Case Reports

Case

A 32-year-old Hispanic man presented to the ED with complications associated with diabetes mellitus (DM), the symptoms of which started approximately 3 days prior to arrival. The patient reported feelings of fatigue, dry mouth, increased thirst, and frequent urination. He denied sweating, nausea, chest pain, shortness of breath, diarrhea, or blood in his urine; he also denied blurry vision or dizziness.

During history intake, the patient informed the emergency physician (EP) that he had been diagnosed with DM and hyperglycemia earlier that day by his primary care physician, who had immediately referred the patient to the ED for urgent management. The patient’s own medical history was noncontributory; however, his father’s history was notable for DM and chronic renal failure. The patient further stated that he was not on any medications. Regarding his social history, he denied cigarette smoking and noted only occasional alcohol consumption.

The patient’s vital signs on presentation were: blood pressure (BP), 116/74 mm Hg; heart rate, 113 beats/minute; respiratory rate, 26 breaths/minute; and temperature, 97.8°F. Oxygen saturation was 97% on room air. On physical examination, the patient was severely anxious, with tachycardia and respiratory distress. He was obese, with a body mass index of 30.9 kg/m² (height, 5 feet, 4 inches; weight, 180 lb).

The patient was started on an intravenous (IV) bolus of 0.9% normal saline (2 L at 20 mL/kg). After a consultation with endocrinology, he was then given a maintenance dose of normal saline IV at 250 cc/h and an IV insulin drip at 0.1 U/kg/h following a bolus of 8 units of insulin IV. His glucose levels were carefully monitored via hourly finger-stick glucose testing.

Although the patient’s condition stabilized, he collapsed while walking to the bathroom. He had agonal respirations and no pulse. Resuscitation efforts were started with bag-valve-mask ventilation, along with emergent advanced cardiac life support (ACLS) treatment, the protocol of which included epinephrine administration (x2) IV push 5 minutes apart, 2 ampules of sodium bicarbonate (50 mEq each) IV push, and calcium gluconate 10% (x1) 10 mL (1 g) IV push. A pulse was re-established, and the patient was intubated.

The patient was diagnosed with diabetic ketoacidosis (DKA) and admitted to the intensive care unit where repeat laboratory evaluation was ordered. Additional pharmacological management included IV administration of dopamine, norepinephrine, phenylephrine, vasopressin, antibiotics (azithromycin, meropenem, and vancomycin), pantoprazole, and subcutaneous heparin.

During treatment, the patient coded a second time and was revived according to ACLS protocols. Shortly thereafter, he coded a third time, but resuscitation efforts failed. Pathology reported no biological cause of death, and the coroner closed the case as death due to DM-related complications.

Diabetic Ketoacidosis

Diabetic ketoacidosis is a major complication of DM.⁴ Although the condition usually occurs in type 1 DM, it can also develop in type 2 DM. Diabetic ketoacidosis may be an inciting event leading to the eventual diagnosis of DM, but can also develop during a concurrent illness such as a urinary tract infection or an eating disorder.⁵ Risk factors for DKA include patients with type 1 or type 2 DM, a family history of DM, obesity, and nonwhite patients whose ethnic background places them at increased risk.⁶ Hispanic,  black, and African American patients are at a greater risk of developing DKA and are more likely to develop “ketosis-prone” type 2 DM.⁷

Patients who do not fit into the definitive categories of type 1 or 2 DM can be classified under ketosis-prone DM.^7,8 Diabetic ketoacidosis acts as the inciting event for the disease and evolves into severe β-cell dysfunction, hence blurring the lines between the archetypal DM categories. Fifty percent of ketosis-prone DM patients are A-β+ (absent autoantibodies, present β-cell function), which indicates that the dysfunction can be partially reversed. Reversal of the condition is largely based on long-term β-cell reserves, which are dependent on tight glycemic control and insulin dependence. Higher incidences of the A-β+ variant of ketosis-prone diabetes are seen in the male population and are often unprovoked.^9-11

Diabetic ketoacidosis is the result of either a decrease or absence of insulin in the body (Table 2).⁴ Without insulin modulating exogenous glucose intake and endogenous glucose production (via glucagon, glycogenolysis, and gluconeogenesis), high levels of glucose are found in the circulation, leading to prominent hyperglycemia (>250 mg/dL or >13.8 mmol/L).⁶ This environment causes the body to switch from carbohydrate metabolism to fatty acid metabolism. As a result, acidic ketone bodies such β-hydroxybutyrate and acetoacetate are produced. These physiological changes in the body cause the signs and symptoms typically found in DKA.

Signs and Symptoms

Over a period of 24 hours, symptoms such as nausea, vomiting, increased thirst, and polyuria develop due to dehydration caused by osmotic diuresis and glucosuria.⁵ Patients may also present with hypotension and tachycardia. Confusion, deep gasping breaths or Kussmaul respirations, and metabolic acidosis result from hyperventilation and failure to compensate for the increased serum concentration of ketone bodies. Ketone production leads to a fruit-like odor in the patient’s breath and ketonuria in the urinalysis. In DKA, laboratory values will indicate metabolic acidosis and abnormal serum electrolytes. In both DM and DKA, increased urea and creatinine due to dehydration, increased ketones, and the presence of diabetic nephropathy are useful indicators of impaired kidney function.¹²

Management and Treatment

Diabetic ketoacidosis can be managed and reversed, especially when recognized and treated early.^6,13 Dehydration in DKA can be corrected with IV fluid replacement. Normal saline (0.9%) can be started at 15 to 20 mL/kg/h or 1 L/h. As the patient’s vital signs stabilize, IV fluids can be titrated to a lower dose of 250 to 500 mL/h. Monitoring BP and electrolytes are key at this point as alterations in sodium levels and glucose levels may require switching to half-normal saline and/or dextrose.

The hyperglycemic state of patients with DKA is managed by IV insulin. An initial bolus of 0.1 U/kg/h can be given, but should only be administered when potassium levels are greater than 3.3 mmol/L.¹⁴ If adequate perfusion can be maintained, then 0.14 U/kg/h can be used instead of a bolus. Glucose levels must be monitored; once the levels decrease to approximately 200 mg/dL, the infusion rate of insulin should be titrated down to 0.05 to 0.1 U/kg/h. Dextrose is then added to maintain glucose levels at approximately 150 to 200 mg/dL.

Electrolytes, especially potassium, must be monitored closely in patients with DKA. Insulin leads to the shift of potassium into cells. The lack of insulin keeps potassium in the extracellular space. Due to osmotic diuresis, potassium is lost in the urine, leading to hypokalemia. Potassium levels in patients with DKA should be maintained at a level between 4 to 5 mmol/L. Patients with potassium levels between 3.3 to 5.2 mmol/L can be started on IV potassium between 20 to 30 mmol/h. If the patient is severely hypokalemic (<3.3 mmol/L), insulin should be withheld, and only IV potassium should be given at a rate of 20 to 30 mmol/h.

Bicarbonate levels can also be managed as acidosis can lead to both neurological and cardiac complications. If the patient’s pH is less than 6.9, the American Diabetes Association recommends starting 100 mmol of sodium bicarbonate in 400 mL sterile water (in addition to potassium chloride at 200 mL/h) for 2 hours. Dosing should be repeated every 2 hours until the patient’s pH is greater than 6.9.

In uncomplicated cases of DKA, the condition is resolved when a patient’s pH is greater than 7.3; glucose level is less than 200 mg/dL; and bicarbonate level is greater than or equal to 18 mmol/L. After patients become hemodynamically stable, they can be discharged and managed at home with a combination of intermediate- or long-acting insulin as well as short- or rapid-acting insulin.

Complications and Mortality

Diabetic ketoacidosis can cause sudden and fluctuating changes in the body. Therefore, it is very important to monitor a patient’s laboratory values very carefully and frequently to avoid any pitfalls. Since patients can present with hyponatremia due to the osmotic draw of glucose in the blood,¹³ sodium levels may have to be corrected. The corrected serum sodium can be calculated by adding 1.6 mmol/L for every 100 mg/dL of glucose (when finger-stick readings are above 200 mg/dL).¹⁵ Patients with DKA can also present with leukocytosis (even in the absence of infection) and hypertriglyceridemia (due to impaired lipoprotein lipase).¹⁵ Serum creatine may be elevated due to blood acetoacetate levels.¹⁵

Interestingly, there are other acute conditions that can mimic DKA.¹⁵ For example, chronic ethanol abuse can lead to ketoacidosis. Unlike DKA, however, alcoholic ketoacidosis does not have profound hyperglycemia, which can help differentiate the two during initial assessment.

Complications due to DKA can arise comprising the patient’s health, including hypoglycemia, hypokalemia, rhabdomyolysis, acute renal failure, pulmonary edema, and shock.¹⁶ Cerebral edema is seen in up to 1% of DKA patients,¹⁵ the cause of which may be due to the severity of the acidosis, high glucose levels, and rapid hydration. Even when cerebral edema is reduced, patients are often neurologically impaired. Mortality rates from DKA deaths due to cerebral edema can be as high as 24%.¹³ In the United States, over 100,000 patients with DM per year are admitted to the hospital for DKA, and 9% of patients with DM suffer from DKA-related complications postdischarge.¹⁵ With current treatment protocols, mortality rates for DKA-associated deaths are now down to 1%.^6,15

Diabetes ketoacidosis-related deaths are usually the result of the following: a triad of DKA symptoms (hyperglycemia, hyperketonemia, and metabolic acidosis),  another underlying comorbid condition (eg, myocardial infarction, sepsis, acute respiratory distress syndrome), or the release of biological markers (ie, catecholamines).^14,15,17 Thus, as previously stated, the management of potassium levels is important as both hyperkalemia and hypokalemia can lead to fatal arrthythmias.¹⁵

Direct mortality from DKA has dropped significantly over the past 20 years, from 8% to less than 1%.⁶ The US Centers for Disease Control and Prevention has observed a downward trend in death and estimates that 2,417 patients died in 2009 due to DKA,¹⁸ and recent postmortem studies have revealed new insights into DKA-related deaths.¹⁹ Blood and vitreous acetone concentrations are strong indicators for predeath hyperglycemia and ketosis (if there are no underlying comorbid and/or pharmacological provocations). Blood acetone levels greater than 0.01 g/dL antemortem are suggestive of DKA. It is recommended that these tests should be performed in sudden deaths which have no biological or anatomical cause of death. Postmortem diagnosis of DKA is made with the following criteria: history of DM, increased vitreous glucose concentrations, and elevated blood/vitreous/urine acetone concentrations (>200 mg/dL). If results of the abovementioned parameters are inconclusive, measurement of lactic acid postmortem is thought to further support a diagnosis of DKA.¹⁹

Patient Counseling and Education

Approximately 33% of patients whose death was associated with DKA had no personal  history of DM.¹⁹ This statistic emphasizes the importance of taking a thorough history, physical examination, blood glucose evaluation, and educating patients about the signs and symptoms of DM and DKA.

Patient counseling and education are important, especially in patients whose racial/ethnic background places them at increased risk of developing DM (eg, patients of black or African American, American Indian, Alaskan Native, Asian American, Hispanic, Native Hawaiian, or Pacific Islander descent).^20,21 Strategies for preventive management include advocating regular glucose monitoring as well as dietary and lifestyle modifications. In patients with DM, successful management of the condition and its comorbidities can help prevent DKA and associated mortality.

Conclusion

As this case demonstrates, despite prompt diagnosis and management, patients with DKA—especially those with uncontrolled, undiagnosed, or advanced DM—are associated with fatal outcomes. In many cases, however, DKA can be successfully managed and reversed, especially when the condition is recognized early. Management includes not only IV therapy to adjust fluid and insulin levels, but also restoring electrolyte balance (especially potassium and bicarbonate). Frequent and careful evaluation of laboratory values is vital to the successful treatment of DKA, as there are numerous pitfalls and complications that the emergency physician can encounter. Patients who either have or are at an increased risk of developing DM or DKA may benefit from preventive measures, including regular glucose monitoring and appropriate diet and lifestyle modifications.

Mr Hassan-Ali is a fourth-year medical student at Windsor University School of Medicine, St Kitts, West Indies. Dr Raziuddin is an internist and an emergency medicine physician at Weiss Memorial, Thorek Memorial, and Westlake Hospitals, Chicago, Illinois.

Case

A 32-year-old Hispanic man presented to the ED with complications associated with diabetes mellitus (DM), the symptoms of which started approximately 3 days prior to arrival. The patient reported feelings of fatigue, dry mouth, increased thirst, and frequent urination. He denied sweating, nausea, chest pain, shortness of breath, diarrhea, or blood in his urine; he also denied blurry vision or dizziness.

During history intake, the patient informed the emergency physician (EP) that he had been diagnosed with DM and hyperglycemia earlier that day by his primary care physician, who had immediately referred the patient to the ED for urgent management. The patient’s own medical history was noncontributory; however, his father’s history was notable for DM and chronic renal failure. The patient further stated that he was not on any medications. Regarding his social history, he denied cigarette smoking and noted only occasional alcohol consumption.

The patient’s vital signs on presentation were: blood pressure (BP), 116/74 mm Hg; heart rate, 113 beats/minute; respiratory rate, 26 breaths/minute; and temperature, 97.8°F. Oxygen saturation was 97% on room air. On physical examination, the patient was severely anxious, with tachycardia and respiratory distress. He was obese, with a body mass index of 30.9 kg/m² (height, 5 feet, 4 inches; weight, 180 lb).

The patient was started on an intravenous (IV) bolus of 0.9% normal saline (2 L at 20 mL/kg). After a consultation with endocrinology, he was then given a maintenance dose of normal saline IV at 250 cc/h and an IV insulin drip at 0.1 U/kg/h following a bolus of 8 units of insulin IV. His glucose levels were carefully monitored via hourly finger-stick glucose testing.

Although the patient’s condition stabilized, he collapsed while walking to the bathroom. He had agonal respirations and no pulse. Resuscitation efforts were started with bag-valve-mask ventilation, along with emergent advanced cardiac life support (ACLS) treatment, the protocol of which included epinephrine administration (x2) IV push 5 minutes apart, 2 ampules of sodium bicarbonate (50 mEq each) IV push, and calcium gluconate 10% (x1) 10 mL (1 g) IV push. A pulse was re-established, and the patient was intubated.

The patient was diagnosed with diabetic ketoacidosis (DKA) and admitted to the intensive care unit where repeat laboratory evaluation was ordered. Additional pharmacological management included IV administration of dopamine, norepinephrine, phenylephrine, vasopressin, antibiotics (azithromycin, meropenem, and vancomycin), pantoprazole, and subcutaneous heparin.

During treatment, the patient coded a second time and was revived according to ACLS protocols. Shortly thereafter, he coded a third time, but resuscitation efforts failed. Pathology reported no biological cause of death, and the coroner closed the case as death due to DM-related complications.

Diabetic Ketoacidosis

Diabetic ketoacidosis is a major complication of DM.⁴ Although the condition usually occurs in type 1 DM, it can also develop in type 2 DM. Diabetic ketoacidosis may be an inciting event leading to the eventual diagnosis of DM, but can also develop during a concurrent illness such as a urinary tract infection or an eating disorder.⁵ Risk factors for DKA include patients with type 1 or type 2 DM, a family history of DM, obesity, and nonwhite patients whose ethnic background places them at increased risk.⁶ Hispanic,  black, and African American patients are at a greater risk of developing DKA and are more likely to develop “ketosis-prone” type 2 DM.⁷

Patients who do not fit into the definitive categories of type 1 or 2 DM can be classified under ketosis-prone DM.^7,8 Diabetic ketoacidosis acts as the inciting event for the disease and evolves into severe β-cell dysfunction, hence blurring the lines between the archetypal DM categories. Fifty percent of ketosis-prone DM patients are A-β+ (absent autoantibodies, present β-cell function), which indicates that the dysfunction can be partially reversed. Reversal of the condition is largely based on long-term β-cell reserves, which are dependent on tight glycemic control and insulin dependence. Higher incidences of the A-β+ variant of ketosis-prone diabetes are seen in the male population and are often unprovoked.^9-11

Diabetic ketoacidosis is the result of either a decrease or absence of insulin in the body (Table 2).⁴ Without insulin modulating exogenous glucose intake and endogenous glucose production (via glucagon, glycogenolysis, and gluconeogenesis), high levels of glucose are found in the circulation, leading to prominent hyperglycemia (>250 mg/dL or >13.8 mmol/L).⁶ This environment causes the body to switch from carbohydrate metabolism to fatty acid metabolism. As a result, acidic ketone bodies such β-hydroxybutyrate and acetoacetate are produced. These physiological changes in the body cause the signs and symptoms typically found in DKA.

Signs and Symptoms

Over a period of 24 hours, symptoms such as nausea, vomiting, increased thirst, and polyuria develop due to dehydration caused by osmotic diuresis and glucosuria.⁵ Patients may also present with hypotension and tachycardia. Confusion, deep gasping breaths or Kussmaul respirations, and metabolic acidosis result from hyperventilation and failure to compensate for the increased serum concentration of ketone bodies. Ketone production leads to a fruit-like odor in the patient’s breath and ketonuria in the urinalysis. In DKA, laboratory values will indicate metabolic acidosis and abnormal serum electrolytes. In both DM and DKA, increased urea and creatinine due to dehydration, increased ketones, and the presence of diabetic nephropathy are useful indicators of impaired kidney function.¹²

Management and Treatment

Diabetic ketoacidosis can be managed and reversed, especially when recognized and treated early.^6,13 Dehydration in DKA can be corrected with IV fluid replacement. Normal saline (0.9%) can be started at 15 to 20 mL/kg/h or 1 L/h. As the patient’s vital signs stabilize, IV fluids can be titrated to a lower dose of 250 to 500 mL/h. Monitoring BP and electrolytes are key at this point as alterations in sodium levels and glucose levels may require switching to half-normal saline and/or dextrose.

The hyperglycemic state of patients with DKA is managed by IV insulin. An initial bolus of 0.1 U/kg/h can be given, but should only be administered when potassium levels are greater than 3.3 mmol/L.¹⁴ If adequate perfusion can be maintained, then 0.14 U/kg/h can be used instead of a bolus. Glucose levels must be monitored; once the levels decrease to approximately 200 mg/dL, the infusion rate of insulin should be titrated down to 0.05 to 0.1 U/kg/h. Dextrose is then added to maintain glucose levels at approximately 150 to 200 mg/dL.

Electrolytes, especially potassium, must be monitored closely in patients with DKA. Insulin leads to the shift of potassium into cells. The lack of insulin keeps potassium in the extracellular space. Due to osmotic diuresis, potassium is lost in the urine, leading to hypokalemia. Potassium levels in patients with DKA should be maintained at a level between 4 to 5 mmol/L. Patients with potassium levels between 3.3 to 5.2 mmol/L can be started on IV potassium between 20 to 30 mmol/h. If the patient is severely hypokalemic (<3.3 mmol/L), insulin should be withheld, and only IV potassium should be given at a rate of 20 to 30 mmol/h.

Bicarbonate levels can also be managed as acidosis can lead to both neurological and cardiac complications. If the patient’s pH is less than 6.9, the American Diabetes Association recommends starting 100 mmol of sodium bicarbonate in 400 mL sterile water (in addition to potassium chloride at 200 mL/h) for 2 hours. Dosing should be repeated every 2 hours until the patient’s pH is greater than 6.9.

In uncomplicated cases of DKA, the condition is resolved when a patient’s pH is greater than 7.3; glucose level is less than 200 mg/dL; and bicarbonate level is greater than or equal to 18 mmol/L. After patients become hemodynamically stable, they can be discharged and managed at home with a combination of intermediate- or long-acting insulin as well as short- or rapid-acting insulin.

Complications and Mortality

Diabetic ketoacidosis can cause sudden and fluctuating changes in the body. Therefore, it is very important to monitor a patient’s laboratory values very carefully and frequently to avoid any pitfalls. Since patients can present with hyponatremia due to the osmotic draw of glucose in the blood,¹³ sodium levels may have to be corrected. The corrected serum sodium can be calculated by adding 1.6 mmol/L for every 100 mg/dL of glucose (when finger-stick readings are above 200 mg/dL).¹⁵ Patients with DKA can also present with leukocytosis (even in the absence of infection) and hypertriglyceridemia (due to impaired lipoprotein lipase).¹⁵ Serum creatine may be elevated due to blood acetoacetate levels.¹⁵

Interestingly, there are other acute conditions that can mimic DKA.¹⁵ For example, chronic ethanol abuse can lead to ketoacidosis. Unlike DKA, however, alcoholic ketoacidosis does not have profound hyperglycemia, which can help differentiate the two during initial assessment.

Complications due to DKA can arise comprising the patient’s health, including hypoglycemia, hypokalemia, rhabdomyolysis, acute renal failure, pulmonary edema, and shock.¹⁶ Cerebral edema is seen in up to 1% of DKA patients,¹⁵ the cause of which may be due to the severity of the acidosis, high glucose levels, and rapid hydration. Even when cerebral edema is reduced, patients are often neurologically impaired. Mortality rates from DKA deaths due to cerebral edema can be as high as 24%.¹³ In the United States, over 100,000 patients with DM per year are admitted to the hospital for DKA, and 9% of patients with DM suffer from DKA-related complications postdischarge.¹⁵ With current treatment protocols, mortality rates for DKA-associated deaths are now down to 1%.^6,15

Diabetes ketoacidosis-related deaths are usually the result of the following: a triad of DKA symptoms (hyperglycemia, hyperketonemia, and metabolic acidosis),  another underlying comorbid condition (eg, myocardial infarction, sepsis, acute respiratory distress syndrome), or the release of biological markers (ie, catecholamines).^14,15,17 Thus, as previously stated, the management of potassium levels is important as both hyperkalemia and hypokalemia can lead to fatal arrthythmias.¹⁵

Direct mortality from DKA has dropped significantly over the past 20 years, from 8% to less than 1%.⁶ The US Centers for Disease Control and Prevention has observed a downward trend in death and estimates that 2,417 patients died in 2009 due to DKA,¹⁸ and recent postmortem studies have revealed new insights into DKA-related deaths.¹⁹ Blood and vitreous acetone concentrations are strong indicators for predeath hyperglycemia and ketosis (if there are no underlying comorbid and/or pharmacological provocations). Blood acetone levels greater than 0.01 g/dL antemortem are suggestive of DKA. It is recommended that these tests should be performed in sudden deaths which have no biological or anatomical cause of death. Postmortem diagnosis of DKA is made with the following criteria: history of DM, increased vitreous glucose concentrations, and elevated blood/vitreous/urine acetone concentrations (>200 mg/dL). If results of the abovementioned parameters are inconclusive, measurement of lactic acid postmortem is thought to further support a diagnosis of DKA.¹⁹

Patient Counseling and Education

Approximately 33% of patients whose death was associated with DKA had no personal  history of DM.¹⁹ This statistic emphasizes the importance of taking a thorough history, physical examination, blood glucose evaluation, and educating patients about the signs and symptoms of DM and DKA.

Patient counseling and education are important, especially in patients whose racial/ethnic background places them at increased risk of developing DM (eg, patients of black or African American, American Indian, Alaskan Native, Asian American, Hispanic, Native Hawaiian, or Pacific Islander descent).^20,21 Strategies for preventive management include advocating regular glucose monitoring as well as dietary and lifestyle modifications. In patients with DM, successful management of the condition and its comorbidities can help prevent DKA and associated mortality.

Conclusion

As this case demonstrates, despite prompt diagnosis and management, patients with DKA—especially those with uncontrolled, undiagnosed, or advanced DM—are associated with fatal outcomes. In many cases, however, DKA can be successfully managed and reversed, especially when the condition is recognized early. Management includes not only IV therapy to adjust fluid and insulin levels, but also restoring electrolyte balance (especially potassium and bicarbonate). Frequent and careful evaluation of laboratory values is vital to the successful treatment of DKA, as there are numerous pitfalls and complications that the emergency physician can encounter. Patients who either have or are at an increased risk of developing DM or DKA may benefit from preventive measures, including regular glucose monitoring and appropriate diet and lifestyle modifications.

Mr Hassan-Ali is a fourth-year medical student at Windsor University School of Medicine, St Kitts, West Indies. Dr Raziuddin is an internist and an emergency medicine physician at Weiss Memorial, Thorek Memorial, and Westlake Hospitals, Chicago, Illinois.

Case

A 32-year-old Hispanic man presented to the ED with complications associated with diabetes mellitus (DM), the symptoms of which started approximately 3 days prior to arrival. The patient reported feelings of fatigue, dry mouth, increased thirst, and frequent urination. He denied sweating, nausea, chest pain, shortness of breath, diarrhea, or blood in his urine; he also denied blurry vision or dizziness.

During history intake, the patient informed the emergency physician (EP) that he had been diagnosed with DM and hyperglycemia earlier that day by his primary care physician, who had immediately referred the patient to the ED for urgent management. The patient’s own medical history was noncontributory; however, his father’s history was notable for DM and chronic renal failure. The patient further stated that he was not on any medications. Regarding his social history, he denied cigarette smoking and noted only occasional alcohol consumption.

The patient’s vital signs on presentation were: blood pressure (BP), 116/74 mm Hg; heart rate, 113 beats/minute; respiratory rate, 26 breaths/minute; and temperature, 97.8°F. Oxygen saturation was 97% on room air. On physical examination, the patient was severely anxious, with tachycardia and respiratory distress. He was obese, with a body mass index of 30.9 kg/m² (height, 5 feet, 4 inches; weight, 180 lb).

The patient was started on an intravenous (IV) bolus of 0.9% normal saline (2 L at 20 mL/kg). After a consultation with endocrinology, he was then given a maintenance dose of normal saline IV at 250 cc/h and an IV insulin drip at 0.1 U/kg/h following a bolus of 8 units of insulin IV. His glucose levels were carefully monitored via hourly finger-stick glucose testing.

Although the patient’s condition stabilized, he collapsed while walking to the bathroom. He had agonal respirations and no pulse. Resuscitation efforts were started with bag-valve-mask ventilation, along with emergent advanced cardiac life support (ACLS) treatment, the protocol of which included epinephrine administration (x2) IV push 5 minutes apart, 2 ampules of sodium bicarbonate (50 mEq each) IV push, and calcium gluconate 10% (x1) 10 mL (1 g) IV push. A pulse was re-established, and the patient was intubated.

The patient was diagnosed with diabetic ketoacidosis (DKA) and admitted to the intensive care unit where repeat laboratory evaluation was ordered. Additional pharmacological management included IV administration of dopamine, norepinephrine, phenylephrine, vasopressin, antibiotics (azithromycin, meropenem, and vancomycin), pantoprazole, and subcutaneous heparin.

During treatment, the patient coded a second time and was revived according to ACLS protocols. Shortly thereafter, he coded a third time, but resuscitation efforts failed. Pathology reported no biological cause of death, and the coroner closed the case as death due to DM-related complications.

Diabetic Ketoacidosis

Diabetic ketoacidosis is a major complication of DM.⁴ Although the condition usually occurs in type 1 DM, it can also develop in type 2 DM. Diabetic ketoacidosis may be an inciting event leading to the eventual diagnosis of DM, but can also develop during a concurrent illness such as a urinary tract infection or an eating disorder.⁵ Risk factors for DKA include patients with type 1 or type 2 DM, a family history of DM, obesity, and nonwhite patients whose ethnic background places them at increased risk.⁶ Hispanic,  black, and African American patients are at a greater risk of developing DKA and are more likely to develop “ketosis-prone” type 2 DM.⁷

Patients who do not fit into the definitive categories of type 1 or 2 DM can be classified under ketosis-prone DM.^7,8 Diabetic ketoacidosis acts as the inciting event for the disease and evolves into severe β-cell dysfunction, hence blurring the lines between the archetypal DM categories. Fifty percent of ketosis-prone DM patients are A-β+ (absent autoantibodies, present β-cell function), which indicates that the dysfunction can be partially reversed. Reversal of the condition is largely based on long-term β-cell reserves, which are dependent on tight glycemic control and insulin dependence. Higher incidences of the A-β+ variant of ketosis-prone diabetes are seen in the male population and are often unprovoked.^9-11

Diabetic ketoacidosis is the result of either a decrease or absence of insulin in the body (Table 2).⁴ Without insulin modulating exogenous glucose intake and endogenous glucose production (via glucagon, glycogenolysis, and gluconeogenesis), high levels of glucose are found in the circulation, leading to prominent hyperglycemia (>250 mg/dL or >13.8 mmol/L).⁶ This environment causes the body to switch from carbohydrate metabolism to fatty acid metabolism. As a result, acidic ketone bodies such β-hydroxybutyrate and acetoacetate are produced. These physiological changes in the body cause the signs and symptoms typically found in DKA.

Signs and Symptoms

Over a period of 24 hours, symptoms such as nausea, vomiting, increased thirst, and polyuria develop due to dehydration caused by osmotic diuresis and glucosuria.⁵ Patients may also present with hypotension and tachycardia. Confusion, deep gasping breaths or Kussmaul respirations, and metabolic acidosis result from hyperventilation and failure to compensate for the increased serum concentration of ketone bodies. Ketone production leads to a fruit-like odor in the patient’s breath and ketonuria in the urinalysis. In DKA, laboratory values will indicate metabolic acidosis and abnormal serum electrolytes. In both DM and DKA, increased urea and creatinine due to dehydration, increased ketones, and the presence of diabetic nephropathy are useful indicators of impaired kidney function.¹²

Management and Treatment

Diabetic ketoacidosis can be managed and reversed, especially when recognized and treated early.^6,13 Dehydration in DKA can be corrected with IV fluid replacement. Normal saline (0.9%) can be started at 15 to 20 mL/kg/h or 1 L/h. As the patient’s vital signs stabilize, IV fluids can be titrated to a lower dose of 250 to 500 mL/h. Monitoring BP and electrolytes are key at this point as alterations in sodium levels and glucose levels may require switching to half-normal saline and/or dextrose.

The hyperglycemic state of patients with DKA is managed by IV insulin. An initial bolus of 0.1 U/kg/h can be given, but should only be administered when potassium levels are greater than 3.3 mmol/L.¹⁴ If adequate perfusion can be maintained, then 0.14 U/kg/h can be used instead of a bolus. Glucose levels must be monitored; once the levels decrease to approximately 200 mg/dL, the infusion rate of insulin should be titrated down to 0.05 to 0.1 U/kg/h. Dextrose is then added to maintain glucose levels at approximately 150 to 200 mg/dL.

Electrolytes, especially potassium, must be monitored closely in patients with DKA. Insulin leads to the shift of potassium into cells. The lack of insulin keeps potassium in the extracellular space. Due to osmotic diuresis, potassium is lost in the urine, leading to hypokalemia. Potassium levels in patients with DKA should be maintained at a level between 4 to 5 mmol/L. Patients with potassium levels between 3.3 to 5.2 mmol/L can be started on IV potassium between 20 to 30 mmol/h. If the patient is severely hypokalemic (<3.3 mmol/L), insulin should be withheld, and only IV potassium should be given at a rate of 20 to 30 mmol/h.

Bicarbonate levels can also be managed as acidosis can lead to both neurological and cardiac complications. If the patient’s pH is less than 6.9, the American Diabetes Association recommends starting 100 mmol of sodium bicarbonate in 400 mL sterile water (in addition to potassium chloride at 200 mL/h) for 2 hours. Dosing should be repeated every 2 hours until the patient’s pH is greater than 6.9.

In uncomplicated cases of DKA, the condition is resolved when a patient’s pH is greater than 7.3; glucose level is less than 200 mg/dL; and bicarbonate level is greater than or equal to 18 mmol/L. After patients become hemodynamically stable, they can be discharged and managed at home with a combination of intermediate- or long-acting insulin as well as short- or rapid-acting insulin.

Complications and Mortality

Diabetic ketoacidosis can cause sudden and fluctuating changes in the body. Therefore, it is very important to monitor a patient’s laboratory values very carefully and frequently to avoid any pitfalls. Since patients can present with hyponatremia due to the osmotic draw of glucose in the blood,¹³ sodium levels may have to be corrected. The corrected serum sodium can be calculated by adding 1.6 mmol/L for every 100 mg/dL of glucose (when finger-stick readings are above 200 mg/dL).¹⁵ Patients with DKA can also present with leukocytosis (even in the absence of infection) and hypertriglyceridemia (due to impaired lipoprotein lipase).¹⁵ Serum creatine may be elevated due to blood acetoacetate levels.¹⁵

Interestingly, there are other acute conditions that can mimic DKA.¹⁵ For example, chronic ethanol abuse can lead to ketoacidosis. Unlike DKA, however, alcoholic ketoacidosis does not have profound hyperglycemia, which can help differentiate the two during initial assessment.

Complications due to DKA can arise comprising the patient’s health, including hypoglycemia, hypokalemia, rhabdomyolysis, acute renal failure, pulmonary edema, and shock.¹⁶ Cerebral edema is seen in up to 1% of DKA patients,¹⁵ the cause of which may be due to the severity of the acidosis, high glucose levels, and rapid hydration. Even when cerebral edema is reduced, patients are often neurologically impaired. Mortality rates from DKA deaths due to cerebral edema can be as high as 24%.¹³ In the United States, over 100,000 patients with DM per year are admitted to the hospital for DKA, and 9% of patients with DM suffer from DKA-related complications postdischarge.¹⁵ With current treatment protocols, mortality rates for DKA-associated deaths are now down to 1%.^6,15

Diabetes ketoacidosis-related deaths are usually the result of the following: a triad of DKA symptoms (hyperglycemia, hyperketonemia, and metabolic acidosis),  another underlying comorbid condition (eg, myocardial infarction, sepsis, acute respiratory distress syndrome), or the release of biological markers (ie, catecholamines).^14,15,17 Thus, as previously stated, the management of potassium levels is important as both hyperkalemia and hypokalemia can lead to fatal arrthythmias.¹⁵

Direct mortality from DKA has dropped significantly over the past 20 years, from 8% to less than 1%.⁶ The US Centers for Disease Control and Prevention has observed a downward trend in death and estimates that 2,417 patients died in 2009 due to DKA,¹⁸ and recent postmortem studies have revealed new insights into DKA-related deaths.¹⁹ Blood and vitreous acetone concentrations are strong indicators for predeath hyperglycemia and ketosis (if there are no underlying comorbid and/or pharmacological provocations). Blood acetone levels greater than 0.01 g/dL antemortem are suggestive of DKA. It is recommended that these tests should be performed in sudden deaths which have no biological or anatomical cause of death. Postmortem diagnosis of DKA is made with the following criteria: history of DM, increased vitreous glucose concentrations, and elevated blood/vitreous/urine acetone concentrations (>200 mg/dL). If results of the abovementioned parameters are inconclusive, measurement of lactic acid postmortem is thought to further support a diagnosis of DKA.¹⁹

Patient Counseling and Education

Approximately 33% of patients whose death was associated with DKA had no personal  history of DM.¹⁹ This statistic emphasizes the importance of taking a thorough history, physical examination, blood glucose evaluation, and educating patients about the signs and symptoms of DM and DKA.

Patient counseling and education are important, especially in patients whose racial/ethnic background places them at increased risk of developing DM (eg, patients of black or African American, American Indian, Alaskan Native, Asian American, Hispanic, Native Hawaiian, or Pacific Islander descent).^20,21 Strategies for preventive management include advocating regular glucose monitoring as well as dietary and lifestyle modifications. In patients with DM, successful management of the condition and its comorbidities can help prevent DKA and associated mortality.

Conclusion

As this case demonstrates, despite prompt diagnosis and management, patients with DKA—especially those with uncontrolled, undiagnosed, or advanced DM—are associated with fatal outcomes. In many cases, however, DKA can be successfully managed and reversed, especially when the condition is recognized early. Management includes not only IV therapy to adjust fluid and insulin levels, but also restoring electrolyte balance (especially potassium and bicarbonate). Frequent and careful evaluation of laboratory values is vital to the successful treatment of DKA, as there are numerous pitfalls and complications that the emergency physician can encounter. Patients who either have or are at an increased risk of developing DM or DKA may benefit from preventive measures, including regular glucose monitoring and appropriate diet and lifestyle modifications.

Mr Hassan-Ali is a fourth-year medical student at Windsor University School of Medicine, St Kitts, West Indies. Dr Raziuddin is an internist and an emergency medicine physician at Weiss Memorial, Thorek Memorial, and Westlake Hospitals, Chicago, Illinois.

Case Report

A 54-year-old Hispanic woman with a history of type 2 diabetes mellitus and hyperlipidemia presented with recurrent painful plaques and nodules on the bilateral lower extremities and a severe burning sensation on the feet of 3 years’ duration. The patient denied experiencing any associated fevers, chills, night sweats, weight loss, joint aches, cough, or shortness of breath. She had a history of pustular psoriasis and reported a positive purified protein derivative (PPD)(tuberculin) skin test approximately 40 years prior.

She presented with a 4×4-cm, poorly defined, tender, indurated plaque on the middle of the left shin and a 2×3-cm, red-brown plaque on the dorsal aspect of the left foot (Figure 1). No lymphadenopathy or any other abnormalities were noted. The clinical differential diagnosis included various panniculitides, such as erythema nodosum, erythema induratum of Bazin (EIB), and lupus panniculitis, as well as other conditions, including polyarteritis nodosa, sarcoidosis, Sweet disease, deep fungal and mycobacterial infections, and cutaneous lymphoma.

Figure 1. Erythematous indurated plaques on the middle of the left shin (A) and on the dorsal aspect of the left foot (B).

Two skin biopsies taken for histopathologic evaluation revealed primarily granulomatous lobular panniculitis with foci of microthrombi and vasculitis (Figure 2). These findings were consistent with nodular vasculitis. Acid-fast bacillus and Gomori methenamine-silver stains were negative for mycobacterial or fungal organisms. Tissue cultures also were negative. Results from a complete blood cell count, chemistry panel, thyroid and liver function tests, hepatitis panel, and rapid plasma reagin test were unremarkable. Immunologic markers, including antinuclear antibody, antineutrophil cytoplasmic antibody, rheumatoid factor, and cryoglobulins, also revealed no abnormalities. A chest radiograph showed scarring in the suprahilar region of the upper lobe of the left lung consistent with a prior case of pulmonary tuberculosis, and exposure to Mycobacterium tuberculosis was confirmed with an IFN-γ release assay (IGRA) result of 1.49 IU/mL (>0.34 IU/mL indicates positive test). These findings from clinical and histopathologic examination as well as laboratory tests were consistent with a diagnosis of EIB.

Figure 2. Granulomatous lobular panniculitis (A)(H&E, original magnification ×40) with foci of microthrombi and vasculitis (B and C)(both H&E, original magnifications ×200).

Standard antituberculosis therapy with rifampin, isoniazid, pyrazinamide, and ethambutol (RIPE) was simplified to rifampin and isoniazid due to her inability to tolerate the full regimen because of gastrointestinal tract upset and diarrhea. After 6 months of therapy, a repeat IGRA decreased to 0.43 IU/mL, and the painful plaques and nodules on the lower extremities and burning sensation in the feet completely resolved.

Comment

Our case of EIB associated with peripheral neuropathy is a unique presentation of lesions on the pretibial area of the bilateral legs and dorsal aspect of the feet. We confirmed the presence of latent tuberculosis infection with a chest radiograph and an IGRA. Symptoms of peripheral neuropathy resolved after antituberculosis treatment, which suggests an immune-mediated mechanism of neuronal damage from circulating tuberculosis antigens.

Pathogenesis

Although erythema induratum was first described by Ernest Bazin in 1861, it was not until the early 1900s that the link between tuberculosis and erythema induratum was made by French dermatologists.^1,2 Around the same time, similar cases of erythema induratum were discovered in England with no evidence of tuberculosis, which led to the distinct classification of erythema induratum of Whitfield (EIW). This classification described these nontuberculoid cases.^1,2 In 1945, Montgomery et al³ in the United States coined the term nodular vasculitis for EIW and categorized its clinical features and histopathology as separate from EIB.³ Today, some authors use EIB, EIW, and nodular vasculitis interchangeably and believe they all are the same entity.² We use EIB for all cases related to tuberculosis and nodular vasulitis when referring to all other etiologies, including nontuberculoid bacterial infections, chronic hepatitis B and C virus, thrombophlebitis, hypothyroidism, and rheumatoid arthritis.^4,5

Erythema induratum of Bazin, lichen scrofulosorum, and papulonecrotic tuberculids are considered tuberculid diseases and are thought to be caused by hypersensitivity reactions to mycobacterial antigens rather than local mycobacterial infections. Tuberculids are believed to be a reaction to an id reaction of circulating mycobacterial antigens in the setting of latent or active tuberculosis infection. The basis for this view is that mycobacteria cannot be cultured or visualized from lesions in tuberculid diseases.⁶ Cutaneous tuberculosis, such as scrofuloderma, miliary tuberculosis, tuberculosis chancre, lupus vulgaris, and gummatous tuberculosis, differ from EIB and other tuberculid diseases in that mycobacteria can be cultured and visualized on histologic examination with Ziehl-Neelsen staining.⁶ The pathology of cutaneous tuberculosis results from a mycobacterial infection of the skin, and cutaneous tuberculosis diseases are categorized as multibacillary or paucibacillary based on the number of organisms visualized in biopsies.

The absence of M tuberculosis organisms in skin lesions has led some to doubt the causal relationship between M tuberculosis and EIB.⁷ However, the advent of polymerase chain reaction (PCR) and specific DNA primers for M tuberculosis has allowed for the detection of M tuberculosis DNA in biopsy specimens, which has further established the relationship between tuberculosis and EIB.⁵ Some authors have suggested that the absence of mycobacteria in EIB and other tuberculid lesions may be due to small numbers of bacilli in the lesions or early destruction of mycobacteria organisms before biopsy.^8,9 These authors consider cutaneous tuberculosis and tuberculids as diseases on the same spectrum, with tuberculids representing one extreme in which there are few mycobacteria organisms present in the lesions.

Presentation

Erythema induratum commonly affects middle-aged women and presents with recurrent crops of tender nodules on the lower extremities.^10-13 Nodules often are most commonly found on the lower calves but also can present on the arms, thighs, feet, or buttocks.¹⁰ Our patient’s presentation was atypical in that lesions were distributed on the pretibial area of the legs and dorsal aspect of the feet. Obesity and venous insufficiency of the lower extremities are believed to be predisposing factors to the development of EIB nodules.² The nodules develop over several weeks and heal over several months with possible ulceration and hyperpigmented scarring.^10,11 Ulcerated nodules often are irregular and shallow with an overlying crust and a bluish border.^11,13 Nodules often are precipitated by cold weather or venostasis.^1,11,12

Silva et al¹⁴ reported a case of EIB on the lower legs associated with a burning sensation on the feet and paresthesia; all known causes of peripheral neuropathy were excluded by a comprehensive laboratory workup. The burning sensation on the feet resolved after several weeks of antituberculosis therapy. Our patient also presented with a burning sensation on the feet that remarkably improved after 6 months of antituberculosis therapy. Peripheral neuropathy could have been a consequence of diabetes mellitus in our patient, though neuronal damage also could be a consequence of hypersensitivity to tuberculosis antigens. Silva et al¹⁴ proposed that macrophages activated by M tuberculosis antigens produce lytic enzymes that can cause tissue necrosis and nerve damage if released into surrounding tissue.

Diagnosis

The diagnosis of EIB is made based on clinical presentation, evidence of prior or current tuberculosis infection, histopathologic findings, and response to antituberculosis therapy.¹⁵ Evidence of active or latent tuberculosis infection typically is gathered by patient history, chest radiograph, tuberculin skin tests, interferon-releasing assays, and PCR of skin biopsies. Tuberculin skin tests in patients with EIB result in reactive induration that is typically more than 20 mm.⁸ In vitro T-lymphocyte proliferation assays in response to PPD have further supported the suggestion that there is a markedly enhanced T-lymphocyte response to M tuberculosis antigens in patients with EIB.¹⁶

IFN-γ release assays have provided useful methods for the detection of latent tuberculosis infection.¹⁷ The IGRA is effective when the tuberculin skin test yields a suspected false-negative or in the context of prior bacille Calmette-Guérin vaccination.¹⁷ IFN-γ release assays also may be preferred to tuberculin skin tests because it provides less discomfort to the patient in the event of a positive hypersensitive reaction to the PPD.

Before the advent of IGRAs, PCR was used to detect M tuberculosis DNA in skin biopsies and to confirm the diagnosis of EIB. Some researchers believe PCR can be an important tool for confirming a diagnosis of EIB, especially in cases and countries where results from the Mantoux test do not have great value.^15,18 A PCR assay for detecting 
M tuberculosis DNA in blood and urine samples also was found helpful in confirming a diagnosis of EIB when skin biopsies were unavailable.^8,19 However, PCR has been shown to have low sensitivity for the diagnosis of EIB because of its ability to detect M tuberculosis DNA ranging from 
0% to 77% of skin biopsy specimens.^20,21 Therefore, a negative PCR for the detection of M tuberculosis DNA in nodules does not exclude a diagnosis of erythema induratum.

Treatment

The mainstay of EIB treatment is a multidrug antituberculosis regimen.^5,8,10-12 Our patient was successfully treated with rifampin and isoniazid and a repeat IGRA was used as a laboratory marker of response to therapy. Single-drug therapy with isoniazid has been shown to result in greater likelihood of EIB relapse in comparison to multidrug regimens.²² Other treatments include potassium iodide and gold, but they are not well-studied.^23-25 Treatment of venous insufficiency with bed rest and nonsteroidal anti-inflammatory drugs for pain also may be helpful.² In cases of nodular vasulitis that are not associated with tuberculosis infection, treatment should be targeted at the underlying cause of the immune response. For example, a case of nodular vasculitis associated with hepatitis C virus did not respond to antituberculosis multidrug therapy, but skin lesions did improve with pegylated interferon and ribavirin.⁴

Case Report

A 54-year-old Hispanic woman with a history of type 2 diabetes mellitus and hyperlipidemia presented with recurrent painful plaques and nodules on the bilateral lower extremities and a severe burning sensation on the feet of 3 years’ duration. The patient denied experiencing any associated fevers, chills, night sweats, weight loss, joint aches, cough, or shortness of breath. She had a history of pustular psoriasis and reported a positive purified protein derivative (PPD)(tuberculin) skin test approximately 40 years prior.

She presented with a 4×4-cm, poorly defined, tender, indurated plaque on the middle of the left shin and a 2×3-cm, red-brown plaque on the dorsal aspect of the left foot (Figure 1). No lymphadenopathy or any other abnormalities were noted. The clinical differential diagnosis included various panniculitides, such as erythema nodosum, erythema induratum of Bazin (EIB), and lupus panniculitis, as well as other conditions, including polyarteritis nodosa, sarcoidosis, Sweet disease, deep fungal and mycobacterial infections, and cutaneous lymphoma.

Figure 1. Erythematous indurated plaques on the middle of the left shin (A) and on the dorsal aspect of the left foot (B).

Two skin biopsies taken for histopathologic evaluation revealed primarily granulomatous lobular panniculitis with foci of microthrombi and vasculitis (Figure 2). These findings were consistent with nodular vasculitis. Acid-fast bacillus and Gomori methenamine-silver stains were negative for mycobacterial or fungal organisms. Tissue cultures also were negative. Results from a complete blood cell count, chemistry panel, thyroid and liver function tests, hepatitis panel, and rapid plasma reagin test were unremarkable. Immunologic markers, including antinuclear antibody, antineutrophil cytoplasmic antibody, rheumatoid factor, and cryoglobulins, also revealed no abnormalities. A chest radiograph showed scarring in the suprahilar region of the upper lobe of the left lung consistent with a prior case of pulmonary tuberculosis, and exposure to Mycobacterium tuberculosis was confirmed with an IFN-γ release assay (IGRA) result of 1.49 IU/mL (>0.34 IU/mL indicates positive test). These findings from clinical and histopathologic examination as well as laboratory tests were consistent with a diagnosis of EIB.

Figure 2. Granulomatous lobular panniculitis (A)(H&E, original magnification ×40) with foci of microthrombi and vasculitis (B and C)(both H&E, original magnifications ×200).

Standard antituberculosis therapy with rifampin, isoniazid, pyrazinamide, and ethambutol (RIPE) was simplified to rifampin and isoniazid due to her inability to tolerate the full regimen because of gastrointestinal tract upset and diarrhea. After 6 months of therapy, a repeat IGRA decreased to 0.43 IU/mL, and the painful plaques and nodules on the lower extremities and burning sensation in the feet completely resolved.

Comment

Our case of EIB associated with peripheral neuropathy is a unique presentation of lesions on the pretibial area of the bilateral legs and dorsal aspect of the feet. We confirmed the presence of latent tuberculosis infection with a chest radiograph and an IGRA. Symptoms of peripheral neuropathy resolved after antituberculosis treatment, which suggests an immune-mediated mechanism of neuronal damage from circulating tuberculosis antigens.

Pathogenesis

Although erythema induratum was first described by Ernest Bazin in 1861, it was not until the early 1900s that the link between tuberculosis and erythema induratum was made by French dermatologists.^1,2 Around the same time, similar cases of erythema induratum were discovered in England with no evidence of tuberculosis, which led to the distinct classification of erythema induratum of Whitfield (EIW). This classification described these nontuberculoid cases.^1,2 In 1945, Montgomery et al³ in the United States coined the term nodular vasculitis for EIW and categorized its clinical features and histopathology as separate from EIB.³ Today, some authors use EIB, EIW, and nodular vasculitis interchangeably and believe they all are the same entity.² We use EIB for all cases related to tuberculosis and nodular vasulitis when referring to all other etiologies, including nontuberculoid bacterial infections, chronic hepatitis B and C virus, thrombophlebitis, hypothyroidism, and rheumatoid arthritis.^4,5

Erythema induratum of Bazin, lichen scrofulosorum, and papulonecrotic tuberculids are considered tuberculid diseases and are thought to be caused by hypersensitivity reactions to mycobacterial antigens rather than local mycobacterial infections. Tuberculids are believed to be a reaction to an id reaction of circulating mycobacterial antigens in the setting of latent or active tuberculosis infection. The basis for this view is that mycobacteria cannot be cultured or visualized from lesions in tuberculid diseases.⁶ Cutaneous tuberculosis, such as scrofuloderma, miliary tuberculosis, tuberculosis chancre, lupus vulgaris, and gummatous tuberculosis, differ from EIB and other tuberculid diseases in that mycobacteria can be cultured and visualized on histologic examination with Ziehl-Neelsen staining.⁶ The pathology of cutaneous tuberculosis results from a mycobacterial infection of the skin, and cutaneous tuberculosis diseases are categorized as multibacillary or paucibacillary based on the number of organisms visualized in biopsies.

The absence of M tuberculosis organisms in skin lesions has led some to doubt the causal relationship between M tuberculosis and EIB.⁷ However, the advent of polymerase chain reaction (PCR) and specific DNA primers for M tuberculosis has allowed for the detection of M tuberculosis DNA in biopsy specimens, which has further established the relationship between tuberculosis and EIB.⁵ Some authors have suggested that the absence of mycobacteria in EIB and other tuberculid lesions may be due to small numbers of bacilli in the lesions or early destruction of mycobacteria organisms before biopsy.^8,9 These authors consider cutaneous tuberculosis and tuberculids as diseases on the same spectrum, with tuberculids representing one extreme in which there are few mycobacteria organisms present in the lesions.

Presentation

Erythema induratum commonly affects middle-aged women and presents with recurrent crops of tender nodules on the lower extremities.^10-13 Nodules often are most commonly found on the lower calves but also can present on the arms, thighs, feet, or buttocks.¹⁰ Our patient’s presentation was atypical in that lesions were distributed on the pretibial area of the legs and dorsal aspect of the feet. Obesity and venous insufficiency of the lower extremities are believed to be predisposing factors to the development of EIB nodules.² The nodules develop over several weeks and heal over several months with possible ulceration and hyperpigmented scarring.^10,11 Ulcerated nodules often are irregular and shallow with an overlying crust and a bluish border.^11,13 Nodules often are precipitated by cold weather or venostasis.^1,11,12

Silva et al¹⁴ reported a case of EIB on the lower legs associated with a burning sensation on the feet and paresthesia; all known causes of peripheral neuropathy were excluded by a comprehensive laboratory workup. The burning sensation on the feet resolved after several weeks of antituberculosis therapy. Our patient also presented with a burning sensation on the feet that remarkably improved after 6 months of antituberculosis therapy. Peripheral neuropathy could have been a consequence of diabetes mellitus in our patient, though neuronal damage also could be a consequence of hypersensitivity to tuberculosis antigens. Silva et al¹⁴ proposed that macrophages activated by M tuberculosis antigens produce lytic enzymes that can cause tissue necrosis and nerve damage if released into surrounding tissue.

Diagnosis

The diagnosis of EIB is made based on clinical presentation, evidence of prior or current tuberculosis infection, histopathologic findings, and response to antituberculosis therapy.¹⁵ Evidence of active or latent tuberculosis infection typically is gathered by patient history, chest radiograph, tuberculin skin tests, interferon-releasing assays, and PCR of skin biopsies. Tuberculin skin tests in patients with EIB result in reactive induration that is typically more than 20 mm.⁸ In vitro T-lymphocyte proliferation assays in response to PPD have further supported the suggestion that there is a markedly enhanced T-lymphocyte response to M tuberculosis antigens in patients with EIB.¹⁶

IFN-γ release assays have provided useful methods for the detection of latent tuberculosis infection.¹⁷ The IGRA is effective when the tuberculin skin test yields a suspected false-negative or in the context of prior bacille Calmette-Guérin vaccination.¹⁷ IFN-γ release assays also may be preferred to tuberculin skin tests because it provides less discomfort to the patient in the event of a positive hypersensitive reaction to the PPD.

Before the advent of IGRAs, PCR was used to detect M tuberculosis DNA in skin biopsies and to confirm the diagnosis of EIB. Some researchers believe PCR can be an important tool for confirming a diagnosis of EIB, especially in cases and countries where results from the Mantoux test do not have great value.^15,18 A PCR assay for detecting 
M tuberculosis DNA in blood and urine samples also was found helpful in confirming a diagnosis of EIB when skin biopsies were unavailable.^8,19 However, PCR has been shown to have low sensitivity for the diagnosis of EIB because of its ability to detect M tuberculosis DNA ranging from 
0% to 77% of skin biopsy specimens.^20,21 Therefore, a negative PCR for the detection of M tuberculosis DNA in nodules does not exclude a diagnosis of erythema induratum.

Treatment

The mainstay of EIB treatment is a multidrug antituberculosis regimen.^5,8,10-12 Our patient was successfully treated with rifampin and isoniazid and a repeat IGRA was used as a laboratory marker of response to therapy. Single-drug therapy with isoniazid has been shown to result in greater likelihood of EIB relapse in comparison to multidrug regimens.²² Other treatments include potassium iodide and gold, but they are not well-studied.^23-25 Treatment of venous insufficiency with bed rest and nonsteroidal anti-inflammatory drugs for pain also may be helpful.² In cases of nodular vasulitis that are not associated with tuberculosis infection, treatment should be targeted at the underlying cause of the immune response. For example, a case of nodular vasculitis associated with hepatitis C virus did not respond to antituberculosis multidrug therapy, but skin lesions did improve with pegylated interferon and ribavirin.⁴

Case Report

A 54-year-old Hispanic woman with a history of type 2 diabetes mellitus and hyperlipidemia presented with recurrent painful plaques and nodules on the bilateral lower extremities and a severe burning sensation on the feet of 3 years’ duration. The patient denied experiencing any associated fevers, chills, night sweats, weight loss, joint aches, cough, or shortness of breath. She had a history of pustular psoriasis and reported a positive purified protein derivative (PPD)(tuberculin) skin test approximately 40 years prior.

She presented with a 4×4-cm, poorly defined, tender, indurated plaque on the middle of the left shin and a 2×3-cm, red-brown plaque on the dorsal aspect of the left foot (Figure 1). No lymphadenopathy or any other abnormalities were noted. The clinical differential diagnosis included various panniculitides, such as erythema nodosum, erythema induratum of Bazin (EIB), and lupus panniculitis, as well as other conditions, including polyarteritis nodosa, sarcoidosis, Sweet disease, deep fungal and mycobacterial infections, and cutaneous lymphoma.

Figure 1. Erythematous indurated plaques on the middle of the left shin (A) and on the dorsal aspect of the left foot (B).

Two skin biopsies taken for histopathologic evaluation revealed primarily granulomatous lobular panniculitis with foci of microthrombi and vasculitis (Figure 2). These findings were consistent with nodular vasculitis. Acid-fast bacillus and Gomori methenamine-silver stains were negative for mycobacterial or fungal organisms. Tissue cultures also were negative. Results from a complete blood cell count, chemistry panel, thyroid and liver function tests, hepatitis panel, and rapid plasma reagin test were unremarkable. Immunologic markers, including antinuclear antibody, antineutrophil cytoplasmic antibody, rheumatoid factor, and cryoglobulins, also revealed no abnormalities. A chest radiograph showed scarring in the suprahilar region of the upper lobe of the left lung consistent with a prior case of pulmonary tuberculosis, and exposure to Mycobacterium tuberculosis was confirmed with an IFN-γ release assay (IGRA) result of 1.49 IU/mL (>0.34 IU/mL indicates positive test). These findings from clinical and histopathologic examination as well as laboratory tests were consistent with a diagnosis of EIB.

Figure 2. Granulomatous lobular panniculitis (A)(H&E, original magnification ×40) with foci of microthrombi and vasculitis (B and C)(both H&E, original magnifications ×200).

Standard antituberculosis therapy with rifampin, isoniazid, pyrazinamide, and ethambutol (RIPE) was simplified to rifampin and isoniazid due to her inability to tolerate the full regimen because of gastrointestinal tract upset and diarrhea. After 6 months of therapy, a repeat IGRA decreased to 0.43 IU/mL, and the painful plaques and nodules on the lower extremities and burning sensation in the feet completely resolved.

Comment

Our case of EIB associated with peripheral neuropathy is a unique presentation of lesions on the pretibial area of the bilateral legs and dorsal aspect of the feet. We confirmed the presence of latent tuberculosis infection with a chest radiograph and an IGRA. Symptoms of peripheral neuropathy resolved after antituberculosis treatment, which suggests an immune-mediated mechanism of neuronal damage from circulating tuberculosis antigens.

Pathogenesis

Although erythema induratum was first described by Ernest Bazin in 1861, it was not until the early 1900s that the link between tuberculosis and erythema induratum was made by French dermatologists.^1,2 Around the same time, similar cases of erythema induratum were discovered in England with no evidence of tuberculosis, which led to the distinct classification of erythema induratum of Whitfield (EIW). This classification described these nontuberculoid cases.^1,2 In 1945, Montgomery et al³ in the United States coined the term nodular vasculitis for EIW and categorized its clinical features and histopathology as separate from EIB.³ Today, some authors use EIB, EIW, and nodular vasculitis interchangeably and believe they all are the same entity.² We use EIB for all cases related to tuberculosis and nodular vasulitis when referring to all other etiologies, including nontuberculoid bacterial infections, chronic hepatitis B and C virus, thrombophlebitis, hypothyroidism, and rheumatoid arthritis.^4,5

Erythema induratum of Bazin, lichen scrofulosorum, and papulonecrotic tuberculids are considered tuberculid diseases and are thought to be caused by hypersensitivity reactions to mycobacterial antigens rather than local mycobacterial infections. Tuberculids are believed to be a reaction to an id reaction of circulating mycobacterial antigens in the setting of latent or active tuberculosis infection. The basis for this view is that mycobacteria cannot be cultured or visualized from lesions in tuberculid diseases.⁶ Cutaneous tuberculosis, such as scrofuloderma, miliary tuberculosis, tuberculosis chancre, lupus vulgaris, and gummatous tuberculosis, differ from EIB and other tuberculid diseases in that mycobacteria can be cultured and visualized on histologic examination with Ziehl-Neelsen staining.⁶ The pathology of cutaneous tuberculosis results from a mycobacterial infection of the skin, and cutaneous tuberculosis diseases are categorized as multibacillary or paucibacillary based on the number of organisms visualized in biopsies.

The absence of M tuberculosis organisms in skin lesions has led some to doubt the causal relationship between M tuberculosis and EIB.⁷ However, the advent of polymerase chain reaction (PCR) and specific DNA primers for M tuberculosis has allowed for the detection of M tuberculosis DNA in biopsy specimens, which has further established the relationship between tuberculosis and EIB.⁵ Some authors have suggested that the absence of mycobacteria in EIB and other tuberculid lesions may be due to small numbers of bacilli in the lesions or early destruction of mycobacteria organisms before biopsy.^8,9 These authors consider cutaneous tuberculosis and tuberculids as diseases on the same spectrum, with tuberculids representing one extreme in which there are few mycobacteria organisms present in the lesions.

Presentation

Erythema induratum commonly affects middle-aged women and presents with recurrent crops of tender nodules on the lower extremities.^10-13 Nodules often are most commonly found on the lower calves but also can present on the arms, thighs, feet, or buttocks.¹⁰ Our patient’s presentation was atypical in that lesions were distributed on the pretibial area of the legs and dorsal aspect of the feet. Obesity and venous insufficiency of the lower extremities are believed to be predisposing factors to the development of EIB nodules.² The nodules develop over several weeks and heal over several months with possible ulceration and hyperpigmented scarring.^10,11 Ulcerated nodules often are irregular and shallow with an overlying crust and a bluish border.^11,13 Nodules often are precipitated by cold weather or venostasis.^1,11,12

Silva et al¹⁴ reported a case of EIB on the lower legs associated with a burning sensation on the feet and paresthesia; all known causes of peripheral neuropathy were excluded by a comprehensive laboratory workup. The burning sensation on the feet resolved after several weeks of antituberculosis therapy. Our patient also presented with a burning sensation on the feet that remarkably improved after 6 months of antituberculosis therapy. Peripheral neuropathy could have been a consequence of diabetes mellitus in our patient, though neuronal damage also could be a consequence of hypersensitivity to tuberculosis antigens. Silva et al¹⁴ proposed that macrophages activated by M tuberculosis antigens produce lytic enzymes that can cause tissue necrosis and nerve damage if released into surrounding tissue.

Diagnosis

The diagnosis of EIB is made based on clinical presentation, evidence of prior or current tuberculosis infection, histopathologic findings, and response to antituberculosis therapy.¹⁵ Evidence of active or latent tuberculosis infection typically is gathered by patient history, chest radiograph, tuberculin skin tests, interferon-releasing assays, and PCR of skin biopsies. Tuberculin skin tests in patients with EIB result in reactive induration that is typically more than 20 mm.⁸ In vitro T-lymphocyte proliferation assays in response to PPD have further supported the suggestion that there is a markedly enhanced T-lymphocyte response to M tuberculosis antigens in patients with EIB.¹⁶

IFN-γ release assays have provided useful methods for the detection of latent tuberculosis infection.¹⁷ The IGRA is effective when the tuberculin skin test yields a suspected false-negative or in the context of prior bacille Calmette-Guérin vaccination.¹⁷ IFN-γ release assays also may be preferred to tuberculin skin tests because it provides less discomfort to the patient in the event of a positive hypersensitive reaction to the PPD.

Before the advent of IGRAs, PCR was used to detect M tuberculosis DNA in skin biopsies and to confirm the diagnosis of EIB. Some researchers believe PCR can be an important tool for confirming a diagnosis of EIB, especially in cases and countries where results from the Mantoux test do not have great value.^15,18 A PCR assay for detecting 
M tuberculosis DNA in blood and urine samples also was found helpful in confirming a diagnosis of EIB when skin biopsies were unavailable.^8,19 However, PCR has been shown to have low sensitivity for the diagnosis of EIB because of its ability to detect M tuberculosis DNA ranging from 
0% to 77% of skin biopsy specimens.^20,21 Therefore, a negative PCR for the detection of M tuberculosis DNA in nodules does not exclude a diagnosis of erythema induratum.

Treatment

The mainstay of EIB treatment is a multidrug antituberculosis regimen.^5,8,10-12 Our patient was successfully treated with rifampin and isoniazid and a repeat IGRA was used as a laboratory marker of response to therapy. Single-drug therapy with isoniazid has been shown to result in greater likelihood of EIB relapse in comparison to multidrug regimens.²² Other treatments include potassium iodide and gold, but they are not well-studied.^23-25 Treatment of venous insufficiency with bed rest and nonsteroidal anti-inflammatory drugs for pain also may be helpful.² In cases of nodular vasulitis that are not associated with tuberculosis infection, treatment should be targeted at the underlying cause of the immune response. For example, a case of nodular vasculitis associated with hepatitis C virus did not respond to antituberculosis multidrug therapy, but skin lesions did improve with pegylated interferon and ribavirin.⁴

Nonislet cell tumor-induced hypoglycemia (NICTH), also known as Doege-Potter syndrome, is a rare paraneoplastic syndrome seen in association with various nonpancreatic tumors, benign and malignant, and comprising mesenchymal, vascular, or epithelial cell types. We report a case of recurrent life-threatening hypoglycemia from a large pelvic solitary fibrous tumor.

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

Nonislet cell tumor-induced hypoglycemia (NICTH), also known as Doege-Potter syndrome, is a rare paraneoplastic syndrome seen in association with various nonpancreatic tumors, benign and malignant, and comprising mesenchymal, vascular, or epithelial cell types. We report a case of recurrent life-threatening hypoglycemia from a large pelvic solitary fibrous tumor.

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

Nonislet cell tumor-induced hypoglycemia (NICTH), also known as Doege-Potter syndrome, is a rare paraneoplastic syndrome seen in association with various nonpancreatic tumors, benign and malignant, and comprising mesenchymal, vascular, or epithelial cell types. We report a case of recurrent life-threatening hypoglycemia from a large pelvic solitary fibrous tumor.

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

Congenital diaphragmatic hernias (CDHs) occur from a disruption in the muscular formation of the diaphragm, resulting in herniation of abdominal contents into the thoracic cavity. A rare diagnosis, most cases are identified in the pediatric and neonatal populations with an overall historical 50% mortality related to the diagnosis.¹ More recent data published in the U.S. and Japan cite an overall survival rate of 67% to 80% secondary to improved understanding of the pathophysiology and subsequent enhancement of neonatal cardiopulmonary support adjuncts.^2,3

Bochladek hernias (posterolateral space) are the most common presentation of CDH, accounting for > 90% of cases. First described by the Giovanni Batista Morgagni in On the Seats and Causes of Disease Investigated by Anatomy, the anteromedial sternocostal location is far less common and accounts for only 2% to 3% of cases.^4,5 More commonly found on the right side of the diaphragm, despite protection from the liver, the right-sided space has been traditionally referred to as the Morgagni space. A left-sided defect is occasionally called the Larrey gap or space, after Napoleon’s surgeon who described the space as a potential location for pericardial drainage of tamponade.^6,7

Related: Colonoscopy Bowel Preparation Instructions

There are a few congenital conditions, such as trisomy 21, Turner syndrome, Prader Willi syndrome, dextrocardia, and Tetralogy of Fallot, that have been associated with Morgagni hernias.⁷ Pulmonary hypertension and respiratory distress are the most common symptoms for neonatal patients; chest pain, sensations of tightness/fullness, reflux, and transient obstructive symptoms constitute the typical symptoms of adult patients with CDH. In this case study, the authors present a case of adult-onset Morgagni hernia as well as a review of the relevant literature.

Case Report

The patient was a 48-year-old man on active-duty who presented to the Naval Medical Center Portsmouth General Surgery clinic in Virginia with a 4-year history of gastroesophageal reflux-related symptoms. Specifically, he reported epigastric fullness, pyrosis, and discomfort that radiated toward his bilateral lower ribs for the previous 4 years. This discomfort was typically associated with the intake of solid food and was followed a few hours later by a loose bowel movement.

The patient was initially treated with antacids and proton pump inhibitors by his primary care physician, with only minimal relief. He also reported several months of chronic cough as well as intermittent episodes of “gasping air hunger” for about 6 years, which had been incidentally brought up during his separation physical examination. A chest X-ray performed during the workup revealed findings suggesting a right diaphragmatic hernia vs a bronchogenic cyst (Figure 1). A computed tomography (CT) of the thorax demonstrated a 3 x 8-cm hernia through the foramen of Morgagni containing a portion of the transverse colon along with intraperitoneal fat (Figures 2 and 3).

The patient underwent repair of this right Morgagni hernia via a laparoscopic approach. Intraoperative findings confirmed preoperative radiologic studies demonstrating colonic and omental contents within an easily reducible hernia sac (Figures 4 and 5). The hernia sac was left in vivo, and a combined direct hernia repair with mesh reinforcement was performed using Surgimesh XB (BG Medical, Barrington, IL) (Figure 6). The patient remained in the hospital for overnight observation and was discharged on postoperative day 1. The patient has since been seen in follow-up and is doing quite well with complete resolution of his reflux and pulmonary symptoms.

Discussion

A recent review of surgical literature revealed that over a 57-year period, 298 cases of Morgagni hernias have been described in adults.⁷ Although previous studies have postulated that a majority of adult patients are asymptomatic, more recent retrospective studies have found about a 70% symptomatic rate of patients with Morgagni hernias.⁷ The natural history of adult presentations lends itself to pulmonary (most common) or chronic upper gastrointestinal symptoms, although an acute presentation with potential volvulus and strangulation of the herniated contents has been described.⁷

Diagnosis is typically confirmed with a chest X-ray, although the CT scan has become more popular in the era of multimodal imaging.^4,7 Multiple methods of repair have been described; however, thoracotomy has been the most widely used approach, and laparoscopy has gained popularity since the early 1990s.⁷ Mesh has been described in more than 60% of cases, and a laparoscopic repair has proven to have a low (< 5%) complication rate and short hospital stay.^8,9 In particular, it has been suggested that a hernia defect larger than 20 to 30 cm² should be repaired with a prosthetic adjunct, such as polypropylene, polytetrafluoroethylene, and bovine pericardium with a 1.5- to 2.5-cm mesh overlap.^7,8

Related: Unusual Congenital Pulmonary Anomaly in an Adult Patient With Dyspnea

There is some controversy about the management of the hernia sac, with about 69% of surgeons choosing not to excise the sac due to concerns of intrathoracic or pericardial injury.⁷ In a separate study, 36 patients were evaluated retrospectively, and the hernia sac was not resected in any of the patients, with long-term follow-up revealing no evidence of recurrence.⁶

Conclusion

To allow for early intervention and avoidance of potentially life-threatening volvulus/strangulation, the medical practitioner has to be aware of this rare diagnosis when performing a workup for vague pulmonary and abdominal symptoms as described here. Disagreement exists over the method of repair and management of the hernia sac as well as the need for mesh buttressing of the defect. A well-planned surgical approach individualized to the patient’s anatomy, surgeon’s expertise, and hernia defect size will provide the best possible outcome with a low operative morbidity.

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 the complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

Congenital diaphragmatic hernias (CDHs) occur from a disruption in the muscular formation of the diaphragm, resulting in herniation of abdominal contents into the thoracic cavity. A rare diagnosis, most cases are identified in the pediatric and neonatal populations with an overall historical 50% mortality related to the diagnosis.¹ More recent data published in the U.S. and Japan cite an overall survival rate of 67% to 80% secondary to improved understanding of the pathophysiology and subsequent enhancement of neonatal cardiopulmonary support adjuncts.^2,3

Bochladek hernias (posterolateral space) are the most common presentation of CDH, accounting for > 90% of cases. First described by the Giovanni Batista Morgagni in On the Seats and Causes of Disease Investigated by Anatomy, the anteromedial sternocostal location is far less common and accounts for only 2% to 3% of cases.^4,5 More commonly found on the right side of the diaphragm, despite protection from the liver, the right-sided space has been traditionally referred to as the Morgagni space. A left-sided defect is occasionally called the Larrey gap or space, after Napoleon’s surgeon who described the space as a potential location for pericardial drainage of tamponade.^6,7

Related: Colonoscopy Bowel Preparation Instructions

There are a few congenital conditions, such as trisomy 21, Turner syndrome, Prader Willi syndrome, dextrocardia, and Tetralogy of Fallot, that have been associated with Morgagni hernias.⁷ Pulmonary hypertension and respiratory distress are the most common symptoms for neonatal patients; chest pain, sensations of tightness/fullness, reflux, and transient obstructive symptoms constitute the typical symptoms of adult patients with CDH. In this case study, the authors present a case of adult-onset Morgagni hernia as well as a review of the relevant literature.

Case Report

The patient was a 48-year-old man on active-duty who presented to the Naval Medical Center Portsmouth General Surgery clinic in Virginia with a 4-year history of gastroesophageal reflux-related symptoms. Specifically, he reported epigastric fullness, pyrosis, and discomfort that radiated toward his bilateral lower ribs for the previous 4 years. This discomfort was typically associated with the intake of solid food and was followed a few hours later by a loose bowel movement.

The patient was initially treated with antacids and proton pump inhibitors by his primary care physician, with only minimal relief. He also reported several months of chronic cough as well as intermittent episodes of “gasping air hunger” for about 6 years, which had been incidentally brought up during his separation physical examination. A chest X-ray performed during the workup revealed findings suggesting a right diaphragmatic hernia vs a bronchogenic cyst (Figure 1). A computed tomography (CT) of the thorax demonstrated a 3 x 8-cm hernia through the foramen of Morgagni containing a portion of the transverse colon along with intraperitoneal fat (Figures 2 and 3).

The patient underwent repair of this right Morgagni hernia via a laparoscopic approach. Intraoperative findings confirmed preoperative radiologic studies demonstrating colonic and omental contents within an easily reducible hernia sac (Figures 4 and 5). The hernia sac was left in vivo, and a combined direct hernia repair with mesh reinforcement was performed using Surgimesh XB (BG Medical, Barrington, IL) (Figure 6). The patient remained in the hospital for overnight observation and was discharged on postoperative day 1. The patient has since been seen in follow-up and is doing quite well with complete resolution of his reflux and pulmonary symptoms.

Discussion

A recent review of surgical literature revealed that over a 57-year period, 298 cases of Morgagni hernias have been described in adults.⁷ Although previous studies have postulated that a majority of adult patients are asymptomatic, more recent retrospective studies have found about a 70% symptomatic rate of patients with Morgagni hernias.⁷ The natural history of adult presentations lends itself to pulmonary (most common) or chronic upper gastrointestinal symptoms, although an acute presentation with potential volvulus and strangulation of the herniated contents has been described.⁷

Diagnosis is typically confirmed with a chest X-ray, although the CT scan has become more popular in the era of multimodal imaging.^4,7 Multiple methods of repair have been described; however, thoracotomy has been the most widely used approach, and laparoscopy has gained popularity since the early 1990s.⁷ Mesh has been described in more than 60% of cases, and a laparoscopic repair has proven to have a low (< 5%) complication rate and short hospital stay.^8,9 In particular, it has been suggested that a hernia defect larger than 20 to 30 cm² should be repaired with a prosthetic adjunct, such as polypropylene, polytetrafluoroethylene, and bovine pericardium with a 1.5- to 2.5-cm mesh overlap.^7,8

Related: Unusual Congenital Pulmonary Anomaly in an Adult Patient With Dyspnea

There is some controversy about the management of the hernia sac, with about 69% of surgeons choosing not to excise the sac due to concerns of intrathoracic or pericardial injury.⁷ In a separate study, 36 patients were evaluated retrospectively, and the hernia sac was not resected in any of the patients, with long-term follow-up revealing no evidence of recurrence.⁶

Conclusion

To allow for early intervention and avoidance of potentially life-threatening volvulus/strangulation, the medical practitioner has to be aware of this rare diagnosis when performing a workup for vague pulmonary and abdominal symptoms as described here. Disagreement exists over the method of repair and management of the hernia sac as well as the need for mesh buttressing of the defect. A well-planned surgical approach individualized to the patient’s anatomy, surgeon’s expertise, and hernia defect size will provide the best possible outcome with a low operative morbidity.

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 the complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

Congenital diaphragmatic hernias (CDHs) occur from a disruption in the muscular formation of the diaphragm, resulting in herniation of abdominal contents into the thoracic cavity. A rare diagnosis, most cases are identified in the pediatric and neonatal populations with an overall historical 50% mortality related to the diagnosis.¹ More recent data published in the U.S. and Japan cite an overall survival rate of 67% to 80% secondary to improved understanding of the pathophysiology and subsequent enhancement of neonatal cardiopulmonary support adjuncts.^2,3

Bochladek hernias (posterolateral space) are the most common presentation of CDH, accounting for > 90% of cases. First described by the Giovanni Batista Morgagni in On the Seats and Causes of Disease Investigated by Anatomy, the anteromedial sternocostal location is far less common and accounts for only 2% to 3% of cases.^4,5 More commonly found on the right side of the diaphragm, despite protection from the liver, the right-sided space has been traditionally referred to as the Morgagni space. A left-sided defect is occasionally called the Larrey gap or space, after Napoleon’s surgeon who described the space as a potential location for pericardial drainage of tamponade.^6,7

Related: Colonoscopy Bowel Preparation Instructions

There are a few congenital conditions, such as trisomy 21, Turner syndrome, Prader Willi syndrome, dextrocardia, and Tetralogy of Fallot, that have been associated with Morgagni hernias.⁷ Pulmonary hypertension and respiratory distress are the most common symptoms for neonatal patients; chest pain, sensations of tightness/fullness, reflux, and transient obstructive symptoms constitute the typical symptoms of adult patients with CDH. In this case study, the authors present a case of adult-onset Morgagni hernia as well as a review of the relevant literature.

Case Report

The patient was a 48-year-old man on active-duty who presented to the Naval Medical Center Portsmouth General Surgery clinic in Virginia with a 4-year history of gastroesophageal reflux-related symptoms. Specifically, he reported epigastric fullness, pyrosis, and discomfort that radiated toward his bilateral lower ribs for the previous 4 years. This discomfort was typically associated with the intake of solid food and was followed a few hours later by a loose bowel movement.

The patient was initially treated with antacids and proton pump inhibitors by his primary care physician, with only minimal relief. He also reported several months of chronic cough as well as intermittent episodes of “gasping air hunger” for about 6 years, which had been incidentally brought up during his separation physical examination. A chest X-ray performed during the workup revealed findings suggesting a right diaphragmatic hernia vs a bronchogenic cyst (Figure 1). A computed tomography (CT) of the thorax demonstrated a 3 x 8-cm hernia through the foramen of Morgagni containing a portion of the transverse colon along with intraperitoneal fat (Figures 2 and 3).

The patient underwent repair of this right Morgagni hernia via a laparoscopic approach. Intraoperative findings confirmed preoperative radiologic studies demonstrating colonic and omental contents within an easily reducible hernia sac (Figures 4 and 5). The hernia sac was left in vivo, and a combined direct hernia repair with mesh reinforcement was performed using Surgimesh XB (BG Medical, Barrington, IL) (Figure 6). The patient remained in the hospital for overnight observation and was discharged on postoperative day 1. The patient has since been seen in follow-up and is doing quite well with complete resolution of his reflux and pulmonary symptoms.

Discussion

A recent review of surgical literature revealed that over a 57-year period, 298 cases of Morgagni hernias have been described in adults.⁷ Although previous studies have postulated that a majority of adult patients are asymptomatic, more recent retrospective studies have found about a 70% symptomatic rate of patients with Morgagni hernias.⁷ The natural history of adult presentations lends itself to pulmonary (most common) or chronic upper gastrointestinal symptoms, although an acute presentation with potential volvulus and strangulation of the herniated contents has been described.⁷

Diagnosis is typically confirmed with a chest X-ray, although the CT scan has become more popular in the era of multimodal imaging.^4,7 Multiple methods of repair have been described; however, thoracotomy has been the most widely used approach, and laparoscopy has gained popularity since the early 1990s.⁷ Mesh has been described in more than 60% of cases, and a laparoscopic repair has proven to have a low (< 5%) complication rate and short hospital stay.^8,9 In particular, it has been suggested that a hernia defect larger than 20 to 30 cm² should be repaired with a prosthetic adjunct, such as polypropylene, polytetrafluoroethylene, and bovine pericardium with a 1.5- to 2.5-cm mesh overlap.^7,8

Related: Unusual Congenital Pulmonary Anomaly in an Adult Patient With Dyspnea

There is some controversy about the management of the hernia sac, with about 69% of surgeons choosing not to excise the sac due to concerns of intrathoracic or pericardial injury.⁷ In a separate study, 36 patients were evaluated retrospectively, and the hernia sac was not resected in any of the patients, with long-term follow-up revealing no evidence of recurrence.⁶

Conclusion

To allow for early intervention and avoidance of potentially life-threatening volvulus/strangulation, the medical practitioner has to be aware of this rare diagnosis when performing a workup for vague pulmonary and abdominal symptoms as described here. Disagreement exists over the method of repair and management of the hernia sac as well as the need for mesh buttressing of the defect. A well-planned surgical approach individualized to the patient’s anatomy, surgeon’s expertise, and hernia defect size will provide the best possible outcome with a low operative morbidity.

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 the complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

Epidermodysplasia verruciformis (EV) is an uncommon autosomal-recessive inherited disorder characterized by disseminated cutaneous warts in predisposed patients who are highly susceptible to genus â-papillomavirus infections. Squaric acid dibutylester (SADBE) is a contact sensitizer agent that has gained general acceptance over the years for the treatment of a variety of dermatologic diseases, including alopecia areata and cutaneous warts. We report the case of a 40-year-old woman with a balanced chromosomal translocation and lymphocytopenia who presented with the sole clinical finding of refractory multiple flat warts that had been present for 25 years. After failed attempts at therapy with oral isotretinoin, cryotherapy with topical trichloroacetic acid, and topical tretinoin, the lesions were successfully eradicated with topical SADBE with prior sensitization.

Case Report

A 40-year-old woman presented with multiple flat warts on the bilateral arms and legs of 25 years’ duration (Figure 1) that had been unsuccessfully treated by an outside physician with imiquimod cream 5% and tazarotene gel 0.1%. Her medical history was remarkable for recurrent upper respiratory tract infections, urinary tract infections, yeast infections, and otitis media. She also reported a history of 6 spontaneous miscarriages that had been attributed to a balanced chromosomal translocation between chromosomes 12 and 14.

Figure 1. Numerous warts on the right shin prior to squaric acid dibutylester sensitization. Figure 2. Histologic analysis of a lesion on the right leg revealed epidermal hyperplasia and koilocytosis (H&E, original magnification ×400).

Laboratory evaluation revealed leukopenia, lymphopenia, and hypogammaglobulinemia, with a white blood cell count of 3600/μL (reference range, 4500–11,000/mL), a lymphocyte count of 12.1% (20%–45%), absolute CD4 count of 77 cells/μL (490–1740 cells/μL), absolute CD8 count of 56 cells/mL (180–1170 cells/μL), and serum IgM level of 17 mg/dL (48–271 mg/dL). Human immunodeficiency virus (HIV) titers were negative.

On physical examination numerous pink, flat-topped papules were noted on the forehead and bilateral arms and legs. Histologic analysis of a tangential plane biopsy of a lesion on the right leg revealed hyperkeratosis of the stratum corneum and epidermal hyperplasia (Figure 2). The epidermis also showed focal papillomatosis with areas of hypergranulosis and viropathic changes; these findings were consistent with a diagnosis of verruca plana. Human papillomavirus (HPV) DNA typing by polymerase chain reaction from the verrucous lesions showed HPV type 20, which has been associated with EV. Based on the patient’s clinical findings and HPV subtype, she was diagnosed with atypical EV.

Subsequent treatment with liquid nitrogen, tretinoin cream 0.1%, and topical trichloroacetic acid 50% failed. She received oral isotretinoin at a dosage of 80 mg daily for 9 months, but the lesions persisted and she developed alopecia and ankle stiffness; therefore, the isotretinoin was discontinued. Candida antigen testing revealed that the patient was anergic, and SADBE sensitization was subsequently initiated. Squaric acid dibutylester was utilized as a sensitizing agent, and it was formulated as 2% and 0.2% solutions in acetone, supplied in 20-mL tinted glass bottles.

Squaric acid dibutylester solution 2% under occlusion was applied to a test area on the right forearm. Three days later, results indicated prominent erythema and inflammation at the application site. Two weeks later, a chronic dermatitic response was noted at the test site (Figure 3). Squaric acid dibutylester 0.2% was then applied to an affected area on the right shin and was kept under occlusion for 48 hours. One month later, no notable changes in the lesions were observed, and no further treatments were performed. Three months later, the patient returned for evaluation and it was noted that the flat warts on the right shin that had been treated with SADBE 0.2% 4 months prior had resolved (Figure 4). Subsequently, it was noted that all of the lesions had regressed, even those that had not been treated with SADBE.

Comment

Epidermodysplasia verruciformis is a rare genodermatosis caused by a group of phylogenetically related viruses¹ belonging to the β-papillomavirus genus.^2,3 It is characterized by a combination of pityriasis versicolor–like lesions, reddish verrucalike plaques, and seborrheic keratosis–like plaques,^1,4 preferentially on sun-exposed areas.⁵ The lesions undergo malignant transformation in 30% to 60% of patients,^3,6 especially into squamous cell carcinomas.⁷ The most frequent HPV types found in EV skin lesions are 5, 8, 9, 12, 14, 15, 17, and 19 to 25; types 5 and 8 are found in 90% of cutaneous squamous cell carcinomas in EV patients.² Human papillomavirus type 20, the type identified in our patient, has been isolated from warts in EV patients,^1,2 though it is not the most common type. It has been shown that more than one HPV type could be present concurrently in the same EV patient,¹ which necessitates close follow-up for skin cancer evaluation in all EV patients, as oncogenic strains may be present in some lesions.

Figure 3. Original squaric acid dibutylester sensitization site on right forearm revealing persistent dermatitis. Figure 4. The right shin after treatment with squaric acid dibutylester sensitization and elicitation.

Epidermodysplasia verruciformis has no particular predisposition for race or geographic location.^1,7 It usually is inherited in an autosomal-recessive fashion^1,4,7 and has been linked to mutations in 2 EV genes located on chromosome 17: EVER1/TCM6 and EVER2/TCM8.⁸ However, approximately 25% of EV cases are not associated with these gene mutations,^5,9 as demonstrated in our patient. Autosomal-dominant or X-linked mutations also have been reported.¹⁰ In our case, a chromosomal abnormality in the form of a balanced chromosomal translocation was present, which is unique. A connection between EV and balanced chromosomal translocation cannot be excluded and warrants further investigation.

Epidermodysplasia verruciformis has been associated with decreased cell-mediated immunity.^1,7 However, nonimmunologic factors likely contribute considering the rarity of EV-like eruptions in immunodeficiency disorders¹¹ as well as its frequent coinfection with HPV type 3¹² and its association with EVER1/TCM6 and EVER2/TCM8.⁸ Epidermodysplasia verruciformis–like lesions have been reported in several immunosuppressed states, including HIV infection,¹³ combined variable immunodeficiency syndrome,¹⁴ IgM deficiency,¹⁵ and CD4⁺ T-cell lymphocytopenia.¹¹ Our patient’s findings fit the latter diagnostic criteria, as she had a chronically low CD4 count of 77 cells/μL, negative HIV titers, and absence of alternative explanation to the lymphopenia. Thus, we could consider her as having EV, as a low CD4 count is a known association. Her immunodeficient state could possibly be attributed to the chromosomal translocation; however, the genetic loci surrounding the chromosomal translocation have not been identified to date, leaving this hypothesis unsubstantiated. Nevertheless, in our otherwise healthy patient, no explanation was found as to why a cell-mediated deficiency would selectively favor a cutaneous HPV infection. According to Zavattaro et al,⁵ a possible cause could be the presence of additional genetic or environmental factors in the patient that predisposed her to this particular infection.

Every patient with EV requires close lifelong observation for skin cancer and education regarding strict sun avoidance and protection.¹ Treatment options for the lesions include topical therapies with imiquimod 5%, immunomodulators, and salicylic acid^16,17; oral isotretinoin¹⁸; and combinations of acitretin and interferon alfa.¹⁹ Physical ablative procedures also have been proposed, including cryotherapy with liquid nitrogen, electrosurgery, surgical excision, and laser therapies.²⁰

Topical immunotherapy with SADBE initially was used to treat refractory alopecia areata and also has been described in the treatment of recalcitrant warts.^21-24 Historically, 2,4-dinitrochlorobenzene was used for contact immunotherapy in wart management but is now avoided due to its mutagenic potential.²⁵ Squaric acid dibutylester and diphenylcyclopropenone currently are the favored contact sensitizers, with a resolution rate of 60% reported in refractory warts.²⁶

Topical immunotherapy involves sensitization of the patient with high-concentration (2%) SADBE on a small surface area until an eczematous dermatitis appears. The rash indicates sensitization has been achieved, and then a lower-concentration SADBE is applied to the warts. Observation of mild contact dermatitis should not be an indication to stop treatment, as this effect is an integral part of therapeutic response. No serious side effects were reported to SADBE; erythema, desquamation, edema, itching, and burning were described.²³

The mechanism of action of SADBE is not clear. The most common proposed theory is the induction of a type IV hypersensitivity reaction in the warts, leading to their destruction. Other authors suggest that wart resolution is caused by a nonspecific inflammatory reaction. An argument in favor of the latter hypothesis is the spontaneous regression of untreated warts in patients treated with SADBE at a remote site, suggesting a mechanism of action beyond a simple cell-mediated process.²³

Epidermodysplasia verruciformis should be included in the differential diagnosis for any eruptive, warty, papular, and plaque-type lesions that appear in immunocompromised individuals. Moreover, the diagnosis of idiopathic CD4⁺ T-cell lymphocytopenia should be considered in any patient with a CD4 count deficit presenting with widespread viral, fungal, or mycobacterial infection with negative HIV test. Appropriate evaluation of the absolute CD4⁺ counts also should be performed. In our case, it was hypothesized that the patient’s balanced chromosomal translocation was related to her lymphopenia and EV, though this correlation has yet to be confirmed. However, it is notable that her son carried the same translocation and has a normal white blood cell count and no evidence of flat warts. This case demonstrates the success of contact immunotherapy in treating these widespread and often recalcitrant lesions.

Epidermodysplasia verruciformis (EV) is an uncommon autosomal-recessive inherited disorder characterized by disseminated cutaneous warts in predisposed patients who are highly susceptible to genus â-papillomavirus infections. Squaric acid dibutylester (SADBE) is a contact sensitizer agent that has gained general acceptance over the years for the treatment of a variety of dermatologic diseases, including alopecia areata and cutaneous warts. We report the case of a 40-year-old woman with a balanced chromosomal translocation and lymphocytopenia who presented with the sole clinical finding of refractory multiple flat warts that had been present for 25 years. After failed attempts at therapy with oral isotretinoin, cryotherapy with topical trichloroacetic acid, and topical tretinoin, the lesions were successfully eradicated with topical SADBE with prior sensitization.

Case Report

A 40-year-old woman presented with multiple flat warts on the bilateral arms and legs of 25 years’ duration (Figure 1) that had been unsuccessfully treated by an outside physician with imiquimod cream 5% and tazarotene gel 0.1%. Her medical history was remarkable for recurrent upper respiratory tract infections, urinary tract infections, yeast infections, and otitis media. She also reported a history of 6 spontaneous miscarriages that had been attributed to a balanced chromosomal translocation between chromosomes 12 and 14.

Figure 1. Numerous warts on the right shin prior to squaric acid dibutylester sensitization. Figure 2. Histologic analysis of a lesion on the right leg revealed epidermal hyperplasia and koilocytosis (H&E, original magnification ×400).

Laboratory evaluation revealed leukopenia, lymphopenia, and hypogammaglobulinemia, with a white blood cell count of 3600/μL (reference range, 4500–11,000/mL), a lymphocyte count of 12.1% (20%–45%), absolute CD4 count of 77 cells/μL (490–1740 cells/μL), absolute CD8 count of 56 cells/mL (180–1170 cells/μL), and serum IgM level of 17 mg/dL (48–271 mg/dL). Human immunodeficiency virus (HIV) titers were negative.

On physical examination numerous pink, flat-topped papules were noted on the forehead and bilateral arms and legs. Histologic analysis of a tangential plane biopsy of a lesion on the right leg revealed hyperkeratosis of the stratum corneum and epidermal hyperplasia (Figure 2). The epidermis also showed focal papillomatosis with areas of hypergranulosis and viropathic changes; these findings were consistent with a diagnosis of verruca plana. Human papillomavirus (HPV) DNA typing by polymerase chain reaction from the verrucous lesions showed HPV type 20, which has been associated with EV. Based on the patient’s clinical findings and HPV subtype, she was diagnosed with atypical EV.

Subsequent treatment with liquid nitrogen, tretinoin cream 0.1%, and topical trichloroacetic acid 50% failed. She received oral isotretinoin at a dosage of 80 mg daily for 9 months, but the lesions persisted and she developed alopecia and ankle stiffness; therefore, the isotretinoin was discontinued. Candida antigen testing revealed that the patient was anergic, and SADBE sensitization was subsequently initiated. Squaric acid dibutylester was utilized as a sensitizing agent, and it was formulated as 2% and 0.2% solutions in acetone, supplied in 20-mL tinted glass bottles.

Squaric acid dibutylester solution 2% under occlusion was applied to a test area on the right forearm. Three days later, results indicated prominent erythema and inflammation at the application site. Two weeks later, a chronic dermatitic response was noted at the test site (Figure 3). Squaric acid dibutylester 0.2% was then applied to an affected area on the right shin and was kept under occlusion for 48 hours. One month later, no notable changes in the lesions were observed, and no further treatments were performed. Three months later, the patient returned for evaluation and it was noted that the flat warts on the right shin that had been treated with SADBE 0.2% 4 months prior had resolved (Figure 4). Subsequently, it was noted that all of the lesions had regressed, even those that had not been treated with SADBE.

Comment

Epidermodysplasia verruciformis is a rare genodermatosis caused by a group of phylogenetically related viruses¹ belonging to the β-papillomavirus genus.^2,3 It is characterized by a combination of pityriasis versicolor–like lesions, reddish verrucalike plaques, and seborrheic keratosis–like plaques,^1,4 preferentially on sun-exposed areas.⁵ The lesions undergo malignant transformation in 30% to 60% of patients,^3,6 especially into squamous cell carcinomas.⁷ The most frequent HPV types found in EV skin lesions are 5, 8, 9, 12, 14, 15, 17, and 19 to 25; types 5 and 8 are found in 90% of cutaneous squamous cell carcinomas in EV patients.² Human papillomavirus type 20, the type identified in our patient, has been isolated from warts in EV patients,^1,2 though it is not the most common type. It has been shown that more than one HPV type could be present concurrently in the same EV patient,¹ which necessitates close follow-up for skin cancer evaluation in all EV patients, as oncogenic strains may be present in some lesions.

Figure 3. Original squaric acid dibutylester sensitization site on right forearm revealing persistent dermatitis. Figure 4. The right shin after treatment with squaric acid dibutylester sensitization and elicitation.

Epidermodysplasia verruciformis has no particular predisposition for race or geographic location.^1,7 It usually is inherited in an autosomal-recessive fashion^1,4,7 and has been linked to mutations in 2 EV genes located on chromosome 17: EVER1/TCM6 and EVER2/TCM8.⁸ However, approximately 25% of EV cases are not associated with these gene mutations,^5,9 as demonstrated in our patient. Autosomal-dominant or X-linked mutations also have been reported.¹⁰ In our case, a chromosomal abnormality in the form of a balanced chromosomal translocation was present, which is unique. A connection between EV and balanced chromosomal translocation cannot be excluded and warrants further investigation.

Epidermodysplasia verruciformis has been associated with decreased cell-mediated immunity.^1,7 However, nonimmunologic factors likely contribute considering the rarity of EV-like eruptions in immunodeficiency disorders¹¹ as well as its frequent coinfection with HPV type 3¹² and its association with EVER1/TCM6 and EVER2/TCM8.⁸ Epidermodysplasia verruciformis–like lesions have been reported in several immunosuppressed states, including HIV infection,¹³ combined variable immunodeficiency syndrome,¹⁴ IgM deficiency,¹⁵ and CD4⁺ T-cell lymphocytopenia.¹¹ Our patient’s findings fit the latter diagnostic criteria, as she had a chronically low CD4 count of 77 cells/μL, negative HIV titers, and absence of alternative explanation to the lymphopenia. Thus, we could consider her as having EV, as a low CD4 count is a known association. Her immunodeficient state could possibly be attributed to the chromosomal translocation; however, the genetic loci surrounding the chromosomal translocation have not been identified to date, leaving this hypothesis unsubstantiated. Nevertheless, in our otherwise healthy patient, no explanation was found as to why a cell-mediated deficiency would selectively favor a cutaneous HPV infection. According to Zavattaro et al,⁵ a possible cause could be the presence of additional genetic or environmental factors in the patient that predisposed her to this particular infection.

Every patient with EV requires close lifelong observation for skin cancer and education regarding strict sun avoidance and protection.¹ Treatment options for the lesions include topical therapies with imiquimod 5%, immunomodulators, and salicylic acid^16,17; oral isotretinoin¹⁸; and combinations of acitretin and interferon alfa.¹⁹ Physical ablative procedures also have been proposed, including cryotherapy with liquid nitrogen, electrosurgery, surgical excision, and laser therapies.²⁰

Topical immunotherapy with SADBE initially was used to treat refractory alopecia areata and also has been described in the treatment of recalcitrant warts.^21-24 Historically, 2,4-dinitrochlorobenzene was used for contact immunotherapy in wart management but is now avoided due to its mutagenic potential.²⁵ Squaric acid dibutylester and diphenylcyclopropenone currently are the favored contact sensitizers, with a resolution rate of 60% reported in refractory warts.²⁶

Topical immunotherapy involves sensitization of the patient with high-concentration (2%) SADBE on a small surface area until an eczematous dermatitis appears. The rash indicates sensitization has been achieved, and then a lower-concentration SADBE is applied to the warts. Observation of mild contact dermatitis should not be an indication to stop treatment, as this effect is an integral part of therapeutic response. No serious side effects were reported to SADBE; erythema, desquamation, edema, itching, and burning were described.²³

The mechanism of action of SADBE is not clear. The most common proposed theory is the induction of a type IV hypersensitivity reaction in the warts, leading to their destruction. Other authors suggest that wart resolution is caused by a nonspecific inflammatory reaction. An argument in favor of the latter hypothesis is the spontaneous regression of untreated warts in patients treated with SADBE at a remote site, suggesting a mechanism of action beyond a simple cell-mediated process.²³

Epidermodysplasia verruciformis should be included in the differential diagnosis for any eruptive, warty, papular, and plaque-type lesions that appear in immunocompromised individuals. Moreover, the diagnosis of idiopathic CD4⁺ T-cell lymphocytopenia should be considered in any patient with a CD4 count deficit presenting with widespread viral, fungal, or mycobacterial infection with negative HIV test. Appropriate evaluation of the absolute CD4⁺ counts also should be performed. In our case, it was hypothesized that the patient’s balanced chromosomal translocation was related to her lymphopenia and EV, though this correlation has yet to be confirmed. However, it is notable that her son carried the same translocation and has a normal white blood cell count and no evidence of flat warts. This case demonstrates the success of contact immunotherapy in treating these widespread and often recalcitrant lesions.

Epidermodysplasia verruciformis (EV) is an uncommon autosomal-recessive inherited disorder characterized by disseminated cutaneous warts in predisposed patients who are highly susceptible to genus â-papillomavirus infections. Squaric acid dibutylester (SADBE) is a contact sensitizer agent that has gained general acceptance over the years for the treatment of a variety of dermatologic diseases, including alopecia areata and cutaneous warts. We report the case of a 40-year-old woman with a balanced chromosomal translocation and lymphocytopenia who presented with the sole clinical finding of refractory multiple flat warts that had been present for 25 years. After failed attempts at therapy with oral isotretinoin, cryotherapy with topical trichloroacetic acid, and topical tretinoin, the lesions were successfully eradicated with topical SADBE with prior sensitization.

Case Report

A 40-year-old woman presented with multiple flat warts on the bilateral arms and legs of 25 years’ duration (Figure 1) that had been unsuccessfully treated by an outside physician with imiquimod cream 5% and tazarotene gel 0.1%. Her medical history was remarkable for recurrent upper respiratory tract infections, urinary tract infections, yeast infections, and otitis media. She also reported a history of 6 spontaneous miscarriages that had been attributed to a balanced chromosomal translocation between chromosomes 12 and 14.

Figure 1. Numerous warts on the right shin prior to squaric acid dibutylester sensitization. Figure 2. Histologic analysis of a lesion on the right leg revealed epidermal hyperplasia and koilocytosis (H&E, original magnification ×400).

Laboratory evaluation revealed leukopenia, lymphopenia, and hypogammaglobulinemia, with a white blood cell count of 3600/μL (reference range, 4500–11,000/mL), a lymphocyte count of 12.1% (20%–45%), absolute CD4 count of 77 cells/μL (490–1740 cells/μL), absolute CD8 count of 56 cells/mL (180–1170 cells/μL), and serum IgM level of 17 mg/dL (48–271 mg/dL). Human immunodeficiency virus (HIV) titers were negative.

On physical examination numerous pink, flat-topped papules were noted on the forehead and bilateral arms and legs. Histologic analysis of a tangential plane biopsy of a lesion on the right leg revealed hyperkeratosis of the stratum corneum and epidermal hyperplasia (Figure 2). The epidermis also showed focal papillomatosis with areas of hypergranulosis and viropathic changes; these findings were consistent with a diagnosis of verruca plana. Human papillomavirus (HPV) DNA typing by polymerase chain reaction from the verrucous lesions showed HPV type 20, which has been associated with EV. Based on the patient’s clinical findings and HPV subtype, she was diagnosed with atypical EV.

Subsequent treatment with liquid nitrogen, tretinoin cream 0.1%, and topical trichloroacetic acid 50% failed. She received oral isotretinoin at a dosage of 80 mg daily for 9 months, but the lesions persisted and she developed alopecia and ankle stiffness; therefore, the isotretinoin was discontinued. Candida antigen testing revealed that the patient was anergic, and SADBE sensitization was subsequently initiated. Squaric acid dibutylester was utilized as a sensitizing agent, and it was formulated as 2% and 0.2% solutions in acetone, supplied in 20-mL tinted glass bottles.

Squaric acid dibutylester solution 2% under occlusion was applied to a test area on the right forearm. Three days later, results indicated prominent erythema and inflammation at the application site. Two weeks later, a chronic dermatitic response was noted at the test site (Figure 3). Squaric acid dibutylester 0.2% was then applied to an affected area on the right shin and was kept under occlusion for 48 hours. One month later, no notable changes in the lesions were observed, and no further treatments were performed. Three months later, the patient returned for evaluation and it was noted that the flat warts on the right shin that had been treated with SADBE 0.2% 4 months prior had resolved (Figure 4). Subsequently, it was noted that all of the lesions had regressed, even those that had not been treated with SADBE.

Comment

Epidermodysplasia verruciformis is a rare genodermatosis caused by a group of phylogenetically related viruses¹ belonging to the β-papillomavirus genus.^2,3 It is characterized by a combination of pityriasis versicolor–like lesions, reddish verrucalike plaques, and seborrheic keratosis–like plaques,^1,4 preferentially on sun-exposed areas.⁵ The lesions undergo malignant transformation in 30% to 60% of patients,^3,6 especially into squamous cell carcinomas.⁷ The most frequent HPV types found in EV skin lesions are 5, 8, 9, 12, 14, 15, 17, and 19 to 25; types 5 and 8 are found in 90% of cutaneous squamous cell carcinomas in EV patients.² Human papillomavirus type 20, the type identified in our patient, has been isolated from warts in EV patients,^1,2 though it is not the most common type. It has been shown that more than one HPV type could be present concurrently in the same EV patient,¹ which necessitates close follow-up for skin cancer evaluation in all EV patients, as oncogenic strains may be present in some lesions.

Figure 3. Original squaric acid dibutylester sensitization site on right forearm revealing persistent dermatitis. Figure 4. The right shin after treatment with squaric acid dibutylester sensitization and elicitation.

Epidermodysplasia verruciformis has no particular predisposition for race or geographic location.^1,7 It usually is inherited in an autosomal-recessive fashion^1,4,7 and has been linked to mutations in 2 EV genes located on chromosome 17: EVER1/TCM6 and EVER2/TCM8.⁸ However, approximately 25% of EV cases are not associated with these gene mutations,^5,9 as demonstrated in our patient. Autosomal-dominant or X-linked mutations also have been reported.¹⁰ In our case, a chromosomal abnormality in the form of a balanced chromosomal translocation was present, which is unique. A connection between EV and balanced chromosomal translocation cannot be excluded and warrants further investigation.

Epidermodysplasia verruciformis has been associated with decreased cell-mediated immunity.^1,7 However, nonimmunologic factors likely contribute considering the rarity of EV-like eruptions in immunodeficiency disorders¹¹ as well as its frequent coinfection with HPV type 3¹² and its association with EVER1/TCM6 and EVER2/TCM8.⁸ Epidermodysplasia verruciformis–like lesions have been reported in several immunosuppressed states, including HIV infection,¹³ combined variable immunodeficiency syndrome,¹⁴ IgM deficiency,¹⁵ and CD4⁺ T-cell lymphocytopenia.¹¹ Our patient’s findings fit the latter diagnostic criteria, as she had a chronically low CD4 count of 77 cells/μL, negative HIV titers, and absence of alternative explanation to the lymphopenia. Thus, we could consider her as having EV, as a low CD4 count is a known association. Her immunodeficient state could possibly be attributed to the chromosomal translocation; however, the genetic loci surrounding the chromosomal translocation have not been identified to date, leaving this hypothesis unsubstantiated. Nevertheless, in our otherwise healthy patient, no explanation was found as to why a cell-mediated deficiency would selectively favor a cutaneous HPV infection. According to Zavattaro et al,⁵ a possible cause could be the presence of additional genetic or environmental factors in the patient that predisposed her to this particular infection.

Every patient with EV requires close lifelong observation for skin cancer and education regarding strict sun avoidance and protection.¹ Treatment options for the lesions include topical therapies with imiquimod 5%, immunomodulators, and salicylic acid^16,17; oral isotretinoin¹⁸; and combinations of acitretin and interferon alfa.¹⁹ Physical ablative procedures also have been proposed, including cryotherapy with liquid nitrogen, electrosurgery, surgical excision, and laser therapies.²⁰

Topical immunotherapy with SADBE initially was used to treat refractory alopecia areata and also has been described in the treatment of recalcitrant warts.^21-24 Historically, 2,4-dinitrochlorobenzene was used for contact immunotherapy in wart management but is now avoided due to its mutagenic potential.²⁵ Squaric acid dibutylester and diphenylcyclopropenone currently are the favored contact sensitizers, with a resolution rate of 60% reported in refractory warts.²⁶

Topical immunotherapy involves sensitization of the patient with high-concentration (2%) SADBE on a small surface area until an eczematous dermatitis appears. The rash indicates sensitization has been achieved, and then a lower-concentration SADBE is applied to the warts. Observation of mild contact dermatitis should not be an indication to stop treatment, as this effect is an integral part of therapeutic response. No serious side effects were reported to SADBE; erythema, desquamation, edema, itching, and burning were described.²³

The mechanism of action of SADBE is not clear. The most common proposed theory is the induction of a type IV hypersensitivity reaction in the warts, leading to their destruction. Other authors suggest that wart resolution is caused by a nonspecific inflammatory reaction. An argument in favor of the latter hypothesis is the spontaneous regression of untreated warts in patients treated with SADBE at a remote site, suggesting a mechanism of action beyond a simple cell-mediated process.²³

Epidermodysplasia verruciformis should be included in the differential diagnosis for any eruptive, warty, papular, and plaque-type lesions that appear in immunocompromised individuals. Moreover, the diagnosis of idiopathic CD4⁺ T-cell lymphocytopenia should be considered in any patient with a CD4 count deficit presenting with widespread viral, fungal, or mycobacterial infection with negative HIV test. Appropriate evaluation of the absolute CD4⁺ counts also should be performed. In our case, it was hypothesized that the patient’s balanced chromosomal translocation was related to her lymphopenia and EV, though this correlation has yet to be confirmed. However, it is notable that her son carried the same translocation and has a normal white blood cell count and no evidence of flat warts. This case demonstrates the success of contact immunotherapy in treating these widespread and often recalcitrant lesions.

Endoleaks are common complications following endovascular aneurysm repairs (EVARs) that may occur any time after surgery. There are 5 types of endoleaks with various etiologies. A type V endoleak (also known as endotension) is not considered a true endoleak but instead is characterized by continued aneurysm expansion without a leak, which is demonstrated via imaging tests.¹ Type V endoleaks typically require open aneurysm repair.² We report the case of a 69-year-old woman who presented to our dermatology office for treatment of a suspected lipoma overlying the right mid sternum that was confirmed to be a type V endoleak via computed tomography angiography.

Case Report

A 69-year-old woman was referred to our dermatology office by her primary care physician for evaluation of a subcutaneous mass overlying the right mid sternum, which was a suspected lipoma. The patient reported that the mass had been present for approximately 2 weeks and was enlarging but otherwise asymptomatic. Her medical history was remarkable for hypertension, an ascending aortic aneurysm, and a subsequent aortic valve replacement approximately 2.5 years prior. Her current medications included amlodipine, lisinopril, nebivolol, ibuprofen, and aspirin. She denied use of alcohol, tobacco, or illicit drugs. A review of systems was noncontributory.

Physical examination revealed a single 3.5×4.5-cm, soft, nonmobile subcutaneous mass located at the site of the thoracotomy scar (Figure 1). The mass appeared to have a central attachment to the sternum. No erythema, swelling, or exudate was noted, and the patient denied tenderness on palpation. The diagnosis of lipoma was questioned, and the patient was referred for ultrasonography and computed tomography angiography. Ultrasonography showed a nonspecific chest wall mass with internal blood flow, and computed tomography angiography showed a large, low-attenuation collection of blood around the entire circumference of the ascending aorta, extending from the aortic root to the arch of the aorta. There was extension of the collection of blood through either the sternocostal junction or the sternotomy defect into the subcutaneous tissue anterior to the sternum (Figure 2). Findings were most consistent with a type V endoleak, and the patient was referred to a cardiothoracic surgeon for treatment. We later learned that our patient died during surgery attempting to repair the aneurysm approximately 2 weeks after her presentation to our office.

Figure 1. Nontender nonmobile subcutaneous mass located overlying the right mid sternum.

Comment

An endoleak is a common complication following an EVAR that is characterized by persistent blood flow within the aneurysm sac. Endoleaks have been described as the Achilles’ heel of EVARs.¹ The goal of an EVAR is to create a complete seal so that the flow of blood completely excludes the aneurysm, thus ultimately preventing an aneurysm rupture. An endoleak results when there is failure to obtain a complete seal due to a variety of different mechanisms. White et al³ first described and classified endoleaks in 1997. The initial terminology used to classify endoleaks was based on timing (primary or secondary/late) and location (graft related/perigraft or non–graft related/retrograde). Today, endoleaks are classified into 5 types, 3 of which are considered true endoleaks and 2 of which are not.⁴ Type I endoleaks result from a failure to create an adequate seal at one of the attachments of the graft to the vessel wall. Type II endoleaks are due to retrograde flow through collateral vessels into the aneurysm sac. They are much more common than type I, occurring in 10% to 25% of abdominal endograft cases. The last true endoleak, type III, occurs due to device failure in the form of disjunction of the components of the graft system (type IIIa) or a defect in the graft fabric (type IIIb). Type IV and type V endoleaks are not considered to be true endoleaks. Type IV endoleaks are due to the porosity of the graft material and have virtually been eliminated by changes in graft materials to decrease porosity. Type V endoleaks are characterized by continued blood flow into the aneurysm without any evidence of a leak on any imaging modality. Type V endoleaks are poorly understood but are believed to be due to pulsation of the graft wall, which is transmitted through the perivascular space to the aneurysm wall.⁴

Figure 2. Transverse (A) and sagittal (B) sections of the computed tomography angiography illustrating a type V endoleak.

Treatment of type V endoleaks is controversial. It is important to characterize the endoleak by various imaging modalities, and if a type V endoleak is confirmed, an open aneurysm repair often is required.² A case of nonsurgical management of a type V endoleak has been described but is rare.⁵ In this case, the patient was referred to our dermatology office by her primary care physician for what appeared to be a benign lipoma, but it proved to be a type V endoleak on further examination. It is imperative that dermatologists are aware of endoleaks as common complications of EVARs, as they can be life threatening and usually require surgical intervention.

Conclusion

Endoleaks are common complications of EVARs. Dermatologists may encounter endoleaks that have been misdiagnosed as benign subcutaneous masses such as lipomas. It is imperative that dermatologists are aware of endoleaks, and patients who present with subcutaneous thoracic masses with a history of aneurysm repair require imaging, including computed tomography angiography, and referral to a cardiothoracic surgeon if appropriate.

Endoleaks are common complications following endovascular aneurysm repairs (EVARs) that may occur any time after surgery. There are 5 types of endoleaks with various etiologies. A type V endoleak (also known as endotension) is not considered a true endoleak but instead is characterized by continued aneurysm expansion without a leak, which is demonstrated via imaging tests.¹ Type V endoleaks typically require open aneurysm repair.² We report the case of a 69-year-old woman who presented to our dermatology office for treatment of a suspected lipoma overlying the right mid sternum that was confirmed to be a type V endoleak via computed tomography angiography.

Case Report

A 69-year-old woman was referred to our dermatology office by her primary care physician for evaluation of a subcutaneous mass overlying the right mid sternum, which was a suspected lipoma. The patient reported that the mass had been present for approximately 2 weeks and was enlarging but otherwise asymptomatic. Her medical history was remarkable for hypertension, an ascending aortic aneurysm, and a subsequent aortic valve replacement approximately 2.5 years prior. Her current medications included amlodipine, lisinopril, nebivolol, ibuprofen, and aspirin. She denied use of alcohol, tobacco, or illicit drugs. A review of systems was noncontributory.

Physical examination revealed a single 3.5×4.5-cm, soft, nonmobile subcutaneous mass located at the site of the thoracotomy scar (Figure 1). The mass appeared to have a central attachment to the sternum. No erythema, swelling, or exudate was noted, and the patient denied tenderness on palpation. The diagnosis of lipoma was questioned, and the patient was referred for ultrasonography and computed tomography angiography. Ultrasonography showed a nonspecific chest wall mass with internal blood flow, and computed tomography angiography showed a large, low-attenuation collection of blood around the entire circumference of the ascending aorta, extending from the aortic root to the arch of the aorta. There was extension of the collection of blood through either the sternocostal junction or the sternotomy defect into the subcutaneous tissue anterior to the sternum (Figure 2). Findings were most consistent with a type V endoleak, and the patient was referred to a cardiothoracic surgeon for treatment. We later learned that our patient died during surgery attempting to repair the aneurysm approximately 2 weeks after her presentation to our office.

Figure 1. Nontender nonmobile subcutaneous mass located overlying the right mid sternum.

Comment

An endoleak is a common complication following an EVAR that is characterized by persistent blood flow within the aneurysm sac. Endoleaks have been described as the Achilles’ heel of EVARs.¹ The goal of an EVAR is to create a complete seal so that the flow of blood completely excludes the aneurysm, thus ultimately preventing an aneurysm rupture. An endoleak results when there is failure to obtain a complete seal due to a variety of different mechanisms. White et al³ first described and classified endoleaks in 1997. The initial terminology used to classify endoleaks was based on timing (primary or secondary/late) and location (graft related/perigraft or non–graft related/retrograde). Today, endoleaks are classified into 5 types, 3 of which are considered true endoleaks and 2 of which are not.⁴ Type I endoleaks result from a failure to create an adequate seal at one of the attachments of the graft to the vessel wall. Type II endoleaks are due to retrograde flow through collateral vessels into the aneurysm sac. They are much more common than type I, occurring in 10% to 25% of abdominal endograft cases. The last true endoleak, type III, occurs due to device failure in the form of disjunction of the components of the graft system (type IIIa) or a defect in the graft fabric (type IIIb). Type IV and type V endoleaks are not considered to be true endoleaks. Type IV endoleaks are due to the porosity of the graft material and have virtually been eliminated by changes in graft materials to decrease porosity. Type V endoleaks are characterized by continued blood flow into the aneurysm without any evidence of a leak on any imaging modality. Type V endoleaks are poorly understood but are believed to be due to pulsation of the graft wall, which is transmitted through the perivascular space to the aneurysm wall.⁴

Figure 2. Transverse (A) and sagittal (B) sections of the computed tomography angiography illustrating a type V endoleak.

Treatment of type V endoleaks is controversial. It is important to characterize the endoleak by various imaging modalities, and if a type V endoleak is confirmed, an open aneurysm repair often is required.² A case of nonsurgical management of a type V endoleak has been described but is rare.⁵ In this case, the patient was referred to our dermatology office by her primary care physician for what appeared to be a benign lipoma, but it proved to be a type V endoleak on further examination. It is imperative that dermatologists are aware of endoleaks as common complications of EVARs, as they can be life threatening and usually require surgical intervention.

Conclusion

Endoleaks are common complications of EVARs. Dermatologists may encounter endoleaks that have been misdiagnosed as benign subcutaneous masses such as lipomas. It is imperative that dermatologists are aware of endoleaks, and patients who present with subcutaneous thoracic masses with a history of aneurysm repair require imaging, including computed tomography angiography, and referral to a cardiothoracic surgeon if appropriate.

Endoleaks are common complications following endovascular aneurysm repairs (EVARs) that may occur any time after surgery. There are 5 types of endoleaks with various etiologies. A type V endoleak (also known as endotension) is not considered a true endoleak but instead is characterized by continued aneurysm expansion without a leak, which is demonstrated via imaging tests.¹ Type V endoleaks typically require open aneurysm repair.² We report the case of a 69-year-old woman who presented to our dermatology office for treatment of a suspected lipoma overlying the right mid sternum that was confirmed to be a type V endoleak via computed tomography angiography.

Case Report

A 69-year-old woman was referred to our dermatology office by her primary care physician for evaluation of a subcutaneous mass overlying the right mid sternum, which was a suspected lipoma. The patient reported that the mass had been present for approximately 2 weeks and was enlarging but otherwise asymptomatic. Her medical history was remarkable for hypertension, an ascending aortic aneurysm, and a subsequent aortic valve replacement approximately 2.5 years prior. Her current medications included amlodipine, lisinopril, nebivolol, ibuprofen, and aspirin. She denied use of alcohol, tobacco, or illicit drugs. A review of systems was noncontributory.

Physical examination revealed a single 3.5×4.5-cm, soft, nonmobile subcutaneous mass located at the site of the thoracotomy scar (Figure 1). The mass appeared to have a central attachment to the sternum. No erythema, swelling, or exudate was noted, and the patient denied tenderness on palpation. The diagnosis of lipoma was questioned, and the patient was referred for ultrasonography and computed tomography angiography. Ultrasonography showed a nonspecific chest wall mass with internal blood flow, and computed tomography angiography showed a large, low-attenuation collection of blood around the entire circumference of the ascending aorta, extending from the aortic root to the arch of the aorta. There was extension of the collection of blood through either the sternocostal junction or the sternotomy defect into the subcutaneous tissue anterior to the sternum (Figure 2). Findings were most consistent with a type V endoleak, and the patient was referred to a cardiothoracic surgeon for treatment. We later learned that our patient died during surgery attempting to repair the aneurysm approximately 2 weeks after her presentation to our office.

Figure 1. Nontender nonmobile subcutaneous mass located overlying the right mid sternum.

Comment

An endoleak is a common complication following an EVAR that is characterized by persistent blood flow within the aneurysm sac. Endoleaks have been described as the Achilles’ heel of EVARs.¹ The goal of an EVAR is to create a complete seal so that the flow of blood completely excludes the aneurysm, thus ultimately preventing an aneurysm rupture. An endoleak results when there is failure to obtain a complete seal due to a variety of different mechanisms. White et al³ first described and classified endoleaks in 1997. The initial terminology used to classify endoleaks was based on timing (primary or secondary/late) and location (graft related/perigraft or non–graft related/retrograde). Today, endoleaks are classified into 5 types, 3 of which are considered true endoleaks and 2 of which are not.⁴ Type I endoleaks result from a failure to create an adequate seal at one of the attachments of the graft to the vessel wall. Type II endoleaks are due to retrograde flow through collateral vessels into the aneurysm sac. They are much more common than type I, occurring in 10% to 25% of abdominal endograft cases. The last true endoleak, type III, occurs due to device failure in the form of disjunction of the components of the graft system (type IIIa) or a defect in the graft fabric (type IIIb). Type IV and type V endoleaks are not considered to be true endoleaks. Type IV endoleaks are due to the porosity of the graft material and have virtually been eliminated by changes in graft materials to decrease porosity. Type V endoleaks are characterized by continued blood flow into the aneurysm without any evidence of a leak on any imaging modality. Type V endoleaks are poorly understood but are believed to be due to pulsation of the graft wall, which is transmitted through the perivascular space to the aneurysm wall.⁴

Figure 2. Transverse (A) and sagittal (B) sections of the computed tomography angiography illustrating a type V endoleak.

Treatment of type V endoleaks is controversial. It is important to characterize the endoleak by various imaging modalities, and if a type V endoleak is confirmed, an open aneurysm repair often is required.² A case of nonsurgical management of a type V endoleak has been described but is rare.⁵ In this case, the patient was referred to our dermatology office by her primary care physician for what appeared to be a benign lipoma, but it proved to be a type V endoleak on further examination. It is imperative that dermatologists are aware of endoleaks as common complications of EVARs, as they can be life threatening and usually require surgical intervention.

Conclusion

Endoleaks are common complications of EVARs. Dermatologists may encounter endoleaks that have been misdiagnosed as benign subcutaneous masses such as lipomas. It is imperative that dermatologists are aware of endoleaks, and patients who present with subcutaneous thoracic masses with a history of aneurysm repair require imaging, including computed tomography angiography, and referral to a cardiothoracic surgeon if appropriate.