Nausea, Vomiting, and Panic Attacks in a 50-Year-Old Woman

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IM BOARD REVIEW a self-test on a CME EDUCATIONAL OBJECTIVE: Readers will consider the possible underlying causes of nausea and panic attacks CREDIT JOSHUA BEAR, MA FRANKLIN A. MICHOTA, JR., MD clinical Case Western Reserve University Department of Hospital Medicine, case School of Medicine, Cleveland, OH Cleveland Clinic

Nausea, vomiting, and panic attacks in a 50-year-old woman

50-year-old woman presents to the was accompanied by symptoms as severe as A emergency department because of re- those she is currently experiencing. peated episodes of vomiting over the past She is otherwise healthy with no chronic 12 hours. She reports eight episodes of non- diseases. Her surgical history includes resec- bloody, nonbilious emesis associated with tion of an angiolipoma from her right arm and palpitations and feelings of anxiety, but dilation and curettage for endometrial polyps. with no fever or diarrhea. She has not trav- She has no personal or family history of psy- eled recently and does not have any sick chiatric illness. contacts. She reports that she never had health ■■ PHYSICAL EXAMINATION problems until 6 months ago, when she began having panic attacks that woke her from sleep. The patient is slender and tremulous but does The episodes first occurred once or twice per not appear diaphoretic. Her blood pressure is week, usually at night, and involved palpita- 176/92 mm Hg, pulse 98, temperature 36.5°C tions and feelings of anxiety that lasted 2 to (97.7°F), and respiratory rate 20 per minute. Headaches 4 hours, but no other associated symptoms. Oxygen saturation by pulse oximetry is 98% are uncommon After a month, the episodes began to occur on room air. She has dry mucus membranes more regularly during the day and were ac- and orthostatic hypotension, but her physi- in panic companied by a pounding headache that be- cal examination is otherwise normal. Elec- disorder gan in the back of her neck and extended up trocardiography (ECG) shows a normal sinus and over her head. Her primary care physician rhythm with a prolonged QTc of 571 ms and prescribed sertraline (Zoloft) and referred her peaked P and T waves. to a neurologist to evaluate the headaches. The neurologic workup included brain mag- ■■ LABORATORY VALUES netic resonance imaging and electroencepha- lography, both of which were normal. • Hemoglobin 15.6 g/dL (reference range After 8 weeks on sertraline, the episodes 11.5–15.5) continued to increase in frequency and sever- • Hematocrit 47.2% (36.0–46.0) ity, and her physician switched her to parox- • Platelet count 448 × 109/L (150–400) etine (Paxil) and added lorazepam (Ativan), • White cell count 18.65 × 109/L (3.70– which did not improve her symptoms. Over 11.00) the past 2 months, during which time she has • Potassium 2.5 mmol/L (3.5–4.0) not been taking any medications, the episodes • Chloride 97 mmol/L (98–110) began to involve nausea and, more recently, • Bicarbonate 21 mmol/L (23–32) vomiting, with episodes occurring as often • Anion gap 20 mmol/L (0–15) as once or twice daily, and with intermittent • Glucose 233 mg/dL (65–100). symptom-free days. None of the prior episodes Sodium, blood urea nitrogen, and creati- nine levels are all within normal limits. Uri- doi:10.3949/ccjm.78a.10082 nalysis suggests a urinary tract infection.

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■■ IS THIS A PANIC ATTACK? ism, caffeine and stimulant use or abuse, asth- ma, cardiac arrhythmias, alcohol withdrawal, Which of the following is not characteris- and, more rarely, complex partial seizures and 1tic of a panic attack? pheochromocytoma.2,4 Many of these condi- □□ Nausea and vomiting tions can be ruled out by the history alone in □□ Onset during sleep a reliable patient. □□ Palpitations Our patient’s electrocardiogram showed □□ Chest pain or discomfort no evidence of ischemia or arrhythmias. Also, □□ Headache her recent negative neurologic workup makes □□ Trembling or shaking seizure activity less likely. Many of this patient’s laboratory abnor- According to the Diagnostic and Statistical malities are easily explained by her repeated Manual of Mental Disorders (Fourth Edition) bouts of vomiting. Specifically, her elevated (DSM-IV), the diagnosis of panic attack re- hemoglobin level and hematocrit are likely quires the presence of intense fear or discom- secondary to volume contraction, while hy- fort and four or more other symptoms that pochloremia is seen following losses of HCl may come from any of six domains: with emesis. Typically, however, patients with • Cardiovascular: palpitations, pounding vomiting have a hypochloremic metabolic al- heart, tachycardia, and chest pain or dis- kalosis, and her low serum bicarbonate level is comfort inconsistent with the history. • Autonomic: sweating, chills or hot flushes, Three factors might be contributing to and trembling or shaking this patient’s hypokalemia. First, in a volume- • Pulmonary: shortness of breath or a smoth- depleted state, the cortical collecting tubules ering sensation secrete potassium in exchange for increased • Neurologic: dizziness or light-headedness sodium reabsorption in an attempt to cor- and paresthesias rect volume status. Second, the alkalotic state • Gastrointestinal: choking and nausea or caused by losses of acid with vomiting results The average abdominal distress in a transcellular shift of potassium ions into patient goes • Psychological: compass derealization, de- cells in exchange for hydrogen ions. Third, in- personalization, and the fear of losing con- creased levels of epinephrine also cause a shift 3 years before trol or “going crazy.”1 of potassium ions into cells.5 Potassium is not receiving Two aspects of the patient’s history may lost directly through nausea and vomiting. the correct be misinterpreted by those unfamiliar with A state of catecholamine excess, such as the symptomatology of panic attack. First, al- during a severe panic attack or in the presence diagnosis of though panic disorder carries an increased risk of a catecholamine-secreting tumor, could ex- pheochromo- of many comorbidities, including migraine, plain many of her abnormalities. In addition headache is not typically associated with the to causing hypokalemia, epinephrine has a cytoma panic attacks themselves.2 Second, while not gluconeogenic effect, whereas norepinephrine a part of the diagnostic criteria, sleep distur- inhibits insulin release, providing a potential bances are common in patients with panic explanation for hyperglycemia in a patient disorder, and 30% to 45% of patients with with no risk factors for diabetes. Finally, cat- the disorder experience recurrent nocturnal echolamine excess contributes to lactic acido- panic attacks.3 Therefore, the correct answer sis, which could help to explain the low serum is headache. bicarbonate level and the elevated anion gap, but unless we take arterial blood gas measure- ■■ The differential diagnosis ments, the patient’s acid-base status cannot be determined. When considering a diagnosis of panic attack While panic attacks do stimulate the sym- or panic disorder, the DSM-IV mandates that pathetic nervous system, certain elements of medical causes of the symptoms must be ex- her history raise the clinical suspicion for an- cluded. Common conditions causing a similar other process. First, the severity of the elec- spectrum of symptoms include hyperthyroid- trolyte abnormalities is suspicious. Second, a

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typical panic attack peaks at 10 minutes and Table 1 begins to subside, whereas this woman’s symptoms have persisted for 12 hours. Finally, the Frequency of signs and symptoms clinical history, in particular the prominence of pheochromocytoma of headaches associated with the symptoms, is inconsistent with classic panic attack. Con- Symptom Frequency (%) sequently, an alternative diagnosis, such as pheochromocytoma, deserves more careful Headache 60–90 evaluation. Palpitations 50–70 Whenever laboratory results do not fit with the clinical scenario or patient, however, one Sweating 55–75 final possibility should always be considered— laboratory error. Errors can be preanalytical Pallor 40–45 (eg, patient misidentification), analytical, or postanalytical. In aggregate, the frequency Nausea 20–40 of errors in laboratory results is 1 in 214 to 8,316.6 Given that even the more conserva- Flushing 10–20 tive estimates show an incidence higher than that of many of the rare diseases for which cli- Weight loss 20–40 nicians may be testing, laboratory error always deserves consideration. Fatigue 25–40 Psychological symptoms (anxiety, panic) 20–40 ■■ Could this be pheochromocytoma? Sustained hypertension 50–60 Pheochromocytoma is a neuroendocrine tumor most commonly arising from the chro- Paroxysmal hypertension 30 maffin cells of the adrenal medulla. However, extra-adrenal pheochromocytoma, generally Orthostatic hypotension 10–50 paraganglioma, accounts for 15% to 20% of these tumors. Although the condition is gen- Hyperglycemia 40 erally considered very rare, autopsy studies Reprinted from Lenders JW, Eisenhofer G, Mannelli M, Pacak K. Phaeochromo- have demonstrated a prevalence of 0.05%, cytoma. The Lancet 2005; 366:665–676. Copyright 2005, with permission from suggesting that many tumors are either missed Elsevier. http://www.sciencedirect.com/science/journal/01406736. or are not clinically significant. The diagnosis is most often sought in hypertensive patients, a population in which to clinical attention, the classic triad of the pheochromocytoma has a prevalence of 0.1% disease consists of headache, palpitations, and to 0.6%.7 diaphoresis. In fact, headache is the single most common symptom at presentation, seen What is the most common presenting symptom of pheochromocytoma? in 60% to 90% of patients (table 1). Palpita- 2 tions occur in 50% to 70%, and diaphoresis is □□ Paroxysmal hypertension seen in 55% to 75%. □□ Sustained hypertension Although 50% to 60% of patients with □□ Nausea pheochromocytoma have sustained hyperten- □□ Cardiomyopathy sion, it may be absent in patients with primar- □□ Headache ily epinephrine-secreting tumors or large tu- □□ Hemorrhagic shock mors that degrade catecholamines, leading to □□ Psychological symptoms such as anxiety normal or low blood pressure. or panic Cardiomyopathy is a rare consequence of untreated pheochromocytoma, caused by the Although hypertension is the symptom that effects of excess circulating catecholamines most commonly brings pheochromocytoma over a long period of time.8 As seen in this

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Lindau, neurofibromatosis type 1, and multiple Table 2 endocrine neoplasia type 2) and in two genes Sensitivity and specificity of biochemical tests related to paraganglioma syndromes are known for pheochromocytoma to be associated with pheochromocytoma.7

Test Sensitivity Specificity Von Hippel-Lindau syndrome Von Hippel-Lindau syndrome affects 1 in Plasma free metanephrines 99% 89% 36,000 live births. It is caused by a mutation of the von Hippel-Lindau gene on chromo- Plasma catecholamines 84% 81% some 3, and 10% to 20% of patients with the syndrome have pheochromocytoma. Other Urine catecholamines 86% 88% associated problems include renal clear-cell Urine fractionated metanephrines 97% 69% carcinomas and cysts, central nervous system and retinal hemangioblastomas, pancreatic Urine total metanephrines 77% 93% tumors and cysts, endolymphatic tumors, and epididymal cysts. Vanillylmandelic acid 64% 95% Neurofibromatosis type 1 Reprinted from Lenders JW, Eisenhofer G, Mannelli M, Pacak K. Phaeochromocytoma. The Lancet 2005; 366:665–676. Copyright 2005, with permission from Elsevier. Neurofibromatosis type 1 affects 1 in 2,500 to http://www.sciencedirect.com/science/journal/01406736. 3,000 individuals and is caused by a mutation of the neurofibromatosis type 1 gene on chromosome 17. The disease is diagnosed by the patient, a prolonged QTc on ECG associated presence of café-au-lait macules, axillary or with elevated levels of norepinephrine and inguinal freckling (or both), dermal or plexi- normetanephrine may be the only red flag.9 form neurofibromas, Lisch nodules, or osseous Pheochromocytoma is typically an ex- lesions, but the condition is associated with tremely well-vascularized tumor, and rupture many other pathologic findings, including Advances in or hemorrhage is a rare but often fatal compli- optic pathway gliomas, cardiovascular abnor- medical care cation. malities, and, in up to 5.7% of patients, pheochromocytoma.11 have greatly ■■ Important family history reduced the Neurofibromatosis type 2 The classic “rule of 10s” suggests that 10% of Neurofibromatosis type 2 affects 1 in 25,000 perioperative pheochromocytomas are hereditary, but in fact live births and is caused by a mutation of the death rate the number may be higher. In a large cohort neurofibromatosis type 2 gene on chromosome for pheochro- of patients with apparently sporadic pheochro- 22. Patients often develop nervous system tu- mocytoma, 25% were found to have germ-line mors, ophthalmologic pathology, and cutane- mocytoma mutations.10 This finding highlights the impor- ous lesions, but the condition is not associated tance not only of obtaining a thorough family with pheochromocytoma.12 history, but also of genetic testing and counsel- ing once the diagnosis has been made. Multiple endocrine neoplasia type 2 Multiple endocrine neoplasia type 2 affects 1 Which hereditary syndrome is not associ- in 35,000 individuals and is caused by an ac- 3ated with pheochromocytoma? tivating mutation of the RET proto-oncogene on chromosome 21. The syndrome is most □□ Von Hippel-Lindau syndrome worrisome because of the 95% lifetime risk of □□ Neurofibromatosis type 1 medullary thyroid carcinoma in affected pa- □□ Neurofibromatosis type 2 tients, but it is also associated with a 50% risk □□ Multiple endocrine neoplasia type 2 of pheochromocytoma and a 20% to 30% risk □□ Paraganglioma syndromes of primary hyperparathyroidism. Pheochro- Germ-line mutations in five genes related mocytoma is the presenting clinical problem to three hereditary syndromes (von Hippel- in 10% to 30% of patients.13

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FIGURE 1

Paraganglioma syndromes Paraganglioma syndromes are caused by mutations in the three genes encoding subunits of FIGURE 2 the succinate dehydrogenase enzyme. These mutations affect 1 in 30,000 to 100,000 indi- if the upper limit of normal is used as a cutoff. viduals and incur a 70% lifetime risk of devel- Some causes of false-positive results include oping pheochromocytoma or paraganglioma.14 caffeine and acetaminophen use, heart and kidney failure, and failure to keep the patient ■■ Testing for and managing supine for 20 minutes prior to sampling. In pheochromocytoma order to increase specificity of the tests, many clinicians now recommend using cutoff values The consequences of untreated pheochro- two to three times the upper limit of normal.15 mocytoma are potentially devastating and Some researchers have also examined plas- Imaging include progression to metastatic disease, ma total metanephrines and found that any studies hypertensive crises, cardiomyopathy, and ad- one of these three biochemical markers at a renal hemorrhage. Nevertheless, the average value two times greater than the upper limit of are used to patient goes 3 years before receiving the cor- normal provides specificity of around 95%.16 confirm 7 rect diagnosis. Consequently, heightened sus- suspected picion and tests with both high sensitivity and Further laboratory tests in our patient specificity are needed. • Serum dopamine 70 pg/mL (reference range pheochromo- 0–20) Which test for pheochromocytoma has • Norepinephrine 2,018 pg/mL (80–520) cytoma, not as 4the highest sensitivity? • Epinephrine 2,479 pg/mL (10–200) an initial □□ Plasma free metanephrines • Free normetanephrine 12 pg/mL (< 0.9) evaluation □□ Plasma catecholamines • Free metanephrine 17.8 pg/mL (< 0.5). □□ Urine total metanephrines In view of these results, imaging studies □□ Urine fractionated metanephrines were ordered (computed tomography, mag- □□ Urine catecholamines netic resonance imaging, radiography), which □□ Urine vanillylmandelic acid demonstrated a large cystic mass in the region of the left adrenal gland displacing the left While all of the above tests can be used, plas- kidney and the spleen (figure 1, FIGURE 2). ma free metanephrines and urine fractionated metanephrines have the highest sensitivities ■■ Value of imaging studies (99% and 97%, respectively) and are, therefore, typically the tests of choice (table 2). Although imaging studies are used to confirm Nonetheless, clinicians need to be aware of the clinically suspected pheochromocytoma, they potential for false-positive results, particularly are inappropriate as a preliminary evaluation.

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Computed tomography has a sensitivity Typically, oral phenoxybenzamine (Dibenzyl- of up to 95% for detecting adrenal tumors ine) 10 mg twice daily is started and titrated and is able to detect tumors larger than upward daily by 10 to 20 mg until a target 0.5 cm, but its specificity may be as low as seated blood pressure of 120/80 mm Hg is 50%.17 Studies utilizing modern imaging obtained. Selective alpha-1 blockers such as equipment report a prevalence of adrenal prazosin (Minipress) and terazosin (Hytrin) incidentaloma of 4%, of which only 1.5% have also been used and have the benefit of to 11% are pheochromocytoma.18 Thus, a preserved alpha-2 catecholamine reuptake while the simultaneous occurrence of pheo- mechanism.17 chromocytoma-like symptoms and an inci- After several days, a beta-blocker may be dentaloma is not common, the potential for added, particularly for patients with arrhyth- unnecessary surgery precludes diagnosis and mias.7 In patients with refractory hyperten- treatment based on symptoms and imaging sion, metyrosine (Demser) can be useful. alone. During surgery, the patient’s hemodynamic Magnetic resonance imaging has similar stability and glucose levels can fluctuate rap- sensitivity and specificity but can better char- idly from sudden releases of catecholamines acterize the tumor’s blood supply and relation- during manipulation of the tumor, as well as ship to other structures. from the sudden loss of catecholamines after Iodine 131 metaiodobenzylguanidine ligation of draining vessels. Advances in med- (MIBG) scanning is a physiologic study that ical care have reduced the perioperative death uses a radiolabeled amine. Since it can iden- rate from 50% to less than 3%.7,19 tify pheochromocytoma regardless of location, MIBG scanning is typically used when pheo- ■■ Case conclusion and follow-up chromocytoma is diagnosed by biochemical testing but CT and MRI fail to locate the le- Two months after her initial presentation, the sion, or as a follow-up test in patients in whom patient underwent open surgery and had the recurrence or metastasis is suspected or docu- mass removed without complications. She Many experts mented. reports that the “panic attacks” have ceased recommend The specificity of MIBG scanning is 95% completely. to 100%, but the need to protect the thyroid The recurrence rate of pheochromocy- lifelong from ablation and the potential need to repeat toma is 13% in patients with sporadic disease follow-up, scans for up to 72 hours make it a poor choice and 33% in patients with familial syndromes. 17 even for for the initial evaluation. The overall recurrence rate with long-term follow-up is 17%, half of recurrences being those without What is the next best step in our patient’s 5management? malignant disease. All patients should there- hereditary fore be followed in the clinic annually for at □□ Treat her hypertension with a beta-blocker least 10 years to identify and treat recurrences syndromes □□ Begin a course of alpha-blockade early,7 and many experts recommend lifelong □□ Urgent surgery follow-up, even for patients without heredi- □□ Observation tary syndromes.17 Nearly every diagnosis in the DSM-IV in- Because of the high concentration of circulat- cludes the caveat that medical causes of dis- ing catecholamines and the instability of the ease must be excluded before psychiatric labels tumor to physical manipulation, appropriate can be applied. Although panic disorder and medical management before surgical resection panic attack are far more common than pheo- is of paramount importance. chromocytoma, just as essential hypertension Beta-blockade can lead to malignant hy- is far more common than pheochromocytoma, pertension due to the unopposed alpha stim- physicians need to remember that pheochro- ulation and must not be begun until alpha- mocytoma can cause symptoms common to blockade has been started. The standard of both illnesses. Thus, while rare conditions are care is to give an alpha-blocker or calcium rare, atypical presentations of common condi- channel blocker 10 to 14 days before surgery. tions may deserve a second glance. ■

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■ References

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ADDRESS: Franklin A. Michota, Jr., MD, Department of Hospi- tal Medicine, M2 Anx, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195; e-mail [email protected].

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