DALLAS – Timing of maternal oxytocin administration did not affect total placental transfusion volume accomplished via delayed umbilical cord clamping, according to a recent randomized, controlled trial.

Of 144 infants born to women who consented to randomization, those whose mothers received intravenous oxytocin within 15 seconds of delivery (n = 70) gained a mean 86 g (standard deviation, 48; 95% confidence interval, 74-97) in the 3 minutes after delivery, before umbilical cord clamping. Infants whose mothers received oxytocin when the umbilical cord was clamped 3 minutes after delivery (n = 74) gained 87 g (SD, 50; 95% CI, 75-98; P for difference between groups = .92). The findings were presented during an abstract session at the meeting sponsored by the Society for Maternal-Fetal Medicine.

Kari Oakes/Frontline Medical News

koakes@frontlinemedcom.com

SOURCE: Satragno D et al. Am J Obstet Gynecol. 2018 Jan;218:S26.

DALLAS – Timing of maternal oxytocin administration did not affect total placental transfusion volume accomplished via delayed umbilical cord clamping, according to a recent randomized, controlled trial.

Of 144 infants born to women who consented to randomization, those whose mothers received intravenous oxytocin within 15 seconds of delivery (n = 70) gained a mean 86 g (standard deviation, 48; 95% confidence interval, 74-97) in the 3 minutes after delivery, before umbilical cord clamping. Infants whose mothers received oxytocin when the umbilical cord was clamped 3 minutes after delivery (n = 74) gained 87 g (SD, 50; 95% CI, 75-98; P for difference between groups = .92). The findings were presented during an abstract session at the meeting sponsored by the Society for Maternal-Fetal Medicine.

Kari Oakes/Frontline Medical News

koakes@frontlinemedcom.com

SOURCE: Satragno D et al. Am J Obstet Gynecol. 2018 Jan;218:S26.

DALLAS – Timing of maternal oxytocin administration did not affect total placental transfusion volume accomplished via delayed umbilical cord clamping, according to a recent randomized, controlled trial.

Of 144 infants born to women who consented to randomization, those whose mothers received intravenous oxytocin within 15 seconds of delivery (n = 70) gained a mean 86 g (standard deviation, 48; 95% confidence interval, 74-97) in the 3 minutes after delivery, before umbilical cord clamping. Infants whose mothers received oxytocin when the umbilical cord was clamped 3 minutes after delivery (n = 74) gained 87 g (SD, 50; 95% CI, 75-98; P for difference between groups = .92). The findings were presented during an abstract session at the meeting sponsored by the Society for Maternal-Fetal Medicine.

Kari Oakes/Frontline Medical News

koakes@frontlinemedcom.com

SOURCE: Satragno D et al. Am J Obstet Gynecol. 2018 Jan;218:S26.

Indiana is the second state to win federal approval to add a work requirement for adult Medicaid recipients who gained coverage under the Affordable Care Act, but a less debated “lockout” provision in its new plan could lead to tens of thousands of enrollees losing coverage.

The federal approval was announced Feb. 2 by Health & Human Services Secretary Alex Azar in Indianapolis.

Medicaid participants who fail to submit their paperwork in a timely manner showing that they still qualify for the program will be blocked from enrollment for 3 months, according to the updated rules.

Since November 2015, more than 91,000 enrollees in Indiana were kicked off Medicaid for failing to complete the eligibility redetermination process, according to state records. The process requires applicants to show proof of income and family size, among other things, to see if they still qualify for the coverage. Until now, these enrollees could simply reapply anytime. Although many of those people likely were no longer eligible, state officials estimate about half of those who failed to comply with its reenrollment rules were still qualified.

Indiana’s Medicaid expansion began in February 2015, providing coverage to 240,000 people who were previously uninsured, helping drop the state’s uninsured rate from 14% in 2013 to 8% last year. The HHS approval extends the program, which was expiring this month, through 2020.

The new lockout builds on one already in place for Indiana residents who failed to pay monthly premiums and had annual incomes above the federal poverty level, or about $12,200 for an individual. They are barred for 6 months from coverage. During the first 2 years of the experiment, about 10,000 Indiana Medicaid enrollees were subject to the lockout for failing to pay the premium for 2 months in a row, according to state data.

In addition, more than 25,000 enrollees were dropped from the program after they failed to make the payments, although half of them found another source of coverage, usually through their jobs.

Another 46,000 were blocked from coverage because they failed to make the initial payment.

“The ‘lockout” is one of the worst policies to hit Medicaid in a long time,” said Joan Alker, executive director of the Georgetown University Center for Children and Families, in Washington. “Forcing people to remain uninsured for months because they missed a paperwork deadline or missed a premium payment is too high a price to pay. From a health policy perspective, it makes no sense because during that period, chronic health conditions such as hypertension or diabetes are just likely to worsen.”

Indiana’s Medicaid expansion is being closely watched in part because it was spearheaded by then-governor Mike Pence, who is now vice president, and his top health consultant, Seema Verma, who now heads the federal Centers for Medicare & Medicaid Services.

The expansion, known as Healthy Indiana, enabled nondisabled adults access to Medicaid. It has elicited criticism from patient advocates for complex and onerous rules that require these poor adults to make payments ranging from $1 to $27 per month into health savings accounts or risk losing their vision and dental benefits or even all their coverage, depending on their income level.

Indiana Medicaid officials said they added the newest lockout provision in an effort to prompt enrollees to get their paperwork submitted in time. The state initially requested a 6-month lockout.

“Enforcement may encourage better compliance,” the state officials wrote in their waiver application to CMS in July.

The new rule will lead to a 1% cut in Medicaid enrollment in the first year, state officials said. It will also lead to a $15 million reduction in Medicaid costs in 2018 and about $32 million in savings in 2019, the state estimated.

The number of Medicaid enrollees losing coverage for failing to comply with redetermining their eligibility has varied dramatically each quarter from a peak of 19,197 from February 2016 to April 2017 to 1,165 from November 2015 to January 2016, state reports show. In the latest state report, 12,470 enrollees lost coverage from August to October 2017.

The Kentucky Medicaid waiver approved by the Trump administration in January included a similar lockout provision for both failing to pay the monthly premiums or providing paperwork on time. Penalties there are 6 months for both measures. But the provision was overshadowed because of the attention to the first federal approval for a Medicaid work requirement.

Like Kentucky, Indiana’s Medicaid waiver’s work requirements, which mandate adult enrollees to work an average of 20 hours a month, go into effect in 2019. But Indiana’s waiver is more lenient. It exempts people aged 60 years and older and its work-hour requirements are gradually phased in over 18 months. For example, enrollees need to work only 5 hours per week until their 10th month on the program.

Most Medicaid adult enrollees do work, go to school, or are too sick to work, studies show.

Indiana also has a long list of exemptions and alternatives to employment. This includes attending school or job training, volunteering or caring for a dependent child or disabled parent. Nurses, doctors and physician assistants can give enrollees an exemption due to illness or injury.

Three patient advocacy groups have filed suit in federal court seeking to block the work requirements.

Robin Rudowitz, associate director for the Kaiser Family Foundation’s Program on Medicaid and the Uninsured, said it’s difficult to gauge whether work requirements or renewal lockouts will have more of an impact on coverage. She noted both provisions apply to most demonstration beneficiaries. (KHN is an editorially independent program of the foundation).

“Any documentation requirement could lead to increased complexity in terms of states administering the requirements and individuals complying,” she said, adding that it could result “in potentially eligible people falling off of coverage.”
 

Kaiser Health News (KHN) is a national health policy news service. It is an editorially independent program of the Henry J. Kaiser Family Foundation which is not affiliated with Kaiser Permanente.

Indiana is the second state to win federal approval to add a work requirement for adult Medicaid recipients who gained coverage under the Affordable Care Act, but a less debated “lockout” provision in its new plan could lead to tens of thousands of enrollees losing coverage.

The federal approval was announced Feb. 2 by Health & Human Services Secretary Alex Azar in Indianapolis.

Medicaid participants who fail to submit their paperwork in a timely manner showing that they still qualify for the program will be blocked from enrollment for 3 months, according to the updated rules.

Since November 2015, more than 91,000 enrollees in Indiana were kicked off Medicaid for failing to complete the eligibility redetermination process, according to state records. The process requires applicants to show proof of income and family size, among other things, to see if they still qualify for the coverage. Until now, these enrollees could simply reapply anytime. Although many of those people likely were no longer eligible, state officials estimate about half of those who failed to comply with its reenrollment rules were still qualified.

Indiana’s Medicaid expansion began in February 2015, providing coverage to 240,000 people who were previously uninsured, helping drop the state’s uninsured rate from 14% in 2013 to 8% last year. The HHS approval extends the program, which was expiring this month, through 2020.

The new lockout builds on one already in place for Indiana residents who failed to pay monthly premiums and had annual incomes above the federal poverty level, or about $12,200 for an individual. They are barred for 6 months from coverage. During the first 2 years of the experiment, about 10,000 Indiana Medicaid enrollees were subject to the lockout for failing to pay the premium for 2 months in a row, according to state data.

In addition, more than 25,000 enrollees were dropped from the program after they failed to make the payments, although half of them found another source of coverage, usually through their jobs.

Another 46,000 were blocked from coverage because they failed to make the initial payment.

“The ‘lockout” is one of the worst policies to hit Medicaid in a long time,” said Joan Alker, executive director of the Georgetown University Center for Children and Families, in Washington. “Forcing people to remain uninsured for months because they missed a paperwork deadline or missed a premium payment is too high a price to pay. From a health policy perspective, it makes no sense because during that period, chronic health conditions such as hypertension or diabetes are just likely to worsen.”

Indiana’s Medicaid expansion is being closely watched in part because it was spearheaded by then-governor Mike Pence, who is now vice president, and his top health consultant, Seema Verma, who now heads the federal Centers for Medicare & Medicaid Services.

The expansion, known as Healthy Indiana, enabled nondisabled adults access to Medicaid. It has elicited criticism from patient advocates for complex and onerous rules that require these poor adults to make payments ranging from $1 to $27 per month into health savings accounts or risk losing their vision and dental benefits or even all their coverage, depending on their income level.

Indiana Medicaid officials said they added the newest lockout provision in an effort to prompt enrollees to get their paperwork submitted in time. The state initially requested a 6-month lockout.

“Enforcement may encourage better compliance,” the state officials wrote in their waiver application to CMS in July.

The new rule will lead to a 1% cut in Medicaid enrollment in the first year, state officials said. It will also lead to a $15 million reduction in Medicaid costs in 2018 and about $32 million in savings in 2019, the state estimated.

The number of Medicaid enrollees losing coverage for failing to comply with redetermining their eligibility has varied dramatically each quarter from a peak of 19,197 from February 2016 to April 2017 to 1,165 from November 2015 to January 2016, state reports show. In the latest state report, 12,470 enrollees lost coverage from August to October 2017.

The Kentucky Medicaid waiver approved by the Trump administration in January included a similar lockout provision for both failing to pay the monthly premiums or providing paperwork on time. Penalties there are 6 months for both measures. But the provision was overshadowed because of the attention to the first federal approval for a Medicaid work requirement.

Like Kentucky, Indiana’s Medicaid waiver’s work requirements, which mandate adult enrollees to work an average of 20 hours a month, go into effect in 2019. But Indiana’s waiver is more lenient. It exempts people aged 60 years and older and its work-hour requirements are gradually phased in over 18 months. For example, enrollees need to work only 5 hours per week until their 10th month on the program.

Most Medicaid adult enrollees do work, go to school, or are too sick to work, studies show.

Indiana also has a long list of exemptions and alternatives to employment. This includes attending school or job training, volunteering or caring for a dependent child or disabled parent. Nurses, doctors and physician assistants can give enrollees an exemption due to illness or injury.

Three patient advocacy groups have filed suit in federal court seeking to block the work requirements.

Robin Rudowitz, associate director for the Kaiser Family Foundation’s Program on Medicaid and the Uninsured, said it’s difficult to gauge whether work requirements or renewal lockouts will have more of an impact on coverage. She noted both provisions apply to most demonstration beneficiaries. (KHN is an editorially independent program of the foundation).

“Any documentation requirement could lead to increased complexity in terms of states administering the requirements and individuals complying,” she said, adding that it could result “in potentially eligible people falling off of coverage.”
 

Kaiser Health News (KHN) is a national health policy news service. It is an editorially independent program of the Henry J. Kaiser Family Foundation which is not affiliated with Kaiser Permanente.

Indiana is the second state to win federal approval to add a work requirement for adult Medicaid recipients who gained coverage under the Affordable Care Act, but a less debated “lockout” provision in its new plan could lead to tens of thousands of enrollees losing coverage.

The federal approval was announced Feb. 2 by Health & Human Services Secretary Alex Azar in Indianapolis.

Medicaid participants who fail to submit their paperwork in a timely manner showing that they still qualify for the program will be blocked from enrollment for 3 months, according to the updated rules.

Since November 2015, more than 91,000 enrollees in Indiana were kicked off Medicaid for failing to complete the eligibility redetermination process, according to state records. The process requires applicants to show proof of income and family size, among other things, to see if they still qualify for the coverage. Until now, these enrollees could simply reapply anytime. Although many of those people likely were no longer eligible, state officials estimate about half of those who failed to comply with its reenrollment rules were still qualified.

Indiana’s Medicaid expansion began in February 2015, providing coverage to 240,000 people who were previously uninsured, helping drop the state’s uninsured rate from 14% in 2013 to 8% last year. The HHS approval extends the program, which was expiring this month, through 2020.

The new lockout builds on one already in place for Indiana residents who failed to pay monthly premiums and had annual incomes above the federal poverty level, or about $12,200 for an individual. They are barred for 6 months from coverage. During the first 2 years of the experiment, about 10,000 Indiana Medicaid enrollees were subject to the lockout for failing to pay the premium for 2 months in a row, according to state data.

In addition, more than 25,000 enrollees were dropped from the program after they failed to make the payments, although half of them found another source of coverage, usually through their jobs.

Another 46,000 were blocked from coverage because they failed to make the initial payment.

“The ‘lockout” is one of the worst policies to hit Medicaid in a long time,” said Joan Alker, executive director of the Georgetown University Center for Children and Families, in Washington. “Forcing people to remain uninsured for months because they missed a paperwork deadline or missed a premium payment is too high a price to pay. From a health policy perspective, it makes no sense because during that period, chronic health conditions such as hypertension or diabetes are just likely to worsen.”

Indiana’s Medicaid expansion is being closely watched in part because it was spearheaded by then-governor Mike Pence, who is now vice president, and his top health consultant, Seema Verma, who now heads the federal Centers for Medicare & Medicaid Services.

The expansion, known as Healthy Indiana, enabled nondisabled adults access to Medicaid. It has elicited criticism from patient advocates for complex and onerous rules that require these poor adults to make payments ranging from $1 to $27 per month into health savings accounts or risk losing their vision and dental benefits or even all their coverage, depending on their income level.

Indiana Medicaid officials said they added the newest lockout provision in an effort to prompt enrollees to get their paperwork submitted in time. The state initially requested a 6-month lockout.

“Enforcement may encourage better compliance,” the state officials wrote in their waiver application to CMS in July.

The new rule will lead to a 1% cut in Medicaid enrollment in the first year, state officials said. It will also lead to a $15 million reduction in Medicaid costs in 2018 and about $32 million in savings in 2019, the state estimated.

The number of Medicaid enrollees losing coverage for failing to comply with redetermining their eligibility has varied dramatically each quarter from a peak of 19,197 from February 2016 to April 2017 to 1,165 from November 2015 to January 2016, state reports show. In the latest state report, 12,470 enrollees lost coverage from August to October 2017.

The Kentucky Medicaid waiver approved by the Trump administration in January included a similar lockout provision for both failing to pay the monthly premiums or providing paperwork on time. Penalties there are 6 months for both measures. But the provision was overshadowed because of the attention to the first federal approval for a Medicaid work requirement.

Like Kentucky, Indiana’s Medicaid waiver’s work requirements, which mandate adult enrollees to work an average of 20 hours a month, go into effect in 2019. But Indiana’s waiver is more lenient. It exempts people aged 60 years and older and its work-hour requirements are gradually phased in over 18 months. For example, enrollees need to work only 5 hours per week until their 10th month on the program.

Most Medicaid adult enrollees do work, go to school, or are too sick to work, studies show.

Indiana also has a long list of exemptions and alternatives to employment. This includes attending school or job training, volunteering or caring for a dependent child or disabled parent. Nurses, doctors and physician assistants can give enrollees an exemption due to illness or injury.

Three patient advocacy groups have filed suit in federal court seeking to block the work requirements.

Robin Rudowitz, associate director for the Kaiser Family Foundation’s Program on Medicaid and the Uninsured, said it’s difficult to gauge whether work requirements or renewal lockouts will have more of an impact on coverage. She noted both provisions apply to most demonstration beneficiaries. (KHN is an editorially independent program of the foundation).

“Any documentation requirement could lead to increased complexity in terms of states administering the requirements and individuals complying,” she said, adding that it could result “in potentially eligible people falling off of coverage.”
 

Kaiser Health News (KHN) is a national health policy news service. It is an editorially independent program of the Henry J. Kaiser Family Foundation which is not affiliated with Kaiser Permanente.

The 2016 Magnetic Resonance Imaging in Multiple Sclerosis (MAGNIMS) criteria have accuracy similar to that of the 2010 McDonald criteria in predicting the development of clinically definite multiple sclerosis (MS), according to a retrospective study.

“Among the different modifications proposed, our results support removal of the distinction between symptomatic and asymptomatic lesions, which simplifies the clinical use of MRI criteria, and suggest that further consideration be given to increasing the number of lesions needed to define periventricular involvement from one to three, because this might slightly increase specificity,” said Massimo Filippi, MD, of the neuroimaging research unit in the division of neuroscience at San Raffaele Scientific Institute at Vita-Salute San Raffaele University in Milan, and colleagues. The report was published online ahead of print December 21, 2017, in Lancet Neurology. “Further effort is still needed to improve cortical lesion assessment, and more studies should be done to evaluate the effect of including optic nerve assessment as an additional dissemination in space [DIS] criterion.”

An Effort to Draft Revisions

In an effort to guide revisions of MS diagnostic criteria, Dr. Filippi and other members of the MAGNIMS network compared the performance of the 2010 McDonald and 2016 MAGNIMS criteria for MS in a cohort of 368 patients with clinically isolated syndrome (CIS) who were screened between June 16, 1995, and January 27, 2017. They used a time-dependent receiver operating characteristic curve analysis to evaluate MRI criteria performance for DIS, dissemination in time (DIT), and DIS plus DIT. Changes to the DIS definition contained in the 2016 MAGNIMS criteria included removal of the distinction between symptomatic and asymptomatic lesions, increasing the number of lesions needed to define periventricular involvement to three, combining cortical and juxtacortical lesions, and inclusion of optic nerve evaluation. For DIT, removal of the distinction between symptomatic and asymptomatic lesions was suggested.

Dr. Filippi and his coauthors at eight centers reported that 189 (51%) of the 368 patients had developed clinically definite MS by the last evaluation, which occurred at a median of 50 months from baseline. At 36 months, DIS alone showed high sensitivity in the 2010 McDonald and 2016 MAGNIMS criteria (91% vs 93%, respectively), similar specificity (33% vs 32%), and similar area under the curve values (AUC, 0.62 vs 0.63). Inclusion of symptomatic lesions did not alter performance. The researchers also found that requiring three periventricular lesions reduced sensitivity to 85% and increased specificity to 40%, but did not affect AUC values (AUC, 0.63). When optic nerve evaluation was included, sensitivity was similar (92%), while specificity decreased to 26%, and AUC declined to 0.59.

The 2016 MAGNIMS and 2010 McDonald criteria achieved similar sensitivity, specificity, and AUC values when compared on the performance of DIT criteria and DIS plus DIT criteria.

“For both sets of criteria, specificity was lower than that of previous studies that evaluated the diagnostic performance of the 2010 McDonald criteria,” the authors wrote. “Several factors could help explain our findings, including the different follow-up durations, the statistical methods (eg, using a time-to-event analysis in our study), and the effect of treatment, which might have delayed or prevented the occurrence of the second attack during the study period.” They acknowledged certain limitations of the study, including its retrospective design and the fact that patients were recruited in highly specialized centers, which may have resulted in the selection of patients at higher risk of conversion to clinically definite MS.

MRI Abnormalities May Not Indicate MS

As MS diagnosis evolves, revisions to existing diagnostic criteria have increased sensitivity, thus helping clinicians establish earlier diagnoses. Although the study by Dr. Filippi et al showed that for both sets of MRI criteria, sensitivity was greater than specificity for predicting clinically definite MS, the modest specificity is cause for concern, said Anne H. Cross, MD, Head of the Neuroimmunology (MS) Section, and Robert N. Naismith, MD, Associate Professor of Neurology, both at Washington University in St. Louis, in an accompanying editorial. They cited one study that emphasized the importance of not misdiagnosing other CNS diseases as MS. “In that study at four academic medical centers, 110 people seen over a period of less than 1.5 years were found to have been misdiagnosed,” said Drs. Cross and Naismith. “[Seventy percent] of the 110 individuals had received disease-modifying therapy, and 31% had unnecessary morbidity. Leading factors contributing to erroneous diagnosis in the study included overreliance on MRI abnormalities in patients with nonspecific neurologic symptoms.”

Vascular and other diseases can cause MRI abnormalities that could meet the 2016 MAGNIMS recommendations or the 2010 and 2017 McDonald MRI criteria, the authors continued. For example, patients with monophasic inflammatory and infectious diseases might have gadolinium-enhancing lesions that meet the 2017 McDonald criteria for DIT, which require only the simultaneous presence of gadolinium-enhancing and gadolinium-negative lesions in the proper locations. For patients with an atypical presentation who meet the 2010 and 2017 McDonald or 2016 MAGNIMS recommendations, clinicians should weigh all of the observed imaging features (including the number of periventricular lesions, along with lesion size, shape, and location) to improve diagnostic specificity and help to limit misdiagnoses, they concluded.

—Doug Brunk

Suggested Reading

Cross AH, Naismith RT. Refining the use of MRI to predict multiple sclerosis. Lancet Neurol. 2017 Dec 21 [Epub ahead of print].

Filippi M, Preziosa P, Meani A, et al. Prediction of a multiple sclerosis diagnosis in patients with clinically isolated syndrome using the 2016 MAGNIMS and 2010 McDonald criteria: a retrospective study. Lancet Neurol. 2017 Dec 21 [Epub ahead of print].

The 2016 Magnetic Resonance Imaging in Multiple Sclerosis (MAGNIMS) criteria have accuracy similar to that of the 2010 McDonald criteria in predicting the development of clinically definite multiple sclerosis (MS), according to a retrospective study.

“Among the different modifications proposed, our results support removal of the distinction between symptomatic and asymptomatic lesions, which simplifies the clinical use of MRI criteria, and suggest that further consideration be given to increasing the number of lesions needed to define periventricular involvement from one to three, because this might slightly increase specificity,” said Massimo Filippi, MD, of the neuroimaging research unit in the division of neuroscience at San Raffaele Scientific Institute at Vita-Salute San Raffaele University in Milan, and colleagues. The report was published online ahead of print December 21, 2017, in Lancet Neurology. “Further effort is still needed to improve cortical lesion assessment, and more studies should be done to evaluate the effect of including optic nerve assessment as an additional dissemination in space [DIS] criterion.”

An Effort to Draft Revisions

In an effort to guide revisions of MS diagnostic criteria, Dr. Filippi and other members of the MAGNIMS network compared the performance of the 2010 McDonald and 2016 MAGNIMS criteria for MS in a cohort of 368 patients with clinically isolated syndrome (CIS) who were screened between June 16, 1995, and January 27, 2017. They used a time-dependent receiver operating characteristic curve analysis to evaluate MRI criteria performance for DIS, dissemination in time (DIT), and DIS plus DIT. Changes to the DIS definition contained in the 2016 MAGNIMS criteria included removal of the distinction between symptomatic and asymptomatic lesions, increasing the number of lesions needed to define periventricular involvement to three, combining cortical and juxtacortical lesions, and inclusion of optic nerve evaluation. For DIT, removal of the distinction between symptomatic and asymptomatic lesions was suggested.

Dr. Filippi and his coauthors at eight centers reported that 189 (51%) of the 368 patients had developed clinically definite MS by the last evaluation, which occurred at a median of 50 months from baseline. At 36 months, DIS alone showed high sensitivity in the 2010 McDonald and 2016 MAGNIMS criteria (91% vs 93%, respectively), similar specificity (33% vs 32%), and similar area under the curve values (AUC, 0.62 vs 0.63). Inclusion of symptomatic lesions did not alter performance. The researchers also found that requiring three periventricular lesions reduced sensitivity to 85% and increased specificity to 40%, but did not affect AUC values (AUC, 0.63). When optic nerve evaluation was included, sensitivity was similar (92%), while specificity decreased to 26%, and AUC declined to 0.59.

The 2016 MAGNIMS and 2010 McDonald criteria achieved similar sensitivity, specificity, and AUC values when compared on the performance of DIT criteria and DIS plus DIT criteria.

“For both sets of criteria, specificity was lower than that of previous studies that evaluated the diagnostic performance of the 2010 McDonald criteria,” the authors wrote. “Several factors could help explain our findings, including the different follow-up durations, the statistical methods (eg, using a time-to-event analysis in our study), and the effect of treatment, which might have delayed or prevented the occurrence of the second attack during the study period.” They acknowledged certain limitations of the study, including its retrospective design and the fact that patients were recruited in highly specialized centers, which may have resulted in the selection of patients at higher risk of conversion to clinically definite MS.

MRI Abnormalities May Not Indicate MS

As MS diagnosis evolves, revisions to existing diagnostic criteria have increased sensitivity, thus helping clinicians establish earlier diagnoses. Although the study by Dr. Filippi et al showed that for both sets of MRI criteria, sensitivity was greater than specificity for predicting clinically definite MS, the modest specificity is cause for concern, said Anne H. Cross, MD, Head of the Neuroimmunology (MS) Section, and Robert N. Naismith, MD, Associate Professor of Neurology, both at Washington University in St. Louis, in an accompanying editorial. They cited one study that emphasized the importance of not misdiagnosing other CNS diseases as MS. “In that study at four academic medical centers, 110 people seen over a period of less than 1.5 years were found to have been misdiagnosed,” said Drs. Cross and Naismith. “[Seventy percent] of the 110 individuals had received disease-modifying therapy, and 31% had unnecessary morbidity. Leading factors contributing to erroneous diagnosis in the study included overreliance on MRI abnormalities in patients with nonspecific neurologic symptoms.”

Vascular and other diseases can cause MRI abnormalities that could meet the 2016 MAGNIMS recommendations or the 2010 and 2017 McDonald MRI criteria, the authors continued. For example, patients with monophasic inflammatory and infectious diseases might have gadolinium-enhancing lesions that meet the 2017 McDonald criteria for DIT, which require only the simultaneous presence of gadolinium-enhancing and gadolinium-negative lesions in the proper locations. For patients with an atypical presentation who meet the 2010 and 2017 McDonald or 2016 MAGNIMS recommendations, clinicians should weigh all of the observed imaging features (including the number of periventricular lesions, along with lesion size, shape, and location) to improve diagnostic specificity and help to limit misdiagnoses, they concluded.

—Doug Brunk

Suggested Reading

Cross AH, Naismith RT. Refining the use of MRI to predict multiple sclerosis. Lancet Neurol. 2017 Dec 21 [Epub ahead of print].

Filippi M, Preziosa P, Meani A, et al. Prediction of a multiple sclerosis diagnosis in patients with clinically isolated syndrome using the 2016 MAGNIMS and 2010 McDonald criteria: a retrospective study. Lancet Neurol. 2017 Dec 21 [Epub ahead of print].

The 2016 Magnetic Resonance Imaging in Multiple Sclerosis (MAGNIMS) criteria have accuracy similar to that of the 2010 McDonald criteria in predicting the development of clinically definite multiple sclerosis (MS), according to a retrospective study.

“Among the different modifications proposed, our results support removal of the distinction between symptomatic and asymptomatic lesions, which simplifies the clinical use of MRI criteria, and suggest that further consideration be given to increasing the number of lesions needed to define periventricular involvement from one to three, because this might slightly increase specificity,” said Massimo Filippi, MD, of the neuroimaging research unit in the division of neuroscience at San Raffaele Scientific Institute at Vita-Salute San Raffaele University in Milan, and colleagues. The report was published online ahead of print December 21, 2017, in Lancet Neurology. “Further effort is still needed to improve cortical lesion assessment, and more studies should be done to evaluate the effect of including optic nerve assessment as an additional dissemination in space [DIS] criterion.”

An Effort to Draft Revisions

In an effort to guide revisions of MS diagnostic criteria, Dr. Filippi and other members of the MAGNIMS network compared the performance of the 2010 McDonald and 2016 MAGNIMS criteria for MS in a cohort of 368 patients with clinically isolated syndrome (CIS) who were screened between June 16, 1995, and January 27, 2017. They used a time-dependent receiver operating characteristic curve analysis to evaluate MRI criteria performance for DIS, dissemination in time (DIT), and DIS plus DIT. Changes to the DIS definition contained in the 2016 MAGNIMS criteria included removal of the distinction between symptomatic and asymptomatic lesions, increasing the number of lesions needed to define periventricular involvement to three, combining cortical and juxtacortical lesions, and inclusion of optic nerve evaluation. For DIT, removal of the distinction between symptomatic and asymptomatic lesions was suggested.

Dr. Filippi and his coauthors at eight centers reported that 189 (51%) of the 368 patients had developed clinically definite MS by the last evaluation, which occurred at a median of 50 months from baseline. At 36 months, DIS alone showed high sensitivity in the 2010 McDonald and 2016 MAGNIMS criteria (91% vs 93%, respectively), similar specificity (33% vs 32%), and similar area under the curve values (AUC, 0.62 vs 0.63). Inclusion of symptomatic lesions did not alter performance. The researchers also found that requiring three periventricular lesions reduced sensitivity to 85% and increased specificity to 40%, but did not affect AUC values (AUC, 0.63). When optic nerve evaluation was included, sensitivity was similar (92%), while specificity decreased to 26%, and AUC declined to 0.59.

The 2016 MAGNIMS and 2010 McDonald criteria achieved similar sensitivity, specificity, and AUC values when compared on the performance of DIT criteria and DIS plus DIT criteria.

“For both sets of criteria, specificity was lower than that of previous studies that evaluated the diagnostic performance of the 2010 McDonald criteria,” the authors wrote. “Several factors could help explain our findings, including the different follow-up durations, the statistical methods (eg, using a time-to-event analysis in our study), and the effect of treatment, which might have delayed or prevented the occurrence of the second attack during the study period.” They acknowledged certain limitations of the study, including its retrospective design and the fact that patients were recruited in highly specialized centers, which may have resulted in the selection of patients at higher risk of conversion to clinically definite MS.

MRI Abnormalities May Not Indicate MS

As MS diagnosis evolves, revisions to existing diagnostic criteria have increased sensitivity, thus helping clinicians establish earlier diagnoses. Although the study by Dr. Filippi et al showed that for both sets of MRI criteria, sensitivity was greater than specificity for predicting clinically definite MS, the modest specificity is cause for concern, said Anne H. Cross, MD, Head of the Neuroimmunology (MS) Section, and Robert N. Naismith, MD, Associate Professor of Neurology, both at Washington University in St. Louis, in an accompanying editorial. They cited one study that emphasized the importance of not misdiagnosing other CNS diseases as MS. “In that study at four academic medical centers, 110 people seen over a period of less than 1.5 years were found to have been misdiagnosed,” said Drs. Cross and Naismith. “[Seventy percent] of the 110 individuals had received disease-modifying therapy, and 31% had unnecessary morbidity. Leading factors contributing to erroneous diagnosis in the study included overreliance on MRI abnormalities in patients with nonspecific neurologic symptoms.”

Vascular and other diseases can cause MRI abnormalities that could meet the 2016 MAGNIMS recommendations or the 2010 and 2017 McDonald MRI criteria, the authors continued. For example, patients with monophasic inflammatory and infectious diseases might have gadolinium-enhancing lesions that meet the 2017 McDonald criteria for DIT, which require only the simultaneous presence of gadolinium-enhancing and gadolinium-negative lesions in the proper locations. For patients with an atypical presentation who meet the 2010 and 2017 McDonald or 2016 MAGNIMS recommendations, clinicians should weigh all of the observed imaging features (including the number of periventricular lesions, along with lesion size, shape, and location) to improve diagnostic specificity and help to limit misdiagnoses, they concluded.

—Doug Brunk

Suggested Reading

Cross AH, Naismith RT. Refining the use of MRI to predict multiple sclerosis. Lancet Neurol. 2017 Dec 21 [Epub ahead of print].

Filippi M, Preziosa P, Meani A, et al. Prediction of a multiple sclerosis diagnosis in patients with clinically isolated syndrome using the 2016 MAGNIMS and 2010 McDonald criteria: a retrospective study. Lancet Neurol. 2017 Dec 21 [Epub ahead of print].

The term blueberry muffin rash historically was used to describe the cutaneous manifestations observed in congenital rubella. The term traditionally describes the result of a postnatal dermal extramedullary hematopoiesis. Today, TORCH (toxoplasmosis, other agents, rubella, cytomegalovirus, herpes) infections and plasma cell dyscrasias are all potential causes of extramedullary hematopoiesis. Herein, we present a unique case of a neonate born with a blueberry muffin rash secondary to extramedullary hematopoiesis induced by hereditary spherocytosis.

Case Report

The dermatology department was consulted to evaluate a 2-day-old male neonate born with a “rash.” The patient was born to a 34-year-old gravida 3, para 2, woman at 39 weeks’ gestation. The mother’s prenatal laboratory values were within reference range and ultrasounds were normal, and she was compliant with her prenatal care. She underwent a normal spontaneous vaginal delivery 3 hours after rupture of membranes without complication. The amniotic fluid and umbilical cord both were clear. There was no use of forceps or any other external aiding devices during the delivery. At the time of delivery, the consulting physician noted that the patient had “skin lesions from head to toe.”

The patient’s parents reported that the rash did not seem to cause any discomfort for the patient. In the 24 hours after birth, the parents reported that the erythema seemed to slightly fade. Physical examination revealed many scattered erythematous to violaceous, nonblanching papulonodules affecting the scalp (Figure 1), face, arms, hands (Figure 2A), back (Figure 2B), buttocks, legs, and feet. Some of the papulonodules were soft while others were firm and indurated. Several lesions had a yellowish hue with some overlying crust. There was no mucosal, genital, or ocular involvement. No erosions, ulcerations, petechiae, ecchymoses, or hepatosplenomegaly were noted on examination.

The patient was otherwise healthy with an Apgar score of 8/9 at 1 and 5 minutes. His birth weight, length, and head circumference were within normal limits. There was no evidence of ABO blood group or Rhesus factor incompatibility. His temperature, vital signs, laboratory values (including calcium level and TORCH titers, which included cytomegalovirus, rubella, toxoplasmosis, and herpes simplex virus), and review of systems all were within reference range. A bone survey of the skull, spine, ribs, arms, pelvis, legs, and feet was within normal limits.

The mother’s placenta was sent for pathology and revealed a lymphoplasmacytic chronic deciduitis and acute subchorionitis consistent with a nonspecific inflammatory response, unlikely to be from an infectious etiology.

A 4-mm punch biopsy was taken from the left thigh and revealed a predominately lymphocytic infiltrate with rare eosinophils and erythrocyte precursors (Figure 3). Immunohistochemical staining was performed showing that the majority of the lymphocytes represented T lymphocytes, which stained positive for CD45 and CD3 and negative for S-100, CD1a, CD30, and CD117. There were scattered CD34⁺ cells, and scattered cells stained positive for myeloperoxidase. No significant CD20 immunoreactivity was noted. There were scattered eosinophils and rare normoblasts but no megakaryocytes. A complete blood cell count (CBC) with differential and reticulocyte count was within reference range.

At 1-, 3-, 8-, 12-, and 28-week follow-up visits, the patient continued to grow and feed appropriately. No new lesions developed during this time, and the preexisting lesions continued to fade into slightly hyperpigmented patches without induration (Figure 4). At 6 months of age, a CBC performed at the time of an upper respiratory infection and otitis media revealed normocytic anemia with a hemoglobin level of 9.9 g/dL (reference range, 14.0–17.5 g/dL), a reticulocyte count of 0.8% (reference range, 0.5%–1.5%), and a lactate dehydrogenase level of 424 U/L (reference range, 100–200 U/L). All red blood cell (RBC) indices were within reference range. Flow cytometry, eosin-5-maleimide, and ektacytometry were performed with results consistent with mild hereditary spherocytosis.

Comment

Dermal extramedullary hematopoiesis is a normal component of embryologic development up until the fifth month of gestation.¹ The term blueberry muffin rash typically is used to describe the cutaneous manifestations of extramedullary hematopoiesis, which commonly is caused by a TORCH infection or hematologic dyscrasia.² It has been suggested that the term be expanded to include neoplastic processes (eg, neuroblastomas) and vascular processes (eg, multiple hemangiomas, blue rubber bleb nevus syndrome, glomangiomas, multifocal lymphangionendotheliomatosis), which although not associated with an extramedullary hematopoiesis, can clinically resemble a blueberry muffin rash.

Because of the potential for serious systemic complications, a cause must be sought for all newborns presenting with a blueberry muffin rash. Our patient’s lack of cardiovascular, otic, and ocular involvement combined with a negative TORCH screen and normal CBC strongly suggested against a TORCH infection. In addition, a normal bone survey and CBC, as well as a lack of petechiae, ecchymoses, and hepatosplenomegaly, were evidence against congenital leukemia.³ With the spontaneously resolving lesions and apparent clinical resolution, a bone marrow biopsy was not performed. The skin biopsy revealed negative staining for S-100 and CD1a, making the diagnosis of congenital self-healing reticulohistiocytosis unlikely. No panniculitis was noted and calcium levels were normal, ruling out subcutaneous fat necrosis of the newborn. The predominantly T-cell lymphocytic infiltrate demonstrated on skin biopsy led us to a differential diagnosis of aleukemic leukemia cutis versus idiopathic dermal extramedullary hematopoiesis; however, normocytic anemia was later identified when the patient’s hemoglobin level dropped to 9.9 g/dL. The abnormal eosin-5-maleimide and ektacytometry results unmasked a hereditary spherocytosis.

Hereditary spherocytosis typically is inherited in an autosomal-dominant manner and may be caused by mutations in ankyrin-1, band 3, spectrin, or protein 4.2 on the erythrocyte membrane. It is the third leading cause of hemolytic anemia in newborns and the leading cause of direct Coombs-negative hemolytic anemia requiring blood transfusion in neonates. It is most common in neonates of Northern European ancestry, affecting 1 in every 1000 to 2000 births.⁴ Presentation may range from asymptomatic to severe anemia with hydrops fetalis. Most neonates have an elevated mean corpuscular hemoglobin and low mean corpuscular volume. Acute illness may cause hemolytic or aplastic crises, possibly explaining our patient’s normocytic anemia discovered on a CBC during an episode of an upper respiratory infection and otitis media.

Treatment options for hereditary spherocytosis include phototherapy for jaundiced neonates, folate supplementation, packed erythrocyte transfusions for symptomatic anemia, and recombinant erythropoietin in neonates.⁴ Splenectomy is curative for the majority of patients and requires immunization against Streptococcus pneumoniae, Haemophilus influenzae type b, and Neisseria meningitidis several weeks preoperatively. Patients with symptomatic gallstones may be treated with cholecystectomy at the time of splenectomy or by laparoscopic cholecystectomy, endoscopic sphincterotomy, cholecystostomy, or extracorporeal cholecystolithotripsy.⁵

Although a PubMed search of articles indexed for MEDLINE using the terms dermal hematopoiesis, extramedullary hematopoiesis, hereditary spherocytosis, and blueberry muffin rash yielded only 1 other known case of blueberry muffin rash caused by hereditary spherocytosis,⁶ other case reports demonstrate extramedullary hematopoiesis in hereditary spherocytosis patients in locations other than the skin. Calhoun et al⁷ described a case of a 9-year-old boy with hereditary spherocytosis who presented with jaundice. Pathologic examination revealed a 5-cm suprarenal mass demonstrating extramedullary hematopoiesis.⁷ A case reported by Xiros et al⁸ described a 64-year-old man with a history of hereditary spherocytosis who presented with hemothorax from paravertebral extramedullary hematopoiesis. De Backer et al⁹ reported a case of a 60-year-old man diagnosed with hereditary spherocytosis after an abnormal CBC who was subsequently found to have paravertebral masses containing extramedullary hematopoiesis.

There is one known case of a blueberry muffin rash caused by hereditary spherocytosis.⁶ A female neonate was born at 38 weeks’ gestation with multiple petechiae and faint purpuric papules. Initial complications included intracranial ventricular hemorrhage, hyperbilirubinemia, and anemia requiring blood transfusions on the first day of life. TORCH titers were negative and a skin biopsy demonstrated a diffuse infiltrate of mature RBCs, normoblasts, and pronormoblasts in the reticular dermis. She was healthy until 3 months of age when she had several days of vomiting and diarrhea. Laboratory workup revealed a hematocrit level of 20.5% (reference range, 41%–50%); a reticulocyte count of 22.6% (reference range, 0.5%–1.5%); and a peripheral blood smear demonstrating polychromatophilia, anisocytosis, and spherocytosis. She was then diagnosed with hereditary spherocytosis.⁶

Hereditary spherocytosis is a known, albeit rare, cause of extramedullary hematopoiesis presenting as blueberry muffin rash. Patients with mild hereditary spherocytosis may have a compensated hemolysis without anemia or spherocytes on peripheral smear, which may explain the lack of severe hemolytic anemia or RBC-predominant pathology in our patient.⁵ Argyle and Zone⁶ proposed that severe hemolysis and hypoxia were the cause of extramedullary hematopoiesis in their patient. Because our patient did not experience a notable hemolytic episode until he had an upper respiratory infection and otitis media at 6 months of age, the pathophysiology is less clear; a compensated hemolytic process may underlie the extramedullary hematopoiesis and normal RBC indices.

Regardless of the precise cause of extramedullary hematopoiesis in our patient, this case of a T lymphocyte–dominant cutaneous infiltrate in a patient with mild hereditary spherocytosis is exceptionally rare and leads us to consider that perhaps there are causes of this pathology that are unknown to us.

The term blueberry muffin rash historically was used to describe the cutaneous manifestations observed in congenital rubella. The term traditionally describes the result of a postnatal dermal extramedullary hematopoiesis. Today, TORCH (toxoplasmosis, other agents, rubella, cytomegalovirus, herpes) infections and plasma cell dyscrasias are all potential causes of extramedullary hematopoiesis. Herein, we present a unique case of a neonate born with a blueberry muffin rash secondary to extramedullary hematopoiesis induced by hereditary spherocytosis.

Case Report

The dermatology department was consulted to evaluate a 2-day-old male neonate born with a “rash.” The patient was born to a 34-year-old gravida 3, para 2, woman at 39 weeks’ gestation. The mother’s prenatal laboratory values were within reference range and ultrasounds were normal, and she was compliant with her prenatal care. She underwent a normal spontaneous vaginal delivery 3 hours after rupture of membranes without complication. The amniotic fluid and umbilical cord both were clear. There was no use of forceps or any other external aiding devices during the delivery. At the time of delivery, the consulting physician noted that the patient had “skin lesions from head to toe.”

The patient’s parents reported that the rash did not seem to cause any discomfort for the patient. In the 24 hours after birth, the parents reported that the erythema seemed to slightly fade. Physical examination revealed many scattered erythematous to violaceous, nonblanching papulonodules affecting the scalp (Figure 1), face, arms, hands (Figure 2A), back (Figure 2B), buttocks, legs, and feet. Some of the papulonodules were soft while others were firm and indurated. Several lesions had a yellowish hue with some overlying crust. There was no mucosal, genital, or ocular involvement. No erosions, ulcerations, petechiae, ecchymoses, or hepatosplenomegaly were noted on examination.

The patient was otherwise healthy with an Apgar score of 8/9 at 1 and 5 minutes. His birth weight, length, and head circumference were within normal limits. There was no evidence of ABO blood group or Rhesus factor incompatibility. His temperature, vital signs, laboratory values (including calcium level and TORCH titers, which included cytomegalovirus, rubella, toxoplasmosis, and herpes simplex virus), and review of systems all were within reference range. A bone survey of the skull, spine, ribs, arms, pelvis, legs, and feet was within normal limits.

The mother’s placenta was sent for pathology and revealed a lymphoplasmacytic chronic deciduitis and acute subchorionitis consistent with a nonspecific inflammatory response, unlikely to be from an infectious etiology.

A 4-mm punch biopsy was taken from the left thigh and revealed a predominately lymphocytic infiltrate with rare eosinophils and erythrocyte precursors (Figure 3). Immunohistochemical staining was performed showing that the majority of the lymphocytes represented T lymphocytes, which stained positive for CD45 and CD3 and negative for S-100, CD1a, CD30, and CD117. There were scattered CD34⁺ cells, and scattered cells stained positive for myeloperoxidase. No significant CD20 immunoreactivity was noted. There were scattered eosinophils and rare normoblasts but no megakaryocytes. A complete blood cell count (CBC) with differential and reticulocyte count was within reference range.

At 1-, 3-, 8-, 12-, and 28-week follow-up visits, the patient continued to grow and feed appropriately. No new lesions developed during this time, and the preexisting lesions continued to fade into slightly hyperpigmented patches without induration (Figure 4). At 6 months of age, a CBC performed at the time of an upper respiratory infection and otitis media revealed normocytic anemia with a hemoglobin level of 9.9 g/dL (reference range, 14.0–17.5 g/dL), a reticulocyte count of 0.8% (reference range, 0.5%–1.5%), and a lactate dehydrogenase level of 424 U/L (reference range, 100–200 U/L). All red blood cell (RBC) indices were within reference range. Flow cytometry, eosin-5-maleimide, and ektacytometry were performed with results consistent with mild hereditary spherocytosis.

Comment

Dermal extramedullary hematopoiesis is a normal component of embryologic development up until the fifth month of gestation.¹ The term blueberry muffin rash typically is used to describe the cutaneous manifestations of extramedullary hematopoiesis, which commonly is caused by a TORCH infection or hematologic dyscrasia.² It has been suggested that the term be expanded to include neoplastic processes (eg, neuroblastomas) and vascular processes (eg, multiple hemangiomas, blue rubber bleb nevus syndrome, glomangiomas, multifocal lymphangionendotheliomatosis), which although not associated with an extramedullary hematopoiesis, can clinically resemble a blueberry muffin rash.

Because of the potential for serious systemic complications, a cause must be sought for all newborns presenting with a blueberry muffin rash. Our patient’s lack of cardiovascular, otic, and ocular involvement combined with a negative TORCH screen and normal CBC strongly suggested against a TORCH infection. In addition, a normal bone survey and CBC, as well as a lack of petechiae, ecchymoses, and hepatosplenomegaly, were evidence against congenital leukemia.³ With the spontaneously resolving lesions and apparent clinical resolution, a bone marrow biopsy was not performed. The skin biopsy revealed negative staining for S-100 and CD1a, making the diagnosis of congenital self-healing reticulohistiocytosis unlikely. No panniculitis was noted and calcium levels were normal, ruling out subcutaneous fat necrosis of the newborn. The predominantly T-cell lymphocytic infiltrate demonstrated on skin biopsy led us to a differential diagnosis of aleukemic leukemia cutis versus idiopathic dermal extramedullary hematopoiesis; however, normocytic anemia was later identified when the patient’s hemoglobin level dropped to 9.9 g/dL. The abnormal eosin-5-maleimide and ektacytometry results unmasked a hereditary spherocytosis.

Hereditary spherocytosis typically is inherited in an autosomal-dominant manner and may be caused by mutations in ankyrin-1, band 3, spectrin, or protein 4.2 on the erythrocyte membrane. It is the third leading cause of hemolytic anemia in newborns and the leading cause of direct Coombs-negative hemolytic anemia requiring blood transfusion in neonates. It is most common in neonates of Northern European ancestry, affecting 1 in every 1000 to 2000 births.⁴ Presentation may range from asymptomatic to severe anemia with hydrops fetalis. Most neonates have an elevated mean corpuscular hemoglobin and low mean corpuscular volume. Acute illness may cause hemolytic or aplastic crises, possibly explaining our patient’s normocytic anemia discovered on a CBC during an episode of an upper respiratory infection and otitis media.

Treatment options for hereditary spherocytosis include phototherapy for jaundiced neonates, folate supplementation, packed erythrocyte transfusions for symptomatic anemia, and recombinant erythropoietin in neonates.⁴ Splenectomy is curative for the majority of patients and requires immunization against Streptococcus pneumoniae, Haemophilus influenzae type b, and Neisseria meningitidis several weeks preoperatively. Patients with symptomatic gallstones may be treated with cholecystectomy at the time of splenectomy or by laparoscopic cholecystectomy, endoscopic sphincterotomy, cholecystostomy, or extracorporeal cholecystolithotripsy.⁵

Although a PubMed search of articles indexed for MEDLINE using the terms dermal hematopoiesis, extramedullary hematopoiesis, hereditary spherocytosis, and blueberry muffin rash yielded only 1 other known case of blueberry muffin rash caused by hereditary spherocytosis,⁶ other case reports demonstrate extramedullary hematopoiesis in hereditary spherocytosis patients in locations other than the skin. Calhoun et al⁷ described a case of a 9-year-old boy with hereditary spherocytosis who presented with jaundice. Pathologic examination revealed a 5-cm suprarenal mass demonstrating extramedullary hematopoiesis.⁷ A case reported by Xiros et al⁸ described a 64-year-old man with a history of hereditary spherocytosis who presented with hemothorax from paravertebral extramedullary hematopoiesis. De Backer et al⁹ reported a case of a 60-year-old man diagnosed with hereditary spherocytosis after an abnormal CBC who was subsequently found to have paravertebral masses containing extramedullary hematopoiesis.

There is one known case of a blueberry muffin rash caused by hereditary spherocytosis.⁶ A female neonate was born at 38 weeks’ gestation with multiple petechiae and faint purpuric papules. Initial complications included intracranial ventricular hemorrhage, hyperbilirubinemia, and anemia requiring blood transfusions on the first day of life. TORCH titers were negative and a skin biopsy demonstrated a diffuse infiltrate of mature RBCs, normoblasts, and pronormoblasts in the reticular dermis. She was healthy until 3 months of age when she had several days of vomiting and diarrhea. Laboratory workup revealed a hematocrit level of 20.5% (reference range, 41%–50%); a reticulocyte count of 22.6% (reference range, 0.5%–1.5%); and a peripheral blood smear demonstrating polychromatophilia, anisocytosis, and spherocytosis. She was then diagnosed with hereditary spherocytosis.⁶

Hereditary spherocytosis is a known, albeit rare, cause of extramedullary hematopoiesis presenting as blueberry muffin rash. Patients with mild hereditary spherocytosis may have a compensated hemolysis without anemia or spherocytes on peripheral smear, which may explain the lack of severe hemolytic anemia or RBC-predominant pathology in our patient.⁵ Argyle and Zone⁶ proposed that severe hemolysis and hypoxia were the cause of extramedullary hematopoiesis in their patient. Because our patient did not experience a notable hemolytic episode until he had an upper respiratory infection and otitis media at 6 months of age, the pathophysiology is less clear; a compensated hemolytic process may underlie the extramedullary hematopoiesis and normal RBC indices.

Regardless of the precise cause of extramedullary hematopoiesis in our patient, this case of a T lymphocyte–dominant cutaneous infiltrate in a patient with mild hereditary spherocytosis is exceptionally rare and leads us to consider that perhaps there are causes of this pathology that are unknown to us.

The term blueberry muffin rash historically was used to describe the cutaneous manifestations observed in congenital rubella. The term traditionally describes the result of a postnatal dermal extramedullary hematopoiesis. Today, TORCH (toxoplasmosis, other agents, rubella, cytomegalovirus, herpes) infections and plasma cell dyscrasias are all potential causes of extramedullary hematopoiesis. Herein, we present a unique case of a neonate born with a blueberry muffin rash secondary to extramedullary hematopoiesis induced by hereditary spherocytosis.

Case Report

The dermatology department was consulted to evaluate a 2-day-old male neonate born with a “rash.” The patient was born to a 34-year-old gravida 3, para 2, woman at 39 weeks’ gestation. The mother’s prenatal laboratory values were within reference range and ultrasounds were normal, and she was compliant with her prenatal care. She underwent a normal spontaneous vaginal delivery 3 hours after rupture of membranes without complication. The amniotic fluid and umbilical cord both were clear. There was no use of forceps or any other external aiding devices during the delivery. At the time of delivery, the consulting physician noted that the patient had “skin lesions from head to toe.”

The patient’s parents reported that the rash did not seem to cause any discomfort for the patient. In the 24 hours after birth, the parents reported that the erythema seemed to slightly fade. Physical examination revealed many scattered erythematous to violaceous, nonblanching papulonodules affecting the scalp (Figure 1), face, arms, hands (Figure 2A), back (Figure 2B), buttocks, legs, and feet. Some of the papulonodules were soft while others were firm and indurated. Several lesions had a yellowish hue with some overlying crust. There was no mucosal, genital, or ocular involvement. No erosions, ulcerations, petechiae, ecchymoses, or hepatosplenomegaly were noted on examination.

The patient was otherwise healthy with an Apgar score of 8/9 at 1 and 5 minutes. His birth weight, length, and head circumference were within normal limits. There was no evidence of ABO blood group or Rhesus factor incompatibility. His temperature, vital signs, laboratory values (including calcium level and TORCH titers, which included cytomegalovirus, rubella, toxoplasmosis, and herpes simplex virus), and review of systems all were within reference range. A bone survey of the skull, spine, ribs, arms, pelvis, legs, and feet was within normal limits.

The mother’s placenta was sent for pathology and revealed a lymphoplasmacytic chronic deciduitis and acute subchorionitis consistent with a nonspecific inflammatory response, unlikely to be from an infectious etiology.

A 4-mm punch biopsy was taken from the left thigh and revealed a predominately lymphocytic infiltrate with rare eosinophils and erythrocyte precursors (Figure 3). Immunohistochemical staining was performed showing that the majority of the lymphocytes represented T lymphocytes, which stained positive for CD45 and CD3 and negative for S-100, CD1a, CD30, and CD117. There were scattered CD34⁺ cells, and scattered cells stained positive for myeloperoxidase. No significant CD20 immunoreactivity was noted. There were scattered eosinophils and rare normoblasts but no megakaryocytes. A complete blood cell count (CBC) with differential and reticulocyte count was within reference range.

At 1-, 3-, 8-, 12-, and 28-week follow-up visits, the patient continued to grow and feed appropriately. No new lesions developed during this time, and the preexisting lesions continued to fade into slightly hyperpigmented patches without induration (Figure 4). At 6 months of age, a CBC performed at the time of an upper respiratory infection and otitis media revealed normocytic anemia with a hemoglobin level of 9.9 g/dL (reference range, 14.0–17.5 g/dL), a reticulocyte count of 0.8% (reference range, 0.5%–1.5%), and a lactate dehydrogenase level of 424 U/L (reference range, 100–200 U/L). All red blood cell (RBC) indices were within reference range. Flow cytometry, eosin-5-maleimide, and ektacytometry were performed with results consistent with mild hereditary spherocytosis.

Comment

Dermal extramedullary hematopoiesis is a normal component of embryologic development up until the fifth month of gestation.¹ The term blueberry muffin rash typically is used to describe the cutaneous manifestations of extramedullary hematopoiesis, which commonly is caused by a TORCH infection or hematologic dyscrasia.² It has been suggested that the term be expanded to include neoplastic processes (eg, neuroblastomas) and vascular processes (eg, multiple hemangiomas, blue rubber bleb nevus syndrome, glomangiomas, multifocal lymphangionendotheliomatosis), which although not associated with an extramedullary hematopoiesis, can clinically resemble a blueberry muffin rash.

Because of the potential for serious systemic complications, a cause must be sought for all newborns presenting with a blueberry muffin rash. Our patient’s lack of cardiovascular, otic, and ocular involvement combined with a negative TORCH screen and normal CBC strongly suggested against a TORCH infection. In addition, a normal bone survey and CBC, as well as a lack of petechiae, ecchymoses, and hepatosplenomegaly, were evidence against congenital leukemia.³ With the spontaneously resolving lesions and apparent clinical resolution, a bone marrow biopsy was not performed. The skin biopsy revealed negative staining for S-100 and CD1a, making the diagnosis of congenital self-healing reticulohistiocytosis unlikely. No panniculitis was noted and calcium levels were normal, ruling out subcutaneous fat necrosis of the newborn. The predominantly T-cell lymphocytic infiltrate demonstrated on skin biopsy led us to a differential diagnosis of aleukemic leukemia cutis versus idiopathic dermal extramedullary hematopoiesis; however, normocytic anemia was later identified when the patient’s hemoglobin level dropped to 9.9 g/dL. The abnormal eosin-5-maleimide and ektacytometry results unmasked a hereditary spherocytosis.

Hereditary spherocytosis typically is inherited in an autosomal-dominant manner and may be caused by mutations in ankyrin-1, band 3, spectrin, or protein 4.2 on the erythrocyte membrane. It is the third leading cause of hemolytic anemia in newborns and the leading cause of direct Coombs-negative hemolytic anemia requiring blood transfusion in neonates. It is most common in neonates of Northern European ancestry, affecting 1 in every 1000 to 2000 births.⁴ Presentation may range from asymptomatic to severe anemia with hydrops fetalis. Most neonates have an elevated mean corpuscular hemoglobin and low mean corpuscular volume. Acute illness may cause hemolytic or aplastic crises, possibly explaining our patient’s normocytic anemia discovered on a CBC during an episode of an upper respiratory infection and otitis media.

Treatment options for hereditary spherocytosis include phototherapy for jaundiced neonates, folate supplementation, packed erythrocyte transfusions for symptomatic anemia, and recombinant erythropoietin in neonates.⁴ Splenectomy is curative for the majority of patients and requires immunization against Streptococcus pneumoniae, Haemophilus influenzae type b, and Neisseria meningitidis several weeks preoperatively. Patients with symptomatic gallstones may be treated with cholecystectomy at the time of splenectomy or by laparoscopic cholecystectomy, endoscopic sphincterotomy, cholecystostomy, or extracorporeal cholecystolithotripsy.⁵

Although a PubMed search of articles indexed for MEDLINE using the terms dermal hematopoiesis, extramedullary hematopoiesis, hereditary spherocytosis, and blueberry muffin rash yielded only 1 other known case of blueberry muffin rash caused by hereditary spherocytosis,⁶ other case reports demonstrate extramedullary hematopoiesis in hereditary spherocytosis patients in locations other than the skin. Calhoun et al⁷ described a case of a 9-year-old boy with hereditary spherocytosis who presented with jaundice. Pathologic examination revealed a 5-cm suprarenal mass demonstrating extramedullary hematopoiesis.⁷ A case reported by Xiros et al⁸ described a 64-year-old man with a history of hereditary spherocytosis who presented with hemothorax from paravertebral extramedullary hematopoiesis. De Backer et al⁹ reported a case of a 60-year-old man diagnosed with hereditary spherocytosis after an abnormal CBC who was subsequently found to have paravertebral masses containing extramedullary hematopoiesis.

There is one known case of a blueberry muffin rash caused by hereditary spherocytosis.⁶ A female neonate was born at 38 weeks’ gestation with multiple petechiae and faint purpuric papules. Initial complications included intracranial ventricular hemorrhage, hyperbilirubinemia, and anemia requiring blood transfusions on the first day of life. TORCH titers were negative and a skin biopsy demonstrated a diffuse infiltrate of mature RBCs, normoblasts, and pronormoblasts in the reticular dermis. She was healthy until 3 months of age when she had several days of vomiting and diarrhea. Laboratory workup revealed a hematocrit level of 20.5% (reference range, 41%–50%); a reticulocyte count of 22.6% (reference range, 0.5%–1.5%); and a peripheral blood smear demonstrating polychromatophilia, anisocytosis, and spherocytosis. She was then diagnosed with hereditary spherocytosis.⁶

Hereditary spherocytosis is a known, albeit rare, cause of extramedullary hematopoiesis presenting as blueberry muffin rash. Patients with mild hereditary spherocytosis may have a compensated hemolysis without anemia or spherocytes on peripheral smear, which may explain the lack of severe hemolytic anemia or RBC-predominant pathology in our patient.⁵ Argyle and Zone⁶ proposed that severe hemolysis and hypoxia were the cause of extramedullary hematopoiesis in their patient. Because our patient did not experience a notable hemolytic episode until he had an upper respiratory infection and otitis media at 6 months of age, the pathophysiology is less clear; a compensated hemolytic process may underlie the extramedullary hematopoiesis and normal RBC indices.

Regardless of the precise cause of extramedullary hematopoiesis in our patient, this case of a T lymphocyte–dominant cutaneous infiltrate in a patient with mild hereditary spherocytosis is exceptionally rare and leads us to consider that perhaps there are causes of this pathology that are unknown to us.

The antiepileptic drug (AED) sodium valproate may reduce the risk of recurrent ischemic stroke, according to data published in the January issue of Stroke. The treatment deserves further evaluation, according to investigators. A randomized controlled trial could confirm its effect on the risk of recurrent stroke, they said.

The Wellcome Trust Case Control Consortium 2 genome-wide association study found an association between a mutation in HDAC9 and an increased risk of ischemic stroke resulting from large artery disease. Valproate is a nonspecific inhibitor of HDAC9 activity and attenuates atherosclerosis in mice deficient in apolipoprotein E. Two large studies found an association between valproate and a decreased risk of incident stroke.

An Analysis of Three Large Cohort Studies

Hugh S. Markus, DM, lead author of the article and a neurologist in the Stroke Research Group at the University of Cambridge in the United Kingdom, and colleagues hypothesized that inhibiting HDAC9 activity could prevent large artery atherosclerotic ischemic stroke. To test this hypothesis, they examined data from three large cohort studies—the South London Stroke Register, the Vitamins to Prevent Stroke Study, and the Oxford Vascular Study. These prospective studies enrolled patients with stroke or transient ischemic attack and had long follow-up periods.

Dr. Markus and colleagues chose recurrent stroke as their primary end point. They examined prescription data for AEDs, as well as other variables such as study, age, sex, and diagnosis of epilepsy. The researchers examined the data using survival analysis and Cox regression.

Valproate Halved Risk of Recurrent Stroke

In all, 11,949 patients were included in the pooled analysis. A total of 168 participants received valproate, and 530 received other AEDs. Recurrent stroke occurred in 17 patients receiving valproate, 1,470 of 11,781 participants who never were prescribed valproate, 105 patients receiving other AEDs, and 1,426 of 11,312 patients not prescribed AEDs.

Throughout follow-up, stroke-free survival was greater among participants receiving valproate than among other participants. At year 15, stroke-free survival was 86% among patients receiving valproate, compared with 74% among patients without valproate exposure.

For nonselective control populations, the difference in survival between valproate exposure and nonexposure was not significant, but the difference between valproate exposure and exposure to other AEDs was significant. For selective control populations, the difference in survival between valproate exposure and no AED exposure was not significant, nor was the difference between valproate exposure and other AED exposure.

Cox hazard models adjusted for all covariates indicated that valproate was associated with a reduced risk of stroke, compared with all patients without valproate exposure (hazard ratio [HR], 0.50). In addition, valproate exposure was associated with reduced risk of stroke, compared with the group prescribed other AEDs (HR, 0.41).

“Although the design of our study is prone to systematic and random error and cannot infer causality, the results provide some evidence for the prestudy hypothesis and suggest that sodium valproate ... may be associated with a reduced stroke recurrence rate,” said Dr. Markus and colleagues. “Sodium valproate is a nonspecific HDAC inhibitor (inhibiting a wide range of HDACs) and has other actions independent of HDAC9 inhibition. Hence, a more specific inhibitor of HDAC9 might have a stronger effect in reducing the risk of recurrent stroke.”

—Erik Greb

Suggested Reading

Brookes RL, Crichton S, Wolfe CDA, et al. Sodium valproate, a histone deacetylase inhibitor, is associated with reduced stroke risk after previous ischemic stroke or transient ischemic attack. Stroke. 2018;49(1):54-61.

The antiepileptic drug (AED) sodium valproate may reduce the risk of recurrent ischemic stroke, according to data published in the January issue of Stroke. The treatment deserves further evaluation, according to investigators. A randomized controlled trial could confirm its effect on the risk of recurrent stroke, they said.

The Wellcome Trust Case Control Consortium 2 genome-wide association study found an association between a mutation in HDAC9 and an increased risk of ischemic stroke resulting from large artery disease. Valproate is a nonspecific inhibitor of HDAC9 activity and attenuates atherosclerosis in mice deficient in apolipoprotein E. Two large studies found an association between valproate and a decreased risk of incident stroke.

An Analysis of Three Large Cohort Studies

Hugh S. Markus, DM, lead author of the article and a neurologist in the Stroke Research Group at the University of Cambridge in the United Kingdom, and colleagues hypothesized that inhibiting HDAC9 activity could prevent large artery atherosclerotic ischemic stroke. To test this hypothesis, they examined data from three large cohort studies—the South London Stroke Register, the Vitamins to Prevent Stroke Study, and the Oxford Vascular Study. These prospective studies enrolled patients with stroke or transient ischemic attack and had long follow-up periods.

Dr. Markus and colleagues chose recurrent stroke as their primary end point. They examined prescription data for AEDs, as well as other variables such as study, age, sex, and diagnosis of epilepsy. The researchers examined the data using survival analysis and Cox regression.

Valproate Halved Risk of Recurrent Stroke

In all, 11,949 patients were included in the pooled analysis. A total of 168 participants received valproate, and 530 received other AEDs. Recurrent stroke occurred in 17 patients receiving valproate, 1,470 of 11,781 participants who never were prescribed valproate, 105 patients receiving other AEDs, and 1,426 of 11,312 patients not prescribed AEDs.

Throughout follow-up, stroke-free survival was greater among participants receiving valproate than among other participants. At year 15, stroke-free survival was 86% among patients receiving valproate, compared with 74% among patients without valproate exposure.

For nonselective control populations, the difference in survival between valproate exposure and nonexposure was not significant, but the difference between valproate exposure and exposure to other AEDs was significant. For selective control populations, the difference in survival between valproate exposure and no AED exposure was not significant, nor was the difference between valproate exposure and other AED exposure.

Cox hazard models adjusted for all covariates indicated that valproate was associated with a reduced risk of stroke, compared with all patients without valproate exposure (hazard ratio [HR], 0.50). In addition, valproate exposure was associated with reduced risk of stroke, compared with the group prescribed other AEDs (HR, 0.41).

“Although the design of our study is prone to systematic and random error and cannot infer causality, the results provide some evidence for the prestudy hypothesis and suggest that sodium valproate ... may be associated with a reduced stroke recurrence rate,” said Dr. Markus and colleagues. “Sodium valproate is a nonspecific HDAC inhibitor (inhibiting a wide range of HDACs) and has other actions independent of HDAC9 inhibition. Hence, a more specific inhibitor of HDAC9 might have a stronger effect in reducing the risk of recurrent stroke.”

—Erik Greb

Suggested Reading

Brookes RL, Crichton S, Wolfe CDA, et al. Sodium valproate, a histone deacetylase inhibitor, is associated with reduced stroke risk after previous ischemic stroke or transient ischemic attack. Stroke. 2018;49(1):54-61.

The antiepileptic drug (AED) sodium valproate may reduce the risk of recurrent ischemic stroke, according to data published in the January issue of Stroke. The treatment deserves further evaluation, according to investigators. A randomized controlled trial could confirm its effect on the risk of recurrent stroke, they said.

The Wellcome Trust Case Control Consortium 2 genome-wide association study found an association between a mutation in HDAC9 and an increased risk of ischemic stroke resulting from large artery disease. Valproate is a nonspecific inhibitor of HDAC9 activity and attenuates atherosclerosis in mice deficient in apolipoprotein E. Two large studies found an association between valproate and a decreased risk of incident stroke.

An Analysis of Three Large Cohort Studies

Hugh S. Markus, DM, lead author of the article and a neurologist in the Stroke Research Group at the University of Cambridge in the United Kingdom, and colleagues hypothesized that inhibiting HDAC9 activity could prevent large artery atherosclerotic ischemic stroke. To test this hypothesis, they examined data from three large cohort studies—the South London Stroke Register, the Vitamins to Prevent Stroke Study, and the Oxford Vascular Study. These prospective studies enrolled patients with stroke or transient ischemic attack and had long follow-up periods.

Dr. Markus and colleagues chose recurrent stroke as their primary end point. They examined prescription data for AEDs, as well as other variables such as study, age, sex, and diagnosis of epilepsy. The researchers examined the data using survival analysis and Cox regression.

Valproate Halved Risk of Recurrent Stroke

In all, 11,949 patients were included in the pooled analysis. A total of 168 participants received valproate, and 530 received other AEDs. Recurrent stroke occurred in 17 patients receiving valproate, 1,470 of 11,781 participants who never were prescribed valproate, 105 patients receiving other AEDs, and 1,426 of 11,312 patients not prescribed AEDs.

Throughout follow-up, stroke-free survival was greater among participants receiving valproate than among other participants. At year 15, stroke-free survival was 86% among patients receiving valproate, compared with 74% among patients without valproate exposure.

For nonselective control populations, the difference in survival between valproate exposure and nonexposure was not significant, but the difference between valproate exposure and exposure to other AEDs was significant. For selective control populations, the difference in survival between valproate exposure and no AED exposure was not significant, nor was the difference between valproate exposure and other AED exposure.

Cox hazard models adjusted for all covariates indicated that valproate was associated with a reduced risk of stroke, compared with all patients without valproate exposure (hazard ratio [HR], 0.50). In addition, valproate exposure was associated with reduced risk of stroke, compared with the group prescribed other AEDs (HR, 0.41).

“Although the design of our study is prone to systematic and random error and cannot infer causality, the results provide some evidence for the prestudy hypothesis and suggest that sodium valproate ... may be associated with a reduced stroke recurrence rate,” said Dr. Markus and colleagues. “Sodium valproate is a nonspecific HDAC inhibitor (inhibiting a wide range of HDACs) and has other actions independent of HDAC9 inhibition. Hence, a more specific inhibitor of HDAC9 might have a stronger effect in reducing the risk of recurrent stroke.”

—Erik Greb

Suggested Reading

Brookes RL, Crichton S, Wolfe CDA, et al. Sodium valproate, a histone deacetylase inhibitor, is associated with reduced stroke risk after previous ischemic stroke or transient ischemic attack. Stroke. 2018;49(1):54-61.

NEW YORK – Anxiety has become a common descriptor for fears, worries, or concerns, but the diagnosis of anxiety as a pathological affective disorder in children requires attention to the age of onset and the types of triggers, according to a presentation at a pediatric psychopharmacology update held by the American Academy of Child and Adolescent Psychiatry.

“Normal anxiety involves predictable triggers like a test in school,” explained John T. Walkup, MD, director of the division of child and adolescent psychiatry at Children’s Hospital, Northwestern University, Chicago. In the absence of the trigger, the symptoms abate or resolve.

Ted Bosworth/Frontline Medical News

AGrigorjeva/Thinkstock

cpnews@frontlinemedcom.com

NEW YORK – Anxiety has become a common descriptor for fears, worries, or concerns, but the diagnosis of anxiety as a pathological affective disorder in children requires attention to the age of onset and the types of triggers, according to a presentation at a pediatric psychopharmacology update held by the American Academy of Child and Adolescent Psychiatry.

“Normal anxiety involves predictable triggers like a test in school,” explained John T. Walkup, MD, director of the division of child and adolescent psychiatry at Children’s Hospital, Northwestern University, Chicago. In the absence of the trigger, the symptoms abate or resolve.

Ted Bosworth/Frontline Medical News

AGrigorjeva/Thinkstock

cpnews@frontlinemedcom.com

NEW YORK – Anxiety has become a common descriptor for fears, worries, or concerns, but the diagnosis of anxiety as a pathological affective disorder in children requires attention to the age of onset and the types of triggers, according to a presentation at a pediatric psychopharmacology update held by the American Academy of Child and Adolescent Psychiatry.

“Normal anxiety involves predictable triggers like a test in school,” explained John T. Walkup, MD, director of the division of child and adolescent psychiatry at Children’s Hospital, Northwestern University, Chicago. In the absence of the trigger, the symptoms abate or resolve.

Ted Bosworth/Frontline Medical News

AGrigorjeva/Thinkstock

cpnews@frontlinemedcom.com

WASHINGTON, DC—In a pediatric epilepsy population, number of antiepileptic drugs (AEDs) used and prior epilepsy surgery may predict sudden unexpected death in epilepsy (SUDEP), according to a study presented at the 71st Annual Meeting of the American Epilepsy Society.

Kishore Vedala, a medical student at the Medical College of Georgia at Augusta University, and colleagues sought to develop a predictive model for at-risk pediatric patients by conducting a matched case–control study.

Using records from the Medical College of Georgia, the researchers identified 11 SUDEP cases that occurred between 2007 and 2017. They compared the cases with 53 controls matched for age, epilepsy duration, and gender. The researchers used a conditional logistic regression model to evaluate the following nine potential predictor variables: mental retardation, seizure frequency, seizure type, prior status epilepticus, number of AEDs, prior epilepsy surgery, vagus nerve stimulator therapy, seizure progression, and awake interictal heart rate variability. They identified the optimum predictor models using Akaike’s information criterion and evaluated model performance using receiver operating characteristic area under the curve (AUC).

Prior status epilepticus (ie, having had a seizure that lasted longer than five minutes), prior epilepsy surgery, and having received three or more AEDs at the same time were significant predictors of SUDEP (odds ratios, 7.83, 4.23, and 4.7, respectively), whereas the other variables were not. The best model used number of AEDs and prior epilepsy surgery (AUC, 0.855). The second-best model used number of AEDs and prior status epilepticus (AUC, 0.839). The third-best model used number of AEDs alone (AUC, 0.807).

—Jake Remaly

WASHINGTON, DC—In a pediatric epilepsy population, number of antiepileptic drugs (AEDs) used and prior epilepsy surgery may predict sudden unexpected death in epilepsy (SUDEP), according to a study presented at the 71st Annual Meeting of the American Epilepsy Society.

Kishore Vedala, a medical student at the Medical College of Georgia at Augusta University, and colleagues sought to develop a predictive model for at-risk pediatric patients by conducting a matched case–control study.

Using records from the Medical College of Georgia, the researchers identified 11 SUDEP cases that occurred between 2007 and 2017. They compared the cases with 53 controls matched for age, epilepsy duration, and gender. The researchers used a conditional logistic regression model to evaluate the following nine potential predictor variables: mental retardation, seizure frequency, seizure type, prior status epilepticus, number of AEDs, prior epilepsy surgery, vagus nerve stimulator therapy, seizure progression, and awake interictal heart rate variability. They identified the optimum predictor models using Akaike’s information criterion and evaluated model performance using receiver operating characteristic area under the curve (AUC).

Prior status epilepticus (ie, having had a seizure that lasted longer than five minutes), prior epilepsy surgery, and having received three or more AEDs at the same time were significant predictors of SUDEP (odds ratios, 7.83, 4.23, and 4.7, respectively), whereas the other variables were not. The best model used number of AEDs and prior epilepsy surgery (AUC, 0.855). The second-best model used number of AEDs and prior status epilepticus (AUC, 0.839). The third-best model used number of AEDs alone (AUC, 0.807).

—Jake Remaly

WASHINGTON, DC—In a pediatric epilepsy population, number of antiepileptic drugs (AEDs) used and prior epilepsy surgery may predict sudden unexpected death in epilepsy (SUDEP), according to a study presented at the 71st Annual Meeting of the American Epilepsy Society.

Kishore Vedala, a medical student at the Medical College of Georgia at Augusta University, and colleagues sought to develop a predictive model for at-risk pediatric patients by conducting a matched case–control study.

Using records from the Medical College of Georgia, the researchers identified 11 SUDEP cases that occurred between 2007 and 2017. They compared the cases with 53 controls matched for age, epilepsy duration, and gender. The researchers used a conditional logistic regression model to evaluate the following nine potential predictor variables: mental retardation, seizure frequency, seizure type, prior status epilepticus, number of AEDs, prior epilepsy surgery, vagus nerve stimulator therapy, seizure progression, and awake interictal heart rate variability. They identified the optimum predictor models using Akaike’s information criterion and evaluated model performance using receiver operating characteristic area under the curve (AUC).

Prior status epilepticus (ie, having had a seizure that lasted longer than five minutes), prior epilepsy surgery, and having received three or more AEDs at the same time were significant predictors of SUDEP (odds ratios, 7.83, 4.23, and 4.7, respectively), whereas the other variables were not. The best model used number of AEDs and prior epilepsy surgery (AUC, 0.855). The second-best model used number of AEDs and prior status epilepticus (AUC, 0.839). The third-best model used number of AEDs alone (AUC, 0.807).

—Jake Remaly

Rituximab is associated with a lower drug discontinuation rate than all other commonly prescribed disease-modifying treatments (DMTs) used as initial therapy for relapsing-remitting multiple sclerosis (MS), according to a retrospective study of patient data from a Swedish MS registry.

In addition, relapse rates were lower with rituximab (Rituxan) than they were with injectable DMTs and dimethyl fumarate (Tecfidera), according to the study, which was published online ahead of print January 8 in JAMA Neurology.

The results suggest that rituximab “can be considered an option” for treatment-naive patients with relapsing-remitting MS, according to Mathias Granqvist, MD, a graduate student in the Department of Clinical Neuroscience at the Karolinska Institute in Stockholm, and his coauthors.

Anti-CD20 agents such as rituximab are “likely to become an additional treatment option” for relapsing-remitting MS, and off-label use of rituximab for this indication has “increased considerably” in Sweden in recent years, the investigators said. Relapsing-remitting MS is not an approved indication for rituximab in the United States, but in Sweden “there is no difference in reimbursement policy ... because all DMTs are covered by the national health insurance, including off-label medications.”

The emergence of new DMTs for relapsing-remitting MS has changed the treatment landscape recently, although in real-world practice, there is a lack of “detailed knowledge about how to tailor therapy,” the authors said. They noted that the majority of patients discontinue traditional first-line treatment with injectable DMTs (ie, interferon beta and glatiramer acetate) within two years, suggesting a need for better treatment options.

To evaluate the real-world effectiveness of rituximab in this setting, Dr. Granqvist and his colleagues selected patient registry data for two Swedish counties that included 494 participants who received a diagnosis of relapsing-remitting MS between January 1, 2012, and October 31, 2015.

The largest subset of patients (215) received injectable DMTs, while 120 received rituximab, 86 received dimethyl fumarate, 50 received natalizumab (Tysabri), 17 received fingolimod (Gilenya), and six received other treatments, according to the authors.

The proportion of patients who stayed on treatment was significantly higher for rituximab versus all other DMTs. Compared with rituximab, the hazard ratios for drug discontinuation, after adjusting for covariates and propensity score, were 11.4 for injectable DMTs, 15.1 for dimethyl fumarate, 5.9 for fingolimod, and 11.3 for natalizumab.

Rituximab-treated patients also had lower rates of clinical relapse, neuroradiologic disease activity, and adverse events, compared with patients who received injectable DMTs or dimethyl fumarate, according to the investigators.

In comparison with fingolimod and natalizumab, rituximab was associated with lower relapse rates and fewer gadolinium-enhancing lesions, but those differences did not reach statistical significance in all analyses.

The study was funded by the Swedish Medical Research Council, among other sources. Study authors reported conflicts of interest related to Biogen, Novartis, and Genzyme.

—Andrew D. Bowser

Suggested Reading

Granqvist M, Boremalm M, Poorghobad A, et al. Comparative effectiveness of rituximab and other initial treatment choices for multiple sclerosis. JAMA Neurol. 2018 Jan 8 [Epub ahead of print].

Rituximab is associated with a lower drug discontinuation rate than all other commonly prescribed disease-modifying treatments (DMTs) used as initial therapy for relapsing-remitting multiple sclerosis (MS), according to a retrospective study of patient data from a Swedish MS registry.

In addition, relapse rates were lower with rituximab (Rituxan) than they were with injectable DMTs and dimethyl fumarate (Tecfidera), according to the study, which was published online ahead of print January 8 in JAMA Neurology.

The results suggest that rituximab “can be considered an option” for treatment-naive patients with relapsing-remitting MS, according to Mathias Granqvist, MD, a graduate student in the Department of Clinical Neuroscience at the Karolinska Institute in Stockholm, and his coauthors.

Anti-CD20 agents such as rituximab are “likely to become an additional treatment option” for relapsing-remitting MS, and off-label use of rituximab for this indication has “increased considerably” in Sweden in recent years, the investigators said. Relapsing-remitting MS is not an approved indication for rituximab in the United States, but in Sweden “there is no difference in reimbursement policy ... because all DMTs are covered by the national health insurance, including off-label medications.”

The emergence of new DMTs for relapsing-remitting MS has changed the treatment landscape recently, although in real-world practice, there is a lack of “detailed knowledge about how to tailor therapy,” the authors said. They noted that the majority of patients discontinue traditional first-line treatment with injectable DMTs (ie, interferon beta and glatiramer acetate) within two years, suggesting a need for better treatment options.

To evaluate the real-world effectiveness of rituximab in this setting, Dr. Granqvist and his colleagues selected patient registry data for two Swedish counties that included 494 participants who received a diagnosis of relapsing-remitting MS between January 1, 2012, and October 31, 2015.

The largest subset of patients (215) received injectable DMTs, while 120 received rituximab, 86 received dimethyl fumarate, 50 received natalizumab (Tysabri), 17 received fingolimod (Gilenya), and six received other treatments, according to the authors.

The proportion of patients who stayed on treatment was significantly higher for rituximab versus all other DMTs. Compared with rituximab, the hazard ratios for drug discontinuation, after adjusting for covariates and propensity score, were 11.4 for injectable DMTs, 15.1 for dimethyl fumarate, 5.9 for fingolimod, and 11.3 for natalizumab.

Rituximab-treated patients also had lower rates of clinical relapse, neuroradiologic disease activity, and adverse events, compared with patients who received injectable DMTs or dimethyl fumarate, according to the investigators.

In comparison with fingolimod and natalizumab, rituximab was associated with lower relapse rates and fewer gadolinium-enhancing lesions, but those differences did not reach statistical significance in all analyses.

The study was funded by the Swedish Medical Research Council, among other sources. Study authors reported conflicts of interest related to Biogen, Novartis, and Genzyme.

—Andrew D. Bowser

Suggested Reading

Granqvist M, Boremalm M, Poorghobad A, et al. Comparative effectiveness of rituximab and other initial treatment choices for multiple sclerosis. JAMA Neurol. 2018 Jan 8 [Epub ahead of print].

Rituximab is associated with a lower drug discontinuation rate than all other commonly prescribed disease-modifying treatments (DMTs) used as initial therapy for relapsing-remitting multiple sclerosis (MS), according to a retrospective study of patient data from a Swedish MS registry.

In addition, relapse rates were lower with rituximab (Rituxan) than they were with injectable DMTs and dimethyl fumarate (Tecfidera), according to the study, which was published online ahead of print January 8 in JAMA Neurology.

The results suggest that rituximab “can be considered an option” for treatment-naive patients with relapsing-remitting MS, according to Mathias Granqvist, MD, a graduate student in the Department of Clinical Neuroscience at the Karolinska Institute in Stockholm, and his coauthors.

Anti-CD20 agents such as rituximab are “likely to become an additional treatment option” for relapsing-remitting MS, and off-label use of rituximab for this indication has “increased considerably” in Sweden in recent years, the investigators said. Relapsing-remitting MS is not an approved indication for rituximab in the United States, but in Sweden “there is no difference in reimbursement policy ... because all DMTs are covered by the national health insurance, including off-label medications.”

The emergence of new DMTs for relapsing-remitting MS has changed the treatment landscape recently, although in real-world practice, there is a lack of “detailed knowledge about how to tailor therapy,” the authors said. They noted that the majority of patients discontinue traditional first-line treatment with injectable DMTs (ie, interferon beta and glatiramer acetate) within two years, suggesting a need for better treatment options.

To evaluate the real-world effectiveness of rituximab in this setting, Dr. Granqvist and his colleagues selected patient registry data for two Swedish counties that included 494 participants who received a diagnosis of relapsing-remitting MS between January 1, 2012, and October 31, 2015.

The largest subset of patients (215) received injectable DMTs, while 120 received rituximab, 86 received dimethyl fumarate, 50 received natalizumab (Tysabri), 17 received fingolimod (Gilenya), and six received other treatments, according to the authors.

The proportion of patients who stayed on treatment was significantly higher for rituximab versus all other DMTs. Compared with rituximab, the hazard ratios for drug discontinuation, after adjusting for covariates and propensity score, were 11.4 for injectable DMTs, 15.1 for dimethyl fumarate, 5.9 for fingolimod, and 11.3 for natalizumab.

Rituximab-treated patients also had lower rates of clinical relapse, neuroradiologic disease activity, and adverse events, compared with patients who received injectable DMTs or dimethyl fumarate, according to the investigators.

In comparison with fingolimod and natalizumab, rituximab was associated with lower relapse rates and fewer gadolinium-enhancing lesions, but those differences did not reach statistical significance in all analyses.

The study was funded by the Swedish Medical Research Council, among other sources. Study authors reported conflicts of interest related to Biogen, Novartis, and Genzyme.

—Andrew D. Bowser

Suggested Reading

Granqvist M, Boremalm M, Poorghobad A, et al. Comparative effectiveness of rituximab and other initial treatment choices for multiple sclerosis. JAMA Neurol. 2018 Jan 8 [Epub ahead of print].

The Diagnosis: Primary Cutaneous Anaplastic Large Cell Lymphoma

Primary cutaneous CD30⁺ lymphoproliferative disorders encompass lymphomatoid papulosis and primary cutaneous anaplastic large cell lymphoma (PCALCL) as well as borderline cases. Primary cutaneous anaplastic large cell lymphoma is a rare disease that is more common in white patients with slight male predominance and median age at diagnosis of 61 years.1 Prognosis is excellent, with a 90% survival rate at 10 years. Although lesions spontaneously regress in 6% to 22% of cases, complete resolution is rare.2 Clinically, the classic presentation is a solitary, rapidly growing, flesh-colored, erythematous nodule or plaque on the arms and legs or trunk, often with ulceration. Proper diagnosis requires clinical, histopathologic, and immunophenotypic correlation.

Histopathologic examination of PCALCL typically reveals large, atypical, Reed-Sternberg-like cells most commonly with anaplastic cytomorphology, but pleomorphic or immunoblastic morphology is not uncommon. Cells are in sheets or nodules, diffusely occupying the dermis and often the subcutaneous fat, with more than 75% of large cells expressing CD30.³ In addition to CD30 positivity, immunophenotype is classically CD4⁺, cutaneous lymphocyte-associated antigen positive, epithelial membrane antigen negative, and anaplastic lymphoma kinase negative; CD2, CD5, and CD3 expression is variable. Interestingly, in our case, there was a minor population of CD8⁺ cells. CD8 expression is seen in less than 5% of PCALCL cases; this phenotype is associated with an indolent disease with favorable prognosis.³ Of note, anaplastic lymphoma kinase positivity corresponding to a t(2;5) translocation is more suggestive of systemic anaplastic large cell lymphoma with secondary skin involvement and more commonly is seen in children. For reasons possibly related to mediators such as epidermal growth factor or transforming growth factor α from CD30⁺ cells, epidermal hyperplasia can be seen in PCALCL.⁴ The subsequent hyperkeratosis, crusting, and ulceration can be difficult to distinguish from lesions such as pyoderma gangrenosum, squamous cell carcinoma, arthropod bite, leukemia cutis, Merkel cell carcinoma (MCC), and metastatic breast cancer.

Skin involvement with leukemia is rare but most commonly is seen in acute myelogenous leukemia, specifically more mature forms such as acute myelomonocytic leukemia and acute monocytic leukemia. Approximately 10% to 20% of acute myelomonocytic leukemia cases have cutaneous involvement.⁵ Although there is a variety of potential skin lesions, the most common is a red-purple papule or nodule, sometimes with hemorrhage or ulceration, on the head, neck, and trunk. Leukemic infiltrates may arise from sites of prior trauma. Histopathology depends on the type of leukemia; however, general features include a normal epidermis without epidermotropism and perivascular, nodular, or diffuse infiltrate of neoplastic cells in the dermis, often with a Grenz zone (Figure 1). Compared to PCALCL, leukemia cutis shows sparing of the papillary dermis (Grenz zone), and the cells have more cytoplasm and show a different immunophenotype. The cells often are fragile and show crush artifact. Acute myelogenous leukemia often will show cytoplasmic granules; however, immature precursor cells may not have granules. The myeloid cells will stain with myeloperoxidase and chloroacetate. Positivity is seen for CD13, CD33, and CD68. Clinical correlation is important because other diseases with nodular or diffuse infiltrates of small cell infiltrates, such as extramedullary hematopoiesis and lymphoma, appear similar. Acute myelogenous leukemia is associated with neutrophilic dermatoses such as Sweet syndrome and pyoderma gangrenosum. Cutaneous eruption resolves with successful treatment of the leukemia.

Breast cancer is the most common cancer to metastasize to the skin in women, accounting for 73% of cutaneous metastases, followed by melanoma, which is responsible for 11%.⁵ The classic presentation is an erythematous patch with spreading borders or a nodule on the trunk. Many cases of metastatic breast cancer with skin involvement may represent direct extension of the cancer into the skin. General histologic clues to cutaneous metastasis include well-circumscribed dermal or subcutaneous nodules of atypical cells with an increase in mitotic activity without connection to the epidermis. Tumor cells may show diffuse, nodular, or single file pattern and may exhibit areas of necrosis. Ductal carcinoma additionally may show ductal or glandular differentiation with surrounding desmoplasia (Figure 2). Immunohistochemistry typically is positive for cytokeratin (CK) 7, estrogen receptor/progesterone receptor, mammaglobin, and gross cystic disease fluid protein-15, and negative for CK20, CK5/6, and thyroid transcription factor-1.

Papulovesicular and nodular lesions appearing as an arthropod bite have been noted in hematologic malignancies, underscoring the importance of histopathology and clinical correlation. Arthropod bites commonly present as red papules, nodules, vesicles, or pustules at the site of the bite. Pseudolymphomatous nodules occasionally develop. Excoriations and further progression to persistent prurigo also may occur. Histopathology shows variable epidermal features including spongiosis, acanthosis, parakeratosis, dermal edema, and superficial and deep perivascular neutrophils (Figure 3). Additionally, lymphocytes sometimes with CD30 positivity may be seen. The presence of eosinophils in interstitial areas, especially in the deep dermis, is a useful clue.

Lack of staining for epithelial and neuroendocrine markers differentiates PCALCL from MCC; specifically CK20, an epithelial marker positive in more than 90% of MCC cases, excludes lymphoma.⁶ Merkel cell carcinoma presents as a solitary, quickly growing, red and often ulcerated nodule or plaque on the head, neck, or legs of elderly patients. The lesions often are in areas of sun damage. Histopathology classically shows a diffuse dermal infiltrate of monotonous round blue cells with a scant cytoplasmic rim and multiple inconspicuous nucleoli in nests, rosettes, or strands in the dermis. There are frequent mitotic figures. The cells are uniform and 2 to 3 times larger than mature lymphocytes. Single-cell necrosis and crush artifact is common. Epidermotropism or coexisting Bowenoid change also may be observed (Figure 4). The term primary neuroendocrine carcinoma of the skin is preferred over Merkel cell carcinoma because the tumor cells share similar morphology to the specialized touch receptor of the basal layer (Merkel cell), but no direct histogenetic relationship has been established.^7,8

Immunohistochemistry is key to diagnosis because MCC stains for both epithelial and neuroendocrine markers. Positivity is seen for neuron-specific enolase, epithelial membrane antigen, neurofilament, synaptophysin, and chromogranin. Because the histology of MCC may resemble small cell carcinoma of the lung, staining for low-molecular-weight keratin such as CK20 and CK7 help to distinguish MCC. Merkel cell carcinoma typically is CK20⁺ and CK7^-, while small cell carcinoma of the lung is the opposite.⁹ The tumor grows aggressively and metastasis is common, thus surgery is the primary approach, but adjuvant chemotherapy and radiation often are given in addition.

The Diagnosis: Primary Cutaneous Anaplastic Large Cell Lymphoma

Primary cutaneous CD30⁺ lymphoproliferative disorders encompass lymphomatoid papulosis and primary cutaneous anaplastic large cell lymphoma (PCALCL) as well as borderline cases. Primary cutaneous anaplastic large cell lymphoma is a rare disease that is more common in white patients with slight male predominance and median age at diagnosis of 61 years.1 Prognosis is excellent, with a 90% survival rate at 10 years. Although lesions spontaneously regress in 6% to 22% of cases, complete resolution is rare.2 Clinically, the classic presentation is a solitary, rapidly growing, flesh-colored, erythematous nodule or plaque on the arms and legs or trunk, often with ulceration. Proper diagnosis requires clinical, histopathologic, and immunophenotypic correlation.

Histopathologic examination of PCALCL typically reveals large, atypical, Reed-Sternberg-like cells most commonly with anaplastic cytomorphology, but pleomorphic or immunoblastic morphology is not uncommon. Cells are in sheets or nodules, diffusely occupying the dermis and often the subcutaneous fat, with more than 75% of large cells expressing CD30.³ In addition to CD30 positivity, immunophenotype is classically CD4⁺, cutaneous lymphocyte-associated antigen positive, epithelial membrane antigen negative, and anaplastic lymphoma kinase negative; CD2, CD5, and CD3 expression is variable. Interestingly, in our case, there was a minor population of CD8⁺ cells. CD8 expression is seen in less than 5% of PCALCL cases; this phenotype is associated with an indolent disease with favorable prognosis.³ Of note, anaplastic lymphoma kinase positivity corresponding to a t(2;5) translocation is more suggestive of systemic anaplastic large cell lymphoma with secondary skin involvement and more commonly is seen in children. For reasons possibly related to mediators such as epidermal growth factor or transforming growth factor α from CD30⁺ cells, epidermal hyperplasia can be seen in PCALCL.⁴ The subsequent hyperkeratosis, crusting, and ulceration can be difficult to distinguish from lesions such as pyoderma gangrenosum, squamous cell carcinoma, arthropod bite, leukemia cutis, Merkel cell carcinoma (MCC), and metastatic breast cancer.

Skin involvement with leukemia is rare but most commonly is seen in acute myelogenous leukemia, specifically more mature forms such as acute myelomonocytic leukemia and acute monocytic leukemia. Approximately 10% to 20% of acute myelomonocytic leukemia cases have cutaneous involvement.⁵ Although there is a variety of potential skin lesions, the most common is a red-purple papule or nodule, sometimes with hemorrhage or ulceration, on the head, neck, and trunk. Leukemic infiltrates may arise from sites of prior trauma. Histopathology depends on the type of leukemia; however, general features include a normal epidermis without epidermotropism and perivascular, nodular, or diffuse infiltrate of neoplastic cells in the dermis, often with a Grenz zone (Figure 1). Compared to PCALCL, leukemia cutis shows sparing of the papillary dermis (Grenz zone), and the cells have more cytoplasm and show a different immunophenotype. The cells often are fragile and show crush artifact. Acute myelogenous leukemia often will show cytoplasmic granules; however, immature precursor cells may not have granules. The myeloid cells will stain with myeloperoxidase and chloroacetate. Positivity is seen for CD13, CD33, and CD68. Clinical correlation is important because other diseases with nodular or diffuse infiltrates of small cell infiltrates, such as extramedullary hematopoiesis and lymphoma, appear similar. Acute myelogenous leukemia is associated with neutrophilic dermatoses such as Sweet syndrome and pyoderma gangrenosum. Cutaneous eruption resolves with successful treatment of the leukemia.

Breast cancer is the most common cancer to metastasize to the skin in women, accounting for 73% of cutaneous metastases, followed by melanoma, which is responsible for 11%.⁵ The classic presentation is an erythematous patch with spreading borders or a nodule on the trunk. Many cases of metastatic breast cancer with skin involvement may represent direct extension of the cancer into the skin. General histologic clues to cutaneous metastasis include well-circumscribed dermal or subcutaneous nodules of atypical cells with an increase in mitotic activity without connection to the epidermis. Tumor cells may show diffuse, nodular, or single file pattern and may exhibit areas of necrosis. Ductal carcinoma additionally may show ductal or glandular differentiation with surrounding desmoplasia (Figure 2). Immunohistochemistry typically is positive for cytokeratin (CK) 7, estrogen receptor/progesterone receptor, mammaglobin, and gross cystic disease fluid protein-15, and negative for CK20, CK5/6, and thyroid transcription factor-1.

Papulovesicular and nodular lesions appearing as an arthropod bite have been noted in hematologic malignancies, underscoring the importance of histopathology and clinical correlation. Arthropod bites commonly present as red papules, nodules, vesicles, or pustules at the site of the bite. Pseudolymphomatous nodules occasionally develop. Excoriations and further progression to persistent prurigo also may occur. Histopathology shows variable epidermal features including spongiosis, acanthosis, parakeratosis, dermal edema, and superficial and deep perivascular neutrophils (Figure 3). Additionally, lymphocytes sometimes with CD30 positivity may be seen. The presence of eosinophils in interstitial areas, especially in the deep dermis, is a useful clue.

Lack of staining for epithelial and neuroendocrine markers differentiates PCALCL from MCC; specifically CK20, an epithelial marker positive in more than 90% of MCC cases, excludes lymphoma.⁶ Merkel cell carcinoma presents as a solitary, quickly growing, red and often ulcerated nodule or plaque on the head, neck, or legs of elderly patients. The lesions often are in areas of sun damage. Histopathology classically shows a diffuse dermal infiltrate of monotonous round blue cells with a scant cytoplasmic rim and multiple inconspicuous nucleoli in nests, rosettes, or strands in the dermis. There are frequent mitotic figures. The cells are uniform and 2 to 3 times larger than mature lymphocytes. Single-cell necrosis and crush artifact is common. Epidermotropism or coexisting Bowenoid change also may be observed (Figure 4). The term primary neuroendocrine carcinoma of the skin is preferred over Merkel cell carcinoma because the tumor cells share similar morphology to the specialized touch receptor of the basal layer (Merkel cell), but no direct histogenetic relationship has been established.^7,8

Immunohistochemistry is key to diagnosis because MCC stains for both epithelial and neuroendocrine markers. Positivity is seen for neuron-specific enolase, epithelial membrane antigen, neurofilament, synaptophysin, and chromogranin. Because the histology of MCC may resemble small cell carcinoma of the lung, staining for low-molecular-weight keratin such as CK20 and CK7 help to distinguish MCC. Merkel cell carcinoma typically is CK20⁺ and CK7^-, while small cell carcinoma of the lung is the opposite.⁹ The tumor grows aggressively and metastasis is common, thus surgery is the primary approach, but adjuvant chemotherapy and radiation often are given in addition.

The Diagnosis: Primary Cutaneous Anaplastic Large Cell Lymphoma

Primary cutaneous CD30⁺ lymphoproliferative disorders encompass lymphomatoid papulosis and primary cutaneous anaplastic large cell lymphoma (PCALCL) as well as borderline cases. Primary cutaneous anaplastic large cell lymphoma is a rare disease that is more common in white patients with slight male predominance and median age at diagnosis of 61 years.1 Prognosis is excellent, with a 90% survival rate at 10 years. Although lesions spontaneously regress in 6% to 22% of cases, complete resolution is rare.2 Clinically, the classic presentation is a solitary, rapidly growing, flesh-colored, erythematous nodule or plaque on the arms and legs or trunk, often with ulceration. Proper diagnosis requires clinical, histopathologic, and immunophenotypic correlation.

Histopathologic examination of PCALCL typically reveals large, atypical, Reed-Sternberg-like cells most commonly with anaplastic cytomorphology, but pleomorphic or immunoblastic morphology is not uncommon. Cells are in sheets or nodules, diffusely occupying the dermis and often the subcutaneous fat, with more than 75% of large cells expressing CD30.³ In addition to CD30 positivity, immunophenotype is classically CD4⁺, cutaneous lymphocyte-associated antigen positive, epithelial membrane antigen negative, and anaplastic lymphoma kinase negative; CD2, CD5, and CD3 expression is variable. Interestingly, in our case, there was a minor population of CD8⁺ cells. CD8 expression is seen in less than 5% of PCALCL cases; this phenotype is associated with an indolent disease with favorable prognosis.³ Of note, anaplastic lymphoma kinase positivity corresponding to a t(2;5) translocation is more suggestive of systemic anaplastic large cell lymphoma with secondary skin involvement and more commonly is seen in children. For reasons possibly related to mediators such as epidermal growth factor or transforming growth factor α from CD30⁺ cells, epidermal hyperplasia can be seen in PCALCL.⁴ The subsequent hyperkeratosis, crusting, and ulceration can be difficult to distinguish from lesions such as pyoderma gangrenosum, squamous cell carcinoma, arthropod bite, leukemia cutis, Merkel cell carcinoma (MCC), and metastatic breast cancer.

Skin involvement with leukemia is rare but most commonly is seen in acute myelogenous leukemia, specifically more mature forms such as acute myelomonocytic leukemia and acute monocytic leukemia. Approximately 10% to 20% of acute myelomonocytic leukemia cases have cutaneous involvement.⁵ Although there is a variety of potential skin lesions, the most common is a red-purple papule or nodule, sometimes with hemorrhage or ulceration, on the head, neck, and trunk. Leukemic infiltrates may arise from sites of prior trauma. Histopathology depends on the type of leukemia; however, general features include a normal epidermis without epidermotropism and perivascular, nodular, or diffuse infiltrate of neoplastic cells in the dermis, often with a Grenz zone (Figure 1). Compared to PCALCL, leukemia cutis shows sparing of the papillary dermis (Grenz zone), and the cells have more cytoplasm and show a different immunophenotype. The cells often are fragile and show crush artifact. Acute myelogenous leukemia often will show cytoplasmic granules; however, immature precursor cells may not have granules. The myeloid cells will stain with myeloperoxidase and chloroacetate. Positivity is seen for CD13, CD33, and CD68. Clinical correlation is important because other diseases with nodular or diffuse infiltrates of small cell infiltrates, such as extramedullary hematopoiesis and lymphoma, appear similar. Acute myelogenous leukemia is associated with neutrophilic dermatoses such as Sweet syndrome and pyoderma gangrenosum. Cutaneous eruption resolves with successful treatment of the leukemia.

Breast cancer is the most common cancer to metastasize to the skin in women, accounting for 73% of cutaneous metastases, followed by melanoma, which is responsible for 11%.⁵ The classic presentation is an erythematous patch with spreading borders or a nodule on the trunk. Many cases of metastatic breast cancer with skin involvement may represent direct extension of the cancer into the skin. General histologic clues to cutaneous metastasis include well-circumscribed dermal or subcutaneous nodules of atypical cells with an increase in mitotic activity without connection to the epidermis. Tumor cells may show diffuse, nodular, or single file pattern and may exhibit areas of necrosis. Ductal carcinoma additionally may show ductal or glandular differentiation with surrounding desmoplasia (Figure 2). Immunohistochemistry typically is positive for cytokeratin (CK) 7, estrogen receptor/progesterone receptor, mammaglobin, and gross cystic disease fluid protein-15, and negative for CK20, CK5/6, and thyroid transcription factor-1.

Papulovesicular and nodular lesions appearing as an arthropod bite have been noted in hematologic malignancies, underscoring the importance of histopathology and clinical correlation. Arthropod bites commonly present as red papules, nodules, vesicles, or pustules at the site of the bite. Pseudolymphomatous nodules occasionally develop. Excoriations and further progression to persistent prurigo also may occur. Histopathology shows variable epidermal features including spongiosis, acanthosis, parakeratosis, dermal edema, and superficial and deep perivascular neutrophils (Figure 3). Additionally, lymphocytes sometimes with CD30 positivity may be seen. The presence of eosinophils in interstitial areas, especially in the deep dermis, is a useful clue.

Lack of staining for epithelial and neuroendocrine markers differentiates PCALCL from MCC; specifically CK20, an epithelial marker positive in more than 90% of MCC cases, excludes lymphoma.⁶ Merkel cell carcinoma presents as a solitary, quickly growing, red and often ulcerated nodule or plaque on the head, neck, or legs of elderly patients. The lesions often are in areas of sun damage. Histopathology classically shows a diffuse dermal infiltrate of monotonous round blue cells with a scant cytoplasmic rim and multiple inconspicuous nucleoli in nests, rosettes, or strands in the dermis. There are frequent mitotic figures. The cells are uniform and 2 to 3 times larger than mature lymphocytes. Single-cell necrosis and crush artifact is common. Epidermotropism or coexisting Bowenoid change also may be observed (Figure 4). The term primary neuroendocrine carcinoma of the skin is preferred over Merkel cell carcinoma because the tumor cells share similar morphology to the specialized touch receptor of the basal layer (Merkel cell), but no direct histogenetic relationship has been established.^7,8

Immunohistochemistry is key to diagnosis because MCC stains for both epithelial and neuroendocrine markers. Positivity is seen for neuron-specific enolase, epithelial membrane antigen, neurofilament, synaptophysin, and chromogranin. Because the histology of MCC may resemble small cell carcinoma of the lung, staining for low-molecular-weight keratin such as CK20 and CK7 help to distinguish MCC. Merkel cell carcinoma typically is CK20⁺ and CK7^-, while small cell carcinoma of the lung is the opposite.⁹ The tumor grows aggressively and metastasis is common, thus surgery is the primary approach, but adjuvant chemotherapy and radiation often are given in addition.

KAUAI, HAWAII – Hilary Baldwin, MD, medical director of the Acne Treatment and Research Center, Morristown, N.J., recently changed how she monitors patients on isotretinoin.

The latest research indicates that ongoing CBCs really aren’t necessary, and that GGT (gamma-glutamyl transferase), which is liver specific, is a far better option than ALT/AST to keep tabs on the liver. Creatine kinase can’t be ignored, either, especially in young, athletic patients, because of the risk of rhabdomyolysis.

In a video interview at the Hawaii Dermatology Seminar provided by Global Academy for Medical Education/Skin Disease Education Foundation, Dr. Baldwin explained the thinking behind her new approach, plus what else needs to be monitored and for how long – and the level of creatine kinase that should raise a red flag for clinicians.

Dr. Baldwin is a speaker, advisor, and/or investigator for a number of companies, including Allergan, Galderma, and La Roche Posay.

SDEF/Global Academy for Medical Education and this news organization are owned by the same parent company.

aotto@frontlinemedcom.com

KAUAI, HAWAII – Hilary Baldwin, MD, medical director of the Acne Treatment and Research Center, Morristown, N.J., recently changed how she monitors patients on isotretinoin.

The latest research indicates that ongoing CBCs really aren’t necessary, and that GGT (gamma-glutamyl transferase), which is liver specific, is a far better option than ALT/AST to keep tabs on the liver. Creatine kinase can’t be ignored, either, especially in young, athletic patients, because of the risk of rhabdomyolysis.

In a video interview at the Hawaii Dermatology Seminar provided by Global Academy for Medical Education/Skin Disease Education Foundation, Dr. Baldwin explained the thinking behind her new approach, plus what else needs to be monitored and for how long – and the level of creatine kinase that should raise a red flag for clinicians.

Dr. Baldwin is a speaker, advisor, and/or investigator for a number of companies, including Allergan, Galderma, and La Roche Posay.

SDEF/Global Academy for Medical Education and this news organization are owned by the same parent company.

aotto@frontlinemedcom.com

KAUAI, HAWAII – Hilary Baldwin, MD, medical director of the Acne Treatment and Research Center, Morristown, N.J., recently changed how she monitors patients on isotretinoin.

The latest research indicates that ongoing CBCs really aren’t necessary, and that GGT (gamma-glutamyl transferase), which is liver specific, is a far better option than ALT/AST to keep tabs on the liver. Creatine kinase can’t be ignored, either, especially in young, athletic patients, because of the risk of rhabdomyolysis.

In a video interview at the Hawaii Dermatology Seminar provided by Global Academy for Medical Education/Skin Disease Education Foundation, Dr. Baldwin explained the thinking behind her new approach, plus what else needs to be monitored and for how long – and the level of creatine kinase that should raise a red flag for clinicians.

Dr. Baldwin is a speaker, advisor, and/or investigator for a number of companies, including Allergan, Galderma, and La Roche Posay.

SDEF/Global Academy for Medical Education and this news organization are owned by the same parent company.

aotto@frontlinemedcom.com