Correspondence *Department of Endocrinology, Royal Devon & Exeter Hospital, Exeter EX2 5DW, UK

Email bijay.vaidya@pms.ac.uk

The case

A 61-year-old lady was admitted to hospital with lower abdominal pain, dysuria and vomiting. She was febrile (temperature 38 °C) and hypotensive (blood pressure 94/53 mmHg). Her medical history included primary hypothyroidism and polymyalgia rheumatica, which was treated with levothyroxine 100 g per day and prednisolone 6 mg per day, respectively. The patient's urine culture test was positive for coliform bacilli, and initially she responded well to intravenous fluid replacement and antibiotic treatment.

On the third day of admission, the patient developed severe right-sided headache and right third nerve palsy with ptosis and ophthalmoplegia (Figure 1). Her visual acuity was 6/7.5 of the right eye and 6/9 of the left eye. Her visual fields were normal on confrontation examination, but subsequent perimetry examination revealed a mild defect in the left superior temporal field. The patient was fully conscious, afebrile and hemodynamically stable. Her white blood cell count was 7.2 10⁹/l (normal range: 3.6–11.0 10⁹/l), erythrocyte sedimentation rate 67 mm/h (normal range 1–20 mm/h) and serum sodium level 137 mmol/l (reference range 132–145 mmol/l). As a result of the history of polymyalgia rheumatica and the concern of giant cell arteritis, the prednisolone dose was increased to 60 mg per day. Magnetic resonance angiography (MRA) was urgently performed to exclude internal carotid artery aneurysm. Although no evidence of aneurysm was found, the MRA revealed a large lesion extending superiorly from the clivus towards the right cerebral peduncle (Figure 2). These findings were confirmed by a CT scan of the brain (Figure 3).

Figure 1 Right partial ptosis and strabismus due to right third nerve palsy.

The photograph was taken 12 days after the onset of symptoms.

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Figure 2 A magnetic resonance angiography scan (taken 2 days after the onset of symptoms) demonstrating a large lesion (arrow) extending from the clivus superiorly above the pituitary fossa, with distortion of the right cerebral peduncle.

 

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Figure 3 CT scan (taken 6 days after the onset of symptoms) demonstrating an enhancing lesion (arrow) with cystic area expanding from the clivus and extending into the suprasellar cistern and right cerebral peduncle.

 

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The proposed differential diagnoses of the lesion seen on the CT scan included chordoma, plasmacytoma or secondary malignancy. The patient was informed of a possibility of a primary or a metastatic brain tumor and her prednisolone was changed to dexamethasone. To exclude metastatic disease, CT scans of the thorax, abdomen and pelvis were carried out but showed no abnormalities. Plasma protein electrophoresis, urinary Bence-Jones protein test and serum tumor marker test (for carcino-embryonic antigen, cancer antigen 125 and carbohydrate antigen 19-9) had normal results. The patient was referred for a neurosurgical examination for consideration of diagnostic biopsy. A possibility of a primary pituitary lesion was raised. Twelve days after the onset of symptoms, an MRI scan of the pituitary gland finally revealed a large pituitary mass containing hemorrhage (Figure 4). The patient's dexamethasone was changed to hydrocortisone (a total of 20 mg daily, three divided doses) and an endocrine assessment was requested.

Figure 4 Nonenhanced MRI scans (taken 12 days after the onset of symptoms) demonstrating a large pituitary macroadenoma extending to the suprasellar region on the right side and containing hemorrhage (arrows).

(A) Coronal and (B) sagittal views of the brain.

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On direct questioning, the patient reported having occasional spontaneous bilateral galactorrhea. She had menopause at the age of 52 years. Subsequent endocrine investigations revealed a massively elevated serum prolactin level (Table 1), which confirmed the diagnosis of pituitary apoplexy due to hemorrhage within a large prolactinoma. Anterior pituitary function tests also indicated deficiencies in the pititary–gonadal and pituitary–adrenal axes. The deficiency in the pituitary–thyroid axis could not be confirmed without stopping the patient's thyroxine treatment, and growth hormone deficiency was not formally assessed.

Table 1 Results of baseline anterior pituitary function tests.^a

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As the patient was fully conscious with stable neuro-ophthalmic signs, a decision for a conservative management was made, following discussion between the endocrinologists, neurosurgeons and ophthalmologists. Hydrocortisone and thyroxine replacement therapy was continued and cabergoline (a dopamine receptor agonist) was commenced. The headache subsided, the third nerve palsy and the visual field defect improved, and the prolactin level fell to normal. The patient's visual acuity improved to 6/5 of the right eye and 6/6 of the left eye. Further MRI examinations of the pituitary gland at 3 and 12 months of follow-up have shown sustained reduction in size of the pituitary mass (Figure 5). The patient, however, has remained hypopituitary, and continues to receive hydrocortisone and thyroxine replacement.

Figure 5 Nonenhanced MRI scan at 12-month follow-up demonstrating noticeable reduction in size of the pituitary macroadenoma following treatment with cabergoline.

 

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Discussion of diagnosis

Pituitary apoplexy is a potentially life-threatening clinical syndrome that is characterized by sudden onset of headache, visual disturbances and decreased consciousness. It is caused by infarction and/or hemorrhage of the pituitary gland, normally in association with a pituitary adenoma. Classical pituitary apoplexy is a relatively rare condition, with an annual incidence of about 1.2 per million.¹ Asymptomatic pituitary hemorrhage (sometimes called 'subclinical pituitary apoplexy'), however, is common, and detected in about 10% of all surgically removed pituitary adenomas.²

The precise mechanism that leads to pituitary apoplexy is poorly understood; however, a number of theories have been postulated. These include rapid expansion of a tumor outgrowing its own blood supply (which leads to ischemic necrosis), growth of a tumor leading to compression of the pituitary portal blood supply against the diaphragma sellae, and intrinsic vasculopathy or fragility of the blood vessels supporting a pituitary tumor.³ The clinicopathological consequences of pituitary apoplexy are caused by a rapid increase in size of the contents of the pituitary fossa and consequent elevation of intrasellar pressure.⁴ Upward enlargement of a pituitary tumor causes compression of the optic chiasm that results in decreased visual acuity and visual field defects, specifically bitemporal hemianopia. Further pressure upon the hypothalamus and midbrain might account for the disturbance of consciousness and vital functions. Lateral extension into the cavernous sinuses might cause pressure on the third, fourth and sixth cranial nerves leading to ocular palsies. Extravasation of blood into the subarachnoid space might result in meningism, and destruction or compression of the normal pituitary gland leads to hypopituitarism.

The common clinical features of pituitary apoplexy are shown in Table 2. The patient described had a typical presentation of pituitary apoplexy with intense headache and right third nerve lesion. Headache in pituitary apoplexy can be retro-orbital, frontal or diffuse. Decreased visual acuity, visual field defects and ocular palsy occur within a few hours after the onset of headache and usually completely develop in 1–2 days. The third nerve is the most common cranial nerve to be affected in pituitary apoplexy. Progressive deterioration in level of consciousness, and in severe cases coma, might occur. Raised white blood cell count and hyponatremia are present in 20–40% of cases.^{5, 6} Symptoms of hypopituitarism, in particular hypocortisolism, might be present.

Table 2 The relative frequencies of presenting features of pituitary apoplexy.a

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Although the majority of patients with pituitary apoplexy have no apparent precipitant, several factors are known to be triggers of this condition (Box 1). Major surgery, in particular coronary artery bypass grafting, has regularly been reported in association with pituitary apoplexy.^{6, 7} Caution should be taken when undertaking major surgery in any patient with a known pituitary tumor and, equally, pituitary apoplexy should be considered in the differential diagnosis of a patient who presents with headaches and neuro-ophthalmic symptoms after major surgery. Acute systemic illness is also considered to be a precipitating factor for pituitary apoplexy,⁷ and urinary sepsis and the associated hypotension might have been the triggering factor for the development of pituitary apoplexy in the patient described.

The clinical symptoms and signs of pituitary apoplexy coincide with those of more common medical emergencies (Box 2). Patients with pituitary apoplexy might, therefore, present to many clinical specialities, which often leads to difficulties and delays in the diagnosis. Furthermore, as in the patient described, the majority of cases of pituitary apoplexy are the first presentation of a pituitary adenoma.^{5, 6, 7, 8} The CT scan is the most commonly used imaging modality in the investigation of acute neurological presentations. Although it can be effective in the diagnosis of pituitary adenomas, the CT scan is not sensitive in the diagnosis of pituitary apoplexy, and identifies the presence of a hemorrhage or infarction within the pituitary gland in only 21–28% of cases.^{5, 6} MRI examination confirms the diagnosis in over 90% of cases, and is the investigation of choice.^{5, 6, 8, 9} As pituitary apoplexy was not included in the initial differential diagnosis of the patient, an MRA was the first investigation performed. This decision led to delay in reaching a final diagnosis, and resulted in undue anxiety of the patient and further inappropriate investigations being performed in the belief that the cause of the clinical presentation was likely to be a malignant brain lesion. In retrospect, the clinical history together with the CT appearance of a cystic lesion should have led to the suspicion of pituitary apoplexy rather than a malignant brain lesion.

The majority of patients with pituitary apoplexy have hypopituitarism at presentation.^{5, 6, 10} Hypotension and hyponatremia should alert the clinician to the possibility of cortisol deficiency. This deficiency can be detected by measurement of a random serum cortisol level, although steroid replacement should be started immediately if hypocortisolism is suspected. A random cortisol level of <200 nmol/l during acute illness is highly suggestive of cortisol deficiency, whereas a cortisol level >550 nmol/l suggests a normal pituitary–adrenal axis. In equivocal cases, an adrenocorticotropic hormone (ACTH) stimulation test (also known as the short Synacthen test) or insulin stress test might be used within a few days when the acute illness has settled. Nevertheless, the result of an ACTH stimulation test might be falsely normal in the acute setting of pituitary apoplexy. Pituitary–thyroid axis, pituitary–gonadal axis, prolactin levels and growth hormone levels should also be assessed. In the case described, the lack of cortisol response following the ACTH stimulation test is likely to have been due to the decreased function of the pituitary–adrenal axis secondary to pituitary apoplexy, although it could also be explained by adrenal suppression caused by the previous use of oral steroids.

Treatment and management

A pragmatic algorithm for the management of pituitary apoplexy is shown in Figure 6. The immediate management is supportive, with attention to fluid and electrolyte balance, and replacement of deficient pituitary hormones, in particular cortisol. Fortuitously, the case patient was already on steroid therapy for polymyalgia rheumatica and the decision had already been taken to increase her prednisolone dose when the possibility of giant cell arteritis was raised.

Figure 6 An algorithm for the management of pituitary apoplexy.

 

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There is a general consensus that a patient with pituitary apoplexy and severe neuro-ophthalmic signs with sudden visual loss, diminished level of consciousness or hypothalamic disturbance should have urgent surgical decompression.^{3, 10, 11} Controversy exists, however, concerning the optimal management of patients with mild and stable neuro-ophthalmic signs. In consequence of the rarity of pituitary apoplexy, no prospective, randomized, controlled trials or consensus guidelines on its management are available. Historically, early surgery for all patients with pituitary apoplexy has been advocated.^{3, 5, 9, 12} Surgery via the transsphenoidal route has a low mortality and morbidity, has favorable neuro-ophthalmic outcomes and occasionally restores normal pituitary function.¹³ Some retrospective studies have suggested that early surgery (within a week of presentation) is associated with better neuro-ophthalmic outcomes than later surgery,^{5, 9} although this finding was not confirmed by other retrospective studies.^{6, 14} It has also long been recognized that mild neuro-ophthalmic signs tend to improve spontaneously in most patients with pituitary apoplexy who are managed conservatively.¹⁵ In the last 5 years, several retrospective studies have suggested that conservative management is safe in those with mild neuro-ophthalmic signs at presentation or in those whose neuro-ophthalmic signs start to resolve early in the clinical course.^{6, 14, 16} In one small, prospective, nonrandomized trial of 12 patients with pituitary apoplexy, all 7 patients managed conservatively showed a resolution or improvement of neuro-ophthalmic symptoms, whereas 5 patients underwent surgery because the symptoms did not improve after one week of conservative management.¹⁷

A close observation is needed in the first few days after starting conservative management, and if neuro-ophthalmic signs fail to improve or deteriorate, the patient should be referred for neurosurgical decompression by a dedicated and experienced pituitary surgeon.⁶ The decision to manage conservatively or with surgical decompression should be made by a multidisciplinary team, including experts in ophthalmology, endocrinology and neurosurgery. The rationale for clinical decisions should be fully explained to the patient when possible and his/her full informed consent should be obtained.

Tumor re-growth occurs in a considerable proportion of patients who present with pituitary apoplexy. Whether managed surgically or conservatively, all patients need long term follow-up with repeat imaging and reassessment of their endocrine status.

Conclusions

Pituitary apoplexy is a rare and potentially life-threatening disease. The differential diagnosis is wide but the characteristic symptom complex should alert the clinician to the possibility of pituitary apoplexy. Immediate management of fluid and electrolyte balance and hydrocortisone replacement are priorities. MRI is the diagnostic imaging modality of choice. Patients with severely diminished visual acuity, decreased level of consciousness and hypothalamic disturbance should urgently undergo neurosurgical decompression. Conservative management of patients with mild and stable neuro-ophthalmic symptoms is probably safe, but multicentre collaborative data collection and analysis would refine management guidelines.

Acknowledgments

Désirée Lie, University of California, Irvine, CA, is the author of and is solely responsible for the content of the learning objectives, questions and answers of the Medscape-accredited continuing medical education activity associated with this article. We thank the patient for giving her written consent to the use of her photograph and other medical images in this Case Study.

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Subject areas under which this article appears: Pituitary gland (including the pineal gland) | Therapy (pharmacotherapy, radiotherapy, nutrition, alternative)