Case Reports

Coronary-subclavian steal syndrome (CSSS) is a rare clinical entity with an incidence of 0.2% to 0.7%.¹ Despite its scarcity, CSSS is a condition that can result in devastating clinical consequences, such as myocardial ischemia, ranging from angina to myocardial infarction (MI) and ischemic cardiomyopathy.²

In 1974, Harjola and Valle first reported the angiographic and physiologic descriptions of CSSS in an asymptomatic patient who was found to have flow reversal in the left internal mammary artery (LIMA) graft in a follow-up coronary angiography performed 11 months after coronary artery bypass grafting (CABG).³ Because of the similarity in the pathophysiology of this condition with vertebral-subclavian steal syndrome, this clinical entity was named coronary-subclavian steal syndrome (CSSS).^4,5

In steal-syndrome phenomena, there is a significant stenosis in the subclavian artery proximal to the origin of an arterial branch, either LIMA or vertebral artery, resulting in lower pressure in the distal subclavian artery. As a result, the negative pressure gradient might be sufficient to cause retrograde flow; consequently causing arterial branch “flow reversal,” and then “steal” flow from the organ—either heart or brain—supplied by that artery.^3,6

Coronary-subclavian steal syndrome is caused by a reversal of flow in a previously constructed internal mammary artery (IMA)-coronary conduit graft. It typically results from hemodynamically significant subclavian artery stenosis proximal to the ipsilateral IMA. The reversal of flow will “steal” the blood from the coronary territory supplied by the IMA conduit.^4,5 The absence of proximal subclavian artery stenosis does not preclude the presence of this syndrome; reversal in the IMA conduit can occur in association with upper extremity hemodialysis fistulae or anomalous connection of the left subclavian artery to the pulmonary artery in d-transposition of the great arteries.² Although the stenosis is most commonly caused by atherosclerotic disease, other clinical entities, including Takayasu vasculitis, radiation, and giant cell arteritis, have been described.⁶ Patients with CSSS usually present with stable or unstable angina as well as arm claudication and various neurologic symptoms.⁵ The consequence of CSSS can include ischemic cardiomyopathy, acute MI,⁷ stroke, and death.^5,8

Case Presentation

A 66-year-old man with a previous MI managed with CABG, permanent atrial fibrillation (AF), and moderate aortic stenosis presented to the ambulatory clinic with recurrent symptoms of stable angina despite being on maximal anti-anginal therapy. A coronary angiogram performed 4 years earlier had revealed significant left main artery disease and total occlusion of the right coronary artery.

Cardiovascular examination revealed an irregular rhythm with a normal S1, variable S2, and a 3/6 systolic ejection murmur heard best at the right second intercostal space with radiation to the carotids. His peripheral pulses were equal and symmetric in the lower extremities, and no peripheral edema was noted. The remainder of the physical examination was otherwise unremarkable. The resting 12-lead electrocardiogram showed AF at a rate of 60 bpm (Figure 1).

A stress test was performed to elucidate a possible coronary distribution for the cause of the chest pain.

Consequently, coronary angiography was performed and showed 95% left main stenosis and total occlusion of the mid-right coronary artery with right dominance, patent LIMA to mid-LAD and patent saphenous venous graft to posterior descending artery grafts (Figure 3)

The patient underwent percutaneous transluminal angioplasty (PTA) of the subclavian stenosis with insertion of an 8 mm x 27 mm balloon-expandable peripheral stent (Figure 5) (Supplemental video 6). The patient tolerated the procedure well without complications and with resolution of his symptoms at a 6-month follow-up.

Discussion

Long-term follow-up of LIMA as a conduit to LAD has shown a 10-year patency of 95% compared with 76% for saphenous vein and an associated 10-year survival of 93.4% for LIMA compared with 88% for saphenous vein graft.^9,10 Because of the superiority of LIMA outcomes, it has become the preferred graft in CABG. However, this approach is associated with 0.1% to 0.2% risk of ischemia related to flow reversal in the LIMA b

Greater awareness and improvement in diagnostic imaging have contributed to the increased incidence of CSSS and its consequences.² Although symptoms related to myocardial ischemia, as in this case, are the most dominant in CSSS, other brachiocephalic symptoms, including vertebral-subclavian steal, transient ischemic attacks, and strokes, have been reported.¹¹ Additionally, the same disease might compromise distal flow, resulting in extremity claudication or even distal microembolization.¹²

It is important to recognize that significant brachiocephalic stenosis has been reported in about 0.2% to 2.5% of patients undergoing elective CABG.^6,8 Therefore, it is essential to screen for brachiocephalic artery disease before undergoing CABG. Different strategies have been suggested, including assessing pressure gradient between the upper extremities as the initial step; CSSS should be considered when the pressure gradient is > 20 mm Hg.

Other strategies include ultrasonic duplex scanning with provocation test using arm exercise or reactive hyperemia.¹³ Many high-volume centers are performing screening by proximal subclavian angiography in all patients undergoing coronary angiography. When significant disease is detected, arch aortography and 4-vessel cerebral angiography is performed.⁶ In addition, other centers have adopted the routine use of computerized tomographic angiography before CABG.¹⁴

Surgical correction of CSSS is considered to be the gold standard and can be accomplished by performing aorta-subclavian bypass, carotid-subclavian bypass, axillo-axillary bypass, or relocation of the IMA graft.² Although this approach is invasive and carries many disadvantages related to patient comfort,surgical revascularization can be performed safely at the time of CABG and may not carry additional risk of morbidity or mortality.¹⁵ Moreover, surgical correction is the preferred modality for treatment of CSSS when the anatomy is not favorable for percutaneous intervention, such as chronic total occlusion of the subclavian artery.¹⁵Alternatively, CSSS can effectively be managed less invasively by percutaneous intervention, including PTA with stent placement,^16,17 thrombectomy¹⁸ or atherectomy of the stenotic subclavian artery.¹⁹

In this patient, PTA was performed with primary stent placement. The lesion was crossed with a sheath, using combined femoral and radial access. After proper positioning, a balloon-expandable stent was deployed that resulted in complete angiographic resolution of the lesion and improvement of symptoms at 6-month follow-up. In line with previous reports, this case demonstrated that percutaneous intervention is a feasible and less invasive approach for management of CSSS.^16,17 The effectiveness of the percutaneous approach has effectiveness equivalent to surgical bypass with minimal complications and good long-term success. Therefore, it has been suggested as first-line therapy in CSSS.^8,16

Although preoperative screening for brachiocephalic disease before undergoing ipsilateral IMA coronary artery bypass can prevent the development of CSSS, there is controversy about the best approach for managing these concomitant conditions. Many institutions use all-vein coronary conduits, but that forgoes the benefit of a LIMA graft. Therefore, others still perform an IMA conduit after brachiocephalic reconstruction. An alternative method is to use free IMA or radial artery conduit. Currently, there are limited data about the use of endovascular treatment for brachiocephalic disease with a CABG.²

Conclusion

Coronary-subclavian steal syndrome is an important clinical condition that is associated with significant morbidity and mortality. In the Sullivan and colleagues report of 27 patients with CSSS, 59.3% had stable angina and 40.7% had acute coronary syndrome, among which 14.8% presented with acute MI.⁷ Therefore, early recognition is essential to prevent catastrophic consequences.

Patients with CSSS usually present with cardiac symptoms, but symptoms related to vertebral-subclavian steal and posterior cerebral insufficiency can coexist. The authors suggest routine preoperative screening for the presence of brachiocephalic disease, using ultrasonic duplex or angiography. This practice is cost-effective and essential to prevent the development of CSSS. Optimal management of brachiocephalic disease prior to CABG is debatable; however, IMA grafting and reconstruction of the brachiocephalic system seems to be a promising approach.

When CSSS develops after CABG, the condition can be successfully treated with percutaneous intervention and outcomes comparable with those of surgical bypass.

Acknowledgments
Special thanks to the division of cardiology at New Jersey VA Health Care System, in particular Steve Tsai, MD; Ronald L. Vaillancourt, RN, and Preciosa Yap, RN.

Coronary-subclavian steal syndrome (CSSS) is a rare clinical entity with an incidence of 0.2% to 0.7%.¹ Despite its scarcity, CSSS is a condition that can result in devastating clinical consequences, such as myocardial ischemia, ranging from angina to myocardial infarction (MI) and ischemic cardiomyopathy.²

In 1974, Harjola and Valle first reported the angiographic and physiologic descriptions of CSSS in an asymptomatic patient who was found to have flow reversal in the left internal mammary artery (LIMA) graft in a follow-up coronary angiography performed 11 months after coronary artery bypass grafting (CABG).³ Because of the similarity in the pathophysiology of this condition with vertebral-subclavian steal syndrome, this clinical entity was named coronary-subclavian steal syndrome (CSSS).^4,5

In steal-syndrome phenomena, there is a significant stenosis in the subclavian artery proximal to the origin of an arterial branch, either LIMA or vertebral artery, resulting in lower pressure in the distal subclavian artery. As a result, the negative pressure gradient might be sufficient to cause retrograde flow; consequently causing arterial branch “flow reversal,” and then “steal” flow from the organ—either heart or brain—supplied by that artery.^3,6

Coronary-subclavian steal syndrome is caused by a reversal of flow in a previously constructed internal mammary artery (IMA)-coronary conduit graft. It typically results from hemodynamically significant subclavian artery stenosis proximal to the ipsilateral IMA. The reversal of flow will “steal” the blood from the coronary territory supplied by the IMA conduit.^4,5 The absence of proximal subclavian artery stenosis does not preclude the presence of this syndrome; reversal in the IMA conduit can occur in association with upper extremity hemodialysis fistulae or anomalous connection of the left subclavian artery to the pulmonary artery in d-transposition of the great arteries.² Although the stenosis is most commonly caused by atherosclerotic disease, other clinical entities, including Takayasu vasculitis, radiation, and giant cell arteritis, have been described.⁶ Patients with CSSS usually present with stable or unstable angina as well as arm claudication and various neurologic symptoms.⁵ The consequence of CSSS can include ischemic cardiomyopathy, acute MI,⁷ stroke, and death.^5,8

Case Presentation

A 66-year-old man with a previous MI managed with CABG, permanent atrial fibrillation (AF), and moderate aortic stenosis presented to the ambulatory clinic with recurrent symptoms of stable angina despite being on maximal anti-anginal therapy. A coronary angiogram performed 4 years earlier had revealed significant left main artery disease and total occlusion of the right coronary artery.

Cardiovascular examination revealed an irregular rhythm with a normal S1, variable S2, and a 3/6 systolic ejection murmur heard best at the right second intercostal space with radiation to the carotids. His peripheral pulses were equal and symmetric in the lower extremities, and no peripheral edema was noted. The remainder of the physical examination was otherwise unremarkable. The resting 12-lead electrocardiogram showed AF at a rate of 60 bpm (Figure 1).

A stress test was performed to elucidate a possible coronary distribution for the cause of the chest pain.

Consequently, coronary angiography was performed and showed 95% left main stenosis and total occlusion of the mid-right coronary artery with right dominance, patent LIMA to mid-LAD and patent saphenous venous graft to posterior descending artery grafts (Figure 3)

The patient underwent percutaneous transluminal angioplasty (PTA) of the subclavian stenosis with insertion of an 8 mm x 27 mm balloon-expandable peripheral stent (Figure 5) (Supplemental video 6). The patient tolerated the procedure well without complications and with resolution of his symptoms at a 6-month follow-up.

Discussion

Long-term follow-up of LIMA as a conduit to LAD has shown a 10-year patency of 95% compared with 76% for saphenous vein and an associated 10-year survival of 93.4% for LIMA compared with 88% for saphenous vein graft.^9,10 Because of the superiority of LIMA outcomes, it has become the preferred graft in CABG. However, this approach is associated with 0.1% to 0.2% risk of ischemia related to flow reversal in the LIMA b

Greater awareness and improvement in diagnostic imaging have contributed to the increased incidence of CSSS and its consequences.² Although symptoms related to myocardial ischemia, as in this case, are the most dominant in CSSS, other brachiocephalic symptoms, including vertebral-subclavian steal, transient ischemic attacks, and strokes, have been reported.¹¹ Additionally, the same disease might compromise distal flow, resulting in extremity claudication or even distal microembolization.¹²

It is important to recognize that significant brachiocephalic stenosis has been reported in about 0.2% to 2.5% of patients undergoing elective CABG.^6,8 Therefore, it is essential to screen for brachiocephalic artery disease before undergoing CABG. Different strategies have been suggested, including assessing pressure gradient between the upper extremities as the initial step; CSSS should be considered when the pressure gradient is > 20 mm Hg.

Other strategies include ultrasonic duplex scanning with provocation test using arm exercise or reactive hyperemia.¹³ Many high-volume centers are performing screening by proximal subclavian angiography in all patients undergoing coronary angiography. When significant disease is detected, arch aortography and 4-vessel cerebral angiography is performed.⁶ In addition, other centers have adopted the routine use of computerized tomographic angiography before CABG.¹⁴

Surgical correction of CSSS is considered to be the gold standard and can be accomplished by performing aorta-subclavian bypass, carotid-subclavian bypass, axillo-axillary bypass, or relocation of the IMA graft.² Although this approach is invasive and carries many disadvantages related to patient comfort,surgical revascularization can be performed safely at the time of CABG and may not carry additional risk of morbidity or mortality.¹⁵ Moreover, surgical correction is the preferred modality for treatment of CSSS when the anatomy is not favorable for percutaneous intervention, such as chronic total occlusion of the subclavian artery.¹⁵Alternatively, CSSS can effectively be managed less invasively by percutaneous intervention, including PTA with stent placement,^16,17 thrombectomy¹⁸ or atherectomy of the stenotic subclavian artery.¹⁹

In this patient, PTA was performed with primary stent placement. The lesion was crossed with a sheath, using combined femoral and radial access. After proper positioning, a balloon-expandable stent was deployed that resulted in complete angiographic resolution of the lesion and improvement of symptoms at 6-month follow-up. In line with previous reports, this case demonstrated that percutaneous intervention is a feasible and less invasive approach for management of CSSS.^16,17 The effectiveness of the percutaneous approach has effectiveness equivalent to surgical bypass with minimal complications and good long-term success. Therefore, it has been suggested as first-line therapy in CSSS.^8,16

Although preoperative screening for brachiocephalic disease before undergoing ipsilateral IMA coronary artery bypass can prevent the development of CSSS, there is controversy about the best approach for managing these concomitant conditions. Many institutions use all-vein coronary conduits, but that forgoes the benefit of a LIMA graft. Therefore, others still perform an IMA conduit after brachiocephalic reconstruction. An alternative method is to use free IMA or radial artery conduit. Currently, there are limited data about the use of endovascular treatment for brachiocephalic disease with a CABG.²

Conclusion

Coronary-subclavian steal syndrome is an important clinical condition that is associated with significant morbidity and mortality. In the Sullivan and colleagues report of 27 patients with CSSS, 59.3% had stable angina and 40.7% had acute coronary syndrome, among which 14.8% presented with acute MI.⁷ Therefore, early recognition is essential to prevent catastrophic consequences.

Patients with CSSS usually present with cardiac symptoms, but symptoms related to vertebral-subclavian steal and posterior cerebral insufficiency can coexist. The authors suggest routine preoperative screening for the presence of brachiocephalic disease, using ultrasonic duplex or angiography. This practice is cost-effective and essential to prevent the development of CSSS. Optimal management of brachiocephalic disease prior to CABG is debatable; however, IMA grafting and reconstruction of the brachiocephalic system seems to be a promising approach.

When CSSS develops after CABG, the condition can be successfully treated with percutaneous intervention and outcomes comparable with those of surgical bypass.

Acknowledgments
Special thanks to the division of cardiology at New Jersey VA Health Care System, in particular Steve Tsai, MD; Ronald L. Vaillancourt, RN, and Preciosa Yap, RN.

Coronary-subclavian steal syndrome (CSSS) is a rare clinical entity with an incidence of 0.2% to 0.7%.¹ Despite its scarcity, CSSS is a condition that can result in devastating clinical consequences, such as myocardial ischemia, ranging from angina to myocardial infarction (MI) and ischemic cardiomyopathy.²

In 1974, Harjola and Valle first reported the angiographic and physiologic descriptions of CSSS in an asymptomatic patient who was found to have flow reversal in the left internal mammary artery (LIMA) graft in a follow-up coronary angiography performed 11 months after coronary artery bypass grafting (CABG).³ Because of the similarity in the pathophysiology of this condition with vertebral-subclavian steal syndrome, this clinical entity was named coronary-subclavian steal syndrome (CSSS).^4,5

In steal-syndrome phenomena, there is a significant stenosis in the subclavian artery proximal to the origin of an arterial branch, either LIMA or vertebral artery, resulting in lower pressure in the distal subclavian artery. As a result, the negative pressure gradient might be sufficient to cause retrograde flow; consequently causing arterial branch “flow reversal,” and then “steal” flow from the organ—either heart or brain—supplied by that artery.^3,6

Coronary-subclavian steal syndrome is caused by a reversal of flow in a previously constructed internal mammary artery (IMA)-coronary conduit graft. It typically results from hemodynamically significant subclavian artery stenosis proximal to the ipsilateral IMA. The reversal of flow will “steal” the blood from the coronary territory supplied by the IMA conduit.^4,5 The absence of proximal subclavian artery stenosis does not preclude the presence of this syndrome; reversal in the IMA conduit can occur in association with upper extremity hemodialysis fistulae or anomalous connection of the left subclavian artery to the pulmonary artery in d-transposition of the great arteries.² Although the stenosis is most commonly caused by atherosclerotic disease, other clinical entities, including Takayasu vasculitis, radiation, and giant cell arteritis, have been described.⁶ Patients with CSSS usually present with stable or unstable angina as well as arm claudication and various neurologic symptoms.⁵ The consequence of CSSS can include ischemic cardiomyopathy, acute MI,⁷ stroke, and death.^5,8

Case Presentation

A 66-year-old man with a previous MI managed with CABG, permanent atrial fibrillation (AF), and moderate aortic stenosis presented to the ambulatory clinic with recurrent symptoms of stable angina despite being on maximal anti-anginal therapy. A coronary angiogram performed 4 years earlier had revealed significant left main artery disease and total occlusion of the right coronary artery.

Cardiovascular examination revealed an irregular rhythm with a normal S1, variable S2, and a 3/6 systolic ejection murmur heard best at the right second intercostal space with radiation to the carotids. His peripheral pulses were equal and symmetric in the lower extremities, and no peripheral edema was noted. The remainder of the physical examination was otherwise unremarkable. The resting 12-lead electrocardiogram showed AF at a rate of 60 bpm (Figure 1).

A stress test was performed to elucidate a possible coronary distribution for the cause of the chest pain.

Consequently, coronary angiography was performed and showed 95% left main stenosis and total occlusion of the mid-right coronary artery with right dominance, patent LIMA to mid-LAD and patent saphenous venous graft to posterior descending artery grafts (Figure 3)

The patient underwent percutaneous transluminal angioplasty (PTA) of the subclavian stenosis with insertion of an 8 mm x 27 mm balloon-expandable peripheral stent (Figure 5) (Supplemental video 6). The patient tolerated the procedure well without complications and with resolution of his symptoms at a 6-month follow-up.

Discussion

Long-term follow-up of LIMA as a conduit to LAD has shown a 10-year patency of 95% compared with 76% for saphenous vein and an associated 10-year survival of 93.4% for LIMA compared with 88% for saphenous vein graft.^9,10 Because of the superiority of LIMA outcomes, it has become the preferred graft in CABG. However, this approach is associated with 0.1% to 0.2% risk of ischemia related to flow reversal in the LIMA b

Greater awareness and improvement in diagnostic imaging have contributed to the increased incidence of CSSS and its consequences.² Although symptoms related to myocardial ischemia, as in this case, are the most dominant in CSSS, other brachiocephalic symptoms, including vertebral-subclavian steal, transient ischemic attacks, and strokes, have been reported.¹¹ Additionally, the same disease might compromise distal flow, resulting in extremity claudication or even distal microembolization.¹²

It is important to recognize that significant brachiocephalic stenosis has been reported in about 0.2% to 2.5% of patients undergoing elective CABG.^6,8 Therefore, it is essential to screen for brachiocephalic artery disease before undergoing CABG. Different strategies have been suggested, including assessing pressure gradient between the upper extremities as the initial step; CSSS should be considered when the pressure gradient is > 20 mm Hg.

Other strategies include ultrasonic duplex scanning with provocation test using arm exercise or reactive hyperemia.¹³ Many high-volume centers are performing screening by proximal subclavian angiography in all patients undergoing coronary angiography. When significant disease is detected, arch aortography and 4-vessel cerebral angiography is performed.⁶ In addition, other centers have adopted the routine use of computerized tomographic angiography before CABG.¹⁴

Surgical correction of CSSS is considered to be the gold standard and can be accomplished by performing aorta-subclavian bypass, carotid-subclavian bypass, axillo-axillary bypass, or relocation of the IMA graft.² Although this approach is invasive and carries many disadvantages related to patient comfort,surgical revascularization can be performed safely at the time of CABG and may not carry additional risk of morbidity or mortality.¹⁵ Moreover, surgical correction is the preferred modality for treatment of CSSS when the anatomy is not favorable for percutaneous intervention, such as chronic total occlusion of the subclavian artery.¹⁵Alternatively, CSSS can effectively be managed less invasively by percutaneous intervention, including PTA with stent placement,^16,17 thrombectomy¹⁸ or atherectomy of the stenotic subclavian artery.¹⁹

In this patient, PTA was performed with primary stent placement. The lesion was crossed with a sheath, using combined femoral and radial access. After proper positioning, a balloon-expandable stent was deployed that resulted in complete angiographic resolution of the lesion and improvement of symptoms at 6-month follow-up. In line with previous reports, this case demonstrated that percutaneous intervention is a feasible and less invasive approach for management of CSSS.^16,17 The effectiveness of the percutaneous approach has effectiveness equivalent to surgical bypass with minimal complications and good long-term success. Therefore, it has been suggested as first-line therapy in CSSS.^8,16

Although preoperative screening for brachiocephalic disease before undergoing ipsilateral IMA coronary artery bypass can prevent the development of CSSS, there is controversy about the best approach for managing these concomitant conditions. Many institutions use all-vein coronary conduits, but that forgoes the benefit of a LIMA graft. Therefore, others still perform an IMA conduit after brachiocephalic reconstruction. An alternative method is to use free IMA or radial artery conduit. Currently, there are limited data about the use of endovascular treatment for brachiocephalic disease with a CABG.²

Conclusion

Coronary-subclavian steal syndrome is an important clinical condition that is associated with significant morbidity and mortality. In the Sullivan and colleagues report of 27 patients with CSSS, 59.3% had stable angina and 40.7% had acute coronary syndrome, among which 14.8% presented with acute MI.⁷ Therefore, early recognition is essential to prevent catastrophic consequences.

Patients with CSSS usually present with cardiac symptoms, but symptoms related to vertebral-subclavian steal and posterior cerebral insufficiency can coexist. The authors suggest routine preoperative screening for the presence of brachiocephalic disease, using ultrasonic duplex or angiography. This practice is cost-effective and essential to prevent the development of CSSS. Optimal management of brachiocephalic disease prior to CABG is debatable; however, IMA grafting and reconstruction of the brachiocephalic system seems to be a promising approach.

When CSSS develops after CABG, the condition can be successfully treated with percutaneous intervention and outcomes comparable with those of surgical bypass.

Acknowledgments
Special thanks to the division of cardiology at New Jersey VA Health Care System, in particular Steve Tsai, MD; Ronald L. Vaillancourt, RN, and Preciosa Yap, RN.

Case

A 26-year-old gravida 3, para 2-0-0-2, aborta 0 whose last menstrual period was 15 weeks 5 days, presented to the ED with complaints of mild vaginal spotting, which she first noted postcoitally the previous day. The patient denied fatigue, lightheadedness, dyspnea, abdominal pain, nausea, or vomiting.

Physical examination revealed a well-appearing patient with normal vital signs. The abdomen was soft and nontender, and the fundus was palpable at the level of the umbilicus. A speculum examination was unremarkable, with normal external genitalia, a closed cervical os, no adnexal masses or tenderness, and no blood in the vaginal vault. Laboratory studies were significant for a serum beta human chorionic gonadotropin (beta-hCG) of 7,442 mIU/mL (reference range for 15 weeks: 12,039-70,971 mIU/mL). The patient was Rh positive with a stable hematocrit.

A bedside ultrasound, performed by an ultrasound-]trained emergency physician (EP), was noted to demonstrate a complex intrauterine mass comprised of several small, rounded anechoic clusters (Figure).

Discussion

Hydatidiform moles are a subset of abnormal pregnancies termed gestational trophoblastic disease (GTD). The two greatest risk factors for GTD are previous GTD and extremis of maternal age.¹ Patients often present to the ED because of painless heavy vaginal bleeding, hyperemesis gravidarum, symptoms of hyperthyroidism, or preeclampsia before 20 weeks.² Clinically, these patients present with an enlarged uterus for gestational age and very high beta-hCG levels, often greater than 100,000 mIU/mL.³ The high beta-hCG levels can lead the patient to present with symptoms of hyperthyroidism, such as severe hypertension, given the similar chemical structures of beta-hCG and thyroid-stimulating hormone.⁴

After a D&C, interval beta-hCG levels need to be obtained to ensure resolution. A patient with beta-hCG levels that do not fall by 10% after 3 weeks, or are still present after 6 months, should be referred to a gynecologic oncologist.^5,6 Furthermore, a chest X-ray is strongly suggested, as the lungs are often the first place of metastasis.⁷

Partial hydatidiform moles are formed by a dispermic fertilization of a normal ovum leading to a triploid pattern, and are clinically distinguished from complete molar pregnancies because affected patients have a uterus that is often small for gestational age.⁸ Also, while the beta-hCG is also abnormally elevated, the median value is more modest at approximately 50,000 mIU/mL.³

According to the American College of Radiology’s Appropriateness Criteria, ultrasound is the gold standard for evaluating gestational trophoblastic disease. While the classic sonographic appearance of a molar pregnancy is described as a “snowstorm” appearance, advancement in technology more clearly demonstrates a “cluster of grapes” or “honeycomb” appearance.⁹ On Doppler mode, increased vascularity peripherally can also be detected due to engorgement of the spiral arteries. While partial moles tend to have more focal lesions, the greatest distinguishing factor is the presence of embryonic or fetal tissue, which is not seen in complete moles. However, due to the heterogeneous appearance of the uterus in all GTD, molar pregnancies can sometimes be misinterpreted as missed abortions or clotted blood, so that pathological confirmation is mandatory for all products of conception in the United States and Canada.^2,10

Summary

This case is of particular interest because it demonstrates an atypical presentation of a partial hydatidiform mole. While most classic presentations include older patients with heavy vaginal bleeding, a smaller uterus than expected, significantly elevated beta-hCGs, and hyperemesis gravidarum, our patient was relatively young with no history of molar pregnancies in the past, a larger-than-expected uterus, and no vaginal bleeding noted. Laboratory values also indicated a significantly lower-than-expected beta-hCG level. As such, bedside ultrasound findings were unexpected but resulted in the prompt diagnosis, an emergent obstetric consultation, and confirmatory radiology imaging. The ED bedside ultrasound findings did demonstrate the characteristic “cluster of grapes” appearance surrounded by the hyperechoic appearance of the spiral arteries (Figure). An intrauterine yolk sac was also identified by ultrasound, which strongly suggested a partial rather than a complete hydatidiform molar pregnancy.

While hydatidiform pregnancies are relatively rare, EPs should be aware of the clinical and sonographic features of these diseases. This case, particularly given the atypical clinical presentation for a partial molar pregnancy, highlights the importance of ultrasound in pregnancy, and the utility of bedside ultrasound in the evaluation of the etiology of vaginal bleeding in the early pregnant patient that presents to the ED.

Case

A 26-year-old gravida 3, para 2-0-0-2, aborta 0 whose last menstrual period was 15 weeks 5 days, presented to the ED with complaints of mild vaginal spotting, which she first noted postcoitally the previous day. The patient denied fatigue, lightheadedness, dyspnea, abdominal pain, nausea, or vomiting.

Physical examination revealed a well-appearing patient with normal vital signs. The abdomen was soft and nontender, and the fundus was palpable at the level of the umbilicus. A speculum examination was unremarkable, with normal external genitalia, a closed cervical os, no adnexal masses or tenderness, and no blood in the vaginal vault. Laboratory studies were significant for a serum beta human chorionic gonadotropin (beta-hCG) of 7,442 mIU/mL (reference range for 15 weeks: 12,039-70,971 mIU/mL). The patient was Rh positive with a stable hematocrit.

A bedside ultrasound, performed by an ultrasound-]trained emergency physician (EP), was noted to demonstrate a complex intrauterine mass comprised of several small, rounded anechoic clusters (Figure).

Discussion

Hydatidiform moles are a subset of abnormal pregnancies termed gestational trophoblastic disease (GTD). The two greatest risk factors for GTD are previous GTD and extremis of maternal age.¹ Patients often present to the ED because of painless heavy vaginal bleeding, hyperemesis gravidarum, symptoms of hyperthyroidism, or preeclampsia before 20 weeks.² Clinically, these patients present with an enlarged uterus for gestational age and very high beta-hCG levels, often greater than 100,000 mIU/mL.³ The high beta-hCG levels can lead the patient to present with symptoms of hyperthyroidism, such as severe hypertension, given the similar chemical structures of beta-hCG and thyroid-stimulating hormone.⁴

After a D&C, interval beta-hCG levels need to be obtained to ensure resolution. A patient with beta-hCG levels that do not fall by 10% after 3 weeks, or are still present after 6 months, should be referred to a gynecologic oncologist.^5,6 Furthermore, a chest X-ray is strongly suggested, as the lungs are often the first place of metastasis.⁷

Partial hydatidiform moles are formed by a dispermic fertilization of a normal ovum leading to a triploid pattern, and are clinically distinguished from complete molar pregnancies because affected patients have a uterus that is often small for gestational age.⁸ Also, while the beta-hCG is also abnormally elevated, the median value is more modest at approximately 50,000 mIU/mL.³

According to the American College of Radiology’s Appropriateness Criteria, ultrasound is the gold standard for evaluating gestational trophoblastic disease. While the classic sonographic appearance of a molar pregnancy is described as a “snowstorm” appearance, advancement in technology more clearly demonstrates a “cluster of grapes” or “honeycomb” appearance.⁹ On Doppler mode, increased vascularity peripherally can also be detected due to engorgement of the spiral arteries. While partial moles tend to have more focal lesions, the greatest distinguishing factor is the presence of embryonic or fetal tissue, which is not seen in complete moles. However, due to the heterogeneous appearance of the uterus in all GTD, molar pregnancies can sometimes be misinterpreted as missed abortions or clotted blood, so that pathological confirmation is mandatory for all products of conception in the United States and Canada.^2,10

Summary

This case is of particular interest because it demonstrates an atypical presentation of a partial hydatidiform mole. While most classic presentations include older patients with heavy vaginal bleeding, a smaller uterus than expected, significantly elevated beta-hCGs, and hyperemesis gravidarum, our patient was relatively young with no history of molar pregnancies in the past, a larger-than-expected uterus, and no vaginal bleeding noted. Laboratory values also indicated a significantly lower-than-expected beta-hCG level. As such, bedside ultrasound findings were unexpected but resulted in the prompt diagnosis, an emergent obstetric consultation, and confirmatory radiology imaging. The ED bedside ultrasound findings did demonstrate the characteristic “cluster of grapes” appearance surrounded by the hyperechoic appearance of the spiral arteries (Figure). An intrauterine yolk sac was also identified by ultrasound, which strongly suggested a partial rather than a complete hydatidiform molar pregnancy.

While hydatidiform pregnancies are relatively rare, EPs should be aware of the clinical and sonographic features of these diseases. This case, particularly given the atypical clinical presentation for a partial molar pregnancy, highlights the importance of ultrasound in pregnancy, and the utility of bedside ultrasound in the evaluation of the etiology of vaginal bleeding in the early pregnant patient that presents to the ED.

Case

A 26-year-old gravida 3, para 2-0-0-2, aborta 0 whose last menstrual period was 15 weeks 5 days, presented to the ED with complaints of mild vaginal spotting, which she first noted postcoitally the previous day. The patient denied fatigue, lightheadedness, dyspnea, abdominal pain, nausea, or vomiting.

Physical examination revealed a well-appearing patient with normal vital signs. The abdomen was soft and nontender, and the fundus was palpable at the level of the umbilicus. A speculum examination was unremarkable, with normal external genitalia, a closed cervical os, no adnexal masses or tenderness, and no blood in the vaginal vault. Laboratory studies were significant for a serum beta human chorionic gonadotropin (beta-hCG) of 7,442 mIU/mL (reference range for 15 weeks: 12,039-70,971 mIU/mL). The patient was Rh positive with a stable hematocrit.

A bedside ultrasound, performed by an ultrasound-]trained emergency physician (EP), was noted to demonstrate a complex intrauterine mass comprised of several small, rounded anechoic clusters (Figure).

Discussion

Hydatidiform moles are a subset of abnormal pregnancies termed gestational trophoblastic disease (GTD). The two greatest risk factors for GTD are previous GTD and extremis of maternal age.¹ Patients often present to the ED because of painless heavy vaginal bleeding, hyperemesis gravidarum, symptoms of hyperthyroidism, or preeclampsia before 20 weeks.² Clinically, these patients present with an enlarged uterus for gestational age and very high beta-hCG levels, often greater than 100,000 mIU/mL.³ The high beta-hCG levels can lead the patient to present with symptoms of hyperthyroidism, such as severe hypertension, given the similar chemical structures of beta-hCG and thyroid-stimulating hormone.⁴

After a D&C, interval beta-hCG levels need to be obtained to ensure resolution. A patient with beta-hCG levels that do not fall by 10% after 3 weeks, or are still present after 6 months, should be referred to a gynecologic oncologist.^5,6 Furthermore, a chest X-ray is strongly suggested, as the lungs are often the first place of metastasis.⁷

Partial hydatidiform moles are formed by a dispermic fertilization of a normal ovum leading to a triploid pattern, and are clinically distinguished from complete molar pregnancies because affected patients have a uterus that is often small for gestational age.⁸ Also, while the beta-hCG is also abnormally elevated, the median value is more modest at approximately 50,000 mIU/mL.³

According to the American College of Radiology’s Appropriateness Criteria, ultrasound is the gold standard for evaluating gestational trophoblastic disease. While the classic sonographic appearance of a molar pregnancy is described as a “snowstorm” appearance, advancement in technology more clearly demonstrates a “cluster of grapes” or “honeycomb” appearance.⁹ On Doppler mode, increased vascularity peripherally can also be detected due to engorgement of the spiral arteries. While partial moles tend to have more focal lesions, the greatest distinguishing factor is the presence of embryonic or fetal tissue, which is not seen in complete moles. However, due to the heterogeneous appearance of the uterus in all GTD, molar pregnancies can sometimes be misinterpreted as missed abortions or clotted blood, so that pathological confirmation is mandatory for all products of conception in the United States and Canada.^2,10

Summary

This case is of particular interest because it demonstrates an atypical presentation of a partial hydatidiform mole. While most classic presentations include older patients with heavy vaginal bleeding, a smaller uterus than expected, significantly elevated beta-hCGs, and hyperemesis gravidarum, our patient was relatively young with no history of molar pregnancies in the past, a larger-than-expected uterus, and no vaginal bleeding noted. Laboratory values also indicated a significantly lower-than-expected beta-hCG level. As such, bedside ultrasound findings were unexpected but resulted in the prompt diagnosis, an emergent obstetric consultation, and confirmatory radiology imaging. The ED bedside ultrasound findings did demonstrate the characteristic “cluster of grapes” appearance surrounded by the hyperechoic appearance of the spiral arteries (Figure). An intrauterine yolk sac was also identified by ultrasound, which strongly suggested a partial rather than a complete hydatidiform molar pregnancy.

While hydatidiform pregnancies are relatively rare, EPs should be aware of the clinical and sonographic features of these diseases. This case, particularly given the atypical clinical presentation for a partial molar pregnancy, highlights the importance of ultrasound in pregnancy, and the utility of bedside ultrasound in the evaluation of the etiology of vaginal bleeding in the early pregnant patient that presents to the ED.

Cardiac ultrasound is among the many beneficial applications of point-of-care (POC) ultrasound in the ED. This modality can prove extremely beneficial in evaluating the critically ill patient. For example, POC cardiac ultrasound not only permits the emergency physician (EP) to diagnose a pericardial effusion and cardiac tamponade, but also perform a pericardiocentesis.¹ The EP can also employ beside ultrasound to estimate an ejection fraction (EF) almost as well as cardiology services,² look for signs of right-heart strain in patients with pulmonary embolism (PE),³ and guide fluid management in patients who have septic shock.⁴ In addition to only taking a few minutes to perform, POC cardiac ultrasound can also drastically change the course of management in some patients. Our case illustrates the use of POC ultrasound to diagnose Takotsubo cardiomyopathy in a 64-year-old patient and guide management when she became unstable prior to cardiac catheterization.

Case

A 64-year-old white woman with a medical history of diabetes, obesity, and nephrolithiasis presented to the ED with chest pain and shortness of breath, which she stated had begun earlier in the day. The patient’s chest pain did not intensify upon exertion, but the shortness of breath worsened when she was in the supine position.

Three months prior, the patient had also presented to our ED with chest pain. Evaluation during that visit included a negative stress echocardiogram with an EF of 55%. At this second visit, an electrocardiogram (ECG) showed new T-wave inversions in the anterior, lateral, and inferior leads. Vital signs at presentation were: blood pressure, 107/63 mm Hg; heart rate, 100 beats/min; respiratory rate, 18 breaths/min; and temperature, 97.9°F. Oxygen saturation was 97% on room air when patient was sitting upright, but decreased to 90% when she was supine. A chest X-ray showed left basilar atelectasis with a trace effusion. Laboratory evaluation was remarkable for the following: troponin I, 2.99 ng/mL; D-dimer, 294 ng/mL; and brain natriuretic peptide, 559 pg/mL.

Given the patient’s vital signs and positive troponin I level, a computed tomography (CT) scan was ordered to assess for a PE. This was done despite the patient’s negative D-dimer results, as it was felt that she was not low-risk for PE. At the same time the CT scan was ordered, a POC cardiac ultrasound was performed to assess for signs of right heart strain.

Discussion

Takotsubo cardiomyopathy is an acute, stress-induced cardiomyopathy that was first described in Japan in the early 1990s.⁵ It is thought to be due to catecholamine-induced dysfunction from a stressful event,^6-8 such as the death of a loved one, which is why it is often referred to as “broken heart syndrome.” However there are case reports highlighting other causes of Takotsubo cardiomyopathy, such as cocaine use,⁹ scuba diving,¹⁰ and diabetic ketoacidosis combined with hypothermia.¹¹

Patients with Takotsubo cardiomyopathy will frequently have ECG abnormalities, including ST-segment elevation or depression, or T-wave changes; troponin levels also may be elevated. The majority of patients (>80%) are postmenopausal women, typically aged 50 to 75 years.^6,12 Echocardiogram findings in Takotsubo cardiomyopathy show significant left ventricular (LV) dysfunction or regional dysfunction that is not in one coronary artery distribution.^12,13 There will often be apical dilation or ballooning with dyskinesia but more preserved function at the base and normal dimensions.^14,15 A negative cardiac catheterization or catheterization in the absence of significant disease is required to confirm the diagnosis.¹⁶ The LV function usually returns to baseline in 1 to 4 weeks, but there can be recurrence in some patients.^6,17 The condition is also associated with a large burden of morbidity and mortality.^6,18 In a case series by Gopalakrishnan et al⁶ of 56 patients, there was an 8.9% in-hospital mortality rate and an additional 17.9% out-of-hospital mortality rate even in patients in whom LV function had returned to normal.

In a review by Gianni et al,¹⁹ 4.2% of patients with Takotsubo cardiomyopathy present with or go into cardiogenic shock at some point during admission, and up to 2% of patients who present with acute myocardial infarction have Takotsubo cardiomyopathy. Patients can go into cardiogenic shock due to depressed EF or LV outflow tract obstruction from hyperkinesis of the basilar segments. Some of these patients may be sent directly to the catheter laboratory based on ST elevations on ECG, in which case the diagnosis is made there. Our patient, however, did not have ST elevation and later became unstable on the floor. Citro et al²⁰ suggest that a patient with a predisposition for Takotsubo cardiomyopathy (eg, postmenopausal patients, those who experienced a trigger event), in the right clinical setting and without ST-segment elevation on ECG, could be managed more conservatively with delayed cardiac angiography or CT angiography (CTA) evaluation of the coronary arteries (sparing the patient an invasive procedure)—as long as ultrasound was consistent with typical Takotsubo cardiomyopathy findings. However, CTA is still needed to make the diagnosis.

At this time, Takotsubo cardiomyopathy should remain an important part of the differential diagnosis for emergency patients who have chest pain—especially for postmenopausal women with a history of significant stressor—as early recognition can lead to better patient care.

Conclusion

This case highlights the importance of POC ultrasound in the management of patients in the ED and after admission. The care of our patient was enhanced by the ability to take a real-time look at her EF and cardiac function at the time of admission through bedside ultrasound. This information guided her management and optimized stabilization.

Cardiac ultrasound is among the many beneficial applications of point-of-care (POC) ultrasound in the ED. This modality can prove extremely beneficial in evaluating the critically ill patient. For example, POC cardiac ultrasound not only permits the emergency physician (EP) to diagnose a pericardial effusion and cardiac tamponade, but also perform a pericardiocentesis.¹ The EP can also employ beside ultrasound to estimate an ejection fraction (EF) almost as well as cardiology services,² look for signs of right-heart strain in patients with pulmonary embolism (PE),³ and guide fluid management in patients who have septic shock.⁴ In addition to only taking a few minutes to perform, POC cardiac ultrasound can also drastically change the course of management in some patients. Our case illustrates the use of POC ultrasound to diagnose Takotsubo cardiomyopathy in a 64-year-old patient and guide management when she became unstable prior to cardiac catheterization.

Case

A 64-year-old white woman with a medical history of diabetes, obesity, and nephrolithiasis presented to the ED with chest pain and shortness of breath, which she stated had begun earlier in the day. The patient’s chest pain did not intensify upon exertion, but the shortness of breath worsened when she was in the supine position.

Three months prior, the patient had also presented to our ED with chest pain. Evaluation during that visit included a negative stress echocardiogram with an EF of 55%. At this second visit, an electrocardiogram (ECG) showed new T-wave inversions in the anterior, lateral, and inferior leads. Vital signs at presentation were: blood pressure, 107/63 mm Hg; heart rate, 100 beats/min; respiratory rate, 18 breaths/min; and temperature, 97.9°F. Oxygen saturation was 97% on room air when patient was sitting upright, but decreased to 90% when she was supine. A chest X-ray showed left basilar atelectasis with a trace effusion. Laboratory evaluation was remarkable for the following: troponin I, 2.99 ng/mL; D-dimer, 294 ng/mL; and brain natriuretic peptide, 559 pg/mL.

Given the patient’s vital signs and positive troponin I level, a computed tomography (CT) scan was ordered to assess for a PE. This was done despite the patient’s negative D-dimer results, as it was felt that she was not low-risk for PE. At the same time the CT scan was ordered, a POC cardiac ultrasound was performed to assess for signs of right heart strain.

Discussion

Takotsubo cardiomyopathy is an acute, stress-induced cardiomyopathy that was first described in Japan in the early 1990s.⁵ It is thought to be due to catecholamine-induced dysfunction from a stressful event,^6-8 such as the death of a loved one, which is why it is often referred to as “broken heart syndrome.” However there are case reports highlighting other causes of Takotsubo cardiomyopathy, such as cocaine use,⁹ scuba diving,¹⁰ and diabetic ketoacidosis combined with hypothermia.¹¹

Patients with Takotsubo cardiomyopathy will frequently have ECG abnormalities, including ST-segment elevation or depression, or T-wave changes; troponin levels also may be elevated. The majority of patients (>80%) are postmenopausal women, typically aged 50 to 75 years.^6,12 Echocardiogram findings in Takotsubo cardiomyopathy show significant left ventricular (LV) dysfunction or regional dysfunction that is not in one coronary artery distribution.^12,13 There will often be apical dilation or ballooning with dyskinesia but more preserved function at the base and normal dimensions.^14,15 A negative cardiac catheterization or catheterization in the absence of significant disease is required to confirm the diagnosis.¹⁶ The LV function usually returns to baseline in 1 to 4 weeks, but there can be recurrence in some patients.^6,17 The condition is also associated with a large burden of morbidity and mortality.^6,18 In a case series by Gopalakrishnan et al⁶ of 56 patients, there was an 8.9% in-hospital mortality rate and an additional 17.9% out-of-hospital mortality rate even in patients in whom LV function had returned to normal.

In a review by Gianni et al,¹⁹ 4.2% of patients with Takotsubo cardiomyopathy present with or go into cardiogenic shock at some point during admission, and up to 2% of patients who present with acute myocardial infarction have Takotsubo cardiomyopathy. Patients can go into cardiogenic shock due to depressed EF or LV outflow tract obstruction from hyperkinesis of the basilar segments. Some of these patients may be sent directly to the catheter laboratory based on ST elevations on ECG, in which case the diagnosis is made there. Our patient, however, did not have ST elevation and later became unstable on the floor. Citro et al²⁰ suggest that a patient with a predisposition for Takotsubo cardiomyopathy (eg, postmenopausal patients, those who experienced a trigger event), in the right clinical setting and without ST-segment elevation on ECG, could be managed more conservatively with delayed cardiac angiography or CT angiography (CTA) evaluation of the coronary arteries (sparing the patient an invasive procedure)—as long as ultrasound was consistent with typical Takotsubo cardiomyopathy findings. However, CTA is still needed to make the diagnosis.

At this time, Takotsubo cardiomyopathy should remain an important part of the differential diagnosis for emergency patients who have chest pain—especially for postmenopausal women with a history of significant stressor—as early recognition can lead to better patient care.

Conclusion

This case highlights the importance of POC ultrasound in the management of patients in the ED and after admission. The care of our patient was enhanced by the ability to take a real-time look at her EF and cardiac function at the time of admission through bedside ultrasound. This information guided her management and optimized stabilization.

Cardiac ultrasound is among the many beneficial applications of point-of-care (POC) ultrasound in the ED. This modality can prove extremely beneficial in evaluating the critically ill patient. For example, POC cardiac ultrasound not only permits the emergency physician (EP) to diagnose a pericardial effusion and cardiac tamponade, but also perform a pericardiocentesis.¹ The EP can also employ beside ultrasound to estimate an ejection fraction (EF) almost as well as cardiology services,² look for signs of right-heart strain in patients with pulmonary embolism (PE),³ and guide fluid management in patients who have septic shock.⁴ In addition to only taking a few minutes to perform, POC cardiac ultrasound can also drastically change the course of management in some patients. Our case illustrates the use of POC ultrasound to diagnose Takotsubo cardiomyopathy in a 64-year-old patient and guide management when she became unstable prior to cardiac catheterization.

Case

A 64-year-old white woman with a medical history of diabetes, obesity, and nephrolithiasis presented to the ED with chest pain and shortness of breath, which she stated had begun earlier in the day. The patient’s chest pain did not intensify upon exertion, but the shortness of breath worsened when she was in the supine position.

Three months prior, the patient had also presented to our ED with chest pain. Evaluation during that visit included a negative stress echocardiogram with an EF of 55%. At this second visit, an electrocardiogram (ECG) showed new T-wave inversions in the anterior, lateral, and inferior leads. Vital signs at presentation were: blood pressure, 107/63 mm Hg; heart rate, 100 beats/min; respiratory rate, 18 breaths/min; and temperature, 97.9°F. Oxygen saturation was 97% on room air when patient was sitting upright, but decreased to 90% when she was supine. A chest X-ray showed left basilar atelectasis with a trace effusion. Laboratory evaluation was remarkable for the following: troponin I, 2.99 ng/mL; D-dimer, 294 ng/mL; and brain natriuretic peptide, 559 pg/mL.

Given the patient’s vital signs and positive troponin I level, a computed tomography (CT) scan was ordered to assess for a PE. This was done despite the patient’s negative D-dimer results, as it was felt that she was not low-risk for PE. At the same time the CT scan was ordered, a POC cardiac ultrasound was performed to assess for signs of right heart strain.

Discussion

Takotsubo cardiomyopathy is an acute, stress-induced cardiomyopathy that was first described in Japan in the early 1990s.⁵ It is thought to be due to catecholamine-induced dysfunction from a stressful event,^6-8 such as the death of a loved one, which is why it is often referred to as “broken heart syndrome.” However there are case reports highlighting other causes of Takotsubo cardiomyopathy, such as cocaine use,⁹ scuba diving,¹⁰ and diabetic ketoacidosis combined with hypothermia.¹¹

Patients with Takotsubo cardiomyopathy will frequently have ECG abnormalities, including ST-segment elevation or depression, or T-wave changes; troponin levels also may be elevated. The majority of patients (>80%) are postmenopausal women, typically aged 50 to 75 years.^6,12 Echocardiogram findings in Takotsubo cardiomyopathy show significant left ventricular (LV) dysfunction or regional dysfunction that is not in one coronary artery distribution.^12,13 There will often be apical dilation or ballooning with dyskinesia but more preserved function at the base and normal dimensions.^14,15 A negative cardiac catheterization or catheterization in the absence of significant disease is required to confirm the diagnosis.¹⁶ The LV function usually returns to baseline in 1 to 4 weeks, but there can be recurrence in some patients.^6,17 The condition is also associated with a large burden of morbidity and mortality.^6,18 In a case series by Gopalakrishnan et al⁶ of 56 patients, there was an 8.9% in-hospital mortality rate and an additional 17.9% out-of-hospital mortality rate even in patients in whom LV function had returned to normal.

In a review by Gianni et al,¹⁹ 4.2% of patients with Takotsubo cardiomyopathy present with or go into cardiogenic shock at some point during admission, and up to 2% of patients who present with acute myocardial infarction have Takotsubo cardiomyopathy. Patients can go into cardiogenic shock due to depressed EF or LV outflow tract obstruction from hyperkinesis of the basilar segments. Some of these patients may be sent directly to the catheter laboratory based on ST elevations on ECG, in which case the diagnosis is made there. Our patient, however, did not have ST elevation and later became unstable on the floor. Citro et al²⁰ suggest that a patient with a predisposition for Takotsubo cardiomyopathy (eg, postmenopausal patients, those who experienced a trigger event), in the right clinical setting and without ST-segment elevation on ECG, could be managed more conservatively with delayed cardiac angiography or CT angiography (CTA) evaluation of the coronary arteries (sparing the patient an invasive procedure)—as long as ultrasound was consistent with typical Takotsubo cardiomyopathy findings. However, CTA is still needed to make the diagnosis.

At this time, Takotsubo cardiomyopathy should remain an important part of the differential diagnosis for emergency patients who have chest pain—especially for postmenopausal women with a history of significant stressor—as early recognition can lead to better patient care.

Conclusion

This case highlights the importance of POC ultrasound in the management of patients in the ED and after admission. The care of our patient was enhanced by the ability to take a real-time look at her EF and cardiac function at the time of admission through bedside ultrasound. This information guided her management and optimized stabilization.

Case

A 16-year-old girl, who recently emigrated from Haiti, was brought to the pediatric ED by her mother for evaluation of a 2-hour history of gastric discomfort. Upon arrival at the ED waiting area, the patient experienced a sudden onset of generalized tonic-clonic movement with altered sensorium, though she did not fall to the ground and was not injured. Vital signs from triage were: blood pressure, 110/76 mm Hg; heart rate, 112 beats/min; respiratory rate, 22 breaths/min; and temperature, 97°F. Oxygen saturation was 98% on room air.

The patient was immediately attached to a cardiac monitor, given oxygen via a face mask, and received airway suctioning. Despite receiving a total of 4 mg of lorazepam, the seizure continued. Physical examination revealed no signs of external injury, but the ongoing generalized status epilepticus made the examination difficult.

What are the causes of refractory seizures in an adolescent patient?

The differential diagnosis for pediatric patients presenting with refractory seizure is the same as that for adult patients and should include treatment noncompliance, infection, vascular event (eg, stroke, hemorrhage), trauma (eg, cerebral contusions), metabolic and electrolyte disturbances, anticonvulsant toxicity, and exposure to a convulsant toxin.

While certain drugs (eg, cocaine) may cause status epilepticus through a secondary effect such as ischemia or a bleed, some drugs can directly cause refractory seizures. A few drugs and toxins are responsible for the majority of such seizures: bupropion; carbon monoxide; diphenhydramine; ethanol (withdrawal); hypoglycemics; lead; theophylline; tramadol; and certain antibiotics, including cephalosporins, penicillins, quinolones, and, in particular, isoniazid (INH).¹

Case Continuation

Upon further history-taking, the patient’s mother informed the ED staff that during a recent visit to a local clinic, her daughter tested positive on routine screening for tuberculosis and was given “some medications.” The patient’s mother further noted that her daughter was scheduled for a follow-up appointment at the same clinic later this morning. She believed the patient had taken “a few” of the prescribed pills at once to “catch-up” on missed doses prior to that appointment, and provided the ED staff with an empty bottle of INH that she had found in her daughter’s purse.

What are the signs and symptoms of acute isoniazid toxicity?

Isoniazid toxicity should be suspected in any patient who has access to INH—even if the drug was prescribed for someone other than the patient. Acute toxicity develops rapidly after the ingestion of supratherapeutic doses of INH and includes nausea, abdominal discomfort, vomiting, dizziness, and excessive fatigue or lethargy. Patients can present with tachycardia, stupor, agitation, mydriasis, increased anion gap metabolic acidosis, and encephalopathy.

Seizures occur due to an INH-induced functional pyridoxine deficiency. Isoniazid inhibits pyridoxine phosphokinase, the enzyme that converts pyridoxine (vitamin B₆) to its physiologically active form, pyridoxal 5’-phosphate (PLP). Because the conversion of glutamate (an excitatory neurotransmitter) to gamma-aminobutyric acid (GABA; the body’s main inhibitory neurotransmitter) is dependent on PLP, an excess of glutamate and a deficiency of GABA occurs following INH overdose. The result is neuroexcitation, which manifests as generalized seizures in affected patients.

The most consequential effect of INH overdose, however, is the development of seizure refractory to conventional therapy, such as benzodiazepines. This occurs because benzodiazepines are indirect-acting GABA agonists, and require the presence of GABA to elicit their effect. Therefore, due to the impairment of GABA synthesis, benzodiazepines are limited or ineffective as anticonvulsants. Although INH doses in excess of 20 mg/kg may result in neuroexcitation, refractory seizures are uncommon with doses <70 mg/kg.

Complications of chronic INH use include hepatotoxicity, and patients will present with jaundice, hepatomegaly, and right upper quadrant pain and tenderness. Isoniazid must be discontinued rapidly in patients demonstrating hepatotoxicity, and the risk/benefit of treatment reconsidered. Patients can also develop peripheral neuropathy while using INH therapeutically, and prophylactic vitamin B₆ supplementation is recommended for certain at-risk patients, such as those who are pregnant or breastfeeding.² Supplementation, however, neither reduces the risk of hepatotoxicity nor prevents onset of seizure following an INH overdose (the B₆ dose is not sufficient enough to exert this effect).

How is acute isoniazid-induced seizure managed?

Management of patients with refractory seizure should initially include an assessment and management of the patient’s airway, breathing, and circulation. Although seizures induced by INH toxicity are often resistant to benzodiazepines, these agents remain the first-line therapy. For patients who fail to respond to a reasonable trial of benzodiazepines (eg, lorazepam 6 mg intravenously [IV]), pyridoxine should be administered.³ The recommended dose is 1 g pyridoxine per every 1 g of INH ingested—if the initial dose ingested is known—with a maximum dose of 5 g pyridoxine. If the initial dose of INH is not known, 70 mg/kg of pyridoxine, up to 5 g, is recommended. Repeated doses of pyridoxine can be administered if the seizure continues, up to a total dose of 10 g in an adult. At extremely high doses, pyridoxine itself can be neurotoxic, limiting the maximal antidotal dose.

Rapid initiation of pyridoxine is a challenge since typical stocks in most EDs are not in an adequate supply required for treatment. Additionally, a typical vial of pyridoxine contains 100 mg, highlighting the rare need to open dozens of vials for a single patient. Drawing up adequate doses of the IV formulation can be a challenge and time-consuming.

Regardless, the most reliable and rapid route of administration for pyridoxine is IV, at a rate of 0.5 to 1 g/min. Even if the seizure resolves prior to completion of the initial dose, the remaining doses should still be administered over a 4- to 6-hour period. Oral or (more likely) nasogastric administration of pyridoxine can be administered if the IV formulation is not available, but neither are optimal routes of delivery. Every effort should be made to stock pyridoxine in the antidote supply in the ED to avoid time delays involving finding, preparing, and administering the drug in these scenarios. Previous studies have found that most EDs are not prepared to handle pyridoxine replacement.^4,5

Since benzodiazepines and barbiturates are GABA agonists with complementary mechanisms of actions to pyridoxine, they should be administered to potentiate the antiseizure effect of pyridoxine. If the seizure does not terminate, the use of propofol or general anesthesia may be required. Once the seizure is terminated, oral activated charcoal can be administered if the ingestion occurred within several hours of presentation. Given the rapid onset of effect of a large dose of INH, most patients will develop seizure shortly after exposure, limiting the benefits of both aggressive gastrointestinal decontamination and delayed activated charcoal. Charcoal also can be used for patients who overdose on INH but do not develop seizures.

Although the utility of a head computed tomography (CT) scan or laboratory studies is limited given the context of the exposure, these are generally obtained for patients with new-onset seizure. Since many patients with INH toxicity do not seize, such a patient may have a lower seizure threshold due to the existence of a subclinical cerebral lesion or metabolic abnormality.

Case Conclusion

The patient’s INH-induced refractory seizure was treated with pyridoxine. Her history suggested that she had ingested an unknown number of INH tablets within an hour. On this initial basis, an IV dose of 5,000 mg of pyridoxine was administered. The patient’s seizures terminated within 2 minutes of the infusion, and no additional doses of pyridoxine were required. Given the lack of concern for self-harm, an acetaminophen concentration was not obtained. A urine toxicology screen was negative for cocaine and amphetamines, and a CT scan of the head was negative for any abnormality. The patient was admitted to the pediatric intensive care unit for status epileptics and was discharged home on hospital day 2 after an uneventful stay.

Case

A 16-year-old girl, who recently emigrated from Haiti, was brought to the pediatric ED by her mother for evaluation of a 2-hour history of gastric discomfort. Upon arrival at the ED waiting area, the patient experienced a sudden onset of generalized tonic-clonic movement with altered sensorium, though she did not fall to the ground and was not injured. Vital signs from triage were: blood pressure, 110/76 mm Hg; heart rate, 112 beats/min; respiratory rate, 22 breaths/min; and temperature, 97°F. Oxygen saturation was 98% on room air.

The patient was immediately attached to a cardiac monitor, given oxygen via a face mask, and received airway suctioning. Despite receiving a total of 4 mg of lorazepam, the seizure continued. Physical examination revealed no signs of external injury, but the ongoing generalized status epilepticus made the examination difficult.

What are the causes of refractory seizures in an adolescent patient?

The differential diagnosis for pediatric patients presenting with refractory seizure is the same as that for adult patients and should include treatment noncompliance, infection, vascular event (eg, stroke, hemorrhage), trauma (eg, cerebral contusions), metabolic and electrolyte disturbances, anticonvulsant toxicity, and exposure to a convulsant toxin.

While certain drugs (eg, cocaine) may cause status epilepticus through a secondary effect such as ischemia or a bleed, some drugs can directly cause refractory seizures. A few drugs and toxins are responsible for the majority of such seizures: bupropion; carbon monoxide; diphenhydramine; ethanol (withdrawal); hypoglycemics; lead; theophylline; tramadol; and certain antibiotics, including cephalosporins, penicillins, quinolones, and, in particular, isoniazid (INH).¹

Case Continuation

Upon further history-taking, the patient’s mother informed the ED staff that during a recent visit to a local clinic, her daughter tested positive on routine screening for tuberculosis and was given “some medications.” The patient’s mother further noted that her daughter was scheduled for a follow-up appointment at the same clinic later this morning. She believed the patient had taken “a few” of the prescribed pills at once to “catch-up” on missed doses prior to that appointment, and provided the ED staff with an empty bottle of INH that she had found in her daughter’s purse.

What are the signs and symptoms of acute isoniazid toxicity?

Isoniazid toxicity should be suspected in any patient who has access to INH—even if the drug was prescribed for someone other than the patient. Acute toxicity develops rapidly after the ingestion of supratherapeutic doses of INH and includes nausea, abdominal discomfort, vomiting, dizziness, and excessive fatigue or lethargy. Patients can present with tachycardia, stupor, agitation, mydriasis, increased anion gap metabolic acidosis, and encephalopathy.

Seizures occur due to an INH-induced functional pyridoxine deficiency. Isoniazid inhibits pyridoxine phosphokinase, the enzyme that converts pyridoxine (vitamin B₆) to its physiologically active form, pyridoxal 5’-phosphate (PLP). Because the conversion of glutamate (an excitatory neurotransmitter) to gamma-aminobutyric acid (GABA; the body’s main inhibitory neurotransmitter) is dependent on PLP, an excess of glutamate and a deficiency of GABA occurs following INH overdose. The result is neuroexcitation, which manifests as generalized seizures in affected patients.

The most consequential effect of INH overdose, however, is the development of seizure refractory to conventional therapy, such as benzodiazepines. This occurs because benzodiazepines are indirect-acting GABA agonists, and require the presence of GABA to elicit their effect. Therefore, due to the impairment of GABA synthesis, benzodiazepines are limited or ineffective as anticonvulsants. Although INH doses in excess of 20 mg/kg may result in neuroexcitation, refractory seizures are uncommon with doses <70 mg/kg.

Complications of chronic INH use include hepatotoxicity, and patients will present with jaundice, hepatomegaly, and right upper quadrant pain and tenderness. Isoniazid must be discontinued rapidly in patients demonstrating hepatotoxicity, and the risk/benefit of treatment reconsidered. Patients can also develop peripheral neuropathy while using INH therapeutically, and prophylactic vitamin B₆ supplementation is recommended for certain at-risk patients, such as those who are pregnant or breastfeeding.² Supplementation, however, neither reduces the risk of hepatotoxicity nor prevents onset of seizure following an INH overdose (the B₆ dose is not sufficient enough to exert this effect).

How is acute isoniazid-induced seizure managed?

Management of patients with refractory seizure should initially include an assessment and management of the patient’s airway, breathing, and circulation. Although seizures induced by INH toxicity are often resistant to benzodiazepines, these agents remain the first-line therapy. For patients who fail to respond to a reasonable trial of benzodiazepines (eg, lorazepam 6 mg intravenously [IV]), pyridoxine should be administered.³ The recommended dose is 1 g pyridoxine per every 1 g of INH ingested—if the initial dose ingested is known—with a maximum dose of 5 g pyridoxine. If the initial dose of INH is not known, 70 mg/kg of pyridoxine, up to 5 g, is recommended. Repeated doses of pyridoxine can be administered if the seizure continues, up to a total dose of 10 g in an adult. At extremely high doses, pyridoxine itself can be neurotoxic, limiting the maximal antidotal dose.

Rapid initiation of pyridoxine is a challenge since typical stocks in most EDs are not in an adequate supply required for treatment. Additionally, a typical vial of pyridoxine contains 100 mg, highlighting the rare need to open dozens of vials for a single patient. Drawing up adequate doses of the IV formulation can be a challenge and time-consuming.

Regardless, the most reliable and rapid route of administration for pyridoxine is IV, at a rate of 0.5 to 1 g/min. Even if the seizure resolves prior to completion of the initial dose, the remaining doses should still be administered over a 4- to 6-hour period. Oral or (more likely) nasogastric administration of pyridoxine can be administered if the IV formulation is not available, but neither are optimal routes of delivery. Every effort should be made to stock pyridoxine in the antidote supply in the ED to avoid time delays involving finding, preparing, and administering the drug in these scenarios. Previous studies have found that most EDs are not prepared to handle pyridoxine replacement.^4,5

Since benzodiazepines and barbiturates are GABA agonists with complementary mechanisms of actions to pyridoxine, they should be administered to potentiate the antiseizure effect of pyridoxine. If the seizure does not terminate, the use of propofol or general anesthesia may be required. Once the seizure is terminated, oral activated charcoal can be administered if the ingestion occurred within several hours of presentation. Given the rapid onset of effect of a large dose of INH, most patients will develop seizure shortly after exposure, limiting the benefits of both aggressive gastrointestinal decontamination and delayed activated charcoal. Charcoal also can be used for patients who overdose on INH but do not develop seizures.

Although the utility of a head computed tomography (CT) scan or laboratory studies is limited given the context of the exposure, these are generally obtained for patients with new-onset seizure. Since many patients with INH toxicity do not seize, such a patient may have a lower seizure threshold due to the existence of a subclinical cerebral lesion or metabolic abnormality.

Case Conclusion

The patient’s INH-induced refractory seizure was treated with pyridoxine. Her history suggested that she had ingested an unknown number of INH tablets within an hour. On this initial basis, an IV dose of 5,000 mg of pyridoxine was administered. The patient’s seizures terminated within 2 minutes of the infusion, and no additional doses of pyridoxine were required. Given the lack of concern for self-harm, an acetaminophen concentration was not obtained. A urine toxicology screen was negative for cocaine and amphetamines, and a CT scan of the head was negative for any abnormality. The patient was admitted to the pediatric intensive care unit for status epileptics and was discharged home on hospital day 2 after an uneventful stay.

Case

A 16-year-old girl, who recently emigrated from Haiti, was brought to the pediatric ED by her mother for evaluation of a 2-hour history of gastric discomfort. Upon arrival at the ED waiting area, the patient experienced a sudden onset of generalized tonic-clonic movement with altered sensorium, though she did not fall to the ground and was not injured. Vital signs from triage were: blood pressure, 110/76 mm Hg; heart rate, 112 beats/min; respiratory rate, 22 breaths/min; and temperature, 97°F. Oxygen saturation was 98% on room air.

The patient was immediately attached to a cardiac monitor, given oxygen via a face mask, and received airway suctioning. Despite receiving a total of 4 mg of lorazepam, the seizure continued. Physical examination revealed no signs of external injury, but the ongoing generalized status epilepticus made the examination difficult.

What are the causes of refractory seizures in an adolescent patient?

The differential diagnosis for pediatric patients presenting with refractory seizure is the same as that for adult patients and should include treatment noncompliance, infection, vascular event (eg, stroke, hemorrhage), trauma (eg, cerebral contusions), metabolic and electrolyte disturbances, anticonvulsant toxicity, and exposure to a convulsant toxin.

While certain drugs (eg, cocaine) may cause status epilepticus through a secondary effect such as ischemia or a bleed, some drugs can directly cause refractory seizures. A few drugs and toxins are responsible for the majority of such seizures: bupropion; carbon monoxide; diphenhydramine; ethanol (withdrawal); hypoglycemics; lead; theophylline; tramadol; and certain antibiotics, including cephalosporins, penicillins, quinolones, and, in particular, isoniazid (INH).¹

Case Continuation

Upon further history-taking, the patient’s mother informed the ED staff that during a recent visit to a local clinic, her daughter tested positive on routine screening for tuberculosis and was given “some medications.” The patient’s mother further noted that her daughter was scheduled for a follow-up appointment at the same clinic later this morning. She believed the patient had taken “a few” of the prescribed pills at once to “catch-up” on missed doses prior to that appointment, and provided the ED staff with an empty bottle of INH that she had found in her daughter’s purse.

What are the signs and symptoms of acute isoniazid toxicity?

Isoniazid toxicity should be suspected in any patient who has access to INH—even if the drug was prescribed for someone other than the patient. Acute toxicity develops rapidly after the ingestion of supratherapeutic doses of INH and includes nausea, abdominal discomfort, vomiting, dizziness, and excessive fatigue or lethargy. Patients can present with tachycardia, stupor, agitation, mydriasis, increased anion gap metabolic acidosis, and encephalopathy.

Seizures occur due to an INH-induced functional pyridoxine deficiency. Isoniazid inhibits pyridoxine phosphokinase, the enzyme that converts pyridoxine (vitamin B₆) to its physiologically active form, pyridoxal 5’-phosphate (PLP). Because the conversion of glutamate (an excitatory neurotransmitter) to gamma-aminobutyric acid (GABA; the body’s main inhibitory neurotransmitter) is dependent on PLP, an excess of glutamate and a deficiency of GABA occurs following INH overdose. The result is neuroexcitation, which manifests as generalized seizures in affected patients.

The most consequential effect of INH overdose, however, is the development of seizure refractory to conventional therapy, such as benzodiazepines. This occurs because benzodiazepines are indirect-acting GABA agonists, and require the presence of GABA to elicit their effect. Therefore, due to the impairment of GABA synthesis, benzodiazepines are limited or ineffective as anticonvulsants. Although INH doses in excess of 20 mg/kg may result in neuroexcitation, refractory seizures are uncommon with doses <70 mg/kg.

Complications of chronic INH use include hepatotoxicity, and patients will present with jaundice, hepatomegaly, and right upper quadrant pain and tenderness. Isoniazid must be discontinued rapidly in patients demonstrating hepatotoxicity, and the risk/benefit of treatment reconsidered. Patients can also develop peripheral neuropathy while using INH therapeutically, and prophylactic vitamin B₆ supplementation is recommended for certain at-risk patients, such as those who are pregnant or breastfeeding.² Supplementation, however, neither reduces the risk of hepatotoxicity nor prevents onset of seizure following an INH overdose (the B₆ dose is not sufficient enough to exert this effect).

How is acute isoniazid-induced seizure managed?

Management of patients with refractory seizure should initially include an assessment and management of the patient’s airway, breathing, and circulation. Although seizures induced by INH toxicity are often resistant to benzodiazepines, these agents remain the first-line therapy. For patients who fail to respond to a reasonable trial of benzodiazepines (eg, lorazepam 6 mg intravenously [IV]), pyridoxine should be administered.³ The recommended dose is 1 g pyridoxine per every 1 g of INH ingested—if the initial dose ingested is known—with a maximum dose of 5 g pyridoxine. If the initial dose of INH is not known, 70 mg/kg of pyridoxine, up to 5 g, is recommended. Repeated doses of pyridoxine can be administered if the seizure continues, up to a total dose of 10 g in an adult. At extremely high doses, pyridoxine itself can be neurotoxic, limiting the maximal antidotal dose.

Rapid initiation of pyridoxine is a challenge since typical stocks in most EDs are not in an adequate supply required for treatment. Additionally, a typical vial of pyridoxine contains 100 mg, highlighting the rare need to open dozens of vials for a single patient. Drawing up adequate doses of the IV formulation can be a challenge and time-consuming.

Regardless, the most reliable and rapid route of administration for pyridoxine is IV, at a rate of 0.5 to 1 g/min. Even if the seizure resolves prior to completion of the initial dose, the remaining doses should still be administered over a 4- to 6-hour period. Oral or (more likely) nasogastric administration of pyridoxine can be administered if the IV formulation is not available, but neither are optimal routes of delivery. Every effort should be made to stock pyridoxine in the antidote supply in the ED to avoid time delays involving finding, preparing, and administering the drug in these scenarios. Previous studies have found that most EDs are not prepared to handle pyridoxine replacement.^4,5

Since benzodiazepines and barbiturates are GABA agonists with complementary mechanisms of actions to pyridoxine, they should be administered to potentiate the antiseizure effect of pyridoxine. If the seizure does not terminate, the use of propofol or general anesthesia may be required. Once the seizure is terminated, oral activated charcoal can be administered if the ingestion occurred within several hours of presentation. Given the rapid onset of effect of a large dose of INH, most patients will develop seizure shortly after exposure, limiting the benefits of both aggressive gastrointestinal decontamination and delayed activated charcoal. Charcoal also can be used for patients who overdose on INH but do not develop seizures.

Although the utility of a head computed tomography (CT) scan or laboratory studies is limited given the context of the exposure, these are generally obtained for patients with new-onset seizure. Since many patients with INH toxicity do not seize, such a patient may have a lower seizure threshold due to the existence of a subclinical cerebral lesion or metabolic abnormality.

Case Conclusion

The patient’s INH-induced refractory seizure was treated with pyridoxine. Her history suggested that she had ingested an unknown number of INH tablets within an hour. On this initial basis, an IV dose of 5,000 mg of pyridoxine was administered. The patient’s seizures terminated within 2 minutes of the infusion, and no additional doses of pyridoxine were required. Given the lack of concern for self-harm, an acetaminophen concentration was not obtained. A urine toxicology screen was negative for cocaine and amphetamines, and a CT scan of the head was negative for any abnormality. The patient was admitted to the pediatric intensive care unit for status epileptics and was discharged home on hospital day 2 after an uneventful stay.

Case

A 41-year-old man presented to our ED with a 4-day history of epigastric pain radiating to the bilateral flanks and back. His medical history was significant for hypertension, for which he was prescribed isosorbide dinitrite 30 mg four times per day; however, he reported that he did not regularly take this medication.

The patient had visited our ED 3 days earlier with the same complaint. Since his blood pressure (BP) reading at the first ED presentation was 213/141 mm Hg, he had been admitted for hypertensive urgency. The patient’s BP was controlled with antihypertensive agents during his stay, but he continued to experience epigastric pain. A basic work-up for abdominal pain was ordered, the results of which were normal. Based on these findings, the patient’s pain was attributed to gastritis, and he was discharged home with instructions to return to the ED if his pain became worse or persisted.

At both ED presentations, the patient denied experiencing any nausea, vomiting, diarrhea, or chest pain. At the second presentation, his triage BP was 158/106 mm Hg. A chest X-ray, complete blood count (CBC), basic metabolic profile (BMP), hepatic panel, and lipase evaluation were all unremarkable, with the exception of a mild increase in creatinine to 1.38 mg/dL. A point-of-care (POC) ultrasound study of the aorta was normal.

Discussion

Isolated DCA is a rare cause of abdominal pain. The first documented case of isolated DCA is often incorrectly attributed to Bauersfeld’s¹ 1947 case series on dissections,but that report described superior mesenteric artery dissection rather than a celiac artery dissection. Watson’s² 1956 dissection series is also incorrectly cited as the first DCA, but that series described a dissection of the splenic artery, which is a branch of the celiac artery. In a 1959 series, Foord and Lewis³ described what is most likely the first report of DCA as an incidental finding at autopsy. More frequent descriptions in recent years are thought to be due to the routine use of abdominal CTA.⁴

Dissection of the celiac artery is a rare occurrence, with less than 100 cases reported, and little evidence exists to guide its management.⁵ These dissections represent 36.8% of all visceral artery dissections,⁶ which themselves are less common than renal, carotid, and vertebral artery dissections.⁷ Dissection of visceral arteries occurs predominantly in men and more often in middle-aged patients.⁸ Risk factors for DCA are thought to mirror risk factors for dissection of other arteries, including atherosclerotic disease, hypertension, connective tissue disorders, trauma, vasculitis, and pregnancy.^9-11

Signs and Symptoms

Patients with DCA typically present with sudden onset of epigastric, flank, and/or chest pain, though 50% of patients may be asymptomatic.¹² This pain is easily overlooked because the physical examination and laboratory studies are typically unremarkable.¹³ Fortunately, DCA is rarely accompanied by fatal organ dysfunction due to collateral flow from other vessels.¹⁴

Diagnosis and Management

While CTA with contrast is considered the mainstay of diagnosis of DCA,¹⁵ optimal treatment for DCA has not been well established. Management options include medical management, operative repair, and endovascular embolization. Medical management is reserved for stable patients without signs of end organ dysfunction. Typical management involves anticoagulation with warfarin for 3 to 6 months and strict BP control accompanied by close surveillance for progression.^10,13 Some clinicians have argued that anticoagulation therapy may be unnecessary and that risk factor modification and BP control alone may be sufficient.^5,6 Others have advocated that surgical management should be favored in cases of persistent pain, development of aneurysm, or threatened or compromised flow to end organs.⁷

Point-of-Care Ultrasound

The American College of Emergency Physicians considers ultrasound of the abdominal aorta a core application of emergency ultrasound.¹⁶ While sensitivity and specificity of emergency ultrasound for abdominal aortic aneurysm are well established, data supporting its use for screening for dissections are less definitive. With a sensitivity of 67% to 80% and a specificity of 99% to 100% with visualization of an intimal flap, aortic dissection screening using ultrasound is less reliable than most emergency physicians (EPs) would prefer.^17,18 There are no published data reporting the sensitivity or specificity of emergency ultrasound for DCA. However, the vascular surgery literature encourages color Doppler ultrasound as part of the initial diagnostic work-up for this rare entity.¹⁹ While this may seem like an area ripe for emergency ultrasound, it is important to note—as seen in our case—that the site of the dissection is not often seen. Instead, the use of Doppler allows a screening for an abnormal flow pattern suggestive of dissection.²⁰

Conclusion

In our case, both resident EPs and an expert fellowship-trained emergency ultrasound attending physician were unable to visualize a dissection—even after knowledge of the lesion was established by CTA. This points out a limitation of emergency ultrasound. While a POC ultrasound may be able to effectively rule in dissections of the aorta and its branches, we cannot reliably rule out these lesions. As EPs continue to expand the use of ultrasound, it is important to balance the desire for efficiency and cost-effectiveness with a high index of suspicion, experience, and clinical acumen.

Case

A 41-year-old man presented to our ED with a 4-day history of epigastric pain radiating to the bilateral flanks and back. His medical history was significant for hypertension, for which he was prescribed isosorbide dinitrite 30 mg four times per day; however, he reported that he did not regularly take this medication.

The patient had visited our ED 3 days earlier with the same complaint. Since his blood pressure (BP) reading at the first ED presentation was 213/141 mm Hg, he had been admitted for hypertensive urgency. The patient’s BP was controlled with antihypertensive agents during his stay, but he continued to experience epigastric pain. A basic work-up for abdominal pain was ordered, the results of which were normal. Based on these findings, the patient’s pain was attributed to gastritis, and he was discharged home with instructions to return to the ED if his pain became worse or persisted.

At both ED presentations, the patient denied experiencing any nausea, vomiting, diarrhea, or chest pain. At the second presentation, his triage BP was 158/106 mm Hg. A chest X-ray, complete blood count (CBC), basic metabolic profile (BMP), hepatic panel, and lipase evaluation were all unremarkable, with the exception of a mild increase in creatinine to 1.38 mg/dL. A point-of-care (POC) ultrasound study of the aorta was normal.

Discussion

Isolated DCA is a rare cause of abdominal pain. The first documented case of isolated DCA is often incorrectly attributed to Bauersfeld’s¹ 1947 case series on dissections,but that report described superior mesenteric artery dissection rather than a celiac artery dissection. Watson’s² 1956 dissection series is also incorrectly cited as the first DCA, but that series described a dissection of the splenic artery, which is a branch of the celiac artery. In a 1959 series, Foord and Lewis³ described what is most likely the first report of DCA as an incidental finding at autopsy. More frequent descriptions in recent years are thought to be due to the routine use of abdominal CTA.⁴

Dissection of the celiac artery is a rare occurrence, with less than 100 cases reported, and little evidence exists to guide its management.⁵ These dissections represent 36.8% of all visceral artery dissections,⁶ which themselves are less common than renal, carotid, and vertebral artery dissections.⁷ Dissection of visceral arteries occurs predominantly in men and more often in middle-aged patients.⁸ Risk factors for DCA are thought to mirror risk factors for dissection of other arteries, including atherosclerotic disease, hypertension, connective tissue disorders, trauma, vasculitis, and pregnancy.^9-11

Signs and Symptoms

Patients with DCA typically present with sudden onset of epigastric, flank, and/or chest pain, though 50% of patients may be asymptomatic.¹² This pain is easily overlooked because the physical examination and laboratory studies are typically unremarkable.¹³ Fortunately, DCA is rarely accompanied by fatal organ dysfunction due to collateral flow from other vessels.¹⁴

Diagnosis and Management

While CTA with contrast is considered the mainstay of diagnosis of DCA,¹⁵ optimal treatment for DCA has not been well established. Management options include medical management, operative repair, and endovascular embolization. Medical management is reserved for stable patients without signs of end organ dysfunction. Typical management involves anticoagulation with warfarin for 3 to 6 months and strict BP control accompanied by close surveillance for progression.^10,13 Some clinicians have argued that anticoagulation therapy may be unnecessary and that risk factor modification and BP control alone may be sufficient.^5,6 Others have advocated that surgical management should be favored in cases of persistent pain, development of aneurysm, or threatened or compromised flow to end organs.⁷

Point-of-Care Ultrasound

The American College of Emergency Physicians considers ultrasound of the abdominal aorta a core application of emergency ultrasound.¹⁶ While sensitivity and specificity of emergency ultrasound for abdominal aortic aneurysm are well established, data supporting its use for screening for dissections are less definitive. With a sensitivity of 67% to 80% and a specificity of 99% to 100% with visualization of an intimal flap, aortic dissection screening using ultrasound is less reliable than most emergency physicians (EPs) would prefer.^17,18 There are no published data reporting the sensitivity or specificity of emergency ultrasound for DCA. However, the vascular surgery literature encourages color Doppler ultrasound as part of the initial diagnostic work-up for this rare entity.¹⁹ While this may seem like an area ripe for emergency ultrasound, it is important to note—as seen in our case—that the site of the dissection is not often seen. Instead, the use of Doppler allows a screening for an abnormal flow pattern suggestive of dissection.²⁰

Conclusion

In our case, both resident EPs and an expert fellowship-trained emergency ultrasound attending physician were unable to visualize a dissection—even after knowledge of the lesion was established by CTA. This points out a limitation of emergency ultrasound. While a POC ultrasound may be able to effectively rule in dissections of the aorta and its branches, we cannot reliably rule out these lesions. As EPs continue to expand the use of ultrasound, it is important to balance the desire for efficiency and cost-effectiveness with a high index of suspicion, experience, and clinical acumen.

Case

A 41-year-old man presented to our ED with a 4-day history of epigastric pain radiating to the bilateral flanks and back. His medical history was significant for hypertension, for which he was prescribed isosorbide dinitrite 30 mg four times per day; however, he reported that he did not regularly take this medication.

The patient had visited our ED 3 days earlier with the same complaint. Since his blood pressure (BP) reading at the first ED presentation was 213/141 mm Hg, he had been admitted for hypertensive urgency. The patient’s BP was controlled with antihypertensive agents during his stay, but he continued to experience epigastric pain. A basic work-up for abdominal pain was ordered, the results of which were normal. Based on these findings, the patient’s pain was attributed to gastritis, and he was discharged home with instructions to return to the ED if his pain became worse or persisted.

At both ED presentations, the patient denied experiencing any nausea, vomiting, diarrhea, or chest pain. At the second presentation, his triage BP was 158/106 mm Hg. A chest X-ray, complete blood count (CBC), basic metabolic profile (BMP), hepatic panel, and lipase evaluation were all unremarkable, with the exception of a mild increase in creatinine to 1.38 mg/dL. A point-of-care (POC) ultrasound study of the aorta was normal.

Discussion

Isolated DCA is a rare cause of abdominal pain. The first documented case of isolated DCA is often incorrectly attributed to Bauersfeld’s¹ 1947 case series on dissections,but that report described superior mesenteric artery dissection rather than a celiac artery dissection. Watson’s² 1956 dissection series is also incorrectly cited as the first DCA, but that series described a dissection of the splenic artery, which is a branch of the celiac artery. In a 1959 series, Foord and Lewis³ described what is most likely the first report of DCA as an incidental finding at autopsy. More frequent descriptions in recent years are thought to be due to the routine use of abdominal CTA.⁴

Dissection of the celiac artery is a rare occurrence, with less than 100 cases reported, and little evidence exists to guide its management.⁵ These dissections represent 36.8% of all visceral artery dissections,⁶ which themselves are less common than renal, carotid, and vertebral artery dissections.⁷ Dissection of visceral arteries occurs predominantly in men and more often in middle-aged patients.⁸ Risk factors for DCA are thought to mirror risk factors for dissection of other arteries, including atherosclerotic disease, hypertension, connective tissue disorders, trauma, vasculitis, and pregnancy.^9-11

Signs and Symptoms

Patients with DCA typically present with sudden onset of epigastric, flank, and/or chest pain, though 50% of patients may be asymptomatic.¹² This pain is easily overlooked because the physical examination and laboratory studies are typically unremarkable.¹³ Fortunately, DCA is rarely accompanied by fatal organ dysfunction due to collateral flow from other vessels.¹⁴

Diagnosis and Management

While CTA with contrast is considered the mainstay of diagnosis of DCA,¹⁵ optimal treatment for DCA has not been well established. Management options include medical management, operative repair, and endovascular embolization. Medical management is reserved for stable patients without signs of end organ dysfunction. Typical management involves anticoagulation with warfarin for 3 to 6 months and strict BP control accompanied by close surveillance for progression.^10,13 Some clinicians have argued that anticoagulation therapy may be unnecessary and that risk factor modification and BP control alone may be sufficient.^5,6 Others have advocated that surgical management should be favored in cases of persistent pain, development of aneurysm, or threatened or compromised flow to end organs.⁷

Point-of-Care Ultrasound

The American College of Emergency Physicians considers ultrasound of the abdominal aorta a core application of emergency ultrasound.¹⁶ While sensitivity and specificity of emergency ultrasound for abdominal aortic aneurysm are well established, data supporting its use for screening for dissections are less definitive. With a sensitivity of 67% to 80% and a specificity of 99% to 100% with visualization of an intimal flap, aortic dissection screening using ultrasound is less reliable than most emergency physicians (EPs) would prefer.^17,18 There are no published data reporting the sensitivity or specificity of emergency ultrasound for DCA. However, the vascular surgery literature encourages color Doppler ultrasound as part of the initial diagnostic work-up for this rare entity.¹⁹ While this may seem like an area ripe for emergency ultrasound, it is important to note—as seen in our case—that the site of the dissection is not often seen. Instead, the use of Doppler allows a screening for an abnormal flow pattern suggestive of dissection.²⁰

Conclusion

In our case, both resident EPs and an expert fellowship-trained emergency ultrasound attending physician were unable to visualize a dissection—even after knowledge of the lesion was established by CTA. This points out a limitation of emergency ultrasound. While a POC ultrasound may be able to effectively rule in dissections of the aorta and its branches, we cannot reliably rule out these lesions. As EPs continue to expand the use of ultrasound, it is important to balance the desire for efficiency and cost-effectiveness with a high index of suspicion, experience, and clinical acumen.

Relapsing polychondritis (RP) is an autoimmune disease affecting cartilaginous structures such as the ears, respiratory passages, joints, and cardiovascular system.^1,2 In rare cases, the systemic effects of this autoimmune process can cause central nervous system (CNS) involvement such as meningoencephalitis (ME).³ In 2011, Wang et al⁴ described 4 cases of RP with ME and reviewed 24 cases from the literature. We present a case of a man with RP-associated ME that was responsive to steroid treatment. We also provide an updated review of the literature.

Case Report

A 44-year-old man developed gradually worsening bilateral ear pain, headaches, and seizures. He was briefly hospitalized and discharged with levetiracetam and quetiapine. However, his mental status continued to deteriorate and he was subsequently hospitalized 3 months later with confusion, hallucinations, and seizures.

On physical examination the patient was disoriented and unable to form cohesive sentences. He had bilateral tenderness, erythema, and edema of the auricles, which notably spared the lobules (Figure 1). The conjunctivae were injected bilaterally, and joint involvement included bilateral knee tenderness and swelling. Neurologic examination revealed questionable meningeal signs but no motor or sensory deficits. An extensive laboratory workup for the etiology of his altered mental status was unremarkable, except for a mildly elevated white blood cell count in the cerebrospinal fluid with predominantly lymphocytes. No infectious etiologies were identified on laboratory testing, and rheumatologic markers were negative including antinuclear antibody, rheumatoid factor, and anti–Sjögren syndrome antigen A/Sjögren syndrome antigen B. Magnetic resonance imaging revealed nonspecific findings of bilateral T2 hyperdensities in the subcortical white matter; however, cerebral angiography revealed no evidence of vasculitis. A biopsy of the right antihelix revealed prominent perichondritis and a neutrophilic inflammatory infiltrate with several lymphocytes and histiocytes (Figure 2). There was degeneration of the cartilaginous tissue with evidence of pyknotic nuclei, eosinophilia, and vacuolization of the chondrocytes. He was diagnosed with RP on the basis of clinical and histologic inflammation of the auricular cartilage, polyarthritis, and ocular inflammation.

Comment

Auricular inflammation is a hallmark of RP and is present in 83% to 95% of patients.^1,3 The affected ears can appear erythematous to violaceous with tender edema of the auricle that spares the lobules where no cartilage is present. The inflammation can extend into the ear canal and cause hearing loss, tinnitus, and vertigo. Histologically, RP can present with a nonspecific leukocytoclastic vasculitis and inflammatory destruction of the cartilage. Therefore, diagnosis of RP is reliant mainly on clinical characteristics rather than pathologic findings. In 1976, McAdam et al⁵ established diagnostic criteria for RP based on the presence of common clinical manifestations (eg, auricular chondritis, seronegative inflammatory polyarthritis, nasal chondritis, ocular inflammation). Michet et al⁶ later proposed major and minor criteria to classify and diagnose RP based on clinical manifestations. Diagnosis of our patient was confirmed by the presence of auricular chondritis, polyarthritis, and ocular inflammation. Diagnosing RP can be difficult because it has many systemic manifestations that can evoke a broad differential diagnosis. The time to diagnosis in our patient was 3 months, but the mean delay in diagnosis for patients with RP and ME is 2.9 years.⁴

The etiology of RP remains unclear, but current evidence supports an immune-mediated process directed toward proteins found in cartilage. Animal studies have suggested that RP may be driven by antibodies to matrillin 1 and type II collagen. There also may be a familial association with HLA-DR4 and genetic predisposition to autoimmune diseases in individuals affected by RP.^1,3 The pathogenesis of CNS involvement in RP is thought to be due to a localized small vessel vasculitis.^7,8 In our patient, however, cerebral angiography was negative for vasculitis, and thus our case may represent another mechanism for CNS involvement. There have been cases of encephalitis in RP caused by pathways other than CNS vasculitis. Kashihara et al⁹ reported a case of RP with encephalitis associated with antiglutamate receptor antibodies found in the cerebrospinal fluid and blood.

Treatment of RP has been based on pathophysiological considerations rather than empiric data due to its rarity. Relapsing polychondritis has been responsive to steroid treatment in reported cases as well as in our patient; however, in cases in which RP did not respond to steroids, infliximab may be effective for RP with ME.¹⁰ Further research regarding the treatment outcomes of RP with ME may be warranted.

Although rare, additional cases of RP with ME have been reported (Table). Wang et al⁴ described a series of 28 patients with RP and ME from 1960 to 2010. A PubMed search of articles indexed for MEDLINE that were published in the English-language literature from 2010 to 2016 was performed using the search terms relapsing polychondritis and nervous system. Including our patient, RP with ME was reported in 17 additional cases since Wang et al⁴ published their findings. These cases involved adults ranging in age from 44 to 73 years who were mainly men (14/17 [82%]). All of the patients presented with bilateral auricular chondritis, except for a case of unilateral ear involvement reported by Storey et al.¹¹ Common neurologic manifestations included fever, headache, and altered mental status. Motor symptoms ranged from dysarthria and agraphia¹² to hemiparesis.¹³ The mechanism of CNS involvement in RP was not identified in most cases; however, Mattiassich et al¹⁴ documented cerebral vasculitis in their patient, and Niwa et al¹⁶ found diffuse cerebral vasculitis on autopsy. Eleven of 17 (65%) cases responded to steroid treatment. Of the 6 cases in which RP did not respond to steroids, 2 patients died despite high-dose steroid treatment,^11,20 2 responded to infliximab,^10,15 1 responded to tocilizumab,²¹ and 1 was lost to follow-up after initial treatment failure.²⁰

Conclusion

Although rare, RP should not be overlooked in the inpatient setting due to its potential for life-threatening systemic effects. Early diagnosis of this condition may be of benefit to this select population of patients, and further research regarding the prognosis, mechanisms, and treatment of RP may be necessary in the future.

Relapsing polychondritis (RP) is an autoimmune disease affecting cartilaginous structures such as the ears, respiratory passages, joints, and cardiovascular system.^1,2 In rare cases, the systemic effects of this autoimmune process can cause central nervous system (CNS) involvement such as meningoencephalitis (ME).³ In 2011, Wang et al⁴ described 4 cases of RP with ME and reviewed 24 cases from the literature. We present a case of a man with RP-associated ME that was responsive to steroid treatment. We also provide an updated review of the literature.

Case Report

A 44-year-old man developed gradually worsening bilateral ear pain, headaches, and seizures. He was briefly hospitalized and discharged with levetiracetam and quetiapine. However, his mental status continued to deteriorate and he was subsequently hospitalized 3 months later with confusion, hallucinations, and seizures.

On physical examination the patient was disoriented and unable to form cohesive sentences. He had bilateral tenderness, erythema, and edema of the auricles, which notably spared the lobules (Figure 1). The conjunctivae were injected bilaterally, and joint involvement included bilateral knee tenderness and swelling. Neurologic examination revealed questionable meningeal signs but no motor or sensory deficits. An extensive laboratory workup for the etiology of his altered mental status was unremarkable, except for a mildly elevated white blood cell count in the cerebrospinal fluid with predominantly lymphocytes. No infectious etiologies were identified on laboratory testing, and rheumatologic markers were negative including antinuclear antibody, rheumatoid factor, and anti–Sjögren syndrome antigen A/Sjögren syndrome antigen B. Magnetic resonance imaging revealed nonspecific findings of bilateral T2 hyperdensities in the subcortical white matter; however, cerebral angiography revealed no evidence of vasculitis. A biopsy of the right antihelix revealed prominent perichondritis and a neutrophilic inflammatory infiltrate with several lymphocytes and histiocytes (Figure 2). There was degeneration of the cartilaginous tissue with evidence of pyknotic nuclei, eosinophilia, and vacuolization of the chondrocytes. He was diagnosed with RP on the basis of clinical and histologic inflammation of the auricular cartilage, polyarthritis, and ocular inflammation.

Comment

Auricular inflammation is a hallmark of RP and is present in 83% to 95% of patients.^1,3 The affected ears can appear erythematous to violaceous with tender edema of the auricle that spares the lobules where no cartilage is present. The inflammation can extend into the ear canal and cause hearing loss, tinnitus, and vertigo. Histologically, RP can present with a nonspecific leukocytoclastic vasculitis and inflammatory destruction of the cartilage. Therefore, diagnosis of RP is reliant mainly on clinical characteristics rather than pathologic findings. In 1976, McAdam et al⁵ established diagnostic criteria for RP based on the presence of common clinical manifestations (eg, auricular chondritis, seronegative inflammatory polyarthritis, nasal chondritis, ocular inflammation). Michet et al⁶ later proposed major and minor criteria to classify and diagnose RP based on clinical manifestations. Diagnosis of our patient was confirmed by the presence of auricular chondritis, polyarthritis, and ocular inflammation. Diagnosing RP can be difficult because it has many systemic manifestations that can evoke a broad differential diagnosis. The time to diagnosis in our patient was 3 months, but the mean delay in diagnosis for patients with RP and ME is 2.9 years.⁴

The etiology of RP remains unclear, but current evidence supports an immune-mediated process directed toward proteins found in cartilage. Animal studies have suggested that RP may be driven by antibodies to matrillin 1 and type II collagen. There also may be a familial association with HLA-DR4 and genetic predisposition to autoimmune diseases in individuals affected by RP.^1,3 The pathogenesis of CNS involvement in RP is thought to be due to a localized small vessel vasculitis.^7,8 In our patient, however, cerebral angiography was negative for vasculitis, and thus our case may represent another mechanism for CNS involvement. There have been cases of encephalitis in RP caused by pathways other than CNS vasculitis. Kashihara et al⁹ reported a case of RP with encephalitis associated with antiglutamate receptor antibodies found in the cerebrospinal fluid and blood.

Treatment of RP has been based on pathophysiological considerations rather than empiric data due to its rarity. Relapsing polychondritis has been responsive to steroid treatment in reported cases as well as in our patient; however, in cases in which RP did not respond to steroids, infliximab may be effective for RP with ME.¹⁰ Further research regarding the treatment outcomes of RP with ME may be warranted.

Although rare, additional cases of RP with ME have been reported (Table). Wang et al⁴ described a series of 28 patients with RP and ME from 1960 to 2010. A PubMed search of articles indexed for MEDLINE that were published in the English-language literature from 2010 to 2016 was performed using the search terms relapsing polychondritis and nervous system. Including our patient, RP with ME was reported in 17 additional cases since Wang et al⁴ published their findings. These cases involved adults ranging in age from 44 to 73 years who were mainly men (14/17 [82%]). All of the patients presented with bilateral auricular chondritis, except for a case of unilateral ear involvement reported by Storey et al.¹¹ Common neurologic manifestations included fever, headache, and altered mental status. Motor symptoms ranged from dysarthria and agraphia¹² to hemiparesis.¹³ The mechanism of CNS involvement in RP was not identified in most cases; however, Mattiassich et al¹⁴ documented cerebral vasculitis in their patient, and Niwa et al¹⁶ found diffuse cerebral vasculitis on autopsy. Eleven of 17 (65%) cases responded to steroid treatment. Of the 6 cases in which RP did not respond to steroids, 2 patients died despite high-dose steroid treatment,^11,20 2 responded to infliximab,^10,15 1 responded to tocilizumab,²¹ and 1 was lost to follow-up after initial treatment failure.²⁰

Conclusion

Although rare, RP should not be overlooked in the inpatient setting due to its potential for life-threatening systemic effects. Early diagnosis of this condition may be of benefit to this select population of patients, and further research regarding the prognosis, mechanisms, and treatment of RP may be necessary in the future.

Relapsing polychondritis (RP) is an autoimmune disease affecting cartilaginous structures such as the ears, respiratory passages, joints, and cardiovascular system.^1,2 In rare cases, the systemic effects of this autoimmune process can cause central nervous system (CNS) involvement such as meningoencephalitis (ME).³ In 2011, Wang et al⁴ described 4 cases of RP with ME and reviewed 24 cases from the literature. We present a case of a man with RP-associated ME that was responsive to steroid treatment. We also provide an updated review of the literature.

Case Report

A 44-year-old man developed gradually worsening bilateral ear pain, headaches, and seizures. He was briefly hospitalized and discharged with levetiracetam and quetiapine. However, his mental status continued to deteriorate and he was subsequently hospitalized 3 months later with confusion, hallucinations, and seizures.

On physical examination the patient was disoriented and unable to form cohesive sentences. He had bilateral tenderness, erythema, and edema of the auricles, which notably spared the lobules (Figure 1). The conjunctivae were injected bilaterally, and joint involvement included bilateral knee tenderness and swelling. Neurologic examination revealed questionable meningeal signs but no motor or sensory deficits. An extensive laboratory workup for the etiology of his altered mental status was unremarkable, except for a mildly elevated white blood cell count in the cerebrospinal fluid with predominantly lymphocytes. No infectious etiologies were identified on laboratory testing, and rheumatologic markers were negative including antinuclear antibody, rheumatoid factor, and anti–Sjögren syndrome antigen A/Sjögren syndrome antigen B. Magnetic resonance imaging revealed nonspecific findings of bilateral T2 hyperdensities in the subcortical white matter; however, cerebral angiography revealed no evidence of vasculitis. A biopsy of the right antihelix revealed prominent perichondritis and a neutrophilic inflammatory infiltrate with several lymphocytes and histiocytes (Figure 2). There was degeneration of the cartilaginous tissue with evidence of pyknotic nuclei, eosinophilia, and vacuolization of the chondrocytes. He was diagnosed with RP on the basis of clinical and histologic inflammation of the auricular cartilage, polyarthritis, and ocular inflammation.

Comment

Auricular inflammation is a hallmark of RP and is present in 83% to 95% of patients.^1,3 The affected ears can appear erythematous to violaceous with tender edema of the auricle that spares the lobules where no cartilage is present. The inflammation can extend into the ear canal and cause hearing loss, tinnitus, and vertigo. Histologically, RP can present with a nonspecific leukocytoclastic vasculitis and inflammatory destruction of the cartilage. Therefore, diagnosis of RP is reliant mainly on clinical characteristics rather than pathologic findings. In 1976, McAdam et al⁵ established diagnostic criteria for RP based on the presence of common clinical manifestations (eg, auricular chondritis, seronegative inflammatory polyarthritis, nasal chondritis, ocular inflammation). Michet et al⁶ later proposed major and minor criteria to classify and diagnose RP based on clinical manifestations. Diagnosis of our patient was confirmed by the presence of auricular chondritis, polyarthritis, and ocular inflammation. Diagnosing RP can be difficult because it has many systemic manifestations that can evoke a broad differential diagnosis. The time to diagnosis in our patient was 3 months, but the mean delay in diagnosis for patients with RP and ME is 2.9 years.⁴

The etiology of RP remains unclear, but current evidence supports an immune-mediated process directed toward proteins found in cartilage. Animal studies have suggested that RP may be driven by antibodies to matrillin 1 and type II collagen. There also may be a familial association with HLA-DR4 and genetic predisposition to autoimmune diseases in individuals affected by RP.^1,3 The pathogenesis of CNS involvement in RP is thought to be due to a localized small vessel vasculitis.^7,8 In our patient, however, cerebral angiography was negative for vasculitis, and thus our case may represent another mechanism for CNS involvement. There have been cases of encephalitis in RP caused by pathways other than CNS vasculitis. Kashihara et al⁹ reported a case of RP with encephalitis associated with antiglutamate receptor antibodies found in the cerebrospinal fluid and blood.

Treatment of RP has been based on pathophysiological considerations rather than empiric data due to its rarity. Relapsing polychondritis has been responsive to steroid treatment in reported cases as well as in our patient; however, in cases in which RP did not respond to steroids, infliximab may be effective for RP with ME.¹⁰ Further research regarding the treatment outcomes of RP with ME may be warranted.

Although rare, additional cases of RP with ME have been reported (Table). Wang et al⁴ described a series of 28 patients with RP and ME from 1960 to 2010. A PubMed search of articles indexed for MEDLINE that were published in the English-language literature from 2010 to 2016 was performed using the search terms relapsing polychondritis and nervous system. Including our patient, RP with ME was reported in 17 additional cases since Wang et al⁴ published their findings. These cases involved adults ranging in age from 44 to 73 years who were mainly men (14/17 [82%]). All of the patients presented with bilateral auricular chondritis, except for a case of unilateral ear involvement reported by Storey et al.¹¹ Common neurologic manifestations included fever, headache, and altered mental status. Motor symptoms ranged from dysarthria and agraphia¹² to hemiparesis.¹³ The mechanism of CNS involvement in RP was not identified in most cases; however, Mattiassich et al¹⁴ documented cerebral vasculitis in their patient, and Niwa et al¹⁶ found diffuse cerebral vasculitis on autopsy. Eleven of 17 (65%) cases responded to steroid treatment. Of the 6 cases in which RP did not respond to steroids, 2 patients died despite high-dose steroid treatment,^11,20 2 responded to infliximab,^10,15 1 responded to tocilizumab,²¹ and 1 was lost to follow-up after initial treatment failure.²⁰

Conclusion

Although rare, RP should not be overlooked in the inpatient setting due to its potential for life-threatening systemic effects. Early diagnosis of this condition may be of benefit to this select population of patients, and further research regarding the prognosis, mechanisms, and treatment of RP may be necessary in the future.

Epidermal nevi can occur in isolation or in association with internal abnormalities. Epidermal nevus syndrome (ENS) is a heterogeneous group of neurocutaneous disorders characterized by mosaicism and epidermal nevi found in association with various systemic abnormalities.^1-4 There are many possible associated systemic findings, including abnormalities of the central nervous, musculoskeletal, renal, and hematologic systems. Epidermal nevi have been associated with internal malignancies. We present the case of a patient with epidermal nevi associated with papillary transitional cell bladder carcinoma. According to a PubMed search of articles indexed for MEDLINE using the search terms transitional cell bladder carcinoma and epidermal nevus, there have only been 4 other cases of transitional cell bladder carcinoma and ENS reported in the literature,^5-8 2 of which were reports of papillary transitional cell bladder carcinoma.^5,6

Case Report

A 29-year-old woman presented to our clinic with a rash that had been present since 3 years of age. The emergency department consulted dermatology for evaluation of what was believed to be contact dermatitis; however, upon questioning the patient, it was revealed that the rash was chronic and persistent.

The rash was nonpruritic and was located on the face, hands (Figure 1), chest, buttocks, thighs, legs, and back (Figure 2). Although asymptomatic, the appearance of the skin caused the patient some emotional distress. As a child she had been evaluated by a dermatologist and a biopsy was performed, but she did not recall the results or have any records. She had been prescribed an oral medication by the dermatologist, but treatment was terminated early due to nausea. The skin lesions did not improve with the short course of treatment.

Eighteen months prior to presentation to our clinic, the patient was discovered to have hematuria on routine examination by her primary care physician. At that time, the patient underwent a workup for hematuria and a mass was discovered in the bladder via cystoscopy. A diagnosis of low-grade papillary transitional cell bladder carcinoma was made, and she underwent a partial cystectomy. No radiation or chemotherapy was required. The remainder of her medical history was only remarkable for asthma, which was well controlled with albuterol. On examination, generalized, hyperpigmented, reticulated patches, macules, and hyperpigmented verrucous plaques were distributed along the Blaschko lines, sparing the face. No limb abnormalities or dental or nail abnormalities were noted. Examination of the axillary and cervical lymph nodes was unremarkable, and no neurological abnormalities were noted. A 3-mm punch biopsy of the mid upper back was performed. Histopathology revealed papillomatous, nonorganoid, nonepidermolytic hyperplasia of the epidermis with elongated rete ridges (Figure 3), which was diagnosed as a nonorganoid nonepidermolytic epidermal nevus.

Comment

Epidermal nevus syndrome is a group of disorders characterized by both local or systematized epidermal nevi and systemic findings. Solomon et al⁴ first coined the term epidermal nevus syndrome more than 40 years ago; however, since then there has been confusion about how to define ENS. Epidermal nevus syndrome has been considered an umbrella term that includes more specific syndromes involving epidermal nevi, such as Proteus syndrome and Schimmelpenning syndrome; conversely, it also has been considered a term for those who do not meet the criteria for more specific syndromes.^1,9 Happle¹ discussed that the genetic variations found in ENS warrant recognition. Simply put, ENS is a heterogeneous group of syndromes that are similar in that they involve epidermal nevi and internal abnormalities but are genetically distinct. The list of definitive ENSs, as suggested by Happle¹ and others, will likely continue to grow.^3,5

The exact pathomechanism of ENS is unknown, but the clinical presentation most likely represents a lethal disorder mitigated by mosaicism.^2,9 Gene defects vary depending on the specific ENS. For instance, the phosphatase and tensin homolog gene, PTEN, mutations have been associated with type 2 segmental Cowden disease. Fibroblast growth factor receptor 3, FGFR3, mutations have been linked to Garcia-Hafner-Happle syndrome.³FGFR3 mutations have been found in nonepidermolytic epidermal nevi, and some suggest that the majority of epidermal nevi exhibit mutations in FGFR3.^5,10,11 On the other hand, other gene defects have not been elucidated, such as in Schimmelpenning syndrome.³

Clinically, ENS may involve nonepidermolytic verrucous nevi, sebaceous nevi, organoid nevi, linear Cowden nevi, and woolly hair nevi. Lesions may be flesh-colored, pink, yellow, or hyperpigmented plaques in a blaschkoid distribution and may be localized or systematized. Nevi typically are present at birth or develop within the first year of life.^9,12,13 Other cutaneous findings may be noted apart from epidermal nevi, including melanocytic nevi, aplasia cutis congenita, and hemangiomas.^13,14

Extracutaneous findings include central nervous system, skeletal, ocular, cardiac, and genitourinary defects, which are often observed in these patients.^3,9,13,14 Central nervous system findings are seen in 50% to 70% of cases, with seizures and mental retardation among the most common.^13-15 Genitourinary abnormalities associated with epidermal nevi, including horseshoe kidney, cystic kidney, duplicated collecting system, testicular and paratesticular tumors, and hypospadias have been documented in the literature.¹⁶ Our patient had a history of papillary transitional cell bladder carcinoma, which is rare for a patient younger than 30 years. The overall median age of diagnosis of bladder cancer is 65 years, and it is more common in men than in women.¹⁷ Transitional cell carcinomas account for approximately 90% of all bladder cancers in the United States. Other common types of bladder cancer include squamous cell carcinoma, adenocarcinoma, and rhabdomyosarcoma.¹⁶ Typically, transitional cell carcinoma is associated with smoking, exposure to aniline dyes, cyclophosphamide, and living in industrialized areas.^16,17 Individuals who work with textiles, dyes, leather, tires, rubber, and/or petroleum; painters; truck drivers; drill press operators; and hairdressers are at an increased risk for development of bladder cancer.¹⁶

Interestingly, it has been shown in some studies that papillary transitional cell bladder carcinoma frequently is associated with FGFR3 mutations, which may be the missing link in the rare finding of papillary transitional cell bladder carcinoma and epidermal nevi.^5,18,19 In addition, PTEN mutations also have been identified in low-grade papillary transitional cell carcinomas of the bladder, another gene linked to an ENS with type 2 segmental Cowden disease.^3,20

Histopathologically, epidermal nevi have 10 different descriptions. Our patient had a nonorganoid nonepidermolytic epidermal nevus characterized by hyperkeratosis, acanthosis, papillomatosis, and elongated rete ridges. Focal acantholysis and epidermolytic hyperkeratosis also is seen in some epidermal nevi but was not seen in this case.^9,21

Simple epidermal nevi occur in approximately 1 in 1000 newborns; however, when a child presents with multiple or systematized epidermal nevi, investigation should be undertaken for other possible associations.^13,14 Of note, there have been several cases of squamous cell, verrucous, basal cell, and adnexal carcinomas arising in linear epidermal nevi.^22-24

Epidermal nevi can be difficult to treat. Some patients are troubled by the appearance of these nevi, especially those with systematized disease. Unfortunately, for patients with multiple nevi or systematized disease, there are no consistently effective treatment options; however, there are case reports^25,26 in the literature citing improvement or cure of epidermal nevi with full-thickness excision, continuous and pulsed CO₂ laser, pulsed dye laser, and erbium-doped YAG laser.²⁵ Other therapies that have been purported to help improve epidermal nevi are topical and oral retinoids, corticosteroids, topical 5-fluorouracil, anthralin, and podophyllin.²⁶

Conclusion

Transitional cell bladder carcinoma is rare in patients in the third decade of life and younger. Given the age of our patient and her concomitant lack of risk factors, such as older age, history of smoking, and exposure to certain chemicals (eg, aniline dyes) and medications (eg, cyclophosphamide), it is more likely that the finding of papillary transitional cell bladder carcinoma and ENS are related. A clear genetic link between ENS and transitional cell papillary bladder carcinoma has yet to be elucidated, but the FGFR3 gene is promising.

Epidermal nevi can occur in isolation or in association with internal abnormalities. Epidermal nevus syndrome (ENS) is a heterogeneous group of neurocutaneous disorders characterized by mosaicism and epidermal nevi found in association with various systemic abnormalities.^1-4 There are many possible associated systemic findings, including abnormalities of the central nervous, musculoskeletal, renal, and hematologic systems. Epidermal nevi have been associated with internal malignancies. We present the case of a patient with epidermal nevi associated with papillary transitional cell bladder carcinoma. According to a PubMed search of articles indexed for MEDLINE using the search terms transitional cell bladder carcinoma and epidermal nevus, there have only been 4 other cases of transitional cell bladder carcinoma and ENS reported in the literature,^5-8 2 of which were reports of papillary transitional cell bladder carcinoma.^5,6

Case Report

A 29-year-old woman presented to our clinic with a rash that had been present since 3 years of age. The emergency department consulted dermatology for evaluation of what was believed to be contact dermatitis; however, upon questioning the patient, it was revealed that the rash was chronic and persistent.

The rash was nonpruritic and was located on the face, hands (Figure 1), chest, buttocks, thighs, legs, and back (Figure 2). Although asymptomatic, the appearance of the skin caused the patient some emotional distress. As a child she had been evaluated by a dermatologist and a biopsy was performed, but she did not recall the results or have any records. She had been prescribed an oral medication by the dermatologist, but treatment was terminated early due to nausea. The skin lesions did not improve with the short course of treatment.

Eighteen months prior to presentation to our clinic, the patient was discovered to have hematuria on routine examination by her primary care physician. At that time, the patient underwent a workup for hematuria and a mass was discovered in the bladder via cystoscopy. A diagnosis of low-grade papillary transitional cell bladder carcinoma was made, and she underwent a partial cystectomy. No radiation or chemotherapy was required. The remainder of her medical history was only remarkable for asthma, which was well controlled with albuterol. On examination, generalized, hyperpigmented, reticulated patches, macules, and hyperpigmented verrucous plaques were distributed along the Blaschko lines, sparing the face. No limb abnormalities or dental or nail abnormalities were noted. Examination of the axillary and cervical lymph nodes was unremarkable, and no neurological abnormalities were noted. A 3-mm punch biopsy of the mid upper back was performed. Histopathology revealed papillomatous, nonorganoid, nonepidermolytic hyperplasia of the epidermis with elongated rete ridges (Figure 3), which was diagnosed as a nonorganoid nonepidermolytic epidermal nevus.

Comment

Epidermal nevus syndrome is a group of disorders characterized by both local or systematized epidermal nevi and systemic findings. Solomon et al⁴ first coined the term epidermal nevus syndrome more than 40 years ago; however, since then there has been confusion about how to define ENS. Epidermal nevus syndrome has been considered an umbrella term that includes more specific syndromes involving epidermal nevi, such as Proteus syndrome and Schimmelpenning syndrome; conversely, it also has been considered a term for those who do not meet the criteria for more specific syndromes.^1,9 Happle¹ discussed that the genetic variations found in ENS warrant recognition. Simply put, ENS is a heterogeneous group of syndromes that are similar in that they involve epidermal nevi and internal abnormalities but are genetically distinct. The list of definitive ENSs, as suggested by Happle¹ and others, will likely continue to grow.^3,5

The exact pathomechanism of ENS is unknown, but the clinical presentation most likely represents a lethal disorder mitigated by mosaicism.^2,9 Gene defects vary depending on the specific ENS. For instance, the phosphatase and tensin homolog gene, PTEN, mutations have been associated with type 2 segmental Cowden disease. Fibroblast growth factor receptor 3, FGFR3, mutations have been linked to Garcia-Hafner-Happle syndrome.³FGFR3 mutations have been found in nonepidermolytic epidermal nevi, and some suggest that the majority of epidermal nevi exhibit mutations in FGFR3.^5,10,11 On the other hand, other gene defects have not been elucidated, such as in Schimmelpenning syndrome.³

Clinically, ENS may involve nonepidermolytic verrucous nevi, sebaceous nevi, organoid nevi, linear Cowden nevi, and woolly hair nevi. Lesions may be flesh-colored, pink, yellow, or hyperpigmented plaques in a blaschkoid distribution and may be localized or systematized. Nevi typically are present at birth or develop within the first year of life.^9,12,13 Other cutaneous findings may be noted apart from epidermal nevi, including melanocytic nevi, aplasia cutis congenita, and hemangiomas.^13,14

Extracutaneous findings include central nervous system, skeletal, ocular, cardiac, and genitourinary defects, which are often observed in these patients.^3,9,13,14 Central nervous system findings are seen in 50% to 70% of cases, with seizures and mental retardation among the most common.^13-15 Genitourinary abnormalities associated with epidermal nevi, including horseshoe kidney, cystic kidney, duplicated collecting system, testicular and paratesticular tumors, and hypospadias have been documented in the literature.¹⁶ Our patient had a history of papillary transitional cell bladder carcinoma, which is rare for a patient younger than 30 years. The overall median age of diagnosis of bladder cancer is 65 years, and it is more common in men than in women.¹⁷ Transitional cell carcinomas account for approximately 90% of all bladder cancers in the United States. Other common types of bladder cancer include squamous cell carcinoma, adenocarcinoma, and rhabdomyosarcoma.¹⁶ Typically, transitional cell carcinoma is associated with smoking, exposure to aniline dyes, cyclophosphamide, and living in industrialized areas.^16,17 Individuals who work with textiles, dyes, leather, tires, rubber, and/or petroleum; painters; truck drivers; drill press operators; and hairdressers are at an increased risk for development of bladder cancer.¹⁶

Interestingly, it has been shown in some studies that papillary transitional cell bladder carcinoma frequently is associated with FGFR3 mutations, which may be the missing link in the rare finding of papillary transitional cell bladder carcinoma and epidermal nevi.^5,18,19 In addition, PTEN mutations also have been identified in low-grade papillary transitional cell carcinomas of the bladder, another gene linked to an ENS with type 2 segmental Cowden disease.^3,20

Histopathologically, epidermal nevi have 10 different descriptions. Our patient had a nonorganoid nonepidermolytic epidermal nevus characterized by hyperkeratosis, acanthosis, papillomatosis, and elongated rete ridges. Focal acantholysis and epidermolytic hyperkeratosis also is seen in some epidermal nevi but was not seen in this case.^9,21

Simple epidermal nevi occur in approximately 1 in 1000 newborns; however, when a child presents with multiple or systematized epidermal nevi, investigation should be undertaken for other possible associations.^13,14 Of note, there have been several cases of squamous cell, verrucous, basal cell, and adnexal carcinomas arising in linear epidermal nevi.^22-24

Epidermal nevi can be difficult to treat. Some patients are troubled by the appearance of these nevi, especially those with systematized disease. Unfortunately, for patients with multiple nevi or systematized disease, there are no consistently effective treatment options; however, there are case reports^25,26 in the literature citing improvement or cure of epidermal nevi with full-thickness excision, continuous and pulsed CO₂ laser, pulsed dye laser, and erbium-doped YAG laser.²⁵ Other therapies that have been purported to help improve epidermal nevi are topical and oral retinoids, corticosteroids, topical 5-fluorouracil, anthralin, and podophyllin.²⁶

Conclusion

Transitional cell bladder carcinoma is rare in patients in the third decade of life and younger. Given the age of our patient and her concomitant lack of risk factors, such as older age, history of smoking, and exposure to certain chemicals (eg, aniline dyes) and medications (eg, cyclophosphamide), it is more likely that the finding of papillary transitional cell bladder carcinoma and ENS are related. A clear genetic link between ENS and transitional cell papillary bladder carcinoma has yet to be elucidated, but the FGFR3 gene is promising.

Epidermal nevi can occur in isolation or in association with internal abnormalities. Epidermal nevus syndrome (ENS) is a heterogeneous group of neurocutaneous disorders characterized by mosaicism and epidermal nevi found in association with various systemic abnormalities.^1-4 There are many possible associated systemic findings, including abnormalities of the central nervous, musculoskeletal, renal, and hematologic systems. Epidermal nevi have been associated with internal malignancies. We present the case of a patient with epidermal nevi associated with papillary transitional cell bladder carcinoma. According to a PubMed search of articles indexed for MEDLINE using the search terms transitional cell bladder carcinoma and epidermal nevus, there have only been 4 other cases of transitional cell bladder carcinoma and ENS reported in the literature,^5-8 2 of which were reports of papillary transitional cell bladder carcinoma.^5,6

Case Report

A 29-year-old woman presented to our clinic with a rash that had been present since 3 years of age. The emergency department consulted dermatology for evaluation of what was believed to be contact dermatitis; however, upon questioning the patient, it was revealed that the rash was chronic and persistent.

The rash was nonpruritic and was located on the face, hands (Figure 1), chest, buttocks, thighs, legs, and back (Figure 2). Although asymptomatic, the appearance of the skin caused the patient some emotional distress. As a child she had been evaluated by a dermatologist and a biopsy was performed, but she did not recall the results or have any records. She had been prescribed an oral medication by the dermatologist, but treatment was terminated early due to nausea. The skin lesions did not improve with the short course of treatment.

Eighteen months prior to presentation to our clinic, the patient was discovered to have hematuria on routine examination by her primary care physician. At that time, the patient underwent a workup for hematuria and a mass was discovered in the bladder via cystoscopy. A diagnosis of low-grade papillary transitional cell bladder carcinoma was made, and she underwent a partial cystectomy. No radiation or chemotherapy was required. The remainder of her medical history was only remarkable for asthma, which was well controlled with albuterol. On examination, generalized, hyperpigmented, reticulated patches, macules, and hyperpigmented verrucous plaques were distributed along the Blaschko lines, sparing the face. No limb abnormalities or dental or nail abnormalities were noted. Examination of the axillary and cervical lymph nodes was unremarkable, and no neurological abnormalities were noted. A 3-mm punch biopsy of the mid upper back was performed. Histopathology revealed papillomatous, nonorganoid, nonepidermolytic hyperplasia of the epidermis with elongated rete ridges (Figure 3), which was diagnosed as a nonorganoid nonepidermolytic epidermal nevus.

Comment

Epidermal nevus syndrome is a group of disorders characterized by both local or systematized epidermal nevi and systemic findings. Solomon et al⁴ first coined the term epidermal nevus syndrome more than 40 years ago; however, since then there has been confusion about how to define ENS. Epidermal nevus syndrome has been considered an umbrella term that includes more specific syndromes involving epidermal nevi, such as Proteus syndrome and Schimmelpenning syndrome; conversely, it also has been considered a term for those who do not meet the criteria for more specific syndromes.^1,9 Happle¹ discussed that the genetic variations found in ENS warrant recognition. Simply put, ENS is a heterogeneous group of syndromes that are similar in that they involve epidermal nevi and internal abnormalities but are genetically distinct. The list of definitive ENSs, as suggested by Happle¹ and others, will likely continue to grow.^3,5

The exact pathomechanism of ENS is unknown, but the clinical presentation most likely represents a lethal disorder mitigated by mosaicism.^2,9 Gene defects vary depending on the specific ENS. For instance, the phosphatase and tensin homolog gene, PTEN, mutations have been associated with type 2 segmental Cowden disease. Fibroblast growth factor receptor 3, FGFR3, mutations have been linked to Garcia-Hafner-Happle syndrome.³FGFR3 mutations have been found in nonepidermolytic epidermal nevi, and some suggest that the majority of epidermal nevi exhibit mutations in FGFR3.^5,10,11 On the other hand, other gene defects have not been elucidated, such as in Schimmelpenning syndrome.³

Clinically, ENS may involve nonepidermolytic verrucous nevi, sebaceous nevi, organoid nevi, linear Cowden nevi, and woolly hair nevi. Lesions may be flesh-colored, pink, yellow, or hyperpigmented plaques in a blaschkoid distribution and may be localized or systematized. Nevi typically are present at birth or develop within the first year of life.^9,12,13 Other cutaneous findings may be noted apart from epidermal nevi, including melanocytic nevi, aplasia cutis congenita, and hemangiomas.^13,14

Extracutaneous findings include central nervous system, skeletal, ocular, cardiac, and genitourinary defects, which are often observed in these patients.^3,9,13,14 Central nervous system findings are seen in 50% to 70% of cases, with seizures and mental retardation among the most common.^13-15 Genitourinary abnormalities associated with epidermal nevi, including horseshoe kidney, cystic kidney, duplicated collecting system, testicular and paratesticular tumors, and hypospadias have been documented in the literature.¹⁶ Our patient had a history of papillary transitional cell bladder carcinoma, which is rare for a patient younger than 30 years. The overall median age of diagnosis of bladder cancer is 65 years, and it is more common in men than in women.¹⁷ Transitional cell carcinomas account for approximately 90% of all bladder cancers in the United States. Other common types of bladder cancer include squamous cell carcinoma, adenocarcinoma, and rhabdomyosarcoma.¹⁶ Typically, transitional cell carcinoma is associated with smoking, exposure to aniline dyes, cyclophosphamide, and living in industrialized areas.^16,17 Individuals who work with textiles, dyes, leather, tires, rubber, and/or petroleum; painters; truck drivers; drill press operators; and hairdressers are at an increased risk for development of bladder cancer.¹⁶

Interestingly, it has been shown in some studies that papillary transitional cell bladder carcinoma frequently is associated with FGFR3 mutations, which may be the missing link in the rare finding of papillary transitional cell bladder carcinoma and epidermal nevi.^5,18,19 In addition, PTEN mutations also have been identified in low-grade papillary transitional cell carcinomas of the bladder, another gene linked to an ENS with type 2 segmental Cowden disease.^3,20

Histopathologically, epidermal nevi have 10 different descriptions. Our patient had a nonorganoid nonepidermolytic epidermal nevus characterized by hyperkeratosis, acanthosis, papillomatosis, and elongated rete ridges. Focal acantholysis and epidermolytic hyperkeratosis also is seen in some epidermal nevi but was not seen in this case.^9,21

Simple epidermal nevi occur in approximately 1 in 1000 newborns; however, when a child presents with multiple or systematized epidermal nevi, investigation should be undertaken for other possible associations.^13,14 Of note, there have been several cases of squamous cell, verrucous, basal cell, and adnexal carcinomas arising in linear epidermal nevi.^22-24

Epidermal nevi can be difficult to treat. Some patients are troubled by the appearance of these nevi, especially those with systematized disease. Unfortunately, for patients with multiple nevi or systematized disease, there are no consistently effective treatment options; however, there are case reports^25,26 in the literature citing improvement or cure of epidermal nevi with full-thickness excision, continuous and pulsed CO₂ laser, pulsed dye laser, and erbium-doped YAG laser.²⁵ Other therapies that have been purported to help improve epidermal nevi are topical and oral retinoids, corticosteroids, topical 5-fluorouracil, anthralin, and podophyllin.²⁶

Conclusion

Transitional cell bladder carcinoma is rare in patients in the third decade of life and younger. Given the age of our patient and her concomitant lack of risk factors, such as older age, history of smoking, and exposure to certain chemicals (eg, aniline dyes) and medications (eg, cyclophosphamide), it is more likely that the finding of papillary transitional cell bladder carcinoma and ENS are related. A clear genetic link between ENS and transitional cell papillary bladder carcinoma has yet to be elucidated, but the FGFR3 gene is promising.

THE CASE

A 44-year-old woman with a 15-year history of type 2 diabetes sought care for a firm, non-tender mass in the medial lower quadrant of her right breast. She hadn’t experienced any skin changes or axillary lymphadenopathy. The patient had immigrated to California from Afghanistan 22 years earlier, at which time she was briefly married to an Afghan man suffering from a chronic cough.

Mammography revealed a 3.5 x 4 x 4 cm lesion at the chest wall, which was highly suspicious for carcinoma (FIGURES 1A AND 1B). Sonography showed a heterogenous hypoechoic and isoechoic mass with posterior acoustic enhancement (FIGURE 1C). An excisional biopsy was performed.

One week postoperatively, the patient presented to the emergency department for a worsening nonproductive cough that intensified when supine, and was associated with subscapular pleuritic pain. She denied fever or weight loss. Biopsy results were pending.

THE DIAGNOSIS

Chest x-rays revealed a large right pleural effusion that was presumed to be malignant (FIGURES 1D AND 1E). Thoracentesis yielded 1.5 liters of tea-colored exudate containing 2800 nucleated cells/mL—63% lymphocytes and 37% neutrophils—and a pleural fluid to serum protein ratio >0.5. Adenosine deaminase was <1 U/L. Fluid Gram stain, acid-fast bacillus (AFB) fluorescent antibody testing, AFB cultures, and cytology were negative. Computed tomography (CT) subsequently demonstrated recurrent effusion without hilar or mediastinal lymphadenopathy or pleural enhancement (FIGURE 1F).

Histologically, the breast mass showed caseating granulomatous inflammation (FIGURES 1G AND 1H). An AFB stain was negative. Polymerase chain reaction (PCR) performed on DNA extracted from the formalin-fixed, paraffin-embedded biopsy material was positive for Mycobacterium tuberculosis.¹ A CT-guided pleural biopsy showed only normal tissue. A follow-up tuberculin skin test (purified protein derivative [PPD]) yielded a 10-mm indurated reaction.

DISCUSSION

Granulomatous lesions, such as foreign body granuloma, idiopathic granulomatous mastitis (IGM), and sarcoidosis can mimic breast carcinoma.^2,3 IGM is associated with elevated prolactin (eg, pregnancy or oral contraceptive use) and is usually subareolar.² Infection, however, is also commonly subareolar. Sarcoidosis rarely exhibits unilateral pleural effusion and usually manifests with bilateral interstitial lung disease, hilar lymphadenopathy, and non-necrotizing granulomas.^3,4

M tuberculosis and other granulomatous infections may also feign breast cancer.^5-13 Breast TB, which is highly uncommon in the developed world, often demonstrates imaging similar to that which was seen in this case. Breast TB may appear nodular with ill-defined contours. Masses are sometimes attached to the chest wall and usually lack microcalcifications on mammography; they are also typically hypoechoic and heterogenous on ultrasound, often showing posterior enhancement.^5,7,8 Like other breast infections, tuberculosis may show cutaneous sinus tract formation, which is seen in about one-third of patients.^6,7 Alternatively, it may manifest as a diffuse mastitis with skin thickening and axillary lymphadenopathy.⁸

Primary breast TB without chest disease comprises up to 86% of mammary tuberculosis.^6,7 Infection may occur via contamination of the skin or nipple.^5-7 Lactation, pregnancy, and other causes of immunosuppression (especially human immunodeficiency virus) have been associated with an increased risk of breast infection.^6-8 This patient was at risk for immunosuppression from longstanding diabetes.¹⁴

Many patients from TB-endemic areas have received the bacille Calmette-Guerin (BCG) vaccine and may exhibit equivocal or false-positive PPD results. Because interferon-gamma release assay TB blood tests (eg, QuantiFERON-TB Gold or T-SPOT.TB) are not affected by BCG, they are not associated with false-positive repeat testing results.¹⁵

Biopsy is necessary to rule out malignancy and diagnose breast TB

A pleural fluid to serum protein ratio >0.5 is consistent with infection, but also with sarcoidosis or malignancy.^3,16 Elevated pleural fluid adenosine deaminase (>40 U/L) is sensitive, albeit nonspecific, for the presence of TB microorganisms. If a lymphocyte-dominant exudate is also present, however, its reliability greatly increases.^16,17 Increased pleural fluid interferon-gamma is also sensitive and specific for TB pleurisy.¹⁸ Culture, along with drug sensitivity testing, should be performed on all unexplained pleural effusions.

This case emphasizes the need for increased awareness of extrapulmonary TB by physicians in developed countries.

A biopsy is often required to diagnose breast TB and should be performed on all suspicious lesions to exclude malignancy.^5-7,9 AFB stains and cultures of aspirate fluids or tissue are often negative.^7,9 PCR or other nucleic acid amplification tests of sputum, body fluids, or biopsy material may be positive in culture-negative cases and can rapidly confirm M tuberculosis infection.^17,19 No testing modality offers 100% sensitivity or specificity; therefore, an additional confirmatory test is desirable.

Possible routes of transmission include activation of latent pulmonary tuberculosis and direct, lymphatic, or hematologic extension to the chest wall and breast.^5-7 In this patient, we believe that activation of a latent breast granuloma may have resulted in a secondary or “sympathetic” pleural effusion, possibly triggered by surgical manipulation. This is compatible with her negative pleural adenosine deaminase result, negative culture, absence of pulmonary parenchymal disease, and negative pleural biopsy. Although we conducted a PubMed search, reviewing material as far back as 1966, we were unable to find a previous case of apparent sympathetic effusion associated with breast TB.

Our patient was treated with daily oral isoniazid, rifabutin, pyrazinamide, and ethambutol for 2 months, followed by isoniazid and rifabutin for 4 months. She has been disease-free for over 10 years.

THE TAKEAWAY

We describe a rare case of breast TB mimicking carcinoma that was associated with unilateral pleural effusion in a woman who had emigrated from Afghanistan. Patients at particular risk for breast TB include immigrants from endemic regions—especially parous females,^6,7 those with a history of TB contacts, and those who are immunosuppressed.⁸ This case emphasizes the need for increased awareness of extrapulmonary TB by physicians in developed countries.

ACKNOWLEDGEMENTS
The authors thank Drs. Margie Scott, Harpreet Dhillon, Samir Vora, Todd Williams, Jeffrey Hawley, and Mr. Sergio Landeros. This report is dedicated to the memory of our friend and colleague in medicine, Dr. Jeanie Care Gillinta.

THE CASE

A 44-year-old woman with a 15-year history of type 2 diabetes sought care for a firm, non-tender mass in the medial lower quadrant of her right breast. She hadn’t experienced any skin changes or axillary lymphadenopathy. The patient had immigrated to California from Afghanistan 22 years earlier, at which time she was briefly married to an Afghan man suffering from a chronic cough.

Mammography revealed a 3.5 x 4 x 4 cm lesion at the chest wall, which was highly suspicious for carcinoma (FIGURES 1A AND 1B). Sonography showed a heterogenous hypoechoic and isoechoic mass with posterior acoustic enhancement (FIGURE 1C). An excisional biopsy was performed.

One week postoperatively, the patient presented to the emergency department for a worsening nonproductive cough that intensified when supine, and was associated with subscapular pleuritic pain. She denied fever or weight loss. Biopsy results were pending.

THE DIAGNOSIS

Chest x-rays revealed a large right pleural effusion that was presumed to be malignant (FIGURES 1D AND 1E). Thoracentesis yielded 1.5 liters of tea-colored exudate containing 2800 nucleated cells/mL—63% lymphocytes and 37% neutrophils—and a pleural fluid to serum protein ratio >0.5. Adenosine deaminase was <1 U/L. Fluid Gram stain, acid-fast bacillus (AFB) fluorescent antibody testing, AFB cultures, and cytology were negative. Computed tomography (CT) subsequently demonstrated recurrent effusion without hilar or mediastinal lymphadenopathy or pleural enhancement (FIGURE 1F).

Histologically, the breast mass showed caseating granulomatous inflammation (FIGURES 1G AND 1H). An AFB stain was negative. Polymerase chain reaction (PCR) performed on DNA extracted from the formalin-fixed, paraffin-embedded biopsy material was positive for Mycobacterium tuberculosis.¹ A CT-guided pleural biopsy showed only normal tissue. A follow-up tuberculin skin test (purified protein derivative [PPD]) yielded a 10-mm indurated reaction.

DISCUSSION

Granulomatous lesions, such as foreign body granuloma, idiopathic granulomatous mastitis (IGM), and sarcoidosis can mimic breast carcinoma.^2,3 IGM is associated with elevated prolactin (eg, pregnancy or oral contraceptive use) and is usually subareolar.² Infection, however, is also commonly subareolar. Sarcoidosis rarely exhibits unilateral pleural effusion and usually manifests with bilateral interstitial lung disease, hilar lymphadenopathy, and non-necrotizing granulomas.^3,4

M tuberculosis and other granulomatous infections may also feign breast cancer.^5-13 Breast TB, which is highly uncommon in the developed world, often demonstrates imaging similar to that which was seen in this case. Breast TB may appear nodular with ill-defined contours. Masses are sometimes attached to the chest wall and usually lack microcalcifications on mammography; they are also typically hypoechoic and heterogenous on ultrasound, often showing posterior enhancement.^5,7,8 Like other breast infections, tuberculosis may show cutaneous sinus tract formation, which is seen in about one-third of patients.^6,7 Alternatively, it may manifest as a diffuse mastitis with skin thickening and axillary lymphadenopathy.⁸

Primary breast TB without chest disease comprises up to 86% of mammary tuberculosis.^6,7 Infection may occur via contamination of the skin or nipple.^5-7 Lactation, pregnancy, and other causes of immunosuppression (especially human immunodeficiency virus) have been associated with an increased risk of breast infection.^6-8 This patient was at risk for immunosuppression from longstanding diabetes.¹⁴

Many patients from TB-endemic areas have received the bacille Calmette-Guerin (BCG) vaccine and may exhibit equivocal or false-positive PPD results. Because interferon-gamma release assay TB blood tests (eg, QuantiFERON-TB Gold or T-SPOT.TB) are not affected by BCG, they are not associated with false-positive repeat testing results.¹⁵

Biopsy is necessary to rule out malignancy and diagnose breast TB

A pleural fluid to serum protein ratio >0.5 is consistent with infection, but also with sarcoidosis or malignancy.^3,16 Elevated pleural fluid adenosine deaminase (>40 U/L) is sensitive, albeit nonspecific, for the presence of TB microorganisms. If a lymphocyte-dominant exudate is also present, however, its reliability greatly increases.^16,17 Increased pleural fluid interferon-gamma is also sensitive and specific for TB pleurisy.¹⁸ Culture, along with drug sensitivity testing, should be performed on all unexplained pleural effusions.

This case emphasizes the need for increased awareness of extrapulmonary TB by physicians in developed countries.

A biopsy is often required to diagnose breast TB and should be performed on all suspicious lesions to exclude malignancy.^5-7,9 AFB stains and cultures of aspirate fluids or tissue are often negative.^7,9 PCR or other nucleic acid amplification tests of sputum, body fluids, or biopsy material may be positive in culture-negative cases and can rapidly confirm M tuberculosis infection.^17,19 No testing modality offers 100% sensitivity or specificity; therefore, an additional confirmatory test is desirable.

Possible routes of transmission include activation of latent pulmonary tuberculosis and direct, lymphatic, or hematologic extension to the chest wall and breast.^5-7 In this patient, we believe that activation of a latent breast granuloma may have resulted in a secondary or “sympathetic” pleural effusion, possibly triggered by surgical manipulation. This is compatible with her negative pleural adenosine deaminase result, negative culture, absence of pulmonary parenchymal disease, and negative pleural biopsy. Although we conducted a PubMed search, reviewing material as far back as 1966, we were unable to find a previous case of apparent sympathetic effusion associated with breast TB.

Our patient was treated with daily oral isoniazid, rifabutin, pyrazinamide, and ethambutol for 2 months, followed by isoniazid and rifabutin for 4 months. She has been disease-free for over 10 years.

THE TAKEAWAY

We describe a rare case of breast TB mimicking carcinoma that was associated with unilateral pleural effusion in a woman who had emigrated from Afghanistan. Patients at particular risk for breast TB include immigrants from endemic regions—especially parous females,^6,7 those with a history of TB contacts, and those who are immunosuppressed.⁸ This case emphasizes the need for increased awareness of extrapulmonary TB by physicians in developed countries.

ACKNOWLEDGEMENTS
The authors thank Drs. Margie Scott, Harpreet Dhillon, Samir Vora, Todd Williams, Jeffrey Hawley, and Mr. Sergio Landeros. This report is dedicated to the memory of our friend and colleague in medicine, Dr. Jeanie Care Gillinta.

THE CASE

A 44-year-old woman with a 15-year history of type 2 diabetes sought care for a firm, non-tender mass in the medial lower quadrant of her right breast. She hadn’t experienced any skin changes or axillary lymphadenopathy. The patient had immigrated to California from Afghanistan 22 years earlier, at which time she was briefly married to an Afghan man suffering from a chronic cough.

Mammography revealed a 3.5 x 4 x 4 cm lesion at the chest wall, which was highly suspicious for carcinoma (FIGURES 1A AND 1B). Sonography showed a heterogenous hypoechoic and isoechoic mass with posterior acoustic enhancement (FIGURE 1C). An excisional biopsy was performed.

One week postoperatively, the patient presented to the emergency department for a worsening nonproductive cough that intensified when supine, and was associated with subscapular pleuritic pain. She denied fever or weight loss. Biopsy results were pending.

THE DIAGNOSIS

Chest x-rays revealed a large right pleural effusion that was presumed to be malignant (FIGURES 1D AND 1E). Thoracentesis yielded 1.5 liters of tea-colored exudate containing 2800 nucleated cells/mL—63% lymphocytes and 37% neutrophils—and a pleural fluid to serum protein ratio >0.5. Adenosine deaminase was <1 U/L. Fluid Gram stain, acid-fast bacillus (AFB) fluorescent antibody testing, AFB cultures, and cytology were negative. Computed tomography (CT) subsequently demonstrated recurrent effusion without hilar or mediastinal lymphadenopathy or pleural enhancement (FIGURE 1F).

Histologically, the breast mass showed caseating granulomatous inflammation (FIGURES 1G AND 1H). An AFB stain was negative. Polymerase chain reaction (PCR) performed on DNA extracted from the formalin-fixed, paraffin-embedded biopsy material was positive for Mycobacterium tuberculosis.¹ A CT-guided pleural biopsy showed only normal tissue. A follow-up tuberculin skin test (purified protein derivative [PPD]) yielded a 10-mm indurated reaction.

DISCUSSION

Granulomatous lesions, such as foreign body granuloma, idiopathic granulomatous mastitis (IGM), and sarcoidosis can mimic breast carcinoma.^2,3 IGM is associated with elevated prolactin (eg, pregnancy or oral contraceptive use) and is usually subareolar.² Infection, however, is also commonly subareolar. Sarcoidosis rarely exhibits unilateral pleural effusion and usually manifests with bilateral interstitial lung disease, hilar lymphadenopathy, and non-necrotizing granulomas.^3,4

M tuberculosis and other granulomatous infections may also feign breast cancer.^5-13 Breast TB, which is highly uncommon in the developed world, often demonstrates imaging similar to that which was seen in this case. Breast TB may appear nodular with ill-defined contours. Masses are sometimes attached to the chest wall and usually lack microcalcifications on mammography; they are also typically hypoechoic and heterogenous on ultrasound, often showing posterior enhancement.^5,7,8 Like other breast infections, tuberculosis may show cutaneous sinus tract formation, which is seen in about one-third of patients.^6,7 Alternatively, it may manifest as a diffuse mastitis with skin thickening and axillary lymphadenopathy.⁸

Primary breast TB without chest disease comprises up to 86% of mammary tuberculosis.^6,7 Infection may occur via contamination of the skin or nipple.^5-7 Lactation, pregnancy, and other causes of immunosuppression (especially human immunodeficiency virus) have been associated with an increased risk of breast infection.^6-8 This patient was at risk for immunosuppression from longstanding diabetes.¹⁴

Many patients from TB-endemic areas have received the bacille Calmette-Guerin (BCG) vaccine and may exhibit equivocal or false-positive PPD results. Because interferon-gamma release assay TB blood tests (eg, QuantiFERON-TB Gold or T-SPOT.TB) are not affected by BCG, they are not associated with false-positive repeat testing results.¹⁵

Biopsy is necessary to rule out malignancy and diagnose breast TB

A pleural fluid to serum protein ratio >0.5 is consistent with infection, but also with sarcoidosis or malignancy.^3,16 Elevated pleural fluid adenosine deaminase (>40 U/L) is sensitive, albeit nonspecific, for the presence of TB microorganisms. If a lymphocyte-dominant exudate is also present, however, its reliability greatly increases.^16,17 Increased pleural fluid interferon-gamma is also sensitive and specific for TB pleurisy.¹⁸ Culture, along with drug sensitivity testing, should be performed on all unexplained pleural effusions.

This case emphasizes the need for increased awareness of extrapulmonary TB by physicians in developed countries.

A biopsy is often required to diagnose breast TB and should be performed on all suspicious lesions to exclude malignancy.^5-7,9 AFB stains and cultures of aspirate fluids or tissue are often negative.^7,9 PCR or other nucleic acid amplification tests of sputum, body fluids, or biopsy material may be positive in culture-negative cases and can rapidly confirm M tuberculosis infection.^17,19 No testing modality offers 100% sensitivity or specificity; therefore, an additional confirmatory test is desirable.

Possible routes of transmission include activation of latent pulmonary tuberculosis and direct, lymphatic, or hematologic extension to the chest wall and breast.^5-7 In this patient, we believe that activation of a latent breast granuloma may have resulted in a secondary or “sympathetic” pleural effusion, possibly triggered by surgical manipulation. This is compatible with her negative pleural adenosine deaminase result, negative culture, absence of pulmonary parenchymal disease, and negative pleural biopsy. Although we conducted a PubMed search, reviewing material as far back as 1966, we were unable to find a previous case of apparent sympathetic effusion associated with breast TB.

Our patient was treated with daily oral isoniazid, rifabutin, pyrazinamide, and ethambutol for 2 months, followed by isoniazid and rifabutin for 4 months. She has been disease-free for over 10 years.

THE TAKEAWAY

We describe a rare case of breast TB mimicking carcinoma that was associated with unilateral pleural effusion in a woman who had emigrated from Afghanistan. Patients at particular risk for breast TB include immigrants from endemic regions—especially parous females,^6,7 those with a history of TB contacts, and those who are immunosuppressed.⁸ This case emphasizes the need for increased awareness of extrapulmonary TB by physicians in developed countries.

ACKNOWLEDGEMENTS
The authors thank Drs. Margie Scott, Harpreet Dhillon, Samir Vora, Todd Williams, Jeffrey Hawley, and Mr. Sergio Landeros. This report is dedicated to the memory of our friend and colleague in medicine, Dr. Jeanie Care Gillinta.

Castleman disease or angiofollicular lymph node hyperplasia is an uncommon cause of an incidental abdominal mass found on imaging. The etiology of Castleman disease is relatively unknown, however, it is thought to be primarily associated with an oversecretion of interleukin-6. The oversecretion of this pro-inflammatory cytokine leads to lymph node hyperplasia. Castleman disease can be classified into 2 categories: unicentric or multicentric. Most cases of unicentric Castleman disease are asymptomatic and are found on routine imaging. It is found predominately in middle-aged persons of equal sex and is managed primarily by surgical resection. We present here a case of a peripancreatic mass diagnosed by surgical excision as Castleman disease, hyaline vascular type.

Click on the PDF icon at the top of this introduction to read the full article.

Castleman disease or angiofollicular lymph node hyperplasia is an uncommon cause of an incidental abdominal mass found on imaging. The etiology of Castleman disease is relatively unknown, however, it is thought to be primarily associated with an oversecretion of interleukin-6. The oversecretion of this pro-inflammatory cytokine leads to lymph node hyperplasia. Castleman disease can be classified into 2 categories: unicentric or multicentric. Most cases of unicentric Castleman disease are asymptomatic and are found on routine imaging. It is found predominately in middle-aged persons of equal sex and is managed primarily by surgical resection. We present here a case of a peripancreatic mass diagnosed by surgical excision as Castleman disease, hyaline vascular type.

Click on the PDF icon at the top of this introduction to read the full article.

Castleman disease or angiofollicular lymph node hyperplasia is an uncommon cause of an incidental abdominal mass found on imaging. The etiology of Castleman disease is relatively unknown, however, it is thought to be primarily associated with an oversecretion of interleukin-6. The oversecretion of this pro-inflammatory cytokine leads to lymph node hyperplasia. Castleman disease can be classified into 2 categories: unicentric or multicentric. Most cases of unicentric Castleman disease are asymptomatic and are found on routine imaging. It is found predominately in middle-aged persons of equal sex and is managed primarily by surgical resection. We present here a case of a peripancreatic mass diagnosed by surgical excision as Castleman disease, hyaline vascular type.

Click on the PDF icon at the top of this introduction to read the full article.