Abstract
The clinical syndrome of hypertension, headache, palpitation, diaphoresis, flushing, and emotional lability is classically associated with pheochromocytoma. Two patients are presented with this constellation of symptoms in whom investigations for pheochromocytoma were unrevealing. Headache was the presenting and most prominent complaint, with daily episodes of short-lasting, intermittent, and paroxysmal attacks. Each paroxysm of headache was associated with a dramatic increase in systolic and diastolic blood pressure. After failure to control the labile fluctuations in blood pressure and headache with several classes of anti-hypertensive medications used in combination, a prompt and persistent response occurred after the administration of clonidine. The pathophysiology of this syndrome and the mechanism of clonidine action are reviewed in the context of a possible failure of the baroreceptor reflex.
Introduction
Most large-scale population-based epidemiologic studies have failed to demonstrate an association between headache and hypertension (1–3). However, the incidence of headache in patients with pheochromocytoma has been estimated to be as high as 80% (4). Paroxysmal headaches associated with pheochromocytoma are short-lasting, often peaking within minutes, and resolve over several minutes. The International Headache Society recognizes headache as a common symptom in patients who develop an acute pressor response (> 25 mmHg increase in diastolic blood pressure) to an exogenous agent and in patients with malignant (accelerated) hypertension, hypertensive encephalopathy, preeclampsia, and eclampsia (5).
Two patients are described who presented with recurrent daily episodes of sudden, severe, short-lasting headaches that were time-locked with an acute and dramatic increase in arterial blood pressure. The mechanism proposed for the inability to buffer the sudden changes in blood pressure in these patients is a failure of the normal baroreceptor reflex. The dramatic response to clonidine and the mechanism underlying this response are discussed.
Case 1
A 62-year-old man was seen for evaluation of severe recurrent headaches of recent onset. He underwent an uncomplicated right carotid endarterectomy (CEA) in December 1997 for an asymptomatic 95% stenosis of the right internal carotid artery. One month later he underwent a 3-vessel coronary artery bypass procedure after he presented with exertional angina. Although the operative records were not available at the time of his consultation, there were no reported intra-operative or post-operative adverse events. On March 31, 3 months after his CEA, he presented with the first of many sudden severe headaches. The headache began in the occipital head region as a dull ache. Within 30 s, the headache rapidly generalized and intensified to a severe throbbing headache associated with facial flushing. The duration of each headache was 30–60 min. There were no associated migrainous symptoms. The patient was hospitalized at another Institution. During each paroxysm of headache, his blood pressure was between 230 and 240 mmHg systolic and 120–130 mmHg diastolic. Between headaches, his blood pressure averaged 130/70 mmHg. He had an extensive evaluation, including two computed tomography (CT) scans of the brain, a magnetic resonance image (MRI) of the brain, 24-h urine study for catecholamines and vanillylmandelic acid, plasma catecholamines, CT scan of the abdomen, and renal arteriogram. All results were normal. Despite the use of doxazosin, 2 mg, and labetalol, 200 mg twice daily, he continued to have severe headaches associated with severe and rapid swings in blood pressure. However, the use of lorazepam 0.5 mg and a barbiturate–acetaminophen combination abbreviated the headache to 15–20 min.
The patient was referred with a diagnosis of hypertension that was thought to be due to the anxiety caused by his headaches. This explanation was reinforced by his partial response to 0.5 mg of lorazepam. The patient had no prior history of headache, nor was there a family history of headache. He had a history of borderline hypertension documented in 1991 (treated briefly with metoprolol), and he had remained normotensive until his current presentation. He had a history of mild untreated hyperlipidaemia and reflux oesophagitis.
Results of his general physical, neurologic, neurovascular, and mental status examinations were completely normal. Sitting blood pressure was 126/80 mmHg, with resting sinus rhythm and heart rate of 76 beats/min. However, during the interview, the patient felt that he was developing a mild occipital headache. His blood pressure at that moment was 178/90 mmHg. As his headache quickly intensified over about 120 s, serial blood pressure measurements were obtained, and the blood pressure had risen to 220/110 mmHg without a change in heart rate. There was mild facial flushing and erythema around the nape of the neck without diaphoresis. The patient appeared mildly anxious and apprehensive.
The patient's evaluation consisted of an electrocardiogram, which showed no evidence of left ventricular hypertrophy. Complete blood cell count, chemistry panel, serum thyrotropin, lipid profile, urinalysis, carotid ultrasonography, and chest radiograph were normal. The record from a 24-h Holter monitor was essentially normal. The patient also had a 24-h continuous blood pressure monitor (Fig. 1). The average blood pressure over the 24-h recording was 134/72 mmHg, but intermittent systolic and diastolic hypertension were readily evident, with maximum values of 212/122 mmHg (Fig. 1b). The patient, with the use of an event recorder, noted the onset of the headaches coincident with a preceding increase in systolic blood pressure, usually to about 180 mmHg (Fig. 1a).
(a) Note the onset of headache (R x ) coincident with but shortly after the abrupt increase in blood pressure (arrows). (b) Cumulative blood pressure (BP) and heart rate (HR) data illustrate the maximum, average, and minimum blood pressures, which demonstrate the wide range in pulse pressure. DIA, Diastolic; SYS, systolic.
The patient was placed on clonidine therapy (0.2 mg at bedtime), while labetalol and doxazosin were discontinued. He noted a marked improvement during the day until about 4 pm, when he would develop headache with increases in blood pressure, but both were less severe. A change in his schedule to 0.1 mg three times a day completely eliminated the paroxysms of hypertension as well as the headaches. He was switched to a clonidine patch (0.2 mg/day) for ease of administration, and he remained headache-free and normotensive at 10-month follow up.
Case 2
In 1992, a 68-year-old man underwent resection of a squamous cell carcinoma involving the epiglottis and pharynx. He received extensive post-operative radiation therapy to the neck, but the records from this treatment were not available at the time of his consultation. He has had solid and liquid dysphagia since that time, with recurrent aspiration pneumonia.
The patient underwent a preoperative stress test before a cholecystectomy in December 1998, and his blood pressure and heart rate were normal. He then presented shortly after surgery with labile hypertension manifested as spells lasting 20–60 min and characterized by a tightness of his face, head, and neck; a throbbing headache in the frontal and vertex region; facial flushing; and anxiety. These episodes were documented to be associated with substantial increases in blood pressure, with systolic blood pressure up to 230 mmHg and diastolic pressure up to 130 mmHg. Numerous β-adrenergic blockers, angiotensin-converting enzyme inhibitors, and diuretics, alone and in combination, did not control his hypertension. His blood pressure occasionally plummeted to as low as 90/40 but his pulse remained relatively stable between 40 and 60 beats/min.
Over the next 4 months he experienced wide fluctuations in blood pressure, with systolic pressures ranging from 90 mmHg to 230 mmHg. He would develop hypertension with even minimal exertion or simply by standing. During these episodes, he described a pain in the posterior neck region and a diffuse throbbing headache associated with facial flushing and anxiety. With recumbency, these symptoms would abate as his blood pressure decreased, sometimes to as low as 90 mmHg systolic.
Recurrent episodes of visual loss developed in the right eye on exposure to bright sunlight. When seen in his physician's office for one of these episodes, his blood pressure was 230/130 mmHg; he was given 4 mg of clonidine, which decreased his pressure immediately to 170/90 mmHg. He returned home, but began feeling lightheaded and had a syncopal episode in which his pressure was measured at 90/40 mmHg. He was admitted to the Intensive Care Unit for 3 days, and his blood pressure was noted to fluctuate markedly. Examination revealed a supine blood pressure of 140/85 mmHg and heart rate of 71 beats/min. After 1 min of walking, his blood pressure increased to 220/110 mmHg, with a resting heart rate of 57 beats/min.
Renal and abdominal ultrasonography and CT and an electrocardiogram were normal. Carotid angiography revealed an occluded right internal carotid artery, with a 40% stenosis on the contralateral side. Measurements of 24-h urine metanephrines and fractionated catecholamines were unremarkable. MRI of the brain was normal. The patient was ultimately placed on therapy with a clonidine patch and had excellent blood pressure control and elimination of his headaches. The patient was scheduled to undergo comprehensive autonomic testing, but elected to defer this because he would have had to discontinue clonidine for a time.
Discussion
These cases demonstrate several intriguing points: (i) the presentation of a stereotypic short-lasting headache associated with paroxysms of severe hypertension in the absence of a pheochromocytoma; (ii) the dramatic response to clonidine; and (iii) the resemblance of this clinical picture to the syndrome of baroreceptor failure.
The arterial baroreceptors play a critical role in the control of arterial pressure in humans by buffering moment-to-moment changes so that acute and excessive fluctuations do not occur (6). Baroreceptors in each carotid sinus relay information regarding vessel distension via the glossopharyngeal nerves to the nucleus of the tractus solitarius. Via intrinsic medullary connections, the nucleus of the tractus solitarius activates cardiac parasympathetic outflow and inhibits sympathetic vasomotor outflow (Fig. 2). Other mechanoreceptors in the aortic arch and great vessels of the thorax transmit similar information via the vagus nerves to the nucleus tractus solitarius and generate similar depressor responses. Because of this functional redundancy, bilateral lesions involving the carotid sinus are frequently required to produce baroreflex failure, although a central lesion in the region of the nucleus of the solitary tract can produce the same effect.
Simplified diagram of the main components of the baroreflex circuit. Excitatory connections are mediated by
In humans, transient hypertension caused by baroreceptor dysfunction has been reported after CEA (7–9), in Takayasu arteritis (10), and after surgical deafferentation of the carotid baroreceptors (11). In these conditions, baroreceptor reflex impairments are usually transient rather than permanent, presumably because of the intrinsic redundancy and compensatory ability of the baroreceptor system.
More commonly however, patients with baroreflex failure present with chronic fluctuating hypertension (6). Hypertensive episodes can occur in response to stress and are often separated by periods of normal or even low arterial pressure at rest. Chronic baroreceptor reflex failure has been described in patients with bilateral lesions of the nucleus of the solitary tract (12) or familial paraganglioma syndrome (13) and after surgical resection of the glossopharyngeal nerves (13). Idiopathic cases, referred to as Page syndrome, have been described (13). The syndrome has also been well described as a delayed consequence in patients who have undergone radiation therapy to the neck for head and neck malignancies (13–15). This may reflect the relative importance of carotid baroreceptor input over the cardiopulmonary afferents.
Patient 1 in this report had a unilateral endarterectomy for asymptomatic carotid occlusive disease. There was no evidence of significant contralateral carotid disease by ultrasonography. Although it has been thought that the loss of carotid baroreceptor input does not cause a long-term impairment in baroreceptor function, a delay of more than 2 days in the expression of hypertensive paroxysms with symptoms lasting up to 2 months has been described in patients undergoing unilateral endarterectomy (16). Lesser degrees of baroreflex failure have occasionally been detected with haemodynamic monitoring during or soon after CEA or carotid body surgery (8, 17, 18). The true incidence of long-term elevations or lability of blood pressure after such operative procedures is not known. Indeed, baroreceptor dysfunction may provide an explanation for the development of post-endarterectomy hypertension and hence a mechanism for the headaches that develop in some patients after CEA (19–24).
The apparent failure of the baroreflex in this patient suggests that either baroreceptor function in some individuals has a unilateral predominance—that baroreceptor reactivity on the opposite side is impaired by reduced vessel compliance and distensibility as a result of age, calcification, and atherosclerosis—or that trauma to the aortic baroreceptors or vagus nerve could have occurred during his coronary artery bypass procedure 1 month after the endarterectomy. Unfortunately, the patient did not wish voluntarily to discontinue clonidine therapy to undergo autonomic testing to assess baroreceptor sensitivity.
Patient 2 presented with an almost identical clinical picture of severe, abrupt, short-lasting headaches that were preceded by sudden increases in systemic blood pressure and accompanied by facial flushing and anxiety. In this case, the loss of a buffering mechanism over fluctuations in arterial pressure was evident, in that paroxysms of hypertension or hypotension could be elicited with minimal exertion, even changing positions. His presentation occurred 6 years after extensive neck radiation, with angiographic evidence of unilateral carotid occlusion. This delay from radiation to baroreceptor failure has been well described (13–15).
In patients with chronic baroreflex failure, the pressor episodes are associated with transient increases in plasma norepinephrine concentration (6). This correlation suggests that these episodes are caused by unrestrained activation of the sympathetic nervous system. A spectrum of symptoms may accompany these pressor episodes, including headache, palpitation, a hot sensation, diaphoresis, cutaneous flushing, and emotional lability (13). These patients had evidence of cutaneous flushing and anxiety, but headache was clearly the dominant clinical manifestation associated with the pressor episodes. Unfortunately, plasma levels of norepinephrine were not evaluated during these episodes in either patient, but this is not a requirement for the diagnosis.
The clinical presentation of baroreflex failure bears a striking resemblance to pheochromocytoma. The normal resting plasma and urinary catecholamine and metanephrine levels together with the normal abdominal CTs in both patients argue against the diagnosis of a pheochromocytoma. Furthermore, although patients with either condition may have increased circulating levels of norepinephrine, the response to clonidine, a centrally acting anti-hypertensive drug, has been used to distinguish between these two conditions, in that patients with baroreflex failure are sensitive to the anti-hypertensive effect of clonidine (25). Clonidine acts at the level of the rostral ventrolateral medulla to produce sympathoinhibition and, perhaps, at the level of the nucleus of the solitary tract, to sensitize baroreflex responses (6) (Fig. 2). Clonidine produces a significant decrease of arterial pressure in patients with baroreflex failure and autonomic dysreflexia, another centrally mediated hypertensive syndrome, but not in patients with pheochromocytoma. Also, the response to a benzodiazepine and barbiturate in this particular patient and others with baroreceptor reflex failure is not surprising given the importance of tonic gamma-aminobutyric acid (GABAergic) control on sympathoexcitatory neurones in the rostral ventrolateral medulla (Fig. 2). Benzodiazepines can be substituted successfully as maintenance therapy in those patients who do not tolerate clonidine.
In conclusion, the episodes of severe short-lasting headache in these patients are believed to have resulted from paroxysms of hypertension, which occurred as a result of failure of the baroreflex. This syndrome should be included in the differential diagnosis for any patient with a clinical picture resembling a pheochromocytoma, particularly if the patient has had neck surgery or radiation. Hypertension in this setting is often resistant to several classes of anti-hypertensive drugs, even in combination, but displays exquisite sensitivity to clonidine.