Patients with Barrett’s esophagus have about a 0.2% annual chance of developing esophageal adenocarcinoma in the 5 years after initial diagnosis, but the likelihood then rises so that about 9% of all patients will develop cancer by 20 years out, according to a study in the September issue of Gastroenterology.

The modeled rates of progression for the early years after diagnosis are substantially lower than are those reported by prospective studies, which involve more intensive surveillance and therefore suffer from detection bias, said Dr. Sonja Kroep of Erasmus Medical Center, Rotterdam, the Netherlands, and her associates. “Clinicians informing their patients about their cancer risk can best use this clinical progression rate, which is not influenced by surveillance-detected cancers,” they wrote.

Past analyses have yielded varying results for the rate at which Barrett’s esophagus with low-grade dysplasia progresses to high-grade dysplasia and esophageal carcinoma. For their study, Dr. Kroep and her associates calibrated a model based on the annual rate of 0.18% reported by population-level studies, and used it to simulate prospective studies and to predict results from both population-based and prospective studies for various follow-up periods (Gastroenterology 2015 Apr 29. pii: S0016-5085(15)00601-0).

For the first 5 years of follow-up, the model predicted a 0.19% annual rate of transformation to esophageal adenocarcinoma for population-based studies and a 0.36% annual rate for prospective studies, the researchers reported. At 20 years, these rates rose to 0.63% and 0.65% annually, for a cumulative incidence rate of 9.1% to 9.5%. Between the 5-year and 20-year thresholds, the gap between rates of progression for the two types of studies narrowed from 91% to 5%. Taken together, the findings suggest that for the first 5 years after a diagnosis of Barrett’s esophagus, rates of progression to esophageal adenocarcinoma reflect those from population-level studies instead of surveillance-based prospective studies, the investigators said. “Clinicians should use this information to explain to patients their short-term and long-term risks if no action is taken, and then discuss the risks and benefits of surveillance,” they added.

In a separate retrospective study, radiofrequency ablation of low-grade esophageal dysplasia was linked to substantially lower rates of progression compared with watchful waiting in the form of endoscopic surveillance, said Dr. Aaron Small of the University of Pennsylvania, Philadelphia, and his associates. Their study included 125 patients with Barrett’s esophagus and low-grade dysplasia who underwent surveillance only, and 45 patients who underwent radiofrequency ablation at three university medical centers.

Over median follow-up periods of more than 2 years, the risk of progression with radiofrequency ablation was significantly lower than with endoscopic surveillance only, even after the researchers controlled for year of diagnosis (adjusted hazard ratio, 0.06; 95% confidence interval, 0.008-0.48; P = .008). The ablation group also had fewer visible macroscopic lesions, although the difference was not significant. “We estimate that for every three patients treated with radiofrequency ablation, one additional patient with low-grade dysplasia will avoid progression to high-grade dysplasia or esophageal adenocarcinoma within 3 years,” the researchers wrote. “Although selection bias cannot be excluded, these findings provide additional evidence for the use of endoscopic ablation therapy for low-grade dysplasia” (Gastroenterology 2015 Apr 24. pii: S0016-5085(15)00569-7).

The study by Dr. Kroep and her associates was funded by grant U01 CA152926, and the investigators reported having no conflicts of interest. The study by Dr. Small and his associates was supported by the National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases and by institutional funds. Dr. Small reported no conflicts of interest, but seven coauthors reported ties with a number of pharmaceutical companies.

Patients with Barrett’s esophagus have about a 0.2% annual chance of developing esophageal adenocarcinoma in the 5 years after initial diagnosis, but the likelihood then rises so that about 9% of all patients will develop cancer by 20 years out, according to a study in the September issue of Gastroenterology.

The modeled rates of progression for the early years after diagnosis are substantially lower than are those reported by prospective studies, which involve more intensive surveillance and therefore suffer from detection bias, said Dr. Sonja Kroep of Erasmus Medical Center, Rotterdam, the Netherlands, and her associates. “Clinicians informing their patients about their cancer risk can best use this clinical progression rate, which is not influenced by surveillance-detected cancers,” they wrote.

Past analyses have yielded varying results for the rate at which Barrett’s esophagus with low-grade dysplasia progresses to high-grade dysplasia and esophageal carcinoma. For their study, Dr. Kroep and her associates calibrated a model based on the annual rate of 0.18% reported by population-level studies, and used it to simulate prospective studies and to predict results from both population-based and prospective studies for various follow-up periods (Gastroenterology 2015 Apr 29. pii: S0016-5085(15)00601-0).

For the first 5 years of follow-up, the model predicted a 0.19% annual rate of transformation to esophageal adenocarcinoma for population-based studies and a 0.36% annual rate for prospective studies, the researchers reported. At 20 years, these rates rose to 0.63% and 0.65% annually, for a cumulative incidence rate of 9.1% to 9.5%. Between the 5-year and 20-year thresholds, the gap between rates of progression for the two types of studies narrowed from 91% to 5%. Taken together, the findings suggest that for the first 5 years after a diagnosis of Barrett’s esophagus, rates of progression to esophageal adenocarcinoma reflect those from population-level studies instead of surveillance-based prospective studies, the investigators said. “Clinicians should use this information to explain to patients their short-term and long-term risks if no action is taken, and then discuss the risks and benefits of surveillance,” they added.

In a separate retrospective study, radiofrequency ablation of low-grade esophageal dysplasia was linked to substantially lower rates of progression compared with watchful waiting in the form of endoscopic surveillance, said Dr. Aaron Small of the University of Pennsylvania, Philadelphia, and his associates. Their study included 125 patients with Barrett’s esophagus and low-grade dysplasia who underwent surveillance only, and 45 patients who underwent radiofrequency ablation at three university medical centers.

Over median follow-up periods of more than 2 years, the risk of progression with radiofrequency ablation was significantly lower than with endoscopic surveillance only, even after the researchers controlled for year of diagnosis (adjusted hazard ratio, 0.06; 95% confidence interval, 0.008-0.48; P = .008). The ablation group also had fewer visible macroscopic lesions, although the difference was not significant. “We estimate that for every three patients treated with radiofrequency ablation, one additional patient with low-grade dysplasia will avoid progression to high-grade dysplasia or esophageal adenocarcinoma within 3 years,” the researchers wrote. “Although selection bias cannot be excluded, these findings provide additional evidence for the use of endoscopic ablation therapy for low-grade dysplasia” (Gastroenterology 2015 Apr 24. pii: S0016-5085(15)00569-7).

The study by Dr. Kroep and her associates was funded by grant U01 CA152926, and the investigators reported having no conflicts of interest. The study by Dr. Small and his associates was supported by the National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases and by institutional funds. Dr. Small reported no conflicts of interest, but seven coauthors reported ties with a number of pharmaceutical companies.

Patients with Barrett’s esophagus have about a 0.2% annual chance of developing esophageal adenocarcinoma in the 5 years after initial diagnosis, but the likelihood then rises so that about 9% of all patients will develop cancer by 20 years out, according to a study in the September issue of Gastroenterology.

The modeled rates of progression for the early years after diagnosis are substantially lower than are those reported by prospective studies, which involve more intensive surveillance and therefore suffer from detection bias, said Dr. Sonja Kroep of Erasmus Medical Center, Rotterdam, the Netherlands, and her associates. “Clinicians informing their patients about their cancer risk can best use this clinical progression rate, which is not influenced by surveillance-detected cancers,” they wrote.

Past analyses have yielded varying results for the rate at which Barrett’s esophagus with low-grade dysplasia progresses to high-grade dysplasia and esophageal carcinoma. For their study, Dr. Kroep and her associates calibrated a model based on the annual rate of 0.18% reported by population-level studies, and used it to simulate prospective studies and to predict results from both population-based and prospective studies for various follow-up periods (Gastroenterology 2015 Apr 29. pii: S0016-5085(15)00601-0).

For the first 5 years of follow-up, the model predicted a 0.19% annual rate of transformation to esophageal adenocarcinoma for population-based studies and a 0.36% annual rate for prospective studies, the researchers reported. At 20 years, these rates rose to 0.63% and 0.65% annually, for a cumulative incidence rate of 9.1% to 9.5%. Between the 5-year and 20-year thresholds, the gap between rates of progression for the two types of studies narrowed from 91% to 5%. Taken together, the findings suggest that for the first 5 years after a diagnosis of Barrett’s esophagus, rates of progression to esophageal adenocarcinoma reflect those from population-level studies instead of surveillance-based prospective studies, the investigators said. “Clinicians should use this information to explain to patients their short-term and long-term risks if no action is taken, and then discuss the risks and benefits of surveillance,” they added.

In a separate retrospective study, radiofrequency ablation of low-grade esophageal dysplasia was linked to substantially lower rates of progression compared with watchful waiting in the form of endoscopic surveillance, said Dr. Aaron Small of the University of Pennsylvania, Philadelphia, and his associates. Their study included 125 patients with Barrett’s esophagus and low-grade dysplasia who underwent surveillance only, and 45 patients who underwent radiofrequency ablation at three university medical centers.

Over median follow-up periods of more than 2 years, the risk of progression with radiofrequency ablation was significantly lower than with endoscopic surveillance only, even after the researchers controlled for year of diagnosis (adjusted hazard ratio, 0.06; 95% confidence interval, 0.008-0.48; P = .008). The ablation group also had fewer visible macroscopic lesions, although the difference was not significant. “We estimate that for every three patients treated with radiofrequency ablation, one additional patient with low-grade dysplasia will avoid progression to high-grade dysplasia or esophageal adenocarcinoma within 3 years,” the researchers wrote. “Although selection bias cannot be excluded, these findings provide additional evidence for the use of endoscopic ablation therapy for low-grade dysplasia” (Gastroenterology 2015 Apr 24. pii: S0016-5085(15)00569-7).

The study by Dr. Kroep and her associates was funded by grant U01 CA152926, and the investigators reported having no conflicts of interest. The study by Dr. Small and his associates was supported by the National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases and by institutional funds. Dr. Small reported no conflicts of interest, but seven coauthors reported ties with a number of pharmaceutical companies.

A personalized PCR test for circulating tumor DNA identified cases of progressive hepatocellular carcinoma, investigators reported in the September issue of Cellular and Molecular Gastroenterology and Hepatology.

Patients with liver cancer who underwent resection or transplantation and were positive for ctDNA had significantly higher rates of recurrence (P <.0102) and metastasis (P <.0386), reported Dr. Atsushi Ono of Hiroshima (Japan) University and the RIKEN Center for Integrative Medical Sciences and associates. The study also found that transcatheter arterial chemoembolization [TACE] increased levels of ctDNA, compared with total cell-free DNA, making the marker easier to detect.

©Jezperklauzen/ThinkStock

“Analyzing cell-free DNA after TACE in unresectable and recurrent cases as a liquid biopsy to establish cancer genome profiles might … guide selection of an individualized therapeutic regimen without requiring percutaneous biopsy,” they added.

Assays for ctDNA have shown promise for diagnosing other cancers and targeting their treatments, but HCC diagnosis relies primarily on imaging, and HCC ctDNA has not been well characterized, noted the investigators. They performed massively parallel whole-genome sequencing of DNA extracted from resected HCCs from 46 patients. They serially measured plasma ctDNA levels before and after surgery using personalized quantitative PCR assays that targeted somatic rearrangements. They also used chemiluminescent immunoassays to test for two conventional tumor markers, alpha-fetoprotein and des-gamma-carboxy prothrombin (Cell Mol Gastroenterol Hepatol. 2015 Jul 2 [doi: 10.1016/j.jcmgh.2015.06.009]).

In all, 25 somatic mutations were present in both primary tumor tissue and in cell-free DNA samples, and 83% of mutations in the primary tumor were detectable in cell-free DNA. Among seven patients who tested positive for ctDNA before surgery, six developed recurrent disease and four developed extrahepatic metastases, Dr. Ono and associates said.

Levels of ctDNA increased as disease progressed and dropped in response to treatment, and one case remained positive for ctDNA even after alpha-fetoprotein and des-gamma-carboxy prothrombin became negative or dropped below threshold after resection. “This suggests that, in some patients, ctDNA might be a better and more sensitive biomarker for HCC than the conventional tumor markers,” they said.

The assay analyzed plasma instead of serum because serum was likely to have more normal cell-free nucleic acids, which would make it harder to detect mutant alleles, the investigators noted. Testing for ctDNA could help address the problem of tumor heterogeneity because ctDNA contains the entire tumor genome, including variants from independent tumors, but the assay will need further validation, especially because its lower limits varied by primer sets, which reduced its sensitivity and meant that some cases went undetected, they added.

The study was funded by the government of Japan, the RIKEN President’s Fund, the Princess Takamatsu Cancer Research Fund, and the Takeda Science Foundation. The investigators declared no competing interests.

A personalized PCR test for circulating tumor DNA identified cases of progressive hepatocellular carcinoma, investigators reported in the September issue of Cellular and Molecular Gastroenterology and Hepatology.

Patients with liver cancer who underwent resection or transplantation and were positive for ctDNA had significantly higher rates of recurrence (P <.0102) and metastasis (P <.0386), reported Dr. Atsushi Ono of Hiroshima (Japan) University and the RIKEN Center for Integrative Medical Sciences and associates. The study also found that transcatheter arterial chemoembolization [TACE] increased levels of ctDNA, compared with total cell-free DNA, making the marker easier to detect.

©Jezperklauzen/ThinkStock

“Analyzing cell-free DNA after TACE in unresectable and recurrent cases as a liquid biopsy to establish cancer genome profiles might … guide selection of an individualized therapeutic regimen without requiring percutaneous biopsy,” they added.

Assays for ctDNA have shown promise for diagnosing other cancers and targeting their treatments, but HCC diagnosis relies primarily on imaging, and HCC ctDNA has not been well characterized, noted the investigators. They performed massively parallel whole-genome sequencing of DNA extracted from resected HCCs from 46 patients. They serially measured plasma ctDNA levels before and after surgery using personalized quantitative PCR assays that targeted somatic rearrangements. They also used chemiluminescent immunoassays to test for two conventional tumor markers, alpha-fetoprotein and des-gamma-carboxy prothrombin (Cell Mol Gastroenterol Hepatol. 2015 Jul 2 [doi: 10.1016/j.jcmgh.2015.06.009]).

In all, 25 somatic mutations were present in both primary tumor tissue and in cell-free DNA samples, and 83% of mutations in the primary tumor were detectable in cell-free DNA. Among seven patients who tested positive for ctDNA before surgery, six developed recurrent disease and four developed extrahepatic metastases, Dr. Ono and associates said.

Levels of ctDNA increased as disease progressed and dropped in response to treatment, and one case remained positive for ctDNA even after alpha-fetoprotein and des-gamma-carboxy prothrombin became negative or dropped below threshold after resection. “This suggests that, in some patients, ctDNA might be a better and more sensitive biomarker for HCC than the conventional tumor markers,” they said.

The assay analyzed plasma instead of serum because serum was likely to have more normal cell-free nucleic acids, which would make it harder to detect mutant alleles, the investigators noted. Testing for ctDNA could help address the problem of tumor heterogeneity because ctDNA contains the entire tumor genome, including variants from independent tumors, but the assay will need further validation, especially because its lower limits varied by primer sets, which reduced its sensitivity and meant that some cases went undetected, they added.

The study was funded by the government of Japan, the RIKEN President’s Fund, the Princess Takamatsu Cancer Research Fund, and the Takeda Science Foundation. The investigators declared no competing interests.

A personalized PCR test for circulating tumor DNA identified cases of progressive hepatocellular carcinoma, investigators reported in the September issue of Cellular and Molecular Gastroenterology and Hepatology.

Patients with liver cancer who underwent resection or transplantation and were positive for ctDNA had significantly higher rates of recurrence (P <.0102) and metastasis (P <.0386), reported Dr. Atsushi Ono of Hiroshima (Japan) University and the RIKEN Center for Integrative Medical Sciences and associates. The study also found that transcatheter arterial chemoembolization [TACE] increased levels of ctDNA, compared with total cell-free DNA, making the marker easier to detect.

©Jezperklauzen/ThinkStock

“Analyzing cell-free DNA after TACE in unresectable and recurrent cases as a liquid biopsy to establish cancer genome profiles might … guide selection of an individualized therapeutic regimen without requiring percutaneous biopsy,” they added.

Assays for ctDNA have shown promise for diagnosing other cancers and targeting their treatments, but HCC diagnosis relies primarily on imaging, and HCC ctDNA has not been well characterized, noted the investigators. They performed massively parallel whole-genome sequencing of DNA extracted from resected HCCs from 46 patients. They serially measured plasma ctDNA levels before and after surgery using personalized quantitative PCR assays that targeted somatic rearrangements. They also used chemiluminescent immunoassays to test for two conventional tumor markers, alpha-fetoprotein and des-gamma-carboxy prothrombin (Cell Mol Gastroenterol Hepatol. 2015 Jul 2 [doi: 10.1016/j.jcmgh.2015.06.009]).

In all, 25 somatic mutations were present in both primary tumor tissue and in cell-free DNA samples, and 83% of mutations in the primary tumor were detectable in cell-free DNA. Among seven patients who tested positive for ctDNA before surgery, six developed recurrent disease and four developed extrahepatic metastases, Dr. Ono and associates said.

Levels of ctDNA increased as disease progressed and dropped in response to treatment, and one case remained positive for ctDNA even after alpha-fetoprotein and des-gamma-carboxy prothrombin became negative or dropped below threshold after resection. “This suggests that, in some patients, ctDNA might be a better and more sensitive biomarker for HCC than the conventional tumor markers,” they said.

The assay analyzed plasma instead of serum because serum was likely to have more normal cell-free nucleic acids, which would make it harder to detect mutant alleles, the investigators noted. Testing for ctDNA could help address the problem of tumor heterogeneity because ctDNA contains the entire tumor genome, including variants from independent tumors, but the assay will need further validation, especially because its lower limits varied by primer sets, which reduced its sensitivity and meant that some cases went undetected, they added.

The study was funded by the government of Japan, the RIKEN President’s Fund, the Princess Takamatsu Cancer Research Fund, and the Takeda Science Foundation. The investigators declared no competing interests.

More bicyclists, more fatalities

BY RICHARD FRANKI
FROM MORBIDITY AND MORTALITY WEEKLY REPORT

Annual mortality among cyclists for all motor vehicle-related deaths was 0.23 per 100,000 in 2012, a decline of 44% since 1975 when the rate was 0.41 per 100,000. But the rate is up from just under 0.20 per 100,000 in 2010. In 2012, the rate topped the Healthy People 2020 goal of 0.22 for the first time since 2008, according to Jason Vargo, PhD, of the University of Wisconsin, Madison, and his associates.¹

The explanation may be that the number of bicyclists has been steadily rising. “The share of total household trips taken by bicycle has doubled over the last 35 years,” with the largest share of that increase occurring in recent years. From 2000 to 2012, for example, “the number of US workers who traveled to work by bicycle increased 61%,” the researchers wrote.

The report was based on data from the Fatality Analysis Reporting System, which limits fatalities to those involving a motor vehicle on a public road.²

Surgical bolt cutters quickly cut titanium ring

BY AMY KARON
FROM EMERGENCY MEDICINE JOURNAL 

“Our method used simple equipment that is readily available in most hospitals at all times, took less than 30 seconds to perform, and could be performed by a sole operator without damage to the underlying finger,” wrote Dr Andrej Salibi and Dr Andrew Morritt at Sheffield (England) Teaching Hospital NHS Foundation.¹

Ring constriction is a fairly common problem that can cause necrosis and loss of the digit if the ring is not removed. Basic ring cutters can sever gold and silver, but not titanium, which has become popular for rings because it is hypoallergenic, durable, lightweight, and strong—so strong that diamond-tipped saws or drills can take up to 15 minutes to cut these rings. Many facilities also lack access to such equipment, and it generates enough heat that an assistant must irrigate the surrounding skin to prevent burns.

The case report described a patient who bathed in warm water at a spa and developed a painful, swollen finger that was constricted by a titanium wedding band. Elevation and lubrication at the ED failed to remove the ring, as did finger binding, and use of a manual ring cutter.

“The fire service was called and attempted removal using specialized cutting equipment, which also failed,” the surgeons wrote. “The patient was then admitted under the plastic surgery service for hand elevation, and further attempts 8 hours later blunted two manual ring cutters.” At this point, the surgeons borrowed a large pair of bolt cutters from the operating room, and quickly severed the ring without harming the finger. Then they applied lateral traction with a pair of paper clips and removed the split ring.

The authors declared no funding sources or conflicts of interest.

Federal plan emphasizes heroin/opioid treatment over incarceration

BY WHITNEY MCKNIGHT
Frontline Medical News 

The increased emphasis will center on geographic areas where heroin and opioid abuse are rampant, specifically: Appalachia; New England; Philadelphia/Camden, New Jersey; metropolitan New York City, particularly northern New Jersey; and the Washington/Baltimore metropolitan region. Public safety officers and first responders will be trained in how to administer naloxone and provide other medical attention for those in the midst of a heroin or opioid overdose. 

The 15 states in the targeted areas will share and leverage data to determine regional patterns of heroin and prescription painkiller-related overdose. These data are expected to delineate where the narcotics—especially those laced with other, more dangerous drugs—are being produced and distributed so that heroin response teams can disrupt the production and distribution of illegal drugs, and respond pre-emptively by expanding resources to communities hardest hit.

In a statement, Michael Botticelli, director of the White House Office of National Drug Control Policy, said the administration’s emphasis on “the national drug challenge as both a public health and public safety issue” is based on viewing drug addiction as “a chronic disease of the brain that can be successfully prevented and treated, and from which one can recover.” 

The initiative also will provide additional funding for similar efforts to address opioid abuse and methamphetamine abuse in the Southwest and along the United States/Mexico border.

“This program demonstrates the importance of linking health to criminal justice in collaboration rather than seeing better, new drug policy as a choice between health and law enforcement,” Dr Robert L. DuPont, former director of the National Institute on Drug Abuse (NIDA) and president of the Institute for Behavior and Health, said in an interview.

Online resource is aid for preventing patient falls

BY MIKE BOCK
Frontline Medical News

Developed in collaboration with seven hospitals and five health care organizations, the fall prevention methodology of the Targeted Solutions Tool could potentially reduce the number of patients injured from a fall from 117 to 45 in a typical 200-bed hospital, avoiding approximately $1 million in costs annually, the agency claims.

Some of the recommendations for reducing in-hospital falls include:

•  Creating awareness among staff
•  Using a validated fall risk assessment tool
•  Engaging patients and their families in the fall safety program
•  Hourly rounding with scheduled restroom use for patients
•  Engaging all hospital staff and patients to ensure no patient walks without  assistance

“Hundreds of thousands of patients fall in hospitals every year; and many of these falls result in moderate to severe injuries that can prolong hospital stays and require the patient to undergo additional treatment,” Dr Erin DuPree, vice president and chief medical officer of the Joint Commission Center for Transforming Healthcare, said in a statement.

The Joint Commission Center for Transforming Healthcare was created in 2008 as a nonprofit affiliate of The Joint Commission.

Dr Lappin is an assistant professor and an attending physician, department of emergency medicine, New York-Presbyterian Hospital/Weill Cornell Medical College, New York.

More bicyclists, more fatalities

BY RICHARD FRANKI
FROM MORBIDITY AND MORTALITY WEEKLY REPORT

Annual mortality among cyclists for all motor vehicle-related deaths was 0.23 per 100,000 in 2012, a decline of 44% since 1975 when the rate was 0.41 per 100,000. But the rate is up from just under 0.20 per 100,000 in 2010. In 2012, the rate topped the Healthy People 2020 goal of 0.22 for the first time since 2008, according to Jason Vargo, PhD, of the University of Wisconsin, Madison, and his associates.¹

The explanation may be that the number of bicyclists has been steadily rising. “The share of total household trips taken by bicycle has doubled over the last 35 years,” with the largest share of that increase occurring in recent years. From 2000 to 2012, for example, “the number of US workers who traveled to work by bicycle increased 61%,” the researchers wrote.

The report was based on data from the Fatality Analysis Reporting System, which limits fatalities to those involving a motor vehicle on a public road.²

Surgical bolt cutters quickly cut titanium ring

BY AMY KARON
FROM EMERGENCY MEDICINE JOURNAL 

“Our method used simple equipment that is readily available in most hospitals at all times, took less than 30 seconds to perform, and could be performed by a sole operator without damage to the underlying finger,” wrote Dr Andrej Salibi and Dr Andrew Morritt at Sheffield (England) Teaching Hospital NHS Foundation.¹

Ring constriction is a fairly common problem that can cause necrosis and loss of the digit if the ring is not removed. Basic ring cutters can sever gold and silver, but not titanium, which has become popular for rings because it is hypoallergenic, durable, lightweight, and strong—so strong that diamond-tipped saws or drills can take up to 15 minutes to cut these rings. Many facilities also lack access to such equipment, and it generates enough heat that an assistant must irrigate the surrounding skin to prevent burns.

The case report described a patient who bathed in warm water at a spa and developed a painful, swollen finger that was constricted by a titanium wedding band. Elevation and lubrication at the ED failed to remove the ring, as did finger binding, and use of a manual ring cutter.

“The fire service was called and attempted removal using specialized cutting equipment, which also failed,” the surgeons wrote. “The patient was then admitted under the plastic surgery service for hand elevation, and further attempts 8 hours later blunted two manual ring cutters.” At this point, the surgeons borrowed a large pair of bolt cutters from the operating room, and quickly severed the ring without harming the finger. Then they applied lateral traction with a pair of paper clips and removed the split ring.

The authors declared no funding sources or conflicts of interest.

Federal plan emphasizes heroin/opioid treatment over incarceration

BY WHITNEY MCKNIGHT
Frontline Medical News 

The increased emphasis will center on geographic areas where heroin and opioid abuse are rampant, specifically: Appalachia; New England; Philadelphia/Camden, New Jersey; metropolitan New York City, particularly northern New Jersey; and the Washington/Baltimore metropolitan region. Public safety officers and first responders will be trained in how to administer naloxone and provide other medical attention for those in the midst of a heroin or opioid overdose. 

The 15 states in the targeted areas will share and leverage data to determine regional patterns of heroin and prescription painkiller-related overdose. These data are expected to delineate where the narcotics—especially those laced with other, more dangerous drugs—are being produced and distributed so that heroin response teams can disrupt the production and distribution of illegal drugs, and respond pre-emptively by expanding resources to communities hardest hit.

In a statement, Michael Botticelli, director of the White House Office of National Drug Control Policy, said the administration’s emphasis on “the national drug challenge as both a public health and public safety issue” is based on viewing drug addiction as “a chronic disease of the brain that can be successfully prevented and treated, and from which one can recover.” 

The initiative also will provide additional funding for similar efforts to address opioid abuse and methamphetamine abuse in the Southwest and along the United States/Mexico border.

“This program demonstrates the importance of linking health to criminal justice in collaboration rather than seeing better, new drug policy as a choice between health and law enforcement,” Dr Robert L. DuPont, former director of the National Institute on Drug Abuse (NIDA) and president of the Institute for Behavior and Health, said in an interview.

Online resource is aid for preventing patient falls

BY MIKE BOCK
Frontline Medical News

Developed in collaboration with seven hospitals and five health care organizations, the fall prevention methodology of the Targeted Solutions Tool could potentially reduce the number of patients injured from a fall from 117 to 45 in a typical 200-bed hospital, avoiding approximately $1 million in costs annually, the agency claims.

Some of the recommendations for reducing in-hospital falls include:

•  Creating awareness among staff
•  Using a validated fall risk assessment tool
•  Engaging patients and their families in the fall safety program
•  Hourly rounding with scheduled restroom use for patients
•  Engaging all hospital staff and patients to ensure no patient walks without  assistance

“Hundreds of thousands of patients fall in hospitals every year; and many of these falls result in moderate to severe injuries that can prolong hospital stays and require the patient to undergo additional treatment,” Dr Erin DuPree, vice president and chief medical officer of the Joint Commission Center for Transforming Healthcare, said in a statement.

The Joint Commission Center for Transforming Healthcare was created in 2008 as a nonprofit affiliate of The Joint Commission.

Dr Lappin is an assistant professor and an attending physician, department of emergency medicine, New York-Presbyterian Hospital/Weill Cornell Medical College, New York.

More bicyclists, more fatalities

BY RICHARD FRANKI
FROM MORBIDITY AND MORTALITY WEEKLY REPORT

Annual mortality among cyclists for all motor vehicle-related deaths was 0.23 per 100,000 in 2012, a decline of 44% since 1975 when the rate was 0.41 per 100,000. But the rate is up from just under 0.20 per 100,000 in 2010. In 2012, the rate topped the Healthy People 2020 goal of 0.22 for the first time since 2008, according to Jason Vargo, PhD, of the University of Wisconsin, Madison, and his associates.¹

The explanation may be that the number of bicyclists has been steadily rising. “The share of total household trips taken by bicycle has doubled over the last 35 years,” with the largest share of that increase occurring in recent years. From 2000 to 2012, for example, “the number of US workers who traveled to work by bicycle increased 61%,” the researchers wrote.

The report was based on data from the Fatality Analysis Reporting System, which limits fatalities to those involving a motor vehicle on a public road.²

Surgical bolt cutters quickly cut titanium ring

BY AMY KARON
FROM EMERGENCY MEDICINE JOURNAL 

“Our method used simple equipment that is readily available in most hospitals at all times, took less than 30 seconds to perform, and could be performed by a sole operator without damage to the underlying finger,” wrote Dr Andrej Salibi and Dr Andrew Morritt at Sheffield (England) Teaching Hospital NHS Foundation.¹

Ring constriction is a fairly common problem that can cause necrosis and loss of the digit if the ring is not removed. Basic ring cutters can sever gold and silver, but not titanium, which has become popular for rings because it is hypoallergenic, durable, lightweight, and strong—so strong that diamond-tipped saws or drills can take up to 15 minutes to cut these rings. Many facilities also lack access to such equipment, and it generates enough heat that an assistant must irrigate the surrounding skin to prevent burns.

The case report described a patient who bathed in warm water at a spa and developed a painful, swollen finger that was constricted by a titanium wedding band. Elevation and lubrication at the ED failed to remove the ring, as did finger binding, and use of a manual ring cutter.

“The fire service was called and attempted removal using specialized cutting equipment, which also failed,” the surgeons wrote. “The patient was then admitted under the plastic surgery service for hand elevation, and further attempts 8 hours later blunted two manual ring cutters.” At this point, the surgeons borrowed a large pair of bolt cutters from the operating room, and quickly severed the ring without harming the finger. Then they applied lateral traction with a pair of paper clips and removed the split ring.

The authors declared no funding sources or conflicts of interest.

Federal plan emphasizes heroin/opioid treatment over incarceration

BY WHITNEY MCKNIGHT
Frontline Medical News 

The increased emphasis will center on geographic areas where heroin and opioid abuse are rampant, specifically: Appalachia; New England; Philadelphia/Camden, New Jersey; metropolitan New York City, particularly northern New Jersey; and the Washington/Baltimore metropolitan region. Public safety officers and first responders will be trained in how to administer naloxone and provide other medical attention for those in the midst of a heroin or opioid overdose. 

The 15 states in the targeted areas will share and leverage data to determine regional patterns of heroin and prescription painkiller-related overdose. These data are expected to delineate where the narcotics—especially those laced with other, more dangerous drugs—are being produced and distributed so that heroin response teams can disrupt the production and distribution of illegal drugs, and respond pre-emptively by expanding resources to communities hardest hit.

In a statement, Michael Botticelli, director of the White House Office of National Drug Control Policy, said the administration’s emphasis on “the national drug challenge as both a public health and public safety issue” is based on viewing drug addiction as “a chronic disease of the brain that can be successfully prevented and treated, and from which one can recover.” 

The initiative also will provide additional funding for similar efforts to address opioid abuse and methamphetamine abuse in the Southwest and along the United States/Mexico border.

“This program demonstrates the importance of linking health to criminal justice in collaboration rather than seeing better, new drug policy as a choice between health and law enforcement,” Dr Robert L. DuPont, former director of the National Institute on Drug Abuse (NIDA) and president of the Institute for Behavior and Health, said in an interview.

Online resource is aid for preventing patient falls

BY MIKE BOCK
Frontline Medical News

Developed in collaboration with seven hospitals and five health care organizations, the fall prevention methodology of the Targeted Solutions Tool could potentially reduce the number of patients injured from a fall from 117 to 45 in a typical 200-bed hospital, avoiding approximately $1 million in costs annually, the agency claims.

Some of the recommendations for reducing in-hospital falls include:

•  Creating awareness among staff
•  Using a validated fall risk assessment tool
•  Engaging patients and their families in the fall safety program
•  Hourly rounding with scheduled restroom use for patients
•  Engaging all hospital staff and patients to ensure no patient walks without  assistance

“Hundreds of thousands of patients fall in hospitals every year; and many of these falls result in moderate to severe injuries that can prolong hospital stays and require the patient to undergo additional treatment,” Dr Erin DuPree, vice president and chief medical officer of the Joint Commission Center for Transforming Healthcare, said in a statement.

The Joint Commission Center for Transforming Healthcare was created in 2008 as a nonprofit affiliate of The Joint Commission.

Dr Lappin is an assistant professor and an attending physician, department of emergency medicine, New York-Presbyterian Hospital/Weill Cornell Medical College, New York.

Missed Preeclampsia

On physical examination, the patient’s vital signs were remarkable for the following: heart rate (HR), 86 beats/minute; blood pressure (BP), 164/94 mm Hg; respiratory rate, 18 breaths/minute; temperature, 98.6^oF. Oxygen saturation was 96% on room air. The head, eye, ear, nose and throat examination was unremarkable. The lungs were clear to auscultation bilaterally, and HR and heart rhythm were normal. The abdomen was soft and nontender without guarding or rebound. The lower extremities were remarkable for 1+ pedal and pretibial edema bilaterally.

The patient presented to the same ED 2 days later, again with the chief complaint of shortness of breath. On examination, her BP was noted to be elevated and she had 1+ dependent edema bilaterally. Again, the EP was concerned for a PE and ordered a repeat CTA scan of the chest. This study, similar to the first, was read as normal, and showed no evidence of PE. The patient was diagnosed again with “shortness of breath of unknown etiology” and discharged home. The patient’s obstetrician-gynecologist (Ob/Gyn) was not consulted; however, the patient was encouraged to follow up with him.

The next day, the patient presented to the same ED via emergency medical services, this time with seizures; she had no prior history of a seizure disorder. On presentation to the ED, she was noted to be postictal, with an elevated BP and tachycardic with an HR of 104 beats/minute. On examination, the lungs were clear to auscultation and the lower extremities exhibited 1+ pedal and pretibial edema. A urinalysis revealed proteinuria. The patient was given 4 g of magnesium sulfate intravenously (IV) and her Ob/Gyn was consulted.

The patient was admitted to the hospital with a diagnosis of eclampsia. She was given an IV drip of magnesium and labetalol for the high BP. Unfortunately, the patient apparently had suffered an anoxic brain injury from the previous seizures and died on hospital day 3.

The family sued the treating EPs and the hospital for failure to diagnose preeclampsia on two separate ED presentations. They noted the patient’s Ob/Gyn was never consulted; no action was taken to treat the hypertension; and no urinalysis was ordered on either visit. The EPs and hospital settled the case prior to trial for several million dollars.

Discussion

This is an incredibly sad case, and the EPs and hospital were right to settle and not go to trial. While PE was a reasonable diagnosis to consider in this patient on her first ED visit, it should not have been the only one in the differential diagnosis. The EP became anchored to this single diagnosis and refused to consider other alternative diagnoses—even after the CTA scan of the chest ruled out PE. Moreover, it appears the EP either never considered the significance of the elevated BP and dependent edema or just ignored these findings. To repeat essentially the same exact workup on the second visit does not make sense—one should “cast a wider net, not the same net.”

The diagnosis of “shortness of breath of unknown etiology” is similarly unacceptable. While this is a common and accepted diagnosis when it pertains to abdominal pain, the same is not true for dyspnea.

Preeclampsia is characterized by hypertension (BP >140/90 mm Hg) and proteinuria; associated symptoms include edema and hyperreflexia. Postpartum preeclampsia occurs infrequently and can develop up to 4 weeks after delivery.¹ In one 10-year retrospective case series, the incidence of preeclampsia in the postpartum period was 5.7%, and nearly 16% went on to develop eclampsia.² In a retrospective study of 22 postpartum preeclamptic patients, the median time to presentation was 5 days postpartum.¹ In a similar retrospective study of 152 patients, 90% of such patients presented within 7 days.³ The patient in this case initially presented on postpartum day 4.

Interestingly, in a study by Al-Safi et al,³ 63% of postpartum preeclamptic patients had no antecedent diagnosis of hypertensive disease during pregnancy. These findings are consistent with the findings of others that 33% to 69% of such patients show no evidence of preeclampsia in the ante- or peripartum period.

The clinical presentation of postpartum preeclampsia is similar to preeclampsia complicating pregnancy after gestation week 20. In the study by Al-Safi et al,³ headache was the most common presenting symptom (69%), followed by shortness of breath (30%), blurry vision (21%), nausea (12.5%), and epigastric abdominal pain (5%). Similarly, Yancey et al¹ found headache (82%) to be the most common presenting symptom in their series. Unfortunately, it is not known whether the patient in this case complained of headache or blurred vision as the published records note neither their presence nor absence.

The management of patients with preeclampsia includes IV magnesium to prevent seizures (ie, eclampsia) and BP control.¹ A bolus of 4 to 6 g IV magnesium sulfate over 15 to 30 minutes is recommended, followed by an infusion of 2 g/h IV. Historically, IV hydralazine has been used to manage preeclamptic patients with a BP greater than 160/110 mm Hg. More recently, however, IV labetalol has become popular.⁵ All such patients require admission to the hospital with Ob/Gyn involvement.

Missed Subdural Hematoma

A 59-year-old man presented to the ED with a chief complaint of headache, the onset of which he stated started gradually 2 days prior. He noted the headache was worse than normal but without associated nausea, vomiting, fever, chills, or change in vision. His past medical history was significant for a lower extremity deep vein thrombosis 3 months prior, for which he was taking warfarin.

The patient’s vital signs were all normal. The physical examination, including a thorough neurological examination, was also normal. The EP ordered a prothrombin time (PT), an international normalized ratio (INR), and a noncontrast CT scan of the head. The PT/INR results were therapeutic at 22 seconds and 2.3. The CT scan was interpreted by radiology services as normal. The patient’s headache was treated with IV prochlorperazine and diphenhydramine. After treatment, the patient reported feeling better and was discharged home with instructions to follow up with his primary care physician.

Over the next several months, the patient presented to the same ED on seven different occasions, each time with the chief complaint of headache. At each of these presentations, the history and physical examination were documented as unremarkable, with no history of trauma. The thoroughness, however, of the documentation varied considerably for each ED encounter. No head CT scan was ordered on the subsequent seven visits, and at each presentation, the patient was treated symptomatically and discharged home.

Two days after his eighth visit to the same hospital ED, the patient presented to a different ED, again with a chief complaint of headache. The EP at this ED ordered a noncontrast CT of the head, which demonstrated a left subdural hematoma. The patient was admitted to the hospital, given IV vitamin K and fresh frozen plasma, and underwent evacuation of the hematoma by neurosurgery. The patient’s hospital course was unremarkable, and he was discharged home without any focal weakness.

The patient, however, claimed that he suffered cognitive impairment as a result of the missed diagnosis. He sued treating EPs at the first ED as well as the hospital for failure to timely diagnose the subdural hematoma, stating that a CT scan should have been performed at each of his ED visits since he was on warfarin. The defense claimed that a CT scan was not warranted for each visit, and that the timing of when and how the brain bleed started was uncertain. At trial, a defense verdict was returned.

Discussion

It is well known that patients receiving warfarin are at an increased risk for intracranial hemorrhage (ICH) following blunt head trauma.¹ The recommendation is that all such patients have a noncontrast CT scan of the head to rule out intracranial bleeding. This is due to the fact that 60% of patients presenting with an immediate traumatic intracranial hemorrhage will have a normal mental status on examination; and 11% will have no history of loss of consciousness, a normal mental status examination, and no physical evidence of trauma above the clavicles.¹ In a study by Hart et al,² subdural hematoma accounted for 44% of all ICH in these types of patients.

More controversial is how to manage patients on warfarin who experience blunt head trauma and have a normal CT scan of the head. Because of the fear for delayed traumatic ICH, many clinicians recommend admitting such patients for neurological observation and repeat head CT scan the next morning.³ Additionally, some clinicians even recommend reversing the warfarin anticoagulation in such patients. ⁴ These recommendations, though, are based on expert consensus rather than on rigorous, prospective multicenter studies.¹  These strategies are also problematic, since such multiple repeat CT scans would not only be incredibly expensive but also would expose the patient to high doses of radiation to the brain. Moreover, the Centers for Medicare and Medicaid Services has now made CT brain scan imaging of patients presenting to the ED with complaint of nontraumatic headache a quality measure they follow. Their goal is to decrease the number of “unnecessary” head CT scans.

The patient in this case denied any history of trauma on the subsequent seven ED visits. Unfortunately, as pointed out, even minor trauma can result in ICH, and patients may not recall the occurrence of the event.

For patients on warfarin who present with headache, a very careful history must be taken—including inquiring about minor traumatic events. Even then, as has been shown, patients may have not experienced a loss of consciousness, have a normal mental status examination, and exhibit no external evidence of head trauma. The clinician is forced to use her or his own best judgment when evaluating such patients in the ED.

Interestingly, the risk of ICH secondary to blunt head trauma in patients on warfarin is increased if they are on concomitant aspirin therapy.² Similarly, the risk of ICH following head trauma in patients on clopidogrel is greater than for those patients taking warfarin,¹ and the risk of ICH in patients taking dabigatran is less than if taking warfarin.²

Missed Preeclampsia

On physical examination, the patient’s vital signs were remarkable for the following: heart rate (HR), 86 beats/minute; blood pressure (BP), 164/94 mm Hg; respiratory rate, 18 breaths/minute; temperature, 98.6^oF. Oxygen saturation was 96% on room air. The head, eye, ear, nose and throat examination was unremarkable. The lungs were clear to auscultation bilaterally, and HR and heart rhythm were normal. The abdomen was soft and nontender without guarding or rebound. The lower extremities were remarkable for 1+ pedal and pretibial edema bilaterally.

The patient presented to the same ED 2 days later, again with the chief complaint of shortness of breath. On examination, her BP was noted to be elevated and she had 1+ dependent edema bilaterally. Again, the EP was concerned for a PE and ordered a repeat CTA scan of the chest. This study, similar to the first, was read as normal, and showed no evidence of PE. The patient was diagnosed again with “shortness of breath of unknown etiology” and discharged home. The patient’s obstetrician-gynecologist (Ob/Gyn) was not consulted; however, the patient was encouraged to follow up with him.

The next day, the patient presented to the same ED via emergency medical services, this time with seizures; she had no prior history of a seizure disorder. On presentation to the ED, she was noted to be postictal, with an elevated BP and tachycardic with an HR of 104 beats/minute. On examination, the lungs were clear to auscultation and the lower extremities exhibited 1+ pedal and pretibial edema. A urinalysis revealed proteinuria. The patient was given 4 g of magnesium sulfate intravenously (IV) and her Ob/Gyn was consulted.

The patient was admitted to the hospital with a diagnosis of eclampsia. She was given an IV drip of magnesium and labetalol for the high BP. Unfortunately, the patient apparently had suffered an anoxic brain injury from the previous seizures and died on hospital day 3.

The family sued the treating EPs and the hospital for failure to diagnose preeclampsia on two separate ED presentations. They noted the patient’s Ob/Gyn was never consulted; no action was taken to treat the hypertension; and no urinalysis was ordered on either visit. The EPs and hospital settled the case prior to trial for several million dollars.

Discussion

This is an incredibly sad case, and the EPs and hospital were right to settle and not go to trial. While PE was a reasonable diagnosis to consider in this patient on her first ED visit, it should not have been the only one in the differential diagnosis. The EP became anchored to this single diagnosis and refused to consider other alternative diagnoses—even after the CTA scan of the chest ruled out PE. Moreover, it appears the EP either never considered the significance of the elevated BP and dependent edema or just ignored these findings. To repeat essentially the same exact workup on the second visit does not make sense—one should “cast a wider net, not the same net.”

The diagnosis of “shortness of breath of unknown etiology” is similarly unacceptable. While this is a common and accepted diagnosis when it pertains to abdominal pain, the same is not true for dyspnea.

Preeclampsia is characterized by hypertension (BP >140/90 mm Hg) and proteinuria; associated symptoms include edema and hyperreflexia. Postpartum preeclampsia occurs infrequently and can develop up to 4 weeks after delivery.¹ In one 10-year retrospective case series, the incidence of preeclampsia in the postpartum period was 5.7%, and nearly 16% went on to develop eclampsia.² In a retrospective study of 22 postpartum preeclamptic patients, the median time to presentation was 5 days postpartum.¹ In a similar retrospective study of 152 patients, 90% of such patients presented within 7 days.³ The patient in this case initially presented on postpartum day 4.

Interestingly, in a study by Al-Safi et al,³ 63% of postpartum preeclamptic patients had no antecedent diagnosis of hypertensive disease during pregnancy. These findings are consistent with the findings of others that 33% to 69% of such patients show no evidence of preeclampsia in the ante- or peripartum period.

The clinical presentation of postpartum preeclampsia is similar to preeclampsia complicating pregnancy after gestation week 20. In the study by Al-Safi et al,³ headache was the most common presenting symptom (69%), followed by shortness of breath (30%), blurry vision (21%), nausea (12.5%), and epigastric abdominal pain (5%). Similarly, Yancey et al¹ found headache (82%) to be the most common presenting symptom in their series. Unfortunately, it is not known whether the patient in this case complained of headache or blurred vision as the published records note neither their presence nor absence.

The management of patients with preeclampsia includes IV magnesium to prevent seizures (ie, eclampsia) and BP control.¹ A bolus of 4 to 6 g IV magnesium sulfate over 15 to 30 minutes is recommended, followed by an infusion of 2 g/h IV. Historically, IV hydralazine has been used to manage preeclamptic patients with a BP greater than 160/110 mm Hg. More recently, however, IV labetalol has become popular.⁵ All such patients require admission to the hospital with Ob/Gyn involvement.

Missed Subdural Hematoma

A 59-year-old man presented to the ED with a chief complaint of headache, the onset of which he stated started gradually 2 days prior. He noted the headache was worse than normal but without associated nausea, vomiting, fever, chills, or change in vision. His past medical history was significant for a lower extremity deep vein thrombosis 3 months prior, for which he was taking warfarin.

The patient’s vital signs were all normal. The physical examination, including a thorough neurological examination, was also normal. The EP ordered a prothrombin time (PT), an international normalized ratio (INR), and a noncontrast CT scan of the head. The PT/INR results were therapeutic at 22 seconds and 2.3. The CT scan was interpreted by radiology services as normal. The patient’s headache was treated with IV prochlorperazine and diphenhydramine. After treatment, the patient reported feeling better and was discharged home with instructions to follow up with his primary care physician.

Over the next several months, the patient presented to the same ED on seven different occasions, each time with the chief complaint of headache. At each of these presentations, the history and physical examination were documented as unremarkable, with no history of trauma. The thoroughness, however, of the documentation varied considerably for each ED encounter. No head CT scan was ordered on the subsequent seven visits, and at each presentation, the patient was treated symptomatically and discharged home.

Two days after his eighth visit to the same hospital ED, the patient presented to a different ED, again with a chief complaint of headache. The EP at this ED ordered a noncontrast CT of the head, which demonstrated a left subdural hematoma. The patient was admitted to the hospital, given IV vitamin K and fresh frozen plasma, and underwent evacuation of the hematoma by neurosurgery. The patient’s hospital course was unremarkable, and he was discharged home without any focal weakness.

The patient, however, claimed that he suffered cognitive impairment as a result of the missed diagnosis. He sued treating EPs at the first ED as well as the hospital for failure to timely diagnose the subdural hematoma, stating that a CT scan should have been performed at each of his ED visits since he was on warfarin. The defense claimed that a CT scan was not warranted for each visit, and that the timing of when and how the brain bleed started was uncertain. At trial, a defense verdict was returned.

Discussion

It is well known that patients receiving warfarin are at an increased risk for intracranial hemorrhage (ICH) following blunt head trauma.¹ The recommendation is that all such patients have a noncontrast CT scan of the head to rule out intracranial bleeding. This is due to the fact that 60% of patients presenting with an immediate traumatic intracranial hemorrhage will have a normal mental status on examination; and 11% will have no history of loss of consciousness, a normal mental status examination, and no physical evidence of trauma above the clavicles.¹ In a study by Hart et al,² subdural hematoma accounted for 44% of all ICH in these types of patients.

More controversial is how to manage patients on warfarin who experience blunt head trauma and have a normal CT scan of the head. Because of the fear for delayed traumatic ICH, many clinicians recommend admitting such patients for neurological observation and repeat head CT scan the next morning.³ Additionally, some clinicians even recommend reversing the warfarin anticoagulation in such patients. ⁴ These recommendations, though, are based on expert consensus rather than on rigorous, prospective multicenter studies.¹  These strategies are also problematic, since such multiple repeat CT scans would not only be incredibly expensive but also would expose the patient to high doses of radiation to the brain. Moreover, the Centers for Medicare and Medicaid Services has now made CT brain scan imaging of patients presenting to the ED with complaint of nontraumatic headache a quality measure they follow. Their goal is to decrease the number of “unnecessary” head CT scans.

The patient in this case denied any history of trauma on the subsequent seven ED visits. Unfortunately, as pointed out, even minor trauma can result in ICH, and patients may not recall the occurrence of the event.

For patients on warfarin who present with headache, a very careful history must be taken—including inquiring about minor traumatic events. Even then, as has been shown, patients may have not experienced a loss of consciousness, have a normal mental status examination, and exhibit no external evidence of head trauma. The clinician is forced to use her or his own best judgment when evaluating such patients in the ED.

Interestingly, the risk of ICH secondary to blunt head trauma in patients on warfarin is increased if they are on concomitant aspirin therapy.² Similarly, the risk of ICH following head trauma in patients on clopidogrel is greater than for those patients taking warfarin,¹ and the risk of ICH in patients taking dabigatran is less than if taking warfarin.²

Missed Preeclampsia

On physical examination, the patient’s vital signs were remarkable for the following: heart rate (HR), 86 beats/minute; blood pressure (BP), 164/94 mm Hg; respiratory rate, 18 breaths/minute; temperature, 98.6^oF. Oxygen saturation was 96% on room air. The head, eye, ear, nose and throat examination was unremarkable. The lungs were clear to auscultation bilaterally, and HR and heart rhythm were normal. The abdomen was soft and nontender without guarding or rebound. The lower extremities were remarkable for 1+ pedal and pretibial edema bilaterally.

The patient presented to the same ED 2 days later, again with the chief complaint of shortness of breath. On examination, her BP was noted to be elevated and she had 1+ dependent edema bilaterally. Again, the EP was concerned for a PE and ordered a repeat CTA scan of the chest. This study, similar to the first, was read as normal, and showed no evidence of PE. The patient was diagnosed again with “shortness of breath of unknown etiology” and discharged home. The patient’s obstetrician-gynecologist (Ob/Gyn) was not consulted; however, the patient was encouraged to follow up with him.

The next day, the patient presented to the same ED via emergency medical services, this time with seizures; she had no prior history of a seizure disorder. On presentation to the ED, she was noted to be postictal, with an elevated BP and tachycardic with an HR of 104 beats/minute. On examination, the lungs were clear to auscultation and the lower extremities exhibited 1+ pedal and pretibial edema. A urinalysis revealed proteinuria. The patient was given 4 g of magnesium sulfate intravenously (IV) and her Ob/Gyn was consulted.

The patient was admitted to the hospital with a diagnosis of eclampsia. She was given an IV drip of magnesium and labetalol for the high BP. Unfortunately, the patient apparently had suffered an anoxic brain injury from the previous seizures and died on hospital day 3.

The family sued the treating EPs and the hospital for failure to diagnose preeclampsia on two separate ED presentations. They noted the patient’s Ob/Gyn was never consulted; no action was taken to treat the hypertension; and no urinalysis was ordered on either visit. The EPs and hospital settled the case prior to trial for several million dollars.

Discussion

This is an incredibly sad case, and the EPs and hospital were right to settle and not go to trial. While PE was a reasonable diagnosis to consider in this patient on her first ED visit, it should not have been the only one in the differential diagnosis. The EP became anchored to this single diagnosis and refused to consider other alternative diagnoses—even after the CTA scan of the chest ruled out PE. Moreover, it appears the EP either never considered the significance of the elevated BP and dependent edema or just ignored these findings. To repeat essentially the same exact workup on the second visit does not make sense—one should “cast a wider net, not the same net.”

The diagnosis of “shortness of breath of unknown etiology” is similarly unacceptable. While this is a common and accepted diagnosis when it pertains to abdominal pain, the same is not true for dyspnea.

Preeclampsia is characterized by hypertension (BP >140/90 mm Hg) and proteinuria; associated symptoms include edema and hyperreflexia. Postpartum preeclampsia occurs infrequently and can develop up to 4 weeks after delivery.¹ In one 10-year retrospective case series, the incidence of preeclampsia in the postpartum period was 5.7%, and nearly 16% went on to develop eclampsia.² In a retrospective study of 22 postpartum preeclamptic patients, the median time to presentation was 5 days postpartum.¹ In a similar retrospective study of 152 patients, 90% of such patients presented within 7 days.³ The patient in this case initially presented on postpartum day 4.

Interestingly, in a study by Al-Safi et al,³ 63% of postpartum preeclamptic patients had no antecedent diagnosis of hypertensive disease during pregnancy. These findings are consistent with the findings of others that 33% to 69% of such patients show no evidence of preeclampsia in the ante- or peripartum period.

The clinical presentation of postpartum preeclampsia is similar to preeclampsia complicating pregnancy after gestation week 20. In the study by Al-Safi et al,³ headache was the most common presenting symptom (69%), followed by shortness of breath (30%), blurry vision (21%), nausea (12.5%), and epigastric abdominal pain (5%). Similarly, Yancey et al¹ found headache (82%) to be the most common presenting symptom in their series. Unfortunately, it is not known whether the patient in this case complained of headache or blurred vision as the published records note neither their presence nor absence.

The management of patients with preeclampsia includes IV magnesium to prevent seizures (ie, eclampsia) and BP control.¹ A bolus of 4 to 6 g IV magnesium sulfate over 15 to 30 minutes is recommended, followed by an infusion of 2 g/h IV. Historically, IV hydralazine has been used to manage preeclamptic patients with a BP greater than 160/110 mm Hg. More recently, however, IV labetalol has become popular.⁵ All such patients require admission to the hospital with Ob/Gyn involvement.

Missed Subdural Hematoma

A 59-year-old man presented to the ED with a chief complaint of headache, the onset of which he stated started gradually 2 days prior. He noted the headache was worse than normal but without associated nausea, vomiting, fever, chills, or change in vision. His past medical history was significant for a lower extremity deep vein thrombosis 3 months prior, for which he was taking warfarin.

The patient’s vital signs were all normal. The physical examination, including a thorough neurological examination, was also normal. The EP ordered a prothrombin time (PT), an international normalized ratio (INR), and a noncontrast CT scan of the head. The PT/INR results were therapeutic at 22 seconds and 2.3. The CT scan was interpreted by radiology services as normal. The patient’s headache was treated with IV prochlorperazine and diphenhydramine. After treatment, the patient reported feeling better and was discharged home with instructions to follow up with his primary care physician.

Over the next several months, the patient presented to the same ED on seven different occasions, each time with the chief complaint of headache. At each of these presentations, the history and physical examination were documented as unremarkable, with no history of trauma. The thoroughness, however, of the documentation varied considerably for each ED encounter. No head CT scan was ordered on the subsequent seven visits, and at each presentation, the patient was treated symptomatically and discharged home.

Two days after his eighth visit to the same hospital ED, the patient presented to a different ED, again with a chief complaint of headache. The EP at this ED ordered a noncontrast CT of the head, which demonstrated a left subdural hematoma. The patient was admitted to the hospital, given IV vitamin K and fresh frozen plasma, and underwent evacuation of the hematoma by neurosurgery. The patient’s hospital course was unremarkable, and he was discharged home without any focal weakness.

The patient, however, claimed that he suffered cognitive impairment as a result of the missed diagnosis. He sued treating EPs at the first ED as well as the hospital for failure to timely diagnose the subdural hematoma, stating that a CT scan should have been performed at each of his ED visits since he was on warfarin. The defense claimed that a CT scan was not warranted for each visit, and that the timing of when and how the brain bleed started was uncertain. At trial, a defense verdict was returned.

Discussion

It is well known that patients receiving warfarin are at an increased risk for intracranial hemorrhage (ICH) following blunt head trauma.¹ The recommendation is that all such patients have a noncontrast CT scan of the head to rule out intracranial bleeding. This is due to the fact that 60% of patients presenting with an immediate traumatic intracranial hemorrhage will have a normal mental status on examination; and 11% will have no history of loss of consciousness, a normal mental status examination, and no physical evidence of trauma above the clavicles.¹ In a study by Hart et al,² subdural hematoma accounted for 44% of all ICH in these types of patients.

More controversial is how to manage patients on warfarin who experience blunt head trauma and have a normal CT scan of the head. Because of the fear for delayed traumatic ICH, many clinicians recommend admitting such patients for neurological observation and repeat head CT scan the next morning.³ Additionally, some clinicians even recommend reversing the warfarin anticoagulation in such patients. ⁴ These recommendations, though, are based on expert consensus rather than on rigorous, prospective multicenter studies.¹  These strategies are also problematic, since such multiple repeat CT scans would not only be incredibly expensive but also would expose the patient to high doses of radiation to the brain. Moreover, the Centers for Medicare and Medicaid Services has now made CT brain scan imaging of patients presenting to the ED with complaint of nontraumatic headache a quality measure they follow. Their goal is to decrease the number of “unnecessary” head CT scans.

The patient in this case denied any history of trauma on the subsequent seven ED visits. Unfortunately, as pointed out, even minor trauma can result in ICH, and patients may not recall the occurrence of the event.

For patients on warfarin who present with headache, a very careful history must be taken—including inquiring about minor traumatic events. Even then, as has been shown, patients may have not experienced a loss of consciousness, have a normal mental status examination, and exhibit no external evidence of head trauma. The clinician is forced to use her or his own best judgment when evaluating such patients in the ED.

Interestingly, the risk of ICH secondary to blunt head trauma in patients on warfarin is increased if they are on concomitant aspirin therapy.² Similarly, the risk of ICH following head trauma in patients on clopidogrel is greater than for those patients taking warfarin,¹ and the risk of ICH in patients taking dabigatran is less than if taking warfarin.²

To the Editor:

Optical coherence tomography (OCT) is a 
noninvasive imaging technique that uses a 
low-power infrared laser light for cutaneous architecture visualization up to 2 mm in depth. Both malignant and nonmalignant lesions on OCT 
imaging have been correlated with histopathologic analysis.¹ We describe the diagnostic features of knuckle pads on OCT.

A 43-year-old-man presented with warts on the right thumb and bilateral feet of several months’ duration with noncontributory medical and social history. Physical examination revealed nontender, well-demarcated, flesh-colored, verrucous papules on the dorsal interphalangeal joints of the right thumb and several toes (Figure 1). Pinpoint vessels were absent on dermoscopy (Figure 2). Histopathologic analysis of a shave biopsy of the lesion on the left second toe revealed dense orthokeratosis with compact keratin, suggestive of reactive hyperkeratosis or a knuckle pad (Figure 3). In situ hybridization failed to demonstrate staining for human papillomavirus types 6, 11, and 16.

Figure 1. Verrucous papules on the left foot.		Figure 2. Corresponding dermoscopy of the left second toe revealed an absence of pinpoint vessels.

Optical coherence tomography demonstrated discrete thickening of the stratum corneum with distinctive granular and coarse textural appearance of the hyperkeratotic stratum corneum compared to normal adjacent skin. This textural difference was attributed to the alteration in collagen deposition of the knuckle pads, consistent with fibrous proliferation. Finally, OCT imaging provided further characterization of the lesion demonstrating the absence of any hair follicles and acrosyringium in areas resembling glabrous skin (Figure 4).

Figure 3. Dense orthokeratosis with compact keratin on histopathology (H&amp;E, original magnification ×40), corresponding to white hyperreflective areas on optical coherence tomography.

Figure 4. Optical coherence tomography revealed the absence of hair follicles and acrosyringium as well as the white hyperreflective areas consistent with orthokeratosis.

Knuckle pads, also known as Garrod pads, were first described by Garrod² in 1893. They are benign, asymptomatic, fibrotic thickenings of the skin. Lesions are smooth, firm, flesh colored, and located on the dorsal aspect of the hands and feet along 
the metacarpophalangeal and interphalangeal 
joints. Knuckle pads are common, can develop at any age, and are observed more frequently in men than in women.³

Primary knuckle pads can be sporadic or associated with other conditions such as palmoplantar keratoderma, acrokeratoelastoidosis costa, fibrosing disorders, or Bart-Pumphrey syndrome.⁴ Secondary knuckle pads, which are more common, occur in sites of repetitive trauma or pressure. Certain occupations (eg, mechanics) or hobbies (eg, boxing) increase the risk for developing knuckle pads.^3,4

The diagnosis of knuckle pads is usually made clinically, though several other conditions mimic knuckle pads, including scars, keloids, calluses, verruca vulgaris, fibromas, and rheumatoid nodules.^3,5 We report a description of knuckle pads that was diagnosed with OCT imaging. Further characterization of both malignant and nonmalignant lesions on OCT imaging will contribute new insights to the role of OCT in the noninvasive diagnosis of skin diseases, pending future studies.

To the Editor:

Optical coherence tomography (OCT) is a 
noninvasive imaging technique that uses a 
low-power infrared laser light for cutaneous architecture visualization up to 2 mm in depth. Both malignant and nonmalignant lesions on OCT 
imaging have been correlated with histopathologic analysis.¹ We describe the diagnostic features of knuckle pads on OCT.

A 43-year-old-man presented with warts on the right thumb and bilateral feet of several months’ duration with noncontributory medical and social history. Physical examination revealed nontender, well-demarcated, flesh-colored, verrucous papules on the dorsal interphalangeal joints of the right thumb and several toes (Figure 1). Pinpoint vessels were absent on dermoscopy (Figure 2). Histopathologic analysis of a shave biopsy of the lesion on the left second toe revealed dense orthokeratosis with compact keratin, suggestive of reactive hyperkeratosis or a knuckle pad (Figure 3). In situ hybridization failed to demonstrate staining for human papillomavirus types 6, 11, and 16.

Figure 1. Verrucous papules on the left foot.		Figure 2. Corresponding dermoscopy of the left second toe revealed an absence of pinpoint vessels.

Optical coherence tomography demonstrated discrete thickening of the stratum corneum with distinctive granular and coarse textural appearance of the hyperkeratotic stratum corneum compared to normal adjacent skin. This textural difference was attributed to the alteration in collagen deposition of the knuckle pads, consistent with fibrous proliferation. Finally, OCT imaging provided further characterization of the lesion demonstrating the absence of any hair follicles and acrosyringium in areas resembling glabrous skin (Figure 4).

Figure 3. Dense orthokeratosis with compact keratin on histopathology (H&amp;E, original magnification ×40), corresponding to white hyperreflective areas on optical coherence tomography.

Figure 4. Optical coherence tomography revealed the absence of hair follicles and acrosyringium as well as the white hyperreflective areas consistent with orthokeratosis.

Knuckle pads, also known as Garrod pads, were first described by Garrod² in 1893. They are benign, asymptomatic, fibrotic thickenings of the skin. Lesions are smooth, firm, flesh colored, and located on the dorsal aspect of the hands and feet along 
the metacarpophalangeal and interphalangeal 
joints. Knuckle pads are common, can develop at any age, and are observed more frequently in men than in women.³

Primary knuckle pads can be sporadic or associated with other conditions such as palmoplantar keratoderma, acrokeratoelastoidosis costa, fibrosing disorders, or Bart-Pumphrey syndrome.⁴ Secondary knuckle pads, which are more common, occur in sites of repetitive trauma or pressure. Certain occupations (eg, mechanics) or hobbies (eg, boxing) increase the risk for developing knuckle pads.^3,4

The diagnosis of knuckle pads is usually made clinically, though several other conditions mimic knuckle pads, including scars, keloids, calluses, verruca vulgaris, fibromas, and rheumatoid nodules.^3,5 We report a description of knuckle pads that was diagnosed with OCT imaging. Further characterization of both malignant and nonmalignant lesions on OCT imaging will contribute new insights to the role of OCT in the noninvasive diagnosis of skin diseases, pending future studies.

To the Editor:

Optical coherence tomography (OCT) is a 
noninvasive imaging technique that uses a 
low-power infrared laser light for cutaneous architecture visualization up to 2 mm in depth. Both malignant and nonmalignant lesions on OCT 
imaging have been correlated with histopathologic analysis.¹ We describe the diagnostic features of knuckle pads on OCT.

A 43-year-old-man presented with warts on the right thumb and bilateral feet of several months’ duration with noncontributory medical and social history. Physical examination revealed nontender, well-demarcated, flesh-colored, verrucous papules on the dorsal interphalangeal joints of the right thumb and several toes (Figure 1). Pinpoint vessels were absent on dermoscopy (Figure 2). Histopathologic analysis of a shave biopsy of the lesion on the left second toe revealed dense orthokeratosis with compact keratin, suggestive of reactive hyperkeratosis or a knuckle pad (Figure 3). In situ hybridization failed to demonstrate staining for human papillomavirus types 6, 11, and 16.

Figure 1. Verrucous papules on the left foot.		Figure 2. Corresponding dermoscopy of the left second toe revealed an absence of pinpoint vessels.

Optical coherence tomography demonstrated discrete thickening of the stratum corneum with distinctive granular and coarse textural appearance of the hyperkeratotic stratum corneum compared to normal adjacent skin. This textural difference was attributed to the alteration in collagen deposition of the knuckle pads, consistent with fibrous proliferation. Finally, OCT imaging provided further characterization of the lesion demonstrating the absence of any hair follicles and acrosyringium in areas resembling glabrous skin (Figure 4).

Figure 3. Dense orthokeratosis with compact keratin on histopathology (H&amp;E, original magnification ×40), corresponding to white hyperreflective areas on optical coherence tomography.

Figure 4. Optical coherence tomography revealed the absence of hair follicles and acrosyringium as well as the white hyperreflective areas consistent with orthokeratosis.

Knuckle pads, also known as Garrod pads, were first described by Garrod² in 1893. They are benign, asymptomatic, fibrotic thickenings of the skin. Lesions are smooth, firm, flesh colored, and located on the dorsal aspect of the hands and feet along 
the metacarpophalangeal and interphalangeal 
joints. Knuckle pads are common, can develop at any age, and are observed more frequently in men than in women.³

Primary knuckle pads can be sporadic or associated with other conditions such as palmoplantar keratoderma, acrokeratoelastoidosis costa, fibrosing disorders, or Bart-Pumphrey syndrome.⁴ Secondary knuckle pads, which are more common, occur in sites of repetitive trauma or pressure. Certain occupations (eg, mechanics) or hobbies (eg, boxing) increase the risk for developing knuckle pads.^3,4

The diagnosis of knuckle pads is usually made clinically, though several other conditions mimic knuckle pads, including scars, keloids, calluses, verruca vulgaris, fibromas, and rheumatoid nodules.^3,5 We report a description of knuckle pads that was diagnosed with OCT imaging. Further characterization of both malignant and nonmalignant lesions on OCT imaging will contribute new insights to the role of OCT in the noninvasive diagnosis of skin diseases, pending future studies.

To the Editor:

A 62-year-old woman with an extensive history of cutaneous and oral lichen planus (OLP) presented with gradual worsening of oral pain refractory to previously successful treatment regimens. The pains were described as sharp sensations originating in the right superior oral cavity, occurring almost constantly over the course of 2 months. On examination, the oral mucosa on the right side showed lacy, white, hyperkeratotic buccal lesions, as well as superficial erythematous erosion on the right upper alveolar ridge mucosa (Figure 1). On the left side, lacy, white, reticular patches were noted along the buccal mucosa. Gingival desquamation with superficial erosions were observed bilaterally, extending to the upper alveolar ridge in some locations. The skin examination revealed resolving, nonirritated, violaceous, flat-topped papules with a white-gray hue on the upper back and vulva.

Figure 1. Erosive oral lichen planus of the right maxillary alveolar ridge.

The rest of the physical examination was benign, including a lack of appreciable lymphadenopathy, a cranial nerve examination without focal deficit, and the presence of fluent unaffected speech. On review of systems, the patient denied fevers, chills, weight loss, or night sweats. She had no history of skin cancer or oropharyngeal cancer. Family history revealed that her father had nonmelanoma skin cancer of the head and neck. She denied heavy alcohol use as well as history of smoking or other oral tobacco products. Laboratory tests revealed a complete blood cell count and comprehensive metabolic panel that was within reference range. Due to the refractory nature of the pain, which was out of character for OLP, the patient was referred to an oral maxillofacial surgeon who extracted right maxillary teeth adjacent to the erosion to obtain an adequate specimen for surgical biopsy of the lesion itself. Histopathology confirmed the diagnosis of chronic erosive OLP with malignant transformation to localized squamous cell carcinoma (SCC) of the right maxilla.

While awaiting treatment, she began to develop unremitting headaches and painful shooting sensations beginning in the right superior oral mucosa, radiating to the ipsilateral naris, nasolabial folds, malar cheek, and temple region. This clinical picture was consistent with neuralgia occurring along the maxillary nerve. A subsequent computed tomography scan revealed local bony destruction of the primary tumor and likely perineural involvement (Figure 2), without notable nodal involvement or metastasis (stage III: T4aN0M0). An otolaryngologist performed a wide alveolar and maxillary excision with lymph node dissection. Surgical margins were deemed as negative and there was no evidence of nodal disease. She was later seen by the oncology and radiation oncology teams and received several courses of chemoradiotherapy.

Figure 2. Coronal (A) and axial (B) computed tomography demonstrated right maxillary bony destruction.

Seven months later, a new indurated ulcer was noted on the left lateral tongue. Biopsy revealed a new primary oral SCC (OSCC), which also was excised by an otolaryngologist. Recent computed tomography did not detect any recurrence or potential metastases, but the patient subsequently was lost to follow-up.

Lichen planus is an idiopathic inflammatory disease most commonly affecting the cutaneous skin as well as the oral mucosa, genital mucosa, nails, and scalp. Oral lichen planus is a relatively common manifestation, found in approximately 1% to 2% of individuals older than 15 years.¹ Epidemiologic studies revealed that OLP is uncommon in children,^2,3 it affects women more frequently than men (approximately 3:1 ratio),³ and its incidence peaks between 30 and 60 years of age.⁴ The literature on malignant transformation of OLP is varied and controversial, with some early investigations such as Krutchkoff et al⁵ concluding that the reported cases often fall short of supporting OLP as a premalignant source of OSCC due to insufficient evidence in claimed case reports supporting the diagnosis of OLP histopathologically, the occurrence of OSCC in sites where OLP lesions did not previously exist, and uncertainty regarding confounding factors such as carcinogen exposure.⁵ In contrast, a longitudinal cohort study reported malignant transformation in 2.4% of 
OLP cases (N=327), with a standardized incidence ratio of 17.7 (95% confidence interval, 8.8-35.3) when compared to a control group.⁶ Current literature has predominantly sided with the notion that OLP, especially the erosive variant, carries the risk for malignant potential⁶ as well as the World Health Organization’s classification of the disorder as precancerous.³

The pathophysiology of OLP and its potential for malignant transformation are unknown. It is believed that cell-mediated immunity, specifically CD8⁺ lymphocytes targeting stratum basale keratinocytes for apoptosis via the caspase cascade, plays a major role in the development of OLP, beginning with Langerhans cell recognition of an unknown basal cell antigen.³ Moreover, it is postulated that antigen expression is induced by certain drugs, infections, and contact allergens such as dental amalgams, explaining their known associations with OLP initiation and exacerbation. The etiology behind OLP developing into OSCC also is poorly understood and many different hypotheses have been suggested. Modified expression of p53, a 53-kd protein, in OLP patients has been demonstrated.⁶ Some investigators propose that a lack of the expected keratinocyte apoptotic response to the cell-mediated attack may be etiologic in cancerous transformation.³ Given their utility in treatment of OLP, there also has been apprehension over the potential for immunosuppressant medications leading to decreased expression of antitumor regulators and development of malignant cells, though it has not been substantiated by current literature.⁶ Finally, some cases of OSCC are believed to have been linked to N-nitrosobenzylmethylamine, a known carcinogen produced by colonized Candida albicans, which also may play a role in OLP treated with immunosuppressants.⁷

Clinically, OLP lesions are known to be more chronic in nature than cutaneous lichen planus.⁷ There are 6 classifications of OLP: reticular (lacy white with Wickham striae), plaquelike, papular, atrophic, bullous, and erosive. The latter 3 are known to be the more symptomatic manifestations.^3,7 Of note, the atrophic and erosive forms are believed to account for the vast majority of cases of malignant transformation of OLP to OSCC. Approximately 90% of patients have involvement of multiple oral sites, with the most common affected areas being the buccal mucosa (90%), gingival margin (56%), and dorsal tongue (34%).⁷ Symptoms include increased sensitivity to foods, intense local pain, and coarse-feeling mucosa. The nature of the disease favors an active-quiescent-active course, with flares occurring after direct irritation (ie, dental procedures, Köbner phenomenon), emotional stress, medication use, and systemic illness.⁷ The differential diagnosis of OLP includes bite trauma, candidiasis, pemphigus, leukoplakia, lichenoid drug reaction, pemphigoid, and graft-versus-host disease.⁴ Red flags of malignant transformation include induration, worsening ulceration in the setting of previously effective therapy, and presence of constitutional symptoms.

Regarding the behavior of OSCC after malignant transformation, the literature seems to suggest a tendency for well-differentiated noninvasive tumors that most often occur on the buccal mucosa (43%), tongue (33%), gingiva (19%), and palate (4.8%).⁸ Interestingly, one study described that only 1 (4.8%) of 21 patients with OLP and OSCC was deemed as having stage II or higher disease at time of diagnosis. Likewise, 90% of the biopsied samples revealed well-differentiated carcinomas.⁸ These findings clearly contrast with our case in which the patient experienced rapid conversion of localized OSCC to more invasive disease. Also of consequence in this study was the finding that a relatively high proportion of patients (29% [6/21]) developed at least one other primary OSCC lesion over the course of follow-up.⁸ This finding is consistent with our patient.

Last, management of OLP lesions is most commonly accomplished with topical steroids such as fluocinolone acetonide or triamcinolone acetonide.³ Treatment of gingival disease may be enhanced with the use of form-fitting trays.² For refractory erosive disease, tacrolimus ointment has been demonstrated as a useful backup therapy but may actually be associated with the development of OSCC through alteration of MAPK and p53.³ Some investigators suggest regular 4-month 
follow-up of OLP patients to detect if acute worsening and or refractoriness to treatment have signified early dysplastic change. Various scoring systems also have been suggested for following up on the severity of OLP lesions.³

The management of OSCC usually is accomplished via surgery, radiation, or both. The decision is dependent on tumor stage and the patient’s individual limitations. It is highly recommended that patients with OSCC arising from OLP be closely followed after diagnosis of cancer, with some sources suggesting follow-up every 2 months for the first 6 to 9 months after diagnosis due to the relatively high rate of discovery of nodal metastases and new primary lesions in that critical time span.⁸ Thereafter, an examination every 4 months is suggested as sufficient for detecting future complications.

To the Editor:

A 62-year-old woman with an extensive history of cutaneous and oral lichen planus (OLP) presented with gradual worsening of oral pain refractory to previously successful treatment regimens. The pains were described as sharp sensations originating in the right superior oral cavity, occurring almost constantly over the course of 2 months. On examination, the oral mucosa on the right side showed lacy, white, hyperkeratotic buccal lesions, as well as superficial erythematous erosion on the right upper alveolar ridge mucosa (Figure 1). On the left side, lacy, white, reticular patches were noted along the buccal mucosa. Gingival desquamation with superficial erosions were observed bilaterally, extending to the upper alveolar ridge in some locations. The skin examination revealed resolving, nonirritated, violaceous, flat-topped papules with a white-gray hue on the upper back and vulva.

Figure 1. Erosive oral lichen planus of the right maxillary alveolar ridge.

The rest of the physical examination was benign, including a lack of appreciable lymphadenopathy, a cranial nerve examination without focal deficit, and the presence of fluent unaffected speech. On review of systems, the patient denied fevers, chills, weight loss, or night sweats. She had no history of skin cancer or oropharyngeal cancer. Family history revealed that her father had nonmelanoma skin cancer of the head and neck. She denied heavy alcohol use as well as history of smoking or other oral tobacco products. Laboratory tests revealed a complete blood cell count and comprehensive metabolic panel that was within reference range. Due to the refractory nature of the pain, which was out of character for OLP, the patient was referred to an oral maxillofacial surgeon who extracted right maxillary teeth adjacent to the erosion to obtain an adequate specimen for surgical biopsy of the lesion itself. Histopathology confirmed the diagnosis of chronic erosive OLP with malignant transformation to localized squamous cell carcinoma (SCC) of the right maxilla.

While awaiting treatment, she began to develop unremitting headaches and painful shooting sensations beginning in the right superior oral mucosa, radiating to the ipsilateral naris, nasolabial folds, malar cheek, and temple region. This clinical picture was consistent with neuralgia occurring along the maxillary nerve. A subsequent computed tomography scan revealed local bony destruction of the primary tumor and likely perineural involvement (Figure 2), without notable nodal involvement or metastasis (stage III: T4aN0M0). An otolaryngologist performed a wide alveolar and maxillary excision with lymph node dissection. Surgical margins were deemed as negative and there was no evidence of nodal disease. She was later seen by the oncology and radiation oncology teams and received several courses of chemoradiotherapy.

Figure 2. Coronal (A) and axial (B) computed tomography demonstrated right maxillary bony destruction.

Seven months later, a new indurated ulcer was noted on the left lateral tongue. Biopsy revealed a new primary oral SCC (OSCC), which also was excised by an otolaryngologist. Recent computed tomography did not detect any recurrence or potential metastases, but the patient subsequently was lost to follow-up.

Lichen planus is an idiopathic inflammatory disease most commonly affecting the cutaneous skin as well as the oral mucosa, genital mucosa, nails, and scalp. Oral lichen planus is a relatively common manifestation, found in approximately 1% to 2% of individuals older than 15 years.¹ Epidemiologic studies revealed that OLP is uncommon in children,^2,3 it affects women more frequently than men (approximately 3:1 ratio),³ and its incidence peaks between 30 and 60 years of age.⁴ The literature on malignant transformation of OLP is varied and controversial, with some early investigations such as Krutchkoff et al⁵ concluding that the reported cases often fall short of supporting OLP as a premalignant source of OSCC due to insufficient evidence in claimed case reports supporting the diagnosis of OLP histopathologically, the occurrence of OSCC in sites where OLP lesions did not previously exist, and uncertainty regarding confounding factors such as carcinogen exposure.⁵ In contrast, a longitudinal cohort study reported malignant transformation in 2.4% of 
OLP cases (N=327), with a standardized incidence ratio of 17.7 (95% confidence interval, 8.8-35.3) when compared to a control group.⁶ Current literature has predominantly sided with the notion that OLP, especially the erosive variant, carries the risk for malignant potential⁶ as well as the World Health Organization’s classification of the disorder as precancerous.³

The pathophysiology of OLP and its potential for malignant transformation are unknown. It is believed that cell-mediated immunity, specifically CD8⁺ lymphocytes targeting stratum basale keratinocytes for apoptosis via the caspase cascade, plays a major role in the development of OLP, beginning with Langerhans cell recognition of an unknown basal cell antigen.³ Moreover, it is postulated that antigen expression is induced by certain drugs, infections, and contact allergens such as dental amalgams, explaining their known associations with OLP initiation and exacerbation. The etiology behind OLP developing into OSCC also is poorly understood and many different hypotheses have been suggested. Modified expression of p53, a 53-kd protein, in OLP patients has been demonstrated.⁶ Some investigators propose that a lack of the expected keratinocyte apoptotic response to the cell-mediated attack may be etiologic in cancerous transformation.³ Given their utility in treatment of OLP, there also has been apprehension over the potential for immunosuppressant medications leading to decreased expression of antitumor regulators and development of malignant cells, though it has not been substantiated by current literature.⁶ Finally, some cases of OSCC are believed to have been linked to N-nitrosobenzylmethylamine, a known carcinogen produced by colonized Candida albicans, which also may play a role in OLP treated with immunosuppressants.⁷

Clinically, OLP lesions are known to be more chronic in nature than cutaneous lichen planus.⁷ There are 6 classifications of OLP: reticular (lacy white with Wickham striae), plaquelike, papular, atrophic, bullous, and erosive. The latter 3 are known to be the more symptomatic manifestations.^3,7 Of note, the atrophic and erosive forms are believed to account for the vast majority of cases of malignant transformation of OLP to OSCC. Approximately 90% of patients have involvement of multiple oral sites, with the most common affected areas being the buccal mucosa (90%), gingival margin (56%), and dorsal tongue (34%).⁷ Symptoms include increased sensitivity to foods, intense local pain, and coarse-feeling mucosa. The nature of the disease favors an active-quiescent-active course, with flares occurring after direct irritation (ie, dental procedures, Köbner phenomenon), emotional stress, medication use, and systemic illness.⁷ The differential diagnosis of OLP includes bite trauma, candidiasis, pemphigus, leukoplakia, lichenoid drug reaction, pemphigoid, and graft-versus-host disease.⁴ Red flags of malignant transformation include induration, worsening ulceration in the setting of previously effective therapy, and presence of constitutional symptoms.

Regarding the behavior of OSCC after malignant transformation, the literature seems to suggest a tendency for well-differentiated noninvasive tumors that most often occur on the buccal mucosa (43%), tongue (33%), gingiva (19%), and palate (4.8%).⁸ Interestingly, one study described that only 1 (4.8%) of 21 patients with OLP and OSCC was deemed as having stage II or higher disease at time of diagnosis. Likewise, 90% of the biopsied samples revealed well-differentiated carcinomas.⁸ These findings clearly contrast with our case in which the patient experienced rapid conversion of localized OSCC to more invasive disease. Also of consequence in this study was the finding that a relatively high proportion of patients (29% [6/21]) developed at least one other primary OSCC lesion over the course of follow-up.⁸ This finding is consistent with our patient.

Last, management of OLP lesions is most commonly accomplished with topical steroids such as fluocinolone acetonide or triamcinolone acetonide.³ Treatment of gingival disease may be enhanced with the use of form-fitting trays.² For refractory erosive disease, tacrolimus ointment has been demonstrated as a useful backup therapy but may actually be associated with the development of OSCC through alteration of MAPK and p53.³ Some investigators suggest regular 4-month 
follow-up of OLP patients to detect if acute worsening and or refractoriness to treatment have signified early dysplastic change. Various scoring systems also have been suggested for following up on the severity of OLP lesions.³

The management of OSCC usually is accomplished via surgery, radiation, or both. The decision is dependent on tumor stage and the patient’s individual limitations. It is highly recommended that patients with OSCC arising from OLP be closely followed after diagnosis of cancer, with some sources suggesting follow-up every 2 months for the first 6 to 9 months after diagnosis due to the relatively high rate of discovery of nodal metastases and new primary lesions in that critical time span.⁸ Thereafter, an examination every 4 months is suggested as sufficient for detecting future complications.

To the Editor:

A 62-year-old woman with an extensive history of cutaneous and oral lichen planus (OLP) presented with gradual worsening of oral pain refractory to previously successful treatment regimens. The pains were described as sharp sensations originating in the right superior oral cavity, occurring almost constantly over the course of 2 months. On examination, the oral mucosa on the right side showed lacy, white, hyperkeratotic buccal lesions, as well as superficial erythematous erosion on the right upper alveolar ridge mucosa (Figure 1). On the left side, lacy, white, reticular patches were noted along the buccal mucosa. Gingival desquamation with superficial erosions were observed bilaterally, extending to the upper alveolar ridge in some locations. The skin examination revealed resolving, nonirritated, violaceous, flat-topped papules with a white-gray hue on the upper back and vulva.

Figure 1. Erosive oral lichen planus of the right maxillary alveolar ridge.

The rest of the physical examination was benign, including a lack of appreciable lymphadenopathy, a cranial nerve examination without focal deficit, and the presence of fluent unaffected speech. On review of systems, the patient denied fevers, chills, weight loss, or night sweats. She had no history of skin cancer or oropharyngeal cancer. Family history revealed that her father had nonmelanoma skin cancer of the head and neck. She denied heavy alcohol use as well as history of smoking or other oral tobacco products. Laboratory tests revealed a complete blood cell count and comprehensive metabolic panel that was within reference range. Due to the refractory nature of the pain, which was out of character for OLP, the patient was referred to an oral maxillofacial surgeon who extracted right maxillary teeth adjacent to the erosion to obtain an adequate specimen for surgical biopsy of the lesion itself. Histopathology confirmed the diagnosis of chronic erosive OLP with malignant transformation to localized squamous cell carcinoma (SCC) of the right maxilla.

While awaiting treatment, she began to develop unremitting headaches and painful shooting sensations beginning in the right superior oral mucosa, radiating to the ipsilateral naris, nasolabial folds, malar cheek, and temple region. This clinical picture was consistent with neuralgia occurring along the maxillary nerve. A subsequent computed tomography scan revealed local bony destruction of the primary tumor and likely perineural involvement (Figure 2), without notable nodal involvement or metastasis (stage III: T4aN0M0). An otolaryngologist performed a wide alveolar and maxillary excision with lymph node dissection. Surgical margins were deemed as negative and there was no evidence of nodal disease. She was later seen by the oncology and radiation oncology teams and received several courses of chemoradiotherapy.

Figure 2. Coronal (A) and axial (B) computed tomography demonstrated right maxillary bony destruction.

Seven months later, a new indurated ulcer was noted on the left lateral tongue. Biopsy revealed a new primary oral SCC (OSCC), which also was excised by an otolaryngologist. Recent computed tomography did not detect any recurrence or potential metastases, but the patient subsequently was lost to follow-up.

Lichen planus is an idiopathic inflammatory disease most commonly affecting the cutaneous skin as well as the oral mucosa, genital mucosa, nails, and scalp. Oral lichen planus is a relatively common manifestation, found in approximately 1% to 2% of individuals older than 15 years.¹ Epidemiologic studies revealed that OLP is uncommon in children,^2,3 it affects women more frequently than men (approximately 3:1 ratio),³ and its incidence peaks between 30 and 60 years of age.⁴ The literature on malignant transformation of OLP is varied and controversial, with some early investigations such as Krutchkoff et al⁵ concluding that the reported cases often fall short of supporting OLP as a premalignant source of OSCC due to insufficient evidence in claimed case reports supporting the diagnosis of OLP histopathologically, the occurrence of OSCC in sites where OLP lesions did not previously exist, and uncertainty regarding confounding factors such as carcinogen exposure.⁵ In contrast, a longitudinal cohort study reported malignant transformation in 2.4% of 
OLP cases (N=327), with a standardized incidence ratio of 17.7 (95% confidence interval, 8.8-35.3) when compared to a control group.⁶ Current literature has predominantly sided with the notion that OLP, especially the erosive variant, carries the risk for malignant potential⁶ as well as the World Health Organization’s classification of the disorder as precancerous.³

The pathophysiology of OLP and its potential for malignant transformation are unknown. It is believed that cell-mediated immunity, specifically CD8⁺ lymphocytes targeting stratum basale keratinocytes for apoptosis via the caspase cascade, plays a major role in the development of OLP, beginning with Langerhans cell recognition of an unknown basal cell antigen.³ Moreover, it is postulated that antigen expression is induced by certain drugs, infections, and contact allergens such as dental amalgams, explaining their known associations with OLP initiation and exacerbation. The etiology behind OLP developing into OSCC also is poorly understood and many different hypotheses have been suggested. Modified expression of p53, a 53-kd protein, in OLP patients has been demonstrated.⁶ Some investigators propose that a lack of the expected keratinocyte apoptotic response to the cell-mediated attack may be etiologic in cancerous transformation.³ Given their utility in treatment of OLP, there also has been apprehension over the potential for immunosuppressant medications leading to decreased expression of antitumor regulators and development of malignant cells, though it has not been substantiated by current literature.⁶ Finally, some cases of OSCC are believed to have been linked to N-nitrosobenzylmethylamine, a known carcinogen produced by colonized Candida albicans, which also may play a role in OLP treated with immunosuppressants.⁷

Clinically, OLP lesions are known to be more chronic in nature than cutaneous lichen planus.⁷ There are 6 classifications of OLP: reticular (lacy white with Wickham striae), plaquelike, papular, atrophic, bullous, and erosive. The latter 3 are known to be the more symptomatic manifestations.^3,7 Of note, the atrophic and erosive forms are believed to account for the vast majority of cases of malignant transformation of OLP to OSCC. Approximately 90% of patients have involvement of multiple oral sites, with the most common affected areas being the buccal mucosa (90%), gingival margin (56%), and dorsal tongue (34%).⁷ Symptoms include increased sensitivity to foods, intense local pain, and coarse-feeling mucosa. The nature of the disease favors an active-quiescent-active course, with flares occurring after direct irritation (ie, dental procedures, Köbner phenomenon), emotional stress, medication use, and systemic illness.⁷ The differential diagnosis of OLP includes bite trauma, candidiasis, pemphigus, leukoplakia, lichenoid drug reaction, pemphigoid, and graft-versus-host disease.⁴ Red flags of malignant transformation include induration, worsening ulceration in the setting of previously effective therapy, and presence of constitutional symptoms.

Regarding the behavior of OSCC after malignant transformation, the literature seems to suggest a tendency for well-differentiated noninvasive tumors that most often occur on the buccal mucosa (43%), tongue (33%), gingiva (19%), and palate (4.8%).⁸ Interestingly, one study described that only 1 (4.8%) of 21 patients with OLP and OSCC was deemed as having stage II or higher disease at time of diagnosis. Likewise, 90% of the biopsied samples revealed well-differentiated carcinomas.⁸ These findings clearly contrast with our case in which the patient experienced rapid conversion of localized OSCC to more invasive disease. Also of consequence in this study was the finding that a relatively high proportion of patients (29% [6/21]) developed at least one other primary OSCC lesion over the course of follow-up.⁸ This finding is consistent with our patient.

Last, management of OLP lesions is most commonly accomplished with topical steroids such as fluocinolone acetonide or triamcinolone acetonide.³ Treatment of gingival disease may be enhanced with the use of form-fitting trays.² For refractory erosive disease, tacrolimus ointment has been demonstrated as a useful backup therapy but may actually be associated with the development of OSCC through alteration of MAPK and p53.³ Some investigators suggest regular 4-month 
follow-up of OLP patients to detect if acute worsening and or refractoriness to treatment have signified early dysplastic change. Various scoring systems also have been suggested for following up on the severity of OLP lesions.³

The management of OSCC usually is accomplished via surgery, radiation, or both. The decision is dependent on tumor stage and the patient’s individual limitations. It is highly recommended that patients with OSCC arising from OLP be closely followed after diagnosis of cancer, with some sources suggesting follow-up every 2 months for the first 6 to 9 months after diagnosis due to the relatively high rate of discovery of nodal metastases and new primary lesions in that critical time span.⁸ Thereafter, an examination every 4 months is suggested as sufficient for detecting future complications.

To the Editor:

A 51-year-old woman presented to her dermatologist with recurrent and progressive upper lip swelling of 2 years’ duration. Her condition was previously evaluated by several other physicians without a diagnosis or resolution of the symptoms. The swelling began on the right side of the upper lip and right cheek; however, over the course of 2 years, the swelling had progressed to involve the entire upper lip with complete sparing of the lower lip. She denied pain but reported numbness of the upper lip. The patient visited her dentist who ruled out periodontal infection as the cause of the swelling. Diphenhydramine provided no relief; however, the cheek swelling resolved after a course of antibiotics prescribed by an ear, nose, and throat physician.

She consulted her primary care physician and was subsequently referred to a neurologist and allergist who were unable to provide a definitive diagnosis or complete relief of the symptoms. She denied any history of hypersensitivity reactions, odontogenic infections, gastrointestinal concerns, or any other signs or symptoms of systemic granulomatous disease.

Figure 1. Upper lip swelling without ulceration, fissuring, or scaling. The lower lip was completely spared.

On physical examination, the upper lip was swollen symmetrically without evidence of ulceration, fissuring, or scaling (Figure 1). Palpation of the upper lip was notable for firm, nontender, nonpitting edema without nodularity. The oral mucosa did not appear swollen or erythematous. Examination did not reveal ulceration or a cobblestone appearance.

A full-thickness skin biopsy of the upper lip was performed. Histopathology revealed perivascular nonnecrotizing granulomas adjacent to ectatic vascular channels with associated lymphoplasmacytic infiltrate (Figure 2). Periodic acid–Schiff stain was negative for fungal hyphae, tissue Gram stain was negative for bacteria, Fite and acid-fast bacillus stains were both negative for acid-fast organisms, and polariscopy was negative for polarizable foreign material. In this clinical context, the morphologic findings were consistent with the diagnosis of granulomatous cheilitis (GC).

Figure 2. Upper lip biopsy showed dermal edema, vascular ectasia, perivascular nonnecrotizing granulomas, and perivascular lymphocyte predominant inflammatory infiltrate (A)(H&E, original magnification ×100). Higher magnification of granulomas with perivascular lymphoplasmacytic infiltrate (B)(H&E, original magnification ×200).

Granulomatous cheilitis is a rare disorder of the lips and orofacial mucosa that was first described by Meischer¹ in 1945 as persistent or recurrent orofacial swelling secondary to lymphatic obstruction by granulomatous proliferation. It often has been described as a monosymptomatic form of Melkersson-Rosenthal syndrome (MRS). In its entirety, MRS constitutes a triad of GC, facial nerve palsy, and lingua plicata (also known as fissured tongue).^2,3 Although many authors agree that GC is associated with MRS, some believe that GC is a distinct entity because the majority of patients who present with GC subsequently do not develop MRS.⁴ Despite its relationship to MRS, the true incidence of GC largely is unknown. The onset of disease usually occurs in early adulthood but can present in middle-aged or older individuals.

The typical course of GC is relapsing and remitting, nontender and nonpitting swelling of the lips that eventually becomes permanent, leading to possible facial distortion and disability. Involvement of the upper lip is the most common, followed by (in order of decreasing frequency) the lower lip and cheeks.⁵ The swelling may be unilateral or bilateral and generally is not associated with ulceration, fissuring, or scaling; however, these complications have been reported in the terminal stages of the disease in which the macrocheilia has become permanent.

Despite the controversy over the etiology, pathophysiology, and classification of GC, it largely is accepted that when a patient presents clinically with a history of recurrent or persistent lip swelling, a 
full-thickness skin biopsy of the involved oral mucosa should be taken. Conditions that are considered in the differential diagnosis of orofacial granulomatosis are systemic granulomatous diseases that are known to have oral manifestations including Crohn disease, sarcoidosis, and mycobacterial infections. Given the many causes of orofacial and labial swelling, GC is a diagnosis of exclusion based on a thorough history and physical examination as well as appropriate diagnostic studies, with the cornerstone of the diagnosis resting on the histologic appearance of the lesion. Histologically, the diagnosis lies in the demonstration of granuloma formation, consisting of collections of epithelioid histiocytes and Langerhans giant cells. Once granuloma formation is documented, special stains are used to rule out other granulomatous diseases.

Intralesional steroids have been reported to provide the greatest improvement; however, in the majority of patients, multiple treatments are required.^6,7 Allen et al⁸ suggested that the efficacy of intralesional therapy increases when preceded by local anesthesia of the lip, thus allowing larger doses of triamcinolone to be tolerated by the patient. Systemic corticosteroids also have been used with moderate success, but the side effects of long-term systemic corticosteroid therapy make this treatment option less appealing.⁹ Other agents with known anti-inflammatory properties also have been used that may offer better side-effect profiles when used for long-term suppressive therapy, including 
clofazimine, dapsone, sulfapyridine, danazol, hydroxychloroquine, and antibiotics such as doxycycline and metronidazole.¹⁰

In severe or recalcitrant cases, surgical intervention by way of a reduction cheiloplasty is considered by some to be an appropriate next step in therapy but is rarely needed. Postoperative intralesional steroid injections are necessary due to reported cases of worsening disease when injections are discontinued after cheiloplasty.^11,12

Our patient was treated with 5 mg of intralesional triamcinolone acetonide with 10 separate injections of 0.5 cc each along the affected portions of the upper lip. She also was given doxycycline 100 mg once daily for 30 days. The patient reported complete resolution of the upper lip swelling 7 days after the initiation of therapy. At 1-month follow-up, she reported that the swelling had completely resolved. However, 1 day prior to the scheduled visit, shortly after finishing the course of doxycycline, she noted recurrent swelling. Due to the concomitant initial administration of both the steroid injections and doxycycline, it was unclear which treatment had provided relief. To avoid, or at least delay, the need for chronic intralesional steroid injections, another course of 40 mg doxycycline daily was prescribed. After 2 weeks, the patient reported that the swelling had markedly improved. The patient has 
maintained remission of the symptoms for approximately 6 months on daily suppressive therapy with 40 mg of doxycycline.

The recurrence of lip swelling after therapy, as in our patient, is typical of GC, and most cases require multiple follow-up visits and frequent alterations in therapy, which is often frustrating for both the patient and physician. However, awareness of this disease entity, its natural course, and the therapeutic options will allow physicians to more appropriately counsel and educate patients of this uncommon 
disease process.

To the Editor:

A 51-year-old woman presented to her dermatologist with recurrent and progressive upper lip swelling of 2 years’ duration. Her condition was previously evaluated by several other physicians without a diagnosis or resolution of the symptoms. The swelling began on the right side of the upper lip and right cheek; however, over the course of 2 years, the swelling had progressed to involve the entire upper lip with complete sparing of the lower lip. She denied pain but reported numbness of the upper lip. The patient visited her dentist who ruled out periodontal infection as the cause of the swelling. Diphenhydramine provided no relief; however, the cheek swelling resolved after a course of antibiotics prescribed by an ear, nose, and throat physician.

She consulted her primary care physician and was subsequently referred to a neurologist and allergist who were unable to provide a definitive diagnosis or complete relief of the symptoms. She denied any history of hypersensitivity reactions, odontogenic infections, gastrointestinal concerns, or any other signs or symptoms of systemic granulomatous disease.

Figure 1. Upper lip swelling without ulceration, fissuring, or scaling. The lower lip was completely spared.

On physical examination, the upper lip was swollen symmetrically without evidence of ulceration, fissuring, or scaling (Figure 1). Palpation of the upper lip was notable for firm, nontender, nonpitting edema without nodularity. The oral mucosa did not appear swollen or erythematous. Examination did not reveal ulceration or a cobblestone appearance.

A full-thickness skin biopsy of the upper lip was performed. Histopathology revealed perivascular nonnecrotizing granulomas adjacent to ectatic vascular channels with associated lymphoplasmacytic infiltrate (Figure 2). Periodic acid–Schiff stain was negative for fungal hyphae, tissue Gram stain was negative for bacteria, Fite and acid-fast bacillus stains were both negative for acid-fast organisms, and polariscopy was negative for polarizable foreign material. In this clinical context, the morphologic findings were consistent with the diagnosis of granulomatous cheilitis (GC).

Figure 2. Upper lip biopsy showed dermal edema, vascular ectasia, perivascular nonnecrotizing granulomas, and perivascular lymphocyte predominant inflammatory infiltrate (A)(H&E, original magnification ×100). Higher magnification of granulomas with perivascular lymphoplasmacytic infiltrate (B)(H&E, original magnification ×200).

Granulomatous cheilitis is a rare disorder of the lips and orofacial mucosa that was first described by Meischer¹ in 1945 as persistent or recurrent orofacial swelling secondary to lymphatic obstruction by granulomatous proliferation. It often has been described as a monosymptomatic form of Melkersson-Rosenthal syndrome (MRS). In its entirety, MRS constitutes a triad of GC, facial nerve palsy, and lingua plicata (also known as fissured tongue).^2,3 Although many authors agree that GC is associated with MRS, some believe that GC is a distinct entity because the majority of patients who present with GC subsequently do not develop MRS.⁴ Despite its relationship to MRS, the true incidence of GC largely is unknown. The onset of disease usually occurs in early adulthood but can present in middle-aged or older individuals.

The typical course of GC is relapsing and remitting, nontender and nonpitting swelling of the lips that eventually becomes permanent, leading to possible facial distortion and disability. Involvement of the upper lip is the most common, followed by (in order of decreasing frequency) the lower lip and cheeks.⁵ The swelling may be unilateral or bilateral and generally is not associated with ulceration, fissuring, or scaling; however, these complications have been reported in the terminal stages of the disease in which the macrocheilia has become permanent.

Despite the controversy over the etiology, pathophysiology, and classification of GC, it largely is accepted that when a patient presents clinically with a history of recurrent or persistent lip swelling, a 
full-thickness skin biopsy of the involved oral mucosa should be taken. Conditions that are considered in the differential diagnosis of orofacial granulomatosis are systemic granulomatous diseases that are known to have oral manifestations including Crohn disease, sarcoidosis, and mycobacterial infections. Given the many causes of orofacial and labial swelling, GC is a diagnosis of exclusion based on a thorough history and physical examination as well as appropriate diagnostic studies, with the cornerstone of the diagnosis resting on the histologic appearance of the lesion. Histologically, the diagnosis lies in the demonstration of granuloma formation, consisting of collections of epithelioid histiocytes and Langerhans giant cells. Once granuloma formation is documented, special stains are used to rule out other granulomatous diseases.

Intralesional steroids have been reported to provide the greatest improvement; however, in the majority of patients, multiple treatments are required.^6,7 Allen et al⁸ suggested that the efficacy of intralesional therapy increases when preceded by local anesthesia of the lip, thus allowing larger doses of triamcinolone to be tolerated by the patient. Systemic corticosteroids also have been used with moderate success, but the side effects of long-term systemic corticosteroid therapy make this treatment option less appealing.⁹ Other agents with known anti-inflammatory properties also have been used that may offer better side-effect profiles when used for long-term suppressive therapy, including 
clofazimine, dapsone, sulfapyridine, danazol, hydroxychloroquine, and antibiotics such as doxycycline and metronidazole.¹⁰

In severe or recalcitrant cases, surgical intervention by way of a reduction cheiloplasty is considered by some to be an appropriate next step in therapy but is rarely needed. Postoperative intralesional steroid injections are necessary due to reported cases of worsening disease when injections are discontinued after cheiloplasty.^11,12

Our patient was treated with 5 mg of intralesional triamcinolone acetonide with 10 separate injections of 0.5 cc each along the affected portions of the upper lip. She also was given doxycycline 100 mg once daily for 30 days. The patient reported complete resolution of the upper lip swelling 7 days after the initiation of therapy. At 1-month follow-up, she reported that the swelling had completely resolved. However, 1 day prior to the scheduled visit, shortly after finishing the course of doxycycline, she noted recurrent swelling. Due to the concomitant initial administration of both the steroid injections and doxycycline, it was unclear which treatment had provided relief. To avoid, or at least delay, the need for chronic intralesional steroid injections, another course of 40 mg doxycycline daily was prescribed. After 2 weeks, the patient reported that the swelling had markedly improved. The patient has 
maintained remission of the symptoms for approximately 6 months on daily suppressive therapy with 40 mg of doxycycline.

The recurrence of lip swelling after therapy, as in our patient, is typical of GC, and most cases require multiple follow-up visits and frequent alterations in therapy, which is often frustrating for both the patient and physician. However, awareness of this disease entity, its natural course, and the therapeutic options will allow physicians to more appropriately counsel and educate patients of this uncommon 
disease process.

To the Editor:

A 51-year-old woman presented to her dermatologist with recurrent and progressive upper lip swelling of 2 years’ duration. Her condition was previously evaluated by several other physicians without a diagnosis or resolution of the symptoms. The swelling began on the right side of the upper lip and right cheek; however, over the course of 2 years, the swelling had progressed to involve the entire upper lip with complete sparing of the lower lip. She denied pain but reported numbness of the upper lip. The patient visited her dentist who ruled out periodontal infection as the cause of the swelling. Diphenhydramine provided no relief; however, the cheek swelling resolved after a course of antibiotics prescribed by an ear, nose, and throat physician.

She consulted her primary care physician and was subsequently referred to a neurologist and allergist who were unable to provide a definitive diagnosis or complete relief of the symptoms. She denied any history of hypersensitivity reactions, odontogenic infections, gastrointestinal concerns, or any other signs or symptoms of systemic granulomatous disease.

Figure 1. Upper lip swelling without ulceration, fissuring, or scaling. The lower lip was completely spared.

On physical examination, the upper lip was swollen symmetrically without evidence of ulceration, fissuring, or scaling (Figure 1). Palpation of the upper lip was notable for firm, nontender, nonpitting edema without nodularity. The oral mucosa did not appear swollen or erythematous. Examination did not reveal ulceration or a cobblestone appearance.

A full-thickness skin biopsy of the upper lip was performed. Histopathology revealed perivascular nonnecrotizing granulomas adjacent to ectatic vascular channels with associated lymphoplasmacytic infiltrate (Figure 2). Periodic acid–Schiff stain was negative for fungal hyphae, tissue Gram stain was negative for bacteria, Fite and acid-fast bacillus stains were both negative for acid-fast organisms, and polariscopy was negative for polarizable foreign material. In this clinical context, the morphologic findings were consistent with the diagnosis of granulomatous cheilitis (GC).

Figure 2. Upper lip biopsy showed dermal edema, vascular ectasia, perivascular nonnecrotizing granulomas, and perivascular lymphocyte predominant inflammatory infiltrate (A)(H&E, original magnification ×100). Higher magnification of granulomas with perivascular lymphoplasmacytic infiltrate (B)(H&E, original magnification ×200).

Granulomatous cheilitis is a rare disorder of the lips and orofacial mucosa that was first described by Meischer¹ in 1945 as persistent or recurrent orofacial swelling secondary to lymphatic obstruction by granulomatous proliferation. It often has been described as a monosymptomatic form of Melkersson-Rosenthal syndrome (MRS). In its entirety, MRS constitutes a triad of GC, facial nerve palsy, and lingua plicata (also known as fissured tongue).^2,3 Although many authors agree that GC is associated with MRS, some believe that GC is a distinct entity because the majority of patients who present with GC subsequently do not develop MRS.⁴ Despite its relationship to MRS, the true incidence of GC largely is unknown. The onset of disease usually occurs in early adulthood but can present in middle-aged or older individuals.

The typical course of GC is relapsing and remitting, nontender and nonpitting swelling of the lips that eventually becomes permanent, leading to possible facial distortion and disability. Involvement of the upper lip is the most common, followed by (in order of decreasing frequency) the lower lip and cheeks.⁵ The swelling may be unilateral or bilateral and generally is not associated with ulceration, fissuring, or scaling; however, these complications have been reported in the terminal stages of the disease in which the macrocheilia has become permanent.

Despite the controversy over the etiology, pathophysiology, and classification of GC, it largely is accepted that when a patient presents clinically with a history of recurrent or persistent lip swelling, a 
full-thickness skin biopsy of the involved oral mucosa should be taken. Conditions that are considered in the differential diagnosis of orofacial granulomatosis are systemic granulomatous diseases that are known to have oral manifestations including Crohn disease, sarcoidosis, and mycobacterial infections. Given the many causes of orofacial and labial swelling, GC is a diagnosis of exclusion based on a thorough history and physical examination as well as appropriate diagnostic studies, with the cornerstone of the diagnosis resting on the histologic appearance of the lesion. Histologically, the diagnosis lies in the demonstration of granuloma formation, consisting of collections of epithelioid histiocytes and Langerhans giant cells. Once granuloma formation is documented, special stains are used to rule out other granulomatous diseases.

Intralesional steroids have been reported to provide the greatest improvement; however, in the majority of patients, multiple treatments are required.^6,7 Allen et al⁸ suggested that the efficacy of intralesional therapy increases when preceded by local anesthesia of the lip, thus allowing larger doses of triamcinolone to be tolerated by the patient. Systemic corticosteroids also have been used with moderate success, but the side effects of long-term systemic corticosteroid therapy make this treatment option less appealing.⁹ Other agents with known anti-inflammatory properties also have been used that may offer better side-effect profiles when used for long-term suppressive therapy, including 
clofazimine, dapsone, sulfapyridine, danazol, hydroxychloroquine, and antibiotics such as doxycycline and metronidazole.¹⁰

In severe or recalcitrant cases, surgical intervention by way of a reduction cheiloplasty is considered by some to be an appropriate next step in therapy but is rarely needed. Postoperative intralesional steroid injections are necessary due to reported cases of worsening disease when injections are discontinued after cheiloplasty.^11,12

Our patient was treated with 5 mg of intralesional triamcinolone acetonide with 10 separate injections of 0.5 cc each along the affected portions of the upper lip. She also was given doxycycline 100 mg once daily for 30 days. The patient reported complete resolution of the upper lip swelling 7 days after the initiation of therapy. At 1-month follow-up, she reported that the swelling had completely resolved. However, 1 day prior to the scheduled visit, shortly after finishing the course of doxycycline, she noted recurrent swelling. Due to the concomitant initial administration of both the steroid injections and doxycycline, it was unclear which treatment had provided relief. To avoid, or at least delay, the need for chronic intralesional steroid injections, another course of 40 mg doxycycline daily was prescribed. After 2 weeks, the patient reported that the swelling had markedly improved. The patient has 
maintained remission of the symptoms for approximately 6 months on daily suppressive therapy with 40 mg of doxycycline.

The recurrence of lip swelling after therapy, as in our patient, is typical of GC, and most cases require multiple follow-up visits and frequent alterations in therapy, which is often frustrating for both the patient and physician. However, awareness of this disease entity, its natural course, and the therapeutic options will allow physicians to more appropriately counsel and educate patients of this uncommon 
disease process.

The Diagnosis: Allergic Contact Dermatitis to 
Para-phenylenediamine

To darken the color of henna and increase penetrance and staining, para-phenylenediamine (PPD) is added.¹ Allergic contact dermatitis is the most common type of hypersensitivity to PPD.² A retrospective study that examined severe adverse events from applying henna dyes in children found that angioedema of mucosal tissues was the most common severe adverse event; others included renal failure and shock.³

Black henna is associated with multiple cultural practices. For example, Indian weddings contain a henna decoration ceremony for the bride based on the belief that the longer the henna lasts, the longer the marriage lasts. Black henna is favored for this practice, as it lasts longer than red henna.

Henna (Lawsonia inermis) is a plant that contains the molecule lawsone (naphthoquinone). Lawsone has an intense affinity for keratin; as a result, lawsone is frequently added to temporary body tattoos and hair dyes to create a relatively permanent change in skin or hair color.⁴ Henna is mixed with hennotannic acid to release the lawsone from the plant. Lawsone and hennotannic acid rarely cause allergic reactions.^1,5-7 Once applied to skin, henna takes a few hours to dry, and the resulting color is orange to red.⁸ Often, PPD is added to henna paste to create a black color, to speed up the drying process, and to increase its longevity.

Para-phenylenediamine has been repeatedly reported to cause allergic contact dermatitis. We describe a case of allergic contact dermatitis secondary to PPD in black henna. Our patient is a clear example that PPD is the allergen in black henna given that there was no reaction to the natural red henna tattoo that was applied at the same time to the palmar surfaces of the hands (Figure). Aside from the bullous reaction to black henna dye described here, other reported presentations include erythema multiforme–like and exudative erythema reactions.^9,10

Contact dermatitis lesions from black henna dye can be treated with topical corticosteroids. Patients may develop residual postinflammatory hyperpigmentation or hypopigmentation, leukoderma, keloids, or scars.^1,11,12

The Diagnosis: Allergic Contact Dermatitis to 
Para-phenylenediamine

To darken the color of henna and increase penetrance and staining, para-phenylenediamine (PPD) is added.¹ Allergic contact dermatitis is the most common type of hypersensitivity to PPD.² A retrospective study that examined severe adverse events from applying henna dyes in children found that angioedema of mucosal tissues was the most common severe adverse event; others included renal failure and shock.³

Black henna is associated with multiple cultural practices. For example, Indian weddings contain a henna decoration ceremony for the bride based on the belief that the longer the henna lasts, the longer the marriage lasts. Black henna is favored for this practice, as it lasts longer than red henna.

Henna (Lawsonia inermis) is a plant that contains the molecule lawsone (naphthoquinone). Lawsone has an intense affinity for keratin; as a result, lawsone is frequently added to temporary body tattoos and hair dyes to create a relatively permanent change in skin or hair color.⁴ Henna is mixed with hennotannic acid to release the lawsone from the plant. Lawsone and hennotannic acid rarely cause allergic reactions.^1,5-7 Once applied to skin, henna takes a few hours to dry, and the resulting color is orange to red.⁸ Often, PPD is added to henna paste to create a black color, to speed up the drying process, and to increase its longevity.

Para-phenylenediamine has been repeatedly reported to cause allergic contact dermatitis. We describe a case of allergic contact dermatitis secondary to PPD in black henna. Our patient is a clear example that PPD is the allergen in black henna given that there was no reaction to the natural red henna tattoo that was applied at the same time to the palmar surfaces of the hands (Figure). Aside from the bullous reaction to black henna dye described here, other reported presentations include erythema multiforme–like and exudative erythema reactions.^9,10

Contact dermatitis lesions from black henna dye can be treated with topical corticosteroids. Patients may develop residual postinflammatory hyperpigmentation or hypopigmentation, leukoderma, keloids, or scars.^1,11,12

The Diagnosis: Allergic Contact Dermatitis to 
Para-phenylenediamine

To darken the color of henna and increase penetrance and staining, para-phenylenediamine (PPD) is added.¹ Allergic contact dermatitis is the most common type of hypersensitivity to PPD.² A retrospective study that examined severe adverse events from applying henna dyes in children found that angioedema of mucosal tissues was the most common severe adverse event; others included renal failure and shock.³

Black henna is associated with multiple cultural practices. For example, Indian weddings contain a henna decoration ceremony for the bride based on the belief that the longer the henna lasts, the longer the marriage lasts. Black henna is favored for this practice, as it lasts longer than red henna.

Henna (Lawsonia inermis) is a plant that contains the molecule lawsone (naphthoquinone). Lawsone has an intense affinity for keratin; as a result, lawsone is frequently added to temporary body tattoos and hair dyes to create a relatively permanent change in skin or hair color.⁴ Henna is mixed with hennotannic acid to release the lawsone from the plant. Lawsone and hennotannic acid rarely cause allergic reactions.^1,5-7 Once applied to skin, henna takes a few hours to dry, and the resulting color is orange to red.⁸ Often, PPD is added to henna paste to create a black color, to speed up the drying process, and to increase its longevity.

Para-phenylenediamine has been repeatedly reported to cause allergic contact dermatitis. We describe a case of allergic contact dermatitis secondary to PPD in black henna. Our patient is a clear example that PPD is the allergen in black henna given that there was no reaction to the natural red henna tattoo that was applied at the same time to the palmar surfaces of the hands (Figure). Aside from the bullous reaction to black henna dye described here, other reported presentations include erythema multiforme–like and exudative erythema reactions.^9,10

Contact dermatitis lesions from black henna dye can be treated with topical corticosteroids. Patients may develop residual postinflammatory hyperpigmentation or hypopigmentation, leukoderma, keloids, or scars.^1,11,12

CASE: Physician defames sedated patient

Our case takes us to the Commonwealth of Virginia. A male patient preparing to undergo a colonoscopy was concerned that, because of grogginess brought on by anesthesia, he might misunderstand postprocedure instructions or advice. He, therefore, turned his cell phone’s record function “on” and put it with his clothes. His clothes were put in a plastic bag, which ended up under the table with him in the operating room.

Following the procedure, as his wife drove him home, the patient replayed the instructions on the cell phone and realized that it had recorded the entire procedure. It quickly became apparent that the medical personnel had engaged in a series of inappropriate and insulting comments at the patient’s expense.

The anesthesiologist, talking to the now-unconscious patient, said, “after five minutes of talking to you in pre-op, I wanted to punch you in the face.” The patient had reported he was taking medication for a mild penile rash. The anesthesiologist warned an assistant not to touch it or “you might get syphilis on your arm or something,” but then noted, “it’s probably tuberculosis of the penis, so you’ll be all right.” There was further mocking of the patient, including a question of whether he was homosexual.

The anesthesiologist and gastroenterologist wanted to avoid talking to the patient after the procedure, and the gastroenterologist instructed an assistant to lie to the patient and convince the patient that the gastroenterologist had already spoken to him following the colonoscopy but, “you just don’t remember it.” In addition, the anesthesiologist announced that she was going to mark “hemorrhoids” on the patient’s chart, which she knew was a 
false diagnosis.

The patient, who is identified only by 
initials, is an attorney.¹ Of course, the smartphone was “good documentation” of what came out of what the health care team said.

The lawsuit

The patient (now plaintiff) claimed that he was verbally brutalized and suffered anxiety, embarrassment, and loss of sleep for 
several months.

On the first day of trial, the gastroenterologist was dismissed from the case. The trial went on against the anesthesiologist and the anesthesia practice.

What’s the verdict?

The patient was awarded $500,000, as follows:

• $100,000 for defamation, ($50,000 each for the syphilis and tuberculosis comments),
• $200,000 for medical malpractice
• $200,000 in punitive damages (including $50,000 the jury found that the anesthesia practice should pay).

Caveat. The above facts about this case come from the plaintiff’s complaint¹ and various professional commentaries and news sources.^2–5 Such sources are not always reliable, so they may not describe accurately all of the relevant events and statements.

Neither of the authors of this column attended the trial or heard the testimony presented. For the purposes of discussing the issues below, however, we treat as true the facts stated above. In addition, some of the legal claims in this case are uncertain. It is entirely possible that an appeal will be made and accepted, and some or all of the damages could be reduced by the trial court or an appellate court. The jury award, therefore, is not necessarily the last word.

Medicolegal takeaways 
from this case

This case raises a number of professional, ethical, and legal issues. Most fundamentally, the health care team is always expected to prioritize the patient’s best interest. Respect for the patient is an essential element of that.

Behaviors such as those reported about these physicians are “absolutely not to engage in any time,” stated President of the American Society of Anesthesiologists 
John Absentein, MD.⁶ A former president of the Academy of Anesthesiology, 
Kathryn McGoldrick, MD, added some common sense advice that such discussions are “not only offensive but frankly stupid.” As she notes, “we can never be certain that our patients are asleep and wouldn’t have recall.”⁷

The actions of the physicians also may violate ethical obligations. The very first principle of medical ethics is that the physician shall provide care “with compassion and respect for human dignity and rights.”⁸

The legal claims included defamation, infliction of emotional distress, privacy (related to medical records), and malpractice. We will take a very brief look at each of those causes of action and then say a word about punitive damages (which the jury awarded in this case).

It is important to remember that state law, rather than federal, is providing the legal principles on which these claims were decided. Federal law might provide some relevant principles in such cases (for example, the First Amendment freedom of speech limits the state defamation rules), but that is the exception. State law is the rule.

Defamation—award of damages

At its core, defamation is publishing (that is, telling someone other than the plaintiff) something untrue that may be harmful to another person. Generally the harm is reputational and the plaintiff may be affected by loss of business, mental suffering, or loss of esteem in the community.⁹

Defamation claims are not typical in health care cases. However, these claims are not rare: instances of health care professionals defaming other health care professionals, patients giving negative “reviews,” or health care professionals releasing false information to employers certainly do exist.

In this case, in addition to saying that the patient had syphilis and tuberculosis (both untrue), the physicians said he was a “wimp.” One interesting concept of 
defamation law that has developed over the centuries is “negligence per se.” This means a falsehood has been published about someone and the falsehood is likely to cause serious reputational harm. Claims that someone has a contagious disease traditionally have been considered negligence per se. Syphilis and tuberculosis fall in that category. On the other hand, saying someone needs to “man up” is usually a matter of opinion, so defamation for such comments is unlikely without special circumstances.

From the anesthesiologist’s perspective, the question is whether anyone who heard the publication really believed that the patient had either of the diseases. A joke that nobody believes to be based on fact generally is not defamatory because it has not harmed the plaintiff.¹⁰ It is apparent that the jury felt the patient had been defamed, however, given the $100,000 award for defamation.

In the United States there is special sensitivity to defamation awards because they may implicate the First Amendment’s protection of free speech. That being the case, this award may be particularly open to review by the judge and appellate courts.

Emotional distress—no award 
of damages

There are 2 kinds of “emotional distress” claimed in this case:

• intentional infliction
• negligent infliction.

Intentional infliction usually requires outrageous conduct by the defendant who acts intentionally or recklessly to inflict severe mental pain on the plaintiff.¹¹ In this case, the element of “intentional” or “reckless” is interesting. While the conduct was outrageous, it is doubtful that there was any way the anesthesiologist could have imagined that these outrageous statements would have been transmitted to the patient/plaintiff.

As for negligent infliction of emotional distress, most states have been wary of opening a Pandora’s Box of litigation. Therefore, they generally require significant physical manifestations of great stress to allow recovery.¹² It appears that the jury did not find the elements of either intentional or negligent infliction of emotional distress in this case.

As a side-note, this kind of emotional distress is viewed by the law as different from emotional distress that is incidental to a physical injury (pain and suffering). All states recognize that form of emotional distress.

Privacy—no award of damages

The privacy of medical records has, of course, become a major concern in the last few years. Both federal and state law provides significant penalties for the unauthorized release of medical information. However, in this case, it does not appear ­that medical information was improp-
erly revealed.¹³

The patient’s complaint suggested that the anesthesiologist’s discussion during the colonoscopy of the medication for the penile rash was unnecessary for health care purposes.¹ Therefore, it claims, the discussion violated the state health records privacy law. At the same time there was no indication in the public reports that this caused any harm 
to the patient.

Medical malpractice—award 
of damages

Malpractice usually involves professional practice that is unacceptable to the profession itself. It most commonly is negligence, or carelessness, that causes injury to the patient. The gross disregard for professional medical standards here was certainly negligence.¹⁴ The plaintiff claimed that discussing the medication for the penile rash and falsification of the medical records 
constituted malpractice.¹

Presumably the jury award for medical malpractice means the jury found that the misconduct of the medical staff caused the emotional harm that the plaintiff experienced (described as embarrassment, loss of sleep, mental anguish, and anxiety), and that those injuries warranted a 
$200,000 award.

Punitive damage—award of damages

The jury also awarded $200,000 in “punitive” or “exemplary” damages. These are unusual damages, given not so much to compensate the victim but rather as a deterrent for the future. Generally the defendant’s conduct must have been egregious and completely unacceptable.¹⁵ Those elements were apparent to the jury from the facts of this case.

What about loss of practice privileges?

It is not unlikely that one or more of the medical professionals might, beyond civil liability, be subject to licensure discipline by the Virginia board. In addition, there are other secondary consequences of this lawsuit. The employment of those involved may be interrupted. (The anesthesiologist is said to have moved to another state, for example.) Hospital privileges also may be affected, as may insurance rates. The results of this award likely will have to be reported to the National Practitioner Data Bank.

As physicians, what’s 
our takeaway?

Conduct unbecoming a physician remains front and center with a recent essay published in the internal medicine literature.¹⁶ The anonymous author attests to witnessing a male gynecologist making sexual comments regarding the patient at the time of vaginal surgery preparation and an obstetrician singing and dancing to a Mexican song while treating his Hispanic patient for postpartum bleeding.

The unusual case of the anesthesiologist that we address was made even more unusual by the fact that it was recorded. Recordings, however, are likely to become ever more common. The advice of everyone’s grandmother is well taken: “Always act as though what you do will be published on the front page of the newspaper.” The ubiquitous presence of video and audio cameras and untold other devices means that someone may well be watching.

Aside from the risk of getting caught, respect for patients and clients is the very foundation of respect and professional care. It is distressing that the anesthesiologist was so disrespectful of a patient. It is equally disappointing that nobody put a stop to it.

Share your thoughts! Send your Letter to the Editor to rbarbieri@frontlinemedcom.com. Please include your name and the city and state in which you practice.

CASE: Physician defames sedated patient

Our case takes us to the Commonwealth of Virginia. A male patient preparing to undergo a colonoscopy was concerned that, because of grogginess brought on by anesthesia, he might misunderstand postprocedure instructions or advice. He, therefore, turned his cell phone’s record function “on” and put it with his clothes. His clothes were put in a plastic bag, which ended up under the table with him in the operating room.

Following the procedure, as his wife drove him home, the patient replayed the instructions on the cell phone and realized that it had recorded the entire procedure. It quickly became apparent that the medical personnel had engaged in a series of inappropriate and insulting comments at the patient’s expense.

The anesthesiologist, talking to the now-unconscious patient, said, “after five minutes of talking to you in pre-op, I wanted to punch you in the face.” The patient had reported he was taking medication for a mild penile rash. The anesthesiologist warned an assistant not to touch it or “you might get syphilis on your arm or something,” but then noted, “it’s probably tuberculosis of the penis, so you’ll be all right.” There was further mocking of the patient, including a question of whether he was homosexual.

The anesthesiologist and gastroenterologist wanted to avoid talking to the patient after the procedure, and the gastroenterologist instructed an assistant to lie to the patient and convince the patient that the gastroenterologist had already spoken to him following the colonoscopy but, “you just don’t remember it.” In addition, the anesthesiologist announced that she was going to mark “hemorrhoids” on the patient’s chart, which she knew was a 
false diagnosis.

The patient, who is identified only by 
initials, is an attorney.¹ Of course, the smartphone was “good documentation” of what came out of what the health care team said.

The lawsuit

The patient (now plaintiff) claimed that he was verbally brutalized and suffered anxiety, embarrassment, and loss of sleep for 
several months.

On the first day of trial, the gastroenterologist was dismissed from the case. The trial went on against the anesthesiologist and the anesthesia practice.

What’s the verdict?

The patient was awarded $500,000, as follows:

• $100,000 for defamation, ($50,000 each for the syphilis and tuberculosis comments),
• $200,000 for medical malpractice
• $200,000 in punitive damages (including $50,000 the jury found that the anesthesia practice should pay).

Caveat. The above facts about this case come from the plaintiff’s complaint¹ and various professional commentaries and news sources.^2–5 Such sources are not always reliable, so they may not describe accurately all of the relevant events and statements.

Neither of the authors of this column attended the trial or heard the testimony presented. For the purposes of discussing the issues below, however, we treat as true the facts stated above. In addition, some of the legal claims in this case are uncertain. It is entirely possible that an appeal will be made and accepted, and some or all of the damages could be reduced by the trial court or an appellate court. The jury award, therefore, is not necessarily the last word.

Medicolegal takeaways 
from this case

This case raises a number of professional, ethical, and legal issues. Most fundamentally, the health care team is always expected to prioritize the patient’s best interest. Respect for the patient is an essential element of that.

Behaviors such as those reported about these physicians are “absolutely not to engage in any time,” stated President of the American Society of Anesthesiologists 
John Absentein, MD.⁶ A former president of the Academy of Anesthesiology, 
Kathryn McGoldrick, MD, added some common sense advice that such discussions are “not only offensive but frankly stupid.” As she notes, “we can never be certain that our patients are asleep and wouldn’t have recall.”⁷

The actions of the physicians also may violate ethical obligations. The very first principle of medical ethics is that the physician shall provide care “with compassion and respect for human dignity and rights.”⁸

The legal claims included defamation, infliction of emotional distress, privacy (related to medical records), and malpractice. We will take a very brief look at each of those causes of action and then say a word about punitive damages (which the jury awarded in this case).

It is important to remember that state law, rather than federal, is providing the legal principles on which these claims were decided. Federal law might provide some relevant principles in such cases (for example, the First Amendment freedom of speech limits the state defamation rules), but that is the exception. State law is the rule.

Defamation—award of damages

At its core, defamation is publishing (that is, telling someone other than the plaintiff) something untrue that may be harmful to another person. Generally the harm is reputational and the plaintiff may be affected by loss of business, mental suffering, or loss of esteem in the community.⁹

Defamation claims are not typical in health care cases. However, these claims are not rare: instances of health care professionals defaming other health care professionals, patients giving negative “reviews,” or health care professionals releasing false information to employers certainly do exist.

In this case, in addition to saying that the patient had syphilis and tuberculosis (both untrue), the physicians said he was a “wimp.” One interesting concept of 
defamation law that has developed over the centuries is “negligence per se.” This means a falsehood has been published about someone and the falsehood is likely to cause serious reputational harm. Claims that someone has a contagious disease traditionally have been considered negligence per se. Syphilis and tuberculosis fall in that category. On the other hand, saying someone needs to “man up” is usually a matter of opinion, so defamation for such comments is unlikely without special circumstances.

From the anesthesiologist’s perspective, the question is whether anyone who heard the publication really believed that the patient had either of the diseases. A joke that nobody believes to be based on fact generally is not defamatory because it has not harmed the plaintiff.¹⁰ It is apparent that the jury felt the patient had been defamed, however, given the $100,000 award for defamation.

In the United States there is special sensitivity to defamation awards because they may implicate the First Amendment’s protection of free speech. That being the case, this award may be particularly open to review by the judge and appellate courts.

Emotional distress—no award 
of damages

There are 2 kinds of “emotional distress” claimed in this case:

• intentional infliction
• negligent infliction.

Intentional infliction usually requires outrageous conduct by the defendant who acts intentionally or recklessly to inflict severe mental pain on the plaintiff.¹¹ In this case, the element of “intentional” or “reckless” is interesting. While the conduct was outrageous, it is doubtful that there was any way the anesthesiologist could have imagined that these outrageous statements would have been transmitted to the patient/plaintiff.

As for negligent infliction of emotional distress, most states have been wary of opening a Pandora’s Box of litigation. Therefore, they generally require significant physical manifestations of great stress to allow recovery.¹² It appears that the jury did not find the elements of either intentional or negligent infliction of emotional distress in this case.

As a side-note, this kind of emotional distress is viewed by the law as different from emotional distress that is incidental to a physical injury (pain and suffering). All states recognize that form of emotional distress.

Privacy—no award of damages

The privacy of medical records has, of course, become a major concern in the last few years. Both federal and state law provides significant penalties for the unauthorized release of medical information. However, in this case, it does not appear ­that medical information was improp-
erly revealed.¹³

The patient’s complaint suggested that the anesthesiologist’s discussion during the colonoscopy of the medication for the penile rash was unnecessary for health care purposes.¹ Therefore, it claims, the discussion violated the state health records privacy law. At the same time there was no indication in the public reports that this caused any harm 
to the patient.

Medical malpractice—award 
of damages

Malpractice usually involves professional practice that is unacceptable to the profession itself. It most commonly is negligence, or carelessness, that causes injury to the patient. The gross disregard for professional medical standards here was certainly negligence.¹⁴ The plaintiff claimed that discussing the medication for the penile rash and falsification of the medical records 
constituted malpractice.¹

Presumably the jury award for medical malpractice means the jury found that the misconduct of the medical staff caused the emotional harm that the plaintiff experienced (described as embarrassment, loss of sleep, mental anguish, and anxiety), and that those injuries warranted a 
$200,000 award.

Punitive damage—award of damages

The jury also awarded $200,000 in “punitive” or “exemplary” damages. These are unusual damages, given not so much to compensate the victim but rather as a deterrent for the future. Generally the defendant’s conduct must have been egregious and completely unacceptable.¹⁵ Those elements were apparent to the jury from the facts of this case.

What about loss of practice privileges?

It is not unlikely that one or more of the medical professionals might, beyond civil liability, be subject to licensure discipline by the Virginia board. In addition, there are other secondary consequences of this lawsuit. The employment of those involved may be interrupted. (The anesthesiologist is said to have moved to another state, for example.) Hospital privileges also may be affected, as may insurance rates. The results of this award likely will have to be reported to the National Practitioner Data Bank.

As physicians, what’s 
our takeaway?

Conduct unbecoming a physician remains front and center with a recent essay published in the internal medicine literature.¹⁶ The anonymous author attests to witnessing a male gynecologist making sexual comments regarding the patient at the time of vaginal surgery preparation and an obstetrician singing and dancing to a Mexican song while treating his Hispanic patient for postpartum bleeding.

The unusual case of the anesthesiologist that we address was made even more unusual by the fact that it was recorded. Recordings, however, are likely to become ever more common. The advice of everyone’s grandmother is well taken: “Always act as though what you do will be published on the front page of the newspaper.” The ubiquitous presence of video and audio cameras and untold other devices means that someone may well be watching.

Aside from the risk of getting caught, respect for patients and clients is the very foundation of respect and professional care. It is distressing that the anesthesiologist was so disrespectful of a patient. It is equally disappointing that nobody put a stop to it.

Share your thoughts! Send your Letter to the Editor to rbarbieri@frontlinemedcom.com. Please include your name and the city and state in which you practice.

CASE: Physician defames sedated patient

Our case takes us to the Commonwealth of Virginia. A male patient preparing to undergo a colonoscopy was concerned that, because of grogginess brought on by anesthesia, he might misunderstand postprocedure instructions or advice. He, therefore, turned his cell phone’s record function “on” and put it with his clothes. His clothes were put in a plastic bag, which ended up under the table with him in the operating room.

Following the procedure, as his wife drove him home, the patient replayed the instructions on the cell phone and realized that it had recorded the entire procedure. It quickly became apparent that the medical personnel had engaged in a series of inappropriate and insulting comments at the patient’s expense.

The anesthesiologist, talking to the now-unconscious patient, said, “after five minutes of talking to you in pre-op, I wanted to punch you in the face.” The patient had reported he was taking medication for a mild penile rash. The anesthesiologist warned an assistant not to touch it or “you might get syphilis on your arm or something,” but then noted, “it’s probably tuberculosis of the penis, so you’ll be all right.” There was further mocking of the patient, including a question of whether he was homosexual.

The anesthesiologist and gastroenterologist wanted to avoid talking to the patient after the procedure, and the gastroenterologist instructed an assistant to lie to the patient and convince the patient that the gastroenterologist had already spoken to him following the colonoscopy but, “you just don’t remember it.” In addition, the anesthesiologist announced that she was going to mark “hemorrhoids” on the patient’s chart, which she knew was a 
false diagnosis.

The patient, who is identified only by 
initials, is an attorney.¹ Of course, the smartphone was “good documentation” of what came out of what the health care team said.

The lawsuit

The patient (now plaintiff) claimed that he was verbally brutalized and suffered anxiety, embarrassment, and loss of sleep for 
several months.

On the first day of trial, the gastroenterologist was dismissed from the case. The trial went on against the anesthesiologist and the anesthesia practice.

What’s the verdict?

The patient was awarded $500,000, as follows:

• $100,000 for defamation, ($50,000 each for the syphilis and tuberculosis comments),
• $200,000 for medical malpractice
• $200,000 in punitive damages (including $50,000 the jury found that the anesthesia practice should pay).

Caveat. The above facts about this case come from the plaintiff’s complaint¹ and various professional commentaries and news sources.^2–5 Such sources are not always reliable, so they may not describe accurately all of the relevant events and statements.

Neither of the authors of this column attended the trial or heard the testimony presented. For the purposes of discussing the issues below, however, we treat as true the facts stated above. In addition, some of the legal claims in this case are uncertain. It is entirely possible that an appeal will be made and accepted, and some or all of the damages could be reduced by the trial court or an appellate court. The jury award, therefore, is not necessarily the last word.

Medicolegal takeaways 
from this case

This case raises a number of professional, ethical, and legal issues. Most fundamentally, the health care team is always expected to prioritize the patient’s best interest. Respect for the patient is an essential element of that.

Behaviors such as those reported about these physicians are “absolutely not to engage in any time,” stated President of the American Society of Anesthesiologists 
John Absentein, MD.⁶ A former president of the Academy of Anesthesiology, 
Kathryn McGoldrick, MD, added some common sense advice that such discussions are “not only offensive but frankly stupid.” As she notes, “we can never be certain that our patients are asleep and wouldn’t have recall.”⁷

The actions of the physicians also may violate ethical obligations. The very first principle of medical ethics is that the physician shall provide care “with compassion and respect for human dignity and rights.”⁸

The legal claims included defamation, infliction of emotional distress, privacy (related to medical records), and malpractice. We will take a very brief look at each of those causes of action and then say a word about punitive damages (which the jury awarded in this case).

It is important to remember that state law, rather than federal, is providing the legal principles on which these claims were decided. Federal law might provide some relevant principles in such cases (for example, the First Amendment freedom of speech limits the state defamation rules), but that is the exception. State law is the rule.

Defamation—award of damages

At its core, defamation is publishing (that is, telling someone other than the plaintiff) something untrue that may be harmful to another person. Generally the harm is reputational and the plaintiff may be affected by loss of business, mental suffering, or loss of esteem in the community.⁹

Defamation claims are not typical in health care cases. However, these claims are not rare: instances of health care professionals defaming other health care professionals, patients giving negative “reviews,” or health care professionals releasing false information to employers certainly do exist.

In this case, in addition to saying that the patient had syphilis and tuberculosis (both untrue), the physicians said he was a “wimp.” One interesting concept of 
defamation law that has developed over the centuries is “negligence per se.” This means a falsehood has been published about someone and the falsehood is likely to cause serious reputational harm. Claims that someone has a contagious disease traditionally have been considered negligence per se. Syphilis and tuberculosis fall in that category. On the other hand, saying someone needs to “man up” is usually a matter of opinion, so defamation for such comments is unlikely without special circumstances.

From the anesthesiologist’s perspective, the question is whether anyone who heard the publication really believed that the patient had either of the diseases. A joke that nobody believes to be based on fact generally is not defamatory because it has not harmed the plaintiff.¹⁰ It is apparent that the jury felt the patient had been defamed, however, given the $100,000 award for defamation.

In the United States there is special sensitivity to defamation awards because they may implicate the First Amendment’s protection of free speech. That being the case, this award may be particularly open to review by the judge and appellate courts.

Emotional distress—no award 
of damages

There are 2 kinds of “emotional distress” claimed in this case:

• intentional infliction
• negligent infliction.

Intentional infliction usually requires outrageous conduct by the defendant who acts intentionally or recklessly to inflict severe mental pain on the plaintiff.¹¹ In this case, the element of “intentional” or “reckless” is interesting. While the conduct was outrageous, it is doubtful that there was any way the anesthesiologist could have imagined that these outrageous statements would have been transmitted to the patient/plaintiff.

As for negligent infliction of emotional distress, most states have been wary of opening a Pandora’s Box of litigation. Therefore, they generally require significant physical manifestations of great stress to allow recovery.¹² It appears that the jury did not find the elements of either intentional or negligent infliction of emotional distress in this case.

As a side-note, this kind of emotional distress is viewed by the law as different from emotional distress that is incidental to a physical injury (pain and suffering). All states recognize that form of emotional distress.

Privacy—no award of damages

The privacy of medical records has, of course, become a major concern in the last few years. Both federal and state law provides significant penalties for the unauthorized release of medical information. However, in this case, it does not appear ­that medical information was improp-
erly revealed.¹³

The patient’s complaint suggested that the anesthesiologist’s discussion during the colonoscopy of the medication for the penile rash was unnecessary for health care purposes.¹ Therefore, it claims, the discussion violated the state health records privacy law. At the same time there was no indication in the public reports that this caused any harm 
to the patient.

Medical malpractice—award 
of damages

Malpractice usually involves professional practice that is unacceptable to the profession itself. It most commonly is negligence, or carelessness, that causes injury to the patient. The gross disregard for professional medical standards here was certainly negligence.¹⁴ The plaintiff claimed that discussing the medication for the penile rash and falsification of the medical records 
constituted malpractice.¹

Presumably the jury award for medical malpractice means the jury found that the misconduct of the medical staff caused the emotional harm that the plaintiff experienced (described as embarrassment, loss of sleep, mental anguish, and anxiety), and that those injuries warranted a 
$200,000 award.

Punitive damage—award of damages

The jury also awarded $200,000 in “punitive” or “exemplary” damages. These are unusual damages, given not so much to compensate the victim but rather as a deterrent for the future. Generally the defendant’s conduct must have been egregious and completely unacceptable.¹⁵ Those elements were apparent to the jury from the facts of this case.

What about loss of practice privileges?

It is not unlikely that one or more of the medical professionals might, beyond civil liability, be subject to licensure discipline by the Virginia board. In addition, there are other secondary consequences of this lawsuit. The employment of those involved may be interrupted. (The anesthesiologist is said to have moved to another state, for example.) Hospital privileges also may be affected, as may insurance rates. The results of this award likely will have to be reported to the National Practitioner Data Bank.

As physicians, what’s 
our takeaway?

Conduct unbecoming a physician remains front and center with a recent essay published in the internal medicine literature.¹⁶ The anonymous author attests to witnessing a male gynecologist making sexual comments regarding the patient at the time of vaginal surgery preparation and an obstetrician singing and dancing to a Mexican song while treating his Hispanic patient for postpartum bleeding.

The unusual case of the anesthesiologist that we address was made even more unusual by the fact that it was recorded. Recordings, however, are likely to become ever more common. The advice of everyone’s grandmother is well taken: “Always act as though what you do will be published on the front page of the newspaper.” The ubiquitous presence of video and audio cameras and untold other devices means that someone may well be watching.

Aside from the risk of getting caught, respect for patients and clients is the very foundation of respect and professional care. It is distressing that the anesthesiologist was so disrespectful of a patient. It is equally disappointing that nobody put a stop to it.

Share your thoughts! Send your Letter to the Editor to rbarbieri@frontlinemedcom.com. Please include your name and the city and state in which you practice.

A 20-year-old woman with Gaucher disease presents with pain in her right ankle and in her back. She has had the ankle pain for the past 12 months and the back pain for the past 2 years. She describes the ankle pain as stabbing and moderately severe. It is constant, present both at rest and during physical activity, but aggravated by walking and twisting movements. She has noticed grinding and clicking sounds as she moves her ankle. The ankle pain has worsened over the past several months.

She says her back pain is similar to her ankle pain but less severe. She also reports generalized mild aches and bone pain. No other joints are involved. She has no history of fever, chills, or trauma.

A COMPLICATED MEDICAL HISTORY

Her Gaucher disease was diagnosed at age 4 when she presented with failure to thrive and with thrombocytopenia and splenomegaly. She and was found to have an N370S/IVS2+1 mutation of the GBA gene. She underwent removal of 90% of her spleen at the time of diagnosis and was on enzyme replacement therapy with imiglucerase until 3 years ago, when the treatment was stopped because the drug had become unavailable (because of a temporary closure of the manufacturing facility), and because she had developed neutralizing antibodies to it. Despite a dosage as high as 120 U/kg every 2 weeks (the recommended range is 2.5 U/kg three times a week up to 60 U/kg every 2 weeks), her anemia and thrombocytopenia worsened to the point that she became dependent on transfusion of red blood cells and platelets. She has also taken glucocorticoids at various times in the past as a premedication before enzyme replacement therapy.

About 3 years ago, she developed dryness of the skin, pruritus, shiny skin, hardening of the skin, and decreased oral aperture, which was diagnosed as scleroderma.

During the past 5 years, she has had multiple episodes of pale coloration of her skin on exposure to cold, suggestive of Raynaud phenomenon. And for the past 5 months, she has noticed a burning sensation in her throat and retrosternal pain, suggestive of gastroesophageal reflux disease.

She is a college student, with no history of smoking or use of alcohol or recreational drugs. She is sexually active, with no history of sexually transmitted disease, and she uses condoms and oral contraceptives for contraception.

Her father and mother are both carriers of Gaucher disease. She is not of Ashkenazi Jewish descent.

FINDINGS ON PHYSICAL EXAMINATION

On physical examination, her temperature, blood pressure, pulse, and respiratory rate are within normal limits. She has extensive tattooing on her upper chest to hide scarring from previous cannulation ports. The right ankle joint is moderately swollen but shows no other signs of inflammation; its range of motion is limited by severe pain. She has tenderness of the spinous processes and paraspinal area, in addition to multiple tender points in the thoracolumbar area. Palpation of the right hip reveals tenderness of the groin and trochanteric bursa.

No lymphadenopathy, hepatomegaly, splenomegaly, or abdominal masses are noted. Neurologic examination is essentially nonfocal.

Her current medications include omeprazole, ergocalciferol, calcium carbonate, gabapentin, citalopram, and celecoxib. She also takes a multivitamin daily.

1. Which is the most likely underlying cause of her ankle pain?

• Rheumatoid arthritis
• Gaucher disease
• Septic arthritis
• Avascular necrosis secondary to steroid use

Rheumatoid arthritis varies in its presentation. It is usually insidious in onset, migratory, and intermittent, with polyarticular or even monoarticular involvement, and it presents with pain, stiffness, and swelling of the joint.¹ Most often affected are the metacarpophalangeal, proximal interphalangeal, wrist, and metatarsophalangeal joints. Involvement of large joints of the upper and lower limbs is also common.² This is not the most likely cause of this patient’s symptoms, based on the history and the current presentation.

Gaucher disease is a lipidosis caused by accumulation of cellular glycolipids, especially glucocerebrosides, due to deficiency of the enzyme beta-glucosidase. Clinical manifestations include hepatomegaly, splenomegaly, and bone marrow disease presenting as anemia, thrombocytopenia, or skeletal disease.³ Skeletal involvement in Gaucher disease includes bone pain, bone infarcts, and lytic lesions.

Whether splenectomy predisposes the patient to bone manifestations is controversial. Some believe that splenectomy decreases the total body reservoir for the storage of glycolipids and predisposes to their deposition in bone, which in turn results in cortical thinning, impaired remodeling, and decreased intraosseous blood flow, leading to osteonecrosis and fractures.⁴ This is more common in patients with type 1 Gaucher disease who have undergone splenectomy. (Types 2 and 3 are much rarer, occurring mainly in children; central nervous system involvement is a key feature. A discussion of these types is beyond the focus of this paper.) However, some studies suggest that the increase in bone manifestations after splenectomy may be simply because of severe disease.⁵ It should be noted that, since the advent of enzyme replacement therapy for Gaucher disease, splenectomy is now rarely performed.⁶

Anemia is also considered an independent risk factor for the development of avascular necrosis in type 1 Gaucher disease.⁷ Osteonecrosis due to Gaucher disease is relatively common in the femur, tibia, and humerus and uncommon in the ankle joints.⁸

Septic arthritis is unlikely in this patient in the absence of fever or signs of inflammation of the joint. Her long-standing history of ankle pain would also be unusual for infection, but a superimposed infectious process should always be suspected in an arthritic joint.

Avascular necrosis secondary to steroid use. Glucocorticoids are notorious for their adverse effects on bone. They induce osteocyte apoptosis and a decrease in bone remodeling, potentially predisposing to osteonecrosis.⁹ There is a high incidence of osteoporosis, osteonecrosis, and fracture risk with glucocorticoid therapy, and the incidence is dose-dependent. Discontinuation of the drug only partially restores fracture risk to baseline levels.^10,11

A meta-analysis of cohort studies with a total sample size of about 42,000 reported an increased risk of fracture at all ages with the use of glucocorticoids.¹² Because the minimum dosage and duration of therapy to prevent glucocorticoid-induced osteoporosis are not known, the only recommendation is to keep the dosage as low as possible.¹³

Glucocorticoid therapy is the most common cause of nontraumatic avascular necrosis. The risk of osteonecrosis in patients on long-term glucocorticoid therapy may be as high as 40%.¹⁴ The risk is increased with prolonged treatment and with high doses, but it can also occur with short-term exposure to high doses. The increased risk has been shown to persist for as long as 2 years after the drugs are discontinued.¹⁵ Glucocorticoid-induced bone disease commonly affects the hip and vertebrae.

At this stage of the workup, we cannot completely rule out glucocorticoid use as the cause. However, after considering this patient’s presentation and the key features of the other diagnoses, her ankle pain and back pain are more likely caused by her preexisting Gaucher disease.

CONTINUED EVALUATION


Initial laboratory tests (Table 1) reveal severe anemia and thrombocytopenia. Bone marrow biopsy of the iliac crest done as part of the workup for these conditions shows extensive bone marrow space replacement by histiocytic infiltrate, consistent with Gaucher disease. No other marrow process is observed.

Radiography of the ankle (Figure 1) shows a subtle lucency in the talar dome with minimal subarticular collapse seen on the lateral view, suggestive of avascular necrosis and diffuse osteopenia. Joint spaces are maintained.

Magnetic resonance imaging (MRI) of the ankle shows numerous bone infarcts with an approximately 15-mm region of mild articular surface collapse in the central and lateral aspect of the talar dome.

MRI of the back shows extensive abnormal bone marrow signal intensity throughout the spine, compatible with a marrow replacement process. Patchy nonexpansile T2/stir hyperintensity with serpiginous enhancement within the T9, T11, T12, L2, and L3 vertebral bodies as well as throughout the entire sacrum is consistent with bone infarct.

2. Based on the results of radiographic studies, which is most likely the immediate cause of her ankle pain?

• Talar avascular necrosis secondary to rheumatoid arthritis
• Talar avascular necrosis secondary to Gaucher disease
• Trauma-induced fracture of the talus
• Plantar fasciitis

Of the bones of the feet, the talus is unique. It is the second largest of the tarsal bones and does not have muscular or tendinous attachments. Sixty percent of the talus bone is covered by articular cartilage,¹⁶ so only a limited area is available for penetration of blood vessels. Also, small nutrient vessels and variations of intraosseous anastomoses with a lack of collateral circulation predispose the talus to osteonecrosis when the vascular supply is compromised.¹⁶

Radiographic evidence of avascular necrosis is the presence of bone that is more radiopaque than normal bone; this is necrotic bone surrounded by osteopenic bone. Avascular necrosis causes hyperemia and resorption of bone. The resorption does not take place in necrotic bone because of the lack of a vascular supply, and so it appears radiopaque, whereas the bone surrounding the necrotic bone becomes osteopenic and radiolucent.

The sclerotic rim of a bone infarct is also enhanced by an attempted healing process in which new bone forms on the surface of necrotic trabeculae, a process known as “creeping substitution.” This gives a typical sclerotic picture of the talus.

MRI is the most sensitive technique for detecting osteonecrosis. A characteristic radiographic pattern is seen with osteonecrosis of the talus starting with talar dome opacity, followed by deformity and, in severe cases, articular collapse and bone fragmentation.¹⁷

The radiograph in our patient’s case is not consistent with features of rheumatoid arthritis or traumatic fracture of the talus. In plantar fasciitis, radiographs are used to rule out other pathologies of the foot, and the only finding may be a bone spur seen at the site of pain. The bone spur is not the cause of pain in plantar fasciitis but may be a result of the plantar fasciitis itself.

Therefore, avascular necrosis secondary to Gaucher disease is most likely the immediate cause of her ankle pain.

THE COURSE OF TREATMENT

The patient is started on enzyme replacement therapy with taliglucerase alfa (see discussion of enzyme replacement below). For the ankle pain, conservative management is prescribed, with application of a splint and a boot.

After 4 months of conservative management, radiography (Figure 2) and magnetic resonance imaging (Figure 3) show progressive deterioration of the talus body, and her ankle pain has worsened. A 6-week trial of an ankle brace also proves futile. Her pain continues to worsen and is not controllable with high doses of pain medication. She requests below-the-knee amputation.

Given the complexity of this patient’s medical condition, fusion of the ankle and hindfoot—which in some patients is preferable to amputation—is not considered because of her extensive bone involvement and ongoing thrombocytopenia, which would impede healing after the procedure. Below-the-knee amputation is performed without complications.

Study of the specimen after amputation reveals talar bone necrosis and bone marrow infiltration by foamy macrophages, consistent with Gaucher disease (Figures 4–6).

GAUCHER DISEASE

Pharmacologic treatments, effective only for type 1 Gaucher disease, target hepatosplenomegaly, cytopenia, and bone manifestations. Two approaches are enzyme replacement therapy—ie, to replace the defective enzyme—and substrate reduction therapy—ie, to reduce the production and thus the accumulation of glucocerebroside. Enzyme replacement is the first choice of therapy; substrate reduction is reserved for patients unable to tolerate enzyme replacement therapy.

Enzyme replacement

Current drugs for enzyme replacement therapy are imiglucerase, taliglucerase alfa, and velaglucerase alfa. The drugs are given by intravenous infusion over 1 to 2 hours in an outpatient clinic or office every 2 weeks.

These drugs are extremely expensive. Currently, the estimated cost of therapy for 1 year would be $432,978 for imiglucerase, $324,870 for taliglucerase alfa, and $368,550 for velaglucerase alfa. (The estimated costs are for 1 year of treatment for a 70-kg patient at 60 U/kg every 2 weeks.)¹⁸ Taliglucerase alfa is less expensive than the other two because it is plant-derived and thus can be more readily produced on a large scale.¹⁹

Substrate reduction

Current drugs for substrate reduction therapy are eliglustat and miglustat. They are given orally. Eliglustat is the first oral drug approved as a first-line treatment for Gaucher disease.²⁰ Miglustat is approved only for mild to moderate disease when enzyme replacement fails or is not tolerated.

Patients can develop antibodies to any of the enzyme replacement drugs. It is not known whether this antibody response differs among the three drugs.²¹

Avascular necrosis of bone can occur in many clinical settings especially after a fracture, particularly of the head of the femur, which leads to interruption of blood supply to the area. Patients with sickle cell disease, those on corticosteroids or bisphosphonates (the latter causing osteonecrosis of the jaw), and those who have pancreatitis or human immunodeficiency virus infection are more prone to this bone complication.

In Gaucher disease, osteonecrosis is associated with splenectomy and severe disease and tends to occur at a younger age than in patients with other diagnoses.⁸ The plasma chitotriosidase activity and pulmonary and activation-regulated chemokines (PARC/CCL18), which are 10 to 40 times higher than normal in symptomatic patients with Gaucher disease, can be used as a biomarker of disease activity.⁸ Only plasma chitotriosidase is clinically available and used on a routine basis.

Bone involvement is seen in approximately 75% of the patients with type 1 Gaucher disease,²² and osteonecrosis is a severe form of bone involvement. Monitoring of patients for bone involvement is recommended. Enzyme replacement therapy for Gaucher disease needs to be started even if visceral disease is absent if the patient has evidence of bone involvement in the form of avascular necrosis.⁷ Prospective studies have shown that enzyme replacement therapy reduces the incidence of osteonecrosis.²³

FOLLOW-UP MANAGEMENT OF OUR PATIENT

Avascular necrosis in Gaucher disease more typically involves the hips and shoulders. In the case of our patient, the talus was the most affected bone. Other contributing factors may have been the use of steroids as a premedication (often unnecessary) for her enzyme replacement therapy, as well as the coexistent scleroderma.²⁴

The decision to switch from imiglucerase, to which she developed antibodies, to taliglucerase was made in the hope that the antibodies would not cross-react. After she started taliglucerase, her complete blood count values improved steadily. She did not require transfusions for more than 1 year. Her platelet count rose to 90 × 10⁹/L, and her hemoglobin to 12 g/dL.

A multidisciplinary approach with regular monitoring and appropriate initiation of therapy is necessary to prevent disastrous complications in patients with Gaucher disease.

A 20-year-old woman with Gaucher disease presents with pain in her right ankle and in her back. She has had the ankle pain for the past 12 months and the back pain for the past 2 years. She describes the ankle pain as stabbing and moderately severe. It is constant, present both at rest and during physical activity, but aggravated by walking and twisting movements. She has noticed grinding and clicking sounds as she moves her ankle. The ankle pain has worsened over the past several months.

She says her back pain is similar to her ankle pain but less severe. She also reports generalized mild aches and bone pain. No other joints are involved. She has no history of fever, chills, or trauma.

A COMPLICATED MEDICAL HISTORY

Her Gaucher disease was diagnosed at age 4 when she presented with failure to thrive and with thrombocytopenia and splenomegaly. She and was found to have an N370S/IVS2+1 mutation of the GBA gene. She underwent removal of 90% of her spleen at the time of diagnosis and was on enzyme replacement therapy with imiglucerase until 3 years ago, when the treatment was stopped because the drug had become unavailable (because of a temporary closure of the manufacturing facility), and because she had developed neutralizing antibodies to it. Despite a dosage as high as 120 U/kg every 2 weeks (the recommended range is 2.5 U/kg three times a week up to 60 U/kg every 2 weeks), her anemia and thrombocytopenia worsened to the point that she became dependent on transfusion of red blood cells and platelets. She has also taken glucocorticoids at various times in the past as a premedication before enzyme replacement therapy.

About 3 years ago, she developed dryness of the skin, pruritus, shiny skin, hardening of the skin, and decreased oral aperture, which was diagnosed as scleroderma.

During the past 5 years, she has had multiple episodes of pale coloration of her skin on exposure to cold, suggestive of Raynaud phenomenon. And for the past 5 months, she has noticed a burning sensation in her throat and retrosternal pain, suggestive of gastroesophageal reflux disease.

She is a college student, with no history of smoking or use of alcohol or recreational drugs. She is sexually active, with no history of sexually transmitted disease, and she uses condoms and oral contraceptives for contraception.

Her father and mother are both carriers of Gaucher disease. She is not of Ashkenazi Jewish descent.

FINDINGS ON PHYSICAL EXAMINATION

On physical examination, her temperature, blood pressure, pulse, and respiratory rate are within normal limits. She has extensive tattooing on her upper chest to hide scarring from previous cannulation ports. The right ankle joint is moderately swollen but shows no other signs of inflammation; its range of motion is limited by severe pain. She has tenderness of the spinous processes and paraspinal area, in addition to multiple tender points in the thoracolumbar area. Palpation of the right hip reveals tenderness of the groin and trochanteric bursa.

No lymphadenopathy, hepatomegaly, splenomegaly, or abdominal masses are noted. Neurologic examination is essentially nonfocal.

Her current medications include omeprazole, ergocalciferol, calcium carbonate, gabapentin, citalopram, and celecoxib. She also takes a multivitamin daily.

1. Which is the most likely underlying cause of her ankle pain?

• Rheumatoid arthritis
• Gaucher disease
• Septic arthritis
• Avascular necrosis secondary to steroid use

Rheumatoid arthritis varies in its presentation. It is usually insidious in onset, migratory, and intermittent, with polyarticular or even monoarticular involvement, and it presents with pain, stiffness, and swelling of the joint.¹ Most often affected are the metacarpophalangeal, proximal interphalangeal, wrist, and metatarsophalangeal joints. Involvement of large joints of the upper and lower limbs is also common.² This is not the most likely cause of this patient’s symptoms, based on the history and the current presentation.

Gaucher disease is a lipidosis caused by accumulation of cellular glycolipids, especially glucocerebrosides, due to deficiency of the enzyme beta-glucosidase. Clinical manifestations include hepatomegaly, splenomegaly, and bone marrow disease presenting as anemia, thrombocytopenia, or skeletal disease.³ Skeletal involvement in Gaucher disease includes bone pain, bone infarcts, and lytic lesions.

Whether splenectomy predisposes the patient to bone manifestations is controversial. Some believe that splenectomy decreases the total body reservoir for the storage of glycolipids and predisposes to their deposition in bone, which in turn results in cortical thinning, impaired remodeling, and decreased intraosseous blood flow, leading to osteonecrosis and fractures.⁴ This is more common in patients with type 1 Gaucher disease who have undergone splenectomy. (Types 2 and 3 are much rarer, occurring mainly in children; central nervous system involvement is a key feature. A discussion of these types is beyond the focus of this paper.) However, some studies suggest that the increase in bone manifestations after splenectomy may be simply because of severe disease.⁵ It should be noted that, since the advent of enzyme replacement therapy for Gaucher disease, splenectomy is now rarely performed.⁶

Anemia is also considered an independent risk factor for the development of avascular necrosis in type 1 Gaucher disease.⁷ Osteonecrosis due to Gaucher disease is relatively common in the femur, tibia, and humerus and uncommon in the ankle joints.⁸

Septic arthritis is unlikely in this patient in the absence of fever or signs of inflammation of the joint. Her long-standing history of ankle pain would also be unusual for infection, but a superimposed infectious process should always be suspected in an arthritic joint.

Avascular necrosis secondary to steroid use. Glucocorticoids are notorious for their adverse effects on bone. They induce osteocyte apoptosis and a decrease in bone remodeling, potentially predisposing to osteonecrosis.⁹ There is a high incidence of osteoporosis, osteonecrosis, and fracture risk with glucocorticoid therapy, and the incidence is dose-dependent. Discontinuation of the drug only partially restores fracture risk to baseline levels.^10,11

A meta-analysis of cohort studies with a total sample size of about 42,000 reported an increased risk of fracture at all ages with the use of glucocorticoids.¹² Because the minimum dosage and duration of therapy to prevent glucocorticoid-induced osteoporosis are not known, the only recommendation is to keep the dosage as low as possible.¹³

Glucocorticoid therapy is the most common cause of nontraumatic avascular necrosis. The risk of osteonecrosis in patients on long-term glucocorticoid therapy may be as high as 40%.¹⁴ The risk is increased with prolonged treatment and with high doses, but it can also occur with short-term exposure to high doses. The increased risk has been shown to persist for as long as 2 years after the drugs are discontinued.¹⁵ Glucocorticoid-induced bone disease commonly affects the hip and vertebrae.

At this stage of the workup, we cannot completely rule out glucocorticoid use as the cause. However, after considering this patient’s presentation and the key features of the other diagnoses, her ankle pain and back pain are more likely caused by her preexisting Gaucher disease.

CONTINUED EVALUATION


Initial laboratory tests (Table 1) reveal severe anemia and thrombocytopenia. Bone marrow biopsy of the iliac crest done as part of the workup for these conditions shows extensive bone marrow space replacement by histiocytic infiltrate, consistent with Gaucher disease. No other marrow process is observed.

Radiography of the ankle (Figure 1) shows a subtle lucency in the talar dome with minimal subarticular collapse seen on the lateral view, suggestive of avascular necrosis and diffuse osteopenia. Joint spaces are maintained.

Magnetic resonance imaging (MRI) of the ankle shows numerous bone infarcts with an approximately 15-mm region of mild articular surface collapse in the central and lateral aspect of the talar dome.

MRI of the back shows extensive abnormal bone marrow signal intensity throughout the spine, compatible with a marrow replacement process. Patchy nonexpansile T2/stir hyperintensity with serpiginous enhancement within the T9, T11, T12, L2, and L3 vertebral bodies as well as throughout the entire sacrum is consistent with bone infarct.

2. Based on the results of radiographic studies, which is most likely the immediate cause of her ankle pain?

• Talar avascular necrosis secondary to rheumatoid arthritis
• Talar avascular necrosis secondary to Gaucher disease
• Trauma-induced fracture of the talus
• Plantar fasciitis

Of the bones of the feet, the talus is unique. It is the second largest of the tarsal bones and does not have muscular or tendinous attachments. Sixty percent of the talus bone is covered by articular cartilage,¹⁶ so only a limited area is available for penetration of blood vessels. Also, small nutrient vessels and variations of intraosseous anastomoses with a lack of collateral circulation predispose the talus to osteonecrosis when the vascular supply is compromised.¹⁶

Radiographic evidence of avascular necrosis is the presence of bone that is more radiopaque than normal bone; this is necrotic bone surrounded by osteopenic bone. Avascular necrosis causes hyperemia and resorption of bone. The resorption does not take place in necrotic bone because of the lack of a vascular supply, and so it appears radiopaque, whereas the bone surrounding the necrotic bone becomes osteopenic and radiolucent.

The sclerotic rim of a bone infarct is also enhanced by an attempted healing process in which new bone forms on the surface of necrotic trabeculae, a process known as “creeping substitution.” This gives a typical sclerotic picture of the talus.

MRI is the most sensitive technique for detecting osteonecrosis. A characteristic radiographic pattern is seen with osteonecrosis of the talus starting with talar dome opacity, followed by deformity and, in severe cases, articular collapse and bone fragmentation.¹⁷

The radiograph in our patient’s case is not consistent with features of rheumatoid arthritis or traumatic fracture of the talus. In plantar fasciitis, radiographs are used to rule out other pathologies of the foot, and the only finding may be a bone spur seen at the site of pain. The bone spur is not the cause of pain in plantar fasciitis but may be a result of the plantar fasciitis itself.

Therefore, avascular necrosis secondary to Gaucher disease is most likely the immediate cause of her ankle pain.

THE COURSE OF TREATMENT

The patient is started on enzyme replacement therapy with taliglucerase alfa (see discussion of enzyme replacement below). For the ankle pain, conservative management is prescribed, with application of a splint and a boot.

After 4 months of conservative management, radiography (Figure 2) and magnetic resonance imaging (Figure 3) show progressive deterioration of the talus body, and her ankle pain has worsened. A 6-week trial of an ankle brace also proves futile. Her pain continues to worsen and is not controllable with high doses of pain medication. She requests below-the-knee amputation.

Given the complexity of this patient’s medical condition, fusion of the ankle and hindfoot—which in some patients is preferable to amputation—is not considered because of her extensive bone involvement and ongoing thrombocytopenia, which would impede healing after the procedure. Below-the-knee amputation is performed without complications.

Study of the specimen after amputation reveals talar bone necrosis and bone marrow infiltration by foamy macrophages, consistent with Gaucher disease (Figures 4–6).

GAUCHER DISEASE

Pharmacologic treatments, effective only for type 1 Gaucher disease, target hepatosplenomegaly, cytopenia, and bone manifestations. Two approaches are enzyme replacement therapy—ie, to replace the defective enzyme—and substrate reduction therapy—ie, to reduce the production and thus the accumulation of glucocerebroside. Enzyme replacement is the first choice of therapy; substrate reduction is reserved for patients unable to tolerate enzyme replacement therapy.

Enzyme replacement

Current drugs for enzyme replacement therapy are imiglucerase, taliglucerase alfa, and velaglucerase alfa. The drugs are given by intravenous infusion over 1 to 2 hours in an outpatient clinic or office every 2 weeks.

These drugs are extremely expensive. Currently, the estimated cost of therapy for 1 year would be $432,978 for imiglucerase, $324,870 for taliglucerase alfa, and $368,550 for velaglucerase alfa. (The estimated costs are for 1 year of treatment for a 70-kg patient at 60 U/kg every 2 weeks.)¹⁸ Taliglucerase alfa is less expensive than the other two because it is plant-derived and thus can be more readily produced on a large scale.¹⁹

Substrate reduction

Current drugs for substrate reduction therapy are eliglustat and miglustat. They are given orally. Eliglustat is the first oral drug approved as a first-line treatment for Gaucher disease.²⁰ Miglustat is approved only for mild to moderate disease when enzyme replacement fails or is not tolerated.

Patients can develop antibodies to any of the enzyme replacement drugs. It is not known whether this antibody response differs among the three drugs.²¹

Avascular necrosis of bone can occur in many clinical settings especially after a fracture, particularly of the head of the femur, which leads to interruption of blood supply to the area. Patients with sickle cell disease, those on corticosteroids or bisphosphonates (the latter causing osteonecrosis of the jaw), and those who have pancreatitis or human immunodeficiency virus infection are more prone to this bone complication.

In Gaucher disease, osteonecrosis is associated with splenectomy and severe disease and tends to occur at a younger age than in patients with other diagnoses.⁸ The plasma chitotriosidase activity and pulmonary and activation-regulated chemokines (PARC/CCL18), which are 10 to 40 times higher than normal in symptomatic patients with Gaucher disease, can be used as a biomarker of disease activity.⁸ Only plasma chitotriosidase is clinically available and used on a routine basis.

Bone involvement is seen in approximately 75% of the patients with type 1 Gaucher disease,²² and osteonecrosis is a severe form of bone involvement. Monitoring of patients for bone involvement is recommended. Enzyme replacement therapy for Gaucher disease needs to be started even if visceral disease is absent if the patient has evidence of bone involvement in the form of avascular necrosis.⁷ Prospective studies have shown that enzyme replacement therapy reduces the incidence of osteonecrosis.²³

FOLLOW-UP MANAGEMENT OF OUR PATIENT

Avascular necrosis in Gaucher disease more typically involves the hips and shoulders. In the case of our patient, the talus was the most affected bone. Other contributing factors may have been the use of steroids as a premedication (often unnecessary) for her enzyme replacement therapy, as well as the coexistent scleroderma.²⁴

The decision to switch from imiglucerase, to which she developed antibodies, to taliglucerase was made in the hope that the antibodies would not cross-react. After she started taliglucerase, her complete blood count values improved steadily. She did not require transfusions for more than 1 year. Her platelet count rose to 90 × 10⁹/L, and her hemoglobin to 12 g/dL.

A multidisciplinary approach with regular monitoring and appropriate initiation of therapy is necessary to prevent disastrous complications in patients with Gaucher disease.

A 20-year-old woman with Gaucher disease presents with pain in her right ankle and in her back. She has had the ankle pain for the past 12 months and the back pain for the past 2 years. She describes the ankle pain as stabbing and moderately severe. It is constant, present both at rest and during physical activity, but aggravated by walking and twisting movements. She has noticed grinding and clicking sounds as she moves her ankle. The ankle pain has worsened over the past several months.

She says her back pain is similar to her ankle pain but less severe. She also reports generalized mild aches and bone pain. No other joints are involved. She has no history of fever, chills, or trauma.

A COMPLICATED MEDICAL HISTORY

Her Gaucher disease was diagnosed at age 4 when she presented with failure to thrive and with thrombocytopenia and splenomegaly. She and was found to have an N370S/IVS2+1 mutation of the GBA gene. She underwent removal of 90% of her spleen at the time of diagnosis and was on enzyme replacement therapy with imiglucerase until 3 years ago, when the treatment was stopped because the drug had become unavailable (because of a temporary closure of the manufacturing facility), and because she had developed neutralizing antibodies to it. Despite a dosage as high as 120 U/kg every 2 weeks (the recommended range is 2.5 U/kg three times a week up to 60 U/kg every 2 weeks), her anemia and thrombocytopenia worsened to the point that she became dependent on transfusion of red blood cells and platelets. She has also taken glucocorticoids at various times in the past as a premedication before enzyme replacement therapy.

About 3 years ago, she developed dryness of the skin, pruritus, shiny skin, hardening of the skin, and decreased oral aperture, which was diagnosed as scleroderma.

During the past 5 years, she has had multiple episodes of pale coloration of her skin on exposure to cold, suggestive of Raynaud phenomenon. And for the past 5 months, she has noticed a burning sensation in her throat and retrosternal pain, suggestive of gastroesophageal reflux disease.

She is a college student, with no history of smoking or use of alcohol or recreational drugs. She is sexually active, with no history of sexually transmitted disease, and she uses condoms and oral contraceptives for contraception.

Her father and mother are both carriers of Gaucher disease. She is not of Ashkenazi Jewish descent.

FINDINGS ON PHYSICAL EXAMINATION

On physical examination, her temperature, blood pressure, pulse, and respiratory rate are within normal limits. She has extensive tattooing on her upper chest to hide scarring from previous cannulation ports. The right ankle joint is moderately swollen but shows no other signs of inflammation; its range of motion is limited by severe pain. She has tenderness of the spinous processes and paraspinal area, in addition to multiple tender points in the thoracolumbar area. Palpation of the right hip reveals tenderness of the groin and trochanteric bursa.

No lymphadenopathy, hepatomegaly, splenomegaly, or abdominal masses are noted. Neurologic examination is essentially nonfocal.

Her current medications include omeprazole, ergocalciferol, calcium carbonate, gabapentin, citalopram, and celecoxib. She also takes a multivitamin daily.

1. Which is the most likely underlying cause of her ankle pain?

• Rheumatoid arthritis
• Gaucher disease
• Septic arthritis
• Avascular necrosis secondary to steroid use

Rheumatoid arthritis varies in its presentation. It is usually insidious in onset, migratory, and intermittent, with polyarticular or even monoarticular involvement, and it presents with pain, stiffness, and swelling of the joint.¹ Most often affected are the metacarpophalangeal, proximal interphalangeal, wrist, and metatarsophalangeal joints. Involvement of large joints of the upper and lower limbs is also common.² This is not the most likely cause of this patient’s symptoms, based on the history and the current presentation.

Gaucher disease is a lipidosis caused by accumulation of cellular glycolipids, especially glucocerebrosides, due to deficiency of the enzyme beta-glucosidase. Clinical manifestations include hepatomegaly, splenomegaly, and bone marrow disease presenting as anemia, thrombocytopenia, or skeletal disease.³ Skeletal involvement in Gaucher disease includes bone pain, bone infarcts, and lytic lesions.

Whether splenectomy predisposes the patient to bone manifestations is controversial. Some believe that splenectomy decreases the total body reservoir for the storage of glycolipids and predisposes to their deposition in bone, which in turn results in cortical thinning, impaired remodeling, and decreased intraosseous blood flow, leading to osteonecrosis and fractures.⁴ This is more common in patients with type 1 Gaucher disease who have undergone splenectomy. (Types 2 and 3 are much rarer, occurring mainly in children; central nervous system involvement is a key feature. A discussion of these types is beyond the focus of this paper.) However, some studies suggest that the increase in bone manifestations after splenectomy may be simply because of severe disease.⁵ It should be noted that, since the advent of enzyme replacement therapy for Gaucher disease, splenectomy is now rarely performed.⁶

Anemia is also considered an independent risk factor for the development of avascular necrosis in type 1 Gaucher disease.⁷ Osteonecrosis due to Gaucher disease is relatively common in the femur, tibia, and humerus and uncommon in the ankle joints.⁸

Septic arthritis is unlikely in this patient in the absence of fever or signs of inflammation of the joint. Her long-standing history of ankle pain would also be unusual for infection, but a superimposed infectious process should always be suspected in an arthritic joint.

Avascular necrosis secondary to steroid use. Glucocorticoids are notorious for their adverse effects on bone. They induce osteocyte apoptosis and a decrease in bone remodeling, potentially predisposing to osteonecrosis.⁹ There is a high incidence of osteoporosis, osteonecrosis, and fracture risk with glucocorticoid therapy, and the incidence is dose-dependent. Discontinuation of the drug only partially restores fracture risk to baseline levels.^10,11

A meta-analysis of cohort studies with a total sample size of about 42,000 reported an increased risk of fracture at all ages with the use of glucocorticoids.¹² Because the minimum dosage and duration of therapy to prevent glucocorticoid-induced osteoporosis are not known, the only recommendation is to keep the dosage as low as possible.¹³

Glucocorticoid therapy is the most common cause of nontraumatic avascular necrosis. The risk of osteonecrosis in patients on long-term glucocorticoid therapy may be as high as 40%.¹⁴ The risk is increased with prolonged treatment and with high doses, but it can also occur with short-term exposure to high doses. The increased risk has been shown to persist for as long as 2 years after the drugs are discontinued.¹⁵ Glucocorticoid-induced bone disease commonly affects the hip and vertebrae.

At this stage of the workup, we cannot completely rule out glucocorticoid use as the cause. However, after considering this patient’s presentation and the key features of the other diagnoses, her ankle pain and back pain are more likely caused by her preexisting Gaucher disease.

CONTINUED EVALUATION


Initial laboratory tests (Table 1) reveal severe anemia and thrombocytopenia. Bone marrow biopsy of the iliac crest done as part of the workup for these conditions shows extensive bone marrow space replacement by histiocytic infiltrate, consistent with Gaucher disease. No other marrow process is observed.

Radiography of the ankle (Figure 1) shows a subtle lucency in the talar dome with minimal subarticular collapse seen on the lateral view, suggestive of avascular necrosis and diffuse osteopenia. Joint spaces are maintained.

Magnetic resonance imaging (MRI) of the ankle shows numerous bone infarcts with an approximately 15-mm region of mild articular surface collapse in the central and lateral aspect of the talar dome.

MRI of the back shows extensive abnormal bone marrow signal intensity throughout the spine, compatible with a marrow replacement process. Patchy nonexpansile T2/stir hyperintensity with serpiginous enhancement within the T9, T11, T12, L2, and L3 vertebral bodies as well as throughout the entire sacrum is consistent with bone infarct.

2. Based on the results of radiographic studies, which is most likely the immediate cause of her ankle pain?

• Talar avascular necrosis secondary to rheumatoid arthritis
• Talar avascular necrosis secondary to Gaucher disease
• Trauma-induced fracture of the talus
• Plantar fasciitis

Of the bones of the feet, the talus is unique. It is the second largest of the tarsal bones and does not have muscular or tendinous attachments. Sixty percent of the talus bone is covered by articular cartilage,¹⁶ so only a limited area is available for penetration of blood vessels. Also, small nutrient vessels and variations of intraosseous anastomoses with a lack of collateral circulation predispose the talus to osteonecrosis when the vascular supply is compromised.¹⁶

Radiographic evidence of avascular necrosis is the presence of bone that is more radiopaque than normal bone; this is necrotic bone surrounded by osteopenic bone. Avascular necrosis causes hyperemia and resorption of bone. The resorption does not take place in necrotic bone because of the lack of a vascular supply, and so it appears radiopaque, whereas the bone surrounding the necrotic bone becomes osteopenic and radiolucent.

The sclerotic rim of a bone infarct is also enhanced by an attempted healing process in which new bone forms on the surface of necrotic trabeculae, a process known as “creeping substitution.” This gives a typical sclerotic picture of the talus.

MRI is the most sensitive technique for detecting osteonecrosis. A characteristic radiographic pattern is seen with osteonecrosis of the talus starting with talar dome opacity, followed by deformity and, in severe cases, articular collapse and bone fragmentation.¹⁷

The radiograph in our patient’s case is not consistent with features of rheumatoid arthritis or traumatic fracture of the talus. In plantar fasciitis, radiographs are used to rule out other pathologies of the foot, and the only finding may be a bone spur seen at the site of pain. The bone spur is not the cause of pain in plantar fasciitis but may be a result of the plantar fasciitis itself.

Therefore, avascular necrosis secondary to Gaucher disease is most likely the immediate cause of her ankle pain.

THE COURSE OF TREATMENT

The patient is started on enzyme replacement therapy with taliglucerase alfa (see discussion of enzyme replacement below). For the ankle pain, conservative management is prescribed, with application of a splint and a boot.

After 4 months of conservative management, radiography (Figure 2) and magnetic resonance imaging (Figure 3) show progressive deterioration of the talus body, and her ankle pain has worsened. A 6-week trial of an ankle brace also proves futile. Her pain continues to worsen and is not controllable with high doses of pain medication. She requests below-the-knee amputation.

Given the complexity of this patient’s medical condition, fusion of the ankle and hindfoot—which in some patients is preferable to amputation—is not considered because of her extensive bone involvement and ongoing thrombocytopenia, which would impede healing after the procedure. Below-the-knee amputation is performed without complications.

Study of the specimen after amputation reveals talar bone necrosis and bone marrow infiltration by foamy macrophages, consistent with Gaucher disease (Figures 4–6).

GAUCHER DISEASE

Pharmacologic treatments, effective only for type 1 Gaucher disease, target hepatosplenomegaly, cytopenia, and bone manifestations. Two approaches are enzyme replacement therapy—ie, to replace the defective enzyme—and substrate reduction therapy—ie, to reduce the production and thus the accumulation of glucocerebroside. Enzyme replacement is the first choice of therapy; substrate reduction is reserved for patients unable to tolerate enzyme replacement therapy.

Enzyme replacement

Current drugs for enzyme replacement therapy are imiglucerase, taliglucerase alfa, and velaglucerase alfa. The drugs are given by intravenous infusion over 1 to 2 hours in an outpatient clinic or office every 2 weeks.

These drugs are extremely expensive. Currently, the estimated cost of therapy for 1 year would be $432,978 for imiglucerase, $324,870 for taliglucerase alfa, and $368,550 for velaglucerase alfa. (The estimated costs are for 1 year of treatment for a 70-kg patient at 60 U/kg every 2 weeks.)¹⁸ Taliglucerase alfa is less expensive than the other two because it is plant-derived and thus can be more readily produced on a large scale.¹⁹

Substrate reduction

Current drugs for substrate reduction therapy are eliglustat and miglustat. They are given orally. Eliglustat is the first oral drug approved as a first-line treatment for Gaucher disease.²⁰ Miglustat is approved only for mild to moderate disease when enzyme replacement fails or is not tolerated.

Patients can develop antibodies to any of the enzyme replacement drugs. It is not known whether this antibody response differs among the three drugs.²¹

Avascular necrosis of bone can occur in many clinical settings especially after a fracture, particularly of the head of the femur, which leads to interruption of blood supply to the area. Patients with sickle cell disease, those on corticosteroids or bisphosphonates (the latter causing osteonecrosis of the jaw), and those who have pancreatitis or human immunodeficiency virus infection are more prone to this bone complication.

In Gaucher disease, osteonecrosis is associated with splenectomy and severe disease and tends to occur at a younger age than in patients with other diagnoses.⁸ The plasma chitotriosidase activity and pulmonary and activation-regulated chemokines (PARC/CCL18), which are 10 to 40 times higher than normal in symptomatic patients with Gaucher disease, can be used as a biomarker of disease activity.⁸ Only plasma chitotriosidase is clinically available and used on a routine basis.

Bone involvement is seen in approximately 75% of the patients with type 1 Gaucher disease,²² and osteonecrosis is a severe form of bone involvement. Monitoring of patients for bone involvement is recommended. Enzyme replacement therapy for Gaucher disease needs to be started even if visceral disease is absent if the patient has evidence of bone involvement in the form of avascular necrosis.⁷ Prospective studies have shown that enzyme replacement therapy reduces the incidence of osteonecrosis.²³

FOLLOW-UP MANAGEMENT OF OUR PATIENT

Avascular necrosis in Gaucher disease more typically involves the hips and shoulders. In the case of our patient, the talus was the most affected bone. Other contributing factors may have been the use of steroids as a premedication (often unnecessary) for her enzyme replacement therapy, as well as the coexistent scleroderma.²⁴

The decision to switch from imiglucerase, to which she developed antibodies, to taliglucerase was made in the hope that the antibodies would not cross-react. After she started taliglucerase, her complete blood count values improved steadily. She did not require transfusions for more than 1 year. Her platelet count rose to 90 × 10⁹/L, and her hemoglobin to 12 g/dL.

A multidisciplinary approach with regular monitoring and appropriate initiation of therapy is necessary to prevent disastrous complications in patients with Gaucher disease.