Case Reports

Case

The patient’s past medical history included one miscarriage, as well as a papillary thyroid carcinoma with resection, which was discovered a few months before her presentation to the ED and after diagnosis of the initial SSS thrombosis.

Physical examination revealed a well-developed, mildly obese female. On arrival at the ED, the patient’s National Institutes of Health Stroke Scale score was 0. Her vital signs and ocular, neurological, and psychiatric examinations were all normal. The social history was negative for tobacco or alcohol use, and she had no family history of deep vein thrombosis (DVT) or pulmonary embolism.

A noncontrast computed tomography (CT) of the head demonstrated a hemorrhagic venous infarction involving the posterior right parietal lobe. Intracranial magnetic resonance venography (MRV) and brain magnetic resonance imaging (MRI) revealed thrombosis of the posterior third of the SSS as the source of the infarction. This sinus had been patent during the patient’s previous hospital admissions.

The patient’s international normalized ratio (INR) was therapeutic on presentation. Warfarin was discontinued, and she was started on an intravenous (IV) heparin drip. For anticoagulation, she was prescribed 20 mg rivaroxaban daily and 2,000 mg levetiracetam daily.

One week after discharge, the patient again presented to the ED with a recurrence of symptoms, including confusion, slurred speech, and headache, which she rated a “5” on a pain scale of 0 to 10. Similar to the previous ED visit, the slurred speech had resolved by the time of examination. The patient did not exhibit facial asymmetry but did complain of bilateral numbness and tingling in both hands. A noncontrast CT of the head showed no changes in the right parietal hemorrhagic venous infarct and intraparenchymal hemorrhage; however, there was an interval increase in edema compared to the prior CT. Rivaroxaban and levetiracetam were continued, and 20 mg simvastatin daily was prescribed.

Overview

Cerebral venous sinus thrombosis is a rare condition with an often varied clinical presentation—the symptoms of which can take hours to weeks to evolve, thus making the diagnosis challenging. In 70% of cases, the SSS and lateral sinuses are individually involved, and in 30% of cases, both regions are affected simultaneously.¹ Only recently have clinicians been able to diagnose this condition antemortem.

Risk Factors and Etiology

Inherited and Acquired hypercoagulable states

Cerebral venous sinus thrombosis (CVST) and cerebrovascular accident (CVA) often result from a hypercoagulable state (HCS), and both acquired and inherited factors place patients at risk. Inherited factors are the most common cause of venous thromboembolism in patients younger than age 40 years. Acquired factors have a combined effect with inherited ones, leading to increased risk of CVST or CVA.²

The patient in this case possessed both acquired and inherited factors of an HCS. Inherited factors can be found through a thrombophilia evaluation. In general, acquired factors of thrombophilia include obesity, a prior history of thrombosis, pregnancy, and cancer and its treatment. A thrombophilia evaluation revealed the patient was homozygous for the 4G allele, which has been shown to increase concentration of plasminogen activator inhibitor (PAI-1) by 30%. An inhibitor to the pathway of fibrinolysis, PAI-1 is a major factor preventing the excessive presence and magnitude of blood clots.³

Pregnancy and the Puerperium

Cerebral vascular sinus thrombosis is most commonly seen in young to middle-aged women. High risk factors include pregnancy and the puerperium due to increased HCS during these periods.⁴ The incidence of CVST in this population is approximately 10 per 100,000 women.⁴

Oral Hormonal Contraceptives

In approximately 10% of CVST cases, oral hormonal contraceptive use in the presence of a coagulation disorder are frequently the cause—as observed in the incidence of DVT in this patient population.

Septic Cerebral Venous Sinus Thrombosis

Septic CVST occurs mainly in children and up to 18% of adult cases in developing countries. It is associated with localized infections (eg, mastoiditis, otitis media, sinusitis, meningitis).

Other Causes

Although rare, other causes of CVST include intracranial hypotension, hydrocephalus, and the use of certain drugs and supplements (eg, corticosteroids, high doses of vitamin A). Each of these potential causes also should be considered when evaluating for CVST.⁴

Symptoms and Signs

Common symptoms and signs of CVST include headache, nausea, vomiting, seizure, and focal neurological deficit. Papilledema is present in 40% of cases, primarily in patients with delayed diagnosis or a chronic course.

Neurological Deficits

Cerebral venous sinus thrombosis may not necessarily cause focal neurological deficits due to numerous pathways of venous drainage and the possibility of reversal of venous blood flow. However, the condition can lead to impaired resorption of CSF causing intracranial hypertension.

Headache

In 70% of cases, headache is the initial symptom of CVST, and it is the only symptom in 16% of cases. With respect to headache presentation, it is important to remember that thunderclap headache is not exclusive to the diagnosis of subarachnoid hemorrhage (SAH). The absence of findings on workup to support the diagnosis of SAH should prompt investigation with MRV and evaluation of CVST.⁴

Seizure

Focal or generalized seizure on initial presentation occurs in 30% to 40% of cases of CVST. When smaller cerebral veins are involved, this can lead to focal edema, neurological deficits, venous infarction, and seizure. Focal deficits are determined by the localization of CVST and associated lesions. Other symptoms may include migraine headache, transient ischemic attack, cranial nerve palsies, and subarachnoid hemorrhage.⁴

Complications

Cerebral venous sinus thrombosis is a rare condition with an often varied clinical presentation—the symptoms of which can take hours to weeks to evolve, thus making the diagnosis challenging.

Complications in patients with CVST occur when venous congestion increases and raises dural venous sinus and cerebral spinal fluid (CSF) pressure. Parenchymal edema with venous infarction and hemorrhage complicates up to 50% of venous sinus thromboses (as seen in this patient).¹ Unfortunately, little is known about long-term risk outcomes or recurrence of CVST.¹

As previously noted, the patient presented with transient slurred speech, mild headache, and bilateral hand tingling. On workup, she was found to have an SSS thrombosis with an associated right intraparenchymal hemorrhage that occurred despite therapeutic INR levels and the initiation of coumadin therapy prior to admission.

Evaluation and Diagnosis

D-Dimer Evaluation

There is a strong association between D-dimer levels above 500 ng/mL and acute CVST. Nevertheless, lower levels do not rule out the diagnosis in a patient presenting with headache.⁴

Imaging Techniques

Important imaging techniques in the evaluation of CVST include CT, MRV, MRI, and magnetic resonance angiography (MRA). The first imaging modality in evaluating a patient with neurological symptoms and headache in the ED is CT, which can show evidence of an infarction that does not respond to an arterial distribution. In the absence of a hemorrhagic component, however, infarct demonstration may be delayed for up to 72 hours.⁵ On contrast CT, an empty delta sign may be apparent due to enhancement of the collateral veins in the SSS walls surrounding a nonenhanced thrombus. The delta sign is not frequently present and may be false due to early division of the SSS.⁵

Computed tomography venography, CT angiography, and MRI can also be utilized to evaluate for CVST. Computed tomography venography is especially useful in identifying the cerebral veins and dural sinuses,⁶ and MRV is an excellent method for visualizing the dural venous sinuses and larger cerebral veins. Single-slice phase-contrast angiography is also a rapid and reliable test for CVST.⁷ Conventional angiography and direct venography should be considered if MR studies are nondiagnostic; however, this test is invasive with associated risks.⁵

Treatment

Heparin therapy should be initiated in patients presenting with dural sinus thrombosis even if pre-existing hemorrhage exists. Patients failing to respond to therapy with worsening neurological deficits may warrant local thrombolysis with tissue plasminogen activator. Identifying those in the acute state of disease is essential as they may have poor prognostic outcomes that may warrant more invasive intervention.¹

Conclusion

Cerebral venous sinus thrombosis is a rare condition with a diverse clinical presentation. As demonstrated in this case, some patients present with stroke-like symptoms of nontraumatic headache, slurred speech, and bilateral hand tingling, which, on workup, reveal SSS thrombosis associated right intraparenchymal hemorrhage.

This case draws attention to the importance of risk stratification in patients with a history of HCS and neurological complaints presenting to the ED. Dural sinus thrombosis may have a vague initial neurological presentation; therefore, early recognition and initiation of therapy will assist in reducing morbidity and mortality.

Dr Orlik is a resident, department of emergency medicine, Akron General Medical Center, Ohio. Mr Kovacs is a student and summer research fellow, department of emergency medicine, Akron General Medical Center, Ohio. Dr Simon is the emergency medicine research director, department of emergency medicine, Akron General Medical Center, Northeast Ohio Medical University.

Case

The patient’s past medical history included one miscarriage, as well as a papillary thyroid carcinoma with resection, which was discovered a few months before her presentation to the ED and after diagnosis of the initial SSS thrombosis.

Physical examination revealed a well-developed, mildly obese female. On arrival at the ED, the patient’s National Institutes of Health Stroke Scale score was 0. Her vital signs and ocular, neurological, and psychiatric examinations were all normal. The social history was negative for tobacco or alcohol use, and she had no family history of deep vein thrombosis (DVT) or pulmonary embolism.

A noncontrast computed tomography (CT) of the head demonstrated a hemorrhagic venous infarction involving the posterior right parietal lobe. Intracranial magnetic resonance venography (MRV) and brain magnetic resonance imaging (MRI) revealed thrombosis of the posterior third of the SSS as the source of the infarction. This sinus had been patent during the patient’s previous hospital admissions.

The patient’s international normalized ratio (INR) was therapeutic on presentation. Warfarin was discontinued, and she was started on an intravenous (IV) heparin drip. For anticoagulation, she was prescribed 20 mg rivaroxaban daily and 2,000 mg levetiracetam daily.

One week after discharge, the patient again presented to the ED with a recurrence of symptoms, including confusion, slurred speech, and headache, which she rated a “5” on a pain scale of 0 to 10. Similar to the previous ED visit, the slurred speech had resolved by the time of examination. The patient did not exhibit facial asymmetry but did complain of bilateral numbness and tingling in both hands. A noncontrast CT of the head showed no changes in the right parietal hemorrhagic venous infarct and intraparenchymal hemorrhage; however, there was an interval increase in edema compared to the prior CT. Rivaroxaban and levetiracetam were continued, and 20 mg simvastatin daily was prescribed.

Overview

Cerebral venous sinus thrombosis is a rare condition with an often varied clinical presentation—the symptoms of which can take hours to weeks to evolve, thus making the diagnosis challenging. In 70% of cases, the SSS and lateral sinuses are individually involved, and in 30% of cases, both regions are affected simultaneously.¹ Only recently have clinicians been able to diagnose this condition antemortem.

Risk Factors and Etiology

Inherited and Acquired hypercoagulable states

Cerebral venous sinus thrombosis (CVST) and cerebrovascular accident (CVA) often result from a hypercoagulable state (HCS), and both acquired and inherited factors place patients at risk. Inherited factors are the most common cause of venous thromboembolism in patients younger than age 40 years. Acquired factors have a combined effect with inherited ones, leading to increased risk of CVST or CVA.²

The patient in this case possessed both acquired and inherited factors of an HCS. Inherited factors can be found through a thrombophilia evaluation. In general, acquired factors of thrombophilia include obesity, a prior history of thrombosis, pregnancy, and cancer and its treatment. A thrombophilia evaluation revealed the patient was homozygous for the 4G allele, which has been shown to increase concentration of plasminogen activator inhibitor (PAI-1) by 30%. An inhibitor to the pathway of fibrinolysis, PAI-1 is a major factor preventing the excessive presence and magnitude of blood clots.³

Pregnancy and the Puerperium

Cerebral vascular sinus thrombosis is most commonly seen in young to middle-aged women. High risk factors include pregnancy and the puerperium due to increased HCS during these periods.⁴ The incidence of CVST in this population is approximately 10 per 100,000 women.⁴

Oral Hormonal Contraceptives

In approximately 10% of CVST cases, oral hormonal contraceptive use in the presence of a coagulation disorder are frequently the cause—as observed in the incidence of DVT in this patient population.

Septic Cerebral Venous Sinus Thrombosis

Septic CVST occurs mainly in children and up to 18% of adult cases in developing countries. It is associated with localized infections (eg, mastoiditis, otitis media, sinusitis, meningitis).

Other Causes

Although rare, other causes of CVST include intracranial hypotension, hydrocephalus, and the use of certain drugs and supplements (eg, corticosteroids, high doses of vitamin A). Each of these potential causes also should be considered when evaluating for CVST.⁴

Symptoms and Signs

Common symptoms and signs of CVST include headache, nausea, vomiting, seizure, and focal neurological deficit. Papilledema is present in 40% of cases, primarily in patients with delayed diagnosis or a chronic course.

Neurological Deficits

Cerebral venous sinus thrombosis may not necessarily cause focal neurological deficits due to numerous pathways of venous drainage and the possibility of reversal of venous blood flow. However, the condition can lead to impaired resorption of CSF causing intracranial hypertension.

Headache

In 70% of cases, headache is the initial symptom of CVST, and it is the only symptom in 16% of cases. With respect to headache presentation, it is important to remember that thunderclap headache is not exclusive to the diagnosis of subarachnoid hemorrhage (SAH). The absence of findings on workup to support the diagnosis of SAH should prompt investigation with MRV and evaluation of CVST.⁴

Seizure

Focal or generalized seizure on initial presentation occurs in 30% to 40% of cases of CVST. When smaller cerebral veins are involved, this can lead to focal edema, neurological deficits, venous infarction, and seizure. Focal deficits are determined by the localization of CVST and associated lesions. Other symptoms may include migraine headache, transient ischemic attack, cranial nerve palsies, and subarachnoid hemorrhage.⁴

Complications

Cerebral venous sinus thrombosis is a rare condition with an often varied clinical presentation—the symptoms of which can take hours to weeks to evolve, thus making the diagnosis challenging.

Complications in patients with CVST occur when venous congestion increases and raises dural venous sinus and cerebral spinal fluid (CSF) pressure. Parenchymal edema with venous infarction and hemorrhage complicates up to 50% of venous sinus thromboses (as seen in this patient).¹ Unfortunately, little is known about long-term risk outcomes or recurrence of CVST.¹

As previously noted, the patient presented with transient slurred speech, mild headache, and bilateral hand tingling. On workup, she was found to have an SSS thrombosis with an associated right intraparenchymal hemorrhage that occurred despite therapeutic INR levels and the initiation of coumadin therapy prior to admission.

Evaluation and Diagnosis

D-Dimer Evaluation

There is a strong association between D-dimer levels above 500 ng/mL and acute CVST. Nevertheless, lower levels do not rule out the diagnosis in a patient presenting with headache.⁴

Imaging Techniques

Important imaging techniques in the evaluation of CVST include CT, MRV, MRI, and magnetic resonance angiography (MRA). The first imaging modality in evaluating a patient with neurological symptoms and headache in the ED is CT, which can show evidence of an infarction that does not respond to an arterial distribution. In the absence of a hemorrhagic component, however, infarct demonstration may be delayed for up to 72 hours.⁵ On contrast CT, an empty delta sign may be apparent due to enhancement of the collateral veins in the SSS walls surrounding a nonenhanced thrombus. The delta sign is not frequently present and may be false due to early division of the SSS.⁵

Computed tomography venography, CT angiography, and MRI can also be utilized to evaluate for CVST. Computed tomography venography is especially useful in identifying the cerebral veins and dural sinuses,⁶ and MRV is an excellent method for visualizing the dural venous sinuses and larger cerebral veins. Single-slice phase-contrast angiography is also a rapid and reliable test for CVST.⁷ Conventional angiography and direct venography should be considered if MR studies are nondiagnostic; however, this test is invasive with associated risks.⁵

Treatment

Heparin therapy should be initiated in patients presenting with dural sinus thrombosis even if pre-existing hemorrhage exists. Patients failing to respond to therapy with worsening neurological deficits may warrant local thrombolysis with tissue plasminogen activator. Identifying those in the acute state of disease is essential as they may have poor prognostic outcomes that may warrant more invasive intervention.¹

Conclusion

Cerebral venous sinus thrombosis is a rare condition with a diverse clinical presentation. As demonstrated in this case, some patients present with stroke-like symptoms of nontraumatic headache, slurred speech, and bilateral hand tingling, which, on workup, reveal SSS thrombosis associated right intraparenchymal hemorrhage.

This case draws attention to the importance of risk stratification in patients with a history of HCS and neurological complaints presenting to the ED. Dural sinus thrombosis may have a vague initial neurological presentation; therefore, early recognition and initiation of therapy will assist in reducing morbidity and mortality.

Dr Orlik is a resident, department of emergency medicine, Akron General Medical Center, Ohio. Mr Kovacs is a student and summer research fellow, department of emergency medicine, Akron General Medical Center, Ohio. Dr Simon is the emergency medicine research director, department of emergency medicine, Akron General Medical Center, Northeast Ohio Medical University.

Case

The patient’s past medical history included one miscarriage, as well as a papillary thyroid carcinoma with resection, which was discovered a few months before her presentation to the ED and after diagnosis of the initial SSS thrombosis.

Physical examination revealed a well-developed, mildly obese female. On arrival at the ED, the patient’s National Institutes of Health Stroke Scale score was 0. Her vital signs and ocular, neurological, and psychiatric examinations were all normal. The social history was negative for tobacco or alcohol use, and she had no family history of deep vein thrombosis (DVT) or pulmonary embolism.

A noncontrast computed tomography (CT) of the head demonstrated a hemorrhagic venous infarction involving the posterior right parietal lobe. Intracranial magnetic resonance venography (MRV) and brain magnetic resonance imaging (MRI) revealed thrombosis of the posterior third of the SSS as the source of the infarction. This sinus had been patent during the patient’s previous hospital admissions.

The patient’s international normalized ratio (INR) was therapeutic on presentation. Warfarin was discontinued, and she was started on an intravenous (IV) heparin drip. For anticoagulation, she was prescribed 20 mg rivaroxaban daily and 2,000 mg levetiracetam daily.

One week after discharge, the patient again presented to the ED with a recurrence of symptoms, including confusion, slurred speech, and headache, which she rated a “5” on a pain scale of 0 to 10. Similar to the previous ED visit, the slurred speech had resolved by the time of examination. The patient did not exhibit facial asymmetry but did complain of bilateral numbness and tingling in both hands. A noncontrast CT of the head showed no changes in the right parietal hemorrhagic venous infarct and intraparenchymal hemorrhage; however, there was an interval increase in edema compared to the prior CT. Rivaroxaban and levetiracetam were continued, and 20 mg simvastatin daily was prescribed.

Overview

Cerebral venous sinus thrombosis is a rare condition with an often varied clinical presentation—the symptoms of which can take hours to weeks to evolve, thus making the diagnosis challenging. In 70% of cases, the SSS and lateral sinuses are individually involved, and in 30% of cases, both regions are affected simultaneously.¹ Only recently have clinicians been able to diagnose this condition antemortem.

Risk Factors and Etiology

Inherited and Acquired hypercoagulable states

Cerebral venous sinus thrombosis (CVST) and cerebrovascular accident (CVA) often result from a hypercoagulable state (HCS), and both acquired and inherited factors place patients at risk. Inherited factors are the most common cause of venous thromboembolism in patients younger than age 40 years. Acquired factors have a combined effect with inherited ones, leading to increased risk of CVST or CVA.²

The patient in this case possessed both acquired and inherited factors of an HCS. Inherited factors can be found through a thrombophilia evaluation. In general, acquired factors of thrombophilia include obesity, a prior history of thrombosis, pregnancy, and cancer and its treatment. A thrombophilia evaluation revealed the patient was homozygous for the 4G allele, which has been shown to increase concentration of plasminogen activator inhibitor (PAI-1) by 30%. An inhibitor to the pathway of fibrinolysis, PAI-1 is a major factor preventing the excessive presence and magnitude of blood clots.³

Pregnancy and the Puerperium

Cerebral vascular sinus thrombosis is most commonly seen in young to middle-aged women. High risk factors include pregnancy and the puerperium due to increased HCS during these periods.⁴ The incidence of CVST in this population is approximately 10 per 100,000 women.⁴

Oral Hormonal Contraceptives

In approximately 10% of CVST cases, oral hormonal contraceptive use in the presence of a coagulation disorder are frequently the cause—as observed in the incidence of DVT in this patient population.

Septic Cerebral Venous Sinus Thrombosis

Septic CVST occurs mainly in children and up to 18% of adult cases in developing countries. It is associated with localized infections (eg, mastoiditis, otitis media, sinusitis, meningitis).

Other Causes

Although rare, other causes of CVST include intracranial hypotension, hydrocephalus, and the use of certain drugs and supplements (eg, corticosteroids, high doses of vitamin A). Each of these potential causes also should be considered when evaluating for CVST.⁴

Symptoms and Signs

Common symptoms and signs of CVST include headache, nausea, vomiting, seizure, and focal neurological deficit. Papilledema is present in 40% of cases, primarily in patients with delayed diagnosis or a chronic course.

Neurological Deficits

Cerebral venous sinus thrombosis may not necessarily cause focal neurological deficits due to numerous pathways of venous drainage and the possibility of reversal of venous blood flow. However, the condition can lead to impaired resorption of CSF causing intracranial hypertension.

Headache

In 70% of cases, headache is the initial symptom of CVST, and it is the only symptom in 16% of cases. With respect to headache presentation, it is important to remember that thunderclap headache is not exclusive to the diagnosis of subarachnoid hemorrhage (SAH). The absence of findings on workup to support the diagnosis of SAH should prompt investigation with MRV and evaluation of CVST.⁴

Seizure

Focal or generalized seizure on initial presentation occurs in 30% to 40% of cases of CVST. When smaller cerebral veins are involved, this can lead to focal edema, neurological deficits, venous infarction, and seizure. Focal deficits are determined by the localization of CVST and associated lesions. Other symptoms may include migraine headache, transient ischemic attack, cranial nerve palsies, and subarachnoid hemorrhage.⁴

Complications

Cerebral venous sinus thrombosis is a rare condition with an often varied clinical presentation—the symptoms of which can take hours to weeks to evolve, thus making the diagnosis challenging.

Complications in patients with CVST occur when venous congestion increases and raises dural venous sinus and cerebral spinal fluid (CSF) pressure. Parenchymal edema with venous infarction and hemorrhage complicates up to 50% of venous sinus thromboses (as seen in this patient).¹ Unfortunately, little is known about long-term risk outcomes or recurrence of CVST.¹

As previously noted, the patient presented with transient slurred speech, mild headache, and bilateral hand tingling. On workup, she was found to have an SSS thrombosis with an associated right intraparenchymal hemorrhage that occurred despite therapeutic INR levels and the initiation of coumadin therapy prior to admission.

Evaluation and Diagnosis

D-Dimer Evaluation

There is a strong association between D-dimer levels above 500 ng/mL and acute CVST. Nevertheless, lower levels do not rule out the diagnosis in a patient presenting with headache.⁴

Imaging Techniques

Important imaging techniques in the evaluation of CVST include CT, MRV, MRI, and magnetic resonance angiography (MRA). The first imaging modality in evaluating a patient with neurological symptoms and headache in the ED is CT, which can show evidence of an infarction that does not respond to an arterial distribution. In the absence of a hemorrhagic component, however, infarct demonstration may be delayed for up to 72 hours.⁵ On contrast CT, an empty delta sign may be apparent due to enhancement of the collateral veins in the SSS walls surrounding a nonenhanced thrombus. The delta sign is not frequently present and may be false due to early division of the SSS.⁵

Computed tomography venography, CT angiography, and MRI can also be utilized to evaluate for CVST. Computed tomography venography is especially useful in identifying the cerebral veins and dural sinuses,⁶ and MRV is an excellent method for visualizing the dural venous sinuses and larger cerebral veins. Single-slice phase-contrast angiography is also a rapid and reliable test for CVST.⁷ Conventional angiography and direct venography should be considered if MR studies are nondiagnostic; however, this test is invasive with associated risks.⁵

Treatment

Heparin therapy should be initiated in patients presenting with dural sinus thrombosis even if pre-existing hemorrhage exists. Patients failing to respond to therapy with worsening neurological deficits may warrant local thrombolysis with tissue plasminogen activator. Identifying those in the acute state of disease is essential as they may have poor prognostic outcomes that may warrant more invasive intervention.¹

Conclusion

Cerebral venous sinus thrombosis is a rare condition with a diverse clinical presentation. As demonstrated in this case, some patients present with stroke-like symptoms of nontraumatic headache, slurred speech, and bilateral hand tingling, which, on workup, reveal SSS thrombosis associated right intraparenchymal hemorrhage.

This case draws attention to the importance of risk stratification in patients with a history of HCS and neurological complaints presenting to the ED. Dural sinus thrombosis may have a vague initial neurological presentation; therefore, early recognition and initiation of therapy will assist in reducing morbidity and mortality.

Dr Orlik is a resident, department of emergency medicine, Akron General Medical Center, Ohio. Mr Kovacs is a student and summer research fellow, department of emergency medicine, Akron General Medical Center, Ohio. Dr Simon is the emergency medicine research director, department of emergency medicine, Akron General Medical Center, Northeast Ohio Medical University.

Brucellosis is a zoonotic disease transmitted to humans through contact with animal hosts or animal products. Infection of total knee or hip arthroplasty by Brucella species is a rare complication with only 18 cases reported in the English literature.^1-12 We describe a case of an infected total hip replacement, its treatment, and 2-year follow-up and review the available literature. The patient provided written informed consent for print and electronic publication of this case report.

Case Report

A 67-year-old Spanish-speaking woman, a native of Mexico, presented with a painful right total hip arthroplasty (THA) 2 years after implantation in Chihuahua, Mexico. The patient reported 1 year of increasing thigh pain with recent onset of start-up pain, and also mild groin pain. The patient reported an uneventful postoperative course without wound drainage and denied any history of fevers, chills, or night sweats after the procedure. Preoperative notes and radiographs were unavailable for review. Radiographic evaluation showed a hybrid construct with a well-fixed–appearing, uncemented acetabular component but a failed cemented femoral stem (Figures 1A, 1B). Although we discussed revision surgery, the patient elected not to proceed with surgery or to undergo evaluation to rule out infection. Nine months later, she returned with worsening pain and requested revision surgery; radiographs showed progressive bone loss around the cement mantle (Figures 2A, 2B).

Hematologic evaluation showed an erythrocyte sedimentation rate (ESR) of 54 mm/h (normal, 0-27 mm/h) and C-reactive protein (CRP) level of 0.24 mg/L (normal, <0.8). An aspiration of the hip with fluoroscopic guidance produced a small sample (0.2 mL) of yellow synovial fluid. There was not enough fluid for cell count, but fluid culture was negative.

The patient was taken to the operating room for revision THA. Because of concern about progressive bone loss and elevated infectious indices, the administration of antibiotics was delayed until we obtained sufficient deep-tissue specimens. Before opening the capsule, we introduced a syringe into the joint and aspirated 10 mL of cloudy yellow synovial fluid that was sent for cell count. Additional findings at surgery included a grossly loose stem with a fragmented cement mantle surrounded by poor bone stock with anterior cortical bone loss and a loose acetabular component with pockets of cavitary bone loss. Frozen section showed up to 5 nucleated cells per high power field, and the cell count showed 1480 nucleated cells/µL (50% polymorphonuclear cells). The equivocal intraoperative findings (cell count and frozen section) and the loose femoral and acetabular components with significant bone loss were sufficiently concerning that we removed the components and placed a cement spacer rather than proceed with revision arthroplasty (Figures 3A, 3B). The surgeon, first assistant, and scrub technician wore body exhaust suits. We performed irrigation of the wound bed with pulse lavage.

Intraoperative cultures (synovial fluid, joint capsule synovium, and femur pseudocapsule) were positive after 8 days and growing B abortus. Infectious disease consultants prescribed rifampin 300 mg twice daily and doxycycline 100 mg twice daily for 5 months. Follow-up ESR and CRP returned to normal range. A preoperative aspiration of the hip was negative as well. The patient returned to the operating room at 6 months for re-implantation using uncemented components; synovial fluid and tissue cultures taken at this time were negative. Two years after re-implantation, the patient is doing well without evidence of infection (Figures 4A, 4B). Additional follow-up will be required to monitor for infection and implant survival. Additional history taken from the patient after the culture results revealed that her development of hip pain was preceded by a febrile illness consistent with brucellosis. 

Because of the nature of the procedure (irrigation and débridement using pulse lavage), we were concerned about aerosolization of Brucella bacteria and possible transmission to all staff present during the procedure. After consulting with the New Mexico Department of Health (NMDOH) and the Centers for Disease Control and Prevention (CDC), all surgical, anesthesia, and support personnel present in the operative suite  and staff who cleaned the room after the procedure were treated prophylactically (rifampin 600 mg daily, doxycycline 100 mg twice daily for 3 weeks) to prevent development of brucellosis.¹³ All 15 operating room personnel who were exposed elected to proceed with antibiotic prophylaxis. In addition to prophylactic antibiotics, serial serologic testing for anti-Brucella antibodies was conducted at baseline and 2, 4, 6, and 24 weeks postexposure to monitor for the development of Brucella infection. There were no conversions to positive antibody status. No personnel complained of symptoms that would indicate development of brucellosis. At the recommendation of NMDOH and CDC, all staff in the operating room during and immediately after the re-implantation procedure wore properly fitting N-95 disposable respiratory masks (3M, St. Paul, Minnesota) to guard against the potential risk of further exposure.

Discussion

Brucellosis is a zoonotic disease transmitted to humans through contact with animal hosts. Transmission can occur via breaks in the skin in direct contact, through the ingestion of unpasteurized dairy products or raw meat, or through ingestion of aerosolized bacteria. Transmission via aerosolization has been described during medical procedures.

Brucella is endemic in India, Middle Eastern and Mediterranean countries, Central Asia, and South America. Brucella species are gram-negative coccobacilli that are capable of surviving within phagocytic cells, making antibiotic treatment difficult. Brucellosis is a febrile illness that occurs after a 1- to 3-week incubation period and is often accompanied by headache, arthralgias, and hepatosplenomegaly. Osteoarticular infection is the most common complication, occurring in 10% to 85% of cases and usually involves the sacroiliac joint and the large joints of the lower extremity. Spondylitis, bursitis, tenosynovitis, endocarditis, colitis, meningitis, and osteomyelitis have also been described.^7,14-17

As mentioned previously, 18 cases of infected THAs and total knee arthroplasties (TKAs) in 16 patients were identified in the English literature: 9 THAs and 9 TKAs.^1-12 With the exception of 1 case reported in Texas, all others were from the Middle East or the Mediterranean region. In these patients, symptom onset occurred from 2 months to 14 years from the time of the index surgery, and symptom duration ranged from 1 month to 2 years prior to presentation. The exposure was not reported in 2 cases, but the remaining patients either ingested unpasteurized dairy products or worked closely with livestock. Laboratory evaluation revealed elevated ESR or CRP in 8 cases. In 7 cases, no laboratory results were reported, although 1 had a draining sinus. In 1 case, the ESR was normal, but a bone scan was positive. Joint aspiration yielded Brucella species in 8 cases, was negative in 3, and not reported in 5 cases (one aspirate yielded Acinetobacter baumanii). Only 3 cases reported a time-to-culture positivity (1 “prolonged” and 2 took 7 days).

Eight cases presented with loose components, while 1 case was not reported, and the remaining were presumed to be well-fixed. In cases that were identified as loose, 5 underwent a 2-stage revision and 2 underwent a 1-stage revision (in one of the 1-stage revisions, the infection was identified only after the revision from intra-operative cultures). Of those with well-fixed components, 7 patients with 9 infected joints (including the case where no preoperative description of the components was reported) were treated with oral antibiotics only (range, 6 weeks to 26 months) and 1 with irrigation and débridement and oral antibiotics. Among those treated only with antibiotics, there were 2 failures (2 joints) leading to revision surgery. The other 5 cases were reportedly doing well between 8 months and 5 years after treatment. There were no reports of transmission to hospital or laboratory personnel in any of these cases nor were there reports of precautions to limit exposure for operating room staff or hospital personnel. 

Failure of TKA or THA secondary to periprosthetic infection by Brucella species is rare, and this represents only the second reported case in the United States.⁴ This case highlights several important principles. Maintaining a high level of suspicion for infection in cases of failed joint arthroplasty is important. In addition, as more international travel occurs and patients are seen from areas where Brucella is endemic, the possibility of this infectious etiology should be considered. Based on reported cases, patients will usually have elevated ESR or CRP; all (except 2 cases in which no exposure was reported) had known exposure to unpasteurized dairy products or livestock. Joint aspiration yielded Brucella species in 8 cases, was negative in 3, and not reported in 5 cases (1 aspirate yielded Acinetobacter baumanii). In this case, ESR and CRP were elevated, and infection was suspected but joint aspiration was negative. The initial aspiration was cultured for 5 days and previous data, as well as that presented here, suggest that prolonged culture may provide diagnostic value.¹⁸ The patient had resided in an endemic area and had exposure to unpasteurized dairy products, but Brucella infection was not considered and, therefore, no precautions were taken.

Of the reported cases, only 1 met major criteria for periprosthetic joint infection (draining sinus) while 10 of the remaining 15 cases were positive for minor criteria of periprosthetic joint infection (elevated ESR or CRP, or positive culture from joint aspiration).¹⁹ Unfortunately, the available case reports did not detail the extent to which preoperative periprosthetic joint infection could be established based on minor criteria for periprosthetic joint infection (elevated joint synovial white blood cell count or neutrophil percentage, intra-articular purulence, or elevated neutrophil count on periprosthetic tissue histologic analysis).¹⁹

Periprosthetic joint infection by Brucella species is so rare that specific recommendations for this infectious etiology based on 18 reported cases would be overreaching. However, Brucella should be considered when evaluating a potentially infected joint replacement where the possibility of exposure exists (eg, travel to or previous residence in endemic areas, close contact with livestock, or ingestion of unpasteurized dairy products in endemic regions), with the potential for transmission to operating room and hospital personnel also considered. If there is concern about Brucella involvement, tissue and fluid specimens should be labeled so that laboratory personnel can take appropriate precautions. Brucella can be cultured using routine techniques on standard, nonselective media, but the culture time-to-growth may be prolonged. Culture plates should be held for 14 days before reporting no growth of Brucella if it is suspected; the New Mexico Department of Health Microbiology Laboratory holds routine cultures for 1 week after a report of no growth. Thus, a suspicion of Brucella should be communicated in order for culture time to be adjusted if the holding of culture plates after an initial report of no growth is not standard practice. If operative intervention is planned and brucellosis is known, personnel should be notified of the possibility of exposure and appropriate measures taken (ie, wearing N-95 respiratory masks during the procedure and considering other methods of irrigation less likely to aerosolize particulates). It is not known if preoperative antibiotic therapy can sufficiently lower the bacterial load to make aerosolization less likely. If brucellosis is suspected but not identified preoperatively, wearing N-95 respiratory masks should be considered during any open procedures. 

Conclusion

In cases of Brucella infection and loose components, 1- or 2-stage revision with appropriate antibiotic therapy is indicated. (There is not enough data to recommend either 1- or 2-stage revision.) Several reports comment on the ability to treat periprosthetic joint infection in the setting of well-fixed components with antibiotic therapy alone. While this appears to have been successful in 7 of 9 infected joints reported in the literature, length of follow-up ranged from 8 months to 5 years, with no report of length of follow-up in some cases. Antibiotic therapy duration ranged from 6 weeks to 26 months, and the antibiotic treatment involved combination therapy with multiple agents reported but, most commonly, doxycycline, rifampin, and streptomycin. With 2 of 9 (22%) joints failing antibiotic therapy alone and those reported to be successful having relatively short-term follow-up, this treatment strategy should be approached with caution.

Brucellosis is a zoonotic disease transmitted to humans through contact with animal hosts or animal products. Infection of total knee or hip arthroplasty by Brucella species is a rare complication with only 18 cases reported in the English literature.^1-12 We describe a case of an infected total hip replacement, its treatment, and 2-year follow-up and review the available literature. The patient provided written informed consent for print and electronic publication of this case report.

Case Report

A 67-year-old Spanish-speaking woman, a native of Mexico, presented with a painful right total hip arthroplasty (THA) 2 years after implantation in Chihuahua, Mexico. The patient reported 1 year of increasing thigh pain with recent onset of start-up pain, and also mild groin pain. The patient reported an uneventful postoperative course without wound drainage and denied any history of fevers, chills, or night sweats after the procedure. Preoperative notes and radiographs were unavailable for review. Radiographic evaluation showed a hybrid construct with a well-fixed–appearing, uncemented acetabular component but a failed cemented femoral stem (Figures 1A, 1B). Although we discussed revision surgery, the patient elected not to proceed with surgery or to undergo evaluation to rule out infection. Nine months later, she returned with worsening pain and requested revision surgery; radiographs showed progressive bone loss around the cement mantle (Figures 2A, 2B).

Hematologic evaluation showed an erythrocyte sedimentation rate (ESR) of 54 mm/h (normal, 0-27 mm/h) and C-reactive protein (CRP) level of 0.24 mg/L (normal, <0.8). An aspiration of the hip with fluoroscopic guidance produced a small sample (0.2 mL) of yellow synovial fluid. There was not enough fluid for cell count, but fluid culture was negative.

The patient was taken to the operating room for revision THA. Because of concern about progressive bone loss and elevated infectious indices, the administration of antibiotics was delayed until we obtained sufficient deep-tissue specimens. Before opening the capsule, we introduced a syringe into the joint and aspirated 10 mL of cloudy yellow synovial fluid that was sent for cell count. Additional findings at surgery included a grossly loose stem with a fragmented cement mantle surrounded by poor bone stock with anterior cortical bone loss and a loose acetabular component with pockets of cavitary bone loss. Frozen section showed up to 5 nucleated cells per high power field, and the cell count showed 1480 nucleated cells/µL (50% polymorphonuclear cells). The equivocal intraoperative findings (cell count and frozen section) and the loose femoral and acetabular components with significant bone loss were sufficiently concerning that we removed the components and placed a cement spacer rather than proceed with revision arthroplasty (Figures 3A, 3B). The surgeon, first assistant, and scrub technician wore body exhaust suits. We performed irrigation of the wound bed with pulse lavage.

Intraoperative cultures (synovial fluid, joint capsule synovium, and femur pseudocapsule) were positive after 8 days and growing B abortus. Infectious disease consultants prescribed rifampin 300 mg twice daily and doxycycline 100 mg twice daily for 5 months. Follow-up ESR and CRP returned to normal range. A preoperative aspiration of the hip was negative as well. The patient returned to the operating room at 6 months for re-implantation using uncemented components; synovial fluid and tissue cultures taken at this time were negative. Two years after re-implantation, the patient is doing well without evidence of infection (Figures 4A, 4B). Additional follow-up will be required to monitor for infection and implant survival. Additional history taken from the patient after the culture results revealed that her development of hip pain was preceded by a febrile illness consistent with brucellosis. 

Because of the nature of the procedure (irrigation and débridement using pulse lavage), we were concerned about aerosolization of Brucella bacteria and possible transmission to all staff present during the procedure. After consulting with the New Mexico Department of Health (NMDOH) and the Centers for Disease Control and Prevention (CDC), all surgical, anesthesia, and support personnel present in the operative suite  and staff who cleaned the room after the procedure were treated prophylactically (rifampin 600 mg daily, doxycycline 100 mg twice daily for 3 weeks) to prevent development of brucellosis.¹³ All 15 operating room personnel who were exposed elected to proceed with antibiotic prophylaxis. In addition to prophylactic antibiotics, serial serologic testing for anti-Brucella antibodies was conducted at baseline and 2, 4, 6, and 24 weeks postexposure to monitor for the development of Brucella infection. There were no conversions to positive antibody status. No personnel complained of symptoms that would indicate development of brucellosis. At the recommendation of NMDOH and CDC, all staff in the operating room during and immediately after the re-implantation procedure wore properly fitting N-95 disposable respiratory masks (3M, St. Paul, Minnesota) to guard against the potential risk of further exposure.

Discussion

Brucellosis is a zoonotic disease transmitted to humans through contact with animal hosts. Transmission can occur via breaks in the skin in direct contact, through the ingestion of unpasteurized dairy products or raw meat, or through ingestion of aerosolized bacteria. Transmission via aerosolization has been described during medical procedures.

Brucella is endemic in India, Middle Eastern and Mediterranean countries, Central Asia, and South America. Brucella species are gram-negative coccobacilli that are capable of surviving within phagocytic cells, making antibiotic treatment difficult. Brucellosis is a febrile illness that occurs after a 1- to 3-week incubation period and is often accompanied by headache, arthralgias, and hepatosplenomegaly. Osteoarticular infection is the most common complication, occurring in 10% to 85% of cases and usually involves the sacroiliac joint and the large joints of the lower extremity. Spondylitis, bursitis, tenosynovitis, endocarditis, colitis, meningitis, and osteomyelitis have also been described.^7,14-17

As mentioned previously, 18 cases of infected THAs and total knee arthroplasties (TKAs) in 16 patients were identified in the English literature: 9 THAs and 9 TKAs.^1-12 With the exception of 1 case reported in Texas, all others were from the Middle East or the Mediterranean region. In these patients, symptom onset occurred from 2 months to 14 years from the time of the index surgery, and symptom duration ranged from 1 month to 2 years prior to presentation. The exposure was not reported in 2 cases, but the remaining patients either ingested unpasteurized dairy products or worked closely with livestock. Laboratory evaluation revealed elevated ESR or CRP in 8 cases. In 7 cases, no laboratory results were reported, although 1 had a draining sinus. In 1 case, the ESR was normal, but a bone scan was positive. Joint aspiration yielded Brucella species in 8 cases, was negative in 3, and not reported in 5 cases (one aspirate yielded Acinetobacter baumanii). Only 3 cases reported a time-to-culture positivity (1 “prolonged” and 2 took 7 days).

Eight cases presented with loose components, while 1 case was not reported, and the remaining were presumed to be well-fixed. In cases that were identified as loose, 5 underwent a 2-stage revision and 2 underwent a 1-stage revision (in one of the 1-stage revisions, the infection was identified only after the revision from intra-operative cultures). Of those with well-fixed components, 7 patients with 9 infected joints (including the case where no preoperative description of the components was reported) were treated with oral antibiotics only (range, 6 weeks to 26 months) and 1 with irrigation and débridement and oral antibiotics. Among those treated only with antibiotics, there were 2 failures (2 joints) leading to revision surgery. The other 5 cases were reportedly doing well between 8 months and 5 years after treatment. There were no reports of transmission to hospital or laboratory personnel in any of these cases nor were there reports of precautions to limit exposure for operating room staff or hospital personnel. 

Failure of TKA or THA secondary to periprosthetic infection by Brucella species is rare, and this represents only the second reported case in the United States.⁴ This case highlights several important principles. Maintaining a high level of suspicion for infection in cases of failed joint arthroplasty is important. In addition, as more international travel occurs and patients are seen from areas where Brucella is endemic, the possibility of this infectious etiology should be considered. Based on reported cases, patients will usually have elevated ESR or CRP; all (except 2 cases in which no exposure was reported) had known exposure to unpasteurized dairy products or livestock. Joint aspiration yielded Brucella species in 8 cases, was negative in 3, and not reported in 5 cases (1 aspirate yielded Acinetobacter baumanii). In this case, ESR and CRP were elevated, and infection was suspected but joint aspiration was negative. The initial aspiration was cultured for 5 days and previous data, as well as that presented here, suggest that prolonged culture may provide diagnostic value.¹⁸ The patient had resided in an endemic area and had exposure to unpasteurized dairy products, but Brucella infection was not considered and, therefore, no precautions were taken.

Of the reported cases, only 1 met major criteria for periprosthetic joint infection (draining sinus) while 10 of the remaining 15 cases were positive for minor criteria of periprosthetic joint infection (elevated ESR or CRP, or positive culture from joint aspiration).¹⁹ Unfortunately, the available case reports did not detail the extent to which preoperative periprosthetic joint infection could be established based on minor criteria for periprosthetic joint infection (elevated joint synovial white blood cell count or neutrophil percentage, intra-articular purulence, or elevated neutrophil count on periprosthetic tissue histologic analysis).¹⁹

Periprosthetic joint infection by Brucella species is so rare that specific recommendations for this infectious etiology based on 18 reported cases would be overreaching. However, Brucella should be considered when evaluating a potentially infected joint replacement where the possibility of exposure exists (eg, travel to or previous residence in endemic areas, close contact with livestock, or ingestion of unpasteurized dairy products in endemic regions), with the potential for transmission to operating room and hospital personnel also considered. If there is concern about Brucella involvement, tissue and fluid specimens should be labeled so that laboratory personnel can take appropriate precautions. Brucella can be cultured using routine techniques on standard, nonselective media, but the culture time-to-growth may be prolonged. Culture plates should be held for 14 days before reporting no growth of Brucella if it is suspected; the New Mexico Department of Health Microbiology Laboratory holds routine cultures for 1 week after a report of no growth. Thus, a suspicion of Brucella should be communicated in order for culture time to be adjusted if the holding of culture plates after an initial report of no growth is not standard practice. If operative intervention is planned and brucellosis is known, personnel should be notified of the possibility of exposure and appropriate measures taken (ie, wearing N-95 respiratory masks during the procedure and considering other methods of irrigation less likely to aerosolize particulates). It is not known if preoperative antibiotic therapy can sufficiently lower the bacterial load to make aerosolization less likely. If brucellosis is suspected but not identified preoperatively, wearing N-95 respiratory masks should be considered during any open procedures. 

Conclusion

In cases of Brucella infection and loose components, 1- or 2-stage revision with appropriate antibiotic therapy is indicated. (There is not enough data to recommend either 1- or 2-stage revision.) Several reports comment on the ability to treat periprosthetic joint infection in the setting of well-fixed components with antibiotic therapy alone. While this appears to have been successful in 7 of 9 infected joints reported in the literature, length of follow-up ranged from 8 months to 5 years, with no report of length of follow-up in some cases. Antibiotic therapy duration ranged from 6 weeks to 26 months, and the antibiotic treatment involved combination therapy with multiple agents reported but, most commonly, doxycycline, rifampin, and streptomycin. With 2 of 9 (22%) joints failing antibiotic therapy alone and those reported to be successful having relatively short-term follow-up, this treatment strategy should be approached with caution.

Brucellosis is a zoonotic disease transmitted to humans through contact with animal hosts or animal products. Infection of total knee or hip arthroplasty by Brucella species is a rare complication with only 18 cases reported in the English literature.^1-12 We describe a case of an infected total hip replacement, its treatment, and 2-year follow-up and review the available literature. The patient provided written informed consent for print and electronic publication of this case report.

Case Report

A 67-year-old Spanish-speaking woman, a native of Mexico, presented with a painful right total hip arthroplasty (THA) 2 years after implantation in Chihuahua, Mexico. The patient reported 1 year of increasing thigh pain with recent onset of start-up pain, and also mild groin pain. The patient reported an uneventful postoperative course without wound drainage and denied any history of fevers, chills, or night sweats after the procedure. Preoperative notes and radiographs were unavailable for review. Radiographic evaluation showed a hybrid construct with a well-fixed–appearing, uncemented acetabular component but a failed cemented femoral stem (Figures 1A, 1B). Although we discussed revision surgery, the patient elected not to proceed with surgery or to undergo evaluation to rule out infection. Nine months later, she returned with worsening pain and requested revision surgery; radiographs showed progressive bone loss around the cement mantle (Figures 2A, 2B).

Hematologic evaluation showed an erythrocyte sedimentation rate (ESR) of 54 mm/h (normal, 0-27 mm/h) and C-reactive protein (CRP) level of 0.24 mg/L (normal, <0.8). An aspiration of the hip with fluoroscopic guidance produced a small sample (0.2 mL) of yellow synovial fluid. There was not enough fluid for cell count, but fluid culture was negative.

The patient was taken to the operating room for revision THA. Because of concern about progressive bone loss and elevated infectious indices, the administration of antibiotics was delayed until we obtained sufficient deep-tissue specimens. Before opening the capsule, we introduced a syringe into the joint and aspirated 10 mL of cloudy yellow synovial fluid that was sent for cell count. Additional findings at surgery included a grossly loose stem with a fragmented cement mantle surrounded by poor bone stock with anterior cortical bone loss and a loose acetabular component with pockets of cavitary bone loss. Frozen section showed up to 5 nucleated cells per high power field, and the cell count showed 1480 nucleated cells/µL (50% polymorphonuclear cells). The equivocal intraoperative findings (cell count and frozen section) and the loose femoral and acetabular components with significant bone loss were sufficiently concerning that we removed the components and placed a cement spacer rather than proceed with revision arthroplasty (Figures 3A, 3B). The surgeon, first assistant, and scrub technician wore body exhaust suits. We performed irrigation of the wound bed with pulse lavage.

Intraoperative cultures (synovial fluid, joint capsule synovium, and femur pseudocapsule) were positive after 8 days and growing B abortus. Infectious disease consultants prescribed rifampin 300 mg twice daily and doxycycline 100 mg twice daily for 5 months. Follow-up ESR and CRP returned to normal range. A preoperative aspiration of the hip was negative as well. The patient returned to the operating room at 6 months for re-implantation using uncemented components; synovial fluid and tissue cultures taken at this time were negative. Two years after re-implantation, the patient is doing well without evidence of infection (Figures 4A, 4B). Additional follow-up will be required to monitor for infection and implant survival. Additional history taken from the patient after the culture results revealed that her development of hip pain was preceded by a febrile illness consistent with brucellosis. 

Because of the nature of the procedure (irrigation and débridement using pulse lavage), we were concerned about aerosolization of Brucella bacteria and possible transmission to all staff present during the procedure. After consulting with the New Mexico Department of Health (NMDOH) and the Centers for Disease Control and Prevention (CDC), all surgical, anesthesia, and support personnel present in the operative suite  and staff who cleaned the room after the procedure were treated prophylactically (rifampin 600 mg daily, doxycycline 100 mg twice daily for 3 weeks) to prevent development of brucellosis.¹³ All 15 operating room personnel who were exposed elected to proceed with antibiotic prophylaxis. In addition to prophylactic antibiotics, serial serologic testing for anti-Brucella antibodies was conducted at baseline and 2, 4, 6, and 24 weeks postexposure to monitor for the development of Brucella infection. There were no conversions to positive antibody status. No personnel complained of symptoms that would indicate development of brucellosis. At the recommendation of NMDOH and CDC, all staff in the operating room during and immediately after the re-implantation procedure wore properly fitting N-95 disposable respiratory masks (3M, St. Paul, Minnesota) to guard against the potential risk of further exposure.

Discussion

Brucellosis is a zoonotic disease transmitted to humans through contact with animal hosts. Transmission can occur via breaks in the skin in direct contact, through the ingestion of unpasteurized dairy products or raw meat, or through ingestion of aerosolized bacteria. Transmission via aerosolization has been described during medical procedures.

Brucella is endemic in India, Middle Eastern and Mediterranean countries, Central Asia, and South America. Brucella species are gram-negative coccobacilli that are capable of surviving within phagocytic cells, making antibiotic treatment difficult. Brucellosis is a febrile illness that occurs after a 1- to 3-week incubation period and is often accompanied by headache, arthralgias, and hepatosplenomegaly. Osteoarticular infection is the most common complication, occurring in 10% to 85% of cases and usually involves the sacroiliac joint and the large joints of the lower extremity. Spondylitis, bursitis, tenosynovitis, endocarditis, colitis, meningitis, and osteomyelitis have also been described.^7,14-17

As mentioned previously, 18 cases of infected THAs and total knee arthroplasties (TKAs) in 16 patients were identified in the English literature: 9 THAs and 9 TKAs.^1-12 With the exception of 1 case reported in Texas, all others were from the Middle East or the Mediterranean region. In these patients, symptom onset occurred from 2 months to 14 years from the time of the index surgery, and symptom duration ranged from 1 month to 2 years prior to presentation. The exposure was not reported in 2 cases, but the remaining patients either ingested unpasteurized dairy products or worked closely with livestock. Laboratory evaluation revealed elevated ESR or CRP in 8 cases. In 7 cases, no laboratory results were reported, although 1 had a draining sinus. In 1 case, the ESR was normal, but a bone scan was positive. Joint aspiration yielded Brucella species in 8 cases, was negative in 3, and not reported in 5 cases (one aspirate yielded Acinetobacter baumanii). Only 3 cases reported a time-to-culture positivity (1 “prolonged” and 2 took 7 days).

Eight cases presented with loose components, while 1 case was not reported, and the remaining were presumed to be well-fixed. In cases that were identified as loose, 5 underwent a 2-stage revision and 2 underwent a 1-stage revision (in one of the 1-stage revisions, the infection was identified only after the revision from intra-operative cultures). Of those with well-fixed components, 7 patients with 9 infected joints (including the case where no preoperative description of the components was reported) were treated with oral antibiotics only (range, 6 weeks to 26 months) and 1 with irrigation and débridement and oral antibiotics. Among those treated only with antibiotics, there were 2 failures (2 joints) leading to revision surgery. The other 5 cases were reportedly doing well between 8 months and 5 years after treatment. There were no reports of transmission to hospital or laboratory personnel in any of these cases nor were there reports of precautions to limit exposure for operating room staff or hospital personnel. 

Failure of TKA or THA secondary to periprosthetic infection by Brucella species is rare, and this represents only the second reported case in the United States.⁴ This case highlights several important principles. Maintaining a high level of suspicion for infection in cases of failed joint arthroplasty is important. In addition, as more international travel occurs and patients are seen from areas where Brucella is endemic, the possibility of this infectious etiology should be considered. Based on reported cases, patients will usually have elevated ESR or CRP; all (except 2 cases in which no exposure was reported) had known exposure to unpasteurized dairy products or livestock. Joint aspiration yielded Brucella species in 8 cases, was negative in 3, and not reported in 5 cases (1 aspirate yielded Acinetobacter baumanii). In this case, ESR and CRP were elevated, and infection was suspected but joint aspiration was negative. The initial aspiration was cultured for 5 days and previous data, as well as that presented here, suggest that prolonged culture may provide diagnostic value.¹⁸ The patient had resided in an endemic area and had exposure to unpasteurized dairy products, but Brucella infection was not considered and, therefore, no precautions were taken.

Of the reported cases, only 1 met major criteria for periprosthetic joint infection (draining sinus) while 10 of the remaining 15 cases were positive for minor criteria of periprosthetic joint infection (elevated ESR or CRP, or positive culture from joint aspiration).¹⁹ Unfortunately, the available case reports did not detail the extent to which preoperative periprosthetic joint infection could be established based on minor criteria for periprosthetic joint infection (elevated joint synovial white blood cell count or neutrophil percentage, intra-articular purulence, or elevated neutrophil count on periprosthetic tissue histologic analysis).¹⁹

Periprosthetic joint infection by Brucella species is so rare that specific recommendations for this infectious etiology based on 18 reported cases would be overreaching. However, Brucella should be considered when evaluating a potentially infected joint replacement where the possibility of exposure exists (eg, travel to or previous residence in endemic areas, close contact with livestock, or ingestion of unpasteurized dairy products in endemic regions), with the potential for transmission to operating room and hospital personnel also considered. If there is concern about Brucella involvement, tissue and fluid specimens should be labeled so that laboratory personnel can take appropriate precautions. Brucella can be cultured using routine techniques on standard, nonselective media, but the culture time-to-growth may be prolonged. Culture plates should be held for 14 days before reporting no growth of Brucella if it is suspected; the New Mexico Department of Health Microbiology Laboratory holds routine cultures for 1 week after a report of no growth. Thus, a suspicion of Brucella should be communicated in order for culture time to be adjusted if the holding of culture plates after an initial report of no growth is not standard practice. If operative intervention is planned and brucellosis is known, personnel should be notified of the possibility of exposure and appropriate measures taken (ie, wearing N-95 respiratory masks during the procedure and considering other methods of irrigation less likely to aerosolize particulates). It is not known if preoperative antibiotic therapy can sufficiently lower the bacterial load to make aerosolization less likely. If brucellosis is suspected but not identified preoperatively, wearing N-95 respiratory masks should be considered during any open procedures. 

Conclusion

In cases of Brucella infection and loose components, 1- or 2-stage revision with appropriate antibiotic therapy is indicated. (There is not enough data to recommend either 1- or 2-stage revision.) Several reports comment on the ability to treat periprosthetic joint infection in the setting of well-fixed components with antibiotic therapy alone. While this appears to have been successful in 7 of 9 infected joints reported in the literature, length of follow-up ranged from 8 months to 5 years, with no report of length of follow-up in some cases. Antibiotic therapy duration ranged from 6 weeks to 26 months, and the antibiotic treatment involved combination therapy with multiple agents reported but, most commonly, doxycycline, rifampin, and streptomycin. With 2 of 9 (22%) joints failing antibiotic therapy alone and those reported to be successful having relatively short-term follow-up, this treatment strategy should be approached with caution.

The incidence of periprosthetic supracondylar fractures of the femur after total knee arthroplasty (TKA) ranges from 0.6% to 2.5%.¹ Treatment of periprosthetic fractures is often complicated by advanced patient age and osteoporosis, which frequently accompanies these fractures. Management of a periprosthetic fracture depends on the relation between the fracture site and the prosthesis, displacement of the prosthesis, integrity of the fixation of the prosthesis, extent of the bone loss caused by fracture comminution or preexisting osteolysis, general health of the patient, and surgeon expertise.^2,3 The aim is to achieve fracture union around a stable, well-aligned arthroplasty with preserved or restored bone stock and therefore to return the patient to previous level of function. Although nonoperative treatments have been shown to be successful,^4,5 in the great majority of cases surgical treatment is advised for these fractures.^6-10 In cases in which bone stock is adequate for fixation rather than replacement of the distal femur, 2 modalities are commonly used: retrograde intramedullary nailing and locking plates. Each has its drawbacks and advantages.^11,12

Although external fixation has been used in the treatment of distal femoral fractures,¹³ it is seldom considered in the treatment of periprosthetic fractures. Several authors have described cases that used external fixators, occasionally spanning the knee. The specific types of external fixators discussed in the literature have included ring fixators,^14-17 hybrid fixators,¹⁸ and uniplanar nonspanning fixators^14,19 (Table). Use of a simple anterior spanning external fixator in treating a periprosthetic femoral fracture has received little attention in the literature.

The patient provided written informed consent for print and electronic publication of this case report.

Case Report

A 54-year-old woman with previous total hip arthroplasty (THA) and ipsilateral TKA tripped on a carpet and sustained a comminuted fracture of the distal femur just above the TKA prosthesis (Figure 1). She was a Jehovah’s Witness and thus refused all blood products. She had an extensive history of osteoporosis, morbid obesity (5 feet tall, 250 pounds; body mass index, 49), diabetes, and rheumatoid arthritis. Evaluation by the internal medicine service revealed severe coronary artery disease on a stress thallium test and anemia with hematocrit of 24%. Given the patient’s medical comorbidities and religious status, and the location of the comminuted distal femur fracture, several treatment options were considered. First was nonoperative treatment with a cast or cast-brace (hinged cast). Because of her body habitus, however, we thought she would very likely experience skin complications, inadequate immobilization of the bone, and significant discomfort. Ultimately, use of a spanning external fixator was chosen as the safest course, given the significant medical risks accompanying a more extensive surgical reconstruction. With the spanning external fixator, the main risks were the inability to fully control fracture alignment and the potential introduction of infection into the functional THA. We thought that, by limiting the amount of time in the fixator and managing the pin site aggressively, we could minimize the risk for infection in this setting.

The procedure was performed with the patient under general anesthesia. During surgery, a lateral image of the femur was used to identify the distal end of the THA prosthesis. A level was marked 2 to 3 cm distal to the tip of this prosthesis, and another about 1 cm above the fracture (noted to be above the most proximal extent of the knee joint). These planned pin-entry sites were prepared from an anterior approach with incisions (using a No. 11 blade) of about 1 cm each. Blunt dissection was carried down to the femur. Each planned pin site was predrilled with a 3.5-mm drill; then, a 5-mm Shanz pin was placed. This process was repeated immediately distal to the tibial component and at the junction of the mid and distal thirds of the tibia (Figure 2). The preliminary external fixator frame was then applied. Once the reduction was satisfactory in the anteroposterior and lateral planes, the fixator clamps were tightened. A second row of bars was then incorporated.

Six weeks after surgery, radiographs showed early callus formation. Removing the external fixator and examining the knee under anesthesia confirmed there was no significant motion through the fracture site. A cast-brace (fiberglass thigh segment, fiberglass lower leg cast with hinged knee segment) was then applied. We remained concerned about skin complications but were encouraged by the early healing achieved with the fixator. The patient was started on a physical therapy program of gait training with a walker and toe-touch weight-bearing on the injured extremity. She also started a limited lower-extremity strengthening program. Three months after surgery, she was tolerating weight-bearing on the injured extremity with no pain. At 6 months, knee radiographs showed fracture consolidation with active range of motion of 10° to 120° and no pain (Figures 3A, 3B). Distal sensation, motor function, and vascular examination were normal. Two years after surgery, radiographs of the right knee showed minor malalignment in the coronal and sagittal planes (Figures 4A, 4B) and complete consolidation of the fracture.

Discussion

Periprosthetic fractures of the femur after TKA often occur in the setting of osteopenia, and some are associated with concurrent implant loosening. In most cases, these fractures require surgical stabilization. Nevertheless, the goals of treatment are to obtain and maintain anatomical alignment and stability to allow early range of motion. Nonoperative options include skeletal traction, cast, pins and plaster, and cast-brace.^3-5,20 Operative options include intramedullary fixation,^12,21 stabilization with various plates,^21-23 revision knee arthroplasty, and arthrodesis.¹ Treatment selection should be based on patient health, fracture displacement, comminution, osteopenia severity, and status of the prosthetic components.

The present case exemplifies some of the highest degrees of medical and surgical risk factors in people with a periprosthetic femoral fracture after TKA. Patients with rheumatoid arthritis, patients having corticosteroid treatment, patients of advanced age, and female patients are all at higher risk for supracondylar femoral fracture.⁹ Our patient had these risk factors on a background of anemia and extensive coronary artery disease. Given her past medical history and refusal of blood products out of religious belief, we thought she was too high risk for extensive surgical treatment for her fracture. In addition, she was not an ideal candidate for nonoperative treatment, as a periprosthetic fracture typically is treated with surgical revision or open reduction and internal fixation. Therefore, we selected an unconventional treatment modality, typically used as a temporizing measure in severe fractures around the knee—a spanning external fixator worn for 6 weeks and a cast-brace for an additional 6 weeks. This led to successful clinical and radiographic outcomes. We consider spanning external fixation a viable option for periprosthetic fractures after TKA in morbidly obese patients with relatively well-aligned fractures and extremely high risk for medical complications associated with traditional open surgery.

The incidence of periprosthetic supracondylar fractures of the femur after total knee arthroplasty (TKA) ranges from 0.6% to 2.5%.¹ Treatment of periprosthetic fractures is often complicated by advanced patient age and osteoporosis, which frequently accompanies these fractures. Management of a periprosthetic fracture depends on the relation between the fracture site and the prosthesis, displacement of the prosthesis, integrity of the fixation of the prosthesis, extent of the bone loss caused by fracture comminution or preexisting osteolysis, general health of the patient, and surgeon expertise.^2,3 The aim is to achieve fracture union around a stable, well-aligned arthroplasty with preserved or restored bone stock and therefore to return the patient to previous level of function. Although nonoperative treatments have been shown to be successful,^4,5 in the great majority of cases surgical treatment is advised for these fractures.^6-10 In cases in which bone stock is adequate for fixation rather than replacement of the distal femur, 2 modalities are commonly used: retrograde intramedullary nailing and locking plates. Each has its drawbacks and advantages.^11,12

Although external fixation has been used in the treatment of distal femoral fractures,¹³ it is seldom considered in the treatment of periprosthetic fractures. Several authors have described cases that used external fixators, occasionally spanning the knee. The specific types of external fixators discussed in the literature have included ring fixators,^14-17 hybrid fixators,¹⁸ and uniplanar nonspanning fixators^14,19 (Table). Use of a simple anterior spanning external fixator in treating a periprosthetic femoral fracture has received little attention in the literature.

The patient provided written informed consent for print and electronic publication of this case report.

Case Report

A 54-year-old woman with previous total hip arthroplasty (THA) and ipsilateral TKA tripped on a carpet and sustained a comminuted fracture of the distal femur just above the TKA prosthesis (Figure 1). She was a Jehovah’s Witness and thus refused all blood products. She had an extensive history of osteoporosis, morbid obesity (5 feet tall, 250 pounds; body mass index, 49), diabetes, and rheumatoid arthritis. Evaluation by the internal medicine service revealed severe coronary artery disease on a stress thallium test and anemia with hematocrit of 24%. Given the patient’s medical comorbidities and religious status, and the location of the comminuted distal femur fracture, several treatment options were considered. First was nonoperative treatment with a cast or cast-brace (hinged cast). Because of her body habitus, however, we thought she would very likely experience skin complications, inadequate immobilization of the bone, and significant discomfort. Ultimately, use of a spanning external fixator was chosen as the safest course, given the significant medical risks accompanying a more extensive surgical reconstruction. With the spanning external fixator, the main risks were the inability to fully control fracture alignment and the potential introduction of infection into the functional THA. We thought that, by limiting the amount of time in the fixator and managing the pin site aggressively, we could minimize the risk for infection in this setting.

The procedure was performed with the patient under general anesthesia. During surgery, a lateral image of the femur was used to identify the distal end of the THA prosthesis. A level was marked 2 to 3 cm distal to the tip of this prosthesis, and another about 1 cm above the fracture (noted to be above the most proximal extent of the knee joint). These planned pin-entry sites were prepared from an anterior approach with incisions (using a No. 11 blade) of about 1 cm each. Blunt dissection was carried down to the femur. Each planned pin site was predrilled with a 3.5-mm drill; then, a 5-mm Shanz pin was placed. This process was repeated immediately distal to the tibial component and at the junction of the mid and distal thirds of the tibia (Figure 2). The preliminary external fixator frame was then applied. Once the reduction was satisfactory in the anteroposterior and lateral planes, the fixator clamps were tightened. A second row of bars was then incorporated.

Six weeks after surgery, radiographs showed early callus formation. Removing the external fixator and examining the knee under anesthesia confirmed there was no significant motion through the fracture site. A cast-brace (fiberglass thigh segment, fiberglass lower leg cast with hinged knee segment) was then applied. We remained concerned about skin complications but were encouraged by the early healing achieved with the fixator. The patient was started on a physical therapy program of gait training with a walker and toe-touch weight-bearing on the injured extremity. She also started a limited lower-extremity strengthening program. Three months after surgery, she was tolerating weight-bearing on the injured extremity with no pain. At 6 months, knee radiographs showed fracture consolidation with active range of motion of 10° to 120° and no pain (Figures 3A, 3B). Distal sensation, motor function, and vascular examination were normal. Two years after surgery, radiographs of the right knee showed minor malalignment in the coronal and sagittal planes (Figures 4A, 4B) and complete consolidation of the fracture.

Discussion

Periprosthetic fractures of the femur after TKA often occur in the setting of osteopenia, and some are associated with concurrent implant loosening. In most cases, these fractures require surgical stabilization. Nevertheless, the goals of treatment are to obtain and maintain anatomical alignment and stability to allow early range of motion. Nonoperative options include skeletal traction, cast, pins and plaster, and cast-brace.^3-5,20 Operative options include intramedullary fixation,^12,21 stabilization with various plates,^21-23 revision knee arthroplasty, and arthrodesis.¹ Treatment selection should be based on patient health, fracture displacement, comminution, osteopenia severity, and status of the prosthetic components.

The present case exemplifies some of the highest degrees of medical and surgical risk factors in people with a periprosthetic femoral fracture after TKA. Patients with rheumatoid arthritis, patients having corticosteroid treatment, patients of advanced age, and female patients are all at higher risk for supracondylar femoral fracture.⁹ Our patient had these risk factors on a background of anemia and extensive coronary artery disease. Given her past medical history and refusal of blood products out of religious belief, we thought she was too high risk for extensive surgical treatment for her fracture. In addition, she was not an ideal candidate for nonoperative treatment, as a periprosthetic fracture typically is treated with surgical revision or open reduction and internal fixation. Therefore, we selected an unconventional treatment modality, typically used as a temporizing measure in severe fractures around the knee—a spanning external fixator worn for 6 weeks and a cast-brace for an additional 6 weeks. This led to successful clinical and radiographic outcomes. We consider spanning external fixation a viable option for periprosthetic fractures after TKA in morbidly obese patients with relatively well-aligned fractures and extremely high risk for medical complications associated with traditional open surgery.

The incidence of periprosthetic supracondylar fractures of the femur after total knee arthroplasty (TKA) ranges from 0.6% to 2.5%.¹ Treatment of periprosthetic fractures is often complicated by advanced patient age and osteoporosis, which frequently accompanies these fractures. Management of a periprosthetic fracture depends on the relation between the fracture site and the prosthesis, displacement of the prosthesis, integrity of the fixation of the prosthesis, extent of the bone loss caused by fracture comminution or preexisting osteolysis, general health of the patient, and surgeon expertise.^2,3 The aim is to achieve fracture union around a stable, well-aligned arthroplasty with preserved or restored bone stock and therefore to return the patient to previous level of function. Although nonoperative treatments have been shown to be successful,^4,5 in the great majority of cases surgical treatment is advised for these fractures.^6-10 In cases in which bone stock is adequate for fixation rather than replacement of the distal femur, 2 modalities are commonly used: retrograde intramedullary nailing and locking plates. Each has its drawbacks and advantages.^11,12

Although external fixation has been used in the treatment of distal femoral fractures,¹³ it is seldom considered in the treatment of periprosthetic fractures. Several authors have described cases that used external fixators, occasionally spanning the knee. The specific types of external fixators discussed in the literature have included ring fixators,^14-17 hybrid fixators,¹⁸ and uniplanar nonspanning fixators^14,19 (Table). Use of a simple anterior spanning external fixator in treating a periprosthetic femoral fracture has received little attention in the literature.

The patient provided written informed consent for print and electronic publication of this case report.

Case Report

A 54-year-old woman with previous total hip arthroplasty (THA) and ipsilateral TKA tripped on a carpet and sustained a comminuted fracture of the distal femur just above the TKA prosthesis (Figure 1). She was a Jehovah’s Witness and thus refused all blood products. She had an extensive history of osteoporosis, morbid obesity (5 feet tall, 250 pounds; body mass index, 49), diabetes, and rheumatoid arthritis. Evaluation by the internal medicine service revealed severe coronary artery disease on a stress thallium test and anemia with hematocrit of 24%. Given the patient’s medical comorbidities and religious status, and the location of the comminuted distal femur fracture, several treatment options were considered. First was nonoperative treatment with a cast or cast-brace (hinged cast). Because of her body habitus, however, we thought she would very likely experience skin complications, inadequate immobilization of the bone, and significant discomfort. Ultimately, use of a spanning external fixator was chosen as the safest course, given the significant medical risks accompanying a more extensive surgical reconstruction. With the spanning external fixator, the main risks were the inability to fully control fracture alignment and the potential introduction of infection into the functional THA. We thought that, by limiting the amount of time in the fixator and managing the pin site aggressively, we could minimize the risk for infection in this setting.

The procedure was performed with the patient under general anesthesia. During surgery, a lateral image of the femur was used to identify the distal end of the THA prosthesis. A level was marked 2 to 3 cm distal to the tip of this prosthesis, and another about 1 cm above the fracture (noted to be above the most proximal extent of the knee joint). These planned pin-entry sites were prepared from an anterior approach with incisions (using a No. 11 blade) of about 1 cm each. Blunt dissection was carried down to the femur. Each planned pin site was predrilled with a 3.5-mm drill; then, a 5-mm Shanz pin was placed. This process was repeated immediately distal to the tibial component and at the junction of the mid and distal thirds of the tibia (Figure 2). The preliminary external fixator frame was then applied. Once the reduction was satisfactory in the anteroposterior and lateral planes, the fixator clamps were tightened. A second row of bars was then incorporated.

Six weeks after surgery, radiographs showed early callus formation. Removing the external fixator and examining the knee under anesthesia confirmed there was no significant motion through the fracture site. A cast-brace (fiberglass thigh segment, fiberglass lower leg cast with hinged knee segment) was then applied. We remained concerned about skin complications but were encouraged by the early healing achieved with the fixator. The patient was started on a physical therapy program of gait training with a walker and toe-touch weight-bearing on the injured extremity. She also started a limited lower-extremity strengthening program. Three months after surgery, she was tolerating weight-bearing on the injured extremity with no pain. At 6 months, knee radiographs showed fracture consolidation with active range of motion of 10° to 120° and no pain (Figures 3A, 3B). Distal sensation, motor function, and vascular examination were normal. Two years after surgery, radiographs of the right knee showed minor malalignment in the coronal and sagittal planes (Figures 4A, 4B) and complete consolidation of the fracture.

Discussion

Periprosthetic fractures of the femur after TKA often occur in the setting of osteopenia, and some are associated with concurrent implant loosening. In most cases, these fractures require surgical stabilization. Nevertheless, the goals of treatment are to obtain and maintain anatomical alignment and stability to allow early range of motion. Nonoperative options include skeletal traction, cast, pins and plaster, and cast-brace.^3-5,20 Operative options include intramedullary fixation,^12,21 stabilization with various plates,^21-23 revision knee arthroplasty, and arthrodesis.¹ Treatment selection should be based on patient health, fracture displacement, comminution, osteopenia severity, and status of the prosthetic components.

The present case exemplifies some of the highest degrees of medical and surgical risk factors in people with a periprosthetic femoral fracture after TKA. Patients with rheumatoid arthritis, patients having corticosteroid treatment, patients of advanced age, and female patients are all at higher risk for supracondylar femoral fracture.⁹ Our patient had these risk factors on a background of anemia and extensive coronary artery disease. Given her past medical history and refusal of blood products out of religious belief, we thought she was too high risk for extensive surgical treatment for her fracture. In addition, she was not an ideal candidate for nonoperative treatment, as a periprosthetic fracture typically is treated with surgical revision or open reduction and internal fixation. Therefore, we selected an unconventional treatment modality, typically used as a temporizing measure in severe fractures around the knee—a spanning external fixator worn for 6 weeks and a cast-brace for an additional 6 weeks. This led to successful clinical and radiographic outcomes. We consider spanning external fixation a viable option for periprosthetic fractures after TKA in morbidly obese patients with relatively well-aligned fractures and extremely high risk for medical complications associated with traditional open surgery.

Emotional stress can induce different responses in the body, particularly in the cardiovascular system. Apical ballooning syndrome (ABS), also known as takotsubo cardiomyopathy and broken heart syndrome, is a transient cardiomyopathy that mimics an acute myocardial infarction (AMI). Dote and colleagues first described this transient entity in Japan in the early 1990s.¹ A case review series reported that 57.2% of patients were Asian, 40% were white.² Mean patient age was 67 years, although cases of ABS have occurred in children and young adults.^3,4

The term tako-tsubo means “octopus trap,” which is the morphology that the left ventricle resembles during systole in patients with this syndrome.⁵ The pathophysiology of ABS is thought to be mediated by a catecholamine surge. The presentation of ABS is indistinguishable from an AMI. The majority of patients present with angina-like chest pain, ischemic changes on an electrocardiogram (ECG), pulmonary edema, and elevation of cardiac enzymes. Apical ballooning syndrome is accompanied by reversible left ventricular apical ballooning in the absence of angiographically significant coronary artery disease.

Typically, echocardiographic findings show a left ventricle with preserved function in the basal segments, moderate-to-severe dysfunction in the mid portion of the left ventricle, and hypokinesis, akinesis, or dyskinesis in the apex. A unique but not exclusive feature of this syndrome is the occurrence of a preceding emotional trigger, usually sudden or unexpected. Most patients are initially treated for an AMI until angiography can rule out coronary obstruction. After several weeks, the left ventricular systolic function usually returns to normal.

Case Presentation

A 49-year-old woman with a history of arterial hypertension, fibromyalgia, peptic ulcer disease, and major depressive disorder with multiple admissions to the psychiatric ward (last admission was 4 weeks prior to the current presentation) presented to the emergency department, reporting severe retrosternal, oppressive chest pain with 9/10 intensity and 3 hours’ duration. The pain was associated with nausea, vomiting, diaphoresis, and palpitations. She reported no previous episodes of exertional angina, fever, illicit drug use, recent illness, or travel. She also reported no prodromal symptoms.

Her initial vital signs were essentially unremarkable, except for mild hypertension (148/84 mm Hg). The physical examination showed an anxious patient in acute distress due to chest pain. A cardiovascular examination revealed a regular heart rate and rhythm, no audible murmurs or gallops, no jugular vein distention, clear breath sounds, and no peripheral edema. The rest of the examination was otherwise unremarkable. An initial 12-lead ECG showed a normal sinus rhythm without any ST-T changes (Figure 1).

The initial cardiac markers were elevated (troponin T 0.36 ng/mL, CK-MB 4.51 ng/mL), as were NT-proBNP levels (1,057 pg/mL). The rest of the laboratory results were essentially unremarkable. The patient was started on aspirin, clopidogrel, enoxaparin, eptifibatide, and IV nitrates. She was admitted to the coronary care unit with a diagnostic impression of non-ST elevation MI. Despite medical management, the patient’s chest pain persisted for several hours from her initial presentation. A repeated 12-lead ECG revealed new borderline (1-1.5 mm) ST segment elevation in V2-V3, suggestive of possible myocardial injury (Figure 2).

A bedside echocardiogram revealed severe wall motion abnor malities, ranging from hypokinesia to dyskinesia of all mid-to-distal left ventricular wall segments with sparing of the basal segment (Figure 3). The estimated left ventricular ejection fraction was 40% to 45%.

In view of these findings, the patient was taken to the catheterization laboratory for emergent coronary angiography, which ruled out significant obstructive coronary disease (Figure 4).

Left ventriculography in right and left anterior oblique projections revealed significant wall motion abnormalities of the mid-to-distal anterolateral and inferior wall segments, sparing the basal and apical segments, giving the appearance of ballooning in systole (Figure 5). The diagnosis of ABS involving the mid ventricular walls was explored.

Subsequent sets of cardiac enzymes at 4 and 8 hours after arrival remained elevated, with a maximum troponin T 0.55 and CK-MB of 11.19. Repeated 12-lead ECG 24 hours post coronary angiography revealed anterolateral T wave inversion (Figure 6).

Noncontrast enhanced cardiac magnetic resonance imaging (MRI) (Figure 7) performed 5 days later revealed wall motion abnormalities highly suggestive of ABS, supporting previous echocardiographic and ventriculography findings. Unfortunately, contrast-enhanced phase for evaluation of delayed enhancement could not be completed, because the patient did not continue the study.

Toxicology tests were negative for sympathomimetic drugs. Metanephrine levels were within the normal range. Viral titers for cytomegalovirus and coxsackie virus also were negative. Inflammatory markers were mildly elevated (erythrocyte sedimentation rate, 22 mm/h; C-reactive protein, 4.2 mg/L).

The patient was treated with supportive care, psychotropic therapy, angiotensin-converting enzyme inhibitor (ACE-I), and beta blocker therapy. Within 9 days, NT-proBNP levels normalized (from peak 8,834 pg/mL to 191.5 pg/mL).

Six weeks later, an echocardiogram confirmed resolution of wall motion abnormalities (Figure 8). Follow-up cardiac MRI showed complete resolution of segmental wall motion abnormalities and the apical ballooning, normal wall thickness, and absent delayed enhancement (Figure 9). These findings further supported the diagnosis of ABS and excluded MI and myocarditis.

Discussion

What is striking about takotsubo cardiomyopathy is that the clinical presentation resembles an AMI. Several studies have reported that 1.7% to 2.2% of patients who had suspected acute coronary syndrome were subsequently diagnosed with takotsubo cardiomyopathy.^6-8 Nearly 90% of reported cases involved postmenopausal women, and this may be related to loss of the cardioprotective effect of estrogen.^5,9

A preceding stressful emotional or physical event is usually identified in about two-thirds of the patients with ABS.⁹ Most common emotional triggers are death of a relative or friend, broken relationships, assaults, and rapes, among others. Physical triggers include severe sepsis, shock, acute respiratory failure, seizures, and intracranial bleeds. Sometimes a specific trigger cannot be identified from the history, but the absence of an emotional or physical trigger does not exclude the diagnosis.

Although the exact pathogenesis of ABS remains unclear, it is likely that multiple factors are involved. Some of the suggested mechanisms are high levels of catecholamines, multivessel epicardial spasm, or coronary microvascular dysfunction.⁴ The catecholamine hypothesis has been supported by the finding that several patients with pheochromocytoma and subarachnoid hemorrhage also present with high levels of catecholamine and a cardiomyopathy resembling ABS. Furthermore, ABS has been reported in patients on catecholamine infusions and those treated with agents that inhibit reuptake of catecholamines.⁵

The presence of multivessel coronary spasm was suggested by early small studies in Japan, but more recent case series have not validated this hypothesis.⁵ The microvascular dysfunction hypothesis is supported by the presence of myocardial ischemia, diagnosed by ECG changes and elevated troponins, in the absence of significant coronary disease. However, it remains unclear whether this is a primary mechanism or a manifestation of a primary process.⁴ Microvascular dysfunction may be more likely related to impairment of myocardial relaxation with extramural coronary compression.

Signs and symptoms of ABS mimic those of AMI, with angina-like chest pain as the main presenting symptom in about 50% of cases.¹⁰ Other symptoms include dyspnea and less commonly, syncope or sudden cardiac death. Decompensated left heart failure occurs in 50% of patients, with severe hemodynamic compromise and cardiogenic shock not being uncommon. Other complications that may occur are tachyarrhythmias (atrial or ventricular) and ventricular thromboembolism.⁴

Common ECG changes in ABS include precordial ST segment elevations, symmetric T wave inversions, and nonspecific T wave changes.^4,10 QT interval prolongation may be seen during the first days. Transient pathologic Q waves may be seen at presentation or afterward. These ECG changes tend to revert after weeks or months of presentation.

Elevation of cardiac biomarkers is usually present in laboratory data. Levels peak at 24 hours, and the degree of elevation is usually less than that seen in patients with an AMI.¹⁰ Most important, the degree of cardiac biomarker elevation is disproportionately low for the extent of involved coronary territory and left ventricular dysfunction. Other laboratory tests that are frequently altered are the BNP and pro-BNP levels, which are usually elevated due to transient left ventricular dysfunction. C-reactive protein elevates in most patients and indicates the presence of an acute inflammatory response.

Early coronary angiography should be performed in all patients with ABS to rule out the presence of a significant obstructive coronary lesion. Patients with ABS often have luminal irregularities or normal coronary vessels. However, concomitant obstructive coronary lesions may be found, especially in elderly patients.

The hallmark of ABS is a characteristic transient contractility abnormality of the left ventricle causing ballooning of the apex, which can be detected on left ventricular angiography or echocardiography. There are 3 distinct variants of ABS, according to the left ventricular myocardial wall segments involved.¹⁰ The classic form of takotsubo is characterized by hypokinesis, dyskinesis, or akinesis of the middle and apical segments of the left ventricle. The basal segment is usually spared and may be hyperdynamic. In the midventricular or apical sparing variant, the wall motion abnormalities are restricted to the midventricular segments, and apical contraction is preserved. This case resembles the atypical variant, because the midventricular segments were affected, whereas apical and basal regions were preserved. A rare variant of takotsubo exists with hypokinesis or akinesis of the base and preserved apical function.

Besides ABS and AMI, an important entity to consider in the differential diagnosis of transient wall motion abnormalities is regional myocarditis. Viral titers are helpful in excluding this condition. Furthermore, prolonged recovery is more commonly seen in myocarditis compared with ABS. Imaging studies are particularly helpful in this scenario.

Cardiac MRI demonstrates the wall motion abnormalities or apical ballooning typical for this condition and can differentiate ABS from myocarditis or MI. It is known that delayed myocardial enhancement is seen with myocardial fibrosis. Typically in ischemic cardiomyopathy, there is wall thinning with associated delayed enhancement that extends from the subendocardium to the epicardium (from 0%-90% of wall thickness) of a particular vascular territory. In myocarditis, the enhancement is usually seen in the involved intramyocardial (mesocardium) region, and the pattern is patchy. In ABS, the delayed enhancement is absent, because there is no fibrosis in the area of regional wall motion abnormalities, and wall thickness is usually normal.^9,10

No evidence-based guidelines for treating ABS are currently available. Most patients are initially treated with antiplatelets/anticoagulant therapy, nitrates, and diuretics if the patient presents with heart failure. Patients should be admitted to an intensive care unit for close cardiac monitoring. Once ABS is diagnosed and significant coronary stenosis is excluded, patients should receive standard supportive care and optimal neurohormonal therapy. This should include beta blocker or combined alpha/beta blocker agents, an ACE-I or angiotensin receptor blocker, and diuretics if appropriate. Once left ventricular function (LVF) is recovered, therapy with inhibitors of the renin-angiotensin system may be discontinued, but patients should remain on long-term alpha or beta blocker therapy, because the sympathetic blockade provided by these agents may prevent recurrences of this disease.¹⁰

Prognosis is generally favorable, and most patients recover to normal LVF over weeks to months. It is important to assess the LVF 4 to 6 weeks after the patient is discharged to confirm the diagnosis of ABS. Recurrence may occur in up to 9% of cases.¹⁰ Long-term mortality is similar compared with the age-matched general population.

Conclusion

Apical ballooning syndrome is a relatively novel cardiomyopathy that has gained important attention among the cardiovascular community, mostly because its clinical presentation mimics that of an acute coronary syndrome. Awareness of this entity will result in a more focused diagnosis and appropriate treatment. Managing both cardiac and emotional components of this disease will have a permanent impact in the reversibility and secondary prevention of this cardiomyopathy.

Acknowledgments
Special thanks to the Radiology Service at the VA Caribbean Healthcare System, in particular Dr. Frances Aulet for interpretation of the cardiac MRI results and assistance with MRI images.

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

Emotional stress can induce different responses in the body, particularly in the cardiovascular system. Apical ballooning syndrome (ABS), also known as takotsubo cardiomyopathy and broken heart syndrome, is a transient cardiomyopathy that mimics an acute myocardial infarction (AMI). Dote and colleagues first described this transient entity in Japan in the early 1990s.¹ A case review series reported that 57.2% of patients were Asian, 40% were white.² Mean patient age was 67 years, although cases of ABS have occurred in children and young adults.^3,4

The term tako-tsubo means “octopus trap,” which is the morphology that the left ventricle resembles during systole in patients with this syndrome.⁵ The pathophysiology of ABS is thought to be mediated by a catecholamine surge. The presentation of ABS is indistinguishable from an AMI. The majority of patients present with angina-like chest pain, ischemic changes on an electrocardiogram (ECG), pulmonary edema, and elevation of cardiac enzymes. Apical ballooning syndrome is accompanied by reversible left ventricular apical ballooning in the absence of angiographically significant coronary artery disease.

Typically, echocardiographic findings show a left ventricle with preserved function in the basal segments, moderate-to-severe dysfunction in the mid portion of the left ventricle, and hypokinesis, akinesis, or dyskinesis in the apex. A unique but not exclusive feature of this syndrome is the occurrence of a preceding emotional trigger, usually sudden or unexpected. Most patients are initially treated for an AMI until angiography can rule out coronary obstruction. After several weeks, the left ventricular systolic function usually returns to normal.

Case Presentation

A 49-year-old woman with a history of arterial hypertension, fibromyalgia, peptic ulcer disease, and major depressive disorder with multiple admissions to the psychiatric ward (last admission was 4 weeks prior to the current presentation) presented to the emergency department, reporting severe retrosternal, oppressive chest pain with 9/10 intensity and 3 hours’ duration. The pain was associated with nausea, vomiting, diaphoresis, and palpitations. She reported no previous episodes of exertional angina, fever, illicit drug use, recent illness, or travel. She also reported no prodromal symptoms.

Her initial vital signs were essentially unremarkable, except for mild hypertension (148/84 mm Hg). The physical examination showed an anxious patient in acute distress due to chest pain. A cardiovascular examination revealed a regular heart rate and rhythm, no audible murmurs or gallops, no jugular vein distention, clear breath sounds, and no peripheral edema. The rest of the examination was otherwise unremarkable. An initial 12-lead ECG showed a normal sinus rhythm without any ST-T changes (Figure 1).

The initial cardiac markers were elevated (troponin T 0.36 ng/mL, CK-MB 4.51 ng/mL), as were NT-proBNP levels (1,057 pg/mL). The rest of the laboratory results were essentially unremarkable. The patient was started on aspirin, clopidogrel, enoxaparin, eptifibatide, and IV nitrates. She was admitted to the coronary care unit with a diagnostic impression of non-ST elevation MI. Despite medical management, the patient’s chest pain persisted for several hours from her initial presentation. A repeated 12-lead ECG revealed new borderline (1-1.5 mm) ST segment elevation in V2-V3, suggestive of possible myocardial injury (Figure 2).

A bedside echocardiogram revealed severe wall motion abnor malities, ranging from hypokinesia to dyskinesia of all mid-to-distal left ventricular wall segments with sparing of the basal segment (Figure 3). The estimated left ventricular ejection fraction was 40% to 45%.

In view of these findings, the patient was taken to the catheterization laboratory for emergent coronary angiography, which ruled out significant obstructive coronary disease (Figure 4).

Left ventriculography in right and left anterior oblique projections revealed significant wall motion abnormalities of the mid-to-distal anterolateral and inferior wall segments, sparing the basal and apical segments, giving the appearance of ballooning in systole (Figure 5). The diagnosis of ABS involving the mid ventricular walls was explored.

Subsequent sets of cardiac enzymes at 4 and 8 hours after arrival remained elevated, with a maximum troponin T 0.55 and CK-MB of 11.19. Repeated 12-lead ECG 24 hours post coronary angiography revealed anterolateral T wave inversion (Figure 6).

Noncontrast enhanced cardiac magnetic resonance imaging (MRI) (Figure 7) performed 5 days later revealed wall motion abnormalities highly suggestive of ABS, supporting previous echocardiographic and ventriculography findings. Unfortunately, contrast-enhanced phase for evaluation of delayed enhancement could not be completed, because the patient did not continue the study.

Toxicology tests were negative for sympathomimetic drugs. Metanephrine levels were within the normal range. Viral titers for cytomegalovirus and coxsackie virus also were negative. Inflammatory markers were mildly elevated (erythrocyte sedimentation rate, 22 mm/h; C-reactive protein, 4.2 mg/L).

The patient was treated with supportive care, psychotropic therapy, angiotensin-converting enzyme inhibitor (ACE-I), and beta blocker therapy. Within 9 days, NT-proBNP levels normalized (from peak 8,834 pg/mL to 191.5 pg/mL).

Six weeks later, an echocardiogram confirmed resolution of wall motion abnormalities (Figure 8). Follow-up cardiac MRI showed complete resolution of segmental wall motion abnormalities and the apical ballooning, normal wall thickness, and absent delayed enhancement (Figure 9). These findings further supported the diagnosis of ABS and excluded MI and myocarditis.

Discussion

What is striking about takotsubo cardiomyopathy is that the clinical presentation resembles an AMI. Several studies have reported that 1.7% to 2.2% of patients who had suspected acute coronary syndrome were subsequently diagnosed with takotsubo cardiomyopathy.^6-8 Nearly 90% of reported cases involved postmenopausal women, and this may be related to loss of the cardioprotective effect of estrogen.^5,9

A preceding stressful emotional or physical event is usually identified in about two-thirds of the patients with ABS.⁹ Most common emotional triggers are death of a relative or friend, broken relationships, assaults, and rapes, among others. Physical triggers include severe sepsis, shock, acute respiratory failure, seizures, and intracranial bleeds. Sometimes a specific trigger cannot be identified from the history, but the absence of an emotional or physical trigger does not exclude the diagnosis.

Although the exact pathogenesis of ABS remains unclear, it is likely that multiple factors are involved. Some of the suggested mechanisms are high levels of catecholamines, multivessel epicardial spasm, or coronary microvascular dysfunction.⁴ The catecholamine hypothesis has been supported by the finding that several patients with pheochromocytoma and subarachnoid hemorrhage also present with high levels of catecholamine and a cardiomyopathy resembling ABS. Furthermore, ABS has been reported in patients on catecholamine infusions and those treated with agents that inhibit reuptake of catecholamines.⁵

The presence of multivessel coronary spasm was suggested by early small studies in Japan, but more recent case series have not validated this hypothesis.⁵ The microvascular dysfunction hypothesis is supported by the presence of myocardial ischemia, diagnosed by ECG changes and elevated troponins, in the absence of significant coronary disease. However, it remains unclear whether this is a primary mechanism or a manifestation of a primary process.⁴ Microvascular dysfunction may be more likely related to impairment of myocardial relaxation with extramural coronary compression.

Signs and symptoms of ABS mimic those of AMI, with angina-like chest pain as the main presenting symptom in about 50% of cases.¹⁰ Other symptoms include dyspnea and less commonly, syncope or sudden cardiac death. Decompensated left heart failure occurs in 50% of patients, with severe hemodynamic compromise and cardiogenic shock not being uncommon. Other complications that may occur are tachyarrhythmias (atrial or ventricular) and ventricular thromboembolism.⁴

Common ECG changes in ABS include precordial ST segment elevations, symmetric T wave inversions, and nonspecific T wave changes.^4,10 QT interval prolongation may be seen during the first days. Transient pathologic Q waves may be seen at presentation or afterward. These ECG changes tend to revert after weeks or months of presentation.

Elevation of cardiac biomarkers is usually present in laboratory data. Levels peak at 24 hours, and the degree of elevation is usually less than that seen in patients with an AMI.¹⁰ Most important, the degree of cardiac biomarker elevation is disproportionately low for the extent of involved coronary territory and left ventricular dysfunction. Other laboratory tests that are frequently altered are the BNP and pro-BNP levels, which are usually elevated due to transient left ventricular dysfunction. C-reactive protein elevates in most patients and indicates the presence of an acute inflammatory response.

Early coronary angiography should be performed in all patients with ABS to rule out the presence of a significant obstructive coronary lesion. Patients with ABS often have luminal irregularities or normal coronary vessels. However, concomitant obstructive coronary lesions may be found, especially in elderly patients.

The hallmark of ABS is a characteristic transient contractility abnormality of the left ventricle causing ballooning of the apex, which can be detected on left ventricular angiography or echocardiography. There are 3 distinct variants of ABS, according to the left ventricular myocardial wall segments involved.¹⁰ The classic form of takotsubo is characterized by hypokinesis, dyskinesis, or akinesis of the middle and apical segments of the left ventricle. The basal segment is usually spared and may be hyperdynamic. In the midventricular or apical sparing variant, the wall motion abnormalities are restricted to the midventricular segments, and apical contraction is preserved. This case resembles the atypical variant, because the midventricular segments were affected, whereas apical and basal regions were preserved. A rare variant of takotsubo exists with hypokinesis or akinesis of the base and preserved apical function.

Besides ABS and AMI, an important entity to consider in the differential diagnosis of transient wall motion abnormalities is regional myocarditis. Viral titers are helpful in excluding this condition. Furthermore, prolonged recovery is more commonly seen in myocarditis compared with ABS. Imaging studies are particularly helpful in this scenario.

Cardiac MRI demonstrates the wall motion abnormalities or apical ballooning typical for this condition and can differentiate ABS from myocarditis or MI. It is known that delayed myocardial enhancement is seen with myocardial fibrosis. Typically in ischemic cardiomyopathy, there is wall thinning with associated delayed enhancement that extends from the subendocardium to the epicardium (from 0%-90% of wall thickness) of a particular vascular territory. In myocarditis, the enhancement is usually seen in the involved intramyocardial (mesocardium) region, and the pattern is patchy. In ABS, the delayed enhancement is absent, because there is no fibrosis in the area of regional wall motion abnormalities, and wall thickness is usually normal.^9,10

No evidence-based guidelines for treating ABS are currently available. Most patients are initially treated with antiplatelets/anticoagulant therapy, nitrates, and diuretics if the patient presents with heart failure. Patients should be admitted to an intensive care unit for close cardiac monitoring. Once ABS is diagnosed and significant coronary stenosis is excluded, patients should receive standard supportive care and optimal neurohormonal therapy. This should include beta blocker or combined alpha/beta blocker agents, an ACE-I or angiotensin receptor blocker, and diuretics if appropriate. Once left ventricular function (LVF) is recovered, therapy with inhibitors of the renin-angiotensin system may be discontinued, but patients should remain on long-term alpha or beta blocker therapy, because the sympathetic blockade provided by these agents may prevent recurrences of this disease.¹⁰

Prognosis is generally favorable, and most patients recover to normal LVF over weeks to months. It is important to assess the LVF 4 to 6 weeks after the patient is discharged to confirm the diagnosis of ABS. Recurrence may occur in up to 9% of cases.¹⁰ Long-term mortality is similar compared with the age-matched general population.

Conclusion

Apical ballooning syndrome is a relatively novel cardiomyopathy that has gained important attention among the cardiovascular community, mostly because its clinical presentation mimics that of an acute coronary syndrome. Awareness of this entity will result in a more focused diagnosis and appropriate treatment. Managing both cardiac and emotional components of this disease will have a permanent impact in the reversibility and secondary prevention of this cardiomyopathy.

Acknowledgments
Special thanks to the Radiology Service at the VA Caribbean Healthcare System, in particular Dr. Frances Aulet for interpretation of the cardiac MRI results and assistance with MRI images.

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

Emotional stress can induce different responses in the body, particularly in the cardiovascular system. Apical ballooning syndrome (ABS), also known as takotsubo cardiomyopathy and broken heart syndrome, is a transient cardiomyopathy that mimics an acute myocardial infarction (AMI). Dote and colleagues first described this transient entity in Japan in the early 1990s.¹ A case review series reported that 57.2% of patients were Asian, 40% were white.² Mean patient age was 67 years, although cases of ABS have occurred in children and young adults.^3,4

The term tako-tsubo means “octopus trap,” which is the morphology that the left ventricle resembles during systole in patients with this syndrome.⁵ The pathophysiology of ABS is thought to be mediated by a catecholamine surge. The presentation of ABS is indistinguishable from an AMI. The majority of patients present with angina-like chest pain, ischemic changes on an electrocardiogram (ECG), pulmonary edema, and elevation of cardiac enzymes. Apical ballooning syndrome is accompanied by reversible left ventricular apical ballooning in the absence of angiographically significant coronary artery disease.

Typically, echocardiographic findings show a left ventricle with preserved function in the basal segments, moderate-to-severe dysfunction in the mid portion of the left ventricle, and hypokinesis, akinesis, or dyskinesis in the apex. A unique but not exclusive feature of this syndrome is the occurrence of a preceding emotional trigger, usually sudden or unexpected. Most patients are initially treated for an AMI until angiography can rule out coronary obstruction. After several weeks, the left ventricular systolic function usually returns to normal.

Case Presentation

A 49-year-old woman with a history of arterial hypertension, fibromyalgia, peptic ulcer disease, and major depressive disorder with multiple admissions to the psychiatric ward (last admission was 4 weeks prior to the current presentation) presented to the emergency department, reporting severe retrosternal, oppressive chest pain with 9/10 intensity and 3 hours’ duration. The pain was associated with nausea, vomiting, diaphoresis, and palpitations. She reported no previous episodes of exertional angina, fever, illicit drug use, recent illness, or travel. She also reported no prodromal symptoms.

Her initial vital signs were essentially unremarkable, except for mild hypertension (148/84 mm Hg). The physical examination showed an anxious patient in acute distress due to chest pain. A cardiovascular examination revealed a regular heart rate and rhythm, no audible murmurs or gallops, no jugular vein distention, clear breath sounds, and no peripheral edema. The rest of the examination was otherwise unremarkable. An initial 12-lead ECG showed a normal sinus rhythm without any ST-T changes (Figure 1).

The initial cardiac markers were elevated (troponin T 0.36 ng/mL, CK-MB 4.51 ng/mL), as were NT-proBNP levels (1,057 pg/mL). The rest of the laboratory results were essentially unremarkable. The patient was started on aspirin, clopidogrel, enoxaparin, eptifibatide, and IV nitrates. She was admitted to the coronary care unit with a diagnostic impression of non-ST elevation MI. Despite medical management, the patient’s chest pain persisted for several hours from her initial presentation. A repeated 12-lead ECG revealed new borderline (1-1.5 mm) ST segment elevation in V2-V3, suggestive of possible myocardial injury (Figure 2).

A bedside echocardiogram revealed severe wall motion abnor malities, ranging from hypokinesia to dyskinesia of all mid-to-distal left ventricular wall segments with sparing of the basal segment (Figure 3). The estimated left ventricular ejection fraction was 40% to 45%.

In view of these findings, the patient was taken to the catheterization laboratory for emergent coronary angiography, which ruled out significant obstructive coronary disease (Figure 4).

Left ventriculography in right and left anterior oblique projections revealed significant wall motion abnormalities of the mid-to-distal anterolateral and inferior wall segments, sparing the basal and apical segments, giving the appearance of ballooning in systole (Figure 5). The diagnosis of ABS involving the mid ventricular walls was explored.

Subsequent sets of cardiac enzymes at 4 and 8 hours after arrival remained elevated, with a maximum troponin T 0.55 and CK-MB of 11.19. Repeated 12-lead ECG 24 hours post coronary angiography revealed anterolateral T wave inversion (Figure 6).

Noncontrast enhanced cardiac magnetic resonance imaging (MRI) (Figure 7) performed 5 days later revealed wall motion abnormalities highly suggestive of ABS, supporting previous echocardiographic and ventriculography findings. Unfortunately, contrast-enhanced phase for evaluation of delayed enhancement could not be completed, because the patient did not continue the study.

Toxicology tests were negative for sympathomimetic drugs. Metanephrine levels were within the normal range. Viral titers for cytomegalovirus and coxsackie virus also were negative. Inflammatory markers were mildly elevated (erythrocyte sedimentation rate, 22 mm/h; C-reactive protein, 4.2 mg/L).

The patient was treated with supportive care, psychotropic therapy, angiotensin-converting enzyme inhibitor (ACE-I), and beta blocker therapy. Within 9 days, NT-proBNP levels normalized (from peak 8,834 pg/mL to 191.5 pg/mL).

Six weeks later, an echocardiogram confirmed resolution of wall motion abnormalities (Figure 8). Follow-up cardiac MRI showed complete resolution of segmental wall motion abnormalities and the apical ballooning, normal wall thickness, and absent delayed enhancement (Figure 9). These findings further supported the diagnosis of ABS and excluded MI and myocarditis.

Discussion

What is striking about takotsubo cardiomyopathy is that the clinical presentation resembles an AMI. Several studies have reported that 1.7% to 2.2% of patients who had suspected acute coronary syndrome were subsequently diagnosed with takotsubo cardiomyopathy.^6-8 Nearly 90% of reported cases involved postmenopausal women, and this may be related to loss of the cardioprotective effect of estrogen.^5,9

A preceding stressful emotional or physical event is usually identified in about two-thirds of the patients with ABS.⁹ Most common emotional triggers are death of a relative or friend, broken relationships, assaults, and rapes, among others. Physical triggers include severe sepsis, shock, acute respiratory failure, seizures, and intracranial bleeds. Sometimes a specific trigger cannot be identified from the history, but the absence of an emotional or physical trigger does not exclude the diagnosis.

Although the exact pathogenesis of ABS remains unclear, it is likely that multiple factors are involved. Some of the suggested mechanisms are high levels of catecholamines, multivessel epicardial spasm, or coronary microvascular dysfunction.⁴ The catecholamine hypothesis has been supported by the finding that several patients with pheochromocytoma and subarachnoid hemorrhage also present with high levels of catecholamine and a cardiomyopathy resembling ABS. Furthermore, ABS has been reported in patients on catecholamine infusions and those treated with agents that inhibit reuptake of catecholamines.⁵

The presence of multivessel coronary spasm was suggested by early small studies in Japan, but more recent case series have not validated this hypothesis.⁵ The microvascular dysfunction hypothesis is supported by the presence of myocardial ischemia, diagnosed by ECG changes and elevated troponins, in the absence of significant coronary disease. However, it remains unclear whether this is a primary mechanism or a manifestation of a primary process.⁴ Microvascular dysfunction may be more likely related to impairment of myocardial relaxation with extramural coronary compression.

Signs and symptoms of ABS mimic those of AMI, with angina-like chest pain as the main presenting symptom in about 50% of cases.¹⁰ Other symptoms include dyspnea and less commonly, syncope or sudden cardiac death. Decompensated left heart failure occurs in 50% of patients, with severe hemodynamic compromise and cardiogenic shock not being uncommon. Other complications that may occur are tachyarrhythmias (atrial or ventricular) and ventricular thromboembolism.⁴

Common ECG changes in ABS include precordial ST segment elevations, symmetric T wave inversions, and nonspecific T wave changes.^4,10 QT interval prolongation may be seen during the first days. Transient pathologic Q waves may be seen at presentation or afterward. These ECG changes tend to revert after weeks or months of presentation.

Elevation of cardiac biomarkers is usually present in laboratory data. Levels peak at 24 hours, and the degree of elevation is usually less than that seen in patients with an AMI.¹⁰ Most important, the degree of cardiac biomarker elevation is disproportionately low for the extent of involved coronary territory and left ventricular dysfunction. Other laboratory tests that are frequently altered are the BNP and pro-BNP levels, which are usually elevated due to transient left ventricular dysfunction. C-reactive protein elevates in most patients and indicates the presence of an acute inflammatory response.

Early coronary angiography should be performed in all patients with ABS to rule out the presence of a significant obstructive coronary lesion. Patients with ABS often have luminal irregularities or normal coronary vessels. However, concomitant obstructive coronary lesions may be found, especially in elderly patients.

The hallmark of ABS is a characteristic transient contractility abnormality of the left ventricle causing ballooning of the apex, which can be detected on left ventricular angiography or echocardiography. There are 3 distinct variants of ABS, according to the left ventricular myocardial wall segments involved.¹⁰ The classic form of takotsubo is characterized by hypokinesis, dyskinesis, or akinesis of the middle and apical segments of the left ventricle. The basal segment is usually spared and may be hyperdynamic. In the midventricular or apical sparing variant, the wall motion abnormalities are restricted to the midventricular segments, and apical contraction is preserved. This case resembles the atypical variant, because the midventricular segments were affected, whereas apical and basal regions were preserved. A rare variant of takotsubo exists with hypokinesis or akinesis of the base and preserved apical function.

Besides ABS and AMI, an important entity to consider in the differential diagnosis of transient wall motion abnormalities is regional myocarditis. Viral titers are helpful in excluding this condition. Furthermore, prolonged recovery is more commonly seen in myocarditis compared with ABS. Imaging studies are particularly helpful in this scenario.

Cardiac MRI demonstrates the wall motion abnormalities or apical ballooning typical for this condition and can differentiate ABS from myocarditis or MI. It is known that delayed myocardial enhancement is seen with myocardial fibrosis. Typically in ischemic cardiomyopathy, there is wall thinning with associated delayed enhancement that extends from the subendocardium to the epicardium (from 0%-90% of wall thickness) of a particular vascular territory. In myocarditis, the enhancement is usually seen in the involved intramyocardial (mesocardium) region, and the pattern is patchy. In ABS, the delayed enhancement is absent, because there is no fibrosis in the area of regional wall motion abnormalities, and wall thickness is usually normal.^9,10

No evidence-based guidelines for treating ABS are currently available. Most patients are initially treated with antiplatelets/anticoagulant therapy, nitrates, and diuretics if the patient presents with heart failure. Patients should be admitted to an intensive care unit for close cardiac monitoring. Once ABS is diagnosed and significant coronary stenosis is excluded, patients should receive standard supportive care and optimal neurohormonal therapy. This should include beta blocker or combined alpha/beta blocker agents, an ACE-I or angiotensin receptor blocker, and diuretics if appropriate. Once left ventricular function (LVF) is recovered, therapy with inhibitors of the renin-angiotensin system may be discontinued, but patients should remain on long-term alpha or beta blocker therapy, because the sympathetic blockade provided by these agents may prevent recurrences of this disease.¹⁰

Prognosis is generally favorable, and most patients recover to normal LVF over weeks to months. It is important to assess the LVF 4 to 6 weeks after the patient is discharged to confirm the diagnosis of ABS. Recurrence may occur in up to 9% of cases.¹⁰ Long-term mortality is similar compared with the age-matched general population.

Conclusion

Apical ballooning syndrome is a relatively novel cardiomyopathy that has gained important attention among the cardiovascular community, mostly because its clinical presentation mimics that of an acute coronary syndrome. Awareness of this entity will result in a more focused diagnosis and appropriate treatment. Managing both cardiac and emotional components of this disease will have a permanent impact in the reversibility and secondary prevention of this cardiomyopathy.

Acknowledgments
Special thanks to the Radiology Service at the VA Caribbean Healthcare System, in particular Dr. Frances Aulet for interpretation of the cardiac MRI results and assistance with MRI images.

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

A 74-year-old woman presented with a 2-day history of exertional dyspnea and palpitations. Her past medical history was significant for metastatic papillary thyroid carcinoma treated with total thyroidectomy and radioactive iodine ablation with levothyroxine for chronic suppressive therapy.

On examination, the patient was afebrile with an oxygen saturation of 98% on room air, heart rate of 92 beats/min, and blood pressure of 100/54 mm Hg. There was trace bilateral lower extremity edema, and her cardiopulmonary examination was unremarkable. The laboratory studies showed a white blood cell count of 24,300/µL (3,400-9,800); platelets 86,000/µL (142,000-362,000); thyroid stimulating hormone 0.009 mlU/L (0.4-4.1); free T4 2.07 ng/dL (0.8-2.0); thyroglobulin antibody titer < 1:10 (< 1:160); thyroid microsomal antibody titer < 1:100 (< 1:1600); and thyroglobulin 17.9 ng/mL (2.0-35.0). Her initial troponin T was undetectable.

An electrocardiogram showed a first-degree atrioventricular block and subsequently a new intermittent third-degree atrioventricular block. A computed tomography angiogram (Figure 1) and cardiac magnetic resonance imaging (Figure 2) revealed a 2.6-cm soft tissue mass in the right ventricular outflow tract along with multiple pulmonary emboli and previously diagnosed pulmonary metastases. A positron emission tomography (PET) scan (not shown) revealed a 3.5-cm PET-avid lesion within the right ventricular outflow tract.

• What is your diagnosis?
• How would you treat this patient? 

[Click through to the next page to see the answer.]

Our Treatment

Diagnosis and Discussion

This patient experienced complete heart block due to a cardiac tumor from papillary thyroid carcinoma metastasis. Complete heart block is not an unprecedented symptom of metastatic disease, but to our knowledge this is the first reported case of heart block secondary to metastatic papillary thyroid cancer.¹ In general, metastatic cardiac tumors, usually associated with cancers of the breast and lung, melanoma, and lymphoma, are more common than are primary cardiac tumors and are often asymptomatic and discovered mostly postmortem.^2,3 The frequency of thyroid metastasis to the heart has been reported to be as low as 0% to 2%, and a review of the literature demonstrated only 13 total cases in the past 30 years.

Theoretical mechanisms for invasion into the heart include lymphatic spread, hematogenous dissemination, or direct right ventricular invasion from the thoracic duct. It has been suggested that the lower blood flow to the myocardium (240 mL/min) relative to bone (600 mL/min) or the brain (750 mL/min) is the reason for a lower likelihood of cardiac involvement in metastatic disease.³ Given the findings in this case, evidence of cardiac conduction abnormalities in the setting of papillary thyroid cancer should raise suspicion for cardiac metastatic disease.

Case Outcome

In this patient, a permanent pacemaker was implanted for high-grade atrioventricular block, with resolution of the palpitations. The pulmonary emboli were concomitantly treated with enoxaparin, and the patient was discharged to a rehabilitation facility. Her prognosis was extremely poor given that survival with cardiac metastasis from any type of cancer is limited to a few weeks to months.³ She was to be reevaluated for experimental chemotherapy after reconditioning. However, not long after discharge she was readmitted in respiratory failure and died.

Acknowledgments
We would like to thank Dr. Kevin Steel, Lt Col, USAF, MC, imaging cardiologist at the Brooke Army Medical Center for his time and effort in accessing and preparing the CT and MRI images for this article.

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect the official policy or position of Federal Practitioner, Frontline Medical Communications Inc., Brooke Army Medical Center, the U.S. Army Medical Department, the U.S. Army Office of the Surgeon General, the Department of the Army, Department of Defense, the U.S. Government, or any other of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

A 74-year-old woman presented with a 2-day history of exertional dyspnea and palpitations. Her past medical history was significant for metastatic papillary thyroid carcinoma treated with total thyroidectomy and radioactive iodine ablation with levothyroxine for chronic suppressive therapy.

On examination, the patient was afebrile with an oxygen saturation of 98% on room air, heart rate of 92 beats/min, and blood pressure of 100/54 mm Hg. There was trace bilateral lower extremity edema, and her cardiopulmonary examination was unremarkable. The laboratory studies showed a white blood cell count of 24,300/µL (3,400-9,800); platelets 86,000/µL (142,000-362,000); thyroid stimulating hormone 0.009 mlU/L (0.4-4.1); free T4 2.07 ng/dL (0.8-2.0); thyroglobulin antibody titer < 1:10 (< 1:160); thyroid microsomal antibody titer < 1:100 (< 1:1600); and thyroglobulin 17.9 ng/mL (2.0-35.0). Her initial troponin T was undetectable.

An electrocardiogram showed a first-degree atrioventricular block and subsequently a new intermittent third-degree atrioventricular block. A computed tomography angiogram (Figure 1) and cardiac magnetic resonance imaging (Figure 2) revealed a 2.6-cm soft tissue mass in the right ventricular outflow tract along with multiple pulmonary emboli and previously diagnosed pulmonary metastases. A positron emission tomography (PET) scan (not shown) revealed a 3.5-cm PET-avid lesion within the right ventricular outflow tract.

• What is your diagnosis?
• How would you treat this patient? 

[Click through to the next page to see the answer.]

Our Treatment

Diagnosis and Discussion

This patient experienced complete heart block due to a cardiac tumor from papillary thyroid carcinoma metastasis. Complete heart block is not an unprecedented symptom of metastatic disease, but to our knowledge this is the first reported case of heart block secondary to metastatic papillary thyroid cancer.¹ In general, metastatic cardiac tumors, usually associated with cancers of the breast and lung, melanoma, and lymphoma, are more common than are primary cardiac tumors and are often asymptomatic and discovered mostly postmortem.^2,3 The frequency of thyroid metastasis to the heart has been reported to be as low as 0% to 2%, and a review of the literature demonstrated only 13 total cases in the past 30 years.

Theoretical mechanisms for invasion into the heart include lymphatic spread, hematogenous dissemination, or direct right ventricular invasion from the thoracic duct. It has been suggested that the lower blood flow to the myocardium (240 mL/min) relative to bone (600 mL/min) or the brain (750 mL/min) is the reason for a lower likelihood of cardiac involvement in metastatic disease.³ Given the findings in this case, evidence of cardiac conduction abnormalities in the setting of papillary thyroid cancer should raise suspicion for cardiac metastatic disease.

Case Outcome

In this patient, a permanent pacemaker was implanted for high-grade atrioventricular block, with resolution of the palpitations. The pulmonary emboli were concomitantly treated with enoxaparin, and the patient was discharged to a rehabilitation facility. Her prognosis was extremely poor given that survival with cardiac metastasis from any type of cancer is limited to a few weeks to months.³ She was to be reevaluated for experimental chemotherapy after reconditioning. However, not long after discharge she was readmitted in respiratory failure and died.

Acknowledgments
We would like to thank Dr. Kevin Steel, Lt Col, USAF, MC, imaging cardiologist at the Brooke Army Medical Center for his time and effort in accessing and preparing the CT and MRI images for this article.

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect the official policy or position of Federal Practitioner, Frontline Medical Communications Inc., Brooke Army Medical Center, the U.S. Army Medical Department, the U.S. Army Office of the Surgeon General, the Department of the Army, Department of Defense, the U.S. Government, or any other of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

A 74-year-old woman presented with a 2-day history of exertional dyspnea and palpitations. Her past medical history was significant for metastatic papillary thyroid carcinoma treated with total thyroidectomy and radioactive iodine ablation with levothyroxine for chronic suppressive therapy.

On examination, the patient was afebrile with an oxygen saturation of 98% on room air, heart rate of 92 beats/min, and blood pressure of 100/54 mm Hg. There was trace bilateral lower extremity edema, and her cardiopulmonary examination was unremarkable. The laboratory studies showed a white blood cell count of 24,300/µL (3,400-9,800); platelets 86,000/µL (142,000-362,000); thyroid stimulating hormone 0.009 mlU/L (0.4-4.1); free T4 2.07 ng/dL (0.8-2.0); thyroglobulin antibody titer < 1:10 (< 1:160); thyroid microsomal antibody titer < 1:100 (< 1:1600); and thyroglobulin 17.9 ng/mL (2.0-35.0). Her initial troponin T was undetectable.

An electrocardiogram showed a first-degree atrioventricular block and subsequently a new intermittent third-degree atrioventricular block. A computed tomography angiogram (Figure 1) and cardiac magnetic resonance imaging (Figure 2) revealed a 2.6-cm soft tissue mass in the right ventricular outflow tract along with multiple pulmonary emboli and previously diagnosed pulmonary metastases. A positron emission tomography (PET) scan (not shown) revealed a 3.5-cm PET-avid lesion within the right ventricular outflow tract.

• What is your diagnosis?
• How would you treat this patient? 

[Click through to the next page to see the answer.]

Our Treatment

Diagnosis and Discussion

This patient experienced complete heart block due to a cardiac tumor from papillary thyroid carcinoma metastasis. Complete heart block is not an unprecedented symptom of metastatic disease, but to our knowledge this is the first reported case of heart block secondary to metastatic papillary thyroid cancer.¹ In general, metastatic cardiac tumors, usually associated with cancers of the breast and lung, melanoma, and lymphoma, are more common than are primary cardiac tumors and are often asymptomatic and discovered mostly postmortem.^2,3 The frequency of thyroid metastasis to the heart has been reported to be as low as 0% to 2%, and a review of the literature demonstrated only 13 total cases in the past 30 years.

Theoretical mechanisms for invasion into the heart include lymphatic spread, hematogenous dissemination, or direct right ventricular invasion from the thoracic duct. It has been suggested that the lower blood flow to the myocardium (240 mL/min) relative to bone (600 mL/min) or the brain (750 mL/min) is the reason for a lower likelihood of cardiac involvement in metastatic disease.³ Given the findings in this case, evidence of cardiac conduction abnormalities in the setting of papillary thyroid cancer should raise suspicion for cardiac metastatic disease.

Case Outcome

In this patient, a permanent pacemaker was implanted for high-grade atrioventricular block, with resolution of the palpitations. The pulmonary emboli were concomitantly treated with enoxaparin, and the patient was discharged to a rehabilitation facility. Her prognosis was extremely poor given that survival with cardiac metastasis from any type of cancer is limited to a few weeks to months.³ She was to be reevaluated for experimental chemotherapy after reconditioning. However, not long after discharge she was readmitted in respiratory failure and died.

Acknowledgments
We would like to thank Dr. Kevin Steel, Lt Col, USAF, MC, imaging cardiologist at the Brooke Army Medical Center for his time and effort in accessing and preparing the CT and MRI images for this article.

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect the official policy or position of Federal Practitioner, Frontline Medical Communications Inc., Brooke Army Medical Center, the U.S. Army Medical Department, the U.S. Army Office of the Surgeon General, the Department of the Army, Department of Defense, the U.S. Government, or any other of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

Pemphigus vulgaris (PV) is a chronic autoimmune intraepithelial bullous disease caused by pathogenic IgG antibodies at the intraepidermal cell-surface proteins desmoglein 1 (DSG1) and desmoglein 3 (DSG3), which are members of the cadherin superfamily of desmosomal proteins and are involved in keratinocyte adhesion. Autoantibody binding to these molecules leads to the loss of cell-cell adhesion in the epithelial suprabasilar layer, producing flaccid blisters on an erythematous base with a positive Nikolsky sign.¹ The blisters frequently rupture, leaving painful nonscarring erosions with the potential for secondary infection.

The clinical phenotype of PV is directly related to the autoantibody profile. Clinically, PV often is mucosal dominant on presentation with painful oropharyngeal involvement and associated IgG antibodies against DSG3. Progression to cutaneous disease, such as on the scalp or axillae, is accompanied by a shift in IgG antibodies against both DSG1 and DSG3.^2,3

Combination therapy with prednisone and mycophenolate mofetil (MMF) has proven to be an effective method of controlling the signs and symptoms of PV⁴; however, the immunosuppressive effects of these medications put the patient at risk for a host of opportunistic infections. Herpes simplex virus (HSV) has been associated with PV lesions of the oral mucosa, though a clear-cut relationship between these 2 entities has yet to be established.⁵ Herpes simplex virus has likewise been confirmed in therapy-resistant exacerbations of PV.⁶ Herpes esophagitis is a rare consequence of treatment with prednisone and MMF that is primarily encountered in patients with a history of solid organ transplantation⁷ and rarely has been reported in PV patients undergoing therapeutic immunosuppression.

Acute odynophagia in patients undergoing systemic treatment of active PV warrants prompt endoscopic evaluation to rule out esophageal pemphigus or superinfection. We report the case of a 35-year-old man with stable but poorly controlled PV who was undergoing systemic treatment and experienced rapid deterioration due to herpes esophagitis from immunosuppression.

Case Report

A 35-year-old man was referred to our clinic for evaluation of blisters on the scalp, oral mucosa, and proximal upper and lower extremities of 4 months’ duration. A biopsy performed by his primary care physician within a month of onset of symptoms was reportedly suggestive of PV; although no direct immunofluorescence had been performed, serum indirect immunofluorescence was highly positive for IgG antibodies toward DSG3 and to a lesser extent DSG1. The blisters failed to improve with a 2-week prednisone taper completed 1 month prior to presentation. The patient was not currently taking any other medications. He had a remote history of fever blisters but no other dermatologic issues.

Initial examination revealed flaccid bullae on an erythematous base involving the posterior scalp as well as tender white erosions to shallow ulcers on the tongue and hard and soft palates. A Tzanck smear (modified Wright-Giemsa stain) of these erosions confirmed acantholytic mucosal cells. Punch biopsies of lesional and perilesional skin from the scalp were obtained for histopathologic confirmation and immunofluorescence. An acantholytic dermatosis with a tombstone pattern along the basement membrane was present on hematoxylin and eosin staining, and direct immunofluorescence was positive for IgG and C3 in an intraepidermal lacelike pattern, confirming a diagnosis of PV.

Despite starting an oral regimen of high-dose corticosteroids (prednisone 80 mg once daily), no improvement was noted at 2-week follow-up. He had developed flaccid blisters on the left axillae and mildly worsened oral erosions. He also reported moderate difficulty eating due to pain with swallowing. Mycophenolate mofetil (500 mg twice daily) was added as combination therapy with the prednisone.

One week later, the patient was unable to eat or drink due to worsening odynophagia. He was admitted as an inpatient for treatment with intravenous methylprednisolone (120 mg every 8 hours) and MMF (1000 mg daily). The gastroenterology department was consulted and an esophagogastroduodenoscopy revealed diffuse areas of denuded and friable mucosa with an overlay of white exudate (Figure 1). Cytology performed on esophageal brushings revealed viral cytopathic changes confirming herpes esophagitis (Figure 2). No esophageal viral cultures were taken. The patient was started on intravenous acyclovir (800 mg 4 times daily), leading to rapid resolution of the odynophagia. He was discharged after 4 days with a course of oral acyclovir (400 mg 4 times daily for 14 days). Tzanck smears and HSV cultures of oral lesions performed immediately following discharge were negative. Combination therapy with MMF (500 mg twice daily) and a slow taper of prednisone (down to 5 mg once daily) was continued past 1 year without flare of his cutaneous disease.

Comment

Although PV may have been considered a fatal disease at one time, treatment with systemic steroids has made it a manageable, albeit relapsing, condition. The development of corticosteroid-sparing, adjuvant immunosuppressives such as MMF has allowed for the more aggressive treatment of this disease with fewer steroid-related side effects.^4,8,9 As seen in solid organ transplant recipients who often utilize combination therapy, the use of adjuvant immunosuppressives is associated with potential complications including bone marrow suppression and an increased risk for infections.^7,10

Odynophagia is among the potential complications in patients with PV and has a wide differential diagnosis. Mucosal lesions of PV previously have been associated with HSV colonization, though a causal relationship has not been corroborated.⁵ Herpes simplex virus is more often detected in PV patients being treated with immunosuppressive agents than in nontreated patient groups.¹¹ Recalcitrant or suddenly exacerbated oral mucosal lesions of PV under appropriate therapy may therefore be the result of HSV superinfection, which has been deferentially referred to as pemphigus herpeticum.¹² Esophageal mucosal involvement by PV also may be more common than previously thought and should be suspected in patients with active oral disease.¹³ Esophagitis secondary to medications or various opportunistic organisms such as Candida, cytomegalovirus, or HSV also should be ruled out in patients taking immunosuppressives.^5,10

Herpes esophagitis primarily occurs in immunocompromised hosts and is well documented in the literature regarding treatment with MMF and prednisone following renal and cardiac transplantation.¹⁰ Prednisone therapy in patients with chronic obstructive pulmonary disease also has been implicated.¹⁴ Reactivation of latent HSV resulting from immunosuppression is most often described, though primary infection also is possible.¹⁵ Patients typically present with acute odynophagia progressing to dysphagia, with complications ranging from sequelae of poor oral intake to esophageal perforation and hemorrhage, but the course generally is self-limited if immune function is promptly restored. Intravenous acyclovir has been known to hasten the recovery process and improve symptoms.¹⁶ Characteristic findings on esophagogastroduodenoscopy in combination with tissue biopsy, viral culture, and/or polymerase chain reaction aid in the diagnosis of herpes esophagitis.^15,16 Our patient had a grossly abnormal esophagogastroduodenoscopy with positive cytology; however, no further diagnostic workup was performed. The cytologic findings and the rapid symptomatic improvement following the initiation of acyclovir helped support HSV as the etiology.

Conclusion

We present a case of herpes esophagitis that complicated the treatment of PV with MMF and prednisone. A diagnosis of herpes esophagitis must be ruled out in patients with PV who are undergoing therapeutic immunosuppression and present with an acute episode of odynophagia that is resistant to upscaling of therapy.

Pemphigus vulgaris (PV) is a chronic autoimmune intraepithelial bullous disease caused by pathogenic IgG antibodies at the intraepidermal cell-surface proteins desmoglein 1 (DSG1) and desmoglein 3 (DSG3), which are members of the cadherin superfamily of desmosomal proteins and are involved in keratinocyte adhesion. Autoantibody binding to these molecules leads to the loss of cell-cell adhesion in the epithelial suprabasilar layer, producing flaccid blisters on an erythematous base with a positive Nikolsky sign.¹ The blisters frequently rupture, leaving painful nonscarring erosions with the potential for secondary infection.

The clinical phenotype of PV is directly related to the autoantibody profile. Clinically, PV often is mucosal dominant on presentation with painful oropharyngeal involvement and associated IgG antibodies against DSG3. Progression to cutaneous disease, such as on the scalp or axillae, is accompanied by a shift in IgG antibodies against both DSG1 and DSG3.^2,3

Combination therapy with prednisone and mycophenolate mofetil (MMF) has proven to be an effective method of controlling the signs and symptoms of PV⁴; however, the immunosuppressive effects of these medications put the patient at risk for a host of opportunistic infections. Herpes simplex virus (HSV) has been associated with PV lesions of the oral mucosa, though a clear-cut relationship between these 2 entities has yet to be established.⁵ Herpes simplex virus has likewise been confirmed in therapy-resistant exacerbations of PV.⁶ Herpes esophagitis is a rare consequence of treatment with prednisone and MMF that is primarily encountered in patients with a history of solid organ transplantation⁷ and rarely has been reported in PV patients undergoing therapeutic immunosuppression.

Acute odynophagia in patients undergoing systemic treatment of active PV warrants prompt endoscopic evaluation to rule out esophageal pemphigus or superinfection. We report the case of a 35-year-old man with stable but poorly controlled PV who was undergoing systemic treatment and experienced rapid deterioration due to herpes esophagitis from immunosuppression.

Case Report

A 35-year-old man was referred to our clinic for evaluation of blisters on the scalp, oral mucosa, and proximal upper and lower extremities of 4 months’ duration. A biopsy performed by his primary care physician within a month of onset of symptoms was reportedly suggestive of PV; although no direct immunofluorescence had been performed, serum indirect immunofluorescence was highly positive for IgG antibodies toward DSG3 and to a lesser extent DSG1. The blisters failed to improve with a 2-week prednisone taper completed 1 month prior to presentation. The patient was not currently taking any other medications. He had a remote history of fever blisters but no other dermatologic issues.

Initial examination revealed flaccid bullae on an erythematous base involving the posterior scalp as well as tender white erosions to shallow ulcers on the tongue and hard and soft palates. A Tzanck smear (modified Wright-Giemsa stain) of these erosions confirmed acantholytic mucosal cells. Punch biopsies of lesional and perilesional skin from the scalp were obtained for histopathologic confirmation and immunofluorescence. An acantholytic dermatosis with a tombstone pattern along the basement membrane was present on hematoxylin and eosin staining, and direct immunofluorescence was positive for IgG and C3 in an intraepidermal lacelike pattern, confirming a diagnosis of PV.

Despite starting an oral regimen of high-dose corticosteroids (prednisone 80 mg once daily), no improvement was noted at 2-week follow-up. He had developed flaccid blisters on the left axillae and mildly worsened oral erosions. He also reported moderate difficulty eating due to pain with swallowing. Mycophenolate mofetil (500 mg twice daily) was added as combination therapy with the prednisone.

One week later, the patient was unable to eat or drink due to worsening odynophagia. He was admitted as an inpatient for treatment with intravenous methylprednisolone (120 mg every 8 hours) and MMF (1000 mg daily). The gastroenterology department was consulted and an esophagogastroduodenoscopy revealed diffuse areas of denuded and friable mucosa with an overlay of white exudate (Figure 1). Cytology performed on esophageal brushings revealed viral cytopathic changes confirming herpes esophagitis (Figure 2). No esophageal viral cultures were taken. The patient was started on intravenous acyclovir (800 mg 4 times daily), leading to rapid resolution of the odynophagia. He was discharged after 4 days with a course of oral acyclovir (400 mg 4 times daily for 14 days). Tzanck smears and HSV cultures of oral lesions performed immediately following discharge were negative. Combination therapy with MMF (500 mg twice daily) and a slow taper of prednisone (down to 5 mg once daily) was continued past 1 year without flare of his cutaneous disease.

Comment

Although PV may have been considered a fatal disease at one time, treatment with systemic steroids has made it a manageable, albeit relapsing, condition. The development of corticosteroid-sparing, adjuvant immunosuppressives such as MMF has allowed for the more aggressive treatment of this disease with fewer steroid-related side effects.^4,8,9 As seen in solid organ transplant recipients who often utilize combination therapy, the use of adjuvant immunosuppressives is associated with potential complications including bone marrow suppression and an increased risk for infections.^7,10

Odynophagia is among the potential complications in patients with PV and has a wide differential diagnosis. Mucosal lesions of PV previously have been associated with HSV colonization, though a causal relationship has not been corroborated.⁵ Herpes simplex virus is more often detected in PV patients being treated with immunosuppressive agents than in nontreated patient groups.¹¹ Recalcitrant or suddenly exacerbated oral mucosal lesions of PV under appropriate therapy may therefore be the result of HSV superinfection, which has been deferentially referred to as pemphigus herpeticum.¹² Esophageal mucosal involvement by PV also may be more common than previously thought and should be suspected in patients with active oral disease.¹³ Esophagitis secondary to medications or various opportunistic organisms such as Candida, cytomegalovirus, or HSV also should be ruled out in patients taking immunosuppressives.^5,10

Herpes esophagitis primarily occurs in immunocompromised hosts and is well documented in the literature regarding treatment with MMF and prednisone following renal and cardiac transplantation.¹⁰ Prednisone therapy in patients with chronic obstructive pulmonary disease also has been implicated.¹⁴ Reactivation of latent HSV resulting from immunosuppression is most often described, though primary infection also is possible.¹⁵ Patients typically present with acute odynophagia progressing to dysphagia, with complications ranging from sequelae of poor oral intake to esophageal perforation and hemorrhage, but the course generally is self-limited if immune function is promptly restored. Intravenous acyclovir has been known to hasten the recovery process and improve symptoms.¹⁶ Characteristic findings on esophagogastroduodenoscopy in combination with tissue biopsy, viral culture, and/or polymerase chain reaction aid in the diagnosis of herpes esophagitis.^15,16 Our patient had a grossly abnormal esophagogastroduodenoscopy with positive cytology; however, no further diagnostic workup was performed. The cytologic findings and the rapid symptomatic improvement following the initiation of acyclovir helped support HSV as the etiology.

Conclusion

We present a case of herpes esophagitis that complicated the treatment of PV with MMF and prednisone. A diagnosis of herpes esophagitis must be ruled out in patients with PV who are undergoing therapeutic immunosuppression and present with an acute episode of odynophagia that is resistant to upscaling of therapy.

Pemphigus vulgaris (PV) is a chronic autoimmune intraepithelial bullous disease caused by pathogenic IgG antibodies at the intraepidermal cell-surface proteins desmoglein 1 (DSG1) and desmoglein 3 (DSG3), which are members of the cadherin superfamily of desmosomal proteins and are involved in keratinocyte adhesion. Autoantibody binding to these molecules leads to the loss of cell-cell adhesion in the epithelial suprabasilar layer, producing flaccid blisters on an erythematous base with a positive Nikolsky sign.¹ The blisters frequently rupture, leaving painful nonscarring erosions with the potential for secondary infection.

The clinical phenotype of PV is directly related to the autoantibody profile. Clinically, PV often is mucosal dominant on presentation with painful oropharyngeal involvement and associated IgG antibodies against DSG3. Progression to cutaneous disease, such as on the scalp or axillae, is accompanied by a shift in IgG antibodies against both DSG1 and DSG3.^2,3

Combination therapy with prednisone and mycophenolate mofetil (MMF) has proven to be an effective method of controlling the signs and symptoms of PV⁴; however, the immunosuppressive effects of these medications put the patient at risk for a host of opportunistic infections. Herpes simplex virus (HSV) has been associated with PV lesions of the oral mucosa, though a clear-cut relationship between these 2 entities has yet to be established.⁵ Herpes simplex virus has likewise been confirmed in therapy-resistant exacerbations of PV.⁶ Herpes esophagitis is a rare consequence of treatment with prednisone and MMF that is primarily encountered in patients with a history of solid organ transplantation⁷ and rarely has been reported in PV patients undergoing therapeutic immunosuppression.

Acute odynophagia in patients undergoing systemic treatment of active PV warrants prompt endoscopic evaluation to rule out esophageal pemphigus or superinfection. We report the case of a 35-year-old man with stable but poorly controlled PV who was undergoing systemic treatment and experienced rapid deterioration due to herpes esophagitis from immunosuppression.

Case Report

A 35-year-old man was referred to our clinic for evaluation of blisters on the scalp, oral mucosa, and proximal upper and lower extremities of 4 months’ duration. A biopsy performed by his primary care physician within a month of onset of symptoms was reportedly suggestive of PV; although no direct immunofluorescence had been performed, serum indirect immunofluorescence was highly positive for IgG antibodies toward DSG3 and to a lesser extent DSG1. The blisters failed to improve with a 2-week prednisone taper completed 1 month prior to presentation. The patient was not currently taking any other medications. He had a remote history of fever blisters but no other dermatologic issues.

Initial examination revealed flaccid bullae on an erythematous base involving the posterior scalp as well as tender white erosions to shallow ulcers on the tongue and hard and soft palates. A Tzanck smear (modified Wright-Giemsa stain) of these erosions confirmed acantholytic mucosal cells. Punch biopsies of lesional and perilesional skin from the scalp were obtained for histopathologic confirmation and immunofluorescence. An acantholytic dermatosis with a tombstone pattern along the basement membrane was present on hematoxylin and eosin staining, and direct immunofluorescence was positive for IgG and C3 in an intraepidermal lacelike pattern, confirming a diagnosis of PV.

Despite starting an oral regimen of high-dose corticosteroids (prednisone 80 mg once daily), no improvement was noted at 2-week follow-up. He had developed flaccid blisters on the left axillae and mildly worsened oral erosions. He also reported moderate difficulty eating due to pain with swallowing. Mycophenolate mofetil (500 mg twice daily) was added as combination therapy with the prednisone.

One week later, the patient was unable to eat or drink due to worsening odynophagia. He was admitted as an inpatient for treatment with intravenous methylprednisolone (120 mg every 8 hours) and MMF (1000 mg daily). The gastroenterology department was consulted and an esophagogastroduodenoscopy revealed diffuse areas of denuded and friable mucosa with an overlay of white exudate (Figure 1). Cytology performed on esophageal brushings revealed viral cytopathic changes confirming herpes esophagitis (Figure 2). No esophageal viral cultures were taken. The patient was started on intravenous acyclovir (800 mg 4 times daily), leading to rapid resolution of the odynophagia. He was discharged after 4 days with a course of oral acyclovir (400 mg 4 times daily for 14 days). Tzanck smears and HSV cultures of oral lesions performed immediately following discharge were negative. Combination therapy with MMF (500 mg twice daily) and a slow taper of prednisone (down to 5 mg once daily) was continued past 1 year without flare of his cutaneous disease.

Comment

Although PV may have been considered a fatal disease at one time, treatment with systemic steroids has made it a manageable, albeit relapsing, condition. The development of corticosteroid-sparing, adjuvant immunosuppressives such as MMF has allowed for the more aggressive treatment of this disease with fewer steroid-related side effects.^4,8,9 As seen in solid organ transplant recipients who often utilize combination therapy, the use of adjuvant immunosuppressives is associated with potential complications including bone marrow suppression and an increased risk for infections.^7,10

Odynophagia is among the potential complications in patients with PV and has a wide differential diagnosis. Mucosal lesions of PV previously have been associated with HSV colonization, though a causal relationship has not been corroborated.⁵ Herpes simplex virus is more often detected in PV patients being treated with immunosuppressive agents than in nontreated patient groups.¹¹ Recalcitrant or suddenly exacerbated oral mucosal lesions of PV under appropriate therapy may therefore be the result of HSV superinfection, which has been deferentially referred to as pemphigus herpeticum.¹² Esophageal mucosal involvement by PV also may be more common than previously thought and should be suspected in patients with active oral disease.¹³ Esophagitis secondary to medications or various opportunistic organisms such as Candida, cytomegalovirus, or HSV also should be ruled out in patients taking immunosuppressives.^5,10

Herpes esophagitis primarily occurs in immunocompromised hosts and is well documented in the literature regarding treatment with MMF and prednisone following renal and cardiac transplantation.¹⁰ Prednisone therapy in patients with chronic obstructive pulmonary disease also has been implicated.¹⁴ Reactivation of latent HSV resulting from immunosuppression is most often described, though primary infection also is possible.¹⁵ Patients typically present with acute odynophagia progressing to dysphagia, with complications ranging from sequelae of poor oral intake to esophageal perforation and hemorrhage, but the course generally is self-limited if immune function is promptly restored. Intravenous acyclovir has been known to hasten the recovery process and improve symptoms.¹⁶ Characteristic findings on esophagogastroduodenoscopy in combination with tissue biopsy, viral culture, and/or polymerase chain reaction aid in the diagnosis of herpes esophagitis.^15,16 Our patient had a grossly abnormal esophagogastroduodenoscopy with positive cytology; however, no further diagnostic workup was performed. The cytologic findings and the rapid symptomatic improvement following the initiation of acyclovir helped support HSV as the etiology.

Conclusion

We present a case of herpes esophagitis that complicated the treatment of PV with MMF and prednisone. A diagnosis of herpes esophagitis must be ruled out in patients with PV who are undergoing therapeutic immunosuppression and present with an acute episode of odynophagia that is resistant to upscaling of therapy.

Case Report

A 50-year-old white woman presented to our clinic for evaluation of what she described as a “very hard red line” on the right upper arm. The lesion had developed suddenly overnight. Several months prior to presentation the patient sustained trauma to the same area in a car accident and she thought the lesion might be related to the resulting nerve damage. Initially she presented to her primary care physician who used ultrasonography of the area to rule out muscle or bone involvement. The patient presented to our dermatology clinic 2 months later with an 18×4-cm, brownish, rectangular, sclerotic, bound-down, hypertrophic plaque that started on the right mid forearm and extended to the right shoulder (Figure 1). Her medical history was notable for high blood pressure, which was controlled with valsartan.

Figure 1. An 18×4-cm, brownish, rectangular, sclerotic, bound-down, hypertrophic plaque that started on the right mid forearm and extended to the right shoulder.

A review of systems was unremarkable. Physical examination revealed a well-developed, well-nourished woman. Examination of the right arm revealed no motion restriction (muscle strength, 5/5) and no pain; however, she described a burning sensation at the site of the lesion. She reported no allergies. A 4-mm punch biopsy was performed and laboratory tests were ordered including an antinuclear antibody (ANA) test with reflex, double-stranded DNA test, DNA antitopoisomerase antibodies test, and Lyme titers (IgM and IgG). Initially, the patient was treated with calcipotriene 0.005%–betamethasone dipropionate 0.064% ointment twice daily; she also was treated empirically for Lyme disease with doxycycline 50 mg twice daily. All laboratory tests were within reference range, and a punch biopsy revealed markedly thickened fibrous septa within the subcutaneous fat. At the edge of the septa there were nodular aggregates of lymphocytes. Due to clinical presentation, laboratory data, and histopathology, solitary morphea profunda (SMP) was diagnosed.

Following histopathologic examination (Figure 2), the patient was instructed to continue treatment with calcipotriene–betamethasone dipropionate as well as doxycycline. A trial of prednisone and/or hydroxychloroquine also was considered pending her response to the initial treatment. At approximately 1-month follow-up, remarkable improvement of the lesion was noted.

Comment

Figure 2. Markedly thickened fibrous septa within the subcutaneous fat with nodular aggregates of lymphocytes (A–C)(all H&E; original magnifications ×2.5, ×5, and ×10, respectively).

There is limited literature available about the diagnosis and treatment of SMP. Our case prompted us to further examine the data to emphasize the necessity of greater research surrounding SMP.

Classification of SMP

Morphea is a localized form of scleroderma, an inflammatory disease that primarily affects the dermis but can extend down to the bone and also can limit motion. There are several types of morphea that are classified according to the extent, depth, and distribution of the lesions, including plaque, generalized, bullous, linear (including morphea en coup de sabre), guttate, nodular, and deep morphea.^1,2 Other subtypes have been described including subcutaneous morphea, eosinophilic fasciitis (EF), pansclerotic morphea, and morphea profunda.³ Linear and deep morphea are characterized by involvement of the deep dermis, subcutaneous tissue, fascia, and/or superficial muscle.^2,4

In 1981, Su and Person⁵ first described morphea profunda (MP). In their study, 22 of 23 patients presented with generalized MP. One patient developed a single lesion,⁵ which ultimately was classified as SMP by Whittaker et al⁶ in 1989.

Epidemiology

Morphea profunda occurs more frequently in females than in males, with sclerosis manifesting over a period of several months.⁷ In 2004, Azad et al⁴ suggested that only 9 cases of SMP had been reported in the literature. Although there is insignificant data to determine the epidemiology of SMP, the authors concluded that it most commonly affects middle-aged individuals with equal sex distribution.⁴ The single plaque in patients with SMP most commonly presents on the shoulder, back, or neck or in the paraspinal area.

Etiology

Because of the limited amount of literature on MP, a definitive etiology is unknown, but investigators have cited many possible causes. Genetic, autoimmune, hormonal, traumatic,⁸ vaccination,^2,8 radiation,⁹ viral, neurogenic, and vascular factors all have been implicated,¹⁰ as well as infectious agents such as Borrelia burgdorferi in the United States,^11,12Borrelia afzelii in Europe,² and Borrelia garinii in Japan.² Because our patient experienced a traumatic episode several months prior to presentation, it is important to investigate trauma as a likely etiology. Furthermore, traumatic events have been reported in 23% of children with linear morphea.¹³

Diagnostic Studies

Morphea profunda is diagnosed clinically and skin biopsy can be used for confirmation. Biopsy requires deep excision down to the muscle, which can aid in determining if the fascia is incorporated. Elevated levels of IgG and IgM have been detected in deep and linear morphea and are known to correlate with disease activity and the development of joint contractures in linear morphea.² Serum procollagen type I has been considered by some as a useful indicator of disease severity.¹⁴ Elevated serum levels of antifibrillin-1 antibodies also have been demonstrated in patients with localized scleroderma (LS).¹⁵ Radiography and magnetic resonance imaging can be used for monitoring and analyzing lesion depth. Furthermore, magnetic resonance imaging can be used to differentiate MP from EF.²

The presence of ANAs in LS is controversial. According to Nguyen et al,² ANAs are present in approximately 46% to 80% of patients with morphea, with a higher prevalence in patients with generalized, linear, and deep subtypes. However, Savoia et al¹⁶ found that patients with morphea typically do not present with ANAs; rather ANAs usually are found in patients with EF.

Pathogenesis

After the inflammatory phase in LS, fibrillar collagen types I and III accumulate, causing dermal fibrosis. The extracellular matrix increases due to the activation of connective tissue growth factor, transforming growth factor β (TGF-β), TGF-β receptors, IL-4, and several other cytokines.¹⁷ The TGF-β receptors combine with the connective tissue growth factor released by fibroblasts to create an autocrine production loop that causes fibroblast and matrix production.¹⁷ As the inflammation progresses to sclerosis, the CD34 count decreases.¹⁸

Physical Findings

In patients with MP, lesions manifest as thickened taut skin with deep, solitary, and sclerotic indurated plaques. Clinically, plaques are mildly inflamed, hyperpigmented, symmetric, and somewhat ill defined, and the skin feels thickened and bound to the underlying fascia and muscle. Plaques usually are smooth and shiny, but areas of both dermal and subcutaneous atrophy may be present, particularly in chronic lesions.¹⁹ Morphea profunda also can be described as having a cobblestone or pseudocellulite appearance. The groove sign is used to describe a depression along the course of a vein and/or between muscle groups. Both clinical presentations may manifest later in the course of disease.²

Histopathology

Su and Person⁵ described 3 main characteristics of MP that stand out histopathologically. First, there is thickening and hyalinization of collagen bundles in the deep dermis, subcutis, and fascia that are prominent between the junction of the dermis and subcutaneous fat. There also are fewer sebaceous glands and hair follicles. Second, MP presents with an increased inflammatory cell infiltrate composed mainly of lymphocytes located around small blood vessels and the interstitium. In some patients, the lymphocytes consist predominantly of collections of plasma cells. Third, MP contains deposits of mucin in deep portions of the dermis with occasional eosinophils and mast cells. The presence of eosinophils allows EF to be a part of this spectrum and to be included as a differential diagnosis.⁵ Eosinophilic fasciitis has a similar presentation to MP because the fibrosis affects the dermis, subcutaneous fat, and underlying structures.²⁰ Although EF presents with the histopathologic characteristic of fascial fibrosis, a clear distinction between EF and morphea has not been established in the literature. Some authors classify EF as a variant of morphea, whereas others consider it as its own entity. We believe EF is its own entity. Eosinophilic fasciitis can be distinguished from morphea because 60% to 80% of patients with EF have peripheral eosinophilia and 20% to 70% of patients with EF have hypergammaglobulinemia. Additionally, morphea does not present as symmetrically or abruptly as EF.²¹

Treatment

To date, there is conflicting literature regarding the treatment regimen for MP. There is controversy regarding whether MP responds to corticosteroids.¹⁹ Different treatment regimens have been discussed for LS, but there is a lack of reports specifically describing therapies for MP and SMP. Because MP and SMP fall under the umbrella of LS, many investigators have reported using the following treatment regimens for patients with MP and SMP: bosentan,²² D-penicillamine,²³ phototherapy,^24-26 retinoids,²⁶ oral steroids,²⁷ methotrexate,^27-29 vitamin D₃ (oral calcitriol),^30,31 cyclosporine,³² mycophenolate mofetil,³³ and extracorporeal photochemotherapy.³⁴

Falanga and Medsger²³ reported 64% (7/11) treatment success with D-penicillamine in patients who exhibited severe LS. Psoralen plus UVA,²⁴ methoxsalen, and UVA1 therapy are widely used in the treatment of LS.²⁵ Kreuter et al²⁵ advocated for phototherapy as the first approach in the management of LS after reporting improvement in all participants in their study (N=64), 2 participants with deep morphea while the rest exhibited other forms of morphea. Ozdemir et al²⁶ proposed that retinoic acid combined with psoralen plus UVA is a good treatment choice for plaque-type LS; however, UVA only has the ability to target the epidermis and dermis, which may not be useful for deep forms of morphea.

Several studies have shown positive results in patients treated with methylprednisolone combined with low-dose methotrexate sodium.^27-29 Kreuter et al³⁰ and Elst et al³¹ proposed that calcitriol is effective in treating LS, whereas Hulshof et al³⁵ indicated that it is not. It should be noted that none of these studies specifically mentioned MP. Martini et al³³ demonstrated success with mycophenolate mofetil in the treatment of 10 LS patients who were resistant to methotrexate sodium and corticosteroids. Although none of the participants in the study had MP, 2 patients had disabling pansclerotic morphea, 3 had generalized morphea, and 5 had linear scleroderma (morphea en coup de sabre) affecting the limbs (n=2) and face (n=3).³³ Because there is no established therapy or consensus for the treatment of MP, we have found success in starting with corticosteroids and then trying alternative therapies.

Prognosis

Morphea has transitioned into systemic scleroderma in a small number of reported cases.^10,16,20,36 Therefore, patient follow-up is imperative to consistently identify systemic evolution. Although visceral complications are rare in the setting of LS, associated clinical findings have been reported, including arthralgia, arthritis, contractures, and carpal tunnel syndrome, as well as pulmonary, esophageal, and cardiac abnormalities.^7,34

Conclusion

The morphologic features observed in our patient appear to correspond most closely to the type of lesion described by Su and Person⁵ and Whittaker et al.⁶ Although our case was clinically difficult to distinguish from linear morphea, the histology suggested SMP over other causes. If our patient’s SMP progressed to the joints, physical therapy would be needed to maintain range of motion and function of the extremities,² and mandatory long-term follow-up would be required due to the risk for relapse after discontinuation of therapy. Our case highlights the inherent difficulties in the treatment of MP. Due to limited reports of SMP and MP in the literature as well as the conflicting views regarding effective and appropriate treatment options, additional investigation of these conditions and therapeutic options are necessary to further understand this debilitating condition.

Case Report

A 50-year-old white woman presented to our clinic for evaluation of what she described as a “very hard red line” on the right upper arm. The lesion had developed suddenly overnight. Several months prior to presentation the patient sustained trauma to the same area in a car accident and she thought the lesion might be related to the resulting nerve damage. Initially she presented to her primary care physician who used ultrasonography of the area to rule out muscle or bone involvement. The patient presented to our dermatology clinic 2 months later with an 18×4-cm, brownish, rectangular, sclerotic, bound-down, hypertrophic plaque that started on the right mid forearm and extended to the right shoulder (Figure 1). Her medical history was notable for high blood pressure, which was controlled with valsartan.

Figure 1. An 18×4-cm, brownish, rectangular, sclerotic, bound-down, hypertrophic plaque that started on the right mid forearm and extended to the right shoulder.

A review of systems was unremarkable. Physical examination revealed a well-developed, well-nourished woman. Examination of the right arm revealed no motion restriction (muscle strength, 5/5) and no pain; however, she described a burning sensation at the site of the lesion. She reported no allergies. A 4-mm punch biopsy was performed and laboratory tests were ordered including an antinuclear antibody (ANA) test with reflex, double-stranded DNA test, DNA antitopoisomerase antibodies test, and Lyme titers (IgM and IgG). Initially, the patient was treated with calcipotriene 0.005%–betamethasone dipropionate 0.064% ointment twice daily; she also was treated empirically for Lyme disease with doxycycline 50 mg twice daily. All laboratory tests were within reference range, and a punch biopsy revealed markedly thickened fibrous septa within the subcutaneous fat. At the edge of the septa there were nodular aggregates of lymphocytes. Due to clinical presentation, laboratory data, and histopathology, solitary morphea profunda (SMP) was diagnosed.

Following histopathologic examination (Figure 2), the patient was instructed to continue treatment with calcipotriene–betamethasone dipropionate as well as doxycycline. A trial of prednisone and/or hydroxychloroquine also was considered pending her response to the initial treatment. At approximately 1-month follow-up, remarkable improvement of the lesion was noted.

Comment

Figure 2. Markedly thickened fibrous septa within the subcutaneous fat with nodular aggregates of lymphocytes (A–C)(all H&E; original magnifications ×2.5, ×5, and ×10, respectively).

There is limited literature available about the diagnosis and treatment of SMP. Our case prompted us to further examine the data to emphasize the necessity of greater research surrounding SMP.

Classification of SMP

Morphea is a localized form of scleroderma, an inflammatory disease that primarily affects the dermis but can extend down to the bone and also can limit motion. There are several types of morphea that are classified according to the extent, depth, and distribution of the lesions, including plaque, generalized, bullous, linear (including morphea en coup de sabre), guttate, nodular, and deep morphea.^1,2 Other subtypes have been described including subcutaneous morphea, eosinophilic fasciitis (EF), pansclerotic morphea, and morphea profunda.³ Linear and deep morphea are characterized by involvement of the deep dermis, subcutaneous tissue, fascia, and/or superficial muscle.^2,4

In 1981, Su and Person⁵ first described morphea profunda (MP). In their study, 22 of 23 patients presented with generalized MP. One patient developed a single lesion,⁵ which ultimately was classified as SMP by Whittaker et al⁶ in 1989.

Epidemiology

Morphea profunda occurs more frequently in females than in males, with sclerosis manifesting over a period of several months.⁷ In 2004, Azad et al⁴ suggested that only 9 cases of SMP had been reported in the literature. Although there is insignificant data to determine the epidemiology of SMP, the authors concluded that it most commonly affects middle-aged individuals with equal sex distribution.⁴ The single plaque in patients with SMP most commonly presents on the shoulder, back, or neck or in the paraspinal area.

Etiology

Because of the limited amount of literature on MP, a definitive etiology is unknown, but investigators have cited many possible causes. Genetic, autoimmune, hormonal, traumatic,⁸ vaccination,^2,8 radiation,⁹ viral, neurogenic, and vascular factors all have been implicated,¹⁰ as well as infectious agents such as Borrelia burgdorferi in the United States,^11,12Borrelia afzelii in Europe,² and Borrelia garinii in Japan.² Because our patient experienced a traumatic episode several months prior to presentation, it is important to investigate trauma as a likely etiology. Furthermore, traumatic events have been reported in 23% of children with linear morphea.¹³

Diagnostic Studies

Morphea profunda is diagnosed clinically and skin biopsy can be used for confirmation. Biopsy requires deep excision down to the muscle, which can aid in determining if the fascia is incorporated. Elevated levels of IgG and IgM have been detected in deep and linear morphea and are known to correlate with disease activity and the development of joint contractures in linear morphea.² Serum procollagen type I has been considered by some as a useful indicator of disease severity.¹⁴ Elevated serum levels of antifibrillin-1 antibodies also have been demonstrated in patients with localized scleroderma (LS).¹⁵ Radiography and magnetic resonance imaging can be used for monitoring and analyzing lesion depth. Furthermore, magnetic resonance imaging can be used to differentiate MP from EF.²

The presence of ANAs in LS is controversial. According to Nguyen et al,² ANAs are present in approximately 46% to 80% of patients with morphea, with a higher prevalence in patients with generalized, linear, and deep subtypes. However, Savoia et al¹⁶ found that patients with morphea typically do not present with ANAs; rather ANAs usually are found in patients with EF.

Pathogenesis

After the inflammatory phase in LS, fibrillar collagen types I and III accumulate, causing dermal fibrosis. The extracellular matrix increases due to the activation of connective tissue growth factor, transforming growth factor β (TGF-β), TGF-β receptors, IL-4, and several other cytokines.¹⁷ The TGF-β receptors combine with the connective tissue growth factor released by fibroblasts to create an autocrine production loop that causes fibroblast and matrix production.¹⁷ As the inflammation progresses to sclerosis, the CD34 count decreases.¹⁸

Physical Findings

In patients with MP, lesions manifest as thickened taut skin with deep, solitary, and sclerotic indurated plaques. Clinically, plaques are mildly inflamed, hyperpigmented, symmetric, and somewhat ill defined, and the skin feels thickened and bound to the underlying fascia and muscle. Plaques usually are smooth and shiny, but areas of both dermal and subcutaneous atrophy may be present, particularly in chronic lesions.¹⁹ Morphea profunda also can be described as having a cobblestone or pseudocellulite appearance. The groove sign is used to describe a depression along the course of a vein and/or between muscle groups. Both clinical presentations may manifest later in the course of disease.²

Histopathology

Su and Person⁵ described 3 main characteristics of MP that stand out histopathologically. First, there is thickening and hyalinization of collagen bundles in the deep dermis, subcutis, and fascia that are prominent between the junction of the dermis and subcutaneous fat. There also are fewer sebaceous glands and hair follicles. Second, MP presents with an increased inflammatory cell infiltrate composed mainly of lymphocytes located around small blood vessels and the interstitium. In some patients, the lymphocytes consist predominantly of collections of plasma cells. Third, MP contains deposits of mucin in deep portions of the dermis with occasional eosinophils and mast cells. The presence of eosinophils allows EF to be a part of this spectrum and to be included as a differential diagnosis.⁵ Eosinophilic fasciitis has a similar presentation to MP because the fibrosis affects the dermis, subcutaneous fat, and underlying structures.²⁰ Although EF presents with the histopathologic characteristic of fascial fibrosis, a clear distinction between EF and morphea has not been established in the literature. Some authors classify EF as a variant of morphea, whereas others consider it as its own entity. We believe EF is its own entity. Eosinophilic fasciitis can be distinguished from morphea because 60% to 80% of patients with EF have peripheral eosinophilia and 20% to 70% of patients with EF have hypergammaglobulinemia. Additionally, morphea does not present as symmetrically or abruptly as EF.²¹

Treatment

To date, there is conflicting literature regarding the treatment regimen for MP. There is controversy regarding whether MP responds to corticosteroids.¹⁹ Different treatment regimens have been discussed for LS, but there is a lack of reports specifically describing therapies for MP and SMP. Because MP and SMP fall under the umbrella of LS, many investigators have reported using the following treatment regimens for patients with MP and SMP: bosentan,²² D-penicillamine,²³ phototherapy,^24-26 retinoids,²⁶ oral steroids,²⁷ methotrexate,^27-29 vitamin D₃ (oral calcitriol),^30,31 cyclosporine,³² mycophenolate mofetil,³³ and extracorporeal photochemotherapy.³⁴

Falanga and Medsger²³ reported 64% (7/11) treatment success with D-penicillamine in patients who exhibited severe LS. Psoralen plus UVA,²⁴ methoxsalen, and UVA1 therapy are widely used in the treatment of LS.²⁵ Kreuter et al²⁵ advocated for phototherapy as the first approach in the management of LS after reporting improvement in all participants in their study (N=64), 2 participants with deep morphea while the rest exhibited other forms of morphea. Ozdemir et al²⁶ proposed that retinoic acid combined with psoralen plus UVA is a good treatment choice for plaque-type LS; however, UVA only has the ability to target the epidermis and dermis, which may not be useful for deep forms of morphea.

Several studies have shown positive results in patients treated with methylprednisolone combined with low-dose methotrexate sodium.^27-29 Kreuter et al³⁰ and Elst et al³¹ proposed that calcitriol is effective in treating LS, whereas Hulshof et al³⁵ indicated that it is not. It should be noted that none of these studies specifically mentioned MP. Martini et al³³ demonstrated success with mycophenolate mofetil in the treatment of 10 LS patients who were resistant to methotrexate sodium and corticosteroids. Although none of the participants in the study had MP, 2 patients had disabling pansclerotic morphea, 3 had generalized morphea, and 5 had linear scleroderma (morphea en coup de sabre) affecting the limbs (n=2) and face (n=3).³³ Because there is no established therapy or consensus for the treatment of MP, we have found success in starting with corticosteroids and then trying alternative therapies.

Prognosis

Morphea has transitioned into systemic scleroderma in a small number of reported cases.^10,16,20,36 Therefore, patient follow-up is imperative to consistently identify systemic evolution. Although visceral complications are rare in the setting of LS, associated clinical findings have been reported, including arthralgia, arthritis, contractures, and carpal tunnel syndrome, as well as pulmonary, esophageal, and cardiac abnormalities.^7,34

Conclusion

The morphologic features observed in our patient appear to correspond most closely to the type of lesion described by Su and Person⁵ and Whittaker et al.⁶ Although our case was clinically difficult to distinguish from linear morphea, the histology suggested SMP over other causes. If our patient’s SMP progressed to the joints, physical therapy would be needed to maintain range of motion and function of the extremities,² and mandatory long-term follow-up would be required due to the risk for relapse after discontinuation of therapy. Our case highlights the inherent difficulties in the treatment of MP. Due to limited reports of SMP and MP in the literature as well as the conflicting views regarding effective and appropriate treatment options, additional investigation of these conditions and therapeutic options are necessary to further understand this debilitating condition.

Case Report

A 50-year-old white woman presented to our clinic for evaluation of what she described as a “very hard red line” on the right upper arm. The lesion had developed suddenly overnight. Several months prior to presentation the patient sustained trauma to the same area in a car accident and she thought the lesion might be related to the resulting nerve damage. Initially she presented to her primary care physician who used ultrasonography of the area to rule out muscle or bone involvement. The patient presented to our dermatology clinic 2 months later with an 18×4-cm, brownish, rectangular, sclerotic, bound-down, hypertrophic plaque that started on the right mid forearm and extended to the right shoulder (Figure 1). Her medical history was notable for high blood pressure, which was controlled with valsartan.

Figure 1. An 18×4-cm, brownish, rectangular, sclerotic, bound-down, hypertrophic plaque that started on the right mid forearm and extended to the right shoulder.

A review of systems was unremarkable. Physical examination revealed a well-developed, well-nourished woman. Examination of the right arm revealed no motion restriction (muscle strength, 5/5) and no pain; however, she described a burning sensation at the site of the lesion. She reported no allergies. A 4-mm punch biopsy was performed and laboratory tests were ordered including an antinuclear antibody (ANA) test with reflex, double-stranded DNA test, DNA antitopoisomerase antibodies test, and Lyme titers (IgM and IgG). Initially, the patient was treated with calcipotriene 0.005%–betamethasone dipropionate 0.064% ointment twice daily; she also was treated empirically for Lyme disease with doxycycline 50 mg twice daily. All laboratory tests were within reference range, and a punch biopsy revealed markedly thickened fibrous septa within the subcutaneous fat. At the edge of the septa there were nodular aggregates of lymphocytes. Due to clinical presentation, laboratory data, and histopathology, solitary morphea profunda (SMP) was diagnosed.

Following histopathologic examination (Figure 2), the patient was instructed to continue treatment with calcipotriene–betamethasone dipropionate as well as doxycycline. A trial of prednisone and/or hydroxychloroquine also was considered pending her response to the initial treatment. At approximately 1-month follow-up, remarkable improvement of the lesion was noted.

Comment

Figure 2. Markedly thickened fibrous septa within the subcutaneous fat with nodular aggregates of lymphocytes (A–C)(all H&E; original magnifications ×2.5, ×5, and ×10, respectively).

There is limited literature available about the diagnosis and treatment of SMP. Our case prompted us to further examine the data to emphasize the necessity of greater research surrounding SMP.

Classification of SMP

Morphea is a localized form of scleroderma, an inflammatory disease that primarily affects the dermis but can extend down to the bone and also can limit motion. There are several types of morphea that are classified according to the extent, depth, and distribution of the lesions, including plaque, generalized, bullous, linear (including morphea en coup de sabre), guttate, nodular, and deep morphea.^1,2 Other subtypes have been described including subcutaneous morphea, eosinophilic fasciitis (EF), pansclerotic morphea, and morphea profunda.³ Linear and deep morphea are characterized by involvement of the deep dermis, subcutaneous tissue, fascia, and/or superficial muscle.^2,4

In 1981, Su and Person⁵ first described morphea profunda (MP). In their study, 22 of 23 patients presented with generalized MP. One patient developed a single lesion,⁵ which ultimately was classified as SMP by Whittaker et al⁶ in 1989.

Epidemiology

Morphea profunda occurs more frequently in females than in males, with sclerosis manifesting over a period of several months.⁷ In 2004, Azad et al⁴ suggested that only 9 cases of SMP had been reported in the literature. Although there is insignificant data to determine the epidemiology of SMP, the authors concluded that it most commonly affects middle-aged individuals with equal sex distribution.⁴ The single plaque in patients with SMP most commonly presents on the shoulder, back, or neck or in the paraspinal area.

Etiology

Because of the limited amount of literature on MP, a definitive etiology is unknown, but investigators have cited many possible causes. Genetic, autoimmune, hormonal, traumatic,⁸ vaccination,^2,8 radiation,⁹ viral, neurogenic, and vascular factors all have been implicated,¹⁰ as well as infectious agents such as Borrelia burgdorferi in the United States,^11,12Borrelia afzelii in Europe,² and Borrelia garinii in Japan.² Because our patient experienced a traumatic episode several months prior to presentation, it is important to investigate trauma as a likely etiology. Furthermore, traumatic events have been reported in 23% of children with linear morphea.¹³

Diagnostic Studies

Morphea profunda is diagnosed clinically and skin biopsy can be used for confirmation. Biopsy requires deep excision down to the muscle, which can aid in determining if the fascia is incorporated. Elevated levels of IgG and IgM have been detected in deep and linear morphea and are known to correlate with disease activity and the development of joint contractures in linear morphea.² Serum procollagen type I has been considered by some as a useful indicator of disease severity.¹⁴ Elevated serum levels of antifibrillin-1 antibodies also have been demonstrated in patients with localized scleroderma (LS).¹⁵ Radiography and magnetic resonance imaging can be used for monitoring and analyzing lesion depth. Furthermore, magnetic resonance imaging can be used to differentiate MP from EF.²

The presence of ANAs in LS is controversial. According to Nguyen et al,² ANAs are present in approximately 46% to 80% of patients with morphea, with a higher prevalence in patients with generalized, linear, and deep subtypes. However, Savoia et al¹⁶ found that patients with morphea typically do not present with ANAs; rather ANAs usually are found in patients with EF.

Pathogenesis

After the inflammatory phase in LS, fibrillar collagen types I and III accumulate, causing dermal fibrosis. The extracellular matrix increases due to the activation of connective tissue growth factor, transforming growth factor β (TGF-β), TGF-β receptors, IL-4, and several other cytokines.¹⁷ The TGF-β receptors combine with the connective tissue growth factor released by fibroblasts to create an autocrine production loop that causes fibroblast and matrix production.¹⁷ As the inflammation progresses to sclerosis, the CD34 count decreases.¹⁸

Physical Findings

In patients with MP, lesions manifest as thickened taut skin with deep, solitary, and sclerotic indurated plaques. Clinically, plaques are mildly inflamed, hyperpigmented, symmetric, and somewhat ill defined, and the skin feels thickened and bound to the underlying fascia and muscle. Plaques usually are smooth and shiny, but areas of both dermal and subcutaneous atrophy may be present, particularly in chronic lesions.¹⁹ Morphea profunda also can be described as having a cobblestone or pseudocellulite appearance. The groove sign is used to describe a depression along the course of a vein and/or between muscle groups. Both clinical presentations may manifest later in the course of disease.²

Histopathology

Su and Person⁵ described 3 main characteristics of MP that stand out histopathologically. First, there is thickening and hyalinization of collagen bundles in the deep dermis, subcutis, and fascia that are prominent between the junction of the dermis and subcutaneous fat. There also are fewer sebaceous glands and hair follicles. Second, MP presents with an increased inflammatory cell infiltrate composed mainly of lymphocytes located around small blood vessels and the interstitium. In some patients, the lymphocytes consist predominantly of collections of plasma cells. Third, MP contains deposits of mucin in deep portions of the dermis with occasional eosinophils and mast cells. The presence of eosinophils allows EF to be a part of this spectrum and to be included as a differential diagnosis.⁵ Eosinophilic fasciitis has a similar presentation to MP because the fibrosis affects the dermis, subcutaneous fat, and underlying structures.²⁰ Although EF presents with the histopathologic characteristic of fascial fibrosis, a clear distinction between EF and morphea has not been established in the literature. Some authors classify EF as a variant of morphea, whereas others consider it as its own entity. We believe EF is its own entity. Eosinophilic fasciitis can be distinguished from morphea because 60% to 80% of patients with EF have peripheral eosinophilia and 20% to 70% of patients with EF have hypergammaglobulinemia. Additionally, morphea does not present as symmetrically or abruptly as EF.²¹

Treatment

To date, there is conflicting literature regarding the treatment regimen for MP. There is controversy regarding whether MP responds to corticosteroids.¹⁹ Different treatment regimens have been discussed for LS, but there is a lack of reports specifically describing therapies for MP and SMP. Because MP and SMP fall under the umbrella of LS, many investigators have reported using the following treatment regimens for patients with MP and SMP: bosentan,²² D-penicillamine,²³ phototherapy,^24-26 retinoids,²⁶ oral steroids,²⁷ methotrexate,^27-29 vitamin D₃ (oral calcitriol),^30,31 cyclosporine,³² mycophenolate mofetil,³³ and extracorporeal photochemotherapy.³⁴

Falanga and Medsger²³ reported 64% (7/11) treatment success with D-penicillamine in patients who exhibited severe LS. Psoralen plus UVA,²⁴ methoxsalen, and UVA1 therapy are widely used in the treatment of LS.²⁵ Kreuter et al²⁵ advocated for phototherapy as the first approach in the management of LS after reporting improvement in all participants in their study (N=64), 2 participants with deep morphea while the rest exhibited other forms of morphea. Ozdemir et al²⁶ proposed that retinoic acid combined with psoralen plus UVA is a good treatment choice for plaque-type LS; however, UVA only has the ability to target the epidermis and dermis, which may not be useful for deep forms of morphea.

Several studies have shown positive results in patients treated with methylprednisolone combined with low-dose methotrexate sodium.^27-29 Kreuter et al³⁰ and Elst et al³¹ proposed that calcitriol is effective in treating LS, whereas Hulshof et al³⁵ indicated that it is not. It should be noted that none of these studies specifically mentioned MP. Martini et al³³ demonstrated success with mycophenolate mofetil in the treatment of 10 LS patients who were resistant to methotrexate sodium and corticosteroids. Although none of the participants in the study had MP, 2 patients had disabling pansclerotic morphea, 3 had generalized morphea, and 5 had linear scleroderma (morphea en coup de sabre) affecting the limbs (n=2) and face (n=3).³³ Because there is no established therapy or consensus for the treatment of MP, we have found success in starting with corticosteroids and then trying alternative therapies.

Prognosis

Morphea has transitioned into systemic scleroderma in a small number of reported cases.^10,16,20,36 Therefore, patient follow-up is imperative to consistently identify systemic evolution. Although visceral complications are rare in the setting of LS, associated clinical findings have been reported, including arthralgia, arthritis, contractures, and carpal tunnel syndrome, as well as pulmonary, esophageal, and cardiac abnormalities.^7,34

Conclusion

The morphologic features observed in our patient appear to correspond most closely to the type of lesion described by Su and Person⁵ and Whittaker et al.⁶ Although our case was clinically difficult to distinguish from linear morphea, the histology suggested SMP over other causes. If our patient’s SMP progressed to the joints, physical therapy would be needed to maintain range of motion and function of the extremities,² and mandatory long-term follow-up would be required due to the risk for relapse after discontinuation of therapy. Our case highlights the inherent difficulties in the treatment of MP. Due to limited reports of SMP and MP in the literature as well as the conflicting views regarding effective and appropriate treatment options, additional investigation of these conditions and therapeutic options are necessary to further understand this debilitating condition.

The panniculitides can be a complex dermatologic entity for both dermatologists and dermatopathologists. The history, clinical examination, and histology need to be correlated to arrive at a differential diagnosis that will ultimately provide a diagnosis for the subcutaneous lesions. Panniculitis is an inflammation of the subcutaneous adipose tissue and can be associated with systemic diseases. According to Peters and Su,¹ “Anatomic location of lesions, presence or absence of ulceration, occurrence of lipoatrophy, history of trauma, association with immunologic or metabolic disorders, and age of the patient are important clinical data to consider in conjunction with the microscopic features.” The panniculitides histologic differences may be subtle because they all include septal and lobular components, but one is usually more dominant in leading to a diagnosis along with the clinical findings.²

Cold panniculitis is a form of traumatic panniculitis. We present a unique case of this condition that was caused by use of a cold therapy unit following surgery to relieve pain.

Case Report

A 37-year-old woman presented for a routine postoperative visit 15 days following arthroscopic repair of a superior labrum anterior posterior tear in the left shoulder with a single suture anchor. The patient reported a rash that had developed 10 days postoperatively on the left upper arm. The rash started as red dots that progressively became larger, painful, and warm to the touch. The rash did not spread anywhere else on the patient’s body, and she denied fever, chills, and pruritus. She had tried using diphenhydramine without relief. The only new medication the patient had started prior to the eruption was oxycodone, which was initiated immediately following surgery. Prior to surgery, the entire left upper extremity including the shoulder had been prepared with a preoperative surgical skin antiseptic. There were no visible signs of the antiseptic on the skin at the time of presentation. The patient reported that she had applied a cold therapy unit to the left upper arm over her clothing for 1 hour every night since surgery. The cold therapy unit frequently is used to help decrease postoperative pain, swelling, inflammation, and narcotic use following surgical procedures.

Physical examination revealed multiple well-defined, erythematous, tender, indurated, warm nodules on the lateral aspect of the left upper arm (Figure 1). No other areas of eruption were noted on the body, and there was no swelling of the left elbow, forearm, wrist, or hand. The left upper extremity demonstrated intact sensation, rapid capillary refill, and a palpable radial pulse. Her weight was 230.1 lb with a body mass index of 35.

Figure 1. Multiple well-defined, erythematous, tender, indurated nodules presented on the lateral aspect of the left upper arm. Figure 2. Punch biopsy showed a superficial and deep perivascular and periadnexal lymphoid infiltrate with involvement of the subcutis (H&E, original magnification ×40).

A 5-mm punch biopsy from a nodule on the left upper arm was performed, and pathology demonstrated vacuolar interface changes with patchy parakeratosis, spongiosis, and dyskeratosis on staining with hematoxylin and eosin. Pandermal and subcutaneous perivascular, periadnexal, and mild interstitial lymphohistiocytic infiltrate with occasional neutrophils and eosinophils were noted (Figure 2). The inflammation extended to the subcutaneous fat involving both septae and lobules with a primarily lobular distribution.

Clinical and pathologic correlation was required to arrive at a definitive diagnosis of cold panniculitis. The epidermal and dermal changes were consistent with a pernio or chilblains type of insult, and the septal and lobular panniculitis was indicative of cold panniculitis. The patient was advised to discontinue use of the cold therapy device as well as any other form of icing of the left shoulder or arm. She continued the oxycodone for pain control. Four weeks postoperatively, only desquamation remained where the nodules had previously appeared, which also eventually resolved.

Comment

Infants and small children are more predisposed to cold panniculitis than adults. In their 2008 review, Quesada-Cortés et al³ found the first report of cold panniculitis by Hochsinger in 1902 in a German pediatric journal, followed by reports from Lemez in 1928 and Haxthausen in 1941, which subsequently described similar cases in infants. Adult cases were not reported until 1963 by Solomon and Beerman⁴ and then in 1980 by Beacham et al.⁵

Etiologies for children have included popsicles, ice packs applied to the face to control supraventricular tachycardia or to the lower extremities after vaccinations, and cold weather exposure.⁶ The chemical composition of fat tissue plays a role in pediatric patients. According to Quesada-Cortés et al,³ subcutaneous fat in newborns is rich in saturated oils such as palmitic and stearic acids that have a higher solidification point. A small decrease in an infant’s temperature may result in crystallization of fat. The subcutaneous fat tends to become more unsaturated with aging with more oleic acid, and the solidification temperature diminishes.⁷

Cryoglobulins and cold agglutinins have not been demonstrated to be a cause of cold panniculitis in infants.⁷ Severe cold exposure or predisposition to certain conditions such as cryofibrinogenemia may occur in some adult patients. Gender does not seem to be a factor in children; however, in adults, women tend to be more predisposed to cold panniculitis secondary to obesity and participation in activities such as cycling, motorcycling, or horseback riding in cold conditions.³

On clinical examination, cold panniculitis features erythematous, firm, tender nodules on the cheeks and chin in infants and small children.² These areas often are exposed to cold weather or wind because they typically are not covered with protective clothing.³ Nodules generally occur 1 to 3 days following exposure to cold and usually resolve spontaneously within 2 weeks.⁸ Popsicle panniculitis is characterized by a reddish discoloration on both cheeks 1 or 2 days after sucking on popsicles or ice cubes. This reaction can be reproduced in a half day by applying an ice cube to the volar forearm for 2 minutes, which can help diagnose and differentiate this subset of cold panniuculits.³ The red area in cold panniculitis eventually turns purple, becomes less indurated, and fades in approximately 3 months, but occasionally residual hyperpigmentation will last for a few months. Ice packs used as treatment of congenital cardiac arrhythmias in some cardiac surgeries and as surface cooling for management of birth asphyxia can produce a similar physical presentation.³

Equestrian panniculitis is characterized by erythematous, violaceous, tender plaques on the upper lateral thighs of young females who participate in horseback riding in the winter while wearing tight-fitting pants.^2,5 These plaques typically occur within several hours and over the next week become painful, violaceous, and indurated or develop red nodules or plaques that can ulcerate or become crusted.³ These lesions usually will spontaneously resolve within 3 weeks, but new areas may occur again during the winter on further exposure with occasional persistent hyperpigmentation. These areas usually disappear at the end of winter with warmer weather or when horseback riding is discontinued. Perniosis also needs to be considered in the differential diagnosis due to the location and appearance of the lesions.³

It is important to obtain the correct specimen for biopsy. According to Peters and Su,¹ a deep excisional biopsy that includes multiple fat lobules in addition to dermis and epidermis is critical. On histology, cold panniculitis usually demonstrates a primarily lobular inflammation. There typically is a superficial and deep perivascular lymphocytic infiltrate in the papillary dermis with edema noted in the connective tissue around the eccrine glands that can appear similar to perniosis on histopathology.⁹ Deposition of mucin, focal panniculitis surrounded by fatty tissue without inflammatory changes within the same field, and fat necrosis with pseudocysts and numerous lipophages also are characteristic features of cold panniculitis.¹⁰ Needlelike clefts are not present in cold panniculitis but appear in subcutaneous fat necrosis of the newborn.¹

Different treatments have been tried, but no substantial impact on the rate of dissipation of the lesions has been noted. The plaques slowly resolve without scarring over 2 to 3 weeks if the cold source is removed.² Application of a heating pad to the affected area has been used with limited success. Vasodilators such as nifedipine have been used but have not been found to be effective.³ Antihistamines also have failed to control the lesions.¹¹

Treatment of cold panniculitis is based on the prevention of further insult versus trying to cure the condition. Avoidance of cold and wind exposure as well as direct contact with ice are key methods in preventing cold panniculitis.

Our patient’s presentation of this condition was unique. Although cold panniculitis lesions usually develop 1 to 3 days after cold exposure, our patient did not develop lesions until 10 days following surgery. The cold therapy unit used by our patient was evaluated in our office and also by the manufacturer and was found to be functioning normally with no defects. The late onset of the lesions was attributed to limited application of the cold therapy unit; our patient used it for only 1 hour every night, whereas application for 6 to 8 hours continuously is normally recommended. The lesions may have occurred sooner had the patient been using a solid ice pack versus the continuous cold circulating water of the cold therapy unit. Pathology was consistent with the patient’s history and physical examination indicating a diagnosis of cold panniculitis. The challenge of treatment was to alleviate the pain of the lesions as well as the postoperative shoulder pain without the aid of any form of cold therapy. The patient only needed a tincture of time, as the lesions resolved after 4 weeks. Patient education was provided on future prevention of this condition by avoiding exposure to cold or applying cold packs directly to the skin.

Acknowledgment

The authors thank the staff at the Office of Scientific Writing and Publication at the Marshfield Clinic Research Foundation, Wisconsin, for their editorial assistance in the preparation of this manuscript.

The panniculitides can be a complex dermatologic entity for both dermatologists and dermatopathologists. The history, clinical examination, and histology need to be correlated to arrive at a differential diagnosis that will ultimately provide a diagnosis for the subcutaneous lesions. Panniculitis is an inflammation of the subcutaneous adipose tissue and can be associated with systemic diseases. According to Peters and Su,¹ “Anatomic location of lesions, presence or absence of ulceration, occurrence of lipoatrophy, history of trauma, association with immunologic or metabolic disorders, and age of the patient are important clinical data to consider in conjunction with the microscopic features.” The panniculitides histologic differences may be subtle because they all include septal and lobular components, but one is usually more dominant in leading to a diagnosis along with the clinical findings.²

Cold panniculitis is a form of traumatic panniculitis. We present a unique case of this condition that was caused by use of a cold therapy unit following surgery to relieve pain.

Case Report

A 37-year-old woman presented for a routine postoperative visit 15 days following arthroscopic repair of a superior labrum anterior posterior tear in the left shoulder with a single suture anchor. The patient reported a rash that had developed 10 days postoperatively on the left upper arm. The rash started as red dots that progressively became larger, painful, and warm to the touch. The rash did not spread anywhere else on the patient’s body, and she denied fever, chills, and pruritus. She had tried using diphenhydramine without relief. The only new medication the patient had started prior to the eruption was oxycodone, which was initiated immediately following surgery. Prior to surgery, the entire left upper extremity including the shoulder had been prepared with a preoperative surgical skin antiseptic. There were no visible signs of the antiseptic on the skin at the time of presentation. The patient reported that she had applied a cold therapy unit to the left upper arm over her clothing for 1 hour every night since surgery. The cold therapy unit frequently is used to help decrease postoperative pain, swelling, inflammation, and narcotic use following surgical procedures.

Physical examination revealed multiple well-defined, erythematous, tender, indurated, warm nodules on the lateral aspect of the left upper arm (Figure 1). No other areas of eruption were noted on the body, and there was no swelling of the left elbow, forearm, wrist, or hand. The left upper extremity demonstrated intact sensation, rapid capillary refill, and a palpable radial pulse. Her weight was 230.1 lb with a body mass index of 35.

Figure 1. Multiple well-defined, erythematous, tender, indurated nodules presented on the lateral aspect of the left upper arm. Figure 2. Punch biopsy showed a superficial and deep perivascular and periadnexal lymphoid infiltrate with involvement of the subcutis (H&E, original magnification ×40).

A 5-mm punch biopsy from a nodule on the left upper arm was performed, and pathology demonstrated vacuolar interface changes with patchy parakeratosis, spongiosis, and dyskeratosis on staining with hematoxylin and eosin. Pandermal and subcutaneous perivascular, periadnexal, and mild interstitial lymphohistiocytic infiltrate with occasional neutrophils and eosinophils were noted (Figure 2). The inflammation extended to the subcutaneous fat involving both septae and lobules with a primarily lobular distribution.

Clinical and pathologic correlation was required to arrive at a definitive diagnosis of cold panniculitis. The epidermal and dermal changes were consistent with a pernio or chilblains type of insult, and the septal and lobular panniculitis was indicative of cold panniculitis. The patient was advised to discontinue use of the cold therapy device as well as any other form of icing of the left shoulder or arm. She continued the oxycodone for pain control. Four weeks postoperatively, only desquamation remained where the nodules had previously appeared, which also eventually resolved.

Comment

Infants and small children are more predisposed to cold panniculitis than adults. In their 2008 review, Quesada-Cortés et al³ found the first report of cold panniculitis by Hochsinger in 1902 in a German pediatric journal, followed by reports from Lemez in 1928 and Haxthausen in 1941, which subsequently described similar cases in infants. Adult cases were not reported until 1963 by Solomon and Beerman⁴ and then in 1980 by Beacham et al.⁵

Etiologies for children have included popsicles, ice packs applied to the face to control supraventricular tachycardia or to the lower extremities after vaccinations, and cold weather exposure.⁶ The chemical composition of fat tissue plays a role in pediatric patients. According to Quesada-Cortés et al,³ subcutaneous fat in newborns is rich in saturated oils such as palmitic and stearic acids that have a higher solidification point. A small decrease in an infant’s temperature may result in crystallization of fat. The subcutaneous fat tends to become more unsaturated with aging with more oleic acid, and the solidification temperature diminishes.⁷

Cryoglobulins and cold agglutinins have not been demonstrated to be a cause of cold panniculitis in infants.⁷ Severe cold exposure or predisposition to certain conditions such as cryofibrinogenemia may occur in some adult patients. Gender does not seem to be a factor in children; however, in adults, women tend to be more predisposed to cold panniculitis secondary to obesity and participation in activities such as cycling, motorcycling, or horseback riding in cold conditions.³

On clinical examination, cold panniculitis features erythematous, firm, tender nodules on the cheeks and chin in infants and small children.² These areas often are exposed to cold weather or wind because they typically are not covered with protective clothing.³ Nodules generally occur 1 to 3 days following exposure to cold and usually resolve spontaneously within 2 weeks.⁸ Popsicle panniculitis is characterized by a reddish discoloration on both cheeks 1 or 2 days after sucking on popsicles or ice cubes. This reaction can be reproduced in a half day by applying an ice cube to the volar forearm for 2 minutes, which can help diagnose and differentiate this subset of cold panniuculits.³ The red area in cold panniculitis eventually turns purple, becomes less indurated, and fades in approximately 3 months, but occasionally residual hyperpigmentation will last for a few months. Ice packs used as treatment of congenital cardiac arrhythmias in some cardiac surgeries and as surface cooling for management of birth asphyxia can produce a similar physical presentation.³

Equestrian panniculitis is characterized by erythematous, violaceous, tender plaques on the upper lateral thighs of young females who participate in horseback riding in the winter while wearing tight-fitting pants.^2,5 These plaques typically occur within several hours and over the next week become painful, violaceous, and indurated or develop red nodules or plaques that can ulcerate or become crusted.³ These lesions usually will spontaneously resolve within 3 weeks, but new areas may occur again during the winter on further exposure with occasional persistent hyperpigmentation. These areas usually disappear at the end of winter with warmer weather or when horseback riding is discontinued. Perniosis also needs to be considered in the differential diagnosis due to the location and appearance of the lesions.³

It is important to obtain the correct specimen for biopsy. According to Peters and Su,¹ a deep excisional biopsy that includes multiple fat lobules in addition to dermis and epidermis is critical. On histology, cold panniculitis usually demonstrates a primarily lobular inflammation. There typically is a superficial and deep perivascular lymphocytic infiltrate in the papillary dermis with edema noted in the connective tissue around the eccrine glands that can appear similar to perniosis on histopathology.⁹ Deposition of mucin, focal panniculitis surrounded by fatty tissue without inflammatory changes within the same field, and fat necrosis with pseudocysts and numerous lipophages also are characteristic features of cold panniculitis.¹⁰ Needlelike clefts are not present in cold panniculitis but appear in subcutaneous fat necrosis of the newborn.¹

Different treatments have been tried, but no substantial impact on the rate of dissipation of the lesions has been noted. The plaques slowly resolve without scarring over 2 to 3 weeks if the cold source is removed.² Application of a heating pad to the affected area has been used with limited success. Vasodilators such as nifedipine have been used but have not been found to be effective.³ Antihistamines also have failed to control the lesions.¹¹

Treatment of cold panniculitis is based on the prevention of further insult versus trying to cure the condition. Avoidance of cold and wind exposure as well as direct contact with ice are key methods in preventing cold panniculitis.

Our patient’s presentation of this condition was unique. Although cold panniculitis lesions usually develop 1 to 3 days after cold exposure, our patient did not develop lesions until 10 days following surgery. The cold therapy unit used by our patient was evaluated in our office and also by the manufacturer and was found to be functioning normally with no defects. The late onset of the lesions was attributed to limited application of the cold therapy unit; our patient used it for only 1 hour every night, whereas application for 6 to 8 hours continuously is normally recommended. The lesions may have occurred sooner had the patient been using a solid ice pack versus the continuous cold circulating water of the cold therapy unit. Pathology was consistent with the patient’s history and physical examination indicating a diagnosis of cold panniculitis. The challenge of treatment was to alleviate the pain of the lesions as well as the postoperative shoulder pain without the aid of any form of cold therapy. The patient only needed a tincture of time, as the lesions resolved after 4 weeks. Patient education was provided on future prevention of this condition by avoiding exposure to cold or applying cold packs directly to the skin.

Acknowledgment

The authors thank the staff at the Office of Scientific Writing and Publication at the Marshfield Clinic Research Foundation, Wisconsin, for their editorial assistance in the preparation of this manuscript.

The panniculitides can be a complex dermatologic entity for both dermatologists and dermatopathologists. The history, clinical examination, and histology need to be correlated to arrive at a differential diagnosis that will ultimately provide a diagnosis for the subcutaneous lesions. Panniculitis is an inflammation of the subcutaneous adipose tissue and can be associated with systemic diseases. According to Peters and Su,¹ “Anatomic location of lesions, presence or absence of ulceration, occurrence of lipoatrophy, history of trauma, association with immunologic or metabolic disorders, and age of the patient are important clinical data to consider in conjunction with the microscopic features.” The panniculitides histologic differences may be subtle because they all include septal and lobular components, but one is usually more dominant in leading to a diagnosis along with the clinical findings.²

Cold panniculitis is a form of traumatic panniculitis. We present a unique case of this condition that was caused by use of a cold therapy unit following surgery to relieve pain.

Case Report

A 37-year-old woman presented for a routine postoperative visit 15 days following arthroscopic repair of a superior labrum anterior posterior tear in the left shoulder with a single suture anchor. The patient reported a rash that had developed 10 days postoperatively on the left upper arm. The rash started as red dots that progressively became larger, painful, and warm to the touch. The rash did not spread anywhere else on the patient’s body, and she denied fever, chills, and pruritus. She had tried using diphenhydramine without relief. The only new medication the patient had started prior to the eruption was oxycodone, which was initiated immediately following surgery. Prior to surgery, the entire left upper extremity including the shoulder had been prepared with a preoperative surgical skin antiseptic. There were no visible signs of the antiseptic on the skin at the time of presentation. The patient reported that she had applied a cold therapy unit to the left upper arm over her clothing for 1 hour every night since surgery. The cold therapy unit frequently is used to help decrease postoperative pain, swelling, inflammation, and narcotic use following surgical procedures.

Physical examination revealed multiple well-defined, erythematous, tender, indurated, warm nodules on the lateral aspect of the left upper arm (Figure 1). No other areas of eruption were noted on the body, and there was no swelling of the left elbow, forearm, wrist, or hand. The left upper extremity demonstrated intact sensation, rapid capillary refill, and a palpable radial pulse. Her weight was 230.1 lb with a body mass index of 35.

Figure 1. Multiple well-defined, erythematous, tender, indurated nodules presented on the lateral aspect of the left upper arm. Figure 2. Punch biopsy showed a superficial and deep perivascular and periadnexal lymphoid infiltrate with involvement of the subcutis (H&E, original magnification ×40).

A 5-mm punch biopsy from a nodule on the left upper arm was performed, and pathology demonstrated vacuolar interface changes with patchy parakeratosis, spongiosis, and dyskeratosis on staining with hematoxylin and eosin. Pandermal and subcutaneous perivascular, periadnexal, and mild interstitial lymphohistiocytic infiltrate with occasional neutrophils and eosinophils were noted (Figure 2). The inflammation extended to the subcutaneous fat involving both septae and lobules with a primarily lobular distribution.

Clinical and pathologic correlation was required to arrive at a definitive diagnosis of cold panniculitis. The epidermal and dermal changes were consistent with a pernio or chilblains type of insult, and the septal and lobular panniculitis was indicative of cold panniculitis. The patient was advised to discontinue use of the cold therapy device as well as any other form of icing of the left shoulder or arm. She continued the oxycodone for pain control. Four weeks postoperatively, only desquamation remained where the nodules had previously appeared, which also eventually resolved.

Comment

Infants and small children are more predisposed to cold panniculitis than adults. In their 2008 review, Quesada-Cortés et al³ found the first report of cold panniculitis by Hochsinger in 1902 in a German pediatric journal, followed by reports from Lemez in 1928 and Haxthausen in 1941, which subsequently described similar cases in infants. Adult cases were not reported until 1963 by Solomon and Beerman⁴ and then in 1980 by Beacham et al.⁵

Etiologies for children have included popsicles, ice packs applied to the face to control supraventricular tachycardia or to the lower extremities after vaccinations, and cold weather exposure.⁶ The chemical composition of fat tissue plays a role in pediatric patients. According to Quesada-Cortés et al,³ subcutaneous fat in newborns is rich in saturated oils such as palmitic and stearic acids that have a higher solidification point. A small decrease in an infant’s temperature may result in crystallization of fat. The subcutaneous fat tends to become more unsaturated with aging with more oleic acid, and the solidification temperature diminishes.⁷

Cryoglobulins and cold agglutinins have not been demonstrated to be a cause of cold panniculitis in infants.⁷ Severe cold exposure or predisposition to certain conditions such as cryofibrinogenemia may occur in some adult patients. Gender does not seem to be a factor in children; however, in adults, women tend to be more predisposed to cold panniculitis secondary to obesity and participation in activities such as cycling, motorcycling, or horseback riding in cold conditions.³

On clinical examination, cold panniculitis features erythematous, firm, tender nodules on the cheeks and chin in infants and small children.² These areas often are exposed to cold weather or wind because they typically are not covered with protective clothing.³ Nodules generally occur 1 to 3 days following exposure to cold and usually resolve spontaneously within 2 weeks.⁸ Popsicle panniculitis is characterized by a reddish discoloration on both cheeks 1 or 2 days after sucking on popsicles or ice cubes. This reaction can be reproduced in a half day by applying an ice cube to the volar forearm for 2 minutes, which can help diagnose and differentiate this subset of cold panniuculits.³ The red area in cold panniculitis eventually turns purple, becomes less indurated, and fades in approximately 3 months, but occasionally residual hyperpigmentation will last for a few months. Ice packs used as treatment of congenital cardiac arrhythmias in some cardiac surgeries and as surface cooling for management of birth asphyxia can produce a similar physical presentation.³

Equestrian panniculitis is characterized by erythematous, violaceous, tender plaques on the upper lateral thighs of young females who participate in horseback riding in the winter while wearing tight-fitting pants.^2,5 These plaques typically occur within several hours and over the next week become painful, violaceous, and indurated or develop red nodules or plaques that can ulcerate or become crusted.³ These lesions usually will spontaneously resolve within 3 weeks, but new areas may occur again during the winter on further exposure with occasional persistent hyperpigmentation. These areas usually disappear at the end of winter with warmer weather or when horseback riding is discontinued. Perniosis also needs to be considered in the differential diagnosis due to the location and appearance of the lesions.³

It is important to obtain the correct specimen for biopsy. According to Peters and Su,¹ a deep excisional biopsy that includes multiple fat lobules in addition to dermis and epidermis is critical. On histology, cold panniculitis usually demonstrates a primarily lobular inflammation. There typically is a superficial and deep perivascular lymphocytic infiltrate in the papillary dermis with edema noted in the connective tissue around the eccrine glands that can appear similar to perniosis on histopathology.⁹ Deposition of mucin, focal panniculitis surrounded by fatty tissue without inflammatory changes within the same field, and fat necrosis with pseudocysts and numerous lipophages also are characteristic features of cold panniculitis.¹⁰ Needlelike clefts are not present in cold panniculitis but appear in subcutaneous fat necrosis of the newborn.¹

Different treatments have been tried, but no substantial impact on the rate of dissipation of the lesions has been noted. The plaques slowly resolve without scarring over 2 to 3 weeks if the cold source is removed.² Application of a heating pad to the affected area has been used with limited success. Vasodilators such as nifedipine have been used but have not been found to be effective.³ Antihistamines also have failed to control the lesions.¹¹

Treatment of cold panniculitis is based on the prevention of further insult versus trying to cure the condition. Avoidance of cold and wind exposure as well as direct contact with ice are key methods in preventing cold panniculitis.

Our patient’s presentation of this condition was unique. Although cold panniculitis lesions usually develop 1 to 3 days after cold exposure, our patient did not develop lesions until 10 days following surgery. The cold therapy unit used by our patient was evaluated in our office and also by the manufacturer and was found to be functioning normally with no defects. The late onset of the lesions was attributed to limited application of the cold therapy unit; our patient used it for only 1 hour every night, whereas application for 6 to 8 hours continuously is normally recommended. The lesions may have occurred sooner had the patient been using a solid ice pack versus the continuous cold circulating water of the cold therapy unit. Pathology was consistent with the patient’s history and physical examination indicating a diagnosis of cold panniculitis. The challenge of treatment was to alleviate the pain of the lesions as well as the postoperative shoulder pain without the aid of any form of cold therapy. The patient only needed a tincture of time, as the lesions resolved after 4 weeks. Patient education was provided on future prevention of this condition by avoiding exposure to cold or applying cold packs directly to the skin.

Acknowledgment

The authors thank the staff at the Office of Scientific Writing and Publication at the Marshfield Clinic Research Foundation, Wisconsin, for their editorial assistance in the preparation of this manuscript.