Key Clinical MessageParoxysmal hypertension, especially when associated with a negative workup for pheochromocytoma, should prompt consideration of pseudopheochromocytoma. This diagnosis requires careful exclusion of other secondary causes of hypertension and highlights the complexity of managing unexplained hypertensive episodes. Clinicians should avoid unnecessary tests and adopt a tailored approach to diagnosis and management.IntroductionSymptomatic paroxysmal hypertension is the hallmark of a pheochromocytoma, a type of neuroendocrine tumor that releases catecholamines, triggering the symptomatic episodes associated with these tumors. Despite the frequently reflexive association between the two, only 2% with this presentation have a pheochromocytoma.1 In the absence of negative radiologic laboratory and radiologic workups, symptomatic paroxysmal hypertension is known as pseudopheochromocytoma.In the current report, we detail a case of pseudopheochromocytoma in a 22-year-old man, which has been a diagnostic conundrum. The case is reported after obtaining informed consent from the patient.Case HistoryA 22-year-old Caucasian male with a PMHx of Lyme Disease, hypermobility, MTHFR mutation, COVID-19 and s/p appendectomy presented to the office to establish care with a primary care provider. At the time of presentation, the patient had been experiencing five months of symptomatic hypertensive episodes for which extensive workup by multiple providers had begun. These episodes consisted of dizziness, palpitations, headache, chest pain, and/or tinnitus, often prompting evaluation in the emergency department, where blood pressures ranged from 173-196/89-110. Outside of these spells, the patient reported posterior headaches, which he likened to a pressure sensation, that worsened when supine and were occasionally accompanied by pulsatile tinnitus. He found that his headaches and elevated blood pressure worsened after eating and drinking. He was also experiencing episodes of dizziness. He denied diarrhea, flushing, weight loss, hypotensive episodes. Baseline blood pressures in office averaged in the 130s/70s. Various workups had been done by providers in the emergency department and in specialty offices in attempt to unearth a diagnosis.Methods (differential diagnosis, investigations and treatment)The patient had multiple EKGs, notable for PVCs, and cardiology evaluation with echocardiogram, holter monitor, and treadmill stress test. Stress testing was normal, the echocardiogram revealed trace tricuspid regurgitation, and the holter study revealed a 0.5% PVC burden. Given the episodic nature of the patient’s symptoms and severe hypertension, workup for a pheochromocytoma was started during an ED visit. CT of the abdomen and pelvis was negative for masses, plasma metanephrines were within normal limits, and CT of the head was unremarkable. The patient traveled home to seek further evaluation with his hometown primary care provider. 24 hour urine collection was done which revealed the following elevations: Vanillylmandelic Acid (VMA) at 10.3 (ULN 7.5), dopamine at 701 (ULN 510), and 5-HIAA at 79 (ULN 14.9). The patient sought evaluation with endocrinology, where further imaging and labs were ordered for concern of a neuroendocrine tumor and workup of secondary hypertension. CT soft tissue of the neck and CT of the chest, both with contrast, were unremarkable. MRI of the abdomen and pelvis was unremarkable. Renal artery ultrasound showed no evidence of stenosis. Renal panel, plasma renin activity, aldosterone, serum plasma metanephrines, IGF-1, chromogranin A, ANA profile, ANCA profile, and sedimentation rate were all within normal limits. To rule out carcinoid, a colonoscopy was done which was unremarkable except for gastropathy.68Ga-DOTATATE PET was negative for evidence of pheochromocytoma or paraganglioma. Tilt table testing was suggestive of POTS, with concurrent transcranial doppler ultrasound showing impaired cerebral blood flow in the left middle cerebral artery.Throughout the course of multiple workups, the patient trialed multiple medications for his hypertensive episodes. Amlodipine worsened his symptoms. Prazosin was ineffective. At the time of writing, the patient was on a regimen of Toprol and Olmesartan. This case remains ongoing with further imaging planned to evaluate both the cervical spine and cervical and cerebral blood flow. Given the negative workup for a catecholamine-secreting tumor, dysautonomia remains a leading working diagnosis for this case.DiscussionPseudopheochromocytoma presents a diagnostic challenge for the clinician. Prior to making this diagnosis, a catecholamine-secreting tumor, such as a pheochromocytoma or a paraganglioma, must be ruled out. Initial workup entails evaluation for significant elevations in plasma fractionated metanephrines and urine fractionated metanephrines and catecholamines.6 Though not observed at the level expected with a catecholamine secreting tumor, mild elevations in catecholamines are commonly observed with pseudopheochromocytoma. It has been proposed that these patients have increased sympathetic tone at baseline, thus explaining these laboratory findings which may be falsely interpreted as a catecholamine-secreting tumor.2 Not only do these elevations have the potential to cloud the clinical picture, but they may also trigger a cascade of unnecessary testing. Observation of urine catecholamines greater than twice the upper limit of normal, urine normetanephrine > 900 μg, urine metanephrines > 400μg or a “significant increase” in fractionated plasma metanephrines warrants imaging, often through adrenal/abdominal MRI or CT.6In the case of a negative workup, pseudopheochromocytoma must be considered in addition to other conditions which may manifest as paroxysmal hypertension: hyperthyroidism, hyperdynamic beta-adrenergic circulatory state, migraine headaches, coronary insufficiency, renovascular hypertension, central nervous system lesions, anxiety, baroreflex failure, carcinoid, and panic disorder.2,4Hypertensive paroxysms associated with pseudopheochromocytoma are unprompted and severe, with blood pressure peaking up to > 200/ > 100 during an episode and accompanied by chest pain, headache, lightheadedness, nausea, palpitations, and flushing.2-5 Episodes may last less than 10 minutes and up to 2 days, occurring daily or less than once a month.2 The exact pathophysiology of these paroxysms remains unclear. Sharabi et. al found that patients with pseudopheochromocytoma showed higher baseline plasma concentrations of epinephrine as well as an exaggerated epinephrine response to glucagon when compared to controls, thus suggesting a component of adrenomedullary hyperfunction in these patients.3 Mann et. al suggested repressed emotions as being an element of the cause of hypertensive paroxysms. In a case series of 10 patients with hypertensive paroxysms and a negative workup for pheochromocytoma, 8 of the patients reported a history of significant emotional trauma (such as being abused as a child or the death of a spouse). It was suggested that repressed emotions may trigger an adrenomedullary response.5 It is worth noting that paroxysmal hypertensive episodes seen in pseudopheochromocytoma can be associated with various etiologies2 and thus no single underlying mechanism can be solely responsible.Once a tumor has been ruled out, the major question becomes: how do we manage these patients? Without a clear etiology, the proper course of management can be vague and often a process of trial and error. As with the case in our patient, multiple medications were trialed and failed. This appears to be a shared experience in patients with pseudopheochromocytoma. Mann et. al reported similar findings in a case series of pseudopheochromocytoma, where multiple patients had failed various antihypertensives, both alone and in combination.4 The same case series reported a successful treatment outcome using both an alpha and beta blockade. Some patients found control through this blockade combination alone whereas others required the addition of a tricyclic antidepressant or selective serotonin reuptake inhibitor.4 Sertraline specifically has been studied for paroxysmal hypertension. Vaclavik et. al studied the effect of sertraline in 47 patients experiencing hypertensive paroxysms. Patients were given 50mg sertraline once a day, to be taken in addition to current medications. After 3 months of sertraline therapy, 28 patients (59.6%) reported full and 14 patients (29.8%) reported partial resolution of their symptoms of paroxysmal hypertension (such as nausea, headache, dyspnea). However, a majority of the patients involved in this study had chronic hypertension at baseline, requiring an average of 3.1 antihypertensives, and were experiencing paroxysmal exacerbations of their blood pressure.7 Though these findings are poorly generalizable to normotensive individuals, the symptomatic improvement observed provides notable support for Mann et. al’s proposition that repressed emotions may play a role in the pathophysiology behind these unexplained hypertensive paroxysms.5ConclusionThe presented case underscores the diagnostic challenge of symptomatic paroxysmal hypertension in the setting of a negative neuroendocrine tumor workup. Symptom etiology often remains elusive despite thorough, sometimes unnecessary, testing. We hope that this case heightens awareness of pseudopheochromocytoma as a differential diagnosis.AuthorshipSarah E. Goodrich, B.S.: Conceptualization; investigation; methodology; project administration; supervision; visualization; writing – original draftDr. Jason P. Browder, D.O.: supervisionReferencesPacak K, Linehan WM, Eisenhofer G, Walther MM, Goldstein DS. Recent advances in genetics, diagnosis, localization, and treatment of pheochromocytoma. Ann Intern Med. 2001;134(4):315-329.Mann SJ. Severe Paroxysmal Hypertension (Pseudopheochromocytoma). In: Berbarie AE, Mancia G, eds. Disorders of Blood Pressure Regulation: Phenotypes, Mechanisms, Therapeutic Options. Cham, Switzerland: Springer International Publishing; 2018:525-540.Sharabi Y, Goldstein DS, Bentho O, et al. Sympathoadrenal function in patients with paroxysmal hypertension: pseudopheochromocytoma. J Hypertens. 2007;25(11):2286-2295.Mann SJ. Severe paroxysmal hypertension (pseudopheochromocytoma): Understanding the cause and treatment. Arch Intern Med. 1999;159(7):670-674.Mann SJ. Severe paroxysmal hypertension. An automatic syndrome and its relationship to repressed emotions. Psychosomatics. 1996;37(5):444-450.Young WF. Endocrine Hypertension. In: Melmed S, Auchus RJ, Goldfine AB, Koenig RJ, Rosen CJ, eds. Williams Textbook of Endocrinology. Philadelphia, PA: Elsevier; 2020:542-572.Vaclavik J, Krenkova E, Vaclavik T, Kamasova M. Effect of sertraline in paroxysmal hypertension. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2018;162(2):116-120.