Paroxysmal hypertension (pseudopheochromocytoma)

INTRODUCTION — The presence of severe and symptomatic paroxysmal hypertension should always generate suspicion of a catecholamine-secreting pheochromocytoma [1]. However, the reality is that this tumor is rarely found among such patients [2]. In one report, the diagnosis was established in only 1 of 300 patients evaluated for pheochromocytoma [3]. Up to 40 percent of patients in this series fulfilled the criteria for panic disorder.

In most patients with paroxysmal hypertension and a negative evaluation for pheochromocytoma, the cause remains unknown, treatment is difficult, and many incur chronic disability. This clinical constellation is sometimes called "pseudopheochromocytoma" [4]. A paucity of data concerning the clinical characteristics and treatment of this disorder exists.

The proposed cause, clinical features (including link to emotions), diagnosis, and management of pseudopheochromocytoma will be reviewed here. The diagnosis and treatment of pheochromocytoma and panic disorder are presented separately:

●(See "Clinical presentation and diagnosis of pheochromocytoma".)

●(See "Treatment of pheochromocytoma in adults".)

●(See "Management of panic disorder with or without agoraphobia in adults".)

PATHOGENESIS — Pseudopheochromocytoma most likely involves activation of the sympathetic nervous system (SNS); this has been inferred from the following observations [5-11]:

●Paroxysmal nature

●Association with tachycardia in some patients

●Increase in plasma catecholamines documented during attacks [5]

●Increase in baseline plasma epinephrine and metanephrines [9]

●Acute blood pressure response to alpha/beta blockade [8]

The mechanism that underlies sympathetic activation is unclear but appears to involve emotional factors.

EPIDEMIOLOGY — The incidence or prevalence of pseudopheochromocytoma has not been reported. However, it is likely to be 50 to 100 times more prevalent than pheochromocytoma, which has an incidence of 0.8 cases per 100,000 patient-years [12]. Pseudopheochromocytoma has been reported in younger and older adults and occurs predominantly in women (>75 percent of cases) [8]. Psychological characteristics typical of patients with pseudopheochromocytoma are described below. (See 'Psychological characteristics' below.)

CLINICAL MANIFESTATIONS — Paroxysmal hypertension (pseudopheochromocytoma) is characterized by abrupt, severe, symptomatic, and transient elevations in blood pressure occurring in patients in whom a pheochromocytoma has been ruled out.

Abrupt, severe, transient blood pressure elevation — Patients with pseudopheochromocytoma typically present with the following features [4,13,14]:

●An abrupt, often severe elevation of blood pressure that is documented by a clinician or home blood pressure monitor.

●Equally abrupt onset of distressful physical symptoms, such as headache, chest pain, dizziness, nausea, palpitations, flushing, and diaphoresis.

●Attacks are not triggered by fear or panic, although fear does occur as a consequence of the frightening physical symptoms.

The duration of episodes can range from 10 minutes to many hours, with frequency ranging from several per day to once every few months. 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 patients who are normotensive between episodes.

Psychological characteristics — Patients with pseudopheochromocytoma usually insist that episodes are unrelated to emotional distress. This feature has tended to discourage consideration of a causal role for emotional factors. However, details of patients' psychosocial history and the success of psychologically based intervention in most cases (as described below) suggest that the disorder is usually related to emotions that have been kept from conscious awareness and therefore are not reported.

In a study that examined patient characteristics, 14 of 21 patients (67 percent) acknowledged a past history of severe emotional stress or trauma (such as physical, emotional, or sexual abuse or trauma, particularly during childhood) despite the insistence by patients that those events bore no lingering emotional impact [8]. The remaining seven individuals did not report a history of overt emotional trauma or abuse, but careful interviewing indicated a lifelong pattern of minimizing awareness of distressful emotions and of not confiding in anyone, sometimes described as a "repressive coping style." Such patients may feel some degree of emotional distress but seem immune to the more severe emotional distress experienced at times by most other people. Other studies have reported similar findings [15].

DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS

Diagnosis — In patients with documented abrupt, severe, transient elevations in blood pressure, several diagnoses should be considered in addition to pseudopheochromocytoma:

●Pheochromocytoma (see 'Pheochromocytoma' below)

●Labile hypertension (see 'Labile hypertension' below)

●Panic disorder (see 'Panic disorder' below)

Pheochromocytoma must be excluded before a diagnosis of pseudopheochromocytoma can be made. Pseudopheochromocytoma can be distinguished from labile hypertension and panic disorder based upon other clinical features.

Differential diagnosis — In addition to pseudopheochromocytoma, the following diagnoses should be considered among patients presenting with paroxysmal hypertension.

Pheochromocytoma — The diagnosis of pheochromocytoma must be excluded in all patients with unprovoked paroxysmal hypertension. Assays of plasma or urine catecholamines are diagnostic in 95 percent of patients with symptoms, and the high sensitivity of the plasma metanephrine assay is also documented [16-18]. Although there is still uncertainty as to the "best" test [16,17,19], most patients with clinically evident pheochromocytoma have very abnormal, rather than mildly abnormal, values. (See "Clinical presentation and diagnosis of pheochromocytoma".)

Labile hypertension — Labile hypertension is widely encountered yet lacks an accepted definition or diagnostic criteria. (See "Labile hypertension".)

Like paroxysmal hypertension, it also manifests with transient blood pressure elevation, but, in contrast to patients with pseudopheochromocytoma, a clear relationship between transient blood pressure elevation and perceived stress or emotional distress is usually evident. Patients know they are upset, and both clinicians and patients attribute the elevated readings to emotional distress. By contrast, patients with pseudopheochromocytoma insist that the disorder is unrelated to psychological factors.

Panic disorder — Panic disorder is characterized by episodes of fear or panic and is commonly associated with physical symptoms such as chest pain, headache, palpitations, flushing, and dizziness, along with some degree of blood pressure elevation [20-24]. Thus, panic disorder and pseudopheochromocytoma share similar physical symptoms. In addition, treatment with an antidepressant agent prevents attacks in both disorders. As mentioned above, panic disorder has been diagnosed in as many as 40 percent of patients evaluated for pseudopheochromocytoma, compared with 5 percent of control patients with hypertension [3].

However, the two disorders differ from each other in that the presentation of pseudopheochromocytoma is dominated by autonomic manifestations (ie, paroxysmal hypertension). In patients with pseudopheochromocytoma, fear occurs only in response to the physical symptoms. By contrast, panic disorder is dominated by emotional manifestations (ie, panic), and accompanying blood pressure changes are milder [25].

The most critical clinical difference is that, in the absence of antecedent panic or emotional distress, both clinicians and patients view pseudopheochromocytoma as an unexplained medical disorder. They rarely consider an emotion-based cause or treatment because, by definition, patients fail to report any triggering emotional distress.

Other causes of abrupt severe hypertension — Many additional disorders, listed below, may present with paroxysmal hypertension. Although such disorders must be considered, they are less common causes of recurrent paroxysmal hypertension and are usually accompanied by clinical features that are characteristic of those disorders [1].

●Anxiety.

●Hyperthyroidism. (See "Overview of the clinical manifestations of hyperthyroidism in adults".)

●Cluster or migraine headaches. (See "Cluster headache: Epidemiology, clinical features, and diagnosis" and "Pathophysiology, clinical manifestations, and diagnosis of migraine in adults".)

●Hypertensive encephalopathy. (See "Moderate to severe hypertensive retinopathy and hypertensive encephalopathy in adults".)

●Coronary insufficiency.

●Renovascular hypertension. (See "Evaluation of secondary hypertension".)

●Central nervous system lesions, such as stroke, tumor, hemorrhage, compression of lateral medulla, and trauma. (See "Clinical diagnosis of stroke subtypes".)

●Seizure disorder.

●Carcinoid. (See "Clinical features of carcinoid syndrome".)

●Drugs – cocaine, lysergic acid diethylamide, amphetamine, and clozapine [26].

●Tyrosine ingestion in patients who are taking a monoamine oxidase inhibitor.

●Baroreflex failure, which is characterized by marked and frequent fluctuations in blood pressure, with both high and low readings [27]. It is caused by hypofunctioning of the baroreflexes that normally buffer blood pressure fluctuations. The disorder is usually a result of injury to carotid baroreceptors, with most patients reporting a history of neck irradiation or surgery.

●Factitious hypertension.

MANAGEMENT

Our approach to management — Pseudopheochromocytoma can be successfully treated in most patients [8,28]. Treatment involves acute intervention at the time of paroxysms and, when clinically indicated (see 'Patients with frequent or severe paroxysms' below), chronic preventive treatment:

Acute management of paroxysms — Our approach to management of acute paroxysms depends upon the severity of the blood pressure elevation, severity of symptoms, and presence or absence of significant comorbidities:

●Patient triage – The decision to refer to an emergency department or to treat in the clinician's office often depends upon clinical judgment. In patients with severe blood pressure elevation or severe symptoms during a paroxysm, or who have a significant comorbid condition that could be exacerbated by marked blood pressure elevation (eg, cardiovascular disease), we typically advise evaluation and management in an emergency department setting. However, serious complications during paroxysms are rare. Thus, in patients who do not have a concerning comorbid condition, who have less severe symptoms, and who have a peak blood pressure below approximately 210/110 mmHg, we usually advise treatment in the clinician's office or self-treatment at home if the clinician is familiar with the patient and with the typical course of paroxysms in that patient. A regimen consisting of clonidine, alprazolam, or a combination of the two usually lowers blood pressure within 60 to 90 minutes, and therefore the response can be assessed quickly. Patients who fail to respond can be advised to seek further evaluation and treatment in an emergency department.

●If treated in the emergency department – In an emergency department setting, we typically treat with an intravenous alpha- and beta-blocking antihypertensive drug (eg, labetalol) plus a short-acting anxiolytic agent (eg, alprazolam). Intravenous administration of labetalol can begin with a bolus of 10 or 20 mg initially, followed by 20 to 40 mg every 10 minutes to a maximum cumulative dose of 200 to 300 mg. If, instead, treatment with an oral agent appears appropriate, administration of clonidine (0.1 or 0.2 mg orally, single dose), an anxiolytic agent such as alprazolam (0.25 to 0.5 mg), or a combination of the two will usually mitigate the paroxysm within 30 to 45 minutes (alprazolam) or 60 to 90 minutes (clonidine).

●If treated in the office or at home – We usually use alprazolam (0.25 to 0.5 mg, single oral dose), clonidine (0.1 mg, single oral dose), or both. Administration of an anxiolytic agent such as alprazolam by itself can be effective in many cases and is a desirable choice both because it has a rapid onset of effect and it does not incur a risk of iatrogenic hypotension following resolution of the paroxysm.

Reliable patients who have responded well to such agents can self-administer medications to avoid frequent visits to the clinic or emergency department. In addition to pharmacologic therapy, we provide reassurance to these patients that serious complications of paroxysms are unlikely. This mitigates the commonly encountered fear of suffering a stroke or death that can exacerbate the paroxysmal blood pressure elevation.

Since hypertensive paroxysms are driven by the sympathetic nervous system (SNS), agents that target the SNS would seem, as has been shown in case series, to be effective in the management of paroxysms [8]. Treatment options include either combined alpha- and beta-adrenergic receptor blockade that blocks the effect of increased SNS tone at receptor sites, an agent such as clonidine that reduces sympathetic flow, or an anxiolytic agent (such as alprazolam) that helps reduce stimulation of the SNS, or a combination of an antihypertensive and anxiolytic agent. (See "Drugs used for the treatment of hypertensive emergencies" and "Management of severe asymptomatic hypertension (hypertensive urgencies) in adults".)

Chronic preventive management — Our approach to chronic preventative management depends upon the frequency and severity of paroxysms and on whether day-to-day functioning of the patient is affected.

Patients with infrequent and mild paroxysms — In patients with mild or infrequent paroxysms, we generally limit treatment to acute management at the time of paroxysms and reassurance, as described above.

Patients with frequent or severe paroxysms — In patients with recurrent paroxysms that produce severe blood pressure elevation or symptoms, or with frequent paroxysms that interfere with day-to-day functioning, we typically prescribe an antidepressant agent if the patient is agreeable. There is no evidence that any one class of antidepressant is more effective than any other.

Antidepressant drugs — Antidepressant agents are the only medications shown to prevent paroxysms and restore quality of life in the majority of patients with severe, frequent, or symptomatic paroxysms [8,29]. Even when the patient rejects the possibility of an emotional basis for the paroxysms, a selective serotonin reuptake inhibitor (eg, paroxetine or citalopram 10 to 20 mg per day, sertraline 50 to 100 mg per day) or a tricyclic antidepressant (eg, desipramine 10 to 75 mg per day) can eliminate attacks. Patients should be informed that, for many of these agents, a period of up to two weeks is usually needed before the main therapeutic effect is evident. There is no evidence that any one class of antidepressant is more effective than any other. These agents can be prescribed by the primary care clinician.

In addition, in some cases, patients who are open to the possibility of an emotional etiology of their paroxysmal hypertension experience resolution of paroxysms with this emotional insight, alleviating the need for pharmacologic management. The role of psychotherapy in treating paroxysmal hypertension has not been studied.

Antihypertensive therapy — The benefit of chronic preventive treatment with combined alpha/beta blockade or any other antihypertensive regimen in preventing or mitigating the severity of paroxysms has not been adequately studied. In patients who are normotensive between paroxysms, we do not institute an antihypertensive regimen due to the risk of hypotension in between hypertensive paroxysms and the absence of proven benefit.

In patients who also have chronic, sustained hypertension, drug therapy of the sustained component of their hypertension need not differ from the treatment of hypertensive patients who do not have paroxysms. Our approach to antihypertensive drug therapy and goal blood pressure is presented elsewhere. (See "Choice of drug therapy in primary (essential) hypertension" and "Goal blood pressure in adults with hypertension", section on 'Goal blood pressure in higher-risk patients'.)

Though unproven, lowering the baseline blood pressure to the normal range might serve to reduce at least somewhat the peak blood pressure that occurs during paroxysms. The possibility that a combination of an alpha- and beta-adrenergic blocker, which reduces blood pressure reactivity to sympathetic stimulation [30], may theoretically be more effective than other agents in reducing the magnitude of the blood pressure spikes during paroxysms, although this has not been adequately studied. Chronic administration of a central alpha agonist (eg, clonidine) is not recommended because of commonly associated side effects such as fatigue.

Psychological intervention — Psychopharmacologic agents can effectively prevent recurrence of paroxysms but cannot cure pseudopheochromocytoma. A cure is sometimes quickly observed in patients who are able to identify the psychological origin of the disorder and gain awareness of repressed emotions [8]. However, many patients, particularly those who have repressed emotions related to severe trauma, are unable to consider such a possibility. Their refusal to pursue a psychological discussion should be honored. No studies have examined the role of psychotherapy, and it is never appropriate to coerce an unwilling patient into psychotherapy, which would likely be fruitless and could potentially be harmful. Patients who don't report a history of severe trauma but who have a repressive coping style are generally also resistant to psychotherapy.

In patients with a history of severe trauma, it may be helpful to empathetically acknowledge the prior trauma and also acknowledge the patient's resilience. Even in patients who are averse to psychological discussions, affirmation of their psychological resilience can sometimes contribute to clinical improvement.

In addition to or in lieu of a psychological intervention, we reassure patients that, although there might be a slight risk, it is highly unlikely that a hypertensive paroxysm will cause a sudden cardiovascular event, such as stroke. This reassurance helps considerably in reducing patients' overwhelming fear of stroke or of dying during a paroxysm. Nevertheless, if blood pressure elevation is extreme (for example, >230/120 mmHg), urgent treatment is warranted. (See 'Acute management of paroxysms' above.)

The effectiveness of different treatment modalities was evaluated in several studies that reported similar responses to treatment [8,15]. Approximately 60 percent of patients were treated with an antidepressant, and 90 percent of these achieved either a complete cessation of paroxysms or a substantial reduction in their frequency. Approximately 10 percent experienced a rapid cessation of paroxysms, without medication, as a result of a psychological intervention that led to awareness of emotions and overwhelming stress that had been repressed from conscious awareness for as long as decades.

Obstacles to successful treatment — The emotional basis of pseudopheochromocytoma is rarely suspected because its manifestations are physical and because patients insist that the paroxysms are not related to stress or emotional distress. Patients view emotional distress as a consequence rather than as a cause of paroxysms. As a result, neither patients nor clinicians are likely to consider an emotional basis, even though the cause and treatment have otherwise remained elusive.

Psychological awareness, whether achieved with or without psychotherapy, offers the possibility of cure but, in many patients, is not an option, since the pertinent repressed emotions may be too overwhelming for patients to confront. In addition, a repressive coping style is rarely amenable to psychotherapy. Therefore, in many cases, a psychopharmacologic rather than psychotherapeutic approach is more likely to be effective.

Some patients will initially refuse either psychotherapeutic or psychopharmacologic intervention. However, the severity of the symptoms and the disruption caused by the disorder will ultimately motivate many patients to accept a therapeutic trial of a psychopharmacologic agent.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Hypertension in adults".)

SUMMARY AND RECOMMENDATIONS

●The presence of severe and symptomatic paroxysmal hypertension should always generate suspicion of a catecholamine-secreting pheochromocytoma. In most patients with paroxysmal hypertension and a negative evaluation for pheochromocytoma, the cause remains unknown, treatment is difficult, and many incur chronic disability. This clinical constellation is sometimes called pseudopheochromocytoma. (See 'Introduction' above.)

●Pseudopheochromocytoma most likely involves activation of the sympathetic nervous system (SNS); the mechanism that underlies sympathetic activation is unclear but appears to involve emotional factors. (See 'Pathogenesis' above.)

●Patients with pseudopheochromocytoma typically present with the following features: an abrupt, unprovoked, and often severe elevation of blood pressure with distressful physical symptoms, such as headache, chest pain, dizziness, nausea, palpitations, flushing, and diaphoresis. Fear and panic occur as a consequence rather than as a trigger of the frightening physical symptoms. (See 'Abrupt, severe, transient blood pressure elevation' above.)

●Patients with pseudopheochromocytoma usually insist that episodes are unrelated to emotional distress. However, the presence in nearly all patients of either a history of severe trauma or a repressive coping style and the response in many to psychologically based interventions (alprazolam, antidepressants, emotional awareness) suggests that the disorder is usually related to repressed emotions. (See 'Psychological characteristics' above.)

●In patients with documented abrupt, severe, transient elevations in blood pressure, several diagnoses should be considered in addition to pseudopheochromocytoma, including pheochromocytoma, labile hypertension, and panic disorder. Pheochromocytoma must be excluded before a diagnosis of pseudopheochromocytoma can be made. Pseudopheochromocytoma can be distinguished from labile hypertension and panic disorder based upon other clinical features. (See 'Pheochromocytoma' above and 'Labile hypertension' above and 'Panic disorder' above.)

●Treatment of pseudopheochromocytoma involves acute intervention and, in some patients with frequent or severe paroxysms, chronic preventive treatment.

Our approach to management of acute paroxysms depends upon the severity of the blood pressure elevation, severity of symptoms, and presence or absence of significant comorbidities (see 'Acute management of paroxysms' above):

•The decision to refer to an emergency department or to treat in the clinician's office often depends upon clinical judgment. In patients with severe blood pressure elevation or severe symptoms during a paroxysm, or who have a significant comorbid condition that could be exacerbated by marked blood pressure elevation (eg, cardiovascular disease), we typically advise evaluation and management in an emergency department setting. However, serious complications during paroxysms are rare. Thus, in patients who do not have a concerning comorbid condition, who have less severe symptoms, and who have a peak blood pressure below approximately 230/110 mmHg, we usually advise treatment in the clinician's office or self-treatment at home if the clinician is familiar with the patient and with the typical course of paroxysms in that patient.

•In an emergency department setting, we typically treat with an intravenous alpha- and beta-blocking antihypertensive drug (eg, labetalol) plus a short-acting anxiolytic agent (eg, alprazolam). If, instead, treatment with an oral agent appears appropriate, administration of clonidine, an anxiolytic agent such as alprazolam, or a combination of the two will usually mitigate the paroxysm.

•When patients are treated in the office or self-treated at home, we usually prescribe alprazolam, clonidine, or both. Reliable patients who have responded well to such agents previously can self-administer medications to avoid frequent visits to the clinic or emergency department. In addition to pharmacologic therapy, we provide reassurance to these patients that serious complications of paroxysms are unlikely. This mitigates the commonly encountered fear of suffering a stroke or death that can exacerbate the paroxysmal blood pressure elevation.

Our approach to chronic preventative management depends upon the frequency and severity of paroxysms and upon whether day-to-day functioning of the patient is affected (see 'Chronic preventive management' above):

•In patients with mild or infrequent paroxysms, we usually limit treatment to acute management of paroxysms and reassurance. In patients who also have chronic, sustained hypertension, the sustained hypertension is treated in the same way as in hypertensive patients who do not have paroxysms.

•In patients with recurrent paroxysms that produce severe blood pressure elevation or physical symptoms, that interfere with day-to-day functioning, or in patients with co-morbidities that place them at risk of complications, we typically treat with antidepressant medication to prevent future paroxysms. In addition, patients who are open to exploring emotional factors related to their paroxysmal hypertension may benefit from a psychological intervention.