Pseudopheochromocytoma

Abstract

Pseudopheochromocytoma (pseudoPHEO) is manifested as severe, symptomatic paroxysmal hypertension without a significant elevation in catecholamine and metanephrine levels and lack of evidence of tumor in the adrenal gland. This condition is difficult for both the patients and the doctors treating them, as there is limited information to suggest an explanation for the symptoms they suffer from. The clinical manifestations are similar but not identical to those with excess circulating catecholamines. The potential mechanism involved in creating the patient’s symptoms includes augmented cardiovascular responsiveness to catecholamines along with heightened sympathetic nervous stimulation. Additionally, the psychological characteristics of this disorder are probably attributed to the component of repressed emotions related to a past traumatic episode or to the repressive coping style. A variety of diagnostic labels are frequently given to these patients before they are actually diagnosed with pseudoPHEO. Management of this condition is challenging as patients are normotensive in between the episodes, thereby leading to hypotension with the use of antihypertensive medications. Antidepressant and anxiolytic medications appear to be effective in preventive management. Thus, a successful management plan can be achieved by strong collaboration between a hypertension specialist and a psychiatrist or a psychologist with expertise in cognitive-behavioral panic management.

Introduction

Pseudopheochromocytoma (pseudoPHEO) is an uncommon disorder usually manifested by severe symptomatic paroxysmal episodes of hypertension (with or without tachyarrhythmia) documented by a physician or by home blood monitoring in no particular setting or trigger, similar to a clinical picture of pheochromocytoma (PHEO), and also having symptoms/signs of nervousness/anxiety, flushing, profuse sweating, palpitations, and headache. Other significant but much less common manifestations may include chest pain, nausea, vomiting, dizziness, paleness, and pseudoseizures¹. Thus, clinical presentations of pseudoPHEO are similar to that of PHEO, particularly symptoms accompanied by recurrent peaks in blood pressure, however, showing no anatomical and biochemical abnormality (exceptions may apply), owing possibly to altered function of the autonomic nervous system or abnormal disposition of catecholamines released from neurons within the brain. Normal plasma catecholamine concentration (some evidence of mild to moderate catecholamine excess may be present) and the absence of an adrenal tumor on imaging studies are useful to delineate pseudoPHEO from a typical PHEO. However, some reports have documented the presence of either elevated plasma dopamine (DA) sulfate levels or increased plasma epinephrine (EPI) levels^2,3. Thus, pseudoPHEO is infrequently associated with an unknown etiology, unidentified pathophysiological mechanisms, and in some with ineffective treatment, using antihypertensive medications. Nevertheless, presence of some amplified cardiovascular responses has shown a possible link between the autonomic nervous system and the pathogenesis of pseudoPHEO³. For a differential diagnosis associated with sustained/episodic secondary hypertension, a physician should always consider renovascular disease, primary aldosteronism, renal parenchymal disease, obstructive sleep apnea, hyperthyroidism, Cushing syndrome, carcinoid syndrome, systemic mastocytosis, panic attacks, and anxiety⁴. Management of these patients is often complex and frustrating to both physicians and patients given the repeated blood pressure surges on a background of either normal baseline blood pressure or sustained hypertension. Due to a possible link to sympathetic nervous system (SNS) overactivity, patients respond well to medications that reduce this overactivity. Anxiolytics, antidepressants, and psychotherapy also play an important role in managing these patients. Severe and long-lasting episodes of paroxysms may require the administration of intravenous agents such as labetalol or nitroprusside but only in a hospital setting.

This current review will focus on patients in whom a diagnosis of PHEO has been excluded but are still presenting with symptoms that resemble catecholamine excess, called pseudoPHEO.

Pathogenesis

In general, the pathogenesis of pseudoPHEO is poorly understood. Initially, patients with this disorder were described as presenting with altered function of the autonomic nervous system or abnormalities in the disposition of catecholamines and their subsequent action on target organs. This proposal was initially made by Page in 1935, when he described a group of women with paroxysmal hypertension and symptoms of flushing, sweating, and palpitations. These symptoms were suggested to be secondary to panic attacks, resulting in “irritation” of sympathetic and parasympathetic centers in diencephalon⁵. Later in the 1980s, Kuchel determined elevated DA levels to be a marker of heightened SNS activation among pseudoPHEO patients¹. In one of his retrospective studies, he demonstrated that among patients mimicking symptoms of PHEO, there was a substantial increase in plasma DA sulfate levels without a corresponding increase in free EPI, norepinephrine (NE), and DA concentration². Therefore, increased DA sulfate levels were hypothesized to be a reservoir of free DA, which when produced in surges, caused episodic hypertension and symptoms resembling the presence of PHEO. However, there was a problem with this hypothesis since an increase in circulating DA levels does not cause an increase in blood pressure or heart rate. Moreover, in 2008 Sharabi et al. reported that patients with pseudoPHEO appeared to have an amplified cardiovascular responsiveness to catecholamines with enhanced adrenal gland release of EPI in response to sympathetic nervous stimulation³. Thus, one could hypothesize that an increased affinity and subsequent stimulation of adrenoceptors by catecholamines or a short catecholamine burst from the SNS could be one of the potential causes behind pseudoPHEO pathogenesis. As stated previously, although elevated catecholamine and/or metanephrine levels are not typical for pseudoPHEO, some studies showed that patients with pseudoPHEO had higher baseline plasma EPI/metanephrine concentrations³. Besides, these patients had a 6-fold increase in plasma EPI levels after sympathetic stimulation with glucagon, but some of these responses can sometimes be seen in normal individuals. These patients also displayed a greater decrease in blood pressure after administration of trimethaphan (nicotinic ganglion blocker inhibiting sympathoneural release of NE) and a greater increase in blood pressure relative to the changes in plasma NE after receiving yohimbine, an α-adrenoceptor agonist stimulating release of this neurotransmitter. Another potentially interesting and well thought out mechanism of pseudoPHEO etiology reported by Mann proposes that the SNS is composed of two limbs, the adrenal and the neural. Different stressors can stimulate one limb of the SNS more than the other. Stimulation of the adrenal limb results in increased secretion of EPI from the adrenal glands, causing increased heart rate and cardiac output, while stimulation of the neural limb causes increased NE release from sympathetic nerve endings in vascular smooth muscle and thus, increased peripheral resistance without a corresponding increase in heart rate. Moreover, for unknown reasons, one limb dominates over the other in different patients with pseudoPHEO⁶. Since most patients with pseudoPHEO do not have elevated catecholamine and metanephrine levels, we view this mechanism possibly existing, but as a very transient and quick one, therefore not leaving a solid, proven trace for elevated plasma or urinary catecholamines/metanephrine levels. Although, if measured during a paroxysm of hypertension and/or palpitations, elevated levels of these biomarkers could be detected (almost impossible to detect outside a hospital setting). However, in patients with episodes of hypertension/tachyarrhythmia lasting for longer periods of time and negative catecholamine and metanephrine levels (usually when they present to a hospital or urgent care), such episodes cannot be explained by catecholamine release. Other mechanisms, perhaps including disbalance of central autonomic centers and catecholamines, must be considered and elucidated in the future, with one possibility being the use of specific functional brain imaging.

Clinical Presentation

PseudoPHEO is frequently a diagnosis of exclusion requiring careful screening for PHEO before the final diagnosis is made. Currently, the extent of influence and pathogenesis of psychological factors on the severe acute rise in blood pressure is unexplained⁷. In a group of 21 patients with pseudoPHEO, Mann described that they typically presented with paroxysmal or episodic hypertension, which was accompanied by physical symptoms such as headache, lightheadedness, dizziness, nausea, diaphoresis, chest pain, and palpitations. The proportion of these paroxysmal events usually extended from every day to less than once per month, and the duration of each episode could last from a few minutes to a few hours, followed by intense fatigue lasting for several days^6,7. In between the episodes, blood pressure was reported to be normal or mildly elevated. Episodic hypertension was considered to be either newly developed and/or already established by episodic paroxysms of high blood pressure (between episodes, the blood pressure is often normal but can be elevated in patients who also have underlying sustained hypertension, or low if antihypertensive agents are prescribed to pseudoPHEO patients who are otherwise normotensive between episodes). The studies from Cornell University and the National Institutes of Health (NIH) described the fear of recurrent attacks without warning, with debilitating clinical manifestations causing restriction of activities resulting in significant disruptions to productivity and normal quality of life^3,7. It also appears to be more common among younger women, aged 40–50 years, per our experience at the NIH (unpublished observations)⁷. Mostly, these patients are unable to identify a trigger to these paroxysms, such as emotional disturbances or another psychic component. A thorough psychosocial analysis often reveals a history of abuse or trauma in the past, often as long ago as childhood^7,8. In 2015, Mann nicely described the association of emotions among those with pseudoPHEO: 1) history of severe abuse or trauma and 2) personality characterized by repressive coping style i.e. lifelong tendency to cope unemotionally with stress^8,9. It is also important to assess whether the syndrome is secondary to another condition, like obstructive sleep apnea, or medications such as tricyclic antidepressants, sympathomimetic agents, and reboxetine - all of which can raise sympathetic activity. But these conditions are usually accompanied by positive biochemistry for PHEO^10,11. Other conditions with similar presentation include systematic mastocytosis, cocaine use, and reninoma¹².

Overall, Mann defined pseudoPHEO associated with the following distinctive features (Table 1):

• Abrupt onset of paroxysmal hypertension

• Elevated blood pressure associated with physical symptoms such as headache, lightheadedness, flushing, diaphoresis, chest pain, and palpitations (commonly seen in patients with PHEO)

• Episodes not provoked by emotional distress and panic, however, during an episode, the distressing physical symptoms do incite a dread of dying

• Negative biochemical testing performed to rule out PHEO

• Evidence of characteristic psychological background revealing a history of abuse, trauma, or a defensive personality

Table 1:

Characteristics of Pseudopheochromocytoma

Clinical features	1. Sudden onset hypertensive paroxysms 2. Associated physical symptoms: chest pain, headache, lightheadedness, diaphoresis, nausea, palpitations, flushing, dyspnea, and weakness 3. Episodes not triggered by emotional distress or panic 4. Past history of severe trauma or abuse
Biochemistry*	Plasma catecholamines: EPI, NE, and DA: WNL Plasma metanephrines: NMN and MN: WNL 24hr Urine catecholamines: EPI, NE, and DA: WNL 24hr Urine metanephrines: NMN and MN: WNL
Diagnosis	1. Clonidine suppression test not needed if there is less suspicion for pheochromocytoma, based on biochemical evaluation. 2 Anatomical/functional imaging, if needed, to rule out pheochromocytoma/paraganglioma

^*Occasionally, patients with diagnosis of pseudopheochromocytoma may have elevated epinephrine levels. Abbreviations: DA, dopamine; EPI, epinephrine; MN, metanephrine; NE, norepinephrine; NMN, normetanephrine; WNL, within normal limits.

Differential Diagnosis (Table 2)

Table 2:

Differential Diagnosis of Pseudopheochromocytoma

Endocrine	Pheochromocytoma, hyperthyroidism, carcinoid, systemic mastocytosis, hypoglycemia, insulinoma, menopausal syndrome, adrenal medullary hyperplasia, Cushing syndrome, primary aldosteronism, reninoma
Pharmacologic	Tricyclic antidepressants, monoamine oxidase inhibitors + ingestion of tyramine, illicit drugs (e.g., cocaine), alcohol withdrawal, abrupt clonidine withdrawal, ingestion of sympathomimetics
Cardiovascular	Ischemic heart disease, arrhythmias, baroreflex failure, renovascular disease, postural orthostatic tachycardia syndrome (POTS), hyperdynamic β adrenergic circulatory state
Neurologic	Migraine headache, cluster headache, stroke, diencephalic autonomic epilepsy, meningioma, hypertensive encephalopathy
Other	Preeclampsia or eclampsia, labile hypertension, obstructive sleep apnea, anxiety or panic disorder, anxiety, post-traumatic stress disorder, acute intermittent porphyria, recurrent idiopathic anaphylaxis, vasculitis

Adapted from Eisenhofer G, Sharabi Y, Pacak K. Unexplained symptomatic paroxysmal hypertension in pseudopheochromocytoma: a stress response disorder? Ann N Y Acad Sci. 2008;1148:469–478.

Pheochromocytoma

The diagnosis of PHEO must be exempted among all patients with unprovoked paroxysmal hypertension⁷. PHEOs are a rare catecholamine secreting neuroendocrine tumor stemming from chromaffin cells of the adrenal medulla¹³. PseudoPHEO mimics the presentation of PHEO from the presence of paroxysmal hypertension along with other signs such as headache, palpitations, sweating, dizziness, and anxiety⁷. In most patients with PHEO, catecholamines are episodically and markedly elevated^14,15. Rarely is PHEO accompanied by a truly negative biochemical testing profile. Therefore, to confirm the diagnosis of PHEO, initial biochemical testing with measurement of plasma or urinary metanephrines is performed¹⁶. Findings of normal levels of plasma or urinary normetanephrine (NMN) and metanephrine (and at some centers, also plasma methoxytyramine) virtually excludes the presence of PHEO, with no further testing for tumor deemed necessary¹⁷. False positive tests and equivocal catecholamine levels in both plasma and urine are ruled out using a clonidine suppression test¹⁶ (in many instances, repeating metanephrines fasting in the morning after 30 min rest will show normal results, avoiding the hassle of going though a dynamic test which may be preserved for those who continue to have elevated normetanephrine level). Modest elevations in catecholamines are seen occasionally among patients with pseudoPHEO due to the activation of the SNS⁶. Concurrent use of medication (NE reuptake inhibitors, tricyclic antidepressants, β-adrenoceptor blockers, monoamine oxidase inhibitors, and recreational drugs including cold and antihistamine medications) and certain foods and drinks (caffeine containing products, cereals, and amine rich foods such as cheese and bananas) can also increase catecholamines and metanephrines and therefore result in modest elevations in their levels^18,19. In 2014, Endocrine Society Clinical Practice Guidelines recommended the use of imaging studies to locate PHEO and paragangliomas once there is clear biochemical evidence. When biochemical evidence to determine the presence of PHEO is excluded, further work-up is redundant. Such patients are advised to undergo a meticulous examination to find out other possible causes of their symptoms and signs that closely resemble to PHEO. Some of these are later discussed below.

The clonidine suppression test, introduced by Bravo et al., works on the principal that clonidine, a central α2-adrenoceptor agonist, suppresses the normal neurogenically mediated release of catecholamine^20,21. However, it does not affect the autonomous secretion of catecholamines from the tumor cells. Thus, the result can be highly predictive of PHEO when interpreting its effects on plasma NE and NMN. Blood pressure and heart rate need to be monitored (to avoid precipitous drop in blood pressure and heart rate) every 5 minutes for 20 minutes before administration of clonidine, then every 15 minutes for 3 hours following. Additionally, blood should be drawn before then 3 hours after clonidine administration, to measure the concentration of plasma catecholamines and metanephrines. Therefore, after administration of clonidine, if plasma NE is suppressed (i.e. concentration below the upper limit or a 50% reduction from baseline) or if plasma NMN is suppressed (i.e. concentration below the upper limit or < 40% from baseline), either of these results would suggest the absence of PHEO²². Antihypertensive and antidepressant medication must be avoided because these may result in false positive test results or a severe hypotensive response to clonidine. In case the patient develops hypotension during the clonidine suppression test, this can be treated by using normal saline.

Panic disorder

The presentation of pseudoPHEO is identical to panic disorder, with common physical symptoms including chest pain, palpitations, dizziness, weakness, and dyspnea. Most of these symptoms are common to those described in the Diagnostic and Statistics Manual (DSM) criteria to indicate panic disorder²³. However, the major difference between these two conditions is that blood pressure elevation in panic disorder is not as high as it is in pseudoPHEO²⁴. Also, paroxysmal hypertension is characterized by extreme blood pressure elevation in the absence of fear or panic. Few patients experience only fear in reaction to physical symptoms⁶. Moreover, headache, the most commonly reported symptom in patients with pseudoPHEO, is not among the symptoms used to define panic disorder from DSM. Wilkinson et al. evidenced the marked increase in sympathetic nerve burst amplitude during a panic attack. They reported a large increase in plasma EPI secretion during spontaneous panic attacks with smaller increase in NE spillover²⁵. However, Villacres et al. reported an increase in baseline plasma EPI levels with normal NE levels among those with panic disorder²⁶. In contrast, Esler’s group in 2007 suggested the role of increased brain serotonin turnover (approximately 4 times higher) in patients with panic disorder²⁷. Therefore, both disorders are related - pseudoPHEO dominated by autonomic manifestations and panic disorder by emotional ones.

Labile Hypertension

PseudoPHEO differs strongly from labile hypertension. In the latter, blood pressure fluctuation is attributed to either stress or emotional distress by both the physician and the patient²⁸. Patients are aware of the fact that their blood pressure is elevated, for example, when they are stressed. The clinical definition of labile hypertension is derived by observing patients experiencing transient but substantial increase in blood pressure, which may be accompanied by symptoms such as headache, palpitations, or flushing, which are resolved spontaneously without requiring any intervention. However, at times, they may present as clinical dilemmas specifically in patients experiencing marked elevation prior to a medical or surgical procedure²⁹. Usually, blood pressure fluctuation is a normal phenomenon. Moreover, a normal lability is potentially harmful in certain medical conditions such as chronic aortic dissection or Marfan syndrome, and possibly in patients with recurrent non-hypertensive cerebral hemorrhage from amyloid angiopathy³⁰. Therefore, in these patients, prophylactic management becomes a necessity.

Post-traumatic stress disorder

Post-traumatic stress disorder (PTSD), included under trauma related stress disorders in DSM 5, requires that the person be subjected to a potentially traumatic event causing significant impact on his/her social and occupational functioning for at least 1 month, without any other medical conditions or effects of toxic drugs³¹. The traumatic event and its impact are usually well appreciated by the patients. However, severe elevation of blood pressure is not frequently observed among patients with PTSD⁶. Moreover, in 1987, Kosten et al. documented the elevation of both EPI and NE among PTSD patients, citing psychological factors as the underlying mechanism responsible for elevation of both hormones³².

Baroreceptor reflex failure

The baroreceptor reflex is characterized by the buffering of abrupt changes in blood pressure while preventing the rise or fall of blood pressure through adjustments in heart rate, cardiac contractility, and vascular tone. Baroreceptor reflex failure is caused due to an underlying condition such as accidental injury, neck surgery, or irradiation and is associated with both hypertension and hypotension³³. Common symptoms observed in these patients include paroxysmal hypertension, tachycardia, diaphoresis, headaches, and emotional instability³⁴. In comparison, pseudoPHEO is described with the presence of paroxysmal hypertension and other associated symptoms as mentioned earlier. These patients have normal hemodynamic responses to the Valsalva maneuver²³. Baroreflex failure can be ruled out using appropriate diagnostic tests to determine baroreflex function. Also, the pressor episodes in baroreceptor reflex failure are occasionally associated with increased plasma NE from unrestrained activation of the SNS³⁴. At times, the bouts of hypertension and associated symptoms of pseudoPHEO are eliminated with psychotherapeutic and psychopharmacological intervention, thus, arguing strongly against baroreceptor failure as a cause⁷.

Management

Treatment of a patient diagnosed with pseudoPHEO is demanding and should be focused on two important aspects: 1) Control of blood pressure and 2) therapy for one of the most common cause of it- panic disorder (pseudoPHEO is an ill-defined clinical syndrome having variable clinical characteristics and multiple causes, one of which is panic disorder) or anxiety state³⁵. However, there are no adequate clinical treatment trials nor recommendations or guidelines to treat these patients. Therefore, a combination of antihypertensive drugs, psychotropic drugs, and psychological intervention is used to treat these patients (Table 3).

Table 3:

Management of Pseudopheochromocytoma:

	Acute management	Preventive management
Anti-hypertensive medication	Severe rise in blood pressure: IV Labetalol bolus 10–20 mg, Increase the dose by 20–40 mg every 10 mins up to a maximum dose of 200–300 mg. IV Nicardipine drip at 5 mg/hr (only in hospital setting)	α-adrenoceptor antagonist – Doxazosin Terazosin Combined α- and β-adrenoceptor antagonist: Carvedilol 25 mg once or twice daily Avoid anxiety, nervousness, situations related to, enough sleep, good diet, environment, avoid stress, etc.
	Mild to moderate rise in blood pressure: Clonidine 0.1 mg or amlodipine 2.5 mg or PO
Psychopharmacologic agent	Rapid acting anxiolytic – Alprazolam 0.25–0.5 mg PO Together with either PO or IV antihypertensive medication	SSRI – Citalopram 10 mg PO Paroxetine 10 mg PO Benzodiazepine – Clonazepam 0.5–1 mg PO (long acting) or Alprazolam 0.25–0.5 mg PO
Psychological/Psychiatric intervention	Reassurance and psychological awareness

Abbreviations: IV, intravenous; PO, per oral; SSRI, selective serotonin reuptake inhibitor; TCA, tricyclic antidepressant.

Antihypertensive drugs

Acute management

Approaches to acute management of pseudoPHEO depend upon the severity of rise in blood pressure, associated symptoms, and the presence or absence of significant comorbidities which put an individual at risk of an acute cerebrovascular or cardiovascular event. Blood pressure above 220/120 mmHg can be considered severe (cutoff could be lower or higher depending on factors such as age, symptoms, routine blood pressure measurement values, and underlying comorbidities). It is advised to evaluate and manage a patient with marked blood pressure elevation associated with a comorbid condition in an emergency unit. To control an intense increase in blood pressure (especially longer lasting) requires use of rapidly acting intravenous medications such as labetalol, sodium nitroprusside, or nicardipine in a hospital setting⁶. When using labetalol, it is given at a bolus dose of 10–20 mg, followed by 20–40 mg every 10 minutes up to a maximum dose of 200–300 mg. If nicardipine is chosen as a first line agent, it is given at a dose of 5 mg/hr with a maximum dose of 30 mg/hr³⁶. A short acting anxiolytic agent such as alprazolam is also given intravenously to modulate the associated symptoms of anxiety^6,7. However, for patients with less severe rise in blood pressure, no associated comorbidities, and treatment requiring special care in office or at home, a regimen consisting of alprazolam (0.25 to 0.50 mg) and clonidine (0.10 mg, single dose) per oral dose is preferred. Combination of these two medications usually lowers the blood pressure in 60–90 minutes³⁷. Oral labetalol is not preferred because of its uncertain bioavailability³⁸. Often, pseudoPHEO patients have a hypertensive emergency, which is stabilized or normalized without intervention or a visit to the emergency room. Such individuals are usually advised to sit in a quiet environment and use mechanisms to “de-stress”, including meditation or deep breathing. A repeat blood pressure measurement is conducted 30 minutes later. If the blood pressure remains elevated, it is recommended to take either a dose of 0.1 mg of clonidine or 2.5 mg of amlodipine, or a low-dose anxiolytic agent orally, depending on the requirements of the individual patient²⁸.

Preventive management

Chronic and preventive management depends upon the frequency and severity of paroxysms and its effect on day-to-day activities. Angiotensin converting enzyme inhibitors (ACEI), angiotensin receptor blockers (ARBs), and diuretics are not very efficient in preventing the episodes of SNS driven paroxysmal hypertension. Also, monotherapy with either α- or β-adrenoceptor blocker would not be beneficial to reduce the SNS mediated blood pressure reactivity. A well tolerated approach would be a combination of α-adrenoceptor blocker and β-adrenoceptor blockers³⁹. However, both carvedilol and labetalol with combined α- and β- adrenoceptor blocker properties have unpredictable bioavailability. Therefore, an α-adrenoceptor blocker such as doxazosin or terazosin combined with a β-adrenoceptor blocker like atenolol or metoprolol seems to be preferable⁶. Also, Garcha et al. reported that transdermal clonidine is useful in prevention of paroxysmal episodes of hypertension. Although, long-term use of centrally acting α-adrenoceptor agonist is not feasible in view of the commonly associated side effect of fatigue. Other centrally active sympathetic suppressants available outside the United States are rilmenidine and moxonidine, with no systemic trials to demonstrate their efficacy among patients with pseudoPHEO. Moreover, individuals who are normotensive in between paroxysms do not require an antihypertensive regimen due to the risk of inducing iatrogenic hypotension and the absence of proven benefit³⁷. Therefore, management of these patients is difficult, since paroxysmal episodes of hypertension often occur several times a week, causing restrictions in lifestyle. These patients can be managed by prescribing antidepressant medication if the patient is agreeable. However, patients with chronic and sustained hypertension are treated similarly to patients with essential hypertension with no paroxysmal episodes (according to the guidelines dictated by American College of Cardiology/American Heart Association (ACC/AHA). Also, for patients with mild or infrequent paroxysms, treatment is limited to acute management at the time of paroxysms and reassurance. The use of antihypertensive medication is never prescribed on an as needed basis. However, in this specific situation, it could be effective to manage hypertensive paroxysm in a patient who is otherwise normotensive at baseline. Moreover, if the initial episode of paroxysmal hypertension is associated with neurological symptoms such as slurring of speech, weakness or blurred vision, the patient should seek care from an emergency room²⁸.

Psychopharmacological Agents

There is no compelling evidence to advocate the use of an antihypertensive regimen for prevention of paroxysmal hypertension. Moreover, the use of antihypertensive agents is limited by the presence of normal blood pressure in between paroxysms. The efficacy of alternatives such as antidepressants and anxiolytics was proposed given the similarity of symptoms from pseudoPHEO to panic disorder and anxiety state^6,28. There is only anecdotal evidence regarding the type or duration of this aspect of therapy, but resolution of symptoms with treatment often occurs in a short period of time in this selected population^7,29,40.

Acute management

Rapid acting anxiolytics such as alprazolam may be used to swiftly terminate attacks of paroxysmal hypertension in some patients. As mentioned earlier, it is given at a dose of 0.25–0.50 mg to those patients with less severe rise in blood pressure. Occasionally, it is used in combination with antihypertensive medications such as clonidine, to manage the significant component of anxiety associated with these paroxysms⁶.

Preventive management

The use of antidepressant medications, such as selective serotonin reuptake inhibitors (SSRI) (paroxetine or citalopram) or tricyclic antidepressants (desipramine) are potent in reducing the frequency or eliminating paroxysms, particularly in patients who do not acknowledge an emotional trigger associated with them⁷. Garcha et al. reported the success of using low doses of SSRIs, such as 10 mg of citalopram or paroxetine daily. A notable response is appreciated by the patients in about three weeks. Mild improvement in symptoms requires titration of the dose up to 20 mg daily. Alternatively, with tricyclic antidepressants like desipramine, 10–25 mg is also useful in curbing these episodes of paroxysms. Recently, a study published by Vaclavik et al. reported the efficacy of using sertraline in the management of patients with paroxysmal hypertension – it led to significant clinical improvement in 75% and complete regression of symptoms in almost half of the patients⁴¹. At times, use of anxiolytics in conjunction with antidepressants is helpful not only to prevent the hypertensive paroxysms but also to improve the quality of life among these patients. For longer acting anxiolytics like clonazepam, 0.5–1.0 mg twice daily can also be helpful in reducing these events^6,28. The treatment of panic attacks and anxiety associated with pseudoPHEO is similar, i.e. clonazepam and SSRI can be given for long-term treatment along with cognitive-behavioral treatment described later in the section³⁵. It should also be noted that SSRIs are also cytochrome P450 enzyme inhibitors, thus interacting with other psychopharmacological drugs and medications for medical illness. These reactions are more commonly seen with paroxetine than with sertraline or fluoxetine⁴². Thus, these medications can be used for chronic management. Moreover, many patients are reluctant to commit to long-term treatment with a psychotropic agent due to the associated social stigma of using these medications for psychological cause. An acceptable approach would be to begin an antidepressant agent among those patients with extremely severe hypertensive paroxysms, >220/120 mm Hg, or with compromised ability to function. At times, delaying the initiation of an antidepressant agent allows for a trial of psychologic intervention⁶.

Psychological Intervention

Antihypertensive agents and psychopharmacological agents may control but might not cure pseudoPHEO. Psychological intervention provides an attractive alternative treatment among those patients who are considering a potential association between pseudoPHEO and emotional factors. However, many patients with repressed emotions related to severe trauma are unable to consider such possibility. In 1999, Mann reported the effectiveness of different treatment modalities among 21 patients with pseudoPHEO who had a mean follow up of 9 months. A successful outcome was achieved in 13 out of 15 evaluable patients. Three of the successfully treated patients responded to psychologic intervention alone whereas the remaining 10 responded to pharmacologic therapy, of which 7 received antidepressant therapy and all received therapy with α- and β-adrenoceptor blockers⁷. Treatment modality with this intervention includes reassurance and psychological awareness. A physician’s confident reassurance that the disorder can be treated and that a catastrophic event or death during a paroxysm is unlikely could reduce associated terror and possibly the number and severity of the attacks. Awareness of repressed emotions behind this disorder is also helpful in reducing or eliminating the paroxysms without any psychotherapy. Later, psychotherapy may be helpful in processing the emotions that arise. Unfortunately, most patients who can repress overwhelming emotions related to unspeakable trauma will defend against awareness and continue to repress those emotions. Furthermore, patients with no history of trauma but a lifelong tendency to repress emotions are resistant to psychotherapy^6,28. The treatment of panic attacks and anxiety among those who address these issues along with other symptoms of pseudoPHEO includes a combination of psychoeducation contributing to symptom induction, stress reducing techniques such as paced breathing, addressing catastrophic cognitions and health anxiety because of the alarming symptoms during the episodes, and deliberate induction of symptoms, thereby desensitizing the patient and reducing avoidance behavior³⁵. Mann reported in 2008 that the wisest course of action for treatment among such patients would be to offer a detailed description of the disease while providing reassurance that the disorder can be favorably managed along with restoration of normal life. At first, a patient’s desire for treatment with psychotherapy and psychological discussion needs to be addressed. If they cannot see the connection between the disorder and trauma/repressed emotions, these therapies should be withheld²⁸.

Obstacles to Successful Treatment

Multiple difficulties can arise while treating a patient diagnosed with pseudoPHEO. Barriers to treatment with antihypertensive agents include 1) ineffectiveness of ACEIs, ARBs, and diuretics, 2) normal blood pressure between paroxysms, and 3) antihypertensive agents unable to prevent paroxysms. One major obstacle to the use of antidepressants is the patient’s refusal to try them as it implies a psychological cause. Finally, many patients, especially those not experiencing distress, hesitate being treated with psychological intervention as these could trigger emotions related to events from the past which might still be affecting them. At times, the mere implication of symptoms relating to an emotional component can cause enough distress to discourage the patient from seeking follow up care. Therefore, patients with pseudoPHEO must be approached sensitively.

Conclusion

This review helps us illustrate how perplexing and difficult it can be for clinicians to reach a diagnosis and establish an appropriate course of therapy in a patient with unexplained symptomatic paroxysmal hypertension. The implications associated with mental health along with the cost of healthcare in terms of diagnostic work-ups, ineffectual treatments, long-term medical care and lost productivity are clearly much higher in patients with pseudoPHEO than for patients with PHEO.

Figure 1.

Pathogenesis of Pseudopheochromocytoma

^*Probably sudden and brisk increase in there activity

^#Extra-adrenal pheochromocytoma are called as paraganglioma

BP blood pressure; CNS central nervous system; HR heart rate; PHEO pheochromocytoma; PTSD post-traumatic stress disorder