ORLANDO – Re-excisions are not needed when clinically excised moderately dysplastic nevi have positive histologic margins, based on results of a retrospective study of 438 patients who were treated at nine academic medical centers in the United States.

M. Alexander Otto/MDedge News

Not a single patient in the study developed melanoma at the excision site after an average follow-up of 6.9 years, and at least 3 years in all cases, said Elizabeth G. Berry, MD, of Emory University, Atlanta, and Atlanta Veterans Administration Medical Center, one of the study investigators.

The finding “really has the potential to change how we manage these lesions. You don’t need to cut [these patients] again. You can watch them. Close observation with routine skin surveillance is reasonable,” Dr. Berry said at the International Investigative Dermatology meeting.

Routine skin exams are essential for patients with a history of dysplastic nevi as these patients are at risk for developing melanoma. Indeed, in this study, 100 patients (22.8%) subsequently developed melanomas at a site other than the location of their biopsy.

The study included 438 patients who had 467 biopsies that indicated incomplete excision of a moderately dysplastic nevus from 1990 to 2014. Patients were at least 18 years old and were an average of 47 years old. About half had a history of dysplastic nevi, and a third had a history of melanoma.

All of their biopsies for moderately dysplastic nevi had positive margins, but patients had no clinically apparent residual pigment at their excision sites. Lesions were equally as likely to be removed by shave and punch biopsies, and the majority of the nevi were located on the trunk. Complete excision was the intent in all cases.

To control for interobserver variability, the centers submitted a total of 40 slides for central dermatopathology review, which found agreement in 35 cases (87.8%). Two of the remaining five cases were downgraded to mild dysplasia, two were upgraded to severe, and one patient was upgraded to melanoma in situ, but hasn’t had a recurrence after 5 years of follow-up.

Controlling for age, sex, and family history, a patient history of dysplastic nevus prior to the biopsy doubled the risk of a subsequent melanoma (P = .017), and a history of melanoma increased it almost eightfold (P less than .001).

Knowing these risk factors, patients with a history of dysplastic nevi “need to have more frequent total body skin exams. What that frequency is, we don’t know,” Dr. Berry said.

The investigators reported they had no relevant disclosures.

aotto@mdedge.com

SOURCE: Kim CC et al. IID 2018, Abstract 571.

ORLANDO – Re-excisions are not needed when clinically excised moderately dysplastic nevi have positive histologic margins, based on results of a retrospective study of 438 patients who were treated at nine academic medical centers in the United States.

M. Alexander Otto/MDedge News

Not a single patient in the study developed melanoma at the excision site after an average follow-up of 6.9 years, and at least 3 years in all cases, said Elizabeth G. Berry, MD, of Emory University, Atlanta, and Atlanta Veterans Administration Medical Center, one of the study investigators.

The finding “really has the potential to change how we manage these lesions. You don’t need to cut [these patients] again. You can watch them. Close observation with routine skin surveillance is reasonable,” Dr. Berry said at the International Investigative Dermatology meeting.

Routine skin exams are essential for patients with a history of dysplastic nevi as these patients are at risk for developing melanoma. Indeed, in this study, 100 patients (22.8%) subsequently developed melanomas at a site other than the location of their biopsy.

The study included 438 patients who had 467 biopsies that indicated incomplete excision of a moderately dysplastic nevus from 1990 to 2014. Patients were at least 18 years old and were an average of 47 years old. About half had a history of dysplastic nevi, and a third had a history of melanoma.

All of their biopsies for moderately dysplastic nevi had positive margins, but patients had no clinically apparent residual pigment at their excision sites. Lesions were equally as likely to be removed by shave and punch biopsies, and the majority of the nevi were located on the trunk. Complete excision was the intent in all cases.

To control for interobserver variability, the centers submitted a total of 40 slides for central dermatopathology review, which found agreement in 35 cases (87.8%). Two of the remaining five cases were downgraded to mild dysplasia, two were upgraded to severe, and one patient was upgraded to melanoma in situ, but hasn’t had a recurrence after 5 years of follow-up.

Controlling for age, sex, and family history, a patient history of dysplastic nevus prior to the biopsy doubled the risk of a subsequent melanoma (P = .017), and a history of melanoma increased it almost eightfold (P less than .001).

Knowing these risk factors, patients with a history of dysplastic nevi “need to have more frequent total body skin exams. What that frequency is, we don’t know,” Dr. Berry said.

The investigators reported they had no relevant disclosures.

aotto@mdedge.com

SOURCE: Kim CC et al. IID 2018, Abstract 571.

ORLANDO – Re-excisions are not needed when clinically excised moderately dysplastic nevi have positive histologic margins, based on results of a retrospective study of 438 patients who were treated at nine academic medical centers in the United States.

M. Alexander Otto/MDedge News

Not a single patient in the study developed melanoma at the excision site after an average follow-up of 6.9 years, and at least 3 years in all cases, said Elizabeth G. Berry, MD, of Emory University, Atlanta, and Atlanta Veterans Administration Medical Center, one of the study investigators.

The finding “really has the potential to change how we manage these lesions. You don’t need to cut [these patients] again. You can watch them. Close observation with routine skin surveillance is reasonable,” Dr. Berry said at the International Investigative Dermatology meeting.

Routine skin exams are essential for patients with a history of dysplastic nevi as these patients are at risk for developing melanoma. Indeed, in this study, 100 patients (22.8%) subsequently developed melanomas at a site other than the location of their biopsy.

The study included 438 patients who had 467 biopsies that indicated incomplete excision of a moderately dysplastic nevus from 1990 to 2014. Patients were at least 18 years old and were an average of 47 years old. About half had a history of dysplastic nevi, and a third had a history of melanoma.

All of their biopsies for moderately dysplastic nevi had positive margins, but patients had no clinically apparent residual pigment at their excision sites. Lesions were equally as likely to be removed by shave and punch biopsies, and the majority of the nevi were located on the trunk. Complete excision was the intent in all cases.

To control for interobserver variability, the centers submitted a total of 40 slides for central dermatopathology review, which found agreement in 35 cases (87.8%). Two of the remaining five cases were downgraded to mild dysplasia, two were upgraded to severe, and one patient was upgraded to melanoma in situ, but hasn’t had a recurrence after 5 years of follow-up.

Controlling for age, sex, and family history, a patient history of dysplastic nevus prior to the biopsy doubled the risk of a subsequent melanoma (P = .017), and a history of melanoma increased it almost eightfold (P less than .001).

Knowing these risk factors, patients with a history of dysplastic nevi “need to have more frequent total body skin exams. What that frequency is, we don’t know,” Dr. Berry said.

The investigators reported they had no relevant disclosures.

aotto@mdedge.com

SOURCE: Kim CC et al. IID 2018, Abstract 571.

BALTIMORE—Older men who nap for more than an hour per day are more likely to develop Parkinson’s disease over 11 years of follow-up, compared with those who nap for less than an hour per day and do not have excessive daytime sleepiness, according to a study described at the 32nd Annual Meeting of the Associated Professional Sleep Societies.

Self-reported daytime sleepiness alone was not associated with increased risk, said Yue Leng, PhD, a postdoctoral researcher at the University of California, San Francisco.

The findings suggest that objective measures of napping might be valuable preclinical markers of Parkinson’s disease.

The mechanism underlying the association is unclear. It is possible that the ongoing degeneration in brain regions involved in the 24-hour sleep–wake cycle leads to increased napping in people who later develop Parkinson’s disease, she said.

“Excessive daytime sleepiness and daytime napping are common in older adults, especially those with Parkinson’s disease,” Dr. Leng said. Whether excessive daytime sleepiness or napping precedes the development of Parkinson’s disease and may be risk factors is not well understood, however. “There is a lack of objectively measured naps and also a lack of longitudinal studies. In fact, we are unaware of any longitudinal studies that have used objectively measured napping in relation to Parkinson’s disease risk.”

To examine the longitudinal association between objectively measured napping duration and risk of Parkinson’s disease, Dr. Leng and colleagues analyzed data from the Osteoporotic Fractures in Men Study (MrOS), a large, longitudinal, multicenter study of community-dwelling older men. They excluded men with Parkinson’s disease at baseline. The analysis included data from more than 2,900 men who had napping and sleep measures at baseline between 2003 and 2005 and were followed up for development of Parkinson’s disease over 11 years.

The investigators used actigraphy to measure napping. Participants wore a sleep watch on the dominant wrist for at least five consecutive 24-hour periods. The researchers defined napping as having at least five consecutive minutes of inactivity outside of the main sleep period. They defined excessive daytime sleepiness as a score greater than 10 on the Epworth Sleepiness Scale.

The researchers identified Par­kinson’s disease using physician diagnosis or Parkinson’s disease medication use. Their analysis adjusted for age, BMI, smoking, physical activity, depression, comorbidities, global cognition scores, medication use, and nighttime sleep variables (ie, efficiency, duration, and apnea–hypopnea index).

“The highest risk was in those who reported daytime sleepiness and had objective napping for at least an hour per day,” Dr. Leng said. These participants had more than twice the risk of developing Parkinson’s disease, compared with a reference group that did not have daytime sleepiness and napped for less than one hour per day (odds ratio, 2.52).

Participants who napped for at least an hour per day but did not report excessive daytime sleepiness also had increased risk (odds ratio, 1.96).

The results indicate that objectively measured napping, rather than self-reported excessive daytime sleepiness, is important for Parkinson’s disease risk, Dr. Leng said.

Sensitivity analyses that excluded patients who developed Parkinson’s disease within two years after baseline and only included physician-confirmed cases of Parkinson’s disease had similar results.

Actigraphy is limited in its ability to differentiate between napping and inactivity, Dr. Leng noted. In addition, the results cannot be generalized to women and younger populations, she said.

—Jake Remaly

Suggested Reading

Leng Y, Goldman SM, Cawthon PM, et al. Excessive daytime sleepiness, objective napping and 11-year risk of Parkinson’s disease in older men. Int J Epidemiol. 2018 Jun 4 [Epub ahead of print].

BALTIMORE—Older men who nap for more than an hour per day are more likely to develop Parkinson’s disease over 11 years of follow-up, compared with those who nap for less than an hour per day and do not have excessive daytime sleepiness, according to a study described at the 32nd Annual Meeting of the Associated Professional Sleep Societies.

Self-reported daytime sleepiness alone was not associated with increased risk, said Yue Leng, PhD, a postdoctoral researcher at the University of California, San Francisco.

The findings suggest that objective measures of napping might be valuable preclinical markers of Parkinson’s disease.

The mechanism underlying the association is unclear. It is possible that the ongoing degeneration in brain regions involved in the 24-hour sleep–wake cycle leads to increased napping in people who later develop Parkinson’s disease, she said.

“Excessive daytime sleepiness and daytime napping are common in older adults, especially those with Parkinson’s disease,” Dr. Leng said. Whether excessive daytime sleepiness or napping precedes the development of Parkinson’s disease and may be risk factors is not well understood, however. “There is a lack of objectively measured naps and also a lack of longitudinal studies. In fact, we are unaware of any longitudinal studies that have used objectively measured napping in relation to Parkinson’s disease risk.”

To examine the longitudinal association between objectively measured napping duration and risk of Parkinson’s disease, Dr. Leng and colleagues analyzed data from the Osteoporotic Fractures in Men Study (MrOS), a large, longitudinal, multicenter study of community-dwelling older men. They excluded men with Parkinson’s disease at baseline. The analysis included data from more than 2,900 men who had napping and sleep measures at baseline between 2003 and 2005 and were followed up for development of Parkinson’s disease over 11 years.

The investigators used actigraphy to measure napping. Participants wore a sleep watch on the dominant wrist for at least five consecutive 24-hour periods. The researchers defined napping as having at least five consecutive minutes of inactivity outside of the main sleep period. They defined excessive daytime sleepiness as a score greater than 10 on the Epworth Sleepiness Scale.

The researchers identified Par­kinson’s disease using physician diagnosis or Parkinson’s disease medication use. Their analysis adjusted for age, BMI, smoking, physical activity, depression, comorbidities, global cognition scores, medication use, and nighttime sleep variables (ie, efficiency, duration, and apnea–hypopnea index).

“The highest risk was in those who reported daytime sleepiness and had objective napping for at least an hour per day,” Dr. Leng said. These participants had more than twice the risk of developing Parkinson’s disease, compared with a reference group that did not have daytime sleepiness and napped for less than one hour per day (odds ratio, 2.52).

Participants who napped for at least an hour per day but did not report excessive daytime sleepiness also had increased risk (odds ratio, 1.96).

The results indicate that objectively measured napping, rather than self-reported excessive daytime sleepiness, is important for Parkinson’s disease risk, Dr. Leng said.

Sensitivity analyses that excluded patients who developed Parkinson’s disease within two years after baseline and only included physician-confirmed cases of Parkinson’s disease had similar results.

Actigraphy is limited in its ability to differentiate between napping and inactivity, Dr. Leng noted. In addition, the results cannot be generalized to women and younger populations, she said.

—Jake Remaly

Suggested Reading

Leng Y, Goldman SM, Cawthon PM, et al. Excessive daytime sleepiness, objective napping and 11-year risk of Parkinson’s disease in older men. Int J Epidemiol. 2018 Jun 4 [Epub ahead of print].

BALTIMORE—Older men who nap for more than an hour per day are more likely to develop Parkinson’s disease over 11 years of follow-up, compared with those who nap for less than an hour per day and do not have excessive daytime sleepiness, according to a study described at the 32nd Annual Meeting of the Associated Professional Sleep Societies.

Self-reported daytime sleepiness alone was not associated with increased risk, said Yue Leng, PhD, a postdoctoral researcher at the University of California, San Francisco.

The findings suggest that objective measures of napping might be valuable preclinical markers of Parkinson’s disease.

The mechanism underlying the association is unclear. It is possible that the ongoing degeneration in brain regions involved in the 24-hour sleep–wake cycle leads to increased napping in people who later develop Parkinson’s disease, she said.

“Excessive daytime sleepiness and daytime napping are common in older adults, especially those with Parkinson’s disease,” Dr. Leng said. Whether excessive daytime sleepiness or napping precedes the development of Parkinson’s disease and may be risk factors is not well understood, however. “There is a lack of objectively measured naps and also a lack of longitudinal studies. In fact, we are unaware of any longitudinal studies that have used objectively measured napping in relation to Parkinson’s disease risk.”

To examine the longitudinal association between objectively measured napping duration and risk of Parkinson’s disease, Dr. Leng and colleagues analyzed data from the Osteoporotic Fractures in Men Study (MrOS), a large, longitudinal, multicenter study of community-dwelling older men. They excluded men with Parkinson’s disease at baseline. The analysis included data from more than 2,900 men who had napping and sleep measures at baseline between 2003 and 2005 and were followed up for development of Parkinson’s disease over 11 years.

The investigators used actigraphy to measure napping. Participants wore a sleep watch on the dominant wrist for at least five consecutive 24-hour periods. The researchers defined napping as having at least five consecutive minutes of inactivity outside of the main sleep period. They defined excessive daytime sleepiness as a score greater than 10 on the Epworth Sleepiness Scale.

The researchers identified Par­kinson’s disease using physician diagnosis or Parkinson’s disease medication use. Their analysis adjusted for age, BMI, smoking, physical activity, depression, comorbidities, global cognition scores, medication use, and nighttime sleep variables (ie, efficiency, duration, and apnea–hypopnea index).

“The highest risk was in those who reported daytime sleepiness and had objective napping for at least an hour per day,” Dr. Leng said. These participants had more than twice the risk of developing Parkinson’s disease, compared with a reference group that did not have daytime sleepiness and napped for less than one hour per day (odds ratio, 2.52).

Participants who napped for at least an hour per day but did not report excessive daytime sleepiness also had increased risk (odds ratio, 1.96).

The results indicate that objectively measured napping, rather than self-reported excessive daytime sleepiness, is important for Parkinson’s disease risk, Dr. Leng said.

Sensitivity analyses that excluded patients who developed Parkinson’s disease within two years after baseline and only included physician-confirmed cases of Parkinson’s disease had similar results.

Actigraphy is limited in its ability to differentiate between napping and inactivity, Dr. Leng noted. In addition, the results cannot be generalized to women and younger populations, she said.

—Jake Remaly

Suggested Reading

Leng Y, Goldman SM, Cawthon PM, et al. Excessive daytime sleepiness, objective napping and 11-year risk of Parkinson’s disease in older men. Int J Epidemiol. 2018 Jun 4 [Epub ahead of print].

Among people with Parkinson’s disease, REM sleep behavior disorder (RBD) is associated with more rapid motor progression in patients with high levels of synuclein and dopaminergic pathology, according to research published online ahead of print August 8 in Neurology. RBD also indicates an increased risk of cognitive decline in patients with high degrees of synuclein and amyloid pathology.

“Our study is the first to link the predictive value of RBD symptoms to the presence of amyloid and synuclein pathology,” said Marios Politis, MD, PhD, Lily Safra Professor of Neurology and Neuroimaging, Consultant Neurologist, and the Director of the Neurodegeneration Imaging Group at King’s College London, and colleagues. “Measuring dopaminergic dysfunction and amyloid and synuclein burden in the screening of patients with RBD at an early stage of Parkinson’s disease, possibly even at the premotor phase of disease, could potentially identify the ones more likely to progress and develop dementia.”

—Erik Greb

Suggested Reading

Pagano G, De Micco R, Yousaf T, et al. REM behavior disorder predicts motor progression and cognitive decline in Parkinson disease. Neurology. 2018 Aug 8 [Epub ahead of print].

Among people with Parkinson’s disease, REM sleep behavior disorder (RBD) is associated with more rapid motor progression in patients with high levels of synuclein and dopaminergic pathology, according to research published online ahead of print August 8 in Neurology. RBD also indicates an increased risk of cognitive decline in patients with high degrees of synuclein and amyloid pathology.

“Our study is the first to link the predictive value of RBD symptoms to the presence of amyloid and synuclein pathology,” said Marios Politis, MD, PhD, Lily Safra Professor of Neurology and Neuroimaging, Consultant Neurologist, and the Director of the Neurodegeneration Imaging Group at King’s College London, and colleagues. “Measuring dopaminergic dysfunction and amyloid and synuclein burden in the screening of patients with RBD at an early stage of Parkinson’s disease, possibly even at the premotor phase of disease, could potentially identify the ones more likely to progress and develop dementia.”

—Erik Greb

Suggested Reading

Pagano G, De Micco R, Yousaf T, et al. REM behavior disorder predicts motor progression and cognitive decline in Parkinson disease. Neurology. 2018 Aug 8 [Epub ahead of print].

Among people with Parkinson’s disease, REM sleep behavior disorder (RBD) is associated with more rapid motor progression in patients with high levels of synuclein and dopaminergic pathology, according to research published online ahead of print August 8 in Neurology. RBD also indicates an increased risk of cognitive decline in patients with high degrees of synuclein and amyloid pathology.

“Our study is the first to link the predictive value of RBD symptoms to the presence of amyloid and synuclein pathology,” said Marios Politis, MD, PhD, Lily Safra Professor of Neurology and Neuroimaging, Consultant Neurologist, and the Director of the Neurodegeneration Imaging Group at King’s College London, and colleagues. “Measuring dopaminergic dysfunction and amyloid and synuclein burden in the screening of patients with RBD at an early stage of Parkinson’s disease, possibly even at the premotor phase of disease, could potentially identify the ones more likely to progress and develop dementia.”

—Erik Greb

Suggested Reading

Pagano G, De Micco R, Yousaf T, et al. REM behavior disorder predicts motor progression and cognitive decline in Parkinson disease. Neurology. 2018 Aug 8 [Epub ahead of print].

Multiday epileptic seizure cycles may occur in many individuals with epilepsy, according to a retrospective cohort study published online ahead of print September 12 in Lancet Neurology.

About 80% of patients in the study showed circadian modulation of their seizure rates, and more than 20% had strong circaseptan (ie, seven-day) rhythms, said Mark J. Cook, MD, a neurologist at St. Vincent’s Hospital in Melbourne, and colleagues.

—Andrew D. Bowser

Suggested Reading

Karoly PJ, Goldenholz DM, Freestone DR, et al. Circadian and circaseptan rhythms in human epilepsy: a retrospective cohort study. Lancet Neurol. 2018 Sep 12 [Epub ahead of print].

Multiday epileptic seizure cycles may occur in many individuals with epilepsy, according to a retrospective cohort study published online ahead of print September 12 in Lancet Neurology.

About 80% of patients in the study showed circadian modulation of their seizure rates, and more than 20% had strong circaseptan (ie, seven-day) rhythms, said Mark J. Cook, MD, a neurologist at St. Vincent’s Hospital in Melbourne, and colleagues.

—Andrew D. Bowser

Suggested Reading

Karoly PJ, Goldenholz DM, Freestone DR, et al. Circadian and circaseptan rhythms in human epilepsy: a retrospective cohort study. Lancet Neurol. 2018 Sep 12 [Epub ahead of print].

Multiday epileptic seizure cycles may occur in many individuals with epilepsy, according to a retrospective cohort study published online ahead of print September 12 in Lancet Neurology.

About 80% of patients in the study showed circadian modulation of their seizure rates, and more than 20% had strong circaseptan (ie, seven-day) rhythms, said Mark J. Cook, MD, a neurologist at St. Vincent’s Hospital in Melbourne, and colleagues.

—Andrew D. Bowser

Suggested Reading

Karoly PJ, Goldenholz DM, Freestone DR, et al. Circadian and circaseptan rhythms in human epilepsy: a retrospective cohort study. Lancet Neurol. 2018 Sep 12 [Epub ahead of print].

Stroke is a strong independent risk factor for all-cause dementia, according to research published online ahead of print August 25 in Alzheimer’s & Dementia. Clinicians should incorporate stroke-prevention strategies into their health interventions to reduce patients’ risk of dementia, said the authors.

“Around a third of dementia cases are thought to be potentially preventable, though this estimate does not take into account the risk associated with stroke,” said David Llewellyn, PhD, Senior Research Fellow at University of Exeter Medical School in the United Kingdom. “Our findings indicate that this figure could be even higher and reinforce the importance of protecting the blood supply to the brain when attempting to reduce the global burden of dementia.”

Meta-Analysis of Previous Research

Stroke is a recognized risk factor for all-cause dementia, but no researchers had previously performed a meta-analysis to quantify the risk. Dr. Llewellyn and colleagues searched Medline, PsycINFO, and Embase databases for prospective studies that investigated the association between prevalent or incident stroke and incident all-cause dementia. They excluded studies that lacked a comparison group or that had a comparison group other than a stroke-free group. The investigators pooled adjusted estimates across studies using random effects meta-analysis and evaluated potential effect modifiers with meta-regression.

Dr. Llewellyn and colleagues identified 11,129 articles, 26 of which were eligible for analysis. They also included 16 studies from a previous systematic review and four studies identified through backward and forward citation searches. In all, 36 studies examined prevalent stroke (1.9 million participants), and 12 studies examined incident stroke (1.3 million participants). The studies were conducted in America, Europe, Asia, and Australia and included more than three million participants. Follow-up periods ranged from nine months to 25 years.

Stroke Affected Dementia Risk

When the researchers pooled results from 22 cohorts of participants who were cognitively normal at baseline, they found that those with prevalent stroke had a higher adjusted risk of incident dementia, compared with those without stroke (hazard ratio [HR], 1.69). Sensitivity analyses did not change the results significantly. Prevalent stroke was associated with a higher risk of incident dementia among men than among women. Sex explained 50.2% of heterogeneity between studies for prevalent stroke.

After combining the adjusted results from eight studies, Dr. Llewellyn and colleagues found that incident stroke more than doubled the risk of incident all-cause dementia, compared with no incident stroke (risk ratio [RR], 2.18). For a sensitivity analysis, the investigators excluded three studies that combined stroke with transient ischemic attack; this adjustment strengthened the association.

The study’s strengths include the investigators’ search of several major databases and their contacts with authors who provided relevant data. The analysis reflects the limitations of the original studies, however. These limitations include selective samples and differences in stroke assessment and dementia diagnosis criteria. In addition, dementia may develop years before it is diagnosed. “More detailed reporting of the interval between stroke occurrence and dementia diagnosis in future studies will help to better characterize the role of time since stroke in the risk of dementia,” said Dr. Llewellyn.

—Erik Greb

Suggested Reading

Kuz´ma E, Lourida I, Moore SF, et al. Stroke and dementia risk: a systematic review and meta-analysis. Alzheimers Dement. 2018 Aug 25 [Epub ahead of print].

Stroke is a strong independent risk factor for all-cause dementia, according to research published online ahead of print August 25 in Alzheimer’s & Dementia. Clinicians should incorporate stroke-prevention strategies into their health interventions to reduce patients’ risk of dementia, said the authors.

“Around a third of dementia cases are thought to be potentially preventable, though this estimate does not take into account the risk associated with stroke,” said David Llewellyn, PhD, Senior Research Fellow at University of Exeter Medical School in the United Kingdom. “Our findings indicate that this figure could be even higher and reinforce the importance of protecting the blood supply to the brain when attempting to reduce the global burden of dementia.”

Meta-Analysis of Previous Research

Stroke is a recognized risk factor for all-cause dementia, but no researchers had previously performed a meta-analysis to quantify the risk. Dr. Llewellyn and colleagues searched Medline, PsycINFO, and Embase databases for prospective studies that investigated the association between prevalent or incident stroke and incident all-cause dementia. They excluded studies that lacked a comparison group or that had a comparison group other than a stroke-free group. The investigators pooled adjusted estimates across studies using random effects meta-analysis and evaluated potential effect modifiers with meta-regression.

Dr. Llewellyn and colleagues identified 11,129 articles, 26 of which were eligible for analysis. They also included 16 studies from a previous systematic review and four studies identified through backward and forward citation searches. In all, 36 studies examined prevalent stroke (1.9 million participants), and 12 studies examined incident stroke (1.3 million participants). The studies were conducted in America, Europe, Asia, and Australia and included more than three million participants. Follow-up periods ranged from nine months to 25 years.

Stroke Affected Dementia Risk

When the researchers pooled results from 22 cohorts of participants who were cognitively normal at baseline, they found that those with prevalent stroke had a higher adjusted risk of incident dementia, compared with those without stroke (hazard ratio [HR], 1.69). Sensitivity analyses did not change the results significantly. Prevalent stroke was associated with a higher risk of incident dementia among men than among women. Sex explained 50.2% of heterogeneity between studies for prevalent stroke.

After combining the adjusted results from eight studies, Dr. Llewellyn and colleagues found that incident stroke more than doubled the risk of incident all-cause dementia, compared with no incident stroke (risk ratio [RR], 2.18). For a sensitivity analysis, the investigators excluded three studies that combined stroke with transient ischemic attack; this adjustment strengthened the association.

The study’s strengths include the investigators’ search of several major databases and their contacts with authors who provided relevant data. The analysis reflects the limitations of the original studies, however. These limitations include selective samples and differences in stroke assessment and dementia diagnosis criteria. In addition, dementia may develop years before it is diagnosed. “More detailed reporting of the interval between stroke occurrence and dementia diagnosis in future studies will help to better characterize the role of time since stroke in the risk of dementia,” said Dr. Llewellyn.

—Erik Greb

Suggested Reading

Kuz´ma E, Lourida I, Moore SF, et al. Stroke and dementia risk: a systematic review and meta-analysis. Alzheimers Dement. 2018 Aug 25 [Epub ahead of print].

Stroke is a strong independent risk factor for all-cause dementia, according to research published online ahead of print August 25 in Alzheimer’s & Dementia. Clinicians should incorporate stroke-prevention strategies into their health interventions to reduce patients’ risk of dementia, said the authors.

“Around a third of dementia cases are thought to be potentially preventable, though this estimate does not take into account the risk associated with stroke,” said David Llewellyn, PhD, Senior Research Fellow at University of Exeter Medical School in the United Kingdom. “Our findings indicate that this figure could be even higher and reinforce the importance of protecting the blood supply to the brain when attempting to reduce the global burden of dementia.”

Meta-Analysis of Previous Research

Stroke is a recognized risk factor for all-cause dementia, but no researchers had previously performed a meta-analysis to quantify the risk. Dr. Llewellyn and colleagues searched Medline, PsycINFO, and Embase databases for prospective studies that investigated the association between prevalent or incident stroke and incident all-cause dementia. They excluded studies that lacked a comparison group or that had a comparison group other than a stroke-free group. The investigators pooled adjusted estimates across studies using random effects meta-analysis and evaluated potential effect modifiers with meta-regression.

Dr. Llewellyn and colleagues identified 11,129 articles, 26 of which were eligible for analysis. They also included 16 studies from a previous systematic review and four studies identified through backward and forward citation searches. In all, 36 studies examined prevalent stroke (1.9 million participants), and 12 studies examined incident stroke (1.3 million participants). The studies were conducted in America, Europe, Asia, and Australia and included more than three million participants. Follow-up periods ranged from nine months to 25 years.

Stroke Affected Dementia Risk

When the researchers pooled results from 22 cohorts of participants who were cognitively normal at baseline, they found that those with prevalent stroke had a higher adjusted risk of incident dementia, compared with those without stroke (hazard ratio [HR], 1.69). Sensitivity analyses did not change the results significantly. Prevalent stroke was associated with a higher risk of incident dementia among men than among women. Sex explained 50.2% of heterogeneity between studies for prevalent stroke.

After combining the adjusted results from eight studies, Dr. Llewellyn and colleagues found that incident stroke more than doubled the risk of incident all-cause dementia, compared with no incident stroke (risk ratio [RR], 2.18). For a sensitivity analysis, the investigators excluded three studies that combined stroke with transient ischemic attack; this adjustment strengthened the association.

The study’s strengths include the investigators’ search of several major databases and their contacts with authors who provided relevant data. The analysis reflects the limitations of the original studies, however. These limitations include selective samples and differences in stroke assessment and dementia diagnosis criteria. In addition, dementia may develop years before it is diagnosed. “More detailed reporting of the interval between stroke occurrence and dementia diagnosis in future studies will help to better characterize the role of time since stroke in the risk of dementia,” said Dr. Llewellyn.

—Erik Greb

Suggested Reading

Kuz´ma E, Lourida I, Moore SF, et al. Stroke and dementia risk: a systematic review and meta-analysis. Alzheimers Dement. 2018 Aug 25 [Epub ahead of print].

Adult-onset Still disease (AOSD) is a systemic inflammatory condition that clinically manifests as spiking fevers, arthralgia, evanescent skin rash, and lymphadenopathy. ¹ The most commonly used criteria for diagnosing AOSD are the Yamaguchi criteria. ² The major criteria include high fever for more than 1 week, arthralgia for more than 2 weeks, leukocytosis, and an evanescent skin rash. The minor criteria consist of sore throat, lymphadenopathy and/or splenomegaly, liver dysfunction, and negative rheumatoid factor and antinuclear antibodies. Classically, the skin rash is described as an evanescent, salmon-colored erythema involving the extremities. Nevertheless, unusual cutaneous eruptions have been reported in AOSD, including persistent pruritic papules and plaques. ³ Importantly, this atypical rash demonstrates specific histologic findings that are not found on routine histopathology of a typical evanescent rash. We describe 2 patients with this atypical cutaneous eruption along with the unique histopathologic findings of AOSD.

Case Reports

Patient 1
A 23-year-old Chinese woman presented with periodic fevers, persistent rash, and joint pain of 2 years’ duration. Her medical history included splenectomy for hepatosplenomegaly as well as evaluation by hematology for lymphadenopathy; a cervical lymph node biopsy showed lymphoid and follicular hyperplasia.

Twenty days later, the patient was referred to the dermatology department for evaluation of the persistent rash. The patient described a history of flushing of the face, severe joint pain in both arms and legs, aching muscles, and persistent sore throat. The patient did not report any history of drug ingestion. Physical examination revealed a fever (temperature, 39.2°C); swollen nontender lymph nodes in the neck, axillae, and groin; and salmon-colored and hyperpigmented patches and thin plaques over the neck, chest, abdomen, and arms (Figure 1). A splenectomy scar also was noted. Peripheral blood was collected for laboratory analyses, which revealed transaminitis and moderate hyperferritinemia (Table). An autoimmune panel was negative for rheumatoid factor, antinuclear antibodies, and antineutrophil cytoplasmic antibodies. The patient was admitted to the hospital, and a skin biopsy was performed. Histology showed superficial dyskeratotic keratinocytes and sparse perivascular infiltration of neutrophils in the upper dermis (Figure 2).

The patient was diagnosed with AOSD based on fulfillment of the Yamaguchi criteria.² She was treated with methylprednisolone 60 mg daily and was discharged 14 days later. At 16-month follow-up, the patient demonstrated complete resolution of symptoms with a maintenance dose of prednisolone (7.5 mg daily).

Patient 2
A 23-year-old black woman presented to the emergency department 3 months postpartum with recurrent high fevers, worsening joint pain, and persistent itchy rash of 2 months’ duration. The patient had no history of travel, autoimmune disease, or sick contacts. She occasionally took aspirin for joint pain. Physical examination revealed a fever (temperature, 39.1°C) along with hyperpigmented patches and thin scaly hyperpigmented papules coalescing into a poorly demarcated V-shaped plaque on the upper back and posterior neck, extending to the chest in a shawl-like distribution (Figure 3). Submental lymphadenopathy was present. The spleen was not palpable.

Peripheral blood was collected for laboratory analysis and demonstrated transaminitis and a markedly high ferritin level (Table). An autoimmune panel was negative for rheumatoid factor, antinuclear antibodies, and antineutrophil cytoplasmic antibodies. Skin biopsy was performed and demonstrated many necrotic keratinocytes, singly and in aggregates, distributed from the spinous layer to the stratum corneum. A neutrophilic infiltrate was present in the papillary dermis (Figure 4).

The patient met the Yamaguchi criteria and was subsequently diagnosed with AOSD. She was treated with intravenous methylprednisolone 20 mg every 8 hours and was discharged 1 week later on oral prednisone 60 mg daily to be tapered over a period of months. At 2-week follow-up, the patient continued to experience rash and joint pain; oral methotrexate 10 mg weekly was added to her regimen, as well as vitamin D, calcium, and folic acid supplementation. At the next 2-week follow-up the patient noted improvement in the rash as well as the joint pain, but both still persisted. Prednisone was decreased to 50 mg daily and methotrexate was increased to 15 mg weekly. The patient continued to show improvement over the subsequent 3 months, during which prednisone was tapered to 10 mg daily and methotrexate was increased to 20 mg weekly. The patient showed resolution of symptoms at 3-month follow-up on this regimen, with plans to continue the prednisone taper and maintain methotrexate dosing.

Comment

Adult-onset Still disease is a systemic inflammatory condition that clinically manifests as spiking fevers, arthralgia, salmon-pink evanescent erythema, and lymphadenopathy.² The condition also can cause liver dysfunction, splenomegaly, pericarditis, pleuritis, renal dysfunction, and a reactive hemophagocytic syndrome.¹ Furthermore, one review of the literature described an association with delayed-onset malignancy.⁴ Early diagnosis is important yet challenging, as AOSD is a diagnosis of exclusion. The Yamaguchi criteria are the most widely used method of diagnosis and demonstrate more than 90% sensitivity.In addition to the Yamaguchi criteria, marked hyperferritinemia is characteristic of AOSD and can act as an indicator of disease activity.⁵ Interestingly, both of our patients had elevated ferritin levels, with patient 2 showing marked elevation (Table). In both patients, all major criteria were fulfilled, except the typical skin rash.

The skin rash in AOSD, classically consisting of an evanescent, salmon-pink erythema predominantly involving the extremities, has been observed in up to 87% of AOSD patients.⁵ The histology of the typical evanescent rash is nonspecific, characterized by a relatively sparse, perivascular, mixed inflammatory infiltrate. Notably, other skin manifestations may be found in patients with AOSD.^1,2,5-16 Persistent pruritic papules and plaques are the most commonly reported nonclassical rash, presenting as erythematous, slightly scaly papules and plaques with a linear configuration typically on the trunk.² Both of our patients presented with this atypical eruption. Importantly, the histopathology of this unique rash displays distinctive features, which can aid in early diagnosis. Findings include dyskeratotic keratinocytes in the cornified layers as well as in the epidermis, and a sparse neutrophilic and/or lymphocytic infiltrate in the papillary dermis without vasculitis. These findings were evident in both histopathologic studies of our patients (Figures 2 and 4). Although not present in our patients, dermal mucin deposition has been demonstrated in some reports.^1,13,15

A 2015 review of the literature yielded 30 cases of AOSD with pruritic persistent papules and plaques.⁴ The study confirmed a linear, erythematous or brown rash on the back and neck in the majority of cases. Histologic findings were congruent with those reported in our 2 cases: necrotic keratinocytes in the upper epidermis with a neutrophilic infiltrate in the upper dermis without vasculitis. Most patients showed rapid resolution of the rash and symptoms with the use of prednisone, prednisolone, or intravenous pulsed methylprednisolone. Interestingly, a range of presentations were noted, including prurigo pigmentosalike urticarial papules; lichenoid papules; and dermatographismlike, dermatomyositislike, and lichen amyloidosis–like rashes.⁴ In our report, patient 2 presented with a rash in a dermat-omyositislike shawl distribution. It has been suggested that patients with dermatomyositislike rashes require more potent immunotherapy as compared to patients with other rash morphologies.⁴ The need for methotrexate in addition to a prednisone taper in the clinical course of patient 2 lends further support to this observation.

Conclusion

A clinically and pathologically distinct form of cutaneous disease—AOSD with persistent pruritic papules and plaques—was observed in our 2 patients. These histopathologic findings facilitated timely diagnosis in both patients. A range of clinical morphologies may exist in AOSD, an awareness of which is paramount. Adult-onset Still disease should be included in the differential diagnosis of a dermatomyositislike presentation in a shawl distribution. Prompt diagnosis is essential to ensure adequate therapy.

Adult-onset Still disease (AOSD) is a systemic inflammatory condition that clinically manifests as spiking fevers, arthralgia, evanescent skin rash, and lymphadenopathy. ¹ The most commonly used criteria for diagnosing AOSD are the Yamaguchi criteria. ² The major criteria include high fever for more than 1 week, arthralgia for more than 2 weeks, leukocytosis, and an evanescent skin rash. The minor criteria consist of sore throat, lymphadenopathy and/or splenomegaly, liver dysfunction, and negative rheumatoid factor and antinuclear antibodies. Classically, the skin rash is described as an evanescent, salmon-colored erythema involving the extremities. Nevertheless, unusual cutaneous eruptions have been reported in AOSD, including persistent pruritic papules and plaques. ³ Importantly, this atypical rash demonstrates specific histologic findings that are not found on routine histopathology of a typical evanescent rash. We describe 2 patients with this atypical cutaneous eruption along with the unique histopathologic findings of AOSD.

Case Reports

Patient 1
A 23-year-old Chinese woman presented with periodic fevers, persistent rash, and joint pain of 2 years’ duration. Her medical history included splenectomy for hepatosplenomegaly as well as evaluation by hematology for lymphadenopathy; a cervical lymph node biopsy showed lymphoid and follicular hyperplasia.

Twenty days later, the patient was referred to the dermatology department for evaluation of the persistent rash. The patient described a history of flushing of the face, severe joint pain in both arms and legs, aching muscles, and persistent sore throat. The patient did not report any history of drug ingestion. Physical examination revealed a fever (temperature, 39.2°C); swollen nontender lymph nodes in the neck, axillae, and groin; and salmon-colored and hyperpigmented patches and thin plaques over the neck, chest, abdomen, and arms (Figure 1). A splenectomy scar also was noted. Peripheral blood was collected for laboratory analyses, which revealed transaminitis and moderate hyperferritinemia (Table). An autoimmune panel was negative for rheumatoid factor, antinuclear antibodies, and antineutrophil cytoplasmic antibodies. The patient was admitted to the hospital, and a skin biopsy was performed. Histology showed superficial dyskeratotic keratinocytes and sparse perivascular infiltration of neutrophils in the upper dermis (Figure 2).

The patient was diagnosed with AOSD based on fulfillment of the Yamaguchi criteria.² She was treated with methylprednisolone 60 mg daily and was discharged 14 days later. At 16-month follow-up, the patient demonstrated complete resolution of symptoms with a maintenance dose of prednisolone (7.5 mg daily).

Patient 2
A 23-year-old black woman presented to the emergency department 3 months postpartum with recurrent high fevers, worsening joint pain, and persistent itchy rash of 2 months’ duration. The patient had no history of travel, autoimmune disease, or sick contacts. She occasionally took aspirin for joint pain. Physical examination revealed a fever (temperature, 39.1°C) along with hyperpigmented patches and thin scaly hyperpigmented papules coalescing into a poorly demarcated V-shaped plaque on the upper back and posterior neck, extending to the chest in a shawl-like distribution (Figure 3). Submental lymphadenopathy was present. The spleen was not palpable.

Peripheral blood was collected for laboratory analysis and demonstrated transaminitis and a markedly high ferritin level (Table). An autoimmune panel was negative for rheumatoid factor, antinuclear antibodies, and antineutrophil cytoplasmic antibodies. Skin biopsy was performed and demonstrated many necrotic keratinocytes, singly and in aggregates, distributed from the spinous layer to the stratum corneum. A neutrophilic infiltrate was present in the papillary dermis (Figure 4).

The patient met the Yamaguchi criteria and was subsequently diagnosed with AOSD. She was treated with intravenous methylprednisolone 20 mg every 8 hours and was discharged 1 week later on oral prednisone 60 mg daily to be tapered over a period of months. At 2-week follow-up, the patient continued to experience rash and joint pain; oral methotrexate 10 mg weekly was added to her regimen, as well as vitamin D, calcium, and folic acid supplementation. At the next 2-week follow-up the patient noted improvement in the rash as well as the joint pain, but both still persisted. Prednisone was decreased to 50 mg daily and methotrexate was increased to 15 mg weekly. The patient continued to show improvement over the subsequent 3 months, during which prednisone was tapered to 10 mg daily and methotrexate was increased to 20 mg weekly. The patient showed resolution of symptoms at 3-month follow-up on this regimen, with plans to continue the prednisone taper and maintain methotrexate dosing.

Comment

Adult-onset Still disease is a systemic inflammatory condition that clinically manifests as spiking fevers, arthralgia, salmon-pink evanescent erythema, and lymphadenopathy.² The condition also can cause liver dysfunction, splenomegaly, pericarditis, pleuritis, renal dysfunction, and a reactive hemophagocytic syndrome.¹ Furthermore, one review of the literature described an association with delayed-onset malignancy.⁴ Early diagnosis is important yet challenging, as AOSD is a diagnosis of exclusion. The Yamaguchi criteria are the most widely used method of diagnosis and demonstrate more than 90% sensitivity.In addition to the Yamaguchi criteria, marked hyperferritinemia is characteristic of AOSD and can act as an indicator of disease activity.⁵ Interestingly, both of our patients had elevated ferritin levels, with patient 2 showing marked elevation (Table). In both patients, all major criteria were fulfilled, except the typical skin rash.

The skin rash in AOSD, classically consisting of an evanescent, salmon-pink erythema predominantly involving the extremities, has been observed in up to 87% of AOSD patients.⁵ The histology of the typical evanescent rash is nonspecific, characterized by a relatively sparse, perivascular, mixed inflammatory infiltrate. Notably, other skin manifestations may be found in patients with AOSD.^1,2,5-16 Persistent pruritic papules and plaques are the most commonly reported nonclassical rash, presenting as erythematous, slightly scaly papules and plaques with a linear configuration typically on the trunk.² Both of our patients presented with this atypical eruption. Importantly, the histopathology of this unique rash displays distinctive features, which can aid in early diagnosis. Findings include dyskeratotic keratinocytes in the cornified layers as well as in the epidermis, and a sparse neutrophilic and/or lymphocytic infiltrate in the papillary dermis without vasculitis. These findings were evident in both histopathologic studies of our patients (Figures 2 and 4). Although not present in our patients, dermal mucin deposition has been demonstrated in some reports.^1,13,15

A 2015 review of the literature yielded 30 cases of AOSD with pruritic persistent papules and plaques.⁴ The study confirmed a linear, erythematous or brown rash on the back and neck in the majority of cases. Histologic findings were congruent with those reported in our 2 cases: necrotic keratinocytes in the upper epidermis with a neutrophilic infiltrate in the upper dermis without vasculitis. Most patients showed rapid resolution of the rash and symptoms with the use of prednisone, prednisolone, or intravenous pulsed methylprednisolone. Interestingly, a range of presentations were noted, including prurigo pigmentosalike urticarial papules; lichenoid papules; and dermatographismlike, dermatomyositislike, and lichen amyloidosis–like rashes.⁴ In our report, patient 2 presented with a rash in a dermat-omyositislike shawl distribution. It has been suggested that patients with dermatomyositislike rashes require more potent immunotherapy as compared to patients with other rash morphologies.⁴ The need for methotrexate in addition to a prednisone taper in the clinical course of patient 2 lends further support to this observation.

Conclusion

A clinically and pathologically distinct form of cutaneous disease—AOSD with persistent pruritic papules and plaques—was observed in our 2 patients. These histopathologic findings facilitated timely diagnosis in both patients. A range of clinical morphologies may exist in AOSD, an awareness of which is paramount. Adult-onset Still disease should be included in the differential diagnosis of a dermatomyositislike presentation in a shawl distribution. Prompt diagnosis is essential to ensure adequate therapy.

Adult-onset Still disease (AOSD) is a systemic inflammatory condition that clinically manifests as spiking fevers, arthralgia, evanescent skin rash, and lymphadenopathy. ¹ The most commonly used criteria for diagnosing AOSD are the Yamaguchi criteria. ² The major criteria include high fever for more than 1 week, arthralgia for more than 2 weeks, leukocytosis, and an evanescent skin rash. The minor criteria consist of sore throat, lymphadenopathy and/or splenomegaly, liver dysfunction, and negative rheumatoid factor and antinuclear antibodies. Classically, the skin rash is described as an evanescent, salmon-colored erythema involving the extremities. Nevertheless, unusual cutaneous eruptions have been reported in AOSD, including persistent pruritic papules and plaques. ³ Importantly, this atypical rash demonstrates specific histologic findings that are not found on routine histopathology of a typical evanescent rash. We describe 2 patients with this atypical cutaneous eruption along with the unique histopathologic findings of AOSD.

Case Reports

Patient 1
A 23-year-old Chinese woman presented with periodic fevers, persistent rash, and joint pain of 2 years’ duration. Her medical history included splenectomy for hepatosplenomegaly as well as evaluation by hematology for lymphadenopathy; a cervical lymph node biopsy showed lymphoid and follicular hyperplasia.

Twenty days later, the patient was referred to the dermatology department for evaluation of the persistent rash. The patient described a history of flushing of the face, severe joint pain in both arms and legs, aching muscles, and persistent sore throat. The patient did not report any history of drug ingestion. Physical examination revealed a fever (temperature, 39.2°C); swollen nontender lymph nodes in the neck, axillae, and groin; and salmon-colored and hyperpigmented patches and thin plaques over the neck, chest, abdomen, and arms (Figure 1). A splenectomy scar also was noted. Peripheral blood was collected for laboratory analyses, which revealed transaminitis and moderate hyperferritinemia (Table). An autoimmune panel was negative for rheumatoid factor, antinuclear antibodies, and antineutrophil cytoplasmic antibodies. The patient was admitted to the hospital, and a skin biopsy was performed. Histology showed superficial dyskeratotic keratinocytes and sparse perivascular infiltration of neutrophils in the upper dermis (Figure 2).

The patient was diagnosed with AOSD based on fulfillment of the Yamaguchi criteria.² She was treated with methylprednisolone 60 mg daily and was discharged 14 days later. At 16-month follow-up, the patient demonstrated complete resolution of symptoms with a maintenance dose of prednisolone (7.5 mg daily).

Patient 2
A 23-year-old black woman presented to the emergency department 3 months postpartum with recurrent high fevers, worsening joint pain, and persistent itchy rash of 2 months’ duration. The patient had no history of travel, autoimmune disease, or sick contacts. She occasionally took aspirin for joint pain. Physical examination revealed a fever (temperature, 39.1°C) along with hyperpigmented patches and thin scaly hyperpigmented papules coalescing into a poorly demarcated V-shaped plaque on the upper back and posterior neck, extending to the chest in a shawl-like distribution (Figure 3). Submental lymphadenopathy was present. The spleen was not palpable.

Peripheral blood was collected for laboratory analysis and demonstrated transaminitis and a markedly high ferritin level (Table). An autoimmune panel was negative for rheumatoid factor, antinuclear antibodies, and antineutrophil cytoplasmic antibodies. Skin biopsy was performed and demonstrated many necrotic keratinocytes, singly and in aggregates, distributed from the spinous layer to the stratum corneum. A neutrophilic infiltrate was present in the papillary dermis (Figure 4).

The patient met the Yamaguchi criteria and was subsequently diagnosed with AOSD. She was treated with intravenous methylprednisolone 20 mg every 8 hours and was discharged 1 week later on oral prednisone 60 mg daily to be tapered over a period of months. At 2-week follow-up, the patient continued to experience rash and joint pain; oral methotrexate 10 mg weekly was added to her regimen, as well as vitamin D, calcium, and folic acid supplementation. At the next 2-week follow-up the patient noted improvement in the rash as well as the joint pain, but both still persisted. Prednisone was decreased to 50 mg daily and methotrexate was increased to 15 mg weekly. The patient continued to show improvement over the subsequent 3 months, during which prednisone was tapered to 10 mg daily and methotrexate was increased to 20 mg weekly. The patient showed resolution of symptoms at 3-month follow-up on this regimen, with plans to continue the prednisone taper and maintain methotrexate dosing.

Comment

Adult-onset Still disease is a systemic inflammatory condition that clinically manifests as spiking fevers, arthralgia, salmon-pink evanescent erythema, and lymphadenopathy.² The condition also can cause liver dysfunction, splenomegaly, pericarditis, pleuritis, renal dysfunction, and a reactive hemophagocytic syndrome.¹ Furthermore, one review of the literature described an association with delayed-onset malignancy.⁴ Early diagnosis is important yet challenging, as AOSD is a diagnosis of exclusion. The Yamaguchi criteria are the most widely used method of diagnosis and demonstrate more than 90% sensitivity.In addition to the Yamaguchi criteria, marked hyperferritinemia is characteristic of AOSD and can act as an indicator of disease activity.⁵ Interestingly, both of our patients had elevated ferritin levels, with patient 2 showing marked elevation (Table). In both patients, all major criteria were fulfilled, except the typical skin rash.

The skin rash in AOSD, classically consisting of an evanescent, salmon-pink erythema predominantly involving the extremities, has been observed in up to 87% of AOSD patients.⁵ The histology of the typical evanescent rash is nonspecific, characterized by a relatively sparse, perivascular, mixed inflammatory infiltrate. Notably, other skin manifestations may be found in patients with AOSD.^1,2,5-16 Persistent pruritic papules and plaques are the most commonly reported nonclassical rash, presenting as erythematous, slightly scaly papules and plaques with a linear configuration typically on the trunk.² Both of our patients presented with this atypical eruption. Importantly, the histopathology of this unique rash displays distinctive features, which can aid in early diagnosis. Findings include dyskeratotic keratinocytes in the cornified layers as well as in the epidermis, and a sparse neutrophilic and/or lymphocytic infiltrate in the papillary dermis without vasculitis. These findings were evident in both histopathologic studies of our patients (Figures 2 and 4). Although not present in our patients, dermal mucin deposition has been demonstrated in some reports.^1,13,15

A 2015 review of the literature yielded 30 cases of AOSD with pruritic persistent papules and plaques.⁴ The study confirmed a linear, erythematous or brown rash on the back and neck in the majority of cases. Histologic findings were congruent with those reported in our 2 cases: necrotic keratinocytes in the upper epidermis with a neutrophilic infiltrate in the upper dermis without vasculitis. Most patients showed rapid resolution of the rash and symptoms with the use of prednisone, prednisolone, or intravenous pulsed methylprednisolone. Interestingly, a range of presentations were noted, including prurigo pigmentosalike urticarial papules; lichenoid papules; and dermatographismlike, dermatomyositislike, and lichen amyloidosis–like rashes.⁴ In our report, patient 2 presented with a rash in a dermat-omyositislike shawl distribution. It has been suggested that patients with dermatomyositislike rashes require more potent immunotherapy as compared to patients with other rash morphologies.⁴ The need for methotrexate in addition to a prednisone taper in the clinical course of patient 2 lends further support to this observation.

Conclusion

A clinically and pathologically distinct form of cutaneous disease—AOSD with persistent pruritic papules and plaques—was observed in our 2 patients. These histopathologic findings facilitated timely diagnosis in both patients. A range of clinical morphologies may exist in AOSD, an awareness of which is paramount. Adult-onset Still disease should be included in the differential diagnosis of a dermatomyositislike presentation in a shawl distribution. Prompt diagnosis is essential to ensure adequate therapy.

A new system that incorporates clinical and serologic data may help classify idiopathic inflammatory myopathies, according to an analysis published online ahead of print September 10 in JAMA Neurology.

By analyzing the patterns of relationships between 47 variables in this observational, retrospective cohort study, investigators identified four clusters of patients that corresponded to known subtypes of idiopathic inflammatory myopathy. Myositis-specific autoantibodies played a key role in predicting whether a patient belonged in a given cluster, according to the investigators. Myositis-specific antibodies known to be associated with certain subgroups were observed in the corresponding clusters that the researchers identified.

“This [finding] emphasizes that muscle biopsy may no longer be necessary for diagnosis of idiopathic inflammatory myopathies in patients with myositis-specific antibodies and corresponding phenotypes,” said Kubéraka Mariampillai, PhD, of the Université Pierre et Marie Curie, Institut National de la Santé et de la Recherche Médicale (INSERM) in Paris, and colleagues.

The study was based on data for 260 patients in the database of the French Myositis Network. Patients’ mean age was 60, and 63% were women.

Investigators conducted a multiple correspondence analysis based on 47 selected variables, including age, ethnicity, historical and recent diagnoses, dermatologic changes, creatine kinase levels, myositis-specific antibodies, and pathologic characteristics. They identified four subgroups of patients corresponding to dermatomyositis, inclusion body myositis, immune-mediated necrotizing myopathy, and antisynthetase syndrome.

Using decisional algorithm trees, investigators found that the pathologic data were “dispensable,” said the authors. The best tree omitted variables related to muscle biopsy and had a 78% correct estimation based on antisynthetase syndrome antibodies, dermatomyositis rash, and finger flexor scores of 3 or less, said the investigators. “The classification quality of the tree was appreciated on the basis of all classification criteria, with an overall sensitivity of 77.0% and a specificity of 92.0%.”

Patients with polymyositis were included in the study, but were grouped mainly in the clusters corresponding to immune-mediated necrotizing myopathy and antisynthetase syndrome. “This finding indicates that patients with polymyositis do not represent a subgroup of patients, and use of this term should probably be discontinued,” Dr. Mariampillai and colleagues concluded.

—Andrew D. Bowser

Suggested Reading

Mariampillai K, Granger B, Amelin D, et al. Development of a new classification system for idiopathic inflammatory myopathies based on clinical manifestations and myositis-specific autoantibodies. JAMA Neurol. 2018 Sep 10 [Epub ahead of print].

A new system that incorporates clinical and serologic data may help classify idiopathic inflammatory myopathies, according to an analysis published online ahead of print September 10 in JAMA Neurology.

By analyzing the patterns of relationships between 47 variables in this observational, retrospective cohort study, investigators identified four clusters of patients that corresponded to known subtypes of idiopathic inflammatory myopathy. Myositis-specific autoantibodies played a key role in predicting whether a patient belonged in a given cluster, according to the investigators. Myositis-specific antibodies known to be associated with certain subgroups were observed in the corresponding clusters that the researchers identified.

“This [finding] emphasizes that muscle biopsy may no longer be necessary for diagnosis of idiopathic inflammatory myopathies in patients with myositis-specific antibodies and corresponding phenotypes,” said Kubéraka Mariampillai, PhD, of the Université Pierre et Marie Curie, Institut National de la Santé et de la Recherche Médicale (INSERM) in Paris, and colleagues.

The study was based on data for 260 patients in the database of the French Myositis Network. Patients’ mean age was 60, and 63% were women.

Investigators conducted a multiple correspondence analysis based on 47 selected variables, including age, ethnicity, historical and recent diagnoses, dermatologic changes, creatine kinase levels, myositis-specific antibodies, and pathologic characteristics. They identified four subgroups of patients corresponding to dermatomyositis, inclusion body myositis, immune-mediated necrotizing myopathy, and antisynthetase syndrome.

Using decisional algorithm trees, investigators found that the pathologic data were “dispensable,” said the authors. The best tree omitted variables related to muscle biopsy and had a 78% correct estimation based on antisynthetase syndrome antibodies, dermatomyositis rash, and finger flexor scores of 3 or less, said the investigators. “The classification quality of the tree was appreciated on the basis of all classification criteria, with an overall sensitivity of 77.0% and a specificity of 92.0%.”

Patients with polymyositis were included in the study, but were grouped mainly in the clusters corresponding to immune-mediated necrotizing myopathy and antisynthetase syndrome. “This finding indicates that patients with polymyositis do not represent a subgroup of patients, and use of this term should probably be discontinued,” Dr. Mariampillai and colleagues concluded.

—Andrew D. Bowser

Suggested Reading

Mariampillai K, Granger B, Amelin D, et al. Development of a new classification system for idiopathic inflammatory myopathies based on clinical manifestations and myositis-specific autoantibodies. JAMA Neurol. 2018 Sep 10 [Epub ahead of print].

A new system that incorporates clinical and serologic data may help classify idiopathic inflammatory myopathies, according to an analysis published online ahead of print September 10 in JAMA Neurology.

By analyzing the patterns of relationships between 47 variables in this observational, retrospective cohort study, investigators identified four clusters of patients that corresponded to known subtypes of idiopathic inflammatory myopathy. Myositis-specific autoantibodies played a key role in predicting whether a patient belonged in a given cluster, according to the investigators. Myositis-specific antibodies known to be associated with certain subgroups were observed in the corresponding clusters that the researchers identified.

“This [finding] emphasizes that muscle biopsy may no longer be necessary for diagnosis of idiopathic inflammatory myopathies in patients with myositis-specific antibodies and corresponding phenotypes,” said Kubéraka Mariampillai, PhD, of the Université Pierre et Marie Curie, Institut National de la Santé et de la Recherche Médicale (INSERM) in Paris, and colleagues.

The study was based on data for 260 patients in the database of the French Myositis Network. Patients’ mean age was 60, and 63% were women.

Investigators conducted a multiple correspondence analysis based on 47 selected variables, including age, ethnicity, historical and recent diagnoses, dermatologic changes, creatine kinase levels, myositis-specific antibodies, and pathologic characteristics. They identified four subgroups of patients corresponding to dermatomyositis, inclusion body myositis, immune-mediated necrotizing myopathy, and antisynthetase syndrome.

Using decisional algorithm trees, investigators found that the pathologic data were “dispensable,” said the authors. The best tree omitted variables related to muscle biopsy and had a 78% correct estimation based on antisynthetase syndrome antibodies, dermatomyositis rash, and finger flexor scores of 3 or less, said the investigators. “The classification quality of the tree was appreciated on the basis of all classification criteria, with an overall sensitivity of 77.0% and a specificity of 92.0%.”

Patients with polymyositis were included in the study, but were grouped mainly in the clusters corresponding to immune-mediated necrotizing myopathy and antisynthetase syndrome. “This finding indicates that patients with polymyositis do not represent a subgroup of patients, and use of this term should probably be discontinued,” Dr. Mariampillai and colleagues concluded.

—Andrew D. Bowser

Suggested Reading

Mariampillai K, Granger B, Amelin D, et al. Development of a new classification system for idiopathic inflammatory myopathies based on clinical manifestations and myositis-specific autoantibodies. JAMA Neurol. 2018 Sep 10 [Epub ahead of print].

ABSTRACT

This study uses a prospective surgical registry to characterize the timing of 10 postoperative adverse events following geriatric hip fracture surgery. There were 19,873 patients identified who were ≥70 years undergoing surgery for hip fracture as part of the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP). The median postoperative day of diagnosis (and interquartile range) for myocardial infarction was 3 (1-5), cardiac arrest requiring cardiopulmonary resuscitation 3 (0-8), stroke 3 (1-10), pneumonia 4 (2-10), pulmonary embolism 4 (2-11), urinary tract infection 7 (2-13), deep vein thrombosis 9 (4-16), sepsis 9 (4-18), mortality 11 (6-19), and surgical site infection 16 (11-22). For the earliest diagnosed adverse events, the rate of adverse events had diminished by postoperative day 30. For the later diagnosed adverse events, the rate of adverse events remained high at postoperative day 30. Findings help to enable more targeted clinical surveillance, inform patient counseling, and determine the duration of follow-up required to study specific adverse events effectively. Orthopedic surgeons should have the lowest threshold for testing for each adverse event during the time period of greatest risk.

Continue to: Geriatric hip fracture surgery is associated with...

Geriatric hip fracture surgery is associated with a higher rate of occurrence of postoperative adverse events than any other commonly performed orthopedic procedure.^1-4 Indeed, the 90-day mortality rate following a geriatric hip fracture surgery may be as high as 15%² and the 30-day morbidity rate as high as 30%.³ Furthermore, more than half of postoperative mortalities following orthopedic procedures occur after surgery for hip fracture.⁴ Therefore, extensive research has been conducted regarding interventions to reduce the rates of adverse events following a hip fracture surgery.^5-12 For example, randomized trials have been conducted involving venous thromboembolism prophylaxis,^5,6nutritional supplementation,⁷ delirium prevention,^8-10 anemia correction,¹¹ geriatrics consultation,⁹ and anesthetic technique.¹²

Despite these extensive research efforts, there is currently little information in the literature regarding when postoperative adverse events occur. A clear depiction of the timing of adverse events could help target clinical surveillance, inform patient counseling, and determine the duration of follow-up required for studies. The reason that the timing of adverse events has not been previously characterized may be that the sample sizes available through standard single- or multi-institutional studies may be insufficient to accurately characterize the timing of rare adverse events (eg, myocardial infarction, stroke, etc.). Moreover, although administrative datasets have become common data sources for investigation of rare postoperative adverse events,^13-16 such data sources often do not contain data on the timing of diagnosis.

The American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) is a relatively new and growing surgical registry.^1,3,13-22 The registry follows up patients undergoing surgical procedures at several hundred community and academic institutions nationwide. Unlike the administrative datasets discussed above, the ACS-NSQIP characterizes the postoperative day of diagnosis of well-defined adverse events during the first 30 postoperative days.²²

In this study, data collected by the ACS-NSQIP are used to characterize the timing of 10 specific postoperative adverse events following a geriatric hip fracture surgery.

Continue to: METHODS...

 

 

METHODS

A retrospective analysis of data collected prospectively through the ACS-NSQIP was conducted. Geriatric patients who underwent hip fracture surgery during 2010 to 2013 were identified. Specific inclusion criteria were (1) International Classification of Diseases, Ninth Revision, diagnosis code 820, (2) primary Current Procedural Terminology codes 27125, 27130, 27235, 27236, 27244, or 27245, and (3) age ≥70 years.

The ACS-NSQIP captures patient demographic, comorbidity, and procedural characteristics at baseline.²² At the end of the 30-day follow-up period, the ACS-NSQIP personnel review both inpatient and outpatient charts to characterize the occurrence vs nonoccurrence of specific postoperative adverse events.^22-25 When an adverse event does occur, the postoperative day of diagnosis is recorded.

For this study, the following adverse event categories were investigated: myocardial infarction, cardiac arrest requiring cardiopulmonary resuscitation, stroke, pneumonia, pulmonary embolism, urinary tract infection, deep vein thrombosis, sepsis (either with or without shock), mortality, and surgical site infection (including superficial surgical site infection, deep surgical site infection, and organ or space surgical site infection). Detailed definitions of each adverse event are provided in ACS-NSQIP materials.²²

First, the 30-day incidence (and the associated 95% confidence interval) was determined for each adverse event. Second, the median postoperative day of diagnosis (and the associated interquartile range) was determined for each adverse event. Third, the postoperative length of stay was used to estimate the proportion of diagnoses occurring prior to vs following discharge for each adverse event. Finally, multivariate Cox proportional hazards models were used to identify independent risk factors for earlier occurrence of postoperative adverse events. The final models were selected using a backward stepwise process that sequentially eliminated variables with the weakest associations until all variables had P < .05.

Because the ACS-NSQIP reports timing data in calendar days, when the postoperative length of stay was equivalent to the postoperative day of diagnosis, it was not possible to ascertain whether the diagnosis occurred prior to or following discharge. For this study, when the postoperative length of stay was equivalent to the postoperative day of diagnosis, the adverse event was considered to have been diagnosed following discharge. The rationale for this is that for most of the adverse events, it was thought to be unlikely that an inpatient would be discharged before the end of the same day as an inpatient diagnosis. However, there was one exception to this rule; when the postoperative day of discharge, the postoperative length of stay, and the postoperative day of death were all equivalent, the adverse event was considered to have occurred prior to discharge. This is because when a patient dies during the initial inpatient stay, the ACS-NSQIP considers the postoperative length of stay to be equivalent to the postoperative day of death. This makes it much more likely that a diagnosis on the final hospital day had occurred in a patient who had not been discharged.

The mandatory ACS-NSQIP statement is “The American College of Surgeons National Surgical Quality Improvement Program and the hospitals participating in the ACS-NSQIP are the source of the data used herein; they have not verified and are not responsible for the statistical validity of the data analysis or the conclusions derived by the authors.”²⁶

Continue to: RESULTS...

 

 

RESULTS

In total, 19,873 geriatric patients undergoing a hip fracture surgery were identified (Table 1). The rates of adverse events ranged from 6.7% for urinary tract infection to 0.6% for pulmonary embolism (Table 2).

Table 1. Patient Population

	Number	Percent
Total	19,873	100.0%
Age
70-74 years	1852	9.3%
75-79 years	2764	13.9%
80-84 years	4328	21.8%
85-89 years	5525	27.8%
≥90 years	5404	27.2%
Sex
Male	5359	27.0%
Female	14,514	73.0%
Body mass index
<30 kg/m2	17,733	89.2%
≥30 kg/m2	2140	10.8%
Functional status
Independent	14,348	72.2%
Dependent	5525	27.8%
Diabetes	3321	16.7%
Congestive heart failure	738	3.7%
Dyspnea on exertion	1542	7.8%
Hypertension	14,265	71.8%
End-stage renal disease	322	1.6%
COPD	2239	11.3%
Current smoker	1506	7.6%

Abbreviation: COPD, chronic obstructive pulmonary disease.

Table 2. Patients with Adverse Events Diagnosed During the First 30 postoperative days (N = 19,873)

Adverse Event	Number	Percent	95% CI
Urinary tract infection	1321	6.7%	6.3%-7.0%
Mortality	1240	6.2%	5.9%-6.6%
Pneumonia	771	3.9%	3.6%-4.2%
Sepsis	428	2.2%	2.0%-2.4%
Myocardial infarction	347	1.8%	1.6%-1.9%
Surgical site infection	247	1.2%	1.1%-1.4%
Deep vein thrombosis	199	1.0%	0.9%-1.1%
Stroke	144	0.7%	0.6%-0.8%
Cardiac arrest	136	0.7%	0.6%-0.8%
Pulmonary embolism	126	0.6%	0.5%-0.7%

Abbreviation: CI, confidence interval.

Figure 1 depicts the timing of postoperative adverse events in detail in histograms and timing curves. For the earliest diagnosed adverse events, the rate of adverse events had diminished by postoperative day 30. For the later diagnosed adverse events, the rate of adverse events remained high at postoperative day 30.

Figure 2 provides the summary statistics for adverse events diagnosed in the first 30 postoperative days. The median postoperative day of diagnosis (and the interquartile range) was 3 (1-5) for myocardial infarction, 3 (0-8) for cardiac arrest requiring cardiopulmonary resuscitation, 3 (1-10) for stroke, 4 (2-10) for pneumonia, 4 (2-11) for pulmonary embolism, 7 (2-13) for urinary tract infection, 9 (4-16) for deep vein thrombosis, 9 (4-18) for sepsis, 11 (6-19) for mortality, and 16 (11-22) for surgical site infection.

Figure 3 depicts the timing of adverse events relative to discharge. The proportions of adverse events diagnosed prior to discharge were 81.0% for myocardial infarction, 77.8% for stroke, 76.1% for cardiac arrest requiring cardiopulmonary resuscitation, 71.9% for pulmonary embolism, 71.1% for pneumonia, 58.0% for urinary tract infection, 52.1% for sepsis, 46.9% for deep vein thrombosis, 44.3% for mortality, and 27.6% for surgical site infection.

Table 3 shows the independent risk factors for earlier occurrence of adverse events. Following multivariate stepwise selection of final models, at least 1 patient characteristic was independently associated with the timing of cardiac arrest, stroke, urinary tract infection, deep vein thrombosis, and death. In contrast, no patient characteristics were independently associated with the timing of myocardial infarction, pneumonia, pulmonary embolism, sepsis, and surgical site infection.

Table 3. Timing of Diagnosis of Adverse Events^a

Adverse events and associated baseline characteristic(s)	Median postoperative day of diagnosis with vs without baseline characteristic	P-valueb
Cardiac arrest
End-stage renal disease	1 vs 3	.005
Stroke
Hypertension	4 vs 2	.025
Dependent functional status	2 vs 4	.027
Urinary tract infection
Female sex	6 vs 8	.009
Deep vein thrombosis
Body mass index ≥30 kg/m2	5 vs 10	.015
Death
End-stage renal disease	10 vs 11	.031

^aBaseline characteristics that were independently associated with the timing of each adverse event were identified through a backwards stepwise selection process initially including all characteristics listed in Table 1, and sequentially excluding characteristics with the weakest associations until only characteristics with P < .05 remained. Independent associations with the timing of cardiac arrest, stroke, urinary tract infection, deep vein thrombosis, and death are shown. There were no characteristics independently associated with timing of myocardial infarction, pneumonia, pulmonary embolism, sepsis, or surgical site infection; hence, these adverse events are not listed in the table.

^bFrom final Cox proportional hazards models identified through multivariate stepwise selection.

Continue to: DISCUSSION...

 

 

DISCUSSION

Adverse events are extremely common following a geriatric hip fracture surgery.^1-4 Despite extensive investigation regarding methods to prevent these events,^5-12 there is limited published description of the timing at which such events occur. This study used a large prospectively followed up cohort of geriatric patients undergoing a hip fracture surgery to deliver a better description of the timing of adverse events than was previously available. The findings of this study should enable more targeted clinical surveillance, inform patient counseling, and help determine the duration of follow-up required for studies on adverse events.

There was wide variability in the timing at which the different postoperative adverse events were diagnosed (Figures 1, 2). Myocardial infarction was diagnosed the earliest, with more than three-fourth of diagnoses in the first postoperative week. Other relatively early-diagnosed adverse events included cardiac arrest requiring cardiopulmonary resuscitation, stroke, pneumonia, and pulmonary embolism.

The latest-diagnosed adverse event was surgical site infection (Figures 1, 2). Surgical site infection was actually the only adverse event with a rate of diagnosis during the first week that was lower than the rate of diagnosis later in the month (as can be seen by the inflection in the timing curve for surgical site infection in Figure 1). Mortality showed a relatively consistent rate of diagnosis throughout the entire first postoperative month. Other relatively late-diagnosed postoperative events, including sepsis, deep vein thrombosis, and urinary tract infection, showed varying degrees of decreased rate of diagnosis near the end of the first postoperative month. Of note, for the later-diagnosed adverse events, the estimated median and interquartile ranges (Figure 2) were presumably quite biased toward earlier diagnosis, as the 30-day follow-up period clearly failed to capture a large proportion of later-occurring adverse events (Figure 1).

Certain risk factors were independently associated with earlier occurrence of adverse events. Perhaps most strikingly, body mass index in the obese range was associated with substantially earlier occurrence of deep vein thrombosis (median of 5 vs 10 days). This finding suggests that clinical monitoring for deep vein thrombosis should be performed earlier in patients with greater body mass index. Also notable is the earlier occurrence of cardiac arrest and death among patients with end-stage renal disease than among those without. Patients with end-stage renal disease may have a greater risk for these adverse events immediately following the cardiac stresses of surgery.²⁷ Similarly, such patients may be more prone to early electrolyte abnormalities and arrhythmia.

Continue to: In addition to its clinical implications, this study...

 

 

In addition to its clinical implications, this study informs about the interpretation of the many studies of adverse events following hip fracture procedures that have been conducted using retrospective data. Several such studies have relied on inpatient-only administrative databases.^{4,13,14,28-35} As clearly demonstrated in Figure 3, for most of the commonly studied adverse events, inpatient-only databases failed to capture a large proportion of adverse events occurring in the first postoperative month. This highlights a substantial limitation of this commonly published type of study that is often not emphasized in the literature.

There has also been an increase in the publication of studies of adverse events following a hip fracture surgery using the ACS-NSQIP data.^{3,13,14,17,18,21} As discussed, the ACS-NSQIP provides data on 30-days of follow-up. This relatively extended follow-up is often touted as a distinct advantage. However, this study demonstrates that even the 30-day follow-up afforded by the ACS-NSQIP is limited in its ability to enable investigation of the later-occurring adverse events (Figure 1). In particular, the rate of surgical site infection shows little sign of slowing by postoperative day 30. Similarly, the rates of mortality, sepsis, deep vein thrombosis, and urinary tract infection remain substantial.

This study does have limitations. First, as discussed, the duration of follow-up is a limitation of any ACS-NSQIP-based investigation, including this study. Second, the ACS-NSQIP does not capture relevant orthopedic-specific outcomes (eg, screw cutout). In addition, it could not be determined with certainty whether adverse events occurring on the final hospital day occurred prior to or following discharge. However, only a small proportion of most of the adverse events was diagnosed on the final hospital day. Finally, the ACS-NSQIP reports on days from the operation until diagnosis of the adverse event. Although some adverse events are probably diagnosed quickly after they have occurred (eg, myocardial infarction and cardiac arrest), other adverse events may have a delayed diagnosis (eg, surgical site infection may be identified days after its initial occurrence during a follow-up examination). Therefore, it is important to note the subtle distinction between occurrence and diagnosis throughout the article. This article reports on the timing of diagnosis, not actual occurrence.

CONCLUSION

The timing of postoperative adverse events has been understudied in the past. This may be due to an inability of standard single- or multi-institutional investigations to achieve sample sizes adequate to study the less commonly occurring adverse events. Using a relatively new prospective surgical registry, this study provides a far more detailed description of the timing of adverse events following surgery than was previously available. The authors anticipate that these data can be used to inform patient counseling, target clinical surveillance, and direct clinical research. The authors chose to study the timing of postoperative adverse events following geriatric hip fracture surgery because of the high rate of adverse events associated with the procedure. However, future ACS-NSQIP studies may involve characterization of the timing of adverse events following other orthopedic and non-orthopedic procedures.

This paper will be judged for the Resident Writer’s Award.

ABSTRACT

This study uses a prospective surgical registry to characterize the timing of 10 postoperative adverse events following geriatric hip fracture surgery. There were 19,873 patients identified who were ≥70 years undergoing surgery for hip fracture as part of the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP). The median postoperative day of diagnosis (and interquartile range) for myocardial infarction was 3 (1-5), cardiac arrest requiring cardiopulmonary resuscitation 3 (0-8), stroke 3 (1-10), pneumonia 4 (2-10), pulmonary embolism 4 (2-11), urinary tract infection 7 (2-13), deep vein thrombosis 9 (4-16), sepsis 9 (4-18), mortality 11 (6-19), and surgical site infection 16 (11-22). For the earliest diagnosed adverse events, the rate of adverse events had diminished by postoperative day 30. For the later diagnosed adverse events, the rate of adverse events remained high at postoperative day 30. Findings help to enable more targeted clinical surveillance, inform patient counseling, and determine the duration of follow-up required to study specific adverse events effectively. Orthopedic surgeons should have the lowest threshold for testing for each adverse event during the time period of greatest risk.

Continue to: Geriatric hip fracture surgery is associated with...

Geriatric hip fracture surgery is associated with a higher rate of occurrence of postoperative adverse events than any other commonly performed orthopedic procedure.^1-4 Indeed, the 90-day mortality rate following a geriatric hip fracture surgery may be as high as 15%² and the 30-day morbidity rate as high as 30%.³ Furthermore, more than half of postoperative mortalities following orthopedic procedures occur after surgery for hip fracture.⁴ Therefore, extensive research has been conducted regarding interventions to reduce the rates of adverse events following a hip fracture surgery.^5-12 For example, randomized trials have been conducted involving venous thromboembolism prophylaxis,^5,6nutritional supplementation,⁷ delirium prevention,^8-10 anemia correction,¹¹ geriatrics consultation,⁹ and anesthetic technique.¹²

Despite these extensive research efforts, there is currently little information in the literature regarding when postoperative adverse events occur. A clear depiction of the timing of adverse events could help target clinical surveillance, inform patient counseling, and determine the duration of follow-up required for studies. The reason that the timing of adverse events has not been previously characterized may be that the sample sizes available through standard single- or multi-institutional studies may be insufficient to accurately characterize the timing of rare adverse events (eg, myocardial infarction, stroke, etc.). Moreover, although administrative datasets have become common data sources for investigation of rare postoperative adverse events,^13-16 such data sources often do not contain data on the timing of diagnosis.

The American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) is a relatively new and growing surgical registry.^1,3,13-22 The registry follows up patients undergoing surgical procedures at several hundred community and academic institutions nationwide. Unlike the administrative datasets discussed above, the ACS-NSQIP characterizes the postoperative day of diagnosis of well-defined adverse events during the first 30 postoperative days.²²

In this study, data collected by the ACS-NSQIP are used to characterize the timing of 10 specific postoperative adverse events following a geriatric hip fracture surgery.

Continue to: METHODS...

 

 

METHODS

A retrospective analysis of data collected prospectively through the ACS-NSQIP was conducted. Geriatric patients who underwent hip fracture surgery during 2010 to 2013 were identified. Specific inclusion criteria were (1) International Classification of Diseases, Ninth Revision, diagnosis code 820, (2) primary Current Procedural Terminology codes 27125, 27130, 27235, 27236, 27244, or 27245, and (3) age ≥70 years.

The ACS-NSQIP captures patient demographic, comorbidity, and procedural characteristics at baseline.²² At the end of the 30-day follow-up period, the ACS-NSQIP personnel review both inpatient and outpatient charts to characterize the occurrence vs nonoccurrence of specific postoperative adverse events.^22-25 When an adverse event does occur, the postoperative day of diagnosis is recorded.

For this study, the following adverse event categories were investigated: myocardial infarction, cardiac arrest requiring cardiopulmonary resuscitation, stroke, pneumonia, pulmonary embolism, urinary tract infection, deep vein thrombosis, sepsis (either with or without shock), mortality, and surgical site infection (including superficial surgical site infection, deep surgical site infection, and organ or space surgical site infection). Detailed definitions of each adverse event are provided in ACS-NSQIP materials.²²

First, the 30-day incidence (and the associated 95% confidence interval) was determined for each adverse event. Second, the median postoperative day of diagnosis (and the associated interquartile range) was determined for each adverse event. Third, the postoperative length of stay was used to estimate the proportion of diagnoses occurring prior to vs following discharge for each adverse event. Finally, multivariate Cox proportional hazards models were used to identify independent risk factors for earlier occurrence of postoperative adverse events. The final models were selected using a backward stepwise process that sequentially eliminated variables with the weakest associations until all variables had P < .05.

Because the ACS-NSQIP reports timing data in calendar days, when the postoperative length of stay was equivalent to the postoperative day of diagnosis, it was not possible to ascertain whether the diagnosis occurred prior to or following discharge. For this study, when the postoperative length of stay was equivalent to the postoperative day of diagnosis, the adverse event was considered to have been diagnosed following discharge. The rationale for this is that for most of the adverse events, it was thought to be unlikely that an inpatient would be discharged before the end of the same day as an inpatient diagnosis. However, there was one exception to this rule; when the postoperative day of discharge, the postoperative length of stay, and the postoperative day of death were all equivalent, the adverse event was considered to have occurred prior to discharge. This is because when a patient dies during the initial inpatient stay, the ACS-NSQIP considers the postoperative length of stay to be equivalent to the postoperative day of death. This makes it much more likely that a diagnosis on the final hospital day had occurred in a patient who had not been discharged.

The mandatory ACS-NSQIP statement is “The American College of Surgeons National Surgical Quality Improvement Program and the hospitals participating in the ACS-NSQIP are the source of the data used herein; they have not verified and are not responsible for the statistical validity of the data analysis or the conclusions derived by the authors.”²⁶

Continue to: RESULTS...

 

 

RESULTS

In total, 19,873 geriatric patients undergoing a hip fracture surgery were identified (Table 1). The rates of adverse events ranged from 6.7% for urinary tract infection to 0.6% for pulmonary embolism (Table 2).

Table 1. Patient Population

	Number	Percent
Total	19,873	100.0%
Age
70-74 years	1852	9.3%
75-79 years	2764	13.9%
80-84 years	4328	21.8%
85-89 years	5525	27.8%
≥90 years	5404	27.2%
Sex
Male	5359	27.0%
Female	14,514	73.0%
Body mass index
<30 kg/m2	17,733	89.2%
≥30 kg/m2	2140	10.8%
Functional status
Independent	14,348	72.2%
Dependent	5525	27.8%
Diabetes	3321	16.7%
Congestive heart failure	738	3.7%
Dyspnea on exertion	1542	7.8%
Hypertension	14,265	71.8%
End-stage renal disease	322	1.6%
COPD	2239	11.3%
Current smoker	1506	7.6%

Abbreviation: COPD, chronic obstructive pulmonary disease.

Table 2. Patients with Adverse Events Diagnosed During the First 30 postoperative days (N = 19,873)

Adverse Event	Number	Percent	95% CI
Urinary tract infection	1321	6.7%	6.3%-7.0%
Mortality	1240	6.2%	5.9%-6.6%
Pneumonia	771	3.9%	3.6%-4.2%
Sepsis	428	2.2%	2.0%-2.4%
Myocardial infarction	347	1.8%	1.6%-1.9%
Surgical site infection	247	1.2%	1.1%-1.4%
Deep vein thrombosis	199	1.0%	0.9%-1.1%
Stroke	144	0.7%	0.6%-0.8%
Cardiac arrest	136	0.7%	0.6%-0.8%
Pulmonary embolism	126	0.6%	0.5%-0.7%

Abbreviation: CI, confidence interval.

Figure 1 depicts the timing of postoperative adverse events in detail in histograms and timing curves. For the earliest diagnosed adverse events, the rate of adverse events had diminished by postoperative day 30. For the later diagnosed adverse events, the rate of adverse events remained high at postoperative day 30.

Figure 2 provides the summary statistics for adverse events diagnosed in the first 30 postoperative days. The median postoperative day of diagnosis (and the interquartile range) was 3 (1-5) for myocardial infarction, 3 (0-8) for cardiac arrest requiring cardiopulmonary resuscitation, 3 (1-10) for stroke, 4 (2-10) for pneumonia, 4 (2-11) for pulmonary embolism, 7 (2-13) for urinary tract infection, 9 (4-16) for deep vein thrombosis, 9 (4-18) for sepsis, 11 (6-19) for mortality, and 16 (11-22) for surgical site infection.

Figure 3 depicts the timing of adverse events relative to discharge. The proportions of adverse events diagnosed prior to discharge were 81.0% for myocardial infarction, 77.8% for stroke, 76.1% for cardiac arrest requiring cardiopulmonary resuscitation, 71.9% for pulmonary embolism, 71.1% for pneumonia, 58.0% for urinary tract infection, 52.1% for sepsis, 46.9% for deep vein thrombosis, 44.3% for mortality, and 27.6% for surgical site infection.

Table 3 shows the independent risk factors for earlier occurrence of adverse events. Following multivariate stepwise selection of final models, at least 1 patient characteristic was independently associated with the timing of cardiac arrest, stroke, urinary tract infection, deep vein thrombosis, and death. In contrast, no patient characteristics were independently associated with the timing of myocardial infarction, pneumonia, pulmonary embolism, sepsis, and surgical site infection.

Table 3. Timing of Diagnosis of Adverse Events^a

Adverse events and associated baseline characteristic(s)	Median postoperative day of diagnosis with vs without baseline characteristic	P-valueb
Cardiac arrest
End-stage renal disease	1 vs 3	.005
Stroke
Hypertension	4 vs 2	.025
Dependent functional status	2 vs 4	.027
Urinary tract infection
Female sex	6 vs 8	.009
Deep vein thrombosis
Body mass index ≥30 kg/m2	5 vs 10	.015
Death
End-stage renal disease	10 vs 11	.031

^aBaseline characteristics that were independently associated with the timing of each adverse event were identified through a backwards stepwise selection process initially including all characteristics listed in Table 1, and sequentially excluding characteristics with the weakest associations until only characteristics with P < .05 remained. Independent associations with the timing of cardiac arrest, stroke, urinary tract infection, deep vein thrombosis, and death are shown. There were no characteristics independently associated with timing of myocardial infarction, pneumonia, pulmonary embolism, sepsis, or surgical site infection; hence, these adverse events are not listed in the table.

^bFrom final Cox proportional hazards models identified through multivariate stepwise selection.

Continue to: DISCUSSION...

 

 

DISCUSSION

Adverse events are extremely common following a geriatric hip fracture surgery.^1-4 Despite extensive investigation regarding methods to prevent these events,^5-12 there is limited published description of the timing at which such events occur. This study used a large prospectively followed up cohort of geriatric patients undergoing a hip fracture surgery to deliver a better description of the timing of adverse events than was previously available. The findings of this study should enable more targeted clinical surveillance, inform patient counseling, and help determine the duration of follow-up required for studies on adverse events.

There was wide variability in the timing at which the different postoperative adverse events were diagnosed (Figures 1, 2). Myocardial infarction was diagnosed the earliest, with more than three-fourth of diagnoses in the first postoperative week. Other relatively early-diagnosed adverse events included cardiac arrest requiring cardiopulmonary resuscitation, stroke, pneumonia, and pulmonary embolism.

The latest-diagnosed adverse event was surgical site infection (Figures 1, 2). Surgical site infection was actually the only adverse event with a rate of diagnosis during the first week that was lower than the rate of diagnosis later in the month (as can be seen by the inflection in the timing curve for surgical site infection in Figure 1). Mortality showed a relatively consistent rate of diagnosis throughout the entire first postoperative month. Other relatively late-diagnosed postoperative events, including sepsis, deep vein thrombosis, and urinary tract infection, showed varying degrees of decreased rate of diagnosis near the end of the first postoperative month. Of note, for the later-diagnosed adverse events, the estimated median and interquartile ranges (Figure 2) were presumably quite biased toward earlier diagnosis, as the 30-day follow-up period clearly failed to capture a large proportion of later-occurring adverse events (Figure 1).

Certain risk factors were independently associated with earlier occurrence of adverse events. Perhaps most strikingly, body mass index in the obese range was associated with substantially earlier occurrence of deep vein thrombosis (median of 5 vs 10 days). This finding suggests that clinical monitoring for deep vein thrombosis should be performed earlier in patients with greater body mass index. Also notable is the earlier occurrence of cardiac arrest and death among patients with end-stage renal disease than among those without. Patients with end-stage renal disease may have a greater risk for these adverse events immediately following the cardiac stresses of surgery.²⁷ Similarly, such patients may be more prone to early electrolyte abnormalities and arrhythmia.

Continue to: In addition to its clinical implications, this study...

 

 

In addition to its clinical implications, this study informs about the interpretation of the many studies of adverse events following hip fracture procedures that have been conducted using retrospective data. Several such studies have relied on inpatient-only administrative databases.^{4,13,14,28-35} As clearly demonstrated in Figure 3, for most of the commonly studied adverse events, inpatient-only databases failed to capture a large proportion of adverse events occurring in the first postoperative month. This highlights a substantial limitation of this commonly published type of study that is often not emphasized in the literature.

There has also been an increase in the publication of studies of adverse events following a hip fracture surgery using the ACS-NSQIP data.^{3,13,14,17,18,21} As discussed, the ACS-NSQIP provides data on 30-days of follow-up. This relatively extended follow-up is often touted as a distinct advantage. However, this study demonstrates that even the 30-day follow-up afforded by the ACS-NSQIP is limited in its ability to enable investigation of the later-occurring adverse events (Figure 1). In particular, the rate of surgical site infection shows little sign of slowing by postoperative day 30. Similarly, the rates of mortality, sepsis, deep vein thrombosis, and urinary tract infection remain substantial.

This study does have limitations. First, as discussed, the duration of follow-up is a limitation of any ACS-NSQIP-based investigation, including this study. Second, the ACS-NSQIP does not capture relevant orthopedic-specific outcomes (eg, screw cutout). In addition, it could not be determined with certainty whether adverse events occurring on the final hospital day occurred prior to or following discharge. However, only a small proportion of most of the adverse events was diagnosed on the final hospital day. Finally, the ACS-NSQIP reports on days from the operation until diagnosis of the adverse event. Although some adverse events are probably diagnosed quickly after they have occurred (eg, myocardial infarction and cardiac arrest), other adverse events may have a delayed diagnosis (eg, surgical site infection may be identified days after its initial occurrence during a follow-up examination). Therefore, it is important to note the subtle distinction between occurrence and diagnosis throughout the article. This article reports on the timing of diagnosis, not actual occurrence.

CONCLUSION

The timing of postoperative adverse events has been understudied in the past. This may be due to an inability of standard single- or multi-institutional investigations to achieve sample sizes adequate to study the less commonly occurring adverse events. Using a relatively new prospective surgical registry, this study provides a far more detailed description of the timing of adverse events following surgery than was previously available. The authors anticipate that these data can be used to inform patient counseling, target clinical surveillance, and direct clinical research. The authors chose to study the timing of postoperative adverse events following geriatric hip fracture surgery because of the high rate of adverse events associated with the procedure. However, future ACS-NSQIP studies may involve characterization of the timing of adverse events following other orthopedic and non-orthopedic procedures.

This paper will be judged for the Resident Writer’s Award.

ABSTRACT

This study uses a prospective surgical registry to characterize the timing of 10 postoperative adverse events following geriatric hip fracture surgery. There were 19,873 patients identified who were ≥70 years undergoing surgery for hip fracture as part of the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP). The median postoperative day of diagnosis (and interquartile range) for myocardial infarction was 3 (1-5), cardiac arrest requiring cardiopulmonary resuscitation 3 (0-8), stroke 3 (1-10), pneumonia 4 (2-10), pulmonary embolism 4 (2-11), urinary tract infection 7 (2-13), deep vein thrombosis 9 (4-16), sepsis 9 (4-18), mortality 11 (6-19), and surgical site infection 16 (11-22). For the earliest diagnosed adverse events, the rate of adverse events had diminished by postoperative day 30. For the later diagnosed adverse events, the rate of adverse events remained high at postoperative day 30. Findings help to enable more targeted clinical surveillance, inform patient counseling, and determine the duration of follow-up required to study specific adverse events effectively. Orthopedic surgeons should have the lowest threshold for testing for each adverse event during the time period of greatest risk.

Continue to: Geriatric hip fracture surgery is associated with...

Geriatric hip fracture surgery is associated with a higher rate of occurrence of postoperative adverse events than any other commonly performed orthopedic procedure.^1-4 Indeed, the 90-day mortality rate following a geriatric hip fracture surgery may be as high as 15%² and the 30-day morbidity rate as high as 30%.³ Furthermore, more than half of postoperative mortalities following orthopedic procedures occur after surgery for hip fracture.⁴ Therefore, extensive research has been conducted regarding interventions to reduce the rates of adverse events following a hip fracture surgery.^5-12 For example, randomized trials have been conducted involving venous thromboembolism prophylaxis,^5,6nutritional supplementation,⁷ delirium prevention,^8-10 anemia correction,¹¹ geriatrics consultation,⁹ and anesthetic technique.¹²

Despite these extensive research efforts, there is currently little information in the literature regarding when postoperative adverse events occur. A clear depiction of the timing of adverse events could help target clinical surveillance, inform patient counseling, and determine the duration of follow-up required for studies. The reason that the timing of adverse events has not been previously characterized may be that the sample sizes available through standard single- or multi-institutional studies may be insufficient to accurately characterize the timing of rare adverse events (eg, myocardial infarction, stroke, etc.). Moreover, although administrative datasets have become common data sources for investigation of rare postoperative adverse events,^13-16 such data sources often do not contain data on the timing of diagnosis.

The American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) is a relatively new and growing surgical registry.^1,3,13-22 The registry follows up patients undergoing surgical procedures at several hundred community and academic institutions nationwide. Unlike the administrative datasets discussed above, the ACS-NSQIP characterizes the postoperative day of diagnosis of well-defined adverse events during the first 30 postoperative days.²²

In this study, data collected by the ACS-NSQIP are used to characterize the timing of 10 specific postoperative adverse events following a geriatric hip fracture surgery.

Continue to: METHODS...

 

 

METHODS

A retrospective analysis of data collected prospectively through the ACS-NSQIP was conducted. Geriatric patients who underwent hip fracture surgery during 2010 to 2013 were identified. Specific inclusion criteria were (1) International Classification of Diseases, Ninth Revision, diagnosis code 820, (2) primary Current Procedural Terminology codes 27125, 27130, 27235, 27236, 27244, or 27245, and (3) age ≥70 years.

The ACS-NSQIP captures patient demographic, comorbidity, and procedural characteristics at baseline.²² At the end of the 30-day follow-up period, the ACS-NSQIP personnel review both inpatient and outpatient charts to characterize the occurrence vs nonoccurrence of specific postoperative adverse events.^22-25 When an adverse event does occur, the postoperative day of diagnosis is recorded.

For this study, the following adverse event categories were investigated: myocardial infarction, cardiac arrest requiring cardiopulmonary resuscitation, stroke, pneumonia, pulmonary embolism, urinary tract infection, deep vein thrombosis, sepsis (either with or without shock), mortality, and surgical site infection (including superficial surgical site infection, deep surgical site infection, and organ or space surgical site infection). Detailed definitions of each adverse event are provided in ACS-NSQIP materials.²²

First, the 30-day incidence (and the associated 95% confidence interval) was determined for each adverse event. Second, the median postoperative day of diagnosis (and the associated interquartile range) was determined for each adverse event. Third, the postoperative length of stay was used to estimate the proportion of diagnoses occurring prior to vs following discharge for each adverse event. Finally, multivariate Cox proportional hazards models were used to identify independent risk factors for earlier occurrence of postoperative adverse events. The final models were selected using a backward stepwise process that sequentially eliminated variables with the weakest associations until all variables had P < .05.

Because the ACS-NSQIP reports timing data in calendar days, when the postoperative length of stay was equivalent to the postoperative day of diagnosis, it was not possible to ascertain whether the diagnosis occurred prior to or following discharge. For this study, when the postoperative length of stay was equivalent to the postoperative day of diagnosis, the adverse event was considered to have been diagnosed following discharge. The rationale for this is that for most of the adverse events, it was thought to be unlikely that an inpatient would be discharged before the end of the same day as an inpatient diagnosis. However, there was one exception to this rule; when the postoperative day of discharge, the postoperative length of stay, and the postoperative day of death were all equivalent, the adverse event was considered to have occurred prior to discharge. This is because when a patient dies during the initial inpatient stay, the ACS-NSQIP considers the postoperative length of stay to be equivalent to the postoperative day of death. This makes it much more likely that a diagnosis on the final hospital day had occurred in a patient who had not been discharged.

The mandatory ACS-NSQIP statement is “The American College of Surgeons National Surgical Quality Improvement Program and the hospitals participating in the ACS-NSQIP are the source of the data used herein; they have not verified and are not responsible for the statistical validity of the data analysis or the conclusions derived by the authors.”²⁶

Continue to: RESULTS...

 

 

RESULTS

In total, 19,873 geriatric patients undergoing a hip fracture surgery were identified (Table 1). The rates of adverse events ranged from 6.7% for urinary tract infection to 0.6% for pulmonary embolism (Table 2).

Table 1. Patient Population

	Number	Percent
Total	19,873	100.0%
Age
70-74 years	1852	9.3%
75-79 years	2764	13.9%
80-84 years	4328	21.8%
85-89 years	5525	27.8%
≥90 years	5404	27.2%
Sex
Male	5359	27.0%
Female	14,514	73.0%
Body mass index
<30 kg/m2	17,733	89.2%
≥30 kg/m2	2140	10.8%
Functional status
Independent	14,348	72.2%
Dependent	5525	27.8%
Diabetes	3321	16.7%
Congestive heart failure	738	3.7%
Dyspnea on exertion	1542	7.8%
Hypertension	14,265	71.8%
End-stage renal disease	322	1.6%
COPD	2239	11.3%
Current smoker	1506	7.6%

Abbreviation: COPD, chronic obstructive pulmonary disease.

Table 2. Patients with Adverse Events Diagnosed During the First 30 postoperative days (N = 19,873)

Adverse Event	Number	Percent	95% CI
Urinary tract infection	1321	6.7%	6.3%-7.0%
Mortality	1240	6.2%	5.9%-6.6%
Pneumonia	771	3.9%	3.6%-4.2%
Sepsis	428	2.2%	2.0%-2.4%
Myocardial infarction	347	1.8%	1.6%-1.9%
Surgical site infection	247	1.2%	1.1%-1.4%
Deep vein thrombosis	199	1.0%	0.9%-1.1%
Stroke	144	0.7%	0.6%-0.8%
Cardiac arrest	136	0.7%	0.6%-0.8%
Pulmonary embolism	126	0.6%	0.5%-0.7%

Abbreviation: CI, confidence interval.

Figure 1 depicts the timing of postoperative adverse events in detail in histograms and timing curves. For the earliest diagnosed adverse events, the rate of adverse events had diminished by postoperative day 30. For the later diagnosed adverse events, the rate of adverse events remained high at postoperative day 30.

Figure 2 provides the summary statistics for adverse events diagnosed in the first 30 postoperative days. The median postoperative day of diagnosis (and the interquartile range) was 3 (1-5) for myocardial infarction, 3 (0-8) for cardiac arrest requiring cardiopulmonary resuscitation, 3 (1-10) for stroke, 4 (2-10) for pneumonia, 4 (2-11) for pulmonary embolism, 7 (2-13) for urinary tract infection, 9 (4-16) for deep vein thrombosis, 9 (4-18) for sepsis, 11 (6-19) for mortality, and 16 (11-22) for surgical site infection.

Figure 3 depicts the timing of adverse events relative to discharge. The proportions of adverse events diagnosed prior to discharge were 81.0% for myocardial infarction, 77.8% for stroke, 76.1% for cardiac arrest requiring cardiopulmonary resuscitation, 71.9% for pulmonary embolism, 71.1% for pneumonia, 58.0% for urinary tract infection, 52.1% for sepsis, 46.9% for deep vein thrombosis, 44.3% for mortality, and 27.6% for surgical site infection.

Table 3 shows the independent risk factors for earlier occurrence of adverse events. Following multivariate stepwise selection of final models, at least 1 patient characteristic was independently associated with the timing of cardiac arrest, stroke, urinary tract infection, deep vein thrombosis, and death. In contrast, no patient characteristics were independently associated with the timing of myocardial infarction, pneumonia, pulmonary embolism, sepsis, and surgical site infection.

Table 3. Timing of Diagnosis of Adverse Events^a

Adverse events and associated baseline characteristic(s)	Median postoperative day of diagnosis with vs without baseline characteristic	P-valueb
Cardiac arrest
End-stage renal disease	1 vs 3	.005
Stroke
Hypertension	4 vs 2	.025
Dependent functional status	2 vs 4	.027
Urinary tract infection
Female sex	6 vs 8	.009
Deep vein thrombosis
Body mass index ≥30 kg/m2	5 vs 10	.015
Death
End-stage renal disease	10 vs 11	.031

^aBaseline characteristics that were independently associated with the timing of each adverse event were identified through a backwards stepwise selection process initially including all characteristics listed in Table 1, and sequentially excluding characteristics with the weakest associations until only characteristics with P < .05 remained. Independent associations with the timing of cardiac arrest, stroke, urinary tract infection, deep vein thrombosis, and death are shown. There were no characteristics independently associated with timing of myocardial infarction, pneumonia, pulmonary embolism, sepsis, or surgical site infection; hence, these adverse events are not listed in the table.

^bFrom final Cox proportional hazards models identified through multivariate stepwise selection.

Continue to: DISCUSSION...

 

 

DISCUSSION

Adverse events are extremely common following a geriatric hip fracture surgery.^1-4 Despite extensive investigation regarding methods to prevent these events,^5-12 there is limited published description of the timing at which such events occur. This study used a large prospectively followed up cohort of geriatric patients undergoing a hip fracture surgery to deliver a better description of the timing of adverse events than was previously available. The findings of this study should enable more targeted clinical surveillance, inform patient counseling, and help determine the duration of follow-up required for studies on adverse events.

There was wide variability in the timing at which the different postoperative adverse events were diagnosed (Figures 1, 2). Myocardial infarction was diagnosed the earliest, with more than three-fourth of diagnoses in the first postoperative week. Other relatively early-diagnosed adverse events included cardiac arrest requiring cardiopulmonary resuscitation, stroke, pneumonia, and pulmonary embolism.

The latest-diagnosed adverse event was surgical site infection (Figures 1, 2). Surgical site infection was actually the only adverse event with a rate of diagnosis during the first week that was lower than the rate of diagnosis later in the month (as can be seen by the inflection in the timing curve for surgical site infection in Figure 1). Mortality showed a relatively consistent rate of diagnosis throughout the entire first postoperative month. Other relatively late-diagnosed postoperative events, including sepsis, deep vein thrombosis, and urinary tract infection, showed varying degrees of decreased rate of diagnosis near the end of the first postoperative month. Of note, for the later-diagnosed adverse events, the estimated median and interquartile ranges (Figure 2) were presumably quite biased toward earlier diagnosis, as the 30-day follow-up period clearly failed to capture a large proportion of later-occurring adverse events (Figure 1).

Certain risk factors were independently associated with earlier occurrence of adverse events. Perhaps most strikingly, body mass index in the obese range was associated with substantially earlier occurrence of deep vein thrombosis (median of 5 vs 10 days). This finding suggests that clinical monitoring for deep vein thrombosis should be performed earlier in patients with greater body mass index. Also notable is the earlier occurrence of cardiac arrest and death among patients with end-stage renal disease than among those without. Patients with end-stage renal disease may have a greater risk for these adverse events immediately following the cardiac stresses of surgery.²⁷ Similarly, such patients may be more prone to early electrolyte abnormalities and arrhythmia.

Continue to: In addition to its clinical implications, this study...

 

 

In addition to its clinical implications, this study informs about the interpretation of the many studies of adverse events following hip fracture procedures that have been conducted using retrospective data. Several such studies have relied on inpatient-only administrative databases.^{4,13,14,28-35} As clearly demonstrated in Figure 3, for most of the commonly studied adverse events, inpatient-only databases failed to capture a large proportion of adverse events occurring in the first postoperative month. This highlights a substantial limitation of this commonly published type of study that is often not emphasized in the literature.

There has also been an increase in the publication of studies of adverse events following a hip fracture surgery using the ACS-NSQIP data.^{3,13,14,17,18,21} As discussed, the ACS-NSQIP provides data on 30-days of follow-up. This relatively extended follow-up is often touted as a distinct advantage. However, this study demonstrates that even the 30-day follow-up afforded by the ACS-NSQIP is limited in its ability to enable investigation of the later-occurring adverse events (Figure 1). In particular, the rate of surgical site infection shows little sign of slowing by postoperative day 30. Similarly, the rates of mortality, sepsis, deep vein thrombosis, and urinary tract infection remain substantial.

This study does have limitations. First, as discussed, the duration of follow-up is a limitation of any ACS-NSQIP-based investigation, including this study. Second, the ACS-NSQIP does not capture relevant orthopedic-specific outcomes (eg, screw cutout). In addition, it could not be determined with certainty whether adverse events occurring on the final hospital day occurred prior to or following discharge. However, only a small proportion of most of the adverse events was diagnosed on the final hospital day. Finally, the ACS-NSQIP reports on days from the operation until diagnosis of the adverse event. Although some adverse events are probably diagnosed quickly after they have occurred (eg, myocardial infarction and cardiac arrest), other adverse events may have a delayed diagnosis (eg, surgical site infection may be identified days after its initial occurrence during a follow-up examination). Therefore, it is important to note the subtle distinction between occurrence and diagnosis throughout the article. This article reports on the timing of diagnosis, not actual occurrence.

CONCLUSION

The timing of postoperative adverse events has been understudied in the past. This may be due to an inability of standard single- or multi-institutional investigations to achieve sample sizes adequate to study the less commonly occurring adverse events. Using a relatively new prospective surgical registry, this study provides a far more detailed description of the timing of adverse events following surgery than was previously available. The authors anticipate that these data can be used to inform patient counseling, target clinical surveillance, and direct clinical research. The authors chose to study the timing of postoperative adverse events following geriatric hip fracture surgery because of the high rate of adverse events associated with the procedure. However, future ACS-NSQIP studies may involve characterization of the timing of adverse events following other orthopedic and non-orthopedic procedures.

This paper will be judged for the Resident Writer’s Award.

To the Editor:

Vemurafenib, a selective BRAF inhibitor, is a chemotherapeutic agent used in the treatment of metastatic melanoma with BRAF mutations. It has been associated with various cutaneous side effects. We report a case of metastatic melanoma with acquired plantar hyperkeratosis secondary to vemurafenib therapy.

A 49-year-old man presented for evaluation of a pigmented plaque on the left pretibial region that had been enlarging over the last 2 months. The lesion had been diagnosed as folliculitis by his primary care physician 1 month prior to the current presentation and was being treated with oral antibiotics. The patient reported occasional bleeding from the lesion but denied other symptoms. Physical examination revealed a 1.4-cm pigmented plaque distributed over the left shin. Excisional biopsy was performed to rule out melanoma. Histopathology revealed well-circumscribed and symmetric proliferation of nested and single atypical melanocytes throughout all layers to the deep reticular dermis, confirming a clinical diagnosis of malignant melanoma. The lesion demonstrated angiolymphatic invasion, mitotic activity, and a Breslow depth of 2.5 mm. The patient underwent wide local excision with 3-cm margins and left inguinal sentinel lymph node biopsy; 2 of 14 lymph nodes were positive for melanoma. Positron emission tomography–computed tomography was negative for further metastatic disease. The patient underwent isolated limb perfusion with ipilimumab, but treatment was discontinued due to regional progression of multiple cutaneous metastases that were positive for the BRAF V600E mutation.

The patient was then started on vemurafenib therapy. Within 2 weeks, the patient reported various cutaneous symptoms, including morbilliform drug eruption covering approximately 70% of the body surface area that resolved with topical steroids and oral antihistamines, as well as the appearance of melanocytic nevi on the posterior neck, back, and abdomen. After 5 months of vemurafenib therapy, the patient began to develop hyperkeratosis of the bilateral soles of the feet (Figure). A diagnosis of acquired plantar hyperkeratosis secondary to vemurafenib therapy was made. Treatment with keratolytics was initiated and vemurafenib was not discontinued. The patient died approximately 1 year after therapy was started.

Metastatic melanoma is challenging to treat and continues to have a high mortality rate; however, newer chemotherapeutic agents targeting specific mutations found in melanoma, including the BRAF V600E mutation, are promising.

The US Food and Drug Administration first approved vemurafenib, a selective BRAF inhibitor, in 2011 for treatment of metastatic melanoma. Activating BRAF mutations have been detected in up to 60% of cutaneous melanomas.¹ In the majority of these mutations, valine (V) is inserted at codon 600 instead of glutamic acid (E); therefore, the mutation is named V600E.² In a phase 3 trial of 675 metastatic melanoma patients with positive V600E who were randomized to receive either vemurafenib or dacarbazine, the overall survival rate in the vemurafenib group improved by 84% versus 64% in the dacarbazine group at 6 months.³

Vemurafenib and other BRAF inhibitors have been associated with multiple cutaneous side effects, including rash, alopecia, squamous cell carcinoma, photosensitivity, evolution of existing nevi, and less commonly palmoplantar hyperkeratosis.^2-5 Constitutional symptoms including arthralgia, nausea, and fatigue also have been commonly reported.^2-5 In several large studies comprising 1138 patients, cutaneous side effects were seen in 92% to 95% of patients.^3,5 Adverse effects caused interruption or modification of therapy in 38% of patients.³

Palmoplantar keratoderma is a known side effect of vemurafenib therapy, but it is less commonly reported than other cutaneous adverse effects. It is believed that vemurafenib has the ability to paradoxically activate the mitogen-activated protein kinase pathway, leading to keratinocyte proliferation in cells without BRAF mutations.^6-8 In the phase 3 trial, approximately 23% to 30% of patients developed some form of hyperkeratosis.⁵ Comparatively, 64% of patients developed a rash and 23% developed cutaneous squamous cell carcinoma. Incidence of palmoplantar hyperkeratosis was similar in the vemurafenib and dabrafenib groups (6% vs 8%).^3,9 Development of keratoderma also has been associated with other multikinase inhibitors (eg, sorafenib, sunitinib).^10,11

In our case, the patient displayed multiple side effects while undergoing vemurafenib therapy. Within the first 2 weeks of therapy, he experienced a drug eruption that affected approximately 70% of the body surface area. The eruption resolved with topical steroids and oral antihistamines. The patient also noted the appearance of several new melanocytic nevi on the posterior neck as well as several evolving nevi on the back and abdomen. Five months into the treatment cycle, the patient began to develop hyperkeratosis on the bilateral plantar feet. Treatment consisted of keratolytics. Vemurafenib therapy was not discontinued secondary to any adverse effects.

Vemurafenib and other BRAF inhibitors are efficacious in the treatment of metastatic melanoma with V600E mutations. The use of these therapies is likely to continue and increase in the future. BRAF inhibitors have been associated with a variety of side effects, including palmoplantar hyperkeratosis. Awareness of and appropriate response to adverse reactions is essential to proper patient care and continuation of potentially life-extending therapies.

To the Editor:

Vemurafenib, a selective BRAF inhibitor, is a chemotherapeutic agent used in the treatment of metastatic melanoma with BRAF mutations. It has been associated with various cutaneous side effects. We report a case of metastatic melanoma with acquired plantar hyperkeratosis secondary to vemurafenib therapy.

A 49-year-old man presented for evaluation of a pigmented plaque on the left pretibial region that had been enlarging over the last 2 months. The lesion had been diagnosed as folliculitis by his primary care physician 1 month prior to the current presentation and was being treated with oral antibiotics. The patient reported occasional bleeding from the lesion but denied other symptoms. Physical examination revealed a 1.4-cm pigmented plaque distributed over the left shin. Excisional biopsy was performed to rule out melanoma. Histopathology revealed well-circumscribed and symmetric proliferation of nested and single atypical melanocytes throughout all layers to the deep reticular dermis, confirming a clinical diagnosis of malignant melanoma. The lesion demonstrated angiolymphatic invasion, mitotic activity, and a Breslow depth of 2.5 mm. The patient underwent wide local excision with 3-cm margins and left inguinal sentinel lymph node biopsy; 2 of 14 lymph nodes were positive for melanoma. Positron emission tomography–computed tomography was negative for further metastatic disease. The patient underwent isolated limb perfusion with ipilimumab, but treatment was discontinued due to regional progression of multiple cutaneous metastases that were positive for the BRAF V600E mutation.

The patient was then started on vemurafenib therapy. Within 2 weeks, the patient reported various cutaneous symptoms, including morbilliform drug eruption covering approximately 70% of the body surface area that resolved with topical steroids and oral antihistamines, as well as the appearance of melanocytic nevi on the posterior neck, back, and abdomen. After 5 months of vemurafenib therapy, the patient began to develop hyperkeratosis of the bilateral soles of the feet (Figure). A diagnosis of acquired plantar hyperkeratosis secondary to vemurafenib therapy was made. Treatment with keratolytics was initiated and vemurafenib was not discontinued. The patient died approximately 1 year after therapy was started.

Metastatic melanoma is challenging to treat and continues to have a high mortality rate; however, newer chemotherapeutic agents targeting specific mutations found in melanoma, including the BRAF V600E mutation, are promising.

The US Food and Drug Administration first approved vemurafenib, a selective BRAF inhibitor, in 2011 for treatment of metastatic melanoma. Activating BRAF mutations have been detected in up to 60% of cutaneous melanomas.¹ In the majority of these mutations, valine (V) is inserted at codon 600 instead of glutamic acid (E); therefore, the mutation is named V600E.² In a phase 3 trial of 675 metastatic melanoma patients with positive V600E who were randomized to receive either vemurafenib or dacarbazine, the overall survival rate in the vemurafenib group improved by 84% versus 64% in the dacarbazine group at 6 months.³

Vemurafenib and other BRAF inhibitors have been associated with multiple cutaneous side effects, including rash, alopecia, squamous cell carcinoma, photosensitivity, evolution of existing nevi, and less commonly palmoplantar hyperkeratosis.^2-5 Constitutional symptoms including arthralgia, nausea, and fatigue also have been commonly reported.^2-5 In several large studies comprising 1138 patients, cutaneous side effects were seen in 92% to 95% of patients.^3,5 Adverse effects caused interruption or modification of therapy in 38% of patients.³

Palmoplantar keratoderma is a known side effect of vemurafenib therapy, but it is less commonly reported than other cutaneous adverse effects. It is believed that vemurafenib has the ability to paradoxically activate the mitogen-activated protein kinase pathway, leading to keratinocyte proliferation in cells without BRAF mutations.^6-8 In the phase 3 trial, approximately 23% to 30% of patients developed some form of hyperkeratosis.⁵ Comparatively, 64% of patients developed a rash and 23% developed cutaneous squamous cell carcinoma. Incidence of palmoplantar hyperkeratosis was similar in the vemurafenib and dabrafenib groups (6% vs 8%).^3,9 Development of keratoderma also has been associated with other multikinase inhibitors (eg, sorafenib, sunitinib).^10,11

In our case, the patient displayed multiple side effects while undergoing vemurafenib therapy. Within the first 2 weeks of therapy, he experienced a drug eruption that affected approximately 70% of the body surface area. The eruption resolved with topical steroids and oral antihistamines. The patient also noted the appearance of several new melanocytic nevi on the posterior neck as well as several evolving nevi on the back and abdomen. Five months into the treatment cycle, the patient began to develop hyperkeratosis on the bilateral plantar feet. Treatment consisted of keratolytics. Vemurafenib therapy was not discontinued secondary to any adverse effects.

Vemurafenib and other BRAF inhibitors are efficacious in the treatment of metastatic melanoma with V600E mutations. The use of these therapies is likely to continue and increase in the future. BRAF inhibitors have been associated with a variety of side effects, including palmoplantar hyperkeratosis. Awareness of and appropriate response to adverse reactions is essential to proper patient care and continuation of potentially life-extending therapies.

To the Editor:

Vemurafenib, a selective BRAF inhibitor, is a chemotherapeutic agent used in the treatment of metastatic melanoma with BRAF mutations. It has been associated with various cutaneous side effects. We report a case of metastatic melanoma with acquired plantar hyperkeratosis secondary to vemurafenib therapy.

A 49-year-old man presented for evaluation of a pigmented plaque on the left pretibial region that had been enlarging over the last 2 months. The lesion had been diagnosed as folliculitis by his primary care physician 1 month prior to the current presentation and was being treated with oral antibiotics. The patient reported occasional bleeding from the lesion but denied other symptoms. Physical examination revealed a 1.4-cm pigmented plaque distributed over the left shin. Excisional biopsy was performed to rule out melanoma. Histopathology revealed well-circumscribed and symmetric proliferation of nested and single atypical melanocytes throughout all layers to the deep reticular dermis, confirming a clinical diagnosis of malignant melanoma. The lesion demonstrated angiolymphatic invasion, mitotic activity, and a Breslow depth of 2.5 mm. The patient underwent wide local excision with 3-cm margins and left inguinal sentinel lymph node biopsy; 2 of 14 lymph nodes were positive for melanoma. Positron emission tomography–computed tomography was negative for further metastatic disease. The patient underwent isolated limb perfusion with ipilimumab, but treatment was discontinued due to regional progression of multiple cutaneous metastases that were positive for the BRAF V600E mutation.

The patient was then started on vemurafenib therapy. Within 2 weeks, the patient reported various cutaneous symptoms, including morbilliform drug eruption covering approximately 70% of the body surface area that resolved with topical steroids and oral antihistamines, as well as the appearance of melanocytic nevi on the posterior neck, back, and abdomen. After 5 months of vemurafenib therapy, the patient began to develop hyperkeratosis of the bilateral soles of the feet (Figure). A diagnosis of acquired plantar hyperkeratosis secondary to vemurafenib therapy was made. Treatment with keratolytics was initiated and vemurafenib was not discontinued. The patient died approximately 1 year after therapy was started.

Metastatic melanoma is challenging to treat and continues to have a high mortality rate; however, newer chemotherapeutic agents targeting specific mutations found in melanoma, including the BRAF V600E mutation, are promising.

The US Food and Drug Administration first approved vemurafenib, a selective BRAF inhibitor, in 2011 for treatment of metastatic melanoma. Activating BRAF mutations have been detected in up to 60% of cutaneous melanomas.¹ In the majority of these mutations, valine (V) is inserted at codon 600 instead of glutamic acid (E); therefore, the mutation is named V600E.² In a phase 3 trial of 675 metastatic melanoma patients with positive V600E who were randomized to receive either vemurafenib or dacarbazine, the overall survival rate in the vemurafenib group improved by 84% versus 64% in the dacarbazine group at 6 months.³

Vemurafenib and other BRAF inhibitors have been associated with multiple cutaneous side effects, including rash, alopecia, squamous cell carcinoma, photosensitivity, evolution of existing nevi, and less commonly palmoplantar hyperkeratosis.^2-5 Constitutional symptoms including arthralgia, nausea, and fatigue also have been commonly reported.^2-5 In several large studies comprising 1138 patients, cutaneous side effects were seen in 92% to 95% of patients.^3,5 Adverse effects caused interruption or modification of therapy in 38% of patients.³

Palmoplantar keratoderma is a known side effect of vemurafenib therapy, but it is less commonly reported than other cutaneous adverse effects. It is believed that vemurafenib has the ability to paradoxically activate the mitogen-activated protein kinase pathway, leading to keratinocyte proliferation in cells without BRAF mutations.^6-8 In the phase 3 trial, approximately 23% to 30% of patients developed some form of hyperkeratosis.⁵ Comparatively, 64% of patients developed a rash and 23% developed cutaneous squamous cell carcinoma. Incidence of palmoplantar hyperkeratosis was similar in the vemurafenib and dabrafenib groups (6% vs 8%).^3,9 Development of keratoderma also has been associated with other multikinase inhibitors (eg, sorafenib, sunitinib).^10,11

In our case, the patient displayed multiple side effects while undergoing vemurafenib therapy. Within the first 2 weeks of therapy, he experienced a drug eruption that affected approximately 70% of the body surface area. The eruption resolved with topical steroids and oral antihistamines. The patient also noted the appearance of several new melanocytic nevi on the posterior neck as well as several evolving nevi on the back and abdomen. Five months into the treatment cycle, the patient began to develop hyperkeratosis on the bilateral plantar feet. Treatment consisted of keratolytics. Vemurafenib therapy was not discontinued secondary to any adverse effects.

Vemurafenib and other BRAF inhibitors are efficacious in the treatment of metastatic melanoma with V600E mutations. The use of these therapies is likely to continue and increase in the future. BRAF inhibitors have been associated with a variety of side effects, including palmoplantar hyperkeratosis. Awareness of and appropriate response to adverse reactions is essential to proper patient care and continuation of potentially life-extending therapies.

ABSTRACT

Nonunion after a proximal tibia fracture is often associated with poor bone stock, (previous) infection, and compromised soft tissues. These conditions make revision internal fixation with double plating difficult. Combining a plate and contralateral 2-pin external fixator, coined composite fixation, can provide an alternative means of obtaining stability without further compromising soft tissues.

Three patients with a proximal tibia nonunion precluding standard internal fixation with double plating were treated with composite fixation. All 3 patients achieved union with deformity correction at a mean of 5.2 months (range, 5-5.5 months). The average range of motion (ROM) arc was 100° (range, 100°-115°) and postoperative ROM returned to pre-injury levels.

Composite fixation can be a helpful adjunct in the treatment of this challenging problem.

Continue to: Operative management of a proximal tibial nonunion...

Operative management of a proximal tibial nonunion is challenging, compromised by limited bone stock, pre-existing hardware, stiffness, poor soft tissue conditions, and infection. The goals of treatment include bone union, re-establishment of both joint stability and lower extremity alignment, restoration of an anatomic articular surface, and recovery of function.¹ Currently, various treatment options such as plate fixation, bone grafting, intramedullary nailing, external fixation, functional bracing, or a combination of these are available.^1-8 Rigid internal fixation is the gold standard for most nonunions. However, sometimes local soft tissues or bone quality preclude standard internal fixation. Bolhofner⁹ described the combination of a single plate and an external fixator on the contralateral side for the management of extra-articular proximal tibial fractures with compromised soft tissues, and the technique known as composite fixation was coined. The external fixator on 1 side and the plate on the other, generate a balanced, stable environment while limiting the use of foreign hardware, thereby avoiding both additional soft-tissue damage and periosteal stripping.^9-11 In this technical article, we describe the indication, technique, and outcomes of 3 patients with proximal tibial nonunions, who were successfully treated with composite fixation.

MATERIALS AND METHODS 

PATIENTS

Between January 2014 and July 2016, 3 patients each with a proximal tibial nonunion that developed after a bicondylar tibial plateau fracture (Schatzker type VI) were treated with composite fixation (Table). The 3 patients were female with an average age of 61 years (range, 60-62 years), and a body mass index of 23.7 kg/m² (range, 19.0-31.9 kg/m²). All 3 patients had sustained a tibial plateau fracture that was primarily treated with open reduction and internal fixation. Two of them had a diagnosis of rheumatoid arthritis and were being treated with methotrexate and Humira (adalimumab) (case 1), and with methotrexate, prednisolone, and etanercept (case 3). The etanercept was discontinued after discussion with the treating rheumatologist when a deep infection developed. Two patients (cases 1 and 2) were referred to us because of their nonunions. All 3 patients developed extra-articular nonunions with compromised bone stock. Two patients had developed deep infections during treatment of their plateau fractures; 1 of these patients underwent a medial gastrocnemius flap for wound coverage (case 1). The second patient (case 3) with a deep infection underwent partial hardware removal, a Masquelet salvage procedure, and revision plate fixation. However, the infection recurred. The hardware was removed, and 2 débridements with conversion to a hybrid external fixator with thin wire fixation were done. Due to her longstanding rheumatoid arthritis, the patient had bilateral valgus knee malalignment causing the ring fixator to strike her contralateral knee when she walked. The period from the initial tibial plateau fracture to our composite fixation averaged 11.3 months (range, 11-12 months). Indications for the use of the composite fixation comprised previously infected soft tissue on the lateral side and inability to walk with a hybrid thin wire fixator because of valgus knees (case 3), a medial gastrocnemius flap (case 2), and poor bone quality (case 1). Follow-up consisted of clinical examination, Timed Up and Go (TUG) test that is a standardized test for mobility, and radiographic evaluation at routine appointments up to 1 year or until healed.¹² At the last follow-up visit, patients filled out the International Knee Documentation Committee (IKDC) subjective knee form.¹³

SURGICAL TECHNIQUE

A fellowship-trained orthopedic trauma surgeon treated all patients. Patients were placed on a radiolucent operating table after general or regional anesthesia. Previous incisions were used. Two patients had a midline incision; the third had both a posteromedial and an anterolateral incision. Five deep tissue cultures were taken after which antibiotics were given intravenously. All unstable or failed hardware was removed. Aggressive débridement of the nonunion was performed. After débridement, multiple holes were drilled with a 2.0 mm drill bit until blood was seen to egress from both sides of the medullary canal. Malalignment of the proximal tibia was corrected and checked fluoroscopically. Fixation was done with an anatomic locking plate (LCP Proximal Tibia Plate 3.5; DePuy Synthes) with a mixture of locking and non-locking screws. In 2 patients, a tricortical graft from the posterior iliac crest was positioned in the defect. Additional autologous bone graft and demineralized bone matrix was added around the nonunion. Although locking screws were used, the fixation did not appear to be strong enough to resist the varus (cases 1 and 2), or the valgus (case 3) deforming forces. Additional fixation was thus needed. However, the contralateral soft tissues were compromised in case 2 (medial gastrocnemius flap), and case 3 (a previously infected area with very tenuous skin laterally), whereas the bone was considered to be of insufficient quality in case 1. The opposite side of the nonunion was stabilized using composite fixation with a 2-pin external fixator to circumvent the need for additional plate fixation. In 2 patients, the plate was placed laterally, and the external fixator medially. In the third patient, the plate was positioned medially, and the external fixator laterally. The plate was always placed first. The external fixator was placed last. Using fluoroscopy, we ensured that the fixator pins would not interfere with the screws. The pins were predrilled and positioned perpendicular to the tibia through small stab incisions. We prefer hydroxyapatite-coated pins (6-mm diameter, XCaliber Bone Screws; Pro-Motion Medical) to increase their holding power in the often osteopenic bone. Postoperative management consisted of toe-touch weight-bearing for 6 weeks and progressed to full weight-bearing at 3 months. Radiographs were taken on postoperative day 1, at 6 weeks, and at 12 weeks until healed. No continuous passive motion was used postoperatively. Antibiotics were continued until cultures were negative. No specific pin care was used. We advised patients to shower daily with the external fixator in place, once the wounds have healed.

Continue to: RESULTS... 

RESULTS

On average, patients were hospitalized for 5 days (range, 3-7 days). There were no postoperative complications. None of the patients developed a clinically significant pin site infection. There were no re-operations during follow-up. All patients achieved union at a mean of 5.2 months (range, 5-5.5 months) (Figure 1).

Deformity correction was achieved in all 3 patients. The average range of motion (ROM) arc was 100° (range, 100°-115°). None of the patients had an extension deficit. TUG test was <8 seconds in all patients. The IKDC knee score averaged 52 (range, 41-66). Of note is that 2 patients already had compromised knee function before the fracture because of rheumatoid arthritis. The Ahlbäck classification of osteoarthritis showed grade 1 in cases 1 and 3, and grade 2 in case 2.¹⁴ Postoperative ROM of the knee returned to pre-injury levels in all patients (Figure 2). The 2-pin external fixator was removed at 9 weeks on average (range, 6-12 weeks) postoperatively in the outpatient clinic. At the last follow-up appointment at an average of 10.3 months (range, 9-12 months), all wounds had healed without infection. All patients had a normal neurovascular examination.

DISCUSSION

Nonunion after a proximal tibial fracture is rare.⁴ In cases when nonunions do develop, they most often pertain to the extra-articular component with the plateau component healed. Surgical exposure for débridements, hardware removal, bone grafting, and revision of fixation carries the risk of wound breakdown, necrosis, and infection. The alternative strategy of composite fixation (a plate combined with a contralateral 2-pin external fixator) to limit additional soft tissue compromise was already described in proximal tibial fractures by Bolhofner.⁹ He treated 41 extra-articular proximal tibial fractures using this composite fixation technique and attained successful results with an average time to union of 12.1 weeks. There was only 1 malunion, 2 wound infections, and 3 delayed unions.

In our practice, we have extrapolated this idea to an extra-articular nonunion that developed after a tibial plateau fracture. With the use of an external fixator, we provided sufficient mechanical stability of the nonunion without unnecessarily compromising previously infected or tenuous soft tissues, a muscle flap, or further devascularizing poor bone. Limitations of this study include the retrospective data and small sample size prone to bias. However, all patients received the same treatment protocol from 1 orthopedic trauma surgeon, follow-up intervals were similar, and data were acquired consistently.

Meanwhile, we have used this technique in a fourth patient with a septic nonunion of a tibial plateau fracture. All 4 patients in whom we have used this method so far have healed successfully.

CONCLUSION

This technique respects both the demand for minimal soft tissue damage and a maximal stable environment without notable perioperative and postoperative complications. It also offers an alternative option for the treatment of a proximal tibial nonunion that is not amenable to invasive revision dual plate fixation. As such, it can be a useful addition to the existing armamentarium of the treating surgeon.

ABSTRACT

Nonunion after a proximal tibia fracture is often associated with poor bone stock, (previous) infection, and compromised soft tissues. These conditions make revision internal fixation with double plating difficult. Combining a plate and contralateral 2-pin external fixator, coined composite fixation, can provide an alternative means of obtaining stability without further compromising soft tissues.

Three patients with a proximal tibia nonunion precluding standard internal fixation with double plating were treated with composite fixation. All 3 patients achieved union with deformity correction at a mean of 5.2 months (range, 5-5.5 months). The average range of motion (ROM) arc was 100° (range, 100°-115°) and postoperative ROM returned to pre-injury levels.

Composite fixation can be a helpful adjunct in the treatment of this challenging problem.

Continue to: Operative management of a proximal tibial nonunion...

Operative management of a proximal tibial nonunion is challenging, compromised by limited bone stock, pre-existing hardware, stiffness, poor soft tissue conditions, and infection. The goals of treatment include bone union, re-establishment of both joint stability and lower extremity alignment, restoration of an anatomic articular surface, and recovery of function.¹ Currently, various treatment options such as plate fixation, bone grafting, intramedullary nailing, external fixation, functional bracing, or a combination of these are available.^1-8 Rigid internal fixation is the gold standard for most nonunions. However, sometimes local soft tissues or bone quality preclude standard internal fixation. Bolhofner⁹ described the combination of a single plate and an external fixator on the contralateral side for the management of extra-articular proximal tibial fractures with compromised soft tissues, and the technique known as composite fixation was coined. The external fixator on 1 side and the plate on the other, generate a balanced, stable environment while limiting the use of foreign hardware, thereby avoiding both additional soft-tissue damage and periosteal stripping.^9-11 In this technical article, we describe the indication, technique, and outcomes of 3 patients with proximal tibial nonunions, who were successfully treated with composite fixation.

MATERIALS AND METHODS 

PATIENTS

Between January 2014 and July 2016, 3 patients each with a proximal tibial nonunion that developed after a bicondylar tibial plateau fracture (Schatzker type VI) were treated with composite fixation (Table). The 3 patients were female with an average age of 61 years (range, 60-62 years), and a body mass index of 23.7 kg/m² (range, 19.0-31.9 kg/m²). All 3 patients had sustained a tibial plateau fracture that was primarily treated with open reduction and internal fixation. Two of them had a diagnosis of rheumatoid arthritis and were being treated with methotrexate and Humira (adalimumab) (case 1), and with methotrexate, prednisolone, and etanercept (case 3). The etanercept was discontinued after discussion with the treating rheumatologist when a deep infection developed. Two patients (cases 1 and 2) were referred to us because of their nonunions. All 3 patients developed extra-articular nonunions with compromised bone stock. Two patients had developed deep infections during treatment of their plateau fractures; 1 of these patients underwent a medial gastrocnemius flap for wound coverage (case 1). The second patient (case 3) with a deep infection underwent partial hardware removal, a Masquelet salvage procedure, and revision plate fixation. However, the infection recurred. The hardware was removed, and 2 débridements with conversion to a hybrid external fixator with thin wire fixation were done. Due to her longstanding rheumatoid arthritis, the patient had bilateral valgus knee malalignment causing the ring fixator to strike her contralateral knee when she walked. The period from the initial tibial plateau fracture to our composite fixation averaged 11.3 months (range, 11-12 months). Indications for the use of the composite fixation comprised previously infected soft tissue on the lateral side and inability to walk with a hybrid thin wire fixator because of valgus knees (case 3), a medial gastrocnemius flap (case 2), and poor bone quality (case 1). Follow-up consisted of clinical examination, Timed Up and Go (TUG) test that is a standardized test for mobility, and radiographic evaluation at routine appointments up to 1 year or until healed.¹² At the last follow-up visit, patients filled out the International Knee Documentation Committee (IKDC) subjective knee form.¹³

SURGICAL TECHNIQUE

A fellowship-trained orthopedic trauma surgeon treated all patients. Patients were placed on a radiolucent operating table after general or regional anesthesia. Previous incisions were used. Two patients had a midline incision; the third had both a posteromedial and an anterolateral incision. Five deep tissue cultures were taken after which antibiotics were given intravenously. All unstable or failed hardware was removed. Aggressive débridement of the nonunion was performed. After débridement, multiple holes were drilled with a 2.0 mm drill bit until blood was seen to egress from both sides of the medullary canal. Malalignment of the proximal tibia was corrected and checked fluoroscopically. Fixation was done with an anatomic locking plate (LCP Proximal Tibia Plate 3.5; DePuy Synthes) with a mixture of locking and non-locking screws. In 2 patients, a tricortical graft from the posterior iliac crest was positioned in the defect. Additional autologous bone graft and demineralized bone matrix was added around the nonunion. Although locking screws were used, the fixation did not appear to be strong enough to resist the varus (cases 1 and 2), or the valgus (case 3) deforming forces. Additional fixation was thus needed. However, the contralateral soft tissues were compromised in case 2 (medial gastrocnemius flap), and case 3 (a previously infected area with very tenuous skin laterally), whereas the bone was considered to be of insufficient quality in case 1. The opposite side of the nonunion was stabilized using composite fixation with a 2-pin external fixator to circumvent the need for additional plate fixation. In 2 patients, the plate was placed laterally, and the external fixator medially. In the third patient, the plate was positioned medially, and the external fixator laterally. The plate was always placed first. The external fixator was placed last. Using fluoroscopy, we ensured that the fixator pins would not interfere with the screws. The pins were predrilled and positioned perpendicular to the tibia through small stab incisions. We prefer hydroxyapatite-coated pins (6-mm diameter, XCaliber Bone Screws; Pro-Motion Medical) to increase their holding power in the often osteopenic bone. Postoperative management consisted of toe-touch weight-bearing for 6 weeks and progressed to full weight-bearing at 3 months. Radiographs were taken on postoperative day 1, at 6 weeks, and at 12 weeks until healed. No continuous passive motion was used postoperatively. Antibiotics were continued until cultures were negative. No specific pin care was used. We advised patients to shower daily with the external fixator in place, once the wounds have healed.

Continue to: RESULTS... 

RESULTS

On average, patients were hospitalized for 5 days (range, 3-7 days). There were no postoperative complications. None of the patients developed a clinically significant pin site infection. There were no re-operations during follow-up. All patients achieved union at a mean of 5.2 months (range, 5-5.5 months) (Figure 1).

Deformity correction was achieved in all 3 patients. The average range of motion (ROM) arc was 100° (range, 100°-115°). None of the patients had an extension deficit. TUG test was <8 seconds in all patients. The IKDC knee score averaged 52 (range, 41-66). Of note is that 2 patients already had compromised knee function before the fracture because of rheumatoid arthritis. The Ahlbäck classification of osteoarthritis showed grade 1 in cases 1 and 3, and grade 2 in case 2.¹⁴ Postoperative ROM of the knee returned to pre-injury levels in all patients (Figure 2). The 2-pin external fixator was removed at 9 weeks on average (range, 6-12 weeks) postoperatively in the outpatient clinic. At the last follow-up appointment at an average of 10.3 months (range, 9-12 months), all wounds had healed without infection. All patients had a normal neurovascular examination.

DISCUSSION

Nonunion after a proximal tibial fracture is rare.⁴ In cases when nonunions do develop, they most often pertain to the extra-articular component with the plateau component healed. Surgical exposure for débridements, hardware removal, bone grafting, and revision of fixation carries the risk of wound breakdown, necrosis, and infection. The alternative strategy of composite fixation (a plate combined with a contralateral 2-pin external fixator) to limit additional soft tissue compromise was already described in proximal tibial fractures by Bolhofner.⁹ He treated 41 extra-articular proximal tibial fractures using this composite fixation technique and attained successful results with an average time to union of 12.1 weeks. There was only 1 malunion, 2 wound infections, and 3 delayed unions.

In our practice, we have extrapolated this idea to an extra-articular nonunion that developed after a tibial plateau fracture. With the use of an external fixator, we provided sufficient mechanical stability of the nonunion without unnecessarily compromising previously infected or tenuous soft tissues, a muscle flap, or further devascularizing poor bone. Limitations of this study include the retrospective data and small sample size prone to bias. However, all patients received the same treatment protocol from 1 orthopedic trauma surgeon, follow-up intervals were similar, and data were acquired consistently.

Meanwhile, we have used this technique in a fourth patient with a septic nonunion of a tibial plateau fracture. All 4 patients in whom we have used this method so far have healed successfully.

CONCLUSION

This technique respects both the demand for minimal soft tissue damage and a maximal stable environment without notable perioperative and postoperative complications. It also offers an alternative option for the treatment of a proximal tibial nonunion that is not amenable to invasive revision dual plate fixation. As such, it can be a useful addition to the existing armamentarium of the treating surgeon.

ABSTRACT

Nonunion after a proximal tibia fracture is often associated with poor bone stock, (previous) infection, and compromised soft tissues. These conditions make revision internal fixation with double plating difficult. Combining a plate and contralateral 2-pin external fixator, coined composite fixation, can provide an alternative means of obtaining stability without further compromising soft tissues.

Three patients with a proximal tibia nonunion precluding standard internal fixation with double plating were treated with composite fixation. All 3 patients achieved union with deformity correction at a mean of 5.2 months (range, 5-5.5 months). The average range of motion (ROM) arc was 100° (range, 100°-115°) and postoperative ROM returned to pre-injury levels.

Composite fixation can be a helpful adjunct in the treatment of this challenging problem.

Continue to: Operative management of a proximal tibial nonunion...

Operative management of a proximal tibial nonunion is challenging, compromised by limited bone stock, pre-existing hardware, stiffness, poor soft tissue conditions, and infection. The goals of treatment include bone union, re-establishment of both joint stability and lower extremity alignment, restoration of an anatomic articular surface, and recovery of function.¹ Currently, various treatment options such as plate fixation, bone grafting, intramedullary nailing, external fixation, functional bracing, or a combination of these are available.^1-8 Rigid internal fixation is the gold standard for most nonunions. However, sometimes local soft tissues or bone quality preclude standard internal fixation. Bolhofner⁹ described the combination of a single plate and an external fixator on the contralateral side for the management of extra-articular proximal tibial fractures with compromised soft tissues, and the technique known as composite fixation was coined. The external fixator on 1 side and the plate on the other, generate a balanced, stable environment while limiting the use of foreign hardware, thereby avoiding both additional soft-tissue damage and periosteal stripping.^9-11 In this technical article, we describe the indication, technique, and outcomes of 3 patients with proximal tibial nonunions, who were successfully treated with composite fixation.

MATERIALS AND METHODS 

PATIENTS

Between January 2014 and July 2016, 3 patients each with a proximal tibial nonunion that developed after a bicondylar tibial plateau fracture (Schatzker type VI) were treated with composite fixation (Table). The 3 patients were female with an average age of 61 years (range, 60-62 years), and a body mass index of 23.7 kg/m² (range, 19.0-31.9 kg/m²). All 3 patients had sustained a tibial plateau fracture that was primarily treated with open reduction and internal fixation. Two of them had a diagnosis of rheumatoid arthritis and were being treated with methotrexate and Humira (adalimumab) (case 1), and with methotrexate, prednisolone, and etanercept (case 3). The etanercept was discontinued after discussion with the treating rheumatologist when a deep infection developed. Two patients (cases 1 and 2) were referred to us because of their nonunions. All 3 patients developed extra-articular nonunions with compromised bone stock. Two patients had developed deep infections during treatment of their plateau fractures; 1 of these patients underwent a medial gastrocnemius flap for wound coverage (case 1). The second patient (case 3) with a deep infection underwent partial hardware removal, a Masquelet salvage procedure, and revision plate fixation. However, the infection recurred. The hardware was removed, and 2 débridements with conversion to a hybrid external fixator with thin wire fixation were done. Due to her longstanding rheumatoid arthritis, the patient had bilateral valgus knee malalignment causing the ring fixator to strike her contralateral knee when she walked. The period from the initial tibial plateau fracture to our composite fixation averaged 11.3 months (range, 11-12 months). Indications for the use of the composite fixation comprised previously infected soft tissue on the lateral side and inability to walk with a hybrid thin wire fixator because of valgus knees (case 3), a medial gastrocnemius flap (case 2), and poor bone quality (case 1). Follow-up consisted of clinical examination, Timed Up and Go (TUG) test that is a standardized test for mobility, and radiographic evaluation at routine appointments up to 1 year or until healed.¹² At the last follow-up visit, patients filled out the International Knee Documentation Committee (IKDC) subjective knee form.¹³

SURGICAL TECHNIQUE

A fellowship-trained orthopedic trauma surgeon treated all patients. Patients were placed on a radiolucent operating table after general or regional anesthesia. Previous incisions were used. Two patients had a midline incision; the third had both a posteromedial and an anterolateral incision. Five deep tissue cultures were taken after which antibiotics were given intravenously. All unstable or failed hardware was removed. Aggressive débridement of the nonunion was performed. After débridement, multiple holes were drilled with a 2.0 mm drill bit until blood was seen to egress from both sides of the medullary canal. Malalignment of the proximal tibia was corrected and checked fluoroscopically. Fixation was done with an anatomic locking plate (LCP Proximal Tibia Plate 3.5; DePuy Synthes) with a mixture of locking and non-locking screws. In 2 patients, a tricortical graft from the posterior iliac crest was positioned in the defect. Additional autologous bone graft and demineralized bone matrix was added around the nonunion. Although locking screws were used, the fixation did not appear to be strong enough to resist the varus (cases 1 and 2), or the valgus (case 3) deforming forces. Additional fixation was thus needed. However, the contralateral soft tissues were compromised in case 2 (medial gastrocnemius flap), and case 3 (a previously infected area with very tenuous skin laterally), whereas the bone was considered to be of insufficient quality in case 1. The opposite side of the nonunion was stabilized using composite fixation with a 2-pin external fixator to circumvent the need for additional plate fixation. In 2 patients, the plate was placed laterally, and the external fixator medially. In the third patient, the plate was positioned medially, and the external fixator laterally. The plate was always placed first. The external fixator was placed last. Using fluoroscopy, we ensured that the fixator pins would not interfere with the screws. The pins were predrilled and positioned perpendicular to the tibia through small stab incisions. We prefer hydroxyapatite-coated pins (6-mm diameter, XCaliber Bone Screws; Pro-Motion Medical) to increase their holding power in the often osteopenic bone. Postoperative management consisted of toe-touch weight-bearing for 6 weeks and progressed to full weight-bearing at 3 months. Radiographs were taken on postoperative day 1, at 6 weeks, and at 12 weeks until healed. No continuous passive motion was used postoperatively. Antibiotics were continued until cultures were negative. No specific pin care was used. We advised patients to shower daily with the external fixator in place, once the wounds have healed.

Continue to: RESULTS... 

RESULTS

On average, patients were hospitalized for 5 days (range, 3-7 days). There were no postoperative complications. None of the patients developed a clinically significant pin site infection. There were no re-operations during follow-up. All patients achieved union at a mean of 5.2 months (range, 5-5.5 months) (Figure 1).

Deformity correction was achieved in all 3 patients. The average range of motion (ROM) arc was 100° (range, 100°-115°). None of the patients had an extension deficit. TUG test was <8 seconds in all patients. The IKDC knee score averaged 52 (range, 41-66). Of note is that 2 patients already had compromised knee function before the fracture because of rheumatoid arthritis. The Ahlbäck classification of osteoarthritis showed grade 1 in cases 1 and 3, and grade 2 in case 2.¹⁴ Postoperative ROM of the knee returned to pre-injury levels in all patients (Figure 2). The 2-pin external fixator was removed at 9 weeks on average (range, 6-12 weeks) postoperatively in the outpatient clinic. At the last follow-up appointment at an average of 10.3 months (range, 9-12 months), all wounds had healed without infection. All patients had a normal neurovascular examination.

DISCUSSION

Nonunion after a proximal tibial fracture is rare.⁴ In cases when nonunions do develop, they most often pertain to the extra-articular component with the plateau component healed. Surgical exposure for débridements, hardware removal, bone grafting, and revision of fixation carries the risk of wound breakdown, necrosis, and infection. The alternative strategy of composite fixation (a plate combined with a contralateral 2-pin external fixator) to limit additional soft tissue compromise was already described in proximal tibial fractures by Bolhofner.⁹ He treated 41 extra-articular proximal tibial fractures using this composite fixation technique and attained successful results with an average time to union of 12.1 weeks. There was only 1 malunion, 2 wound infections, and 3 delayed unions.

In our practice, we have extrapolated this idea to an extra-articular nonunion that developed after a tibial plateau fracture. With the use of an external fixator, we provided sufficient mechanical stability of the nonunion without unnecessarily compromising previously infected or tenuous soft tissues, a muscle flap, or further devascularizing poor bone. Limitations of this study include the retrospective data and small sample size prone to bias. However, all patients received the same treatment protocol from 1 orthopedic trauma surgeon, follow-up intervals were similar, and data were acquired consistently.

Meanwhile, we have used this technique in a fourth patient with a septic nonunion of a tibial plateau fracture. All 4 patients in whom we have used this method so far have healed successfully.

CONCLUSION

This technique respects both the demand for minimal soft tissue damage and a maximal stable environment without notable perioperative and postoperative complications. It also offers an alternative option for the treatment of a proximal tibial nonunion that is not amenable to invasive revision dual plate fixation. As such, it can be a useful addition to the existing armamentarium of the treating surgeon.