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Cerebrovascular disease
Research paper
Neurological manifestations of phaeochromocytomas and secretory paragangliomas: a reappraisal
  1. Neil E Anderson1,
  2. Kong Chung1,
  3. Ernie Willoughby1,
  4. Michael S Croxson2
  1. 1Department of Neurology, Auckland Hospital, Auckland, New Zealand
  2. 2Department of Endocrinology, Auckland District Health Board, Auckland, New Zealand
  1. Correspondence to Dr Neil E Anderson, Department of Neurology, Auckland City Hospital, Private Bag 92024, Auckland 1, New Zealand; neila{at}adhb.govt.nz

Abstract

Objective To determine the frequency and range of neurological manifestations of phaeochromocytomas and secretory paragangliomas.

Methods A retrospective review of case notes of patients admitted to Auckland Hospital from 1985 to 2011 with a discharge diagnosis of phaeochromocytoma or secretory paraganglioma.

Results Ninety-three patients were admitted with a phaeochromocytoma or secretory paraganglioma. Sixty-eight patients (73%) had neurological symptoms, but only 15 patients (16%) received a neurological consultation. Neurological manifestations occurred in three main clinical contexts. First, paroxysmal symptoms occurred in 66 of 93 patients (71%). Neurological symptoms were common features of these attacks and included headache (47 patients), anxiety (24 patients), tremulousness (15 patients) and dizziness (12 patients). The headaches typically had an explosive onset. Delay in diagnosis was common. Second, 28 patients (30%) had an acute crisis, which was associated with neurological symptoms in 11 (39%) of the episodes: headache (10 patients); seizures (five patients); strokes (three patients); delirium (three patients) and subarachnoid haemorrhage (one patient). Third, five of six patients with a head and neck secretory paraganglioma had neurological symptoms related to infiltration of the middle ear or compression of cranial nerves. Reversible cerebral vasoconstriction syndrome (RCVS) was documented in three patients.

Conclusions Neurological manifestations of phaeochromocytomas and secretory paragangliomas were common, and these tumours can present with various neurological manifestations. The paroxysmal symptoms can be incorrectly attributed to other headache syndromes, panic attacks or cerebral vasculitis. RCVS may play a role in the pathogenesis of the neurological symptoms associated with acute crises and paroxysmal attacks.

  • Headache
  • Cerebrovascular Disease

http://dx.doi.org/10.1136/jnnp-2012-303028

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    Introduction

    Phaeochromocytomas are catecholamine-secreting tumours arising from chromaffin cells in the adrenal medulla. Extra-adrenal catecholamine-secreting chromaffin cell tumours, referred to in this paper as secretory paragangliomas, can originate in sympathetic paraganglia of the thorax, abdomen, pelvis and occasionally the head and neck.1 ,2 The clinical presentation of secretory adrenal and extra-adrenal tumours is similar, but extra-adrenal tumours have a greater risk of malignant transformation.2 The diagnosis of phaeochromocytomas and secretory paragangliomas is challenging, because the clinical manifestations are diverse and may mimic other disorders.2–5 Prompt diagnosis and treatment cures the condition, but delayed diagnosis can result in serious cardiovascular and neurological complications.

    Many patients with a phaeochromocytoma or secretory paraganglioma present with neurological symptoms. In 1966 Thomas and colleagues6 described the neurological manifestations in 100 patients with phaeochromocytomas. In 1976 Lance and Hinterberger7 described the pattern of headaches in 27 phaeochromocytoma patients. Since then, however, there have been no further reports of the neurological manifestations in a large series of patients with phaeochromocytomas. We retrospectively studied 93 patients who have presented to a general hospital with a secretory adrenal or extra-adrenal tumour in the past 26 years. The neurological manifestations of these tumours are described and the pathogenesis of the neurological complications is discussed.

    Methods

    The records of patients who had been discharged from Auckland Hospital between January 1985 and November 2011 with a diagnosis of phaeochromocytoma or paraganglioma were reviewed. The criteria for the diagnosis of phaeochromocytoma or secretory paraganglioma were: (1) elevated 24-h urine or plasma levels of adrenaline, noradrenaline, metanephrine or normetanephrine on two or more occasions in the absence of systemic illness or pharmacological agents that interfere with the production or measurement of catecholamines; (2) evidence of a tumour on contrast-enhanced CT or MRI; and (3) resolution of the symptoms and normalisation of 24-h urine and plasma catecholamines after resection of the tumour. Histological confirmation of the diagnosis was obtained in 91 of 93 (98%) of the patients. The two patients without histological confirmation had imaging and biochemical abnormalities typical of a paraganglioma. Patients with non-secretory paragangliomas and patients taking vasoactive substances were excluded.

    Gender, ethnicity, age, symptoms, signs and investigations were recorded. Special attention was paid to the frequency and the nature of the neurological symptoms. The presence of neurological symptoms (headache, anxiety, tremor, dizziness, paraesthesias, blurred vision, weakness, confusion, coma, seizures) was determined retrospectively. Paroxysmal attacks were defined as transient symptoms lasting less than 24 h. An acute crisis was defined as the sudden onset of cardiovascular or neurological symptoms persisting more than 24 h. Criteria for the diagnosis of reversible cerebral vasoconstriction syndrome (RCVS) were: (1) multiple cerebral artery constrictions demonstrated with catheter or magnetic resonance angiography; (2) absence of aneurysmal subarachnoid haemorrhage; (3) normal or near normal cerebrospinal fluid (CSF) with protein concentration less than 0.80 g/l and leucocyte count less than 10×106/l; and (4) severe acute headache.8

    Results

    We identified 93 patients, 47 males and 46 females, aged 9–84 years (mean 42.2 years, median 44 years) with a diagnosis of phaeochromocytoma or secretory paraganglioma. There were 63 adrenal tumours, 30 retroperitoneal tumours and eight head and neck tumours (five jugulotympanic tumours and three carotid body tumours). Seven patients had tumours at more than one site, which were synchronous in three and metachronous in four. Neurological symptoms were present in 68 of 93 patients (73%), but a neurological consultation was obtained in only 15 (16%).

    Presenting symptoms

    The most common reasons for presentation were episodic paroxysmal symptoms, acute crisis, an incidental mass and hypertension (figure 1). In retrospect, 45–55% of the patients presenting with an acute crisis, hypertension or an incidental mass had experienced paroxysmal symptoms before presentation. At presentation, paroxysmal symptoms had occurred in 66 patients (71%) and an acute crisis in 28 patients (30%).

    Figure 1
    Figure 1

    Principal reasons for presentation in 93 patients with phaeochromocytoma or secretory paraganglioma. *Other reasons for presentation: cardiomyopathy (one), chest pain (one), persistent tachycardia and flushing (one), psychiatric disorder (one) and multiple endocrine neoplasia 2A.

    Paroxysmal symptoms

    The most common symptoms during paroxysmal attacks were palpitations, sweating, headache, fearfulness and anxiety (figure 2). In 27 patients (41%) the triad of headaches, palpitations and sweating occurred during their attacks. The attacks were usually stereotyped (46/57 patients in whom this information was recorded) and the onset was abrupt in 21 of 24 (88%). The duration of the attacks was recorded in 31 patients: 30 min or less in 19 patients (61%); 30–60 min in three patients (10%); and over 60 min in three patients (10%). In six patients (19%) the length of the attacks varied from a few minutes to more than 1 h. The attacks had been occurring from several days to 10 years before presentation (median 2 years). Some patients experienced attacks several times a day or several times a week, but in others the episodes occurred only a few times each year.

    Figure 2
    Figure 2

    Symptoms experienced during paroxysmal attacks in 66 patients.

    In 27 patients (41%) the attacks were triggered. In 13 patients the attacks consistently developed during sleep, just after waking in three patients and during exercise in seven patients. Triggers reported by other patients were stress, warm temperatures, large meals, laughter, bending, abdominal pressure and lying in certain positions. Thirty-nine patients (59%) did not report a precipitant.

    Headache was part of the attack in 47 (71%) of the patients who had paroxysmal symptoms. When the characteristics of the headaches were recorded, the headaches were typically abrupt in onset (16/19 patients); severe, throbbing and bilateral (16/19 patients); and brief (≤30 min in 20/25 patients). In four patients, however, the headaches were unilateral, and two patients described their headaches as a dull ache or pressure. In four patients headache was the only symptom during attacks, but in most patients the headache was accompanied by other symptoms: palpitations (37 patients); sweating (34 patients); anxiety (17 patients); pallor (13 patients); and tremulousness (12 patients). Fatigue, paraesthesias, blurred vision, generalised weakness, faintness and dizziness occurred less frequently. In 10 patients the headaches were associated with nausea, but vomiting (five patients) and photophobia (two patients) were uncommon, and no patient had phonophobia. In seven patients in whom a paroxysmal episode with headache was witnessed, there was a transient elevation in blood pressure during the attack.

    Most patients who presented with paroxysmal symptoms were not investigated with brain imaging. In two patients, however, angiography showed multifocal cerebral vasoconstriction, which at first was incorrectly attributed to cerebral vasculitis. In one of these patients the vasoconstriction had resolved when angiography was repeated 8 months later (figure 3A, B). The other patient is described below.

    Figure 3
    Figure 3

    (A) Left carotid angiogram showing irregularities in the calibre of multiple branches of the middle and anterior cerebral arteries. (B) Repeat left carotid angiogram 8 months later showing resolution of the abnormalities seen in the first angiogram.

    Patient 1

    A 45-year-old woman was referred following recurrent episodes of severe headache. Two weeks earlier she suddenly felt faint while sitting. Several seconds later, she developed a severe throbbing occipital headache, vomiting, dizziness, blurred vision, photophobia, generalised weakness and numbness of the hands. The initial headache improved, but she continued to have recurrent severe headaches, which often woke her during the night. On some occasions the headache was associated with vomiting and photophobia. Most of these episodes lasted 30 min. Baseline blood pressure was 120/70 mm Hg. During an episode the patient was observed to be cold and clammy and the systolic blood pressure was 190 mm Hg. The neurological examination was normal. Head CT, CSF opening pressure and CSF constituents were normal. Angiography performed when the patient was asymptomatic showed multifocal narrowing in branches of the pericallosal, posterior cerebral and anterior cerebral arteries (figure 4A, B). Initially, it was thought she had cerebral vasculitis, and prednisone 60 mg/day was started. The 24-h urine adrenaline was 2.35 µmol/day (normal 0.00–0.11 µmol/day) and the urine noradrenaline was 3.33 µmol/day (normal 0.08–0.47 µmol/day). CT of the abdomen identified a right adrenal phaeochromocytoma. Her symptoms resolved after the tumour was removed.

    Figure 4
    Figure 4

    (A) Right carotid angiogram in patient 1: irregularities in branches of the middle and anterior cerebral arteries.  (B) Left vertebral angiogram in patient 1 showing focal changes in the calibre of the posterior cerebral arteries.

    Acute crises

    Twenty-eight of the 93 patients (30%) experienced a sudden worsening of their symptoms that persisted for more than 24 h. Twenty-one of these 28 patients also had brief paroxysmal attacks. The crisis occurred during exercise in two patients, postpartum in one patient and during general anaesthesia in 11 patients. There was no precipitant in the other 14 patients.

    In 27 patients (96%) the crisis was associated with cardiovascular abnormalities: markedly elevated or labile blood pressure; pulmonary oedema; arrhythmias and left ventricular dysfunction. Five patients developed multiple organ system failure. One of these patients, a 13-year-old girl, developed headache, vomiting and abdominal pain during exercise followed by peripheral vasoconstriction, pulmonary oedema, lactic acidosis, hyperglycaemia, leucocytosis, acute renal failure and delirium. At times her blood pressure was markedly elevated, but on other occasions her blood pressure was unrecordable.

    In 11 patients (39%) the crisis was associated with neurological symptoms. Severe headache was the most common neurological symptom during a crisis (10 patients). Two patients sustained an ischaemic stroke; one of these patients (patient 2) had multiple ischaemic strokes associated with RCVS and the other had dilated cardiomyopathy, left ventricular thrombus and a cardioembolic infarct. Other neurological complications were tonic–clonic seizures (five patients), delirium (three patients), intracerebral and subarachnoid haemorrhage (one patient) and cortical blindness (one patient). In three patients MRI was consistent with posterior reversible encephalopathy syndrome (PRES). In all patients blood pressure was significantly elevated during the acute crisis (range 170/90–290/130 mm Hg), but in two patients periods of profound hypotension (systolic blood pressure <60 mm Hg) were recorded.

    In eight patients neurological symptoms dominated the clinical picture. Two of these patients are described below.

    Patient 2

    Twenty-four hours following delivery a multiparous 32-year-old woman developed a severe bitemporal headache and labile hypertension with blood pressure recordings up to 210/120 mm Hg. Her blood pressure had been normal during pregnancy. Exacerbations of the headache were associated with forceful, slow beating of the heart, sweating, tremulousness and anxiety. The initial neurological examination, MRI, magnetic resonance angiography and CSF were normal. The random urine protein concentration was 0.07 g/l. The patient was treated with antihypertensive medications. On day 8 postpartum she had two tonic–clonic seizures and afterwards she was drowsy and complained that she could not see. The examination showed a left homonymous hemianopia, visual simultagnosia, dyslexia and dysgraphia. Repeat MRI showed T2 hyperintensities with restricted diffusion in both occipital lobes and the left parietal lobe. She became increasingly drowsy and by day 17 she was comatose. Another MRI revealed more widespread T2 abnormalities. The right middle cerebral artery was reduced in calibre. CT identified a right adrenal tumour. Urinary noradrenaline excretion was 3.4 μmol/day, but the 24-h urine adrenaline was normal. By day 19 there were wild swings in her blood pressure and pulse rate. CT showed swelling of the right hemisphere and subarachnoid haemorrhage over the left hemisphere. She died on day 20 before surgery was possible. An autopsy was not obtained.

    Patient 3

    A previously healthy 15-year-old girl woke with a severe headache, vomiting, dizziness, blurred vision and then had a tonic–clonic seizure. The examination showed normal mental state, unsteady gait and normal visual fields. Blood pressure was 140/100 mm Hg. Imaging showed haemorrhage in the left parieto-occipital lobe, subarachnoid blood overlying the right hemisphere and T2 hyperintensity in the white matter of both cerebral hemispheres in a pattern consistent with PRES. Left carotid arteriography was normal. The plasma noradrenaline was 39 200 pmol/l (normal 470–3800 pmol/l) and the 24-h urine noradrenaline was 4.03 µmol/day. MRI of the abdomen identified a right adrenal phaeochromocytoma. Her symptoms resolved and blood pressure normalised after resection of the tumour.

    Non-paroxysmal symptoms

    Forty-three patients (46%) were known to have hypertension before presentation and elevated blood pressures were recorded in 84 patients (90%). Five of the six patients with a head and neck paraganglioma had neurological symptoms attributable to infiltration of the middle ear or compression of cranial nerves by the tumour. Three of these patients also had paroxysmal symptoms related to catecholamine secretion.

    Other persistent, non-paroxysmal symptoms were abdominal or flank pain (12 patients), weight loss (10 patients), sweating (nine patients), fatigue (six patients), headache (six patients), tremulousness (six patients), insomnia (four patients), chronic anxiety (four patients), heat intolerance (three patients) and constipation (three patients). A 49-year-old man presented with an atypical manic state with insomnia, distractibility, pressured speech, grandiose ideas, increased self-esteem and excessive jocularity. Examination showed mildly elevated blood pressure, tachycardia and normal cognitive function. CT was normal.

    Discussion

    Neurological symptoms occurred in three clinical contexts: as part of the brief paroxysmal attacks; during acute crises; and in patients with a secretory head and neck paraganglioma. Paroxysmal attacks were the most common mode of presentation in our patients as well as in other clinical studies.6 ,7 ,9 The attacks typically had an abrupt onset and brief duration and the frequency of the episodes varied from several attacks a day to occasional episodes every few months. Headache was one of the most common symptoms during the paroxysmal attacks. The headache usually had a rapid onset and was severe, throbbing, bilateral and generalised. In some patients the location, severity and duration of the headache resembled cluster headache, but ipsilateral autonomic features were not observed. In other patients unilateral headaches were associated with nausea, vomiting and blurred vision leading to confusion with migraine. The headaches are often eased by standing, but aggravated by lying, movement, coughing, sneezing, bending and straining.6 ,7 ,9 Phaeochromocytoma should be considered in the differential diagnosis of headaches that develop during sleep and with exercise.10

    The presence of other symptoms, especially palpitations and sweating, is an important clue that headaches are caused by a phaeochromocytoma. In four patients, however, headache was the only symptom in their paroxysmal attacks. The palpitations may take the form of rapid beating of the heart or a slow, forceful heart beat.6 ,9 Episodic cold sweating and pallor affecting the face and upper body have been common symptoms in some studies.6 ,9 Flushing is not typical of a phaeochromocytoma,2 but it was reported by 12 of our patients and was a common feature in other series.7 Visual symptoms occurred in 6% of our patients during paroxysmal attacks. The visual symptoms can include scintillating scotomata, ‘snowy vision’ and cortical blindness.6 ,9 In 36% of our patients restlessness, tremulousness, anxiety, nervousness and fearfulness occurred during paroxysmal attacks, often suggesting a diagnosis of panic attacks. The attacks can be associated with hyperventilation, which may account for paraesthesias in the upper limbs and face in some patients, but in other cases the sensory symptoms may reflect peripheral ischaemia. Eighteen per cent of our patients reported dizziness during attacks. Rarely, dopamine-secreting tumours can cause recurrent syncope.11 Other paroxysmal symptoms of neurological significance include generalised weakness and mental confusion.

    The paroxysmal symptoms can mimic a wide variety of other conditions. The differential diagnosis of relevance to neurologists includes panic attacks, cocaine or amphetamine abuse, carcinoid syndrome, mast cell disorders, diencephalic or autonomic epilepsy, migraine, cluster headache, benign hypnic headache, baroreflex failure, postural orthostatic tachycardia syndrome, cerebral vasculitis, colloid cyst and Morvan's syndrome.5 ,6 A syndrome of ‘pseudophaeochromocytoma’ characterised by episodes of hypertension, palpitations, headache, sweating, and flushing rather than pallor, without a catecholamine-secreting tumour may be caused by exaggerated cardiovascular responsiveness to catecholamines.12

    Acute crises are probably caused by a sudden, massive release of catecholamines by the tumour. Cardiovascular manifestations typically dominate the clinical picture.13 Although blood pressure is usually elevated, patients may have severe hypotension and a clinical picture resembling septicaemic shock. Multi-organ system failure with lactic acidosis, encephalopathy, pulmonary oedema, hyperpyrexia, hyperglycaemia and acute renal failure secondary to rhabdomyolysis can develop.14 Headache, strokes, seizures and delirium can occur during an acute crisis, and the neurological manifestations may dominate the clinical picture. In large series ischaemic stroke and intracerebral haemorrhage occurred in 4–5% of patients with a phaeochromocytoma.6 ,9 ,15 In Auckland, 3% of the patients had a stroke. Cerebral infarction may be secondary to small-vessel disease resulting from chronic hypertension, embolism from a mural thrombus in patients with dilated cardiomyopathy or myocardial infarction, or internal carotid artery dissection, but most strokes are probably caused by RCVS.16–22 Intracerebral haemorrhage can complicate RCVS, or small-vessel disease caused by chronic hypertension.17 ,23–26 Tumour thromboembolisation, disseminated intravascular coagulopathy and non-bacterial thrombotic endocarditis can cause stroke in patients with a malignant paraganglioma.27 ,28

    RCVS, or Call–Fleming syndrome, may be an important cause of the paroxysmal neurological symptoms and neurological complications of acute crises. RCVS was first reported in a patient with a phaeochromocytoma in 1961, and since then it has been documented in several more patients.29 RCVS is characterised by recurrent explosive headaches, sometimes associated with focal neurological symptoms. Angiography shows reversible multifocal narrowing in large and medium-sized cerebral arteries. High levels of circulating catecholamines probably cause the vasoconstriction.30 Complications of RCVS include cortical subarachnoid haemorrhage, intracerebral haemorrhage, seizures, transient ischaemic attacks and cerebral infarction.8 Most of our patients were not investigated with angiography, but three patients had evidence of cerebral vasoconstriction. In two of these patients angiography was not repeated and reversibility was not demonstrated. Although RCVS may play an important role in the pathogenesis of the neurological symptoms, confirmation of this hypothesis will require a prospective angiographic study.

    The angiographic abnormalities of RCVS resemble central nervous system vasculitis. Two of our patients were initially treated as if they had cerebral vasculitis. Accurate distinction between RCVS and cerebral vasculitis is important, because steroids have been implicated in triggering acute crises in patients with phaeochromocytoma.14 ,20 ,31 In one retrospective study, there was a worse outcome in patients with RCVS who received steroids.8

    Visual symptoms, including cortical blindness accompanied by headaches, seizures, drowsiness, confusion or coma, have been reported in patients with phaeochromocytoma.6 This constellation of symptoms is usually caused by PRES, which overlaps RCVS and may have a similar pathophysiology.8

    The presentation of phaeochromocytomas can mimic psychiatric disorders. The paroxysmal attacks may resemble panic attacks, while other patients can present with chronic anxiety, depression or psychosis.7 ,32 ,33 In our series one patient presented with a manic disorder.

    Most head and neck paragangliomas are non-secretory, but 5% of these tumours secrete catecholamines.1 Two of our patients with a head and neck secretory paraganglioma presented with symptoms related to the local effects of the tumour. Carotid body and vagal body paragangliomas typically present with an enlarging neck mass, while patients with jugulotympanic paragangliomas develop pulsatile tinnitus and conductive hearing loss, with a tumour visible behind the tympanic membrane. Large head and neck paragangliomas can compress or invade the lower cranial nerves and oculosympathetic nerve fibres leading to facial weakness, sensorineural deafness, vestibular symptoms, dysphagia, hoarseness, dysarthria and Horner's syndrome.34 The combination of auditory and neurological symptoms related to the mass effect of a head and neck paraganglioma and symptoms related to catecholamine secretion can cause diagnostic confusion.

    Phaeochromocytomas and secretory paragangliomas present with diverse clinical manifestations. Almost three-quarters of these patients have neurological symptoms, which can be incorrectly attributed to other diagnoses. Neurological symptoms occur in three clinical contexts: (1) thunderclap headaches and other neurological symptoms can occur during paroxysmal attacks; (2) headache, seizures, delirium and strokes are common features during acute crises; (3) patients with secretory head and neck paragangliomas develop neurological symptoms due to infiltration of the middle ear or compression of the adjacent cranial nerves, in addition to symptoms of catecholamine secretion. In some patients the presenting symptoms mimic panic attacks, chronic anxiety state and, rarely, other psychiatric disorders. Rapid diagnosis can avoid the devastating neurological and cardiovascular complications of these tumours.

    Acknowledgments

    Sarah Anderson's assistance with data management is gratefully acknowledged.

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    Footnotes

    • Contributors All authors contributed to the conception and design of the study, the acquisition of data, analysis and interpretation of the data, drafting of the article, revising the article and have given approval of the final version.

    • Funding None.

    • Competing interests None.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Data sharing statement The authors are prepared to share data gathered during this retrospective case review. The data can be obtained by contacting the corresponding author.