctuant area was unsuccessful. Progressive increases in pain and thigh swelling prompted hospital admission. Percutaneous irrigation and debridement was performed as described by Tseng and Tornetta.⁶¹ A suction drain was placed within the residual dead space, and constant wall suction was applied in addition to hip compression using a spica wrap. The player returned to practice 22 days after the injury and missed a total of 3 games without any residual deficit.

Conclusion

Quadriceps and hamstring injuries occur frequently in football and are generally treated conservatively. While return to competition following hamstring strains is relatively quick, a high rate of injury recurrence highlights the importance of targeted rehabilitation and conditioning. Rarely, complications from quadriceps contusions, including acute compartment syndrome and myositis ossificans, may require operative intervention if unresponsive to conservative treatment. MLLs are rare in sports, but usually involve the thigh when they occur in football players. Team physicians must maintain a heightened degree of awareness of this injury as it may require operative intervention.

Acknowledgements: The authors would like to thank Jonathon Baker, MD and David Rubin, MD for their assistance in providing radiographic images for this paper.

Am J Orthop. 2016;45(6):E308-E318. Copyright Frontline Medical Communications Inc. 2016. All rights reserved.

American football has the highest injury rate of any team sport in the United States at the high school, collegiate, and professional levels.^1-3 Muscle strains and contusions constitute a large proportion of football injuries. For example, at the high school level, muscle strains comprise 12% to 24% of all injuries;² at the collegiate level, they account for approximately 20% of all practice injuries, with nearly half of all strains occurring within the thigh.^1,4 Among a single National Football League (NFL) team, Feeley and colleagues⁵ reported that muscle strains accounted for 46% of practice and 22% of preseason game injuries. The hamstrings, followed by the quadriceps, are the most commonly strained muscle groups among both professional and amateur athletes,^5,6 with hamstring and quadriceps injuries making up approximately 13% of all injuries among NFL players.⁷ Given the relatively large surface area and muscle volume of the anterior and posterior thigh, as well as the activities and maneuvers necessitated by the various football positions, it is not surprising that the thigh is frequently involved in football-related injuries.

The purpose of this review is to describe the clinical manifestations of thigh-related soft-tissue injuries seen in football players. Two of these conditions—muscle strains and contusions—are relatively common, while a third condition—the Morel-Lavallée lesion—is a rare, yet relevant injury that warrants discussion.

Quadriceps Contusion

Pathophysiology

Contusion to the quadriceps muscle is a common injury in contact sports generally resulting from a direct blow from a helmet, knee, or shoulder.⁸ Bleeding within the musculature causes swelling, pain, stiffness, and limitation of quadriceps excursion, ultimately resulting in loss of knee flexion and an inability to run or squat. The injury is typically confined to a single quadriceps muscle.⁸ The use of thigh padding, though helpful, does not completely eliminate the risk of this injury.

History and Physical Examination

Immediately after injury, the athlete may complain only of thigh pain. However, swelling, pain, and diminished range of knee motion may develop within the first 24 hours depending on the severity of injury and how quickly treatment is instituted.⁸ Jackson and Feagin⁹ developed an injury grading system for quadriceps contusions based on the limitation of knee flexion observed (Table 1).

Imaging

A quadriceps contusion is a clinical diagnosis based on a typical history and physical examination; therefore, advanced imaging usually does not need to be obtained except to gauge the severity of injury, to rule out concurrent injuries (ie, tendon rupture), and to identify the presence of a hematoma that may necessitate aspiration. Plain radiographs are typically unremarkable in the acute setting. Appearance on magnetic resonance imaging (MRI) varies by injury severity, with increased signal throughout the affected muscle belly and a diffuse, feathery appearance centered at the point of impact on short TI inversion recovery (STIR) and T2-weighted images reflecting edema and possibly hematoma (Figures 1A-1C).^8,11

Treatment

Treatment of a quadriceps contusion is nonoperative and consists of a 3-phase recovery.¹⁰ The first phase lasts approximately 2 days and consists of rest, ice, compression, and elevation (RICE) to limit hemorrhage. The knee should be rested in a flexed position to maintain quadriceps muscle fiber length in order to promote muscle compression and limit knee stiffness. For severe contusions in which there is a question of an acute thigh compartment syndrome, compression should be avoided with appropriate treatment based on typical symptoms and intra-compartmental pressure measurement.¹² Nonsteroidal anti-inflammatory drugs (NSAIDs) may be administered to diminish pain as well as the risk of myositis ossificans. While there is no data on the efficacy of NSAIDs in preventing myositis ossificans following quadriceps contusions, both COX-2 selective (ie, celecoxib) and nonselective (ie, naproxen, indomethacin) COX inhibitors have been demonstrated to significantly reduce the incidence of heterotopic ossification following hip surgery—a condition occurring from a similar pathophysiologic process as myositis ossificans.^13-17 However, this class of drugs should not be given any sooner than 48 to 72 hours after injury to decrease further bleeding risk, given its inhibitory effect on platelet function.¹⁸ Narcotic pain medications are rarely required.

The second phase focuses on restoring active and passive knee and hip flexion and begins when permitted by pain.⁸ Icing, pain control, and physical therapy modalities are also continued in order to reduce pain and swelling as knee motion is progressed. The third phase begins once full range of knee and hip motion is restored and consists of quadriceps strengthening and functional rehabilitation of the lower extremity.^8,19 Return to athletic activities and eventually competition should take place when a full, painless range of motion is restored and strength returns to baseline. Isokinetic strength testing may be utilized to more accurately assess strength and endurance. Noncontact, position-specific drills are incorporated as clinical improvement allows. A full recovery should be expected within 4 weeks of injury, with faster resolution and return to play seen in less severe contusions depending on the athlete’s position.⁸ Continued quadriceps stretching is recommended to prevent recurrence once the athlete returns to play. A protective hard shell may also be utilized both during rehabilitation as well as once the athlete returns to play in order to protect the thigh from reinjury, which may increase the risk of myositis ossificans.⁸

Complications

A prolonged recovery or persistent symptoms should alert the treating physician to the possibility of complications, including myositis ossificans.^8,20 Myositis ossificans typically results from moderate to severe contusions, which may present initially as a painful, indurated mass that later becomes quite firm. This mass may be seen on plain radiographs as early as 2 to 4 weeks following injury if the athlete complains of persistent pain or a palpable thigh mass (Figure 2).⁹

Mani-Babu and colleagues²³ reported a case of a 14-year-old male football player who sustained a quadriceps contusion after a direct blow from an opponent’s helmet to the lateral thigh. Persistent pain and limitation of motion at 2 months follow-up prompted imaging studies that demonstrated myositis ossificans. The patient was treated with intravenous pamidronate (a bisphosphonate) twice over a 3-month period and demonstrated a full recovery within 5 months.

Acute compartment syndrome of the thigh has also been reported following severe quadriceps contusions, with the majority occurring in the anterior compartment.^12,24-28 When injury from blunt trauma extends into and disrupts the muscular layer adjacent to the femur, vascular disruption can cause hematoma formation, muscle edema, and significant swelling, thereby increasing intracompartmental pressure. The relatively large volume of the anterior thigh compartment and lack of a rigid deep fascial envelope may be protective from the development of compartment syndrome compared to other sites.²⁸ It can be difficult to distinguish a severe contusion from a compartment syndrome, as both can occur from the same mechanism and have similar presenting signs and symptoms. Signs of a compartment syndrome include pain out of proportion to the injury that is aggravated by passive stretch of the quadriceps muscles, an increasingly firm muscle compartment to palpation, and neurovascular deficits.²⁹ Both acute compartment syndrome and a severe contusion may present with significant pain, inability to bear weight, tense swelling, tenderness to palpation, and pain with passive knee flexion.²⁴ While the successful conservative treatment of athletes with acute compartment syndrome of the thigh has been reported, it is important to closely monitor the patient’s condition and consider intracompartmental pressure monitoring if the patient’s clinical condition deteriorates.¹² An acute fasciotomy should be strongly considered when intracompartmental pressures are within 30 mm Hg of diastolic pressure.^24-27 Fortunately, it is highly uncommon for thigh compartment pressure to rise to this level. Percutaneous compartment decompression using liposuction equipment or a large cannula has been described to decrease intracompartmental pressure, potentially expediting recovery and minimizing morbidity.¹⁸ Interestingly, reports of fasciotomies for acute thigh compartment syndrome following closed athletic injuries have not described necrotic or non-contractile muscle typical of an acute compartment syndrome, calling into question the need for fasciotomy following closed blunt athletic trauma to the thigh.¹⁸

Quadriceps Strain

Pathophysiology

Acute quadriceps strains occur during sudden forceful eccentric contraction of the extensor mechanism. Occasionally, in the absence of a clear mechanism, these injuries mistakenly appear as a contusion resulting from a direct blow to the thigh.^30,31 The rectus femoris is the most frequently strained quadriceps muscle due, in part, to its superficial location and predominance of type II muscle fibers, which are more likely to be strained.^11,32 Although classically described as occurring along the distal portion of the rectus femoris at the musculotendinous junction, quadriceps strains most commonly occur at the mid to proximal aspect of the rectus femoris.^30,33 The quadriceps muscle complex crosses 2 joints and, as a result, is more predisposed to eccentric injury than mono-articular muscles.³⁴ We have had a subset of complete myotendinous tears of the rectus femoris that occur in the plant leg of placekickers that result in significant disability.

Risk Factors

Quadriceps and thigh injuries comprise approximately 4.5% of injuries among NFL players.⁷ Several risk factors for quadriceps strains have been described. In a study of Australian Rules football players, Orchard³⁵ demonstrated that for all muscle strains, the strongest risk factor was a recent history of the same injury, with the next strongest risk factor being a past history of the same injury. Increasing age was found to be a risk factor for hamstring strains but not quadriceps strains. Muscle fatigue may also contribute to injury susceptibility.³⁶

History and Physical Examination

Injuries typically occur during kicking, jumping, or a sudden change in direction while running.³⁰ Athletes may localize pain anywhere along the quadriceps muscle, although strains most commonly occur at the proximal to mid portion of the rectus femoris.^30,33 The grading system for quadriceps strains described by Kary³⁰ is based on level of pain, quadriceps strength, and the presence or absence of a palpable defect (Table 2).

The athlete typically walks with an antalgic gait. Visible swelling and/or ecchymosis may be present depending on when the athlete is seen, as ecchymosis may develop within the first 24 hours of injury. The examiner should palpate along the entire length of the injured muscle. High-grade strains or complete tears may present with a bulge or defect in the muscle belly, but in most cases no defect will be palpable. There may be loss of knee flexion similar to a quadriceps contusion. Strength testing should be performed in both the sitting and prone position with the hip both flexed and extended to assess resisted knee extension strength.³⁰ Loss of strength is proportional to the degree of injury.

Imaging

While most quadriceps strains are adequately diagnosed clinically without the need for imaging studies, ultrasound or MRI can be used to evaluate for partial or complete rupture.^30,33 In milder cases, MRI usually demonstrates interstitial edema and hemorrhage with a feathery appearance on STIR and T2-weighted imaging (Figures 3A-3C).¹¹

Treatment

Acute treatment of quadriceps strains focuses on minimizing bleeding using the principles of RICE treatment.³⁷ NSAIDs may be used immediately to assist with pain control.³⁰ COX-2-specific NSAIDs are preferred due to their lack of any inhibitory effect on platelet function in order to reduce the risk of further bleeding within the muscle compartment. For the first 24 to 72 hours following injury, the quadriceps should be maintained relatively immobilized to prevent further injury.³⁸ High-grade injuries might necessitate crutches for ambulatory assistance.

Depending on injury severity, the active phase of treatment usually begins within 5 days of injury and consists of stretching and knee/hip range of motion. An active warm-up should precede rehabilitation exercises to activate neural pathways within the muscle and improve muscle elasticity.³⁸ Ballistic stretching should be avoided to prevent additional injury to the muscle fibers. Strengthening should proceed when the athlete recovers a pain-free range of motion. When isometric exercises can be completed at increasing degrees of knee flexion, isotonic exercises may be implemented into the rehabilitation program.³⁰ Return to football can be considered when the athlete has recovered knee and hip range of motion, is pain-free, and has near-normal strength compared to the contralateral side. The athlete should also perform satisfactorily in simulated position-specific activities in a noncontact fashion prior to return to full competition.³⁰

Hamstring Strain

Pathophysiology

Hamstring strains are the most common noncontact injuries in football resulting from excessive muscle stretching during eccentric contraction generally occurring at the musculotendinous junction.^5,39 Because the hamstrings cross both the hip and knee, simultaneous hip flexion and knee extension results in maximal lengthening, making them most vulnerable to injury at the terminal swing phase of gait just prior to heel strike.^39-42 The long head of the biceps femoris undergoes the greatest stretch, reaching 110% of resting length during terminal swing phase and is the most commonly injured hamstring muscle.^43,44 Injury occurs when the force of eccentric contraction, and resulting muscle strain, exceeds the mechanical limits of the tissue.^42,45 It remains to be shown whether hamstring strains occur as a result of accumulated microscopic muscle damage or secondary to a single event that exceeds the mechanical limits of the muscle.⁴²

Epidemiology and Risk Factors

The majority of hamstring strains are sustained during noncontact activities, with most athletes citing sprinting as the activity at the time of injury.³ Approximately 93% of injuries occur during noncontact activities among defensive backs and wide receivers.³ Hamstring strains are the second-most common injury among NFL players, comprising approximately 9% of all injuries,^5,7 with 16% to 31% of these injuries associated with recurrence.^3,5,35,46 Using the NFL’s Injury Surveillance System, Elliott and colleagues³ reported 1716 hamstring strains over a 10-year period (1989-1998). Fifty-one percent of hamstring strains occurred during the 7-week preseason, with a greater than 4-fold increased injury rate noted during the preseason compared to the 16-week regular season. An increased incidence in the preseason is partially attributable to relative deconditioning over the offseason. Defensive backs, wide receivers, and special teams players accounted for the majority of injured players, suggesting that speed position players and those who must “backpedal” (run backwards) are at an increased risk for injury.

Several risk factors for hamstring strain have been described, including prior injury, older age, quadriceps-hamstring strength imbalances, limited hip and knee flexibility, and fatigue.^39,42,47 Inadequate rehabilitation and premature return to competition are also likely important factors predisposing to recurrent injury.^39,48

History and Physical Examination

The majority of hamstring strains occur in the acute setting when the player experiences the sudden onset of pain in the posterior thigh during strenuous exercise, most commonly while sprinting.³⁹ The injury typically occurs in the early or late stage of practice or competition due, in part, to inadequate warm-up or fatigue. The athlete may describe an audible pop and an inability to continue play, depending on injury severity.

Physical examination may demonstrate palpable induration and tenderness immediately or shortly after injury. In the setting of severe strains, there can be significant thigh swelling and ecchymosis, and in complete ruptures, a palpable defect.³⁹ The affected muscle should be palpated along its entire length, and is best performed prone with the knee flexed to 90° as well as with the knee partially extended to place it under mild tension. Injury severity can be assessed by determining the restriction of passive knee extension while the athlete is lying supine with the hip flexed to 90°. The severity of hamstring strains varies from minor damage of a few myofibers without loss of structural integrity to complete muscle rupture.

Imaging

Similar to other muscle strains, hamstring strains are a clinical diagnosis and generally do not necessitate advanced imaging studies except to assess the degree of damage (ie, partial vs complete rupture) and to rule out other injuries, especially if the athlete fails to respond to treatment. Plain radiographs in acute cases are usually unremarkable. However, more severe injuries may go on to develop myositis ossificans similar to quadriceps soft tissue injuries (Figure 5).

Figures 6A, 6B).

Treatment

Most hamstring strains respond to conservative treatment, with operative intervention rarely indicated except for proximal or distal tendon avulsions.³⁹ Like other muscle strains, initial management consists of RICE. COX-2-selective NSAIDs are preferred initially following injury. During a brief period of immobilization, the leg should be extended as much as tolerated to maximize muscle length, limit hematoma formation, and reduce the risk of contracture.³⁹ Controlled mobilization should begin as soon as tolerated by the athlete.³⁹ Isometric exercises and a stretching program should be started early in the rehabilitation period, with isotonic exercises added as motion and pain improve. Active stretching should be initiated and progressed to passive, static stretching as guided by pain.

The late phase of rehabilitation and long-term conditioning protocols should incorporate eccentric training once the athlete is pain-free, performing isotonic and isokinetic exercises. Eccentric exercises best strengthen the hamstrings at their most susceptible point, prepares the athlete for functional activities, and minimizes the risk of reinjury,^3,50,51 Elliot and colleagues³ reported an order of magnitude decrease in hamstring injuries in high-risk athletes with identifiable hamstring muscle weakness after implementing an eccentric strengthening program and progressive sprint training. Similarly, in a large cohort of elite soccer players, correction of strength deficits in players with prior hamstring injuries led to similar rates of injury compared to athletes without strength deficits or prior injury.⁵² Those athletes with persistent weakness who did not undergo rehabilitation had significantly higher rates of reinjury.

Various injections containing local anesthetics, corticosteroids, platelet-rich plasma (PRP), and other substances have been administered to football players following acute muscle strains in an effort to alleviate pain and safely return the athlete to competition. Some practitioners have been reluctant to administer injections (especially those containing corticosteroids) due to a potentially increased risk of tendinopathy or rupture.³¹ Drakos and colleagues⁵³ reported their outcomes following muscle and ligament strains treated with combined corticosteroid and local anesthetic injections on one NFL team. While quadriceps and hamstring strains were associated with the most missed games among all muscle strains, these injections resulted in no adverse events or progression of injury severity. Similarly, Levine and colleagues ⁵¹ administered intramuscular corticosteroid injections to 58 NFL players with high-grade hamstring injuries that had a palpable defect within the muscle belly. They reported no complications or strength deficits at final examination. In a case-control study, Rettig and colleagues⁴⁶ administered PRP injections under ultrasound guidance in 5 NFL players with hamstring injuries. Compared to players treated with a focused rehabilitation program only, there were no significant differences in recovery or return to play.

The decision to return to play should be based on a clinical assessment considering pain, strength, motion, and flexibility. Player position should also be considered. Return-to-play guidelines describing the appropriate progression through rehabilitation and return to sport have been described and can be used as a template for the rehabilitation of football players.⁵⁴ It should be noted that primary hamstring strains are associated with decreased athletic performance and an increased risk of more severe reinjury after return to sport.^55,56

Morel-Lavallée Lesion

Pathophysiology

Morel-Lavallée lesions (MLLs) are uncommon football injuries, but often occur in the thigh.^57,58 An MLL is a posttraumatic soft tissue injury in which deforming forces of pressure and shear cause a closed, soft tissue degloving injury; in this injury, the skin and subcutaneous tissues are separated from the underlying fascia, disrupting perforating blood vessels. The resulting space between the fascia and subcutaneous tissue fills with blood, lymphatics, and necrotic fat, resulting in a hematoma/seroma that can be a nidus for bacterial infection.⁵⁸ The most common anatomic regions are the anterior distal thigh and lateral hip. Both of these areas are commonly involved in both direct contact and shear forces following a fall to the ground.

History and Physical Examination

Athletes with MLLs typically present with the insidious onset of a fluid collection within the thigh following a fall to the ground, usually while sliding or diving on the playing surface.^57,58 The fluid collection can be associated with thigh tightness and may extend distally into the suprapatellar region or proximally over the greater trochanter. Thigh swelling, ecchymosis, and palpable fluctuance are seen in most cases. Progressive increases in pain and thigh swelling may be seen in severe injuries, but thigh compartments generally remain soft and nontender. Signs and symptoms of an MLL do not typically manifest immediately following the athletic event. Tejwani and colleagues⁵⁸ reported a case series of MLLs of the knee in 27 NFL players from a single team over a 14-year period, with an average of 3 days between injury and evaluation by the medical staff. The mechanism of injury was a shearing blow from the knee striking the playing surface in 81% of cases and direct contact to the knee from another player in 19% of cases; all cases occurred in game situations. No affected players were wearing kneepads at the time of injury.

Imaging

Plain radiography may reveal a noncalcified soft tissue mass over the involved area and is not usually helpful except to rule out an underlying fracture. The appearance of an MLL on ultrasound is nonspecific and variable, often described as anechoic, hypoechoic, or hyperechoic depending on the presence of hemolymphatic fluid sedimentation and varying amounts of internal fat debris. MRI is the imaging modality of choice and typically shows a well-defined oval or fusiform, fluid-filled mass with tapering margins blending with adjacent fascial planes.

Treatment

Similar to quadriceps contusions, treatment goals for MLLs are evacuation of the fluid collection, prevention of fluid recurrence, a full range of active knee flexion, and prompt return to play.^57,58 Initial treatment for smaller lesions consists of cryotherapy, compression wrapping of the involved area, and immediate active and passive range of motion of the hip and knee. While MLLs were traditionally treated with serial open debridements, less invasive approaches—including elastic compression, aspiration, percutaneous irrigation with debridement and suction drainage, or liposuction and drainage followed by suction therapy—have been recently described.^57,58,60,61 Less invasive approaches aim to minimize soft tissue dissection and disruption of the vascular supply while accelerating rehabilitation. The presence of a surrounding capsule on MRI makes conservative or minimally invasive approaches less likely to be successful and may necessitate an open procedure.⁶² Antibiotics should be used preoperatively due to the presence of a dead space containing necrotic debris that makes infection a potential complication. While elite contact athletes can expect to return to competition long before complete resolution of an MLL, there is a risk of further delamination and lesion expansion due to re-injury prior to compete healing.

Tejwani and colleagues⁵⁸ performed aspiration at the area of palpable fluctuance in the thigh or suprapatellar region using a 14-gauge needle in those athletes who failed to improve with conservative treatments alone. Mean time to resolution of the fluid collection was 16 days following aspiration. Fifty-two percent of the athletes were successfully treated with cryotherapy, compression, and motion exercises alone; 48% were treated with at least one aspiration, with a mean of 2.7 aspirations per knee. In 11% of cases that failed to resolve after multiple aspirations, doxycycline sclerodesis was performed immediately following an aspiration. Patients treated with sclerodesis had no return of the fluid collection and returned to play the following day.

Matava and colleagues⁵⁷ described the case of an NFL player who sustained a closed MLL of the lateral hip while diving onto an artificial turf surface attempting to catch a pass. Despite immediate thigh pain and swelling, he was able to continue play. Immediately following the game, the player was examined and had a tense thigh with ecchymosis extending into the trochanteric region. Aspiration of the fluctuant area was unsuccessful. Progressive increases in pain and thigh swelling prompted hospital admission. Percutaneous irrigation and debridement was performed as described by Tseng and Tornetta.⁶¹ A suction drain was placed within the residual dead space, and constant wall suction was applied in addition to hip compression using a spica wrap. The player returned to practice 22 days after the injury and missed a total of 3 games without any residual deficit.

Conclusion

Quadriceps and hamstring injuries occur frequently in football and are generally treated conservatively. While return to competition following hamstring strains is relatively quick, a high rate of injury recurrence highlights the importance of targeted rehabilitation and conditioning. Rarely, complications from quadriceps contusions, including acute compartment syndrome and myositis ossificans, may require operative intervention if unresponsive to conservative treatment. MLLs are rare in sports, but usually involve the thigh when they occur in football players. Team physicians must maintain a heightened degree of awareness of this injury as it may require operative intervention.

Acknowledgements: The authors would like to thank Jonathon Baker, MD and David Rubin, MD for their assistance in providing radiographic images for this paper.

Am J Orthop. 2016;45(6):E308-E318. Copyright Frontline Medical Communications Inc. 2016. All rights reserved.

American football has the highest injury rate of any team sport in the United States at the high school, collegiate, and professional levels.^1-3 Muscle strains and contusions constitute a large proportion of football injuries. For example, at the high school level, muscle strains comprise 12% to 24% of all injuries;² at the collegiate level, they account for approximately 20% of all practice injuries, with nearly half of all strains occurring within the thigh.^1,4 Among a single National Football League (NFL) team, Feeley and colleagues⁵ reported that muscle strains accounted for 46% of practice and 22% of preseason game injuries. The hamstrings, followed by the quadriceps, are the most commonly strained muscle groups among both professional and amateur athletes,^5,6 with hamstring and quadriceps injuries making up approximately 13% of all injuries among NFL players.⁷ Given the relatively large surface area and muscle volume of the anterior and posterior thigh, as well as the activities and maneuvers necessitated by the various football positions, it is not surprising that the thigh is frequently involved in football-related injuries.

The purpose of this review is to describe the clinical manifestations of thigh-related soft-tissue injuries seen in football players. Two of these conditions—muscle strains and contusions—are relatively common, while a third condition—the Morel-Lavallée lesion—is a rare, yet relevant injury that warrants discussion.

Quadriceps Contusion

Pathophysiology

Contusion to the quadriceps muscle is a common injury in contact sports generally resulting from a direct blow from a helmet, knee, or shoulder.⁸ Bleeding within the musculature causes swelling, pain, stiffness, and limitation of quadriceps excursion, ultimately resulting in loss of knee flexion and an inability to run or squat. The injury is typically confined to a single quadriceps muscle.⁸ The use of thigh padding, though helpful, does not completely eliminate the risk of this injury.

History and Physical Examination

Immediately after injury, the athlete may complain only of thigh pain. However, swelling, pain, and diminished range of knee motion may develop within the first 24 hours depending on the severity of injury and how quickly treatment is instituted.⁸ Jackson and Feagin⁹ developed an injury grading system for quadriceps contusions based on the limitation of knee flexion observed (Table 1).

Imaging

A quadriceps contusion is a clinical diagnosis based on a typical history and physical examination; therefore, advanced imaging usually does not need to be obtained except to gauge the severity of injury, to rule out concurrent injuries (ie, tendon rupture), and to identify the presence of a hematoma that may necessitate aspiration. Plain radiographs are typically unremarkable in the acute setting. Appearance on magnetic resonance imaging (MRI) varies by injury severity, with increased signal throughout the affected muscle belly and a diffuse, feathery appearance centered at the point of impact on short TI inversion recovery (STIR) and T2-weighted images reflecting edema and possibly hematoma (Figures 1A-1C).^8,11

Treatment

Treatment of a quadriceps contusion is nonoperative and consists of a 3-phase recovery.¹⁰ The first phase lasts approximately 2 days and consists of rest, ice, compression, and elevation (RICE) to limit hemorrhage. The knee should be rested in a flexed position to maintain quadriceps muscle fiber length in order to promote muscle compression and limit knee stiffness. For severe contusions in which there is a question of an acute thigh compartment syndrome, compression should be avoided with appropriate treatment based on typical symptoms and intra-compartmental pressure measurement.¹² Nonsteroidal anti-inflammatory drugs (NSAIDs) may be administered to diminish pain as well as the risk of myositis ossificans. While there is no data on the efficacy of NSAIDs in preventing myositis ossificans following quadriceps contusions, both COX-2 selective (ie, celecoxib) and nonselective (ie, naproxen, indomethacin) COX inhibitors have been demonstrated to significantly reduce the incidence of heterotopic ossification following hip surgery—a condition occurring from a similar pathophysiologic process as myositis ossificans.^13-17 However, this class of drugs should not be given any sooner than 48 to 72 hours after injury to decrease further bleeding risk, given its inhibitory effect on platelet function.¹⁸ Narcotic pain medications are rarely required.

The second phase focuses on restoring active and passive knee and hip flexion and begins when permitted by pain.⁸ Icing, pain control, and physical therapy modalities are also continued in order to reduce pain and swelling as knee motion is progressed. The third phase begins once full range of knee and hip motion is restored and consists of quadriceps strengthening and functional rehabilitation of the lower extremity.^8,19 Return to athletic activities and eventually competition should take place when a full, painless range of motion is restored and strength returns to baseline. Isokinetic strength testing may be utilized to more accurately assess strength and endurance. Noncontact, position-specific drills are incorporated as clinical improvement allows. A full recovery should be expected within 4 weeks of injury, with faster resolution and return to play seen in less severe contusions depending on the athlete’s position.⁸ Continued quadriceps stretching is recommended to prevent recurrence once the athlete returns to play. A protective hard shell may also be utilized both during rehabilitation as well as once the athlete returns to play in order to protect the thigh from reinjury, which may increase the risk of myositis ossificans.⁸

Complications

A prolonged recovery or persistent symptoms should alert the treating physician to the possibility of complications, including myositis ossificans.^8,20 Myositis ossificans typically results from moderate to severe contusions, which may present initially as a painful, indurated mass that later becomes quite firm. This mass may be seen on plain radiographs as early as 2 to 4 weeks following injury if the athlete complains of persistent pain or a palpable thigh mass (Figure 2).⁹

Mani-Babu and colleagues²³ reported a case of a 14-year-old male football player who sustained a quadriceps contusion after a direct blow from an opponent’s helmet to the lateral thigh. Persistent pain and limitation of motion at 2 months follow-up prompted imaging studies that demonstrated myositis ossificans. The patient was treated with intravenous pamidronate (a bisphosphonate) twice over a 3-month period and demonstrated a full recovery within 5 months.

Acute compartment syndrome of the thigh has also been reported following severe quadriceps contusions, with the majority occurring in the anterior compartment.^12,24-28 When injury from blunt trauma extends into and disrupts the muscular layer adjacent to the femur, vascular disruption can cause hematoma formation, muscle edema, and significant swelling, thereby increasing intracompartmental pressure. The relatively large volume of the anterior thigh compartment and lack of a rigid deep fascial envelope may be protective from the development of compartment syndrome compared to other sites.²⁸ It can be difficult to distinguish a severe contusion from a compartment syndrome, as both can occur from the same mechanism and have similar presenting signs and symptoms. Signs of a compartment syndrome include pain out of proportion to the injury that is aggravated by passive stretch of the quadriceps muscles, an increasingly firm muscle compartment to palpation, and neurovascular deficits.²⁹ Both acute compartment syndrome and a severe contusion may present with significant pain, inability to bear weight, tense swelling, tenderness to palpation, and pain with passive knee flexion.²⁴ While the successful conservative treatment of athletes with acute compartment syndrome of the thigh has been reported, it is important to closely monitor the patient’s condition and consider intracompartmental pressure monitoring if the patient’s clinical condition deteriorates.¹² An acute fasciotomy should be strongly considered when intracompartmental pressures are within 30 mm Hg of diastolic pressure.^24-27 Fortunately, it is highly uncommon for thigh compartment pressure to rise to this level. Percutaneous compartment decompression using liposuction equipment or a large cannula has been described to decrease intracompartmental pressure, potentially expediting recovery and minimizing morbidity.¹⁸ Interestingly, reports of fasciotomies for acute thigh compartment syndrome following closed athletic injuries have not described necrotic or non-contractile muscle typical of an acute compartment syndrome, calling into question the need for fasciotomy following closed blunt athletic trauma to the thigh.¹⁸

Quadriceps Strain

Pathophysiology

Acute quadriceps strains occur during sudden forceful eccentric contraction of the extensor mechanism. Occasionally, in the absence of a clear mechanism, these injuries mistakenly appear as a contusion resulting from a direct blow to the thigh.^30,31 The rectus femoris is the most frequently strained quadriceps muscle due, in part, to its superficial location and predominance of type II muscle fibers, which are more likely to be strained.^11,32 Although classically described as occurring along the distal portion of the rectus femoris at the musculotendinous junction, quadriceps strains most commonly occur at the mid to proximal aspect of the rectus femoris.^30,33 The quadriceps muscle complex crosses 2 joints and, as a result, is more predisposed to eccentric injury than mono-articular muscles.³⁴ We have had a subset of complete myotendinous tears of the rectus femoris that occur in the plant leg of placekickers that result in significant disability.

Risk Factors

Quadriceps and thigh injuries comprise approximately 4.5% of injuries among NFL players.⁷ Several risk factors for quadriceps strains have been described. In a study of Australian Rules football players, Orchard³⁵ demonstrated that for all muscle strains, the strongest risk factor was a recent history of the same injury, with the next strongest risk factor being a past history of the same injury. Increasing age was found to be a risk factor for hamstring strains but not quadriceps strains. Muscle fatigue may also contribute to injury susceptibility.³⁶

History and Physical Examination

Injuries typically occur during kicking, jumping, or a sudden change in direction while running.³⁰ Athletes may localize pain anywhere along the quadriceps muscle, although strains most commonly occur at the proximal to mid portion of the rectus femoris.^30,33 The grading system for quadriceps strains described by Kary³⁰ is based on level of pain, quadriceps strength, and the presence or absence of a palpable defect (Table 2).

The athlete typically walks with an antalgic gait. Visible swelling and/or ecchymosis may be present depending on when the athlete is seen, as ecchymosis may develop within the first 24 hours of injury. The examiner should palpate along the entire length of the injured muscle. High-grade strains or complete tears may present with a bulge or defect in the muscle belly, but in most cases no defect will be palpable. There may be loss of knee flexion similar to a quadriceps contusion. Strength testing should be performed in both the sitting and prone position with the hip both flexed and extended to assess resisted knee extension strength.³⁰ Loss of strength is proportional to the degree of injury.

Imaging

While most quadriceps strains are adequately diagnosed clinically without the need for imaging studies, ultrasound or MRI can be used to evaluate for partial or complete rupture.^30,33 In milder cases, MRI usually demonstrates interstitial edema and hemorrhage with a feathery appearance on STIR and T2-weighted imaging (Figures 3A-3C).¹¹

Treatment

Acute treatment of quadriceps strains focuses on minimizing bleeding using the principles of RICE treatment.³⁷ NSAIDs may be used immediately to assist with pain control.³⁰ COX-2-specific NSAIDs are preferred due to their lack of any inhibitory effect on platelet function in order to reduce the risk of further bleeding within the muscle compartment. For the first 24 to 72 hours following injury, the quadriceps should be maintained relatively immobilized to prevent further injury.³⁸ High-grade injuries might necessitate crutches for ambulatory assistance.

Depending on injury severity, the active phase of treatment usually begins within 5 days of injury and consists of stretching and knee/hip range of motion. An active warm-up should precede rehabilitation exercises to activate neural pathways within the muscle and improve muscle elasticity.³⁸ Ballistic stretching should be avoided to prevent additional injury to the muscle fibers. Strengthening should proceed when the athlete recovers a pain-free range of motion. When isometric exercises can be completed at increasing degrees of knee flexion, isotonic exercises may be implemented into the rehabilitation program.³⁰ Return to football can be considered when the athlete has recovered knee and hip range of motion, is pain-free, and has near-normal strength compared to the contralateral side. The athlete should also perform satisfactorily in simulated position-specific activities in a noncontact fashion prior to return to full competition.³⁰

Hamstring Strain

Pathophysiology

Hamstring strains are the most common noncontact injuries in football resulting from excessive muscle stretching during eccentric contraction generally occurring at the musculotendinous junction.^5,39 Because the hamstrings cross both the hip and knee, simultaneous hip flexion and knee extension results in maximal lengthening, making them most vulnerable to injury at the terminal swing phase of gait just prior to heel strike.^39-42 The long head of the biceps femoris undergoes the greatest stretch, reaching 110% of resting length during terminal swing phase and is the most commonly injured hamstring muscle.^43,44 Injury occurs when the force of eccentric contraction, and resulting muscle strain, exceeds the mechanical limits of the tissue.^42,45 It remains to be shown whether hamstring strains occur as a result of accumulated microscopic muscle damage or secondary to a single event that exceeds the mechanical limits of the muscle.⁴²

Epidemiology and Risk Factors

The majority of hamstring strains are sustained during noncontact activities, with most athletes citing sprinting as the activity at the time of injury.³ Approximately 93% of injuries occur during noncontact activities among defensive backs and wide receivers.³ Hamstring strains are the second-most common injury among NFL players, comprising approximately 9% of all injuries,^5,7 with 16% to 31% of these injuries associated with recurrence.^3,5,35,46 Using the NFL’s Injury Surveillance System, Elliott and colleagues³ reported 1716 hamstring strains over a 10-year period (1989-1998). Fifty-one percent of hamstring strains occurred during the 7-week preseason, with a greater than 4-fold increased injury rate noted during the preseason compared to the 16-week regular season. An increased incidence in the preseason is partially attributable to relative deconditioning over the offseason. Defensive backs, wide receivers, and special teams players accounted for the majority of injured players, suggesting that speed position players and those who must “backpedal” (run backwards) are at an increased risk for injury.

Several risk factors for hamstring strain have been described, including prior injury, older age, quadriceps-hamstring strength imbalances, limited hip and knee flexibility, and fatigue.^39,42,47 Inadequate rehabilitation and premature return to competition are also likely important factors predisposing to recurrent injury.^39,48

History and Physical Examination

The majority of hamstring strains occur in the acute setting when the player experiences the sudden onset of pain in the posterior thigh during strenuous exercise, most commonly while sprinting.³⁹ The injury typically occurs in the early or late stage of practice or competition due, in part, to inadequate warm-up or fatigue. The athlete may describe an audible pop and an inability to continue play, depending on injury severity.

Physical examination may demonstrate palpable induration and tenderness immediately or shortly after injury. In the setting of severe strains, there can be significant thigh swelling and ecchymosis, and in complete ruptures, a palpable defect.³⁹ The affected muscle should be palpated along its entire length, and is best performed prone with the knee flexed to 90° as well as with the knee partially extended to place it under mild tension. Injury severity can be assessed by determining the restriction of passive knee extension while the athlete is lying supine with the hip flexed to 90°. The severity of hamstring strains varies from minor damage of a few myofibers without loss of structural integrity to complete muscle rupture.

Imaging

Similar to other muscle strains, hamstring strains are a clinical diagnosis and generally do not necessitate advanced imaging studies except to assess the degree of damage (ie, partial vs complete rupture) and to rule out other injuries, especially if the athlete fails to respond to treatment. Plain radiographs in acute cases are usually unremarkable. However, more severe injuries may go on to develop myositis ossificans similar to quadriceps soft tissue injuries (Figure 5).

Figures 6A, 6B).

Treatment

Most hamstring strains respond to conservative treatment, with operative intervention rarely indicated except for proximal or distal tendon avulsions.³⁹ Like other muscle strains, initial management consists of RICE. COX-2-selective NSAIDs are preferred initially following injury. During a brief period of immobilization, the leg should be extended as much as tolerated to maximize muscle length, limit hematoma formation, and reduce the risk of contracture.³⁹ Controlled mobilization should begin as soon as tolerated by the athlete.³⁹ Isometric exercises and a stretching program should be started early in the rehabilitation period, with isotonic exercises added as motion and pain improve. Active stretching should be initiated and progressed to passive, static stretching as guided by pain.

The late phase of rehabilitation and long-term conditioning protocols should incorporate eccentric training once the athlete is pain-free, performing isotonic and isokinetic exercises. Eccentric exercises best strengthen the hamstrings at their most susceptible point, prepares the athlete for functional activities, and minimizes the risk of reinjury,^3,50,51 Elliot and colleagues³ reported an order of magnitude decrease in hamstring injuries in high-risk athletes with identifiable hamstring muscle weakness after implementing an eccentric strengthening program and progressive sprint training. Similarly, in a large cohort of elite soccer players, correction of strength deficits in players with prior hamstring injuries led to similar rates of injury compared to athletes without strength deficits or prior injury.⁵² Those athletes with persistent weakness who did not undergo rehabilitation had significantly higher rates of reinjury.

Various injections containing local anesthetics, corticosteroids, platelet-rich plasma (PRP), and other substances have been administered to football players following acute muscle strains in an effort to alleviate pain and safely return the athlete to competition. Some practitioners have been reluctant to administer injections (especially those containing corticosteroids) due to a potentially increased risk of tendinopathy or rupture.³¹ Drakos and colleagues⁵³ reported their outcomes following muscle and ligament strains treated with combined corticosteroid and local anesthetic injections on one NFL team. While quadriceps and hamstring strains were associated with the most missed games among all muscle strains, these injections resulted in no adverse events or progression of injury severity. Similarly, Levine and colleagues ⁵¹ administered intramuscular corticosteroid injections to 58 NFL players with high-grade hamstring injuries that had a palpable defect within the muscle belly. They reported no complications or strength deficits at final examination. In a case-control study, Rettig and colleagues⁴⁶ administered PRP injections under ultrasound guidance in 5 NFL players with hamstring injuries. Compared to players treated with a focused rehabilitation program only, there were no significant differences in recovery or return to play.

The decision to return to play should be based on a clinical assessment considering pain, strength, motion, and flexibility. Player position should also be considered. Return-to-play guidelines describing the appropriate progression through rehabilitation and return to sport have been described and can be used as a template for the rehabilitation of football players.⁵⁴ It should be noted that primary hamstring strains are associated with decreased athletic performance and an increased risk of more severe reinjury after return to sport.^55,56

Morel-Lavallée Lesion

Pathophysiology

Morel-Lavallée lesions (MLLs) are uncommon football injuries, but often occur in the thigh.^57,58 An MLL is a posttraumatic soft tissue injury in which deforming forces of pressure and shear cause a closed, soft tissue degloving injury; in this injury, the skin and subcutaneous tissues are separated from the underlying fascia, disrupting perforating blood vessels. The resulting space between the fascia and subcutaneous tissue fills with blood, lymphatics, and necrotic fat, resulting in a hematoma/seroma that can be a nidus for bacterial infection.⁵⁸ The most common anatomic regions are the anterior distal thigh and lateral hip. Both of these areas are commonly involved in both direct contact and shear forces following a fall to the ground.

History and Physical Examination

Athletes with MLLs typically present with the insidious onset of a fluid collection within the thigh following a fall to the ground, usually while sliding or diving on the playing surface.^57,58 The fluid collection can be associated with thigh tightness and may extend distally into the suprapatellar region or proximally over the greater trochanter. Thigh swelling, ecchymosis, and palpable fluctuance are seen in most cases. Progressive increases in pain and thigh swelling may be seen in severe injuries, but thigh compartments generally remain soft and nontender. Signs and symptoms of an MLL do not typically manifest immediately following the athletic event. Tejwani and colleagues⁵⁸ reported a case series of MLLs of the knee in 27 NFL players from a single team over a 14-year period, with an average of 3 days between injury and evaluation by the medical staff. The mechanism of injury was a shearing blow from the knee striking the playing surface in 81% of cases and direct contact to the knee from another player in 19% of cases; all cases occurred in game situations. No affected players were wearing kneepads at the time of injury.

Imaging

Plain radiography may reveal a noncalcified soft tissue mass over the involved area and is not usually helpful except to rule out an underlying fracture. The appearance of an MLL on ultrasound is nonspecific and variable, often described as anechoic, hypoechoic, or hyperechoic depending on the presence of hemolymphatic fluid sedimentation and varying amounts of internal fat debris. MRI is the imaging modality of choice and typically shows a well-defined oval or fusiform, fluid-filled mass with tapering margins blending with adjacent fascial planes.

Treatment

Similar to quadriceps contusions, treatment goals for MLLs are evacuation of the fluid collection, prevention of fluid recurrence, a full range of active knee flexion, and prompt return to play.^57,58 Initial treatment for smaller lesions consists of cryotherapy, compression wrapping of the involved area, and immediate active and passive range of motion of the hip and knee. While MLLs were traditionally treated with serial open debridements, less invasive approaches—including elastic compression, aspiration, percutaneous irrigation with debridement and suction drainage, or liposuction and drainage followed by suction therapy—have been recently described.^57,58,60,61 Less invasive approaches aim to minimize soft tissue dissection and disruption of the vascular supply while accelerating rehabilitation. The presence of a surrounding capsule on MRI makes conservative or minimally invasive approaches less likely to be successful and may necessitate an open procedure.⁶² Antibiotics should be used preoperatively due to the presence of a dead space containing necrotic debris that makes infection a potential complication. While elite contact athletes can expect to return to competition long before complete resolution of an MLL, there is a risk of further delamination and lesion expansion due to re-injury prior to compete healing.

Tejwani and colleagues⁵⁸ performed aspiration at the area of palpable fluctuance in the thigh or suprapatellar region using a 14-gauge needle in those athletes who failed to improve with conservative treatments alone. Mean time to resolution of the fluid collection was 16 days following aspiration. Fifty-two percent of the athletes were successfully treated with cryotherapy, compression, and motion exercises alone; 48% were treated with at least one aspiration, with a mean of 2.7 aspirations per knee. In 11% of cases that failed to resolve after multiple aspirations, doxycycline sclerodesis was performed immediately following an aspiration. Patients treated with sclerodesis had no return of the fluid collection and returned to play the following day.

Matava and colleagues⁵⁷ described the case of an NFL player who sustained a closed MLL of the lateral hip while diving onto an artificial turf surface attempting to catch a pass. Despite immediate thigh pain and swelling, he was able to continue play. Immediately following the game, the player was examined and had a tense thigh with ecchymosis extending into the trochanteric region. Aspiration of the fluctuant area was unsuccessful. Progressive increases in pain and thigh swelling prompted hospital admission. Percutaneous irrigation and debridement was performed as described by Tseng and Tornetta.⁶¹ A suction drain was placed within the residual dead space, and constant wall suction was applied in addition to hip compression using a spica wrap. The player returned to practice 22 days after the injury and missed a total of 3 games without any residual deficit.

Conclusion

Quadriceps and hamstring injuries occur frequently in football and are generally treated conservatively. While return to competition following hamstring strains is relatively quick, a high rate of injury recurrence highlights the importance of targeted rehabilitation and conditioning. Rarely, complications from quadriceps contusions, including acute compartment syndrome and myositis ossificans, may require operative intervention if unresponsive to conservative treatment. MLLs are rare in sports, but usually involve the thigh when they occur in football players. Team physicians must maintain a heightened degree of awareness of this injury as it may require operative intervention.

Acknowledgements: The authors would like to thank Jonathon Baker, MD and David Rubin, MD for their assistance in providing radiographic images for this paper.

Am J Orthop. 2016;45(6):E308-E318. Copyright Frontline Medical Communications Inc. 2016. All rights reserved.

In “What’s Hot and What’s Not in Our National Organizations, An Emergency Medicine Panel, Parts 1 and 2” (Emergency Medicine, April 2016 and May 2016, respectively), we published highlights from a panel discussion that took place at the annual retreat of the Association of Academic Chairs in Emergency Medicine in Tempe, Arizona in February 2016. That discussion included seven EM organizations: the American Academy of Emergency Medicine (AAEM), AAEM Resident and Student Association (AAEM/RSA), American Board of Emergency Medicine (ABEM), American College of Emergency Physicians (ACEP), Council of Residency Directors in Emergency Medicine (CORD), Emergency Medicine Residents’ Association (EMRA), and Society for Academic Emergency Medicine (SAEM). In this issue, we follow up with reports from the American College of Osteopathic Emergency Physicians (ACOEP) and the American Osteopathic Board of Emergency Medicine (AOBEM).

American College of Osteopathic Emergency Physicians

John C. Prestosh, DO, FACOEP-DPresident, ACOEP

Strategic Planning. The Board of Directors of ACOEP has recently adopted a revised mission statement and goals for the organization. The ACOEP “promotes patient-centric, holistic emergency care consistent with the osteopathic philosophy practiced by all emergency medicine professionals.” This statement is based on the belief that many non-osteopathic professionals practice aspects of holistic medicine, and will allow ACOEP to be a “home” for these practitioners. ACOEP’s goals are member engagement and value, advocacy and involvement, education and knowledge, improving awareness, and college strength and sustainability.

Workplace Issues. The ACOEP is aware of the issues emergency physicians (EPs) and professionals face every day. Therefore, we are including items for EPs on these issues in our educational programs. Upcoming events will include workshops on dealing with an active shooter scenario, ultrasound, and advanced airway management, which will be included in our Scientific Assembly in November.

The ACOEP is also a member of the White House Task Force addressing the opioid epidemic. Realizing there are times when opiates are necessary adjuncts to patient care, we also want to help educate physicians on the usage of alternative pain-relieving treatment plans when indicated.

Single Accreditation System and College Sustainability. Graduate medical education is undergoing an unprecedented change. The Single Accreditation System is currently being implemented with a target date of July 1, 2020 for all residency programs to fall under the jurisdiction of the Accreditation Council for Graduate Medical Education (ACGME) for accreditation. There is much anticipation regarding the changes that will occur.

We anticipate some American Osteopathic Association-accredited EM programs will become 3-year programs, thus precluding graduating residents from AOBEM certification. However, we expect a number of ACGME-accredited EM programs to establish “osteopathic-focused” tracks in which both DOs and MDs will learn osteopathic tenets and procedures to broaden their practice of EM. We anticipate this will allow residents to be certified by the AOBEM.

We believe the ACOEP can be a “home” for MD residents graduating from “osteopathic-focused” ACGME programs. Furthermore, the ACOEP is ready to amend its bylaws to offer active membership with full voting rights to MDs. We do not want to remain a closed organization, but are striving to have both DO and MD EPs belong to our College.

American Osteopathic Board of Emergency Medicine

Donald Phillips, DO, FACOEP-D, Executive Physician Director, AOBEM

Primary Certification News. The date for the 2017 Part I Examination (written examination) has been published. All candidates are advised that the examination has been moved from March to September beginning in 2017. Applications for Part I will be available on January 2, 2017. The deadline to submit the application is April 1, 2017. The examination will be administered at Prometric Testing Centers nationwide on September 12, 2017. Part II Examinations (oral examinations) are in March and November. Please refer to the AOBEM Web page at www.aobem.org for dates.

Subspecialty Certifications. AOBEM offers subspecialty certification opportunities to its diplomates in the following areas:

• Emergency medical services
• Hospice and palliative medicine
• Medical toxicology
• Sports medicine
• Undersea and hyperbaric medicine
• Internal medicine critical care
• Surgical critical care.

AOBEM and the American Osteopathic Board of Pediatrics are also engaged in the development of a pediatric EM subspecialty examination.

Osteopathic Continuous Certification (OCC). AOBEM continues to refine and evolve the OCC process. The Board has received approval to begin allowing group data for the Practice Performance Assessment portion of OCC. Diplomates may submit group data provided at least 30% of the charts reviewed are patients that the diplomate cared for personally. Diplomates may also submit unique projects that are not on the list of “preapproved” projects. It is recognized that many of our diplomates are involved in very advanced care systems. Many times, these systems have useful projects that will meet criteria for this component. If you wish to submit data for a unique project, they will be welcomed, but the Board asks that you contact us to have them approved before beginning the project.

Continuous Osteopathic Learning Assessments (COLAs) are a vital component. They demonstrate the diplomate is maintaining currency across the entire specialty of EM. We invite diplomates and candidates to submit journal articles they feel are significant to a topic for potential inclusion in the official list of COLA articles.

Candidates and diplomates are advised to keep apprised of important dates and announcements via the AOBEM Web page at www.aobem.org.

In “What’s Hot and What’s Not in Our National Organizations, An Emergency Medicine Panel, Parts 1 and 2” (Emergency Medicine, April 2016 and May 2016, respectively), we published highlights from a panel discussion that took place at the annual retreat of the Association of Academic Chairs in Emergency Medicine in Tempe, Arizona in February 2016. That discussion included seven EM organizations: the American Academy of Emergency Medicine (AAEM), AAEM Resident and Student Association (AAEM/RSA), American Board of Emergency Medicine (ABEM), American College of Emergency Physicians (ACEP), Council of Residency Directors in Emergency Medicine (CORD), Emergency Medicine Residents’ Association (EMRA), and Society for Academic Emergency Medicine (SAEM). In this issue, we follow up with reports from the American College of Osteopathic Emergency Physicians (ACOEP) and the American Osteopathic Board of Emergency Medicine (AOBEM).

American College of Osteopathic Emergency Physicians

John C. Prestosh, DO, FACOEP-DPresident, ACOEP

Strategic Planning. The Board of Directors of ACOEP has recently adopted a revised mission statement and goals for the organization. The ACOEP “promotes patient-centric, holistic emergency care consistent with the osteopathic philosophy practiced by all emergency medicine professionals.” This statement is based on the belief that many non-osteopathic professionals practice aspects of holistic medicine, and will allow ACOEP to be a “home” for these practitioners. ACOEP’s goals are member engagement and value, advocacy and involvement, education and knowledge, improving awareness, and college strength and sustainability.

Workplace Issues. The ACOEP is aware of the issues emergency physicians (EPs) and professionals face every day. Therefore, we are including items for EPs on these issues in our educational programs. Upcoming events will include workshops on dealing with an active shooter scenario, ultrasound, and advanced airway management, which will be included in our Scientific Assembly in November.

The ACOEP is also a member of the White House Task Force addressing the opioid epidemic. Realizing there are times when opiates are necessary adjuncts to patient care, we also want to help educate physicians on the usage of alternative pain-relieving treatment plans when indicated.

Single Accreditation System and College Sustainability. Graduate medical education is undergoing an unprecedented change. The Single Accreditation System is currently being implemented with a target date of July 1, 2020 for all residency programs to fall under the jurisdiction of the Accreditation Council for Graduate Medical Education (ACGME) for accreditation. There is much anticipation regarding the changes that will occur.

We anticipate some American Osteopathic Association-accredited EM programs will become 3-year programs, thus precluding graduating residents from AOBEM certification. However, we expect a number of ACGME-accredited EM programs to establish “osteopathic-focused” tracks in which both DOs and MDs will learn osteopathic tenets and procedures to broaden their practice of EM. We anticipate this will allow residents to be certified by the AOBEM.

We believe the ACOEP can be a “home” for MD residents graduating from “osteopathic-focused” ACGME programs. Furthermore, the ACOEP is ready to amend its bylaws to offer active membership with full voting rights to MDs. We do not want to remain a closed organization, but are striving to have both DO and MD EPs belong to our College.

American Osteopathic Board of Emergency Medicine

Donald Phillips, DO, FACOEP-D, Executive Physician Director, AOBEM

Primary Certification News. The date for the 2017 Part I Examination (written examination) has been published. All candidates are advised that the examination has been moved from March to September beginning in 2017. Applications for Part I will be available on January 2, 2017. The deadline to submit the application is April 1, 2017. The examination will be administered at Prometric Testing Centers nationwide on September 12, 2017. Part II Examinations (oral examinations) are in March and November. Please refer to the AOBEM Web page at www.aobem.org for dates.

Subspecialty Certifications. AOBEM offers subspecialty certification opportunities to its diplomates in the following areas:

• Emergency medical services
• Hospice and palliative medicine
• Medical toxicology
• Sports medicine
• Undersea and hyperbaric medicine
• Internal medicine critical care
• Surgical critical care.

AOBEM and the American Osteopathic Board of Pediatrics are also engaged in the development of a pediatric EM subspecialty examination.

Osteopathic Continuous Certification (OCC). AOBEM continues to refine and evolve the OCC process. The Board has received approval to begin allowing group data for the Practice Performance Assessment portion of OCC. Diplomates may submit group data provided at least 30% of the charts reviewed are patients that the diplomate cared for personally. Diplomates may also submit unique projects that are not on the list of “preapproved” projects. It is recognized that many of our diplomates are involved in very advanced care systems. Many times, these systems have useful projects that will meet criteria for this component. If you wish to submit data for a unique project, they will be welcomed, but the Board asks that you contact us to have them approved before beginning the project.

Continuous Osteopathic Learning Assessments (COLAs) are a vital component. They demonstrate the diplomate is maintaining currency across the entire specialty of EM. We invite diplomates and candidates to submit journal articles they feel are significant to a topic for potential inclusion in the official list of COLA articles.

Candidates and diplomates are advised to keep apprised of important dates and announcements via the AOBEM Web page at www.aobem.org.

In “What’s Hot and What’s Not in Our National Organizations, An Emergency Medicine Panel, Parts 1 and 2” (Emergency Medicine, April 2016 and May 2016, respectively), we published highlights from a panel discussion that took place at the annual retreat of the Association of Academic Chairs in Emergency Medicine in Tempe, Arizona in February 2016. That discussion included seven EM organizations: the American Academy of Emergency Medicine (AAEM), AAEM Resident and Student Association (AAEM/RSA), American Board of Emergency Medicine (ABEM), American College of Emergency Physicians (ACEP), Council of Residency Directors in Emergency Medicine (CORD), Emergency Medicine Residents’ Association (EMRA), and Society for Academic Emergency Medicine (SAEM). In this issue, we follow up with reports from the American College of Osteopathic Emergency Physicians (ACOEP) and the American Osteopathic Board of Emergency Medicine (AOBEM).

American College of Osteopathic Emergency Physicians

John C. Prestosh, DO, FACOEP-DPresident, ACOEP

Strategic Planning. The Board of Directors of ACOEP has recently adopted a revised mission statement and goals for the organization. The ACOEP “promotes patient-centric, holistic emergency care consistent with the osteopathic philosophy practiced by all emergency medicine professionals.” This statement is based on the belief that many non-osteopathic professionals practice aspects of holistic medicine, and will allow ACOEP to be a “home” for these practitioners. ACOEP’s goals are member engagement and value, advocacy and involvement, education and knowledge, improving awareness, and college strength and sustainability.

Workplace Issues. The ACOEP is aware of the issues emergency physicians (EPs) and professionals face every day. Therefore, we are including items for EPs on these issues in our educational programs. Upcoming events will include workshops on dealing with an active shooter scenario, ultrasound, and advanced airway management, which will be included in our Scientific Assembly in November.

The ACOEP is also a member of the White House Task Force addressing the opioid epidemic. Realizing there are times when opiates are necessary adjuncts to patient care, we also want to help educate physicians on the usage of alternative pain-relieving treatment plans when indicated.

Single Accreditation System and College Sustainability. Graduate medical education is undergoing an unprecedented change. The Single Accreditation System is currently being implemented with a target date of July 1, 2020 for all residency programs to fall under the jurisdiction of the Accreditation Council for Graduate Medical Education (ACGME) for accreditation. There is much anticipation regarding the changes that will occur.

We anticipate some American Osteopathic Association-accredited EM programs will become 3-year programs, thus precluding graduating residents from AOBEM certification. However, we expect a number of ACGME-accredited EM programs to establish “osteopathic-focused” tracks in which both DOs and MDs will learn osteopathic tenets and procedures to broaden their practice of EM. We anticipate this will allow residents to be certified by the AOBEM.

We believe the ACOEP can be a “home” for MD residents graduating from “osteopathic-focused” ACGME programs. Furthermore, the ACOEP is ready to amend its bylaws to offer active membership with full voting rights to MDs. We do not want to remain a closed organization, but are striving to have both DO and MD EPs belong to our College.

American Osteopathic Board of Emergency Medicine

Donald Phillips, DO, FACOEP-D, Executive Physician Director, AOBEM

Primary Certification News. The date for the 2017 Part I Examination (written examination) has been published. All candidates are advised that the examination has been moved from March to September beginning in 2017. Applications for Part I will be available on January 2, 2017. The deadline to submit the application is April 1, 2017. The examination will be administered at Prometric Testing Centers nationwide on September 12, 2017. Part II Examinations (oral examinations) are in March and November. Please refer to the AOBEM Web page at www.aobem.org for dates.

Subspecialty Certifications. AOBEM offers subspecialty certification opportunities to its diplomates in the following areas:

• Emergency medical services
• Hospice and palliative medicine
• Medical toxicology
• Sports medicine
• Undersea and hyperbaric medicine
• Internal medicine critical care
• Surgical critical care.

AOBEM and the American Osteopathic Board of Pediatrics are also engaged in the development of a pediatric EM subspecialty examination.

Osteopathic Continuous Certification (OCC). AOBEM continues to refine and evolve the OCC process. The Board has received approval to begin allowing group data for the Practice Performance Assessment portion of OCC. Diplomates may submit group data provided at least 30% of the charts reviewed are patients that the diplomate cared for personally. Diplomates may also submit unique projects that are not on the list of “preapproved” projects. It is recognized that many of our diplomates are involved in very advanced care systems. Many times, these systems have useful projects that will meet criteria for this component. If you wish to submit data for a unique project, they will be welcomed, but the Board asks that you contact us to have them approved before beginning the project.

Continuous Osteopathic Learning Assessments (COLAs) are a vital component. They demonstrate the diplomate is maintaining currency across the entire specialty of EM. We invite diplomates and candidates to submit journal articles they feel are significant to a topic for potential inclusion in the official list of COLA articles.

Candidates and diplomates are advised to keep apprised of important dates and announcements via the AOBEM Web page at www.aobem.org.

Patient safety has received increased attention since the late 1990s. In 1999, The Institute of Medicine published “To Err is Human: Building a Safer Health System,”¹ followed by “Crossing the Quality Chasm: A New Health System for the 21st Century”² in 2001 to document patient-safety issues and recommend improvements in medical care to reduce errors. These reports and other patient-safety studies, however, likely underestimate the extent of medical errors and preventable harm. After these reports appeared, many specialties began to seriously evaluate their own safety issues.

Among the specialties, emergency medicine (EM) identified several problem areas and attempted to determine the epidemiology of errors. One study of 62 urban EDs found that at least 7% of patients who presented for myocardial infarctions (MIs), asthma exacerbations, or joint dislocations requiring reduction with procedural sedation experienced an actual or near-miss adverse event.³ Another study showed that up to 12% of all return visits to the ED within 7 days were related to adverse events.⁴

The ED setting itself undoubtedly contributes significantly to the risk of harm. This article illustrates and discusses ED patient-safety issues, and offers some recommendations for improvement in care and prevention of harm.
 

The ED Setting

The ED is unlike any other area of the hospital or health-care setting. Patients seek care for both primary care and urgent care complaints at any time of the day or night, on any day of the week, when no other source of care is available. Emergency physicians (EPs) are required to care for multiple patients of different ages while prioritizing care of the critically ill who have MI, stroke, sepsis, respiratory distress, or multisystem trauma. For many ED patients, diagnosis and treatment can be complex.

The ED setting is fast-paced and requires quick thinking, a broad depth of knowledge about many medical conditions, and a broad range of skills to perform emergent and life-saving procedures. Often, patients are presenting to a hospital ED for the first time, with incomplete medical records. They may not know their medical conditions or medications, or be in a position to communicate this information. Any of these situations alone can lead to an adverse event; in combination, they can significantly increase the risk for harm. In addition, ED overcrowding due to limited availability of inpatient hospital beds may consume resources and staffing needed to care for active ED patients and new patients coming through the door.

Safety factors in the ED can be categorized as those related to patients, providers, or the environment/systems (Table 1).^5-7 When a large academic urban ED studied its errors, two-thirds were attributed to systems issues.⁵

Culture of Safety

Developing and maintaining a “culture of safety” is a commitment to minimize adverse events when performing high-risk jobs that can result in harm.⁸ This concept originated in other industries such as the airline and nuclear energy industries. Organizations and companies are considered high-reliability organizations (HROs) when they are dedicated to preventing harm at all staff levels—from the frontline to the corporate level. These HROs promote the reporting of errors and “near misses” without fear of blame or loss of employment.⁸ In the ED, a culture of safety encourages teamwork, event reporting, communication openness, transparency with feedback and learning from errors, and administrator collaboration for safety.⁹

In EDs with a strong safety culture, near misses are more likely to be intercepted to reduce patient harm.³ Teamwork training improves communication and reduces errors.¹⁰ One such program, Team Strategies and Tools to Enhance Performance and Patient Safety (TeamSTEPPS), was developed by a joint effort of the US Department of Defense and Agency for Healthcare Research and Quality to promote interprofessional communication between all providers in the hospital. This program provides many tools, including one to obtain attention in difficult situations and one to escalate concerns to focus on an important safety issue.¹¹ One ED’s experience with TeamSTEPPS led it to identify specific steps to ensure continued success after the initial start. To maintain the high level of teamwork and successful communication, this ED recognized a need for continued champions at all staff levels and all new staff members were required to go through the training.¹²

Another important aspect of a strong safety culture is creating an environment that promotes reporting of adverse events and near misses. The culture should allow a person involved in an adverse event to feel comfortable reporting such events. In one study of 522 “unintended events” at 10 EDs in the Netherlands, nurses reported 85% of events, and resident physicians reported 13% of events. Approximately 83% of reports were filed by a person involved in the event.¹³ This study highlights EDs that foster a “no blame” environment, where staff members feel comfortable admitting mistakes, and there is no fear of punishment or concern for job loss. When administration supports such reporting, the true safety problems in the ED are identified and can be targeted for improvement.
 

Medication Safety

Case Scenario 1

A 65-year-old woman presented to the ED with atrial fibrillation with a rapid ventricular rate of 165 beats/minute. Her heart rate was controlled with intravenous (IV) diltiazem, and a heparin infusion was ordered based on her estimated weight of 150 lb. As the pharmacist prepared the infusion, she rechecked the patient’s weight and discovered that the heparin order had been placed using pounds instead of kilograms. The pharmacist discussed the order with the physician, and the order was changed to avoid a double-dosing error.

Discussion

Many medications are required to treat critical illnesses and complex medical conditions; such polypharmacy is further complicated by the sheer volume of patients seen in the ED. The wide range of medications used in the ED and the different doses appropriate for age, gender, and body weight can lead to patient harm when the prescriber is confused. In addition, many medications can be administered via multiple routes, including IV, intramuscular, subcutaneous, or oral. In situations where a critically ill patient is close to death, verbal orders are often used and then followed by computer orders when the physician is able to leave the bedside. Clinicians may be simultaneously treating multiple patients with similar conditions or with similar names. In addition, due to the acuity of patient complaints, “high-alert” medications are often used in the ED,¹⁴ such as paralytics, opioids, anticoagulants, antithrombotics, insulins, sedatives, and vasopressors.¹⁵ Considering all of these factors, it is not surprising that up to 60% of ED patients experienced medication errors in one study.¹⁶ Fortunately, most of these errors do not result in immediate patient harm, but have the potential to lead to harm.¹⁷

The addition of a pharmacist to the ED 24 hours a day, 7 days a week can greatly improve medication safety. Emergency department pharmacists are available for immediate bedside consultation or discussion of a medication order, and can intercept prescribing errors in the ordering system before they are administered and before they result in patient harm.¹⁸ In general, medication errors are 13.5 times less likely to occur when a pharmacist is on duty in the ED.¹⁹ Pharmacists can recommend appropriate antibiotic dosing,²⁰ as well as aid in the timely administration of medications for such emergent conditions and procedures as stroke, MI, trauma, and rapid-sequence intubation. In our ED, the pharmacists also ensure that look-alike/sound-alike (LASA) medications are not confused. Importantly, in overcrowded EDs, the pharmacist reviews medication orders for all inpatients boarding in the ED and ensures that the nurses obtain the appropriate medications from the automated dispensing cabinets. In some instances, neither the EP nor the ED nurses may be familiar with proper doses and scheduling of medications typically used only in the inpatient service.

Pharmacists can prevent errors with formulation confusion, LASA confusion, weight-based dose errors, and dosing frequency errors. They also can ensure that the most up-to-date evidence is used to support a medication ordered, ensuring best practices and adherence to hospital policies. Table 2¹⁴ summarizes additional information on best practices for medication safety in the ED.

Discharge Process

Case Scenario 2

A 55-year-old man on warfarin presented to the ED with cough, dyspnea, and fever. His chest X-ray revealed right lower lobe pneumonia. He was prescribed levofloxacin and discharged home. His discharge instructions included a discussion of pneumonia, fever control, and the importance of taking his antibiotic appropriately, but he was not told to have his international normalized ratio (INR) checked regularly while taking levofloxacin. When the patient returned to the ED 5 days later because of rectal bleeding, his INR was elevated to 6 (normal range in a patient taking warfarin is 2.0-3.0).

Discussion

When patients who do not require admission to the hospital are discharged home, they need instructions to ensure that they fully understand the nature of their problem and what they need to do to get better. For the provider, the discharge process must include three tasks: communicating crucial information (diagnosis and return precautions), verifying the patient’s comprehension of the information presented, and addressing and correcting specific concerns and misunderstandings.²¹ The encounter must be standardized but also be flexible enough to ensure patient understanding across a wide range of health care literacy and cultural backgrounds.²¹ Patients frequently are not given appropriate verbal and written instructions, and if they do not understand their diagnosis, they may not follow up when necessary; may not realize that they need to take specific medications; or may not take their newly prescribed medications as intended.

In an evaluation of written discharge instructions, only 76% included a diagnosis or an explanation of the patient’s symptoms, and only 34% provided instructions on when and how to return.²² Another study of the discharge process showed that the average verbal discharge exchange lasted only 76 seconds and that 65% of instructions were not complete. Patients were often not given a diagnosis, an explanation of their prescriptions, or proper return precautions.²³ Deficits in the discharge process places patients at risk for medical and medication errors.

The discharge exchange must provide information on the diagnosis, what was done in the ED, and what needs to happen next. This must be done both verbally and in writing, in the patient’s native language, and at his or her health-literacy level. There should be time for the patients and those accompanying them and who are also responsible for their health to ask questions to ensure that everyone understands what has taken place and what must be done after leaving the ED. Patients should be given information on all prescription and over-the-counter medications they are instructed to take, as well as any changes to their previously prescribed medications.

Patients should be told specifically with whom to follow up and within what time frame. If possible, the exact time and location of a follow-up appointment should be provided. For patients with lower health literacy and less understanding of the health-care system, a process should be in place to help them navigate and ensure they get to necessary appointments.²¹
 

Handoffs and Transitions of Care

Case Scenario 3

A 70-year-old man with hypertension and hyperlipidemia had an episode of chest pain and was evaluated in the ED for possible myocardial ischemia. His initial electrocardiogram was interpreted as nonischemic and his troponin level was below detection 30 minutes after the episode. As the initial provider was leaving the ED, he endorsed the patient to the oncoming EP, with instructions to follow up on the chest X-ray interpretation. The initial provider, however, did not tell the oncoming EP to check the results of a repeat troponin determination. The patient was discharged home after the second troponin test had been sent to the laboratory, but before the results had been checked.

Discussion

Emergency department patients still under evaluation or in the process of being admitted to the inpatient hospital are “handed off” to the next shift of providers. Handoffs, or transitions of care, place patients at high risk for adverse events or bad outcomes. Important information can be lost whenever care is transferred to another provider. For example, there can be a lack of communication about pending tests that require follow-up, the need for further testing, or contingency planning for any problems that may arise. Loss of information and lack of follow-up can lead to diagnostic error and improper disposition.

According to the Joint Commission and a 2006 National Patient Safety Goal, handoffs should be standardized.²⁴ The four stages for safe ED-provider-to-ED-provider handoffs are pre-turnover, arrival of new provider, meeting of providers, and post-turnover.²⁵ During pre-turnover, the initial provider should review what has happened in the patient’s care and the next steps needed to finalize patient disposition. The arrival of the new provider signals the start of a new shift. During the meeting with the new provider, important information should be verbally transmitted to the oncoming provider.²⁵ This meeting needs to be standardized to include a patient summary, tasks and tests to follow up, and contingency planning. Many tools can aid in transitions of care, including verbal mnemonics, tools to integrate with the medical record, and tools to develop a complete process for transition of care. Post-turnover is completed by the oncoming provider as he or she finishes any tasks related to the patient’s care to ensure the treatment plan is completed.²⁵

There are many ways to improve the safety of handoffs. First, the number of handoffs should be limited. Having more patients dispositioned by the provider who initiated their care reduces the risk of an adverse event. This can be accomplished by having overlapping shifts to allow out-going providers time to complete care for their patients. During handoffs, interruptions and distractions should be limited to give the off-going provider appropriate time to present a succinct but complete overview of the patient’s care and communicate all outstanding tasks as “to-do” or “action lists,” with contingency planning for any changes in the patient’s status, test results, etc. There should be time for the oncoming provider to ask questions to ensure he or she is clear about the next steps.²⁵ At the end of the transition, there should be some signal that the patient’s care is passed on to the oncoming provider and the outgoing physician should leave the patient-care area to finish documentation.

Many ED patients will need transition from “ED patient” to “admitted patient”—ie, admission to the hospital and transfer of care to an inpatient service provider. Studies on transitions of care from the ED to an inpatient medical service have found multiple barriers to a seamless transition of care. These include communication failures; information technology failures; inability of inpatient providers to review vital signs, laboratory values, and medications given; a change of the inpatient team to whom the patient was assigned; and patient transfers to areas remote from the ED and/or inpatient floors, such as to a dialysis unit. In one survey, 29% of respondents reported that a patient of theirs had experienced an adverse event or near misses due to a poor handoff between the ED and medical service.²⁶ Just as there needs to be a standardized process for ED-provider-to-ED-provider handoffs, there also should be a standardized process for ED-to-inpatient or -outpatient service provider handoffs. There should be verbal and possibly written transmission of vital information, with patient summaries, “to-do” lists of follow-ups, situational knowledge with contingency planning, and time for questions (Table 3).^25,26 The Joint Commission’s Transitions of Care Portal (https://www.jointcommission.org
/toc.aspx) offers tools to help facilities formalize this process.

Health Information Technology

Case Scenario 4

An EM intern was instructed to order a dose of morphine for a patient with a fractured hip. The intern used electronic ordering. Afterward, the nurse caring for the patient asked the attending EP if she really wanted to order patient-controlled morphine analgesia for the patient. Upon reviewing the order, the attending discovered the intern had selected the first morphine on the drop-down list instead of scrolling down to find the range of individual doses available.

Discussion

The use of electronic health records (EHRs) and health information technology (HIT) systems has both improved patient care and introduced new errors. Physician handwriting may no longer be a problem, but some hospitals use several types of EHRs simultaneously, with different systems for inpatients, outpatients, and EDs. In these settings, there may not be a seamless system to allow for review of inpatient, outpatient, and ED records. Additional concerns include communication failure, misidentification of patient orders, poor data display, and “alert fatigue.”²⁷ Communication failures include the lack of bedside or face-to-face discussion among care providers. Physicians may enter orders at a computer away from the nursing station and never directly inform the nurse about the plan for the patient.

Incorrect patient orders are usually self-explanatory. Other errors include choosing the wrong LASA medication from a drop-down list or ordering imaging studies for the wrong side of the patient’s body. Poor data display may not alert providers of two or more patients with the same last name or allow vital signs to be displayed in a meaningful way. Other data-display problems include the inability to distinguish abnormal results from normal results because the system uses the same display color for both. Conversely, alert fatigue occurs when too many warning messages appear while providers are trying to enter orders for patient care. These warnings can range from important messages such as allergy identification or severe drug interactions to noncritical alerts about the cost of a test.

Recommendations to improve patient safety with the use of EHRs or HIT systems involve having a frontline staff champion to identify areas for performance improvement and having a review process to identify and examine safety issues with these technologies. A multidisciplinary group, including frontline staff, can usually develop effective solutions to these safety issues.²⁷
 

Conclusion

The ED is a high-risk setting for errors because it features high-acuity patients, patients of widely divergent ages, the frequent need to use high-alert medications, the need to simultaneously care for multiple patients, many interruptions and distractions, and the lack of an established relationship with patients. This environment can lead to communication failures in handoffs and transitions of care, medication errors, and poor follow-up due to poor discharge processes. Additional difficulties arise when HIT systems, such as EHRs, are not set up to ensure the success of frontline staff caring for ill patients. The ED can become a much safer place by establishing strategies such as those outlined in this article to reduce error in all of these areas.

Patient safety has received increased attention since the late 1990s. In 1999, The Institute of Medicine published “To Err is Human: Building a Safer Health System,”¹ followed by “Crossing the Quality Chasm: A New Health System for the 21st Century”² in 2001 to document patient-safety issues and recommend improvements in medical care to reduce errors. These reports and other patient-safety studies, however, likely underestimate the extent of medical errors and preventable harm. After these reports appeared, many specialties began to seriously evaluate their own safety issues.

Among the specialties, emergency medicine (EM) identified several problem areas and attempted to determine the epidemiology of errors. One study of 62 urban EDs found that at least 7% of patients who presented for myocardial infarctions (MIs), asthma exacerbations, or joint dislocations requiring reduction with procedural sedation experienced an actual or near-miss adverse event.³ Another study showed that up to 12% of all return visits to the ED within 7 days were related to adverse events.⁴

The ED setting itself undoubtedly contributes significantly to the risk of harm. This article illustrates and discusses ED patient-safety issues, and offers some recommendations for improvement in care and prevention of harm.
 

The ED Setting

The ED is unlike any other area of the hospital or health-care setting. Patients seek care for both primary care and urgent care complaints at any time of the day or night, on any day of the week, when no other source of care is available. Emergency physicians (EPs) are required to care for multiple patients of different ages while prioritizing care of the critically ill who have MI, stroke, sepsis, respiratory distress, or multisystem trauma. For many ED patients, diagnosis and treatment can be complex.

The ED setting is fast-paced and requires quick thinking, a broad depth of knowledge about many medical conditions, and a broad range of skills to perform emergent and life-saving procedures. Often, patients are presenting to a hospital ED for the first time, with incomplete medical records. They may not know their medical conditions or medications, or be in a position to communicate this information. Any of these situations alone can lead to an adverse event; in combination, they can significantly increase the risk for harm. In addition, ED overcrowding due to limited availability of inpatient hospital beds may consume resources and staffing needed to care for active ED patients and new patients coming through the door.

Safety factors in the ED can be categorized as those related to patients, providers, or the environment/systems (Table 1).^5-7 When a large academic urban ED studied its errors, two-thirds were attributed to systems issues.⁵

Culture of Safety

Developing and maintaining a “culture of safety” is a commitment to minimize adverse events when performing high-risk jobs that can result in harm.⁸ This concept originated in other industries such as the airline and nuclear energy industries. Organizations and companies are considered high-reliability organizations (HROs) when they are dedicated to preventing harm at all staff levels—from the frontline to the corporate level. These HROs promote the reporting of errors and “near misses” without fear of blame or loss of employment.⁸ In the ED, a culture of safety encourages teamwork, event reporting, communication openness, transparency with feedback and learning from errors, and administrator collaboration for safety.⁹

In EDs with a strong safety culture, near misses are more likely to be intercepted to reduce patient harm.³ Teamwork training improves communication and reduces errors.¹⁰ One such program, Team Strategies and Tools to Enhance Performance and Patient Safety (TeamSTEPPS), was developed by a joint effort of the US Department of Defense and Agency for Healthcare Research and Quality to promote interprofessional communication between all providers in the hospital. This program provides many tools, including one to obtain attention in difficult situations and one to escalate concerns to focus on an important safety issue.¹¹ One ED’s experience with TeamSTEPPS led it to identify specific steps to ensure continued success after the initial start. To maintain the high level of teamwork and successful communication, this ED recognized a need for continued champions at all staff levels and all new staff members were required to go through the training.¹²

Another important aspect of a strong safety culture is creating an environment that promotes reporting of adverse events and near misses. The culture should allow a person involved in an adverse event to feel comfortable reporting such events. In one study of 522 “unintended events” at 10 EDs in the Netherlands, nurses reported 85% of events, and resident physicians reported 13% of events. Approximately 83% of reports were filed by a person involved in the event.¹³ This study highlights EDs that foster a “no blame” environment, where staff members feel comfortable admitting mistakes, and there is no fear of punishment or concern for job loss. When administration supports such reporting, the true safety problems in the ED are identified and can be targeted for improvement.
 

Medication Safety

Case Scenario 1

A 65-year-old woman presented to the ED with atrial fibrillation with a rapid ventricular rate of 165 beats/minute. Her heart rate was controlled with intravenous (IV) diltiazem, and a heparin infusion was ordered based on her estimated weight of 150 lb. As the pharmacist prepared the infusion, she rechecked the patient’s weight and discovered that the heparin order had been placed using pounds instead of kilograms. The pharmacist discussed the order with the physician, and the order was changed to avoid a double-dosing error.

Discussion

Many medications are required to treat critical illnesses and complex medical conditions; such polypharmacy is further complicated by the sheer volume of patients seen in the ED. The wide range of medications used in the ED and the different doses appropriate for age, gender, and body weight can lead to patient harm when the prescriber is confused. In addition, many medications can be administered via multiple routes, including IV, intramuscular, subcutaneous, or oral. In situations where a critically ill patient is close to death, verbal orders are often used and then followed by computer orders when the physician is able to leave the bedside. Clinicians may be simultaneously treating multiple patients with similar conditions or with similar names. In addition, due to the acuity of patient complaints, “high-alert” medications are often used in the ED,¹⁴ such as paralytics, opioids, anticoagulants, antithrombotics, insulins, sedatives, and vasopressors.¹⁵ Considering all of these factors, it is not surprising that up to 60% of ED patients experienced medication errors in one study.¹⁶ Fortunately, most of these errors do not result in immediate patient harm, but have the potential to lead to harm.¹⁷

The addition of a pharmacist to the ED 24 hours a day, 7 days a week can greatly improve medication safety. Emergency department pharmacists are available for immediate bedside consultation or discussion of a medication order, and can intercept prescribing errors in the ordering system before they are administered and before they result in patient harm.¹⁸ In general, medication errors are 13.5 times less likely to occur when a pharmacist is on duty in the ED.¹⁹ Pharmacists can recommend appropriate antibiotic dosing,²⁰ as well as aid in the timely administration of medications for such emergent conditions and procedures as stroke, MI, trauma, and rapid-sequence intubation. In our ED, the pharmacists also ensure that look-alike/sound-alike (LASA) medications are not confused. Importantly, in overcrowded EDs, the pharmacist reviews medication orders for all inpatients boarding in the ED and ensures that the nurses obtain the appropriate medications from the automated dispensing cabinets. In some instances, neither the EP nor the ED nurses may be familiar with proper doses and scheduling of medications typically used only in the inpatient service.

Pharmacists can prevent errors with formulation confusion, LASA confusion, weight-based dose errors, and dosing frequency errors. They also can ensure that the most up-to-date evidence is used to support a medication ordered, ensuring best practices and adherence to hospital policies. Table 2¹⁴ summarizes additional information on best practices for medication safety in the ED.

Discharge Process

Case Scenario 2

A 55-year-old man on warfarin presented to the ED with cough, dyspnea, and fever. His chest X-ray revealed right lower lobe pneumonia. He was prescribed levofloxacin and discharged home. His discharge instructions included a discussion of pneumonia, fever control, and the importance of taking his antibiotic appropriately, but he was not told to have his international normalized ratio (INR) checked regularly while taking levofloxacin. When the patient returned to the ED 5 days later because of rectal bleeding, his INR was elevated to 6 (normal range in a patient taking warfarin is 2.0-3.0).

Discussion

When patients who do not require admission to the hospital are discharged home, they need instructions to ensure that they fully understand the nature of their problem and what they need to do to get better. For the provider, the discharge process must include three tasks: communicating crucial information (diagnosis and return precautions), verifying the patient’s comprehension of the information presented, and addressing and correcting specific concerns and misunderstandings.²¹ The encounter must be standardized but also be flexible enough to ensure patient understanding across a wide range of health care literacy and cultural backgrounds.²¹ Patients frequently are not given appropriate verbal and written instructions, and if they do not understand their diagnosis, they may not follow up when necessary; may not realize that they need to take specific medications; or may not take their newly prescribed medications as intended.

In an evaluation of written discharge instructions, only 76% included a diagnosis or an explanation of the patient’s symptoms, and only 34% provided instructions on when and how to return.²² Another study of the discharge process showed that the average verbal discharge exchange lasted only 76 seconds and that 65% of instructions were not complete. Patients were often not given a diagnosis, an explanation of their prescriptions, or proper return precautions.²³ Deficits in the discharge process places patients at risk for medical and medication errors.

The discharge exchange must provide information on the diagnosis, what was done in the ED, and what needs to happen next. This must be done both verbally and in writing, in the patient’s native language, and at his or her health-literacy level. There should be time for the patients and those accompanying them and who are also responsible for their health to ask questions to ensure that everyone understands what has taken place and what must be done after leaving the ED. Patients should be given information on all prescription and over-the-counter medications they are instructed to take, as well as any changes to their previously prescribed medications.

Patients should be told specifically with whom to follow up and within what time frame. If possible, the exact time and location of a follow-up appointment should be provided. For patients with lower health literacy and less understanding of the health-care system, a process should be in place to help them navigate and ensure they get to necessary appointments.²¹
 

Handoffs and Transitions of Care

Case Scenario 3

A 70-year-old man with hypertension and hyperlipidemia had an episode of chest pain and was evaluated in the ED for possible myocardial ischemia. His initial electrocardiogram was interpreted as nonischemic and his troponin level was below detection 30 minutes after the episode. As the initial provider was leaving the ED, he endorsed the patient to the oncoming EP, with instructions to follow up on the chest X-ray interpretation. The initial provider, however, did not tell the oncoming EP to check the results of a repeat troponin determination. The patient was discharged home after the second troponin test had been sent to the laboratory, but before the results had been checked.

Discussion

Emergency department patients still under evaluation or in the process of being admitted to the inpatient hospital are “handed off” to the next shift of providers. Handoffs, or transitions of care, place patients at high risk for adverse events or bad outcomes. Important information can be lost whenever care is transferred to another provider. For example, there can be a lack of communication about pending tests that require follow-up, the need for further testing, or contingency planning for any problems that may arise. Loss of information and lack of follow-up can lead to diagnostic error and improper disposition.

According to the Joint Commission and a 2006 National Patient Safety Goal, handoffs should be standardized.²⁴ The four stages for safe ED-provider-to-ED-provider handoffs are pre-turnover, arrival of new provider, meeting of providers, and post-turnover.²⁵ During pre-turnover, the initial provider should review what has happened in the patient’s care and the next steps needed to finalize patient disposition. The arrival of the new provider signals the start of a new shift. During the meeting with the new provider, important information should be verbally transmitted to the oncoming provider.²⁵ This meeting needs to be standardized to include a patient summary, tasks and tests to follow up, and contingency planning. Many tools can aid in transitions of care, including verbal mnemonics, tools to integrate with the medical record, and tools to develop a complete process for transition of care. Post-turnover is completed by the oncoming provider as he or she finishes any tasks related to the patient’s care to ensure the treatment plan is completed.²⁵

There are many ways to improve the safety of handoffs. First, the number of handoffs should be limited. Having more patients dispositioned by the provider who initiated their care reduces the risk of an adverse event. This can be accomplished by having overlapping shifts to allow out-going providers time to complete care for their patients. During handoffs, interruptions and distractions should be limited to give the off-going provider appropriate time to present a succinct but complete overview of the patient’s care and communicate all outstanding tasks as “to-do” or “action lists,” with contingency planning for any changes in the patient’s status, test results, etc. There should be time for the oncoming provider to ask questions to ensure he or she is clear about the next steps.²⁵ At the end of the transition, there should be some signal that the patient’s care is passed on to the oncoming provider and the outgoing physician should leave the patient-care area to finish documentation.

Many ED patients will need transition from “ED patient” to “admitted patient”—ie, admission to the hospital and transfer of care to an inpatient service provider. Studies on transitions of care from the ED to an inpatient medical service have found multiple barriers to a seamless transition of care. These include communication failures; information technology failures; inability of inpatient providers to review vital signs, laboratory values, and medications given; a change of the inpatient team to whom the patient was assigned; and patient transfers to areas remote from the ED and/or inpatient floors, such as to a dialysis unit. In one survey, 29% of respondents reported that a patient of theirs had experienced an adverse event or near misses due to a poor handoff between the ED and medical service.²⁶ Just as there needs to be a standardized process for ED-provider-to-ED-provider handoffs, there also should be a standardized process for ED-to-inpatient or -outpatient service provider handoffs. There should be verbal and possibly written transmission of vital information, with patient summaries, “to-do” lists of follow-ups, situational knowledge with contingency planning, and time for questions (Table 3).^25,26 The Joint Commission’s Transitions of Care Portal (https://www.jointcommission.org
/toc.aspx) offers tools to help facilities formalize this process.

Health Information Technology

Case Scenario 4

An EM intern was instructed to order a dose of morphine for a patient with a fractured hip. The intern used electronic ordering. Afterward, the nurse caring for the patient asked the attending EP if she really wanted to order patient-controlled morphine analgesia for the patient. Upon reviewing the order, the attending discovered the intern had selected the first morphine on the drop-down list instead of scrolling down to find the range of individual doses available.

Discussion

The use of electronic health records (EHRs) and health information technology (HIT) systems has both improved patient care and introduced new errors. Physician handwriting may no longer be a problem, but some hospitals use several types of EHRs simultaneously, with different systems for inpatients, outpatients, and EDs. In these settings, there may not be a seamless system to allow for review of inpatient, outpatient, and ED records. Additional concerns include communication failure, misidentification of patient orders, poor data display, and “alert fatigue.”²⁷ Communication failures include the lack of bedside or face-to-face discussion among care providers. Physicians may enter orders at a computer away from the nursing station and never directly inform the nurse about the plan for the patient.

Incorrect patient orders are usually self-explanatory. Other errors include choosing the wrong LASA medication from a drop-down list or ordering imaging studies for the wrong side of the patient’s body. Poor data display may not alert providers of two or more patients with the same last name or allow vital signs to be displayed in a meaningful way. Other data-display problems include the inability to distinguish abnormal results from normal results because the system uses the same display color for both. Conversely, alert fatigue occurs when too many warning messages appear while providers are trying to enter orders for patient care. These warnings can range from important messages such as allergy identification or severe drug interactions to noncritical alerts about the cost of a test.

Recommendations to improve patient safety with the use of EHRs or HIT systems involve having a frontline staff champion to identify areas for performance improvement and having a review process to identify and examine safety issues with these technologies. A multidisciplinary group, including frontline staff, can usually develop effective solutions to these safety issues.²⁷
 

Conclusion

The ED is a high-risk setting for errors because it features high-acuity patients, patients of widely divergent ages, the frequent need to use high-alert medications, the need to simultaneously care for multiple patients, many interruptions and distractions, and the lack of an established relationship with patients. This environment can lead to communication failures in handoffs and transitions of care, medication errors, and poor follow-up due to poor discharge processes. Additional difficulties arise when HIT systems, such as EHRs, are not set up to ensure the success of frontline staff caring for ill patients. The ED can become a much safer place by establishing strategies such as those outlined in this article to reduce error in all of these areas.

Patient safety has received increased attention since the late 1990s. In 1999, The Institute of Medicine published “To Err is Human: Building a Safer Health System,”¹ followed by “Crossing the Quality Chasm: A New Health System for the 21st Century”² in 2001 to document patient-safety issues and recommend improvements in medical care to reduce errors. These reports and other patient-safety studies, however, likely underestimate the extent of medical errors and preventable harm. After these reports appeared, many specialties began to seriously evaluate their own safety issues.

Among the specialties, emergency medicine (EM) identified several problem areas and attempted to determine the epidemiology of errors. One study of 62 urban EDs found that at least 7% of patients who presented for myocardial infarctions (MIs), asthma exacerbations, or joint dislocations requiring reduction with procedural sedation experienced an actual or near-miss adverse event.³ Another study showed that up to 12% of all return visits to the ED within 7 days were related to adverse events.⁴

The ED setting itself undoubtedly contributes significantly to the risk of harm. This article illustrates and discusses ED patient-safety issues, and offers some recommendations for improvement in care and prevention of harm.
 

The ED Setting

The ED is unlike any other area of the hospital or health-care setting. Patients seek care for both primary care and urgent care complaints at any time of the day or night, on any day of the week, when no other source of care is available. Emergency physicians (EPs) are required to care for multiple patients of different ages while prioritizing care of the critically ill who have MI, stroke, sepsis, respiratory distress, or multisystem trauma. For many ED patients, diagnosis and treatment can be complex.

The ED setting is fast-paced and requires quick thinking, a broad depth of knowledge about many medical conditions, and a broad range of skills to perform emergent and life-saving procedures. Often, patients are presenting to a hospital ED for the first time, with incomplete medical records. They may not know their medical conditions or medications, or be in a position to communicate this information. Any of these situations alone can lead to an adverse event; in combination, they can significantly increase the risk for harm. In addition, ED overcrowding due to limited availability of inpatient hospital beds may consume resources and staffing needed to care for active ED patients and new patients coming through the door.

Safety factors in the ED can be categorized as those related to patients, providers, or the environment/systems (Table 1).^5-7 When a large academic urban ED studied its errors, two-thirds were attributed to systems issues.⁵

Culture of Safety

Developing and maintaining a “culture of safety” is a commitment to minimize adverse events when performing high-risk jobs that can result in harm.⁸ This concept originated in other industries such as the airline and nuclear energy industries. Organizations and companies are considered high-reliability organizations (HROs) when they are dedicated to preventing harm at all staff levels—from the frontline to the corporate level. These HROs promote the reporting of errors and “near misses” without fear of blame or loss of employment.⁸ In the ED, a culture of safety encourages teamwork, event reporting, communication openness, transparency with feedback and learning from errors, and administrator collaboration for safety.⁹

In EDs with a strong safety culture, near misses are more likely to be intercepted to reduce patient harm.³ Teamwork training improves communication and reduces errors.¹⁰ One such program, Team Strategies and Tools to Enhance Performance and Patient Safety (TeamSTEPPS), was developed by a joint effort of the US Department of Defense and Agency for Healthcare Research and Quality to promote interprofessional communication between all providers in the hospital. This program provides many tools, including one to obtain attention in difficult situations and one to escalate concerns to focus on an important safety issue.¹¹ One ED’s experience with TeamSTEPPS led it to identify specific steps to ensure continued success after the initial start. To maintain the high level of teamwork and successful communication, this ED recognized a need for continued champions at all staff levels and all new staff members were required to go through the training.¹²

Another important aspect of a strong safety culture is creating an environment that promotes reporting of adverse events and near misses. The culture should allow a person involved in an adverse event to feel comfortable reporting such events. In one study of 522 “unintended events” at 10 EDs in the Netherlands, nurses reported 85% of events, and resident physicians reported 13% of events. Approximately 83% of reports were filed by a person involved in the event.¹³ This study highlights EDs that foster a “no blame” environment, where staff members feel comfortable admitting mistakes, and there is no fear of punishment or concern for job loss. When administration supports such reporting, the true safety problems in the ED are identified and can be targeted for improvement.
 

Medication Safety

Case Scenario 1

A 65-year-old woman presented to the ED with atrial fibrillation with a rapid ventricular rate of 165 beats/minute. Her heart rate was controlled with intravenous (IV) diltiazem, and a heparin infusion was ordered based on her estimated weight of 150 lb. As the pharmacist prepared the infusion, she rechecked the patient’s weight and discovered that the heparin order had been placed using pounds instead of kilograms. The pharmacist discussed the order with the physician, and the order was changed to avoid a double-dosing error.

Discussion

Many medications are required to treat critical illnesses and complex medical conditions; such polypharmacy is further complicated by the sheer volume of patients seen in the ED. The wide range of medications used in the ED and the different doses appropriate for age, gender, and body weight can lead to patient harm when the prescriber is confused. In addition, many medications can be administered via multiple routes, including IV, intramuscular, subcutaneous, or oral. In situations where a critically ill patient is close to death, verbal orders are often used and then followed by computer orders when the physician is able to leave the bedside. Clinicians may be simultaneously treating multiple patients with similar conditions or with similar names. In addition, due to the acuity of patient complaints, “high-alert” medications are often used in the ED,¹⁴ such as paralytics, opioids, anticoagulants, antithrombotics, insulins, sedatives, and vasopressors.¹⁵ Considering all of these factors, it is not surprising that up to 60% of ED patients experienced medication errors in one study.¹⁶ Fortunately, most of these errors do not result in immediate patient harm, but have the potential to lead to harm.¹⁷

The addition of a pharmacist to the ED 24 hours a day, 7 days a week can greatly improve medication safety. Emergency department pharmacists are available for immediate bedside consultation or discussion of a medication order, and can intercept prescribing errors in the ordering system before they are administered and before they result in patient harm.¹⁸ In general, medication errors are 13.5 times less likely to occur when a pharmacist is on duty in the ED.¹⁹ Pharmacists can recommend appropriate antibiotic dosing,²⁰ as well as aid in the timely administration of medications for such emergent conditions and procedures as stroke, MI, trauma, and rapid-sequence intubation. In our ED, the pharmacists also ensure that look-alike/sound-alike (LASA) medications are not confused. Importantly, in overcrowded EDs, the pharmacist reviews medication orders for all inpatients boarding in the ED and ensures that the nurses obtain the appropriate medications from the automated dispensing cabinets. In some instances, neither the EP nor the ED nurses may be familiar with proper doses and scheduling of medications typically used only in the inpatient service.

Pharmacists can prevent errors with formulation confusion, LASA confusion, weight-based dose errors, and dosing frequency errors. They also can ensure that the most up-to-date evidence is used to support a medication ordered, ensuring best practices and adherence to hospital policies. Table 2¹⁴ summarizes additional information on best practices for medication safety in the ED.

Discharge Process

Case Scenario 2

A 55-year-old man on warfarin presented to the ED with cough, dyspnea, and fever. His chest X-ray revealed right lower lobe pneumonia. He was prescribed levofloxacin and discharged home. His discharge instructions included a discussion of pneumonia, fever control, and the importance of taking his antibiotic appropriately, but he was not told to have his international normalized ratio (INR) checked regularly while taking levofloxacin. When the patient returned to the ED 5 days later because of rectal bleeding, his INR was elevated to 6 (normal range in a patient taking warfarin is 2.0-3.0).

Discussion

When patients who do not require admission to the hospital are discharged home, they need instructions to ensure that they fully understand the nature of their problem and what they need to do to get better. For the provider, the discharge process must include three tasks: communicating crucial information (diagnosis and return precautions), verifying the patient’s comprehension of the information presented, and addressing and correcting specific concerns and misunderstandings.²¹ The encounter must be standardized but also be flexible enough to ensure patient understanding across a wide range of health care literacy and cultural backgrounds.²¹ Patients frequently are not given appropriate verbal and written instructions, and if they do not understand their diagnosis, they may not follow up when necessary; may not realize that they need to take specific medications; or may not take their newly prescribed medications as intended.

In an evaluation of written discharge instructions, only 76% included a diagnosis or an explanation of the patient’s symptoms, and only 34% provided instructions on when and how to return.²² Another study of the discharge process showed that the average verbal discharge exchange lasted only 76 seconds and that 65% of instructions were not complete. Patients were often not given a diagnosis, an explanation of their prescriptions, or proper return precautions.²³ Deficits in the discharge process places patients at risk for medical and medication errors.

The discharge exchange must provide information on the diagnosis, what was done in the ED, and what needs to happen next. This must be done both verbally and in writing, in the patient’s native language, and at his or her health-literacy level. There should be time for the patients and those accompanying them and who are also responsible for their health to ask questions to ensure that everyone understands what has taken place and what must be done after leaving the ED. Patients should be given information on all prescription and over-the-counter medications they are instructed to take, as well as any changes to their previously prescribed medications.

Patients should be told specifically with whom to follow up and within what time frame. If possible, the exact time and location of a follow-up appointment should be provided. For patients with lower health literacy and less understanding of the health-care system, a process should be in place to help them navigate and ensure they get to necessary appointments.²¹
 

Handoffs and Transitions of Care

Case Scenario 3

A 70-year-old man with hypertension and hyperlipidemia had an episode of chest pain and was evaluated in the ED for possible myocardial ischemia. His initial electrocardiogram was interpreted as nonischemic and his troponin level was below detection 30 minutes after the episode. As the initial provider was leaving the ED, he endorsed the patient to the oncoming EP, with instructions to follow up on the chest X-ray interpretation. The initial provider, however, did not tell the oncoming EP to check the results of a repeat troponin determination. The patient was discharged home after the second troponin test had been sent to the laboratory, but before the results had been checked.

Discussion

Emergency department patients still under evaluation or in the process of being admitted to the inpatient hospital are “handed off” to the next shift of providers. Handoffs, or transitions of care, place patients at high risk for adverse events or bad outcomes. Important information can be lost whenever care is transferred to another provider. For example, there can be a lack of communication about pending tests that require follow-up, the need for further testing, or contingency planning for any problems that may arise. Loss of information and lack of follow-up can lead to diagnostic error and improper disposition.

According to the Joint Commission and a 2006 National Patient Safety Goal, handoffs should be standardized.²⁴ The four stages for safe ED-provider-to-ED-provider handoffs are pre-turnover, arrival of new provider, meeting of providers, and post-turnover.²⁵ During pre-turnover, the initial provider should review what has happened in the patient’s care and the next steps needed to finalize patient disposition. The arrival of the new provider signals the start of a new shift. During the meeting with the new provider, important information should be verbally transmitted to the oncoming provider.²⁵ This meeting needs to be standardized to include a patient summary, tasks and tests to follow up, and contingency planning. Many tools can aid in transitions of care, including verbal mnemonics, tools to integrate with the medical record, and tools to develop a complete process for transition of care. Post-turnover is completed by the oncoming provider as he or she finishes any tasks related to the patient’s care to ensure the treatment plan is completed.²⁵

There are many ways to improve the safety of handoffs. First, the number of handoffs should be limited. Having more patients dispositioned by the provider who initiated their care reduces the risk of an adverse event. This can be accomplished by having overlapping shifts to allow out-going providers time to complete care for their patients. During handoffs, interruptions and distractions should be limited to give the off-going provider appropriate time to present a succinct but complete overview of the patient’s care and communicate all outstanding tasks as “to-do” or “action lists,” with contingency planning for any changes in the patient’s status, test results, etc. There should be time for the oncoming provider to ask questions to ensure he or she is clear about the next steps.²⁵ At the end of the transition, there should be some signal that the patient’s care is passed on to the oncoming provider and the outgoing physician should leave the patient-care area to finish documentation.

Many ED patients will need transition from “ED patient” to “admitted patient”—ie, admission to the hospital and transfer of care to an inpatient service provider. Studies on transitions of care from the ED to an inpatient medical service have found multiple barriers to a seamless transition of care. These include communication failures; information technology failures; inability of inpatient providers to review vital signs, laboratory values, and medications given; a change of the inpatient team to whom the patient was assigned; and patient transfers to areas remote from the ED and/or inpatient floors, such as to a dialysis unit. In one survey, 29% of respondents reported that a patient of theirs had experienced an adverse event or near misses due to a poor handoff between the ED and medical service.²⁶ Just as there needs to be a standardized process for ED-provider-to-ED-provider handoffs, there also should be a standardized process for ED-to-inpatient or -outpatient service provider handoffs. There should be verbal and possibly written transmission of vital information, with patient summaries, “to-do” lists of follow-ups, situational knowledge with contingency planning, and time for questions (Table 3).^25,26 The Joint Commission’s Transitions of Care Portal (https://www.jointcommission.org
/toc.aspx) offers tools to help facilities formalize this process.

Health Information Technology

Case Scenario 4

An EM intern was instructed to order a dose of morphine for a patient with a fractured hip. The intern used electronic ordering. Afterward, the nurse caring for the patient asked the attending EP if she really wanted to order patient-controlled morphine analgesia for the patient. Upon reviewing the order, the attending discovered the intern had selected the first morphine on the drop-down list instead of scrolling down to find the range of individual doses available.

Discussion

The use of electronic health records (EHRs) and health information technology (HIT) systems has both improved patient care and introduced new errors. Physician handwriting may no longer be a problem, but some hospitals use several types of EHRs simultaneously, with different systems for inpatients, outpatients, and EDs. In these settings, there may not be a seamless system to allow for review of inpatient, outpatient, and ED records. Additional concerns include communication failure, misidentification of patient orders, poor data display, and “alert fatigue.”²⁷ Communication failures include the lack of bedside or face-to-face discussion among care providers. Physicians may enter orders at a computer away from the nursing station and never directly inform the nurse about the plan for the patient.

Incorrect patient orders are usually self-explanatory. Other errors include choosing the wrong LASA medication from a drop-down list or ordering imaging studies for the wrong side of the patient’s body. Poor data display may not alert providers of two or more patients with the same last name or allow vital signs to be displayed in a meaningful way. Other data-display problems include the inability to distinguish abnormal results from normal results because the system uses the same display color for both. Conversely, alert fatigue occurs when too many warning messages appear while providers are trying to enter orders for patient care. These warnings can range from important messages such as allergy identification or severe drug interactions to noncritical alerts about the cost of a test.

Recommendations to improve patient safety with the use of EHRs or HIT systems involve having a frontline staff champion to identify areas for performance improvement and having a review process to identify and examine safety issues with these technologies. A multidisciplinary group, including frontline staff, can usually develop effective solutions to these safety issues.²⁷
 

Conclusion

The ED is a high-risk setting for errors because it features high-acuity patients, patients of widely divergent ages, the frequent need to use high-alert medications, the need to simultaneously care for multiple patients, many interruptions and distractions, and the lack of an established relationship with patients. This environment can lead to communication failures in handoffs and transitions of care, medication errors, and poor follow-up due to poor discharge processes. Additional difficulties arise when HIT systems, such as EHRs, are not set up to ensure the success of frontline staff caring for ill patients. The ED can become a much safer place by establishing strategies such as those outlined in this article to reduce error in all of these areas.

From the Division of Adult Infectious Diseases, University of Colorado Denver, Aurora, CO, and the Department of Veterans Affairs, Eastern Colorado Healthcare System, Denver, CO.

Abstract

• Objective: To review the published literature on methicillin-resistant Staphylococcus aureus (MRSA) infections among patients recently discharged from hospital, with a focus on possible prevention measures.
• Methods: Literature review.
• Results: MRSA is a major cause of post-discharge infections. Risk factors for post-discharge MRSA include colonization, dependent ambulatory status, duration of hospitalization > 5 days, discharge to a long-term care facility, presence of a central venous catheter (CVC), presence of a non-CVC invasive device, a chronic wound in the post-discharge period, hemodialysis, systemic corticosteroids, and receiving anti-MRSA antimicrobial agents. Potential approaches to control include prevention of incident colonization during hospital stay, removal of nonessential CVCs and other devices, good wound debridement and care, and antimicrobial stewardship. Hand hygiene and environmental cleaning are horizontal measures that are also recommended. Decolonization may be useful in selected cases.
• Conclusion: Post-discharge MRSA infections are an important and underestimated source of morbidity and mortality. The future research agenda should include identification of post-discharge patients who are most likely to benefit from decolonization strategies, and testing those strategies.

Methicillin-resistant Staphylococcus aureus (MRSA) is a leading cause of morbidity and mortality due to infections of the bloodstream, lung, surgical sites, bone, and skin and soft tissues. The mortality associated with S. aureus bloodstream infections is 14% to 45% [1–4]. A bloodstream infection caused by MRSA is associated with a twofold increased mortality as compared to one caused by methicillin-sensitive S. aureus [5]. MRSA pneumonia carries a mortality of 8%, which increases to 39% when bacteremia is also present [6]. S. aureus bloodstream infection also carries a high risk of functional disability, with 65% of patients in a recent series requiring nursing home care in the recovery period [7]. In 2011 there were more than 11,000 deaths due to invasive MRSA infection in the United States [8]. Clearly S. aureus, and particularly MRSA, is a pathogen of major clinical significance.

Methicillin resistance was described in 1961, soon after methicillin became available in the 1950s. Prevalence of MRSA remained low until the 1980s, when it rapidly increased in health care settings. The predominant health care–associated strain in the United States is USA100, a member of clonal complex 5. Community-acquired MRSA infection has garnered much attention since it was recognized in 1996 [9]. The predominant community-associated strain has been USA300, a member of clonal complex 8 [10]. Following its emergence in the community, USA300 became a significant health care–associated pathogen as well [11]. The larger share of MRSA disease remains health care–associated [8]. The most recent data from the Center for Disease Control and Prevention Active Bacterial Core Surveillance system indicate that 77.6% of invasive MRSA infection is health care–associated, resulting in 9127 deaths in 2011 [8].

This article reviews the published literature on MRSA infections among patients recently discharged from hospital, with a focus on possible prevention measures.

MRSA Epidemiologic Categories

Epidemiologic investigations of MRSA categorize infections according to the presumed acquisition site, ie, in the community or in a health care setting. Older literature refers to nosocomial MRSA infection, which is now commonly referred to as hospital-onset health care–associated (HO-HCA) MRSA. A common definition of HO-HCA MRSA infection is an infection with the first positive culture on hospital day 4 or later [12]. Community-onset health care–associated MRSA (CO-HCA MRSA) is defined as infection that is diagnosed in the outpatient setting, or prior to day 4 of hospitalization, in a patient with recent health care exposure, eg, hospitalization within the past year, hemodialysis, surgery, or presence of a central venous catheter at time of presentation to the hospital [12]. Community-associated MRSA (CA-MSRSA) is infection in patients who do not meet criteria for either type of health care associated MRSA. Post-discharge MRSA infections would be included in the CO-HCA MRSA group.

Infection Control Programs

Classic infection control programs, developed in the 1960s, focused on infections that presented more than 48 to 72 hours after admission and prior to discharge from hospital. In that era, the average length of hospital stay was 1 week or more, and there was sufficient time for health care–associated infections to become clinically apparent. In recent years, length of stay has progressively shortened [13]. As hospital stays shortened, the risk that an infection caused by a health care–acquired pathogen would be identified after discharge grew. More recent studies have documented that the majority of HO-HCA infections become apparent after the index hospitalization [8,14].

Data from the Active Bacterial Core Surveillance System quantify the burden of CO-HCA MRSA disease at a national level [8,14]. However, it is not readily detected by many hospital infection surveillance programs. Avery et al studied a database constructed with California state mandated reports of MRSA infection and identified cases with MRSA present on admission. They then searched for a previous admission, within 30 days. If a prior admission was identified, the MRSA case was assigned to the hospital that had recently discharged the patient. Using this approach, they found that the incidence of health care–associated MRSA infection increased from 12.2 cases/10,000 admissions when traditional surveillance methods were used to 35.7/10,000 admissions using the revised method of assignment of health care exposure [15]. These data suggest that post-discharge MRSA disease is underappreciated by hospital infection control programs.

Lessons from Hospital-Onset MRSA

The morbidity and mortality associated with MRSA have led to the development of vigorous infection control programs to reduce the risk of health care–associated MRSA infection [16–18]. Vertical infection control strategies, ie, those focused on MRSA specifically, have included active screening for colonization, and nursing colonized patients in contact precautions. Since colonization is the antecedent to infection in most cases, prevention of transmission of MRSA from patient to patient should prevent most infections. There is ample evidence that colonized patients contaminate their immediate environment with MRSA, creating a reservoir of resistant pathogens that can be transmitted to other patients on the hands and clothing of health care workers [19,20]. Quasi-experimental studies of active screening and isolation strategies have shown decreases in MRSA transmission and infection following implementation [18]. The only randomized comparative trial of active screening and isolation versus usual care did not demonstrate benefit, possibly due to delays in lab confirmation of colonization status [21]. Horizontal infection control strategies are applied to all patients, regardless of colonization with resistant pathogens, in an attempt to decrease health care–associated infections with all pathogens. Examples of horizontal strategies are hand hygiene, environmental cleaning, and the prevention bundles for central line–associated bloodstream infection.

The Burden of Community-Onset MRSA

CO-HCA MRSA represents 60% of the burden of invasive MRSA infection [8]. While this category includes cases that have not been hospitalized, eg, patients on hemodialysis, post-discharge MRSA infection accounts for the majority of cases [15]. Recent data indicate that the incidence of HO-HCA MRSA decreased 54.2% between 2005 and 2011 [8]. This decrease in HO-HCA MRSA infection occurred concurrently with widespread implementation of vigorous horizontal infection control measures, such as bundled prevention strategies for central line–associated bloodstream infection and ventilator-associated pneumonia. The decline in CO-HCA MRSA infection has been much less steep, at 27.7%. The majority of the CO-HCA infections are in post-discharge patients. Furthermore, the incidence of CO-HCA MRSA infection may be underestimated [15].

Post-Discharge MRSA Colonization and Infection

Hospital-associated MRSA infection is reportable in many jurisdictions, but post-discharge MRSA infection is not a specific reportable condition, limiting the available surveillance data. Avery et al [15] studied ICD-9 code data for all hospitals in Orange County, California, and found that 23.5/10,000 hospital admissions were associated with a post-discharge MRSA infection. This nearly tripled the incidence of health care–associated MRSA infection, compared to surveillance that included only hospital-onset cases. Future research should refine these observations, as ICD-9 code data correlate imperfectly with chart reviews and have not yet been well validated for MRSA research.

The CDC estimated that in 2011 there were 48,353 CO-HCA MRSA infections resulting in 10,934 deaths. This estimate is derived from study of the Active Bacterial Core surveillance sample [8]. In that sample, 79% of CO-HCA MRSA infections occurred in patients hospitalized within the last year. Thus, we can estimate that there were 34,249 post-discharge MRSA infections resulting in 8638 deaths in the United States in 2011.

MRSA colonization is the antecedent to infection in the majority of cases [22]. Thus we can assess the health care burden of post-discharge MRSA by analyzing colonization as well as infection. Furthermore, the risk of MRSA colonization of household members can be addressed. Lucet et al evaluated hospital inpatients preparing for discharge to a home health care setting, and found that 12.7% of them were colonized with MRSA at the time of discharge, and 45% of them remained colonized for more than a year [23]. Patients who regained independence in activities of daily living were more likely to become free of MRSA colonization. The study provided no data on the risk of MRSA infection in the colonized patients. 19.1% of household contacts became colonized with MRSA, demonstrating that the burden of MRSA extends beyond the index patient. None of the colonized household contacts developed MRSA infection during the study period.

Risk Factors for Post-Discharge MRSA

Case control studies of patients with post-discharge invasive MRSA have shed light on risk factors for infection. While many risk factors are not modifiable, these studies may provide a road map to development of prevention strategies for the post-discharge setting. A study of hospitals in New York that participated in the Active Bacterial Core surveillance system identified a statistically significant increased risk of MRSA invasive infection among patients with several factors associated with physical disability, including a physical therapy evaluation, dependent ambulatory status, duration of hospitalization > 5 days, and discharge to a long-term care facility. Additional risk factors identified in the bivariate analysis were presence of a central venous catheter, hemodialysis, systemic corticosteroids, and receiving anti-MRSA antimicrobial agents. When subjected to multivariate analysis, however, the most significant and potent risk factor was a previous positive MRSA clinical culture (matched odds ratio 23, P < 0.001). Other significant risk factors in the multivariate analysis were hemodialysis, presence of a central venous catheter in the outpatient setting, and a visit to the emergency department [24]. A second, larger, multistate study also based on data from the Active Bacterial Core surveillance system showed that 5 risk factors were significantly associated with post-discharge invasive MRSA infection: (1) MRSA colonization, (2) a central venous catheter (CVC) present at discharge, (3) presence of a non-CVC invasive device, (4) a chronic wound in the post-discharge period, and (5) discharge to a nursing home. MRSA colonization was associated with a 7.7-fold increased odds of invasive MRSA infection, a much greater increase than any of the other risk factors [25]. Based on these results, strategies to consider include enhanced infection measures for prevention of incident MRSA colonization in the inpatient setting, decolonization therapy for those who become colonized, removal of non-essential medical devices, including central venous catheters, excellent nursing care for essential devices and wounds, hand hygiene, environmental cleaning, and antimicrobial stewardship.

Development of Strategies to Decrease Post-Discharge MRSA

While the epidemiology of post-discharge health care–associated MRSA infections has become a topic of interest to researchers, approaches to control are in their infancy. Few of the approaches have been subjected to rigorous study in the post-discharge environment. Nevertheless, some low risk, common sense strategies may be considered. Furthermore, an outline of research objectives may be constructed.

Prevention of Colonization in the Inpatient Setting

Robust infection control measures must be implemented in inpatient settings to prevent incident MRSA colonization [16,17]. Key recommendations include surveillance and monitoring of MRSA infections, adherence to standard hand hygiene guidance, environmental cleanliness, and use of dedicated equipment for patients who are colonized or infected with MRSA. Active screening for asymptomatic MRSA carriage and isolation of carriers may be implemented if routine measures are not successful.

Decolonization

Despite the best infection control programs, some patients will be colonized with MRSA at the time of hospital discharge. As detailed above, MRSA colonization is a potent risk factor for infection in the post-discharge setting, as well as in hospital inpatients [22]. A logical approach to this would be to attempt to eradicate colonization. There are several strategies for decolonization therapy, which may be used alone or in combination, including nasal mupirocin, nasal povidone-iodine, systemic antistaphylococcal drugs alone or in combination with oral rifampin, chlorhexidine bathing, or bleach baths [26–29].

A preliminary step in approaching the idea of post-discharge decolonization therapy is to show that patients can be successfully decolonized. With those data in hand, randomized trials seeking to demonstrate a decrease in invasive MRSA infections can be planned. Decolonization using nasal mupirocin has an initial success rate of 60% to 100% in a variety of patient populations [30–35]. Poor adherence to the decolonization protocol may limit success in the outpatient setting. Patients are more likely to resolve their MRSA colonization spontaneously when they regain their general health and independence in activities of daily living [23]. Colonization of other household members may provide a reservoir of MRSA leading to recolonization of the index case. Treatment of the household members may be offered, to provide more durable maintenance of the decolonized state [35]. When chronically ill patients who have been decolonized are followed longitudinally, up to 39% become colonized again, most often with the same strain [30,31]. Attempts to maintain a MRSA-free state in nursing home residents using prolonged mupirocin therapy resulted in emergence of mupirocin resistance [31]. Thus decolonization can be achieved, but is difficult to maintain, especially in debilitated, chronically ill patients. Mupirocin resistance can occur, limiting success of decolonization therapies.

Successful decolonization has been proven to reduce the risk of MRSA infection in the perioperative, dialysis, and intensive care unit settings [33,36–38]. In dialysis patients the risk of S. aureus bloodstream infection, including MRSA, can be reduced 59% with the use of mupirocin decolonization of the nares, with or without treatment of dialysis access exit sites [37]. A placebo-controlled trial demonstrated that decolonization of the nares with mupirocin reduced surgical site infections with S. aureus. All S. aureus isolates in the study were methicillin-susceptible. A second randomized controlled trial of nasal mupirocin did not achieve a statistically significant decrease in S. aureus surgical site infections, but it showed that mupirocin decolonization therapy decreased nosocomial S. aureus infections among nasal carriers [33]. 99.2% of isolates in that study et al were methicillin-susceptible. Quasi-experimental studies have shown similar benefits for surgical patients who are colonized with MRSA [39–41]. A more recent randomized trial, in ICU patients, demonstrated decreased incidence of invasive infection in patients treated with nasal mupirocin and chlorhexidine baths [38]. The common themeof these studies is that they enrolled patients who had a short-term condition, eg, surgery or critical illness, placing them at high risk for invasive MRSA infection. This maximizes the potential benefit of decolonization and minimizes the risk of emergence of resistance. Furthermore, adherence to decolonization protocols is likely to be high in the perioperative and ICU settings. To extrapolate the ICU and perioperative data to the post-discharge setting would be imprudent.

In summary, decolonization may be a useful strategy to reduce invasive MRSA infection in post-discharge patients, but more data are needed for most patient populations. The evidence for decolonization therapy is strongest for dialysis patients, in whom implementation of routine decolonization of MRSA colonized nares is a useful intervention [37]. There are not yet clinical trials of decolonization therapy in patients at time of hospital discharge showing a reduction in invasive MRSA infection. Decolonization strategies have important drawbacks, including emergence of resistance to mupirocin, chlorhexidine, and systemic agents. Furthermore, there is a risk of hypersensitivity reactions, Clostridium difficile infection, and potential for negative impacts onthe normal microbiome. The potential for lesser efficacy in a chronically ill outpatient population must also be considered in the post-discharge setting. Randomized controlled trials with invasive infection outcomes should be performed prior to implementing routine decolonization therapy of hospital discharge patients.

Care of Invasive Devices

Discharge with a central venous catheter was associated with a 2.16-fold increased risk of invasive MRSA infection; other invasive devices were associated with a 3.03-fold increased risk [25]. Clinicians must carefully assess patients nearing discharge for any opportunity to remove invasive devices. Idle devices have been reported in inpatient settings [42] and could occur in other settings. Antimicrobial therapy is a common indication for an outpatient central venous catheter and can also be associated with increased risk of invasive MRSA infection [25,43]. Duration and route of administration of antimicrobial agents should be carefully considered, with an eye to switching to oral therapy whenever possible. When a central venous catheter must be utilized, it should be maintained as carefully as in the inpatient setting. Tools for reducing risk of catheter-associated bloodstream infection include keeping the site dry, scrubbing the hub whenever accessing the catheter, aseptic techniques for dressing changes, and chlorhexidine sponges at the insertion site [44,45]. Reporting of central line–associated bloodstream infection rates by home care agencies is an important quality measure.

Wound Care

The presence of a chronic wound in the post-discharge period is associated with a 4.41-fold increased risk of invasive MRSA infection [25]. Although randomized controlled trials are lacking, it is prudent to ensure that wounds are fully debrided to remove devitalized tissue that can be fertile ground for a MRSA infection. The burden of organisms on a chronic wound is often very large, creating high risk of resistance when exposed to antimicrobial agents. Decolonization therapy is not likely to meet with durable success in such cases and should probably be avoided, except in special circumstances, eg, in preparation for cardiothoracic surgery.

Infection Control in Nursing Home Settings

In the Active Bacterial Core cohort, discharge to a nursing home was associated with a 2.1- to 2.65-fold increased risk of invasive MRSA infection [24,25]. It is notable that the authors controlled for the Charlson comorbidity index, suggesting that nursing home care is more than a marker for comorbidity [25]. The tension between the demands of careful infection control and the home-like setting that is desirable for long-term care creates challenges in the prevention of invasive MRSA infection. Nevertheless, careful management of invasive devices and wounds and antimicrobial stewardship are strategies that may reduce the risk of invasive MRSA infection in long-term care settings. Contact precautions for colonized nursing home residents are recommended only during an outbreak [46]. Staff should be trained in proper application of standard precautions, including use of gowns and gloves when handling body fluids. A study of an aggressive program of screening, decolonization with nasal mupirocin and chlorhexidine bathing, enhanced hand hygiene and environmental cleaning demonstrated a significant reduction in MRSA colonization [47]. An increase in mupirocin resistance during the study led to a switch to retapamulin for nasal application. The Association of Practitioners of Infection Control has issued guidance for MRSA prevention in long-term care facilities [48]. The guidance focuses on surveillance for MRSA infection, performing a MRSA risk assessment, hand hygiene, and environmental cleaning.

Antimicrobial Stewardship

Antimicrobial therapy, especially with fluoroquinolones and third- or fourth-generation cephalosporins, is associated with increased risk of MRSA colonization and infection [43,49,50]. Implementation of an antimicrobial stewardship program, coupled with infection control measures, in a region of Scotland resulted in decreased incidence of MRSA infections among hospital inpatients and in the surrounding community [51]. Thus a robust antimicrobial stewardship program is likely to reduce post-discharge MRSA infections.

Role of Hand Hygiene

The importance of hand hygiene in the prevention of infection has been observed for nearly 2 centuries [52]. Multiple quasi-experimental studies have demonstrated a decreased infection rate when hand hygiene practices for health care workers were introduced or strengthened. A randomized trial in a newborn nursery documented a decrease in transmission of S. aureus when nurses washed their hands after handling a colonized infant [53]. In addition to health care providers, patient hand hygiene can reduce health care–associated infections [54]. Traditional handwashing with soap and water will be familiar to most patients and families. Waterless hand hygiene, typically using alcohol-based hand rubs, is more efficacious and convenient for cleaning hands that are not visibly soiled [52]. If products containing emollients are used, it can also reduce skin drying and cracking. Patients and families should be taught to wash their hands before and after manipulating any medical devices and caring for wounds. Education of patients and family members on the techniques and importance of hand hygiene during hospitalization and at the time of discharge is a simple, low-cost strategy to reduce post-discharge MRSA infections. Teaching can be incorporated into the daily care of patients by nursing and medical staff, both verbally and by example. As a horizontal infection control measure, hand hygiene education has the additional benefit of reducing infections due to all pathogens.

Role of Environmental Cleaning in the Home Setting

Multiple studies have found that the immediate environment of patients who are colonized or infected with MRSA is contaminated with the organism, with greater organism burdens associated with infected patients compared to those who are only colonized [55–59]. Greater environmental contamination is observed when MRSA is present in the urine or wounds of patients [59]. This can lead to transmission of MRSA to family members [23,60,61]. Risk factors for transmission include participation in the care of the patient, older age, and being the partner of the case patient. For the patient, there can be transmission to uninfected body sites and a cycle of recolonization and re-infection. Successful decolonization strategies have included frequent laundering of bedclothes and towels, as well as screening and decolonization of family members. While these strategies may succeed in decolonization, there is no consensus on efficacy in preventing infection in patients or family members. More research in this area is needed, particularly for decolonization strategies, which carry risk of resistance. Attention to cleanliness in the home is a basic hygiene measure that can be recommended.

Conclusion

Post-discharge MRSA infections are an important and underestimated source of morbidity and mortality. Strategies for prevention include infection control measures to prevent incident colonization during hospitalization, removal of any nonessential invasive devices, nursing care for essential devices, wound care, avoiding nonessential antimicrobial therapy, hand hygiene for patients and caregivers, and cleaning of the home environment. Decolonization therapies currently play a limited role, particularly in outbreak situations. The future research agenda should include identification of post-discharge patients who are most likely to benefit from decolonization strategies, and testing those strategies.

Corresponding author: Mary Bessesen, MD, InfectiousDiseases (111L), 1055 Clermont St., Denver, CO 80220, [email protected].

From the Division of Adult Infectious Diseases, University of Colorado Denver, Aurora, CO, and the Department of Veterans Affairs, Eastern Colorado Healthcare System, Denver, CO.

Abstract

• Objective: To review the published literature on methicillin-resistant Staphylococcus aureus (MRSA) infections among patients recently discharged from hospital, with a focus on possible prevention measures.
• Methods: Literature review.
• Results: MRSA is a major cause of post-discharge infections. Risk factors for post-discharge MRSA include colonization, dependent ambulatory status, duration of hospitalization > 5 days, discharge to a long-term care facility, presence of a central venous catheter (CVC), presence of a non-CVC invasive device, a chronic wound in the post-discharge period, hemodialysis, systemic corticosteroids, and receiving anti-MRSA antimicrobial agents. Potential approaches to control include prevention of incident colonization during hospital stay, removal of nonessential CVCs and other devices, good wound debridement and care, and antimicrobial stewardship. Hand hygiene and environmental cleaning are horizontal measures that are also recommended. Decolonization may be useful in selected cases.
• Conclusion: Post-discharge MRSA infections are an important and underestimated source of morbidity and mortality. The future research agenda should include identification of post-discharge patients who are most likely to benefit from decolonization strategies, and testing those strategies.

Methicillin-resistant Staphylococcus aureus (MRSA) is a leading cause of morbidity and mortality due to infections of the bloodstream, lung, surgical sites, bone, and skin and soft tissues. The mortality associated with S. aureus bloodstream infections is 14% to 45% [1–4]. A bloodstream infection caused by MRSA is associated with a twofold increased mortality as compared to one caused by methicillin-sensitive S. aureus [5]. MRSA pneumonia carries a mortality of 8%, which increases to 39% when bacteremia is also present [6]. S. aureus bloodstream infection also carries a high risk of functional disability, with 65% of patients in a recent series requiring nursing home care in the recovery period [7]. In 2011 there were more than 11,000 deaths due to invasive MRSA infection in the United States [8]. Clearly S. aureus, and particularly MRSA, is a pathogen of major clinical significance.

Methicillin resistance was described in 1961, soon after methicillin became available in the 1950s. Prevalence of MRSA remained low until the 1980s, when it rapidly increased in health care settings. The predominant health care–associated strain in the United States is USA100, a member of clonal complex 5. Community-acquired MRSA infection has garnered much attention since it was recognized in 1996 [9]. The predominant community-associated strain has been USA300, a member of clonal complex 8 [10]. Following its emergence in the community, USA300 became a significant health care–associated pathogen as well [11]. The larger share of MRSA disease remains health care–associated [8]. The most recent data from the Center for Disease Control and Prevention Active Bacterial Core Surveillance system indicate that 77.6% of invasive MRSA infection is health care–associated, resulting in 9127 deaths in 2011 [8].

This article reviews the published literature on MRSA infections among patients recently discharged from hospital, with a focus on possible prevention measures.

MRSA Epidemiologic Categories