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Severe Paroxysmal Hypertension:Pseudopheochromocytoma
  JOHTN
SECONDARY HYPERTENSION
Severe Paroxysmal Hypertension:
Pseudopheochromocytoma
Samuel J Mann
Professor
Department of Clinical Medicine, New York Presbyterian Hospital -Weill/Cornell Medical School, New York, USA
Correspondence Author: Samuel J Mann, Professor, Departmentof Clinical Medicine, New York Presbyterian Hospital - Weill/Cornell Medical School, New York, USA,
Phone: +2127462200
e-mail: sjmann@med.cornell.edu
 
ABSTRACT
Paroxysmal hypertension always engenders a search for acatecholamine-secreting pheochromocytoma (pheo). However,in 98% of cases, a pheo is not found, and the cause andmanagement of the paroxysmal hypertension have remaineda largely unstudied mystery. This review presents an approachto understanding and successfully treating this disorder, whichis increasingly known as "pseudopheochromocytoma," or"pseudopheo." Patients with this disorder experience sudden,unprovoked, and symptomatic blood pressure elevations that arelikely linked to stimulation of the sympathetic nervous system.Psychological characteristics associated with this disordersuggest a basis in repressed emotion related either to prioremotional trauma or to a repressive (nonemotional) coping style.Based on this understanding, successful intervention is possiblein most of the cases. Hypertensive paroxysms can usually bemanaged acutely with an anxiolytic agent, such as alprazolam,an antihypertensive agent that targets the sympatheticnervous system, such as clonidine, or a combination of thetwo. Severe paroxysms may require an intravenous agent,such as labetalol or nitroprusside. In patients with severeand/or frequent paroxysms, recurrence of paroxysms can beprevented in most of the cases with an antidepressant drug. Theimportance of reassurance cannot be overstated. The possiblerole of psychotherapeutic intervention requires further study.Fortunately, with appropriately selected intervention, paroxysmscan be effectively treated or eliminated in most patients.
Keywords: Catecholamines, Hypertension, Labile hyper-tension,Paroxysmal hypertension, Pheochromocytoma,Pseudopheochromocytoma.
How to cite this article: Mann SJ. Severe ParoxysmalHypertension: Pseudopheochromocytoma. Hypertens J2016;2(2):96-102.
Source of support: Nil
Conflict of interest: None
 
 

INTRODUCTION

Although paroxysmal hypertension is a textbooksymptom of pheochromocytoma (pheo) and alwaysengenders suspicion of a pheo, less than 2% of patientswith this disorder actually have this tumor.1 This is not surprising given the rarity of pheo.2 Typically, diagnosticevaluation of paroxysmal hypertension reaches a deadend, leaving patients with an unexplained, difficult-totreat,and often disabling disorder, reasonably calledpseudopheochromocytoma (pseudopheo).

Although thousands of articles deal with managementof patients who have a pheo, very few deal with the98% of patients who do not have it. Doctors and researcherssimply do not know what to do with these patients.In this article, the origin, mechanisms, diagnosis, differentialdiagnosis, and treatment of this disorder willbe reviewed.
 
CLINICAL DESCRIPTION OF PAROXYSMAL
HYPERTENSION (PSEUDOPHEOCHROMOCYTOMA


Characteristics of pseudopheo are summarized in Tables 1and 2.3,4 The frequency of paroxysms ranges from dailyto less than once a month. The duration of the paroxysmscan range from < 10 minutes to as long as 2 days. Physical symptoms, such as chest pain, lightheadedness, headache,diaphoresis, nausea, palpitations, dyspnea, and weakness,typically accompany the blood pressure elevation. Thesesymptoms are common to both pheo and pseudopheo, anddo not reliably distinguish one from the other (Table 2).Paroxysms often result in emergency room (ER) visitsand hospitalizations. The fear of recurrent attacks, whichtypically occur without warning, leads many patients torestrict their activity, and in some cases to leave their job.Thus, the disorder can have a considerable clinical andfinancial impact.

Table 1: Clinical presentation of paroxysmal hypertension in aseries of 21 patients3
Severe Paroxysmal Hypertension:Pseudopheochromocytoma
 
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Severe Paroxysmal Hypertension: Pseudopheochromocytoma

Table 2: Symptomatology of pseudopheochromocytoma vspheochromocytoma3
Severe Paroxysmal Hypertension:Pseudopheochromocytoma

DEFINITION OF THE SYNDROME
OF PSEUDOPHEO


The following characteristic features are typically seenin patients with pseudopheo (Table 3):
  • Hypertensive paroxysms that are characterized bysudden onset
    Patients typically describe an abrupt onset, with noparticular setting or trigger.
  • Blood pressure elevation is associated with physicalsymptoms, such as headache, flushing, fatigue, anddizziness
    Blood pressure elevation is not asymptomatic. Thephysical symptoms do not distinguish between pheoand pseudopheo.5
  • Episodes are not triggered by emotional distress orby panic
    Unlike panic attacks, hypertensive paroxysms arenot heralded by panic or emotional distress. Patientstypically insist that paroxysms occur "out of the blue."However, once an episode has begun, the severephysical symptoms do characteristically provoke afear of dying or stroke.
  • Biochemical tests have been performed and do notsupport the diagnosis of pheochromocytoma.
    The possibility of a pheo must be considered in anypatient with paroxysmal hypertension. This requires assessing blood or urine levels of catecholamines orcatecholamine metabolites, as discussed below.
  • In most cases, psychosocial inquiry reveals either apast history of severe trauma or abuse, or a defensive,very even-keeled personality style
    A characteristic psychological background is evidentin most patients with pseudopheo, as discussedbelow. Its presence in a patient with normal catecholaminestudies strongly supports the diagnosisof pseudopheo and adds reassurance that a pheo isnot being missed.

 
Table 3: Clinical features of pseudopheochromocytoma
Severe Paroxysmal Hypertension:Pseudopheochromocytoma

PSEUDOPHEO AND THE SYMPATHETIC
NERVOUS SYSTEM


The sudden elevations in blood pressure in pseudopheoare linked to the sympathetic nervous system (SNS),which governs instantaneous changes in blood pressure.Evidence of increases in catecholamine levels duringparoxysms and the other evidence of increasedcatecholamine levels support this notion.4,6-8

PSYCHOLOGICAL ROOTS OF PSEUDOPHEO

Despite the continuing mystery of the origin of pseudopheoand of the sympathetic nervous system (SNS)activation underlying it, the possibility of a psychosomaticetiology is widely overlooked. This is understandable sinceparoxysms are dominated by hemodynamic changes andphysical symptoms and patients typically do not report orview stress or emotional distress as a contributory factor.

A breakthrough in understanding the origin ofpseudopheo occurred with the observation that mostpatients, upon psychosocial inquiry, acknowledged a pasthistory of unusually severe trauma or abuse, often fromas long ago as childhood.4 Remarkably, most patientsclaimed that they were free of any lingering emotionaleffects, which strongly suggest that they had repressedtrauma-related emotions. They had vivid memories of thetrauma, but did not feel or suffer from the powerful andpainful emotions related to it. The clues lay in the storyrather than in reported emotional distress.

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Repression of painful emotion is a normal and valuabledefense mechanism, and it is protective againstoverwhelming emotional distress. The ability to repressemotion in the aftermath of severe trauma offers an explanationfor the resilience of some victims of severe traumawho survive without apparent psychological sequelae.9

The history of severe past trauma reported by mostpatients with pseudopheo suggested that the absenceof overt psychological effects should not exclude apsychological basis for the disorder. This mind/bodyparadigm in pseudopheo is thus the opposite of theusual approach to understanding psychosomaticillnesses in that it focuses on the absence rather thanthe presence of emotional distress related to previousmajor events. Patients might have experienced severeemotional distress immediately following the trauma,but eventually repressed and no longer experience therelated emotions. Unfortunately, the concept of repressedemotion and the possible role of repressed emotion in ahypertensive disorder are not widely considered, eventhough no alternative understanding or treatments ofpseudopheo have emerged.

REPRESSED EMOTION IN PATIENTS WITH
PSEUDOPHEO: TWO PATTERNS


Two patterns of unawareness of emotion appear to beassociated with pseudopheo: A past history of severeabuse or trauma and a personality characterized by arepressive coping style.

Roughly two-thirds of patients acknowledge a historyof severe trauma, but strikingly insist that they suffer nolingering effects.3 Their resilience and their ability to thrivein the aftermath of trauma can be attributed to repressionof overwhelming emotion.9 In most of the remainingpatients, a repressive coping style is evident, which ischaracterized by a lifelong tendency to cope unemotionallywith stress.3,10 Such individuals tend to be very evenkeeled,without experiencing ups and downs. Since theyreport little emotional distress, physicians rarely considertheir medical condition to be linked to psychological factors.A repressive coping style is usually a pattern developedin childhood and it could be a result of psychosocialexperience or inherent personality from birth. Such individualsare not buffeted by emotions, and the experienceof depression or anxiety may be foreign to them.

DIFFERENTIAL DIAGNOSIS OF PSEUDOPHEO

Although paroxysmal hypertension can occur in manyconditions, only a few truly resemble pseudopheo andneed to be differentiated from it (Table 4). These includepheo, of course, as well as panic disorder and labilehypertension.
 
Table 4: Differential diagnosis of pheochromocytoma3
Severe Paroxysmal Hypertension:Pseudopheochromocytoma

Pheochromocytoma

It is of course a priority to exclude the presence of apheo. The measurement of plasma metanephrine levelshas a high sensitivity and specificity for identifying apheo, and it is widely employed for pheo screening.11If levels of plasma catecholamines or metanephrinesare markedly elevated, radiological studies to identifya pheo are indicated. However, mild elevations arefrequently encountered, which usually represent falsepositives, perhaps largely reflecting a 30% false-positiverate associated with lack of adherence to fasting state,supine position, and rest before sampling.12 The increasedsympathetic tone in patients with pseudopheo might alsocontribute to a higher false-positive rate. Thus, althoughradiologic imaging is sometimes obtained by physicianssuspicious of a pheo in patients with normal or onlymildly elevated metanephrines, an unending search fora pheo is unlikely to be of value.

Traditionally, a clonidine suppression test wasperformed in patients with mild elevation of plasmacatecholamines.13 However, this test currently is notwidely employed.

Although there is no clearly established protocol withregard to further work-up, a reasonable approach wouldbe to screen for pheo with plasma metanephrines in allpatients with paroxysmal hypertension. Because of therarity of pheo, magnetic resonance imaging should be reserved for patients with metanephrine values that aremarkedly elevated or with persistent mild elevation onrepeated testing and with severe manifestations or a highdegree of physician concern.14
 
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CONDITIONS THAT COMMONLY MIMIC
PSEUDOPHEO


Panic Disorder

Both panic disorder and pseudopheo are characterized bysudden episodes of severely distressing physical symptoms,such as headache, dyspnea, dizziness, weakness, anddiaphoresis. Thus, physical symptomatology does notallow the differentiation of the two disorders.

However, the two conditions differ in that in panicdisorder panic attacks are dominated by the emotionalmanifestation of panic, with less prominent elevationof blood pressure , usually averaging 20 mm Hg orless.15 In contrast, pseudopheo is dominated by the autonomicmanifestation of the blood pressure elevation(40-100 mm Hg or more), without panic attacks.3 Panicdoes not trigger hypertensive paroxysms; it occurs as aresult of the frightening physical symptoms. It was theperspective of viewing hypertensive paroxysms in pseudopheoas the autonomic equivalent of panic attacks thatled to consideration of treating it with an antidepressant,in the same way that panic disorder is treated.

Labile Hypertension

Many individuals with essential hypertension experienceconsiderable fluctuation in their blood pressure, oftenat times of stress or emotional distress. Blood pressureelevation can occur without physical symptoms or canbe accompanied by symptoms, such as headache orpalpitations.

Labile hypertension differs strongly from pseudopheo;in the former, most patients readily attributetheir blood pressure fluctuations to stress and emotionaldistress. In some patients, blood pressure increases areassociated with symptoms resulting from anxiety orhyperventilation.16 Blood pressure lability is much moreprevalent and should not be misconstrued as pseudopheoin the absence of the aforementioned characteristics.

Other Diagnoses

Many other conditions (some are commonly and othersare rarely encountered) can also cause paroxysmalhypertension (Table 4). However, few present withparoxysmal hypertension as their only manifestation,without other signs or symptoms that are moretypical of those conditions. In the absence of signs orsymptoms characteristic of these conditions, they are unlikely to provide a diagnosis, whereas pseudopheo isoverwhelmingly likely.

 
The use of illicit drugs, such as cocaine or amphetaminescan cause severe blood pressure elevation.However, patients with pseudopheo are so symptomaticand frightened that they are highly unlikely to continueusing, and deny that they are using, these drugs. Theuse of drugs, such as monoamine oxidase inhibitors orthe sudden withdrawal from clonidine will be readilyevident from the history.

Baroreceptor failure causes considerable blood pressurelability, but is unlikely to be seen in the absenceof a condition predisposing to its development, such asprior neck surgery or irradiation.17,18 In addition, markedblood pressure fluctuations of this disorder are regularlyobserved, while with pseudopheo, blood pressure elevationsare seen only during paroxysms without abnormallability or hypotension at other times.

Posttraumatic stress disorder (PTSD), like pseudopheo,is associated with prior trauma and with elevated plasmanorepinephrine levels.19 However, severe blood pressureelevation is not characteristic. Further, unlike patientswith pseudopheo, patients with PTSD are very aware ofprior trauma and its impacts.

Are tests to exclude these entities truly needed in thepatient who presents with paroxysmal hypertension?Usually not, although each case must be assessed basedon the accompanying clinical signs and symptoms.Further, as mentioned above, the presence or absence ofthe characteristic psychological profile of pseudopheosupports the diagnosis and argues for treatment directedat pseudopheo rather than endless testing for veryunlikely causes. A clear response to treatment directedat pseudopheo then further supports the diagnosis.

APPROACH TO TREATMENT

The treatment of paroxysmal hypertension has been amajor dilemma, and there is a paucity of treatment trials.Diuretics, angiotensin-converting enzyme inhibitors(ACEIs), and angiotensin II receptor blockers (ARBs)would not be expected to prevent hypertensive surgesdriven by the SNS. Further, it is difficult to prescribean aggressive antihypertensive regimen in patientswhose blood pressure is normal in between paroxysms,due to the risk of iatrogenic hypotension. Nevertheless,patients need treatment, and successful approachesbased on understanding the origin of pseudopheo havebeen reported.3,20 With these approaches, paroxysmalhypertension can be successfully managed in mostpatients, enabling their resumption of a normal life.Treatment involves acute treatment of paroxysms as wellas preventive treatment (Table 5).

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Table 5: Treatment3
Severe Paroxysmal Hypertension:Pseudopheochromocytoma

ACUTE MANAGEMENT OF HYPERTENSIVE
PAROXYSMS


In the acute management of paroxysms, there is a role forantihypertensive agents, psychotropic agents, or a combinationof both. The choice of treatment depends on theseverity and frequency of paroxysms. For paroxysms withsevere blood pressure elevation, treatment with a rapidactingintravenous agent, such as labetalol, or, rarely,nitroprusside, may be needed. Concomitant treatmentwith a quickly effective anxiolytic agent like alprazolamcan be helpful in shortening the duration of the paroxysmand the severity of blood pressure elevation.3,21

For milder paroxysms, oral treatment is usually appropriateand effective, consisting of an oral sympatholyticagent, such as clonidine, an anxiolytic agent, such asalprazolam, or a combination of both. In patients with ahistory of previous uncomplicated paroxysms and who areknown to have responded to these agents, self-treatmentat home, rather than management in an ER or hospital,is a realistic option. Oral labetalol is another alternative,although it might not be effective in rapid metabolizers oflipophilic beta-blockers.22 Agents, such as ACEIs, ARBs,and diuretics do not appear well suited for acute treatmentof SNS-mediated blood pressure elevations.

PREVENTIVE MANAGEMENT

There is no compelling evidence that antihypertensiveagents can prevent paroxysms. It is also unclear whetheror not they mitigate the magnitude of the blood pressure spike during paroxysms. Further, dosing of antihypertensiveagents is often limited by the normal blood pressurebetween paroxysms.
 
The efficacy of the alternative of prescribing an antidepressantagent was originally suggested by the similarityof pseudopheo to panic disorder. This promise has beenborne out in reports indicating that antidepressant drugsare highly effective in preventing paroxysms in mostpatients, at dosages used in treating panic disorder, andare the most effective treatment available for preventingparoxysms.3,4,20 Initially, the high response rate reportedin two retrospective case series was recently confirmedin a prospective study in which the antidepressant sertraline,given at a 50 mg dose, eliminated paroxysms in61% of patients, and reduced or eliminated them in 90%of patients.20 These results also strongly support the suggestedpsychosomatic basis of this disorder.

Which patients are candidates for long-term treatmentwith an antidepressant agent? In patients who havemild or infrequent paroxysms or who improve withpsychological intervention (see below), it is reasonableto initially limit treatment to acute management ofparoxysms with alprazolam or clonidine. However, inpatients who continue to experience severe symptoms,severe blood pressure elevations, or frequent paroxysmsthat interfere with their functioning, an antidepressantagent is very likely to be effective and should be stronglyconsidered. There is no evidence that any class ofantidepressant agents is more effective than any other.

PSYCHOLOGICAL INTERVENTION

There are no trials regarding the psychological aspects oftreating patients with pseudopheo. However, attendingto psychological aspects of treatment appears to playan important role in the management of patients withpseudopheo.3,4 Reassurance appears to be very helpful.Less commonly, psychological intervention centered on ashift in awareness regarding the role of past events mightlead, in some cases, to a dramatic reduction or cessationin paroxysms, as discussed below.

REASSURANCE

The following are the three aspects of reassurance thatappear to play an important role:
  • Reassurance that a hypertensive paroxysm is highlyunlikely to cause stroke or sudden death
    Symptomatic hypertensive paroxysms are terrifyingto patients, regularly provoking fear of suffering astroke or of dying during a paroxysm. Many treatingphysicians share that fear. However, the occurrence ofacute cardiovascular events during a paroxysm hasnot been reported, supporting the likelihood that the risk of an event is very low. Similarly, regular weightliftingcauses acute and severe elevation in bloodpressure, with peak mean arterial pressure averaging160 mm Hg (equivalent to a systolic/diastolic pressureof 220/130) in normotensive weightlifters, yet it hasnot been reported to be associated with acute stroke.23Reassurance by a physician that stroke or death is veryunlikely to occur during a paroxysm can be extremelyhelpful in reducing the fear of the patient and thesympathetic stimulation that is aggravated by fear.
 
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  • Reassurance that the patient will be able to resume anormal life
    Many patients have come to view themselves aschronically ill with no hope of improvement or returnto a normal life. The reassurance that the disorder canusually be successfully treated and that they will beable to resume a normal life would seem to be, andin clinical experience, helpful to patients.
  • Reassurance that the patient is psychologically healthy.
    Many patients resist an explanation of the disorder ashaving psychological roots, partly because it impliespsychological weakness or illness. This concernalso provokes resistance to consideration of thepsychopharmacologic interventions that offer the bestchance of clinical improvement.
The fact that many patients with pseudopheo aresuccessful survivors of severe trauma actually offerstestimony of psychological strength, not weakness,rooted in successful repression that enabled avoidanceof the severe and long-standing psychologicalsequelae that might otherwise have resulted from thetrauma. Reassurance that the disorder is not indicativeof psychopathology or psychological weaknessincreases the likelihood of patients' acceptance ofits psychodynamic origin. This reassurance mightincrease patients' acceptance of the psychosomaticetiology of the disorder as well as treatment with anantidepressant.

AWARENESS

In treating physical symptoms that result from psychologicaldistress, the usual paradigm of psychologicalintervention consists of stress reduction techniques orpsychotherapy to relieve emotional distress. This paradigmdoes not fit pseudopheo, which is characterized bythe absence of perceived emotional distress. Strikingly,in pseudopheo, it is a shift to conscious awareness ofpainful emotion that might be helpful in amelioratingthe disorder.21 However, most pseudopheo patients donot appear to be interested in, or capable of, dealing withtrauma-related emotions; further, such interventionsmay be unhelpful and could perhaps be harmful.9,21Many successful survivors of severe trauma depend on repressing trauma-related emotions.9 Of necessity, theycontinue to defend against awareness and probablybenefit from doing so.9 Thus, they are unlikely to beinterested in, or to benefit from, psychotherapy aimedat emotional awareness.21 This is analogous to the lackof benefit and the risk of harm associated with efforts tobring up trauma-related emotions in successful traumasurvivors.9 The dictum that it is always best to deal withthe past is not inherently true.

 
In the absence of adequate study, the wisest coursemight be to reassure the patient that the disorder can besuccessfully managed and normal life can be resumed.If the patient wishes to pursue the psychological originof the disorder, it can be encouraged. If not, thenpsychological discussion and psychotherapy should notbe urged.

OBSTACLES TO SUCCESSFUL TREATMENT

Barriers to treatment with antihypertensive agentsinclude the ineffectiveness of ACEIs, ARBs, and diuretics,and the normal blood pressure between paroxysms thatlimits the aggressiveness of antihypertensive therapy.Further, an antihypertensive regimen is unlikely toprevent paroxysms.

Barriers to treatment with antidepressants includepatients' antipathy to the idea of taking one and intoleranceto agents that are tried. Some patients will refuseto try an antidepressant no matter how severely symptomaticthey are because its use implies a psychologicalcause. However, many such patients will eventually agreeto try one because they are severely symptomatic and noother treatment has helped. The newer serotonin-specificreuptake inhibitors (SSRIs) are well tolerated in most, butin some patients, it is difficult to reach an effective doseof any drug.

Finally, there are major barriers to acceptance ofa psychological origin of the disorder. Because themanifestations of pseudopheo are physical rather thanpsychological and are not triggered by obvious currentstressors, its emotional basis is usually not suspected byeither patient or physician. Further, many trauma survivorsneed to avoid psychological discussion or awareness.This is the reason why psychological awareness is not anoption for most.

Clearly, the treatment of pseudopheo is a challengeand an art. However, fortunately, in most cases, successfultreatment is achievable, and a normal quality of life canbe restored.

CONCLUSION

Despite all the attention given to pheochromocytoma,> 98% of patients with paroxysmal hypertension have pseudopheo, whose origin and treatment have receivedremarkably little attention. The obscurity of its origin isattributable to its link to repressed emotion, a phenomenonessentially unrecognized by patients, physicians,and even psychologically oriented medical clinicians andresearchers. Further, it is a disorder for which patientsseek out physicians, not psychologists, and therefore, ithas remained under the radar of psychologists.

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If catecholamine studies are normal, the characteristicpsychological background usually allows a confidentdiagnosis and greatly reduces concern that a pheoor other obscure cause is being missed. Treatment issuccessful in most patients. The main components aretreatment at the time of paroxysms with an anxiolyticagent and/or an antihypertensive agent directed at theSNS, usually clonidine, and preventive treatment withan antidepressant agent.

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