Psychiatric Emergencies for Physicians: Clinical Management and Approach to Distinguishing Pheochromocytoma From Psychiatric and Thyrotoxic Diseases in the Emergency Department

The Journal of Emergency Medicine, Vol. -, No. -, pp. 1–5, 2017 Ó 2017 Elsevier Inc. All rights reserved. 0736-4679/$ - see front matter

Selected Topics: Psychiatric Emergencies

PSYCHIATRIC EMERGENCIES FOR PHYSICIANS: CLINICAL MANAGEMENT AND APPROACH TO DISTINGUISHING PHEOCHROMOCYTOMA FROM PSYCHIATRIC AND THYROTOXIC DISEASES IN THE EMERGENCY DEPARTMENT Albert Leung, MD,* Leslie Zun, MD,† Kimberly Nordstrom, MD, JD,‡ and Michael P. Wilson, MD, PHD§ *Department of Emergency Medicine, University of Chicago, Chicago, Illinois, †Department of Emergency Medicine, Mount Sinai Hospital, Chicago, Illinois, ‡University of Colorado School of Medicine, Aurora, Colorado, and §Department of Emergency Medicine, Director of Behavioral Emergencies Research, University of California–San Diego, San Diego, California Corresponding Address: Albert Leung, MD, Department of Emergency Medicine, University of Chicago, 1912 South Lee Parkway, Chicago, IL 60616-5202

CLINICAL SCENARIO

medications. Her thyroid laboratory values were within normal limits (thyroid-stimulating hormone 2.8 mU/mL, free triiodothyronine 416 pg/dL, and free thyroxine 1.24 ng/dL). However, her plasma catecholamine level was 1463 pg/mL, and an abdomen/pelvic computed tomography scan revealed a left adrenal mass that was suspicious for pheochromocytoma.

A 35-year-old woman with a history of neurofibromatosis type 1, hyperthyroidism, and generalized anxiety disorder presented to the emergency department (ED) with chest palpitations, headache, anxiety, and diaphoresis. She had these symptoms intermittently for the past several months, but was particularly distressed on this day. On arrival, she appeared frantic and her hair was disheveled. Her vital signs were as follows: temperature 35.8 C, blood pressure 172/94 mm Hg, heart rate 132 bpm, respiratory rate 29 breaths/min, and oxygen saturation 97%. Her clinical examination was notable for mild agitation, facial pallor, tachycardia, and cafe´ au lait spots over her trunk and extremities. Her feet were soiled from walking barefoot outdoors. Her medications included methimazole and lorazepam, but she stated that she had been nonadherent with her medications because she had not seen her behavioral therapist in years. During the historytaking and physical examination, she appeared distracted and gave nervous glances around the ED. She did not have a chronic history of hypertension, and she was not taking any antihypertensive agents or other psychoactive

CLINICAL PRESENTATION OF A PHEOCHROMOCYTOMA Although the differential diagnosis for this clinical presentation is broad, there are certain features that suggest a pheochromocytoma, such as the classic symptoms of palpitations, headache, anxiety, and diaphoresis. The intermittent nature of these symptoms and the history of neurofibromatosis, which is often associated with pheochromocytomas, further support this diagnosis. A pheochromocytoma is a neuroendocrine-secreting tumor that produces excess catecholamines (epinephrine and norepinephrine) and subsequent metabolites (1). The first case report of a pheochromocytoma in the literature was in 1886 by Frankel (2). In 1906, Alezais and Peyron were the first to describe extra-adrenal chromaffin tumors, defining them as paragangliomas (2). By 1912,

Reprints are not available from the authors.

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Pick further distinguished intra-adrenal chromaffin tumors as pheochromocytomas and extra-adrenal chromaffin tumors as paragangliomas (2). Pheochromocytomas have an annual incidence of 2 to 8 cases per million individuals (3,4). However, the incidence increases to 0.1% to 1% among people with hypertension, and further increases to 5% if there is an incidentally discovered adrenal mass (5–8). The peak incidence is in the third to fifth decades of life, with no particular sex specificity (9,10). Pheochromocytomas may be either adrenal (85%) or extra-adrenal in origin (15%), with malignancy in #40% of cases (11). Extra-adrenal paraganglioma tumors originate in the paraganglia of the sympathetic nervous system. Approximately 95% of extra-adrenal pheochromocytomas are located in the abdomen (12). However, the head, neck, and thoracic region are other potential sites, as defined in the Glenner and Grimley classification system (Table 1). Extra-adrenal sites occur in 15% of adult and 30% of pediatric pheochromocytoma cases (13). Definitive management is usually surgical, with Roux performing the first successful surgical resection of a pheochromocytoma in 1926 (13). Mayo reported the first successful removal of a paraganglioma in the same year (13). WHAT KEY FINDINGS LEAD TO THE DIAGNOSIS? The paroxysmal nature of these symptoms may make it difficult to distinguish between a psychiatric and a medical illness. Thyroid storm, general anxiety, and panic disorders can also present with these findings. However, pheochromocytomas present with a classic constellation of symptoms, including headache, palpitations, anxiety, diaphoresis, hypertension, tremor, and facial pallor. Certain clues in the patient’s history may help provide a distinction. Such examples include an association with neurofibromatosis or the complaint of intermittent diaphoresis and flushing. Confounding the diagnosis in this case is the patient’s history of hyperthyroidism, generalized anxiety disorder, and her nonadherence with behavioral therapy. In addition,

Table 1. Glenner and Grimley Classification System for Extra-Adrenal Pheochromocytoma Branchiomeric: Head Intravagal: Neck Aorticosympathetic: Along the length of the aorta, between the renal arteries, around the iliac bifurcation, the organ of Zuckerkandl Visceroautonomic: Blood vessels or visceral organs (e.g., bladder)

symptoms such as anxiety, diaphoresis, flushing, palpitations, and tachycardia can all be seen with a panic attack. Panic attacks are more common in those with generalized anxiety disorder. The actual diagnosis of pheochromocytomas is made with biochemical laboratory markers through plasma or urine testing. Tumor size generally does not dictate the malignant potential for extra-adrenal paraganglioma tumors, to an extent. Tumor size $5 cm strongly predicts persistent or recurrent disease and mortality (13). WHAT OTHER DIAGNOSES SHOULD YOU CONSIDER? The symptoms of pheochromocytoma are nonspecific and overlap considerably with diseases associated with endocrine, cardiovascular, psychologic, pharmacologic, and neurologic systems. The differential diagnosis for patients presenting with symptoms caused by pheochromocytoma is broad. Endocrine etiologies include thyrotoxicosis, medullary thyroid carcinoma, primary hypogonadism (e.g., menopausal syndrome), intestinal carcinoid tumor, pancreatic tumors (e.g., insulinoma), carbohydrate intolerance, and hypoglycemia. Psychiatric etiologies include anxiety and panic attacks, somatization disorder, hyperventilation, and factitious disorders (Table 2). In addition, there are several genetic syndromes that include pheochromocytoma as a part of their diagnosis. These include multiple endocrine neoplasia type 2A and 2B, neurofibromatosis type 1, von Hippel–Lindau syndrome, and hereditary paraganglioma syndrome (14). These diagnoses are typically made in the outpatient setting in collaboration with endocrinologists and oncologists.

Table 2. Differential Diagnosis for Pheochromocytoma Endocrine Hyperthyroidism/thyrotoxicosis Medullary thyroid carcinoma Insulinoma Intestinal carcinoid tumor Hypoglycemia Carbohydrate intolerance Cardiovascular Labile essential hypertension Renovascular disease Psychologic Anxiety disorder Panic attacks Somatization disorder Hyperventilation Factitious disorder Genetic syndromes Multiple endocrine neoplasia type 2 Neurofibromatosis von Hippel–Lindau syndrome

Distinguishing Pheochromocytoma in the ED

DISTINGUISHING PHEOCHROMOCYTOMA FROM THYROID STORM Thyroid storm may have a similar presentation as pheochromocytoma, but the patient’s history and thyroid studies can be used to readily distinguish the two clinical entities. Hyperthermia is present in almost all cases of thyroid storm (15). In addition, heat intolerance, weight loss, increased appetite, skin erythema, and peripheral edema are features more commonly seen in thyroid storm than pheochromocytoma. The time course of symptoms also plays an important role. Patients with pheochromocytoma typically manifest symptoms on a paroxysmal basis, whereas thyroid storm is a rapidly progressive thyrotoxicosis that requires emergent supportive measures. Laboratory studies will definitively diagnose thyroid storm in the ED. Low levels of thyroid-stimulating hormone with elevated free thyroxine and free triiodothyronine levels establish the diagnosis. Free thyroid levels are preferred to total thyroid values because the unbound hormone is responsible for the clinical symptoms. DIAGNOSING PHEOCHROMOCYTOMAS The initial screening evaluation includes biochemical testing in the form of a 24-hour urine collection for catecholamines. In the ED, the most practical screening test is for plasma-free fractionated metanephrines. The sensitivity of the urine assay ranges from 77% to 90%, but the test is highly specific (98%). On the other hand, the plasma-free fractionated metanephrines has a high sensitivity (97–99%) but a lower specificity (85%) (16). A combination of a plasma catecholamine level $2000 pg/mL and urinary metanephrines $1.8 mg/24 hours has a diagnostic accuracy near 98% (17). It is prudent to review the patient’s home medication list, because there are several pharmacologic agents that may falsely elevate serum levels of catecholamines during diagnostic evaluation, such as tricyclic antidepressants, cyclobenzaprine, amphetamines, psychoactive agents, and withdrawal from clonidine and other drugs (18) (Table 3). These medications are not known to provoke a catecholamine surge that would induce symptoms, but it may falsely elevate catecholamine levels to 500 to 1000 pg/mL. A plasma catecholamine level <500 pg/mL essentially rules out a pheochromocytoma (17). Concentrations from 500 to 1000 pg/mL require additional testing, and levels >1000 pg/mL are essentially diagnostic for a pheochromocytoma (17). Caffeine, cigarette smoking, and sympathomimetic agents may also increase catecholamine levels through adrenergic receptors and should be avoided within 24 hours

3 Table 3. Medications that May Increase Serum Levels of Catecholamines and Metanephrines Selective serotonin reuptake inhibitors Monoamine oxidase inhibitors Prochlorperazine Reserpine Ethanol Tricyclic antidepressants Levodopa Amphetamines Buspirone Drugs containing adrenergic receptor agonists Withdrawal from clonidine and other drugs

before blood testing. Screening questions regarding these substances should be asked in the ED to better interpret the laboratory results (19,20). On the other hand, a-adrenergic–receptor blockers and b-adrenergic– receptor blockers may mask clinical symptoms and signs associated with a pheochromocytoma. Definitive diagnosis includes not only biochemical confirmation of catecholamine excess but anatomic localization of the neuroendocrine tumor with follow-up imaging. Computed tomography and magnetic resonance imaging of the abdomen and pelvis are the most common imaging modalities. The sensitivity for computed tomography is 93% to 100% for adrenal tumors, but decreases to 90% for extra-adrenal pheochromocytomas (16). Magnetic resonance imaging scans may be more useful for detecting extra-adrenal tumors. However, the specificity for both imaging modalities is poor (approximately 50%). A diagnostic alternative includes scintigraphy with 131I- or 123 I-labeled metaiodobenzylguanidine, which offers superior specificity (95–100%) but poor sensitivity (77–90%). AS AN EMERGENCY PHYSICIAN, WHAT DO YOU NEED TO KNOW ABOUT PHEOCHROMOCYTOMAS? As a physician in the ED, it is important to maintain pheochromocytoma in the differential diagnosis when evaluating a hypertensive patient with associated symptoms, especially if these associated symptoms are intermittent. In the emergency medicine setting, pheochromocytomas may require management of lifethreatening acute hypertensive emergencies and consultation with endocrinology and general surgery. In addition, patients with known pheochromocytoma and chronic hypertension should be evaluated for specific end-organ complications. Long-standing hypertension can damage multiple organ systems, including the cardiovascular, cerebrovascular, renal, gastrointestinal systems, and ocular structures. Sustained hypertension from elevated levels of plasma norepinephrine leads to increased arterial stiffness. The

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degree of vessel stiffness correlates directly with the level of urinary norepinephrine (21). In addition, pheochromocytomas further damage the cardiovascular system by causing vasoconstriction of the coronary arteries along with increased inotropy on the heart through activation of a- and b-adrenergic receptors. Together, these mechanisms strain the heart, ultimately leading to myocardial ischemia and infarction (22). In patients without coronary artery disease, ischemic events may occur despite a normal coronary angiogram (23). Another long-term effect on the heart includes cardiomyopathy of all subtypes (e.g., hypertrophic, dilated, or obstructive). The patient may further be at risk for peripheral vascular disease, tissue ischemia/necrosis, gangrene, and aortic dissection (24). Neurologic concerns include hypertensive encephalopathy and stroke (25). The symptoms and clinical examination findings associated with hypertensive encephalopathy include headache, altered mental status, papilledema, and cerebral infarction (26). The body’s natural response to systemic hypertension is to autoregulate cerebral blood flow via vasoconstriction, a phenomenon known as the Bayliss response (27). Hypertensive encephalopathy is thought to be caused by disruption of this autoregulation process over time, resulting in vasodilation and subsequent hypoperfusion and ischemia (28). These vascular changes lead to headaches and altered mental status over time. Renal failure may develop because of vasoconstriction of the renal arteries or rhabdomyolysis. Tissue ischemia within skeletal muscles may lead to acute tubular necrosis from myoglobinuria, and laboratory tests would be expected to show elevated serum creatinine kinase and urinary myoglobin. Other organs susceptible to ischemia include the gastrointestinal and ocular systems. The emergency physician should evaluate for intestinal ischemia if the patient presents with sharp, severe abdominal pain (29). If the patient complains of visual symptoms, a screening should be conducted for hypertensive retinopathy. Retinal examination findings may include microaneurysms, hemorrhages, cotton wool spots, and venous bleeding (30). HOW SHOULD YOU STABILIZE THIS PATIENT?  Clinical screening for cardiovascular, cerebrovascular, renal, gastrointestinal, and visual symptoms by physical examination  Plasma metanephrines and computed tomography imaging of the abdomen and pelvis are recommended for the initial diagnostic evaluation  Blood pressure control is paramount in acute hypertensive crisis if there is clinical evidence of endorgan dysfunction, as per usual treatment

 Phentolamine, nitroprusside, nitroglycerin, diltiazem, and phenoxybenzamine are recommended agents for blood pressure management  Treatment is directed toward symptom management and supportive care  Consult endocrinology and general surgery to initiate interdisciplinary care for the patient WHAT ARE THE MOST IMPORTANT STEPS IN THE MANAGEMENT OF THIS PATIENT? In the ED, it is critical to accurately monitor the patient’s blood pressure. The indication for medical therapy in the ED setting is primarily for blood pressure control. Phentolamine is a reversible nonselective a-adrenergic antagonist that is a first-line agent often used during hypertensive emergencies caused by pheochromocytoma. It may lead to a more pronounced reflex tachycardia compared to selective a1 blockers. Nitroprusside and nitroglycerin are effective, shortacting, antihypertensive agents that can acutely manage a hypertensive crisis. Oral agents, such as calcium channel blockers (e.g., diltiazem) and phenoxybenzamine, are also known to achieve good control of blood pressure through different mechanisms. Calcium channel blockers are relatively short-acting vasodilators that have less risk for dangerous hypotension than phenoxybenzamine. Phenoxybenzamine is a noncompetitive a1 and a2 blocker that decreases the degree of vasoconstriction and stabilizes blood pressure (31). This is the recommended blood pressure agent before definitive treatment. Another therapeutic agent is metyrosine, which decreases the amount of catecholamines synthesized by binding to tyrosine hydroxylase and converting the product to an inactive metabolite (32). After adequate blood pressure control in the ED, surgical resection remains the definitive treatment for pheochromocytoma. For metastatic disease not amenable to surgical management, treatment alternatives include radiation and chemotherapy, along with surgical debulking. CLINICAL BOTTOM LINES  Include pheochromocytoma on the differential for individuals presenting in hypertensive crisis noting intermittent associated symptoms  Review the patient’s home medication list for potential interference with biochemical assays  Evaluate for end-organ damage caused by hypertensive emergency

Distinguishing Pheochromocytoma in the ED

 Blood pressure management is important in the ED  Surgical management is usually the definitive treatment for pheochromocytoma

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