Case Reports

Torsades de pointes (TdP) is a life-threatening ventricular arrhythmia that is associated with both congenital and acquired QT interval prolongation. QT interval prolongation is commonly observed in acute alcohol withdrawal and cirrhotic cardiomyopathy.^1-3 In both conditions, there is a positive correlation between the degree of QT interval prolongation and disease severity.^4,5 The precise mechanisms of QT interval prolongation in these conditions are not well understood. One hypothesis is that autonomic hyperexcitability results in altered ventricular repolarization and QT interval prolongation. This mechanism of QT prolongation has been found in acute alcohol withdrawal independent of electrolyte abnormalities, use of QT-prolonging medications, and cirrhosis.^1,2,6

The authors report the case of a veteran who was hospitalized for acute alcohol withdrawal and decompensated cirrhosis and was found to have a newly prolonged QT interval. On hospital day 3, the patient developed TdP, which required external defibrillation. Despite correction of electrolyte abnormalities, abstinence from alcohol, avoidance of QT-prolonging medications, and exclusion of cardiac ischemia, there was significant and persistent prolongation of the QT interval—ultimately attributed to cirrhotic cardiomyopathy. Acquired QT interval prolongation is common in both acute alcohol withdrawal and cirrhosis.This case highlights the importance of close monitoring of the QT interval and TdP susceptibility in patients being treated for acute alcohol withdrawal, particularly those with cirrhosis.

Case Report

A 66-year-old male veteran with a 35-year history of alcohol dependence presented for alcohol detoxification. He reported having drunk at least 32 ounces of vodka every day of the preceding 5 years and reported having unsuccessfully attempted self-detoxification several times. Prior detoxification efforts were unsuccessful because of intractable nausea and tremulousness. Additional presenting symptoms included lethargy, anorexia, and a fall with transient right-side hemiparesis (findings on magnetic resonance imaging of the head had been normal).

His medical history included type 2 diabetes, tobacco dependence, and macular degeneration. The only medication being taken was glargine 25 units daily. On admission, the patient was afebrile (98.1°F), normotensive (103/77 mm Hg), and oriented to person, place, and time. Examination also revealed a protuberant abdomen with caput medusae, and no shifting dullness or lower extremity edema. The neurologic examination was nonfocal.

Laboratory test results on admission were significant for elevated serum alcohol level (243.8 mg/dL); elevated levels of aspartate aminotransferase (144 units/L) alanine aminotransferase (25 units/L), and total bilirubin (4.2 mg/L); hypoalbuminemia; normocalemia; hypomagnesemia; normal corrected calcium level; and normal renal function (0.84 mg/dL)(Table). The patient’s admission Child-Pugh score of 10 indicated class C liver disease. Admission electrocardiogram (EKG) revealed normal sinus rhythm, first-degree atrioventricular block, and prolongation of the QTc interval (519 ms). Six years earlier, the patient’s QTc interval had been 409 ms (Figures 1 and 2). As QT interval depends on heart rate, it is most commonly expressed as corrected QT, or QTc, where QTc = QT/(√RR).

Symptom-triggered therapy for alcohol withdrawal was instituted, and the patient’s electrolyte abnormalities were corrected. Telemetry monitoring demonstrated polymorphic ventricular ectopy, including a 6.8-s run of polymorphic ventricular tachycardia and several shorter runs (4-10 beats) of nonsustained ventricular tachycardia, prompting initiation of a low-dose beta blocker. Based on elevated scores on the symptom-triggered scale for alcohol withdrawal, the Clinical Institute Withdrawal Assessement for Alcohol Withdrawal (CIWA), several doses of oral lorazepam were given for withdrawal symptoms.

The patient became increasingly confused, and new-onset nystagmus was noted. These findings raised concern for Wernicke encephalopathy, so the patient was empirically started on IV high-dose thiamine supplementation. The CIWA scores remained high, and there were frequent episodes of ventricular ectopy during the first 2 hospital days. Interval EKG revealed further prolongation of the QTc interval (549 ms) without evidence of cardiac ischemia (Figure 3). Cardiac enzymes were negative, and electrolyte levels were within normal limits.

Discussion

Alcohol dependence is a common chronic and relapsing disease that often requires controlled detoxification. Investigators have found a high incidence of QT interval prolongation in alcohol withdrawal and hepatic disease.^3,6 Common causes of QT interval prolongation in this setting are poor nutrition, electrolyte abnormalities (particularly hypocalcemia and hypomagnesemia), and use of certain medications.^1-3,7,8 In addition, alcohol is directly toxic to the renal tubules, resulting in renal wasting of divalent cations, which may persist up to 30 days after the most recent alcohol exposure.^9,10

The patient in this case report was initially thought to have hypomagnesemia-induced long QT syndrome (leading to TdP cardiac arrest), but the authors’ review of laboratory test results revealed the QT interval remained markedly prolonged, despite adequate correction of hypomagnesemia implicating the hyperadrenergic state of acute alcohol withdrawal in QT interval prolongation and TdP cardiac arrest. Interestingly, the QT interval remained prolonged 2 months after TdP arrest, despite sustained normalization of electrolyte levels and the absence of active ischemia or use of QT-prolonging medications.

Given the exclusion of other causes of QT interval prolongation, the authors hypothesized that autonomic hyperactivity of acute alcohol withdrawal and resultant QT interval prolongation were potentiated by underlying cirrhotic cardiomyopathy, a well described cause of QT interval prolongation. Cirrhotic cardiomyopathy is thought to cause QT interval prolongation by delayed repolarization of cardiomyocytes and promotion of sympatho-adrenergic hyperactivity.⁶ In other case series, TdP development has been associated with severe withdrawal symptoms, particularly delirium tremens.² In cirrhosis, QT interval prolongation often is described as an early manifestation of cirrhotic cardiomyopathy, irrespective of the underlying etiology, and precedes systolic and diastolic dysfunction.⁶

The magnitude of QT prolongation has been associated with severity of liver disease as expressed by Child-Pugh score, with reports of QT normalization after liver transplantation.^4,5 Patients with higher Child-Pugh scores should be considered to be at elevated risk for malignant ventricular arrhythmias. The authors recommend checking an EKG on admission of any patient who has liver disease or has presented for alcohol withdrawal. Patients with a prolonged QTc interval should be monitored on telemetry. The authors also recommend aggressive repletion of electrolytes, particularly potassium and magnesium, in patients who present with cirrhosis and alcohol withdrawal.

Avoidance of QT-prolonging medications is advisable for all patients with a long QT interval. Beta blockers shorten the QT interval in cirrhotic patients, but the role of beta blockers in preventing malignant arrhythmias in this group of patients is not yet clear.¹¹ The present patient’s QT interval had been normal before he developed cirrhotic liver disease. His presentation was suggestive of acquired long QT syndrome, likely caused by cirrhotic cardiomyopathy given the exhaustive exclusion of other causes of QT interval prolongation.

Conclusion

This case highlights the importance of close monitoring of the QT interval in patients being treated for acute alcohol withdrawal, particularly those with cirrhosis, and suggests that timely and aggressive management of withdrawal, repletion of electrolytes, and telemetry monitoring may prevent life-threatening arrhythmia.

Torsades de pointes (TdP) is a life-threatening ventricular arrhythmia that is associated with both congenital and acquired QT interval prolongation. QT interval prolongation is commonly observed in acute alcohol withdrawal and cirrhotic cardiomyopathy.^1-3 In both conditions, there is a positive correlation between the degree of QT interval prolongation and disease severity.^4,5 The precise mechanisms of QT interval prolongation in these conditions are not well understood. One hypothesis is that autonomic hyperexcitability results in altered ventricular repolarization and QT interval prolongation. This mechanism of QT prolongation has been found in acute alcohol withdrawal independent of electrolyte abnormalities, use of QT-prolonging medications, and cirrhosis.^1,2,6

The authors report the case of a veteran who was hospitalized for acute alcohol withdrawal and decompensated cirrhosis and was found to have a newly prolonged QT interval. On hospital day 3, the patient developed TdP, which required external defibrillation. Despite correction of electrolyte abnormalities, abstinence from alcohol, avoidance of QT-prolonging medications, and exclusion of cardiac ischemia, there was significant and persistent prolongation of the QT interval—ultimately attributed to cirrhotic cardiomyopathy. Acquired QT interval prolongation is common in both acute alcohol withdrawal and cirrhosis.This case highlights the importance of close monitoring of the QT interval and TdP susceptibility in patients being treated for acute alcohol withdrawal, particularly those with cirrhosis.

Case Report

A 66-year-old male veteran with a 35-year history of alcohol dependence presented for alcohol detoxification. He reported having drunk at least 32 ounces of vodka every day of the preceding 5 years and reported having unsuccessfully attempted self-detoxification several times. Prior detoxification efforts were unsuccessful because of intractable nausea and tremulousness. Additional presenting symptoms included lethargy, anorexia, and a fall with transient right-side hemiparesis (findings on magnetic resonance imaging of the head had been normal).

His medical history included type 2 diabetes, tobacco dependence, and macular degeneration. The only medication being taken was glargine 25 units daily. On admission, the patient was afebrile (98.1°F), normotensive (103/77 mm Hg), and oriented to person, place, and time. Examination also revealed a protuberant abdomen with caput medusae, and no shifting dullness or lower extremity edema. The neurologic examination was nonfocal.

Laboratory test results on admission were significant for elevated serum alcohol level (243.8 mg/dL); elevated levels of aspartate aminotransferase (144 units/L) alanine aminotransferase (25 units/L), and total bilirubin (4.2 mg/L); hypoalbuminemia; normocalemia; hypomagnesemia; normal corrected calcium level; and normal renal function (0.84 mg/dL)(Table). The patient’s admission Child-Pugh score of 10 indicated class C liver disease. Admission electrocardiogram (EKG) revealed normal sinus rhythm, first-degree atrioventricular block, and prolongation of the QTc interval (519 ms). Six years earlier, the patient’s QTc interval had been 409 ms (Figures 1 and 2). As QT interval depends on heart rate, it is most commonly expressed as corrected QT, or QTc, where QTc = QT/(√RR).

Symptom-triggered therapy for alcohol withdrawal was instituted, and the patient’s electrolyte abnormalities were corrected. Telemetry monitoring demonstrated polymorphic ventricular ectopy, including a 6.8-s run of polymorphic ventricular tachycardia and several shorter runs (4-10 beats) of nonsustained ventricular tachycardia, prompting initiation of a low-dose beta blocker. Based on elevated scores on the symptom-triggered scale for alcohol withdrawal, the Clinical Institute Withdrawal Assessement for Alcohol Withdrawal (CIWA), several doses of oral lorazepam were given for withdrawal symptoms.

The patient became increasingly confused, and new-onset nystagmus was noted. These findings raised concern for Wernicke encephalopathy, so the patient was empirically started on IV high-dose thiamine supplementation. The CIWA scores remained high, and there were frequent episodes of ventricular ectopy during the first 2 hospital days. Interval EKG revealed further prolongation of the QTc interval (549 ms) without evidence of cardiac ischemia (Figure 3). Cardiac enzymes were negative, and electrolyte levels were within normal limits.

Discussion

Alcohol dependence is a common chronic and relapsing disease that often requires controlled detoxification. Investigators have found a high incidence of QT interval prolongation in alcohol withdrawal and hepatic disease.^3,6 Common causes of QT interval prolongation in this setting are poor nutrition, electrolyte abnormalities (particularly hypocalcemia and hypomagnesemia), and use of certain medications.^1-3,7,8 In addition, alcohol is directly toxic to the renal tubules, resulting in renal wasting of divalent cations, which may persist up to 30 days after the most recent alcohol exposure.^9,10

The patient in this case report was initially thought to have hypomagnesemia-induced long QT syndrome (leading to TdP cardiac arrest), but the authors’ review of laboratory test results revealed the QT interval remained markedly prolonged, despite adequate correction of hypomagnesemia implicating the hyperadrenergic state of acute alcohol withdrawal in QT interval prolongation and TdP cardiac arrest. Interestingly, the QT interval remained prolonged 2 months after TdP arrest, despite sustained normalization of electrolyte levels and the absence of active ischemia or use of QT-prolonging medications.

Given the exclusion of other causes of QT interval prolongation, the authors hypothesized that autonomic hyperactivity of acute alcohol withdrawal and resultant QT interval prolongation were potentiated by underlying cirrhotic cardiomyopathy, a well described cause of QT interval prolongation. Cirrhotic cardiomyopathy is thought to cause QT interval prolongation by delayed repolarization of cardiomyocytes and promotion of sympatho-adrenergic hyperactivity.⁶ In other case series, TdP development has been associated with severe withdrawal symptoms, particularly delirium tremens.² In cirrhosis, QT interval prolongation often is described as an early manifestation of cirrhotic cardiomyopathy, irrespective of the underlying etiology, and precedes systolic and diastolic dysfunction.⁶

The magnitude of QT prolongation has been associated with severity of liver disease as expressed by Child-Pugh score, with reports of QT normalization after liver transplantation.^4,5 Patients with higher Child-Pugh scores should be considered to be at elevated risk for malignant ventricular arrhythmias. The authors recommend checking an EKG on admission of any patient who has liver disease or has presented for alcohol withdrawal. Patients with a prolonged QTc interval should be monitored on telemetry. The authors also recommend aggressive repletion of electrolytes, particularly potassium and magnesium, in patients who present with cirrhosis and alcohol withdrawal.

Avoidance of QT-prolonging medications is advisable for all patients with a long QT interval. Beta blockers shorten the QT interval in cirrhotic patients, but the role of beta blockers in preventing malignant arrhythmias in this group of patients is not yet clear.¹¹ The present patient’s QT interval had been normal before he developed cirrhotic liver disease. His presentation was suggestive of acquired long QT syndrome, likely caused by cirrhotic cardiomyopathy given the exhaustive exclusion of other causes of QT interval prolongation.

Conclusion

This case highlights the importance of close monitoring of the QT interval in patients being treated for acute alcohol withdrawal, particularly those with cirrhosis, and suggests that timely and aggressive management of withdrawal, repletion of electrolytes, and telemetry monitoring may prevent life-threatening arrhythmia.

Torsades de pointes (TdP) is a life-threatening ventricular arrhythmia that is associated with both congenital and acquired QT interval prolongation. QT interval prolongation is commonly observed in acute alcohol withdrawal and cirrhotic cardiomyopathy.^1-3 In both conditions, there is a positive correlation between the degree of QT interval prolongation and disease severity.^4,5 The precise mechanisms of QT interval prolongation in these conditions are not well understood. One hypothesis is that autonomic hyperexcitability results in altered ventricular repolarization and QT interval prolongation. This mechanism of QT prolongation has been found in acute alcohol withdrawal independent of electrolyte abnormalities, use of QT-prolonging medications, and cirrhosis.^1,2,6

The authors report the case of a veteran who was hospitalized for acute alcohol withdrawal and decompensated cirrhosis and was found to have a newly prolonged QT interval. On hospital day 3, the patient developed TdP, which required external defibrillation. Despite correction of electrolyte abnormalities, abstinence from alcohol, avoidance of QT-prolonging medications, and exclusion of cardiac ischemia, there was significant and persistent prolongation of the QT interval—ultimately attributed to cirrhotic cardiomyopathy. Acquired QT interval prolongation is common in both acute alcohol withdrawal and cirrhosis.This case highlights the importance of close monitoring of the QT interval and TdP susceptibility in patients being treated for acute alcohol withdrawal, particularly those with cirrhosis.

Case Report

A 66-year-old male veteran with a 35-year history of alcohol dependence presented for alcohol detoxification. He reported having drunk at least 32 ounces of vodka every day of the preceding 5 years and reported having unsuccessfully attempted self-detoxification several times. Prior detoxification efforts were unsuccessful because of intractable nausea and tremulousness. Additional presenting symptoms included lethargy, anorexia, and a fall with transient right-side hemiparesis (findings on magnetic resonance imaging of the head had been normal).

His medical history included type 2 diabetes, tobacco dependence, and macular degeneration. The only medication being taken was glargine 25 units daily. On admission, the patient was afebrile (98.1°F), normotensive (103/77 mm Hg), and oriented to person, place, and time. Examination also revealed a protuberant abdomen with caput medusae, and no shifting dullness or lower extremity edema. The neurologic examination was nonfocal.

Laboratory test results on admission were significant for elevated serum alcohol level (243.8 mg/dL); elevated levels of aspartate aminotransferase (144 units/L) alanine aminotransferase (25 units/L), and total bilirubin (4.2 mg/L); hypoalbuminemia; normocalemia; hypomagnesemia; normal corrected calcium level; and normal renal function (0.84 mg/dL)(Table). The patient’s admission Child-Pugh score of 10 indicated class C liver disease. Admission electrocardiogram (EKG) revealed normal sinus rhythm, first-degree atrioventricular block, and prolongation of the QTc interval (519 ms). Six years earlier, the patient’s QTc interval had been 409 ms (Figures 1 and 2). As QT interval depends on heart rate, it is most commonly expressed as corrected QT, or QTc, where QTc = QT/(√RR).

Symptom-triggered therapy for alcohol withdrawal was instituted, and the patient’s electrolyte abnormalities were corrected. Telemetry monitoring demonstrated polymorphic ventricular ectopy, including a 6.8-s run of polymorphic ventricular tachycardia and several shorter runs (4-10 beats) of nonsustained ventricular tachycardia, prompting initiation of a low-dose beta blocker. Based on elevated scores on the symptom-triggered scale for alcohol withdrawal, the Clinical Institute Withdrawal Assessement for Alcohol Withdrawal (CIWA), several doses of oral lorazepam were given for withdrawal symptoms.

The patient became increasingly confused, and new-onset nystagmus was noted. These findings raised concern for Wernicke encephalopathy, so the patient was empirically started on IV high-dose thiamine supplementation. The CIWA scores remained high, and there were frequent episodes of ventricular ectopy during the first 2 hospital days. Interval EKG revealed further prolongation of the QTc interval (549 ms) without evidence of cardiac ischemia (Figure 3). Cardiac enzymes were negative, and electrolyte levels were within normal limits.

Discussion

Alcohol dependence is a common chronic and relapsing disease that often requires controlled detoxification. Investigators have found a high incidence of QT interval prolongation in alcohol withdrawal and hepatic disease.^3,6 Common causes of QT interval prolongation in this setting are poor nutrition, electrolyte abnormalities (particularly hypocalcemia and hypomagnesemia), and use of certain medications.^1-3,7,8 In addition, alcohol is directly toxic to the renal tubules, resulting in renal wasting of divalent cations, which may persist up to 30 days after the most recent alcohol exposure.^9,10

The patient in this case report was initially thought to have hypomagnesemia-induced long QT syndrome (leading to TdP cardiac arrest), but the authors’ review of laboratory test results revealed the QT interval remained markedly prolonged, despite adequate correction of hypomagnesemia implicating the hyperadrenergic state of acute alcohol withdrawal in QT interval prolongation and TdP cardiac arrest. Interestingly, the QT interval remained prolonged 2 months after TdP arrest, despite sustained normalization of electrolyte levels and the absence of active ischemia or use of QT-prolonging medications.

Given the exclusion of other causes of QT interval prolongation, the authors hypothesized that autonomic hyperactivity of acute alcohol withdrawal and resultant QT interval prolongation were potentiated by underlying cirrhotic cardiomyopathy, a well described cause of QT interval prolongation. Cirrhotic cardiomyopathy is thought to cause QT interval prolongation by delayed repolarization of cardiomyocytes and promotion of sympatho-adrenergic hyperactivity.⁶ In other case series, TdP development has been associated with severe withdrawal symptoms, particularly delirium tremens.² In cirrhosis, QT interval prolongation often is described as an early manifestation of cirrhotic cardiomyopathy, irrespective of the underlying etiology, and precedes systolic and diastolic dysfunction.⁶

The magnitude of QT prolongation has been associated with severity of liver disease as expressed by Child-Pugh score, with reports of QT normalization after liver transplantation.^4,5 Patients with higher Child-Pugh scores should be considered to be at elevated risk for malignant ventricular arrhythmias. The authors recommend checking an EKG on admission of any patient who has liver disease or has presented for alcohol withdrawal. Patients with a prolonged QTc interval should be monitored on telemetry. The authors also recommend aggressive repletion of electrolytes, particularly potassium and magnesium, in patients who present with cirrhosis and alcohol withdrawal.

Avoidance of QT-prolonging medications is advisable for all patients with a long QT interval. Beta blockers shorten the QT interval in cirrhotic patients, but the role of beta blockers in preventing malignant arrhythmias in this group of patients is not yet clear.¹¹ The present patient’s QT interval had been normal before he developed cirrhotic liver disease. His presentation was suggestive of acquired long QT syndrome, likely caused by cirrhotic cardiomyopathy given the exhaustive exclusion of other causes of QT interval prolongation.

Conclusion

This case highlights the importance of close monitoring of the QT interval in patients being treated for acute alcohol withdrawal, particularly those with cirrhosis, and suggests that timely and aggressive management of withdrawal, repletion of electrolytes, and telemetry monitoring may prevent life-threatening arrhythmia.

Bullous pemphigoid (BP) is the most common autoimmune blistering disease. The classic presentation of BP is a generalized, pruritic, bullous eruption in elderly patients, which is occasionally preceded by an urticarial prodrome. Immunopathologically, BP is characterized by IgG and sometimes IgE autoantibodies that target basement membrane zone proteins BP180 and BP230 of the epidermis.¹

The diagnosis of BP should be suspected when an elderly patient presents with tense blisters and can be confirmed via diagnostic testing, including tissue histology and direct immunofluorescence (DIF) as the gold standard, as well as indirect immunofluorescence (IIF), enzyme-linked immunosorbent assay (ELISA), and most recently biochip technology as supportive tests.² Since its advent, ELISA has gained popularity as a trustworthy diagnostic test for BP. The specificity of ELISA for BP diagnosis is reported to be 98% to 100%, which leads clinicians to believe that a positive ELISA equals certain diagnosis of BP; however, misdiagnosis of BP based on a positive ELISA result can occur.^3-13 The treatment of BP often involves lifelong immunosuppressive therapy. Complications of immunosuppressive therapy contribute to morbidity and mortality in these patients, thus an accurate diagnosis is paramount before introducing therapy.¹⁴

We present the case of a 74-year-old man with a history of a pruritic nonbullous eruption who was diagnosed with BP and treated for 3 years based on positive ELISA results in the absence of confirmatory histology or DIF.

Case Report

A 74-year-old man with diabetes mellitus, hypertension, hyperlipidemia, benign prostatic hypertrophy, and obstructive sleep apnea presented for further evaluation and confirmation of a prior diagnosis of BP by an outside dermatologist. He reported a pruritic rash on the trunk, back, and extremities of 3 years’ duration. He denied occurrence of blisters at any time.

On presentation to an outside dermatologist 3 years ago, a biopsy was performed along with serologic studies due to the patient’s age and the possibility of an urticarial prodrome in BP. The biopsy revealed epidermal acanthosis, subepidermal separation, and a perivascular and interstitial infiltrate of lymphocytes and eosinophils in the papillary dermis. Direct immunofluorescence was nondiagnostic with a weak discontinuous pattern of IgG and IgA linearly along the basement membrane zone as well as few scattered and clumped cytoid bodies of IgM and IgA. Indirect immunofluoresence revealed a positive IgG titer of 1:40 on monkey esophagus substrate and a positive epidermal pattern on human split-skin substrate with a titer of 1:80. An ELISA for IgG autoantibodies against BP180 and BP230 yielded 15 U and 6 U, respectively (cut off value, 9 U). Based on the positive ELISA for IgG against BP180, a diagnosis of BP was made.

Over the following 3 years, the treatment included prednisone, tetracycline, nicotinamide, doxycycline, and dapsone. Therapy was suboptimal due to the patient’s comorbidities and socioeconomic status. Poorly controlled diabetes mellitus precluded consistent use of prednisone as recommended for BP. Tetracycline and nicotinamide were transiently effective in controlling the patient’s symptoms but were discontinued due to changes in his health insurance. Doxycycline and dapsone were ineffective. Throughout this 3-year period, the patient remained blister free, but the pruritic eruption was persistent.

The patient presented to our clinic due to his frustration with the lack of improvement and doubts about the BP diagnosis given the persistent absence of bullous lesions. Physical examination revealed numerous eroded, scaly, crusted papules on erythematous edematous plaques on all extremities, trunk, and back (Figure 1). The head, neck, face, and oral mucosa were spared. His history and clinical findings were atypical for BP and skin biopsies were performed. Histology revealed epidermal erosion with parakeratosis, spongiosis, and superficial perivascular lymphocytic inflammation with rare eosinophils without subepidermal split (Figure 2). Direct immunofluorescence was negative for IgG, IgA, IgM, C3, and C1q. Additionally, further review of the initial histology by another dermatopathologist revealed that the subepidermal separation reported was more likely artifactual clefts. These findings were not consistent with BP.

Given the patient’s clinical history, lack of bullae, and twice-negative DIF, the diagnosis was determined to be more consistent with eczematous spongiotic dermatitis. He refused a referral for phototherapy due to scheduling inconvenience. The patient was started on cyclosporine 0.5 mg/kg twice daily. After 10 days of treatment, he returned for follow-up and reported notable improvement in the pruritus. On physical examination, his dermatitis was improved with decreased erythema and inflammation.

The patient is being continued on extensive dry skin care with thick moisturizers and additional topical corticosteroid application on an as-needed basis.

Comment

Chronic immunosuppression contributes to morbidity and mortality in patients with BP; therefore, accurate diagnosis of BP is of utmost importance.¹⁴ A meta-analysis described ELISA as a test with high sensitivity and specificity (87% and 98%–100%, respectively) for diagnosis of BP.³ Nevertheless, there are opportunities for misdiagnosis using ELISA, as demonstrated in our case. To determine if the reported sensitivity and specificity of ELISA is accurate and reliable for clinical use, individual studies from the meta-analysis were reviewed.^{4,5,7-10,13,15} Issues identified in our review included dissimilar diagnostic procedures and patient populations among individual studies, several reports of positive ELISA in patients without BP, and a lack of explanation for these false-positive results.

There are notable differences in diagnostic procedures and patient populations among reports that establish the sensitivity and specificity of ELISA for BP diagnosis.^3-13 Studies have detected IgG that targets the NC16A domain of the BP180 kD antigen, the C-terminal of the BP180 kD antigen, or the entire ectodomain of the BP180 kD antigen. Study patient populations varied in disease activity, stage, and treatment. Control patients included healthy patients as well as those with many dermatoses, including pemphigus vulgaris, systemic scleroderma, systemic lupus erythematosus, rheumatoid arthritis, lichen planus, and discoid lupus erythematosus.^3-13 Due to these differences between individual studies, we believe the results that determine the overall sensitivity and specificity of ELISA for BP diagnosis must be interpreted with caution. For ELISA statistics to be clinically applicable to a specific patient, he/she should be similar to the patients studied. Therefore, we believe each study must be evaluated individually for applicability, given the differences that exist between them.

Furthermore, there have been several reports of false-positive ELISA results in patients with other dermatologic disorders, specifically in elderly patients with pruritus who do not fulfill clinical criteria for diagnosis with BP.^16-18 In a population of elderly patients with pruritus for which no specific dermatological or systemic cause was identified, Hofmann et al¹⁸ found that 12% (3/25) of patients showed IgG reactivity to BP180 despite having negative DIF results. In another study of elderly patients with pruritic dermatoses, Feliciani et al¹⁷ found that 33% (5/15) of patients had IgG reactivity against BP230 or BP180, though they did not fulfill BP criteria based on clinical presentation and showed negative DIF and IIF results. These findings suggest that IgG reactivity against BP autoantibodies as determined by ELISA is not uncommon in pruritic diseases of the elderly.

Explanations for false-positive ELISA results were rare. A few authors suggested that false-positives could be attributed to an excessively low cutoff value,^7-9 which was consistent with reports that the titer of autoantibodies to BP180 correlates with disease severity, suggesting that the higher titer of antibodies correlates with more severe disease and likely more accurate diagnosis.^10,19,20 It is important to consider that patients who have low titers of BP180 autoantibodies with inconsistent clinical characteristics and DIF results may not truly have BP. Furthermore, to determine the clinical value of ELISA in identifying patients in the initial phase of BP, sera of BP patients should be compared with sera of elderly patients with pruritic skin disorders because they comprise the patient population that often requires diagnosis.¹⁸

Given the issues identified in our review of the literature, the published sensitivity and specificity of ELISA for BP diagnosis are likely overstated. In conclusion, ELISA should not be relied on as a single criterion adequate for diagnosis of BP.^12,21 Rather, the diagnosis of BP can be obtained with a positive predictive value of 95% when a patient meets 3 of 4 clinical criteria (ie, absence of atrophic scars, absence of head and neck involvement, absence of mucosal involvement, and older than 70 years) and demonstrates linear deposits of predominantly IgG and/or C3 along the basement membrane zone of a perilesional biopsy on DIF.¹⁵ The gold standard for diagnosis of BP remains clinical presentation along with DIF, which can be supported by histology, IIF, and ELISA.²²

Bullous pemphigoid (BP) is the most common autoimmune blistering disease. The classic presentation of BP is a generalized, pruritic, bullous eruption in elderly patients, which is occasionally preceded by an urticarial prodrome. Immunopathologically, BP is characterized by IgG and sometimes IgE autoantibodies that target basement membrane zone proteins BP180 and BP230 of the epidermis.¹

The diagnosis of BP should be suspected when an elderly patient presents with tense blisters and can be confirmed via diagnostic testing, including tissue histology and direct immunofluorescence (DIF) as the gold standard, as well as indirect immunofluorescence (IIF), enzyme-linked immunosorbent assay (ELISA), and most recently biochip technology as supportive tests.² Since its advent, ELISA has gained popularity as a trustworthy diagnostic test for BP. The specificity of ELISA for BP diagnosis is reported to be 98% to 100%, which leads clinicians to believe that a positive ELISA equals certain diagnosis of BP; however, misdiagnosis of BP based on a positive ELISA result can occur.^3-13 The treatment of BP often involves lifelong immunosuppressive therapy. Complications of immunosuppressive therapy contribute to morbidity and mortality in these patients, thus an accurate diagnosis is paramount before introducing therapy.¹⁴

We present the case of a 74-year-old man with a history of a pruritic nonbullous eruption who was diagnosed with BP and treated for 3 years based on positive ELISA results in the absence of confirmatory histology or DIF.

Case Report

A 74-year-old man with diabetes mellitus, hypertension, hyperlipidemia, benign prostatic hypertrophy, and obstructive sleep apnea presented for further evaluation and confirmation of a prior diagnosis of BP by an outside dermatologist. He reported a pruritic rash on the trunk, back, and extremities of 3 years’ duration. He denied occurrence of blisters at any time.

On presentation to an outside dermatologist 3 years ago, a biopsy was performed along with serologic studies due to the patient’s age and the possibility of an urticarial prodrome in BP. The biopsy revealed epidermal acanthosis, subepidermal separation, and a perivascular and interstitial infiltrate of lymphocytes and eosinophils in the papillary dermis. Direct immunofluorescence was nondiagnostic with a weak discontinuous pattern of IgG and IgA linearly along the basement membrane zone as well as few scattered and clumped cytoid bodies of IgM and IgA. Indirect immunofluoresence revealed a positive IgG titer of 1:40 on monkey esophagus substrate and a positive epidermal pattern on human split-skin substrate with a titer of 1:80. An ELISA for IgG autoantibodies against BP180 and BP230 yielded 15 U and 6 U, respectively (cut off value, 9 U). Based on the positive ELISA for IgG against BP180, a diagnosis of BP was made.

Over the following 3 years, the treatment included prednisone, tetracycline, nicotinamide, doxycycline, and dapsone. Therapy was suboptimal due to the patient’s comorbidities and socioeconomic status. Poorly controlled diabetes mellitus precluded consistent use of prednisone as recommended for BP. Tetracycline and nicotinamide were transiently effective in controlling the patient’s symptoms but were discontinued due to changes in his health insurance. Doxycycline and dapsone were ineffective. Throughout this 3-year period, the patient remained blister free, but the pruritic eruption was persistent.

The patient presented to our clinic due to his frustration with the lack of improvement and doubts about the BP diagnosis given the persistent absence of bullous lesions. Physical examination revealed numerous eroded, scaly, crusted papules on erythematous edematous plaques on all extremities, trunk, and back (Figure 1). The head, neck, face, and oral mucosa were spared. His history and clinical findings were atypical for BP and skin biopsies were performed. Histology revealed epidermal erosion with parakeratosis, spongiosis, and superficial perivascular lymphocytic inflammation with rare eosinophils without subepidermal split (Figure 2). Direct immunofluorescence was negative for IgG, IgA, IgM, C3, and C1q. Additionally, further review of the initial histology by another dermatopathologist revealed that the subepidermal separation reported was more likely artifactual clefts. These findings were not consistent with BP.

Given the patient’s clinical history, lack of bullae, and twice-negative DIF, the diagnosis was determined to be more consistent with eczematous spongiotic dermatitis. He refused a referral for phototherapy due to scheduling inconvenience. The patient was started on cyclosporine 0.5 mg/kg twice daily. After 10 days of treatment, he returned for follow-up and reported notable improvement in the pruritus. On physical examination, his dermatitis was improved with decreased erythema and inflammation.

The patient is being continued on extensive dry skin care with thick moisturizers and additional topical corticosteroid application on an as-needed basis.

Comment

Chronic immunosuppression contributes to morbidity and mortality in patients with BP; therefore, accurate diagnosis of BP is of utmost importance.¹⁴ A meta-analysis described ELISA as a test with high sensitivity and specificity (87% and 98%–100%, respectively) for diagnosis of BP.³ Nevertheless, there are opportunities for misdiagnosis using ELISA, as demonstrated in our case. To determine if the reported sensitivity and specificity of ELISA is accurate and reliable for clinical use, individual studies from the meta-analysis were reviewed.^{4,5,7-10,13,15} Issues identified in our review included dissimilar diagnostic procedures and patient populations among individual studies, several reports of positive ELISA in patients without BP, and a lack of explanation for these false-positive results.

There are notable differences in diagnostic procedures and patient populations among reports that establish the sensitivity and specificity of ELISA for BP diagnosis.^3-13 Studies have detected IgG that targets the NC16A domain of the BP180 kD antigen, the C-terminal of the BP180 kD antigen, or the entire ectodomain of the BP180 kD antigen. Study patient populations varied in disease activity, stage, and treatment. Control patients included healthy patients as well as those with many dermatoses, including pemphigus vulgaris, systemic scleroderma, systemic lupus erythematosus, rheumatoid arthritis, lichen planus, and discoid lupus erythematosus.^3-13 Due to these differences between individual studies, we believe the results that determine the overall sensitivity and specificity of ELISA for BP diagnosis must be interpreted with caution. For ELISA statistics to be clinically applicable to a specific patient, he/she should be similar to the patients studied. Therefore, we believe each study must be evaluated individually for applicability, given the differences that exist between them.

Furthermore, there have been several reports of false-positive ELISA results in patients with other dermatologic disorders, specifically in elderly patients with pruritus who do not fulfill clinical criteria for diagnosis with BP.^16-18 In a population of elderly patients with pruritus for which no specific dermatological or systemic cause was identified, Hofmann et al¹⁸ found that 12% (3/25) of patients showed IgG reactivity to BP180 despite having negative DIF results. In another study of elderly patients with pruritic dermatoses, Feliciani et al¹⁷ found that 33% (5/15) of patients had IgG reactivity against BP230 or BP180, though they did not fulfill BP criteria based on clinical presentation and showed negative DIF and IIF results. These findings suggest that IgG reactivity against BP autoantibodies as determined by ELISA is not uncommon in pruritic diseases of the elderly.

Explanations for false-positive ELISA results were rare. A few authors suggested that false-positives could be attributed to an excessively low cutoff value,^7-9 which was consistent with reports that the titer of autoantibodies to BP180 correlates with disease severity, suggesting that the higher titer of antibodies correlates with more severe disease and likely more accurate diagnosis.^10,19,20 It is important to consider that patients who have low titers of BP180 autoantibodies with inconsistent clinical characteristics and DIF results may not truly have BP. Furthermore, to determine the clinical value of ELISA in identifying patients in the initial phase of BP, sera of BP patients should be compared with sera of elderly patients with pruritic skin disorders because they comprise the patient population that often requires diagnosis.¹⁸

Given the issues identified in our review of the literature, the published sensitivity and specificity of ELISA for BP diagnosis are likely overstated. In conclusion, ELISA should not be relied on as a single criterion adequate for diagnosis of BP.^12,21 Rather, the diagnosis of BP can be obtained with a positive predictive value of 95% when a patient meets 3 of 4 clinical criteria (ie, absence of atrophic scars, absence of head and neck involvement, absence of mucosal involvement, and older than 70 years) and demonstrates linear deposits of predominantly IgG and/or C3 along the basement membrane zone of a perilesional biopsy on DIF.¹⁵ The gold standard for diagnosis of BP remains clinical presentation along with DIF, which can be supported by histology, IIF, and ELISA.²²

Bullous pemphigoid (BP) is the most common autoimmune blistering disease. The classic presentation of BP is a generalized, pruritic, bullous eruption in elderly patients, which is occasionally preceded by an urticarial prodrome. Immunopathologically, BP is characterized by IgG and sometimes IgE autoantibodies that target basement membrane zone proteins BP180 and BP230 of the epidermis.¹

The diagnosis of BP should be suspected when an elderly patient presents with tense blisters and can be confirmed via diagnostic testing, including tissue histology and direct immunofluorescence (DIF) as the gold standard, as well as indirect immunofluorescence (IIF), enzyme-linked immunosorbent assay (ELISA), and most recently biochip technology as supportive tests.² Since its advent, ELISA has gained popularity as a trustworthy diagnostic test for BP. The specificity of ELISA for BP diagnosis is reported to be 98% to 100%, which leads clinicians to believe that a positive ELISA equals certain diagnosis of BP; however, misdiagnosis of BP based on a positive ELISA result can occur.^3-13 The treatment of BP often involves lifelong immunosuppressive therapy. Complications of immunosuppressive therapy contribute to morbidity and mortality in these patients, thus an accurate diagnosis is paramount before introducing therapy.¹⁴

We present the case of a 74-year-old man with a history of a pruritic nonbullous eruption who was diagnosed with BP and treated for 3 years based on positive ELISA results in the absence of confirmatory histology or DIF.

Case Report

A 74-year-old man with diabetes mellitus, hypertension, hyperlipidemia, benign prostatic hypertrophy, and obstructive sleep apnea presented for further evaluation and confirmation of a prior diagnosis of BP by an outside dermatologist. He reported a pruritic rash on the trunk, back, and extremities of 3 years’ duration. He denied occurrence of blisters at any time.

On presentation to an outside dermatologist 3 years ago, a biopsy was performed along with serologic studies due to the patient’s age and the possibility of an urticarial prodrome in BP. The biopsy revealed epidermal acanthosis, subepidermal separation, and a perivascular and interstitial infiltrate of lymphocytes and eosinophils in the papillary dermis. Direct immunofluorescence was nondiagnostic with a weak discontinuous pattern of IgG and IgA linearly along the basement membrane zone as well as few scattered and clumped cytoid bodies of IgM and IgA. Indirect immunofluoresence revealed a positive IgG titer of 1:40 on monkey esophagus substrate and a positive epidermal pattern on human split-skin substrate with a titer of 1:80. An ELISA for IgG autoantibodies against BP180 and BP230 yielded 15 U and 6 U, respectively (cut off value, 9 U). Based on the positive ELISA for IgG against BP180, a diagnosis of BP was made.

Over the following 3 years, the treatment included prednisone, tetracycline, nicotinamide, doxycycline, and dapsone. Therapy was suboptimal due to the patient’s comorbidities and socioeconomic status. Poorly controlled diabetes mellitus precluded consistent use of prednisone as recommended for BP. Tetracycline and nicotinamide were transiently effective in controlling the patient’s symptoms but were discontinued due to changes in his health insurance. Doxycycline and dapsone were ineffective. Throughout this 3-year period, the patient remained blister free, but the pruritic eruption was persistent.

The patient presented to our clinic due to his frustration with the lack of improvement and doubts about the BP diagnosis given the persistent absence of bullous lesions. Physical examination revealed numerous eroded, scaly, crusted papules on erythematous edematous plaques on all extremities, trunk, and back (Figure 1). The head, neck, face, and oral mucosa were spared. His history and clinical findings were atypical for BP and skin biopsies were performed. Histology revealed epidermal erosion with parakeratosis, spongiosis, and superficial perivascular lymphocytic inflammation with rare eosinophils without subepidermal split (Figure 2). Direct immunofluorescence was negative for IgG, IgA, IgM, C3, and C1q. Additionally, further review of the initial histology by another dermatopathologist revealed that the subepidermal separation reported was more likely artifactual clefts. These findings were not consistent with BP.

Given the patient’s clinical history, lack of bullae, and twice-negative DIF, the diagnosis was determined to be more consistent with eczematous spongiotic dermatitis. He refused a referral for phototherapy due to scheduling inconvenience. The patient was started on cyclosporine 0.5 mg/kg twice daily. After 10 days of treatment, he returned for follow-up and reported notable improvement in the pruritus. On physical examination, his dermatitis was improved with decreased erythema and inflammation.

The patient is being continued on extensive dry skin care with thick moisturizers and additional topical corticosteroid application on an as-needed basis.

Comment

Chronic immunosuppression contributes to morbidity and mortality in patients with BP; therefore, accurate diagnosis of BP is of utmost importance.¹⁴ A meta-analysis described ELISA as a test with high sensitivity and specificity (87% and 98%–100%, respectively) for diagnosis of BP.³ Nevertheless, there are opportunities for misdiagnosis using ELISA, as demonstrated in our case. To determine if the reported sensitivity and specificity of ELISA is accurate and reliable for clinical use, individual studies from the meta-analysis were reviewed.^{4,5,7-10,13,15} Issues identified in our review included dissimilar diagnostic procedures and patient populations among individual studies, several reports of positive ELISA in patients without BP, and a lack of explanation for these false-positive results.

There are notable differences in diagnostic procedures and patient populations among reports that establish the sensitivity and specificity of ELISA for BP diagnosis.^3-13 Studies have detected IgG that targets the NC16A domain of the BP180 kD antigen, the C-terminal of the BP180 kD antigen, or the entire ectodomain of the BP180 kD antigen. Study patient populations varied in disease activity, stage, and treatment. Control patients included healthy patients as well as those with many dermatoses, including pemphigus vulgaris, systemic scleroderma, systemic lupus erythematosus, rheumatoid arthritis, lichen planus, and discoid lupus erythematosus.^3-13 Due to these differences between individual studies, we believe the results that determine the overall sensitivity and specificity of ELISA for BP diagnosis must be interpreted with caution. For ELISA statistics to be clinically applicable to a specific patient, he/she should be similar to the patients studied. Therefore, we believe each study must be evaluated individually for applicability, given the differences that exist between them.

Furthermore, there have been several reports of false-positive ELISA results in patients with other dermatologic disorders, specifically in elderly patients with pruritus who do not fulfill clinical criteria for diagnosis with BP.^16-18 In a population of elderly patients with pruritus for which no specific dermatological or systemic cause was identified, Hofmann et al¹⁸ found that 12% (3/25) of patients showed IgG reactivity to BP180 despite having negative DIF results. In another study of elderly patients with pruritic dermatoses, Feliciani et al¹⁷ found that 33% (5/15) of patients had IgG reactivity against BP230 or BP180, though they did not fulfill BP criteria based on clinical presentation and showed negative DIF and IIF results. These findings suggest that IgG reactivity against BP autoantibodies as determined by ELISA is not uncommon in pruritic diseases of the elderly.

Explanations for false-positive ELISA results were rare. A few authors suggested that false-positives could be attributed to an excessively low cutoff value,^7-9 which was consistent with reports that the titer of autoantibodies to BP180 correlates with disease severity, suggesting that the higher titer of antibodies correlates with more severe disease and likely more accurate diagnosis.^10,19,20 It is important to consider that patients who have low titers of BP180 autoantibodies with inconsistent clinical characteristics and DIF results may not truly have BP. Furthermore, to determine the clinical value of ELISA in identifying patients in the initial phase of BP, sera of BP patients should be compared with sera of elderly patients with pruritic skin disorders because they comprise the patient population that often requires diagnosis.¹⁸

Given the issues identified in our review of the literature, the published sensitivity and specificity of ELISA for BP diagnosis are likely overstated. In conclusion, ELISA should not be relied on as a single criterion adequate for diagnosis of BP.^12,21 Rather, the diagnosis of BP can be obtained with a positive predictive value of 95% when a patient meets 3 of 4 clinical criteria (ie, absence of atrophic scars, absence of head and neck involvement, absence of mucosal involvement, and older than 70 years) and demonstrates linear deposits of predominantly IgG and/or C3 along the basement membrane zone of a perilesional biopsy on DIF.¹⁵ The gold standard for diagnosis of BP remains clinical presentation along with DIF, which can be supported by histology, IIF, and ELISA.²²

Take-Home Points

• History and physical examination are key in identifying possible etiologies of orthopedic infections.
• If identified in the acute setting, periprosthetic infections can successfully be treated with irrigation, débridement, and polyethylene liner exchange.
• Discussion with an interdisciplinary medical team, including infectious disease specialists, can aide in improved diagnosis and treatment of periprosthetic infections.

Periprosthetic infection is a leading cause of morbidity after total joint arthroplasty.¹ Despite advances in modern surgical practices, infection rates continue to range from 1% to 3% among all arthroplasty procedures performed in the United States.^2-5 The most common causes of periprosthetic infection include Staphylococcus aureus, streptococcus, enterococcus, Escherichia coli, and Pseudomonas aeruginosa.⁶ However, many other pathogens that cause periprosthetic infection should be considered in the clinical setting. In this case report, periprosthetic knee infection with P shigelloides occurred after consumption of raw oysters.

P shigelloides is a gram-negative facultative anaerobic organism in the Vibrionaceae family,⁷ which also includes Vibrio vulnificus and Vibrio parahaemolyticus. P shigelloides is most well-known for causing diarrhea and septicemia in people who have consumed raw oysters or shellfish in the United States.^8,9 Although P shigelloides infection is rare, there have been clinically significant outbreaks from contaminated water in Japan,¹⁰ consumption of freshwater fish in the Democratic Republic of the Congo,¹¹ and consumption of raw oysters in the United States.^8,9 Children and immunosuppressed people are most susceptible to the disease, which most commonly manifests as self-limiting watery diarrhea, with septicemia only in advanced cases.¹²There are very few reports of P shigelloides in the orthopedic population. In the medical literature, we found only 1 case of septic arthritis in a native knee; disease progression resulted in the patient’s death.¹³In this article, we report a case of P shigelloides septicemia that caused periprosthetic knee infection in a chemically and biologically immunosuppressed patient. The patient provided written informed consent for print and electronic publication of this case report.

Case Report

Out of concern about a periprosthetic knee infection, a 66-year-old man was transferred from a regional medical center to our tertiary referral center. The patient reported a 3-day history of significant knee pain, swelling, and erythema that started the day after he consumed raw oysters at a seafood bar. He was unable to bear weight on the right knee and remained at home 1 day before presenting to the regional medical center.

The patient had undergone elective right total knee arthroplasty 18 months earlier, without previous issue (Figures A, B), and had a medical history of type 2 diabetes mellitus, psoriatic arthritis, hypertension, hyperlipidemia, hypothyroidism, and benign prostatic hypertrophy.

Discussion

This case is a reminder that periprosthetic knee infection can occur from a variety of pathologic organisms and that obtaining a complete history is an important part of any diagnostic work-up. Although P shigelloides infection is rare, our patient had important historical findings that led to suspicion of Vibrionaceae infection: recent consumption of raw oysters, immunosuppression with etanercept and prednisone for psoriatic arthritis, and diabetes with hemoglobin A_1c of 9.9% and presenting blood sugar of 338 mg/dL. His positive blood cultures represented P shigelloides septicemia, which seeded the knee prosthesis and led to acute periprosthetic infection. To our knowledge, this is the first report of P shigelloides periprosthetic infection in the orthopedic literature. The only other reported case of P shigelloides septicemia leading to septic arthritis in a native knee occurred in a 68-year-old Australian man who had end-stage liver disease and eventually died from complications of the P shigelloides infection.¹³

Although P shigelloides infection is rare, outbreaks have occurred around the world.^7-11,14 Infections are most commonly associated with consumption of raw shellfish or freshwater fish or with water contamination.¹² In the United States, the only described vector for disease has been consumption of raw oysters and shellfish—in particular, those harvested from the warm waters of the Gulf Coast.^8,9P shigelloides usually causes a self-limiting watery diarrhea. However, in children and immunosuppressed patients, P shigelloides can lead to life-threatening septicemia.¹² In the United States, P shigelloides cases often occur in the summer, likely related to the easy growth of the bacteria from shellfish in the Gulf Coast’s warm water and mud.⁸ This predilection for summer infections has been documented around the world.¹⁵Our patient reported eating raw oysters imported to the US Southwest from an unknown location. He likely was susceptible to P shigelloides infection, as he was immunosuppressed with etanercept and prednisone. However, there were no traditional diarrheal symptoms. Case reports have described nondiarrheal symptoms in children and other immunosuppressed people.¹²There is much to learn from this case report. Most important, it highlights the need to obtain a complete history and perform a thorough physical examination. Our patient’s 2 key historical findings, immunosuppressive medication use and raw oyster consumption, point strongly toward Vibrionaceae infection. Although a majority of periprosthetic infections are caused by common organisms, such as Staphylococcus and Streptococcus species, orthopedic clinicians should continue to expand their knowledge of periprosthetic infections, as many other pathogens can cause disease.

Am J Orthop. 2017;46(1):E32-E34. Copyright Frontline Medical Communications Inc. 2017. All rights reserved.

Take-Home Points

• History and physical examination are key in identifying possible etiologies of orthopedic infections.
• If identified in the acute setting, periprosthetic infections can successfully be treated with irrigation, débridement, and polyethylene liner exchange.
• Discussion with an interdisciplinary medical team, including infectious disease specialists, can aide in improved diagnosis and treatment of periprosthetic infections.

Periprosthetic infection is a leading cause of morbidity after total joint arthroplasty.¹ Despite advances in modern surgical practices, infection rates continue to range from 1% to 3% among all arthroplasty procedures performed in the United States.^2-5 The most common causes of periprosthetic infection include Staphylococcus aureus, streptococcus, enterococcus, Escherichia coli, and Pseudomonas aeruginosa.⁶ However, many other pathogens that cause periprosthetic infection should be considered in the clinical setting. In this case report, periprosthetic knee infection with P shigelloides occurred after consumption of raw oysters.

P shigelloides is a gram-negative facultative anaerobic organism in the Vibrionaceae family,⁷ which also includes Vibrio vulnificus and Vibrio parahaemolyticus. P shigelloides is most well-known for causing diarrhea and septicemia in people who have consumed raw oysters or shellfish in the United States.^8,9 Although P shigelloides infection is rare, there have been clinically significant outbreaks from contaminated water in Japan,¹⁰ consumption of freshwater fish in the Democratic Republic of the Congo,¹¹ and consumption of raw oysters in the United States.^8,9 Children and immunosuppressed people are most susceptible to the disease, which most commonly manifests as self-limiting watery diarrhea, with septicemia only in advanced cases.¹²There are very few reports of P shigelloides in the orthopedic population. In the medical literature, we found only 1 case of septic arthritis in a native knee; disease progression resulted in the patient’s death.¹³In this article, we report a case of P shigelloides septicemia that caused periprosthetic knee infection in a chemically and biologically immunosuppressed patient. The patient provided written informed consent for print and electronic publication of this case report.

Case Report

Out of concern about a periprosthetic knee infection, a 66-year-old man was transferred from a regional medical center to our tertiary referral center. The patient reported a 3-day history of significant knee pain, swelling, and erythema that started the day after he consumed raw oysters at a seafood bar. He was unable to bear weight on the right knee and remained at home 1 day before presenting to the regional medical center.

The patient had undergone elective right total knee arthroplasty 18 months earlier, without previous issue (Figures A, B), and had a medical history of type 2 diabetes mellitus, psoriatic arthritis, hypertension, hyperlipidemia, hypothyroidism, and benign prostatic hypertrophy.

Discussion

This case is a reminder that periprosthetic knee infection can occur from a variety of pathologic organisms and that obtaining a complete history is an important part of any diagnostic work-up. Although P shigelloides infection is rare, our patient had important historical findings that led to suspicion of Vibrionaceae infection: recent consumption of raw oysters, immunosuppression with etanercept and prednisone for psoriatic arthritis, and diabetes with hemoglobin A_1c of 9.9% and presenting blood sugar of 338 mg/dL. His positive blood cultures represented P shigelloides septicemia, which seeded the knee prosthesis and led to acute periprosthetic infection. To our knowledge, this is the first report of P shigelloides periprosthetic infection in the orthopedic literature. The only other reported case of P shigelloides septicemia leading to septic arthritis in a native knee occurred in a 68-year-old Australian man who had end-stage liver disease and eventually died from complications of the P shigelloides infection.¹³

Although P shigelloides infection is rare, outbreaks have occurred around the world.^7-11,14 Infections are most commonly associated with consumption of raw shellfish or freshwater fish or with water contamination.¹² In the United States, the only described vector for disease has been consumption of raw oysters and shellfish—in particular, those harvested from the warm waters of the Gulf Coast.^8,9P shigelloides usually causes a self-limiting watery diarrhea. However, in children and immunosuppressed patients, P shigelloides can lead to life-threatening septicemia.¹² In the United States, P shigelloides cases often occur in the summer, likely related to the easy growth of the bacteria from shellfish in the Gulf Coast’s warm water and mud.⁸ This predilection for summer infections has been documented around the world.¹⁵Our patient reported eating raw oysters imported to the US Southwest from an unknown location. He likely was susceptible to P shigelloides infection, as he was immunosuppressed with etanercept and prednisone. However, there were no traditional diarrheal symptoms. Case reports have described nondiarrheal symptoms in children and other immunosuppressed people.¹²There is much to learn from this case report. Most important, it highlights the need to obtain a complete history and perform a thorough physical examination. Our patient’s 2 key historical findings, immunosuppressive medication use and raw oyster consumption, point strongly toward Vibrionaceae infection. Although a majority of periprosthetic infections are caused by common organisms, such as Staphylococcus and Streptococcus species, orthopedic clinicians should continue to expand their knowledge of periprosthetic infections, as many other pathogens can cause disease.

Am J Orthop. 2017;46(1):E32-E34. Copyright Frontline Medical Communications Inc. 2017. All rights reserved.

Take-Home Points

• History and physical examination are key in identifying possible etiologies of orthopedic infections.
• If identified in the acute setting, periprosthetic infections can successfully be treated with irrigation, débridement, and polyethylene liner exchange.
• Discussion with an interdisciplinary medical team, including infectious disease specialists, can aide in improved diagnosis and treatment of periprosthetic infections.

Periprosthetic infection is a leading cause of morbidity after total joint arthroplasty.¹ Despite advances in modern surgical practices, infection rates continue to range from 1% to 3% among all arthroplasty procedures performed in the United States.^2-5 The most common causes of periprosthetic infection include Staphylococcus aureus, streptococcus, enterococcus, Escherichia coli, and Pseudomonas aeruginosa.⁶ However, many other pathogens that cause periprosthetic infection should be considered in the clinical setting. In this case report, periprosthetic knee infection with P shigelloides occurred after consumption of raw oysters.

P shigelloides is a gram-negative facultative anaerobic organism in the Vibrionaceae family,⁷ which also includes Vibrio vulnificus and Vibrio parahaemolyticus. P shigelloides is most well-known for causing diarrhea and septicemia in people who have consumed raw oysters or shellfish in the United States.^8,9 Although P shigelloides infection is rare, there have been clinically significant outbreaks from contaminated water in Japan,¹⁰ consumption of freshwater fish in the Democratic Republic of the Congo,¹¹ and consumption of raw oysters in the United States.^8,9 Children and immunosuppressed people are most susceptible to the disease, which most commonly manifests as self-limiting watery diarrhea, with septicemia only in advanced cases.¹²There are very few reports of P shigelloides in the orthopedic population. In the medical literature, we found only 1 case of septic arthritis in a native knee; disease progression resulted in the patient’s death.¹³In this article, we report a case of P shigelloides septicemia that caused periprosthetic knee infection in a chemically and biologically immunosuppressed patient. The patient provided written informed consent for print and electronic publication of this case report.

Case Report

Out of concern about a periprosthetic knee infection, a 66-year-old man was transferred from a regional medical center to our tertiary referral center. The patient reported a 3-day history of significant knee pain, swelling, and erythema that started the day after he consumed raw oysters at a seafood bar. He was unable to bear weight on the right knee and remained at home 1 day before presenting to the regional medical center.

The patient had undergone elective right total knee arthroplasty 18 months earlier, without previous issue (Figures A, B), and had a medical history of type 2 diabetes mellitus, psoriatic arthritis, hypertension, hyperlipidemia, hypothyroidism, and benign prostatic hypertrophy.

Discussion

This case is a reminder that periprosthetic knee infection can occur from a variety of pathologic organisms and that obtaining a complete history is an important part of any diagnostic work-up. Although P shigelloides infection is rare, our patient had important historical findings that led to suspicion of Vibrionaceae infection: recent consumption of raw oysters, immunosuppression with etanercept and prednisone for psoriatic arthritis, and diabetes with hemoglobin A_1c of 9.9% and presenting blood sugar of 338 mg/dL. His positive blood cultures represented P shigelloides septicemia, which seeded the knee prosthesis and led to acute periprosthetic infection. To our knowledge, this is the first report of P shigelloides periprosthetic infection in the orthopedic literature. The only other reported case of P shigelloides septicemia leading to septic arthritis in a native knee occurred in a 68-year-old Australian man who had end-stage liver disease and eventually died from complications of the P shigelloides infection.¹³

Although P shigelloides infection is rare, outbreaks have occurred around the world.^7-11,14 Infections are most commonly associated with consumption of raw shellfish or freshwater fish or with water contamination.¹² In the United States, the only described vector for disease has been consumption of raw oysters and shellfish—in particular, those harvested from the warm waters of the Gulf Coast.^8,9P shigelloides usually causes a self-limiting watery diarrhea. However, in children and immunosuppressed patients, P shigelloides can lead to life-threatening septicemia.¹² In the United States, P shigelloides cases often occur in the summer, likely related to the easy growth of the bacteria from shellfish in the Gulf Coast’s warm water and mud.⁸ This predilection for summer infections has been documented around the world.¹⁵Our patient reported eating raw oysters imported to the US Southwest from an unknown location. He likely was susceptible to P shigelloides infection, as he was immunosuppressed with etanercept and prednisone. However, there were no traditional diarrheal symptoms. Case reports have described nondiarrheal symptoms in children and other immunosuppressed people.¹²There is much to learn from this case report. Most important, it highlights the need to obtain a complete history and perform a thorough physical examination. Our patient’s 2 key historical findings, immunosuppressive medication use and raw oyster consumption, point strongly toward Vibrionaceae infection. Although a majority of periprosthetic infections are caused by common organisms, such as Staphylococcus and Streptococcus species, orthopedic clinicians should continue to expand their knowledge of periprosthetic infections, as many other pathogens can cause disease.

Am J Orthop. 2017;46(1):E32-E34. Copyright Frontline Medical Communications Inc. 2017. All rights reserved.

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

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

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

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

Case Presentation

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

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

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

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

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

Discussion

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

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

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

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

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

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

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

Conclusion

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

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

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

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

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

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

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

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

Case Presentation

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

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

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

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

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

Discussion

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

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

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

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

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

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

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

Conclusion

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

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

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

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

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

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

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

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

Case Presentation

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

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

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

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

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

Discussion

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

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

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

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

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

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

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

Conclusion

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

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

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

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

Case

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

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

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

Discussion

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

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

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

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

Summary

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

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

Case

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

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

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

Discussion

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

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

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

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

Summary

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

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

Case

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

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

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

Discussion

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

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

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

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

Summary

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

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

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

Case

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

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

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

Discussion

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

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

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

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

Conclusion

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

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

Case

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

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

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

Discussion

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

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

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

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

Conclusion

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

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

Case

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

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

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

Discussion

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

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

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

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

Conclusion

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

Case

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

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

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

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

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

Case Continuation

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

What are the signs and symptoms of acute isoniazid toxicity?

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

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

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

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

How is acute isoniazid-induced seizure managed?

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

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

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

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

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

Case Conclusion

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

Case

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

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

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

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

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

Case Continuation

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

What are the signs and symptoms of acute isoniazid toxicity?

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

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

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

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

How is acute isoniazid-induced seizure managed?

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

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

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

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

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

Case Conclusion

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

Case

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

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

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

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

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

Case Continuation

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

What are the signs and symptoms of acute isoniazid toxicity?

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

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

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

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

How is acute isoniazid-induced seizure managed?

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

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

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

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

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

Case Conclusion

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

Case

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

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

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

Discussion

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

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

Signs and Symptoms

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

Diagnosis and Management

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

Point-of-Care Ultrasound

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

Conclusion

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

Case

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

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

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

Discussion

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

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

Signs and Symptoms

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

Diagnosis and Management

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

Point-of-Care Ultrasound

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

Conclusion

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

Case

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

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

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

Discussion

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

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

Signs and Symptoms

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

Diagnosis and Management

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

Point-of-Care Ultrasound

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

Conclusion

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

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

Case Report

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

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

Comment

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

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

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

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

Conclusion

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

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

Case Report

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

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

Comment

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

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

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

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

Conclusion

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

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

Case Report

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

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

Comment

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

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

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

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

Conclusion

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