Introduction

Acute hemorrhagic necrosis of a pituitary adenoma in a young patient with acromegaly was first documented as a pathologic entity by Bleibtreu in 1905. The clinical syndrome associated with massive infarction, necrosis, and hemorrhage of a pituitary tumor received little attention until the report of Brougham and colleagues in 1950, which described five postmortem cases of acute degenerative changes in pituitary adenomas, together with the pertinent clinical data, and called the clinical pathologic entity pituitary apoplexy. The authors suggested that the apoplectiform event was the culmination of the outstripping of its blood supply by a rapidly growing adenoma.

There are now hundreds of case reports of pituitary apoplexy in the literature, which have provided useful data on the incidence, predisposing factors, pathologic findings, putative pathophysiologic mechanisms, clinical features, radiologic concomitants, and treatment of this fascinating condition.

The term pituitary apoplexy represents a form of medical short­hand describing a complex series of clinical events occurring as a consequence of the fulminant expansion of a pituitary tumor by infarction, hemorrhage, or hemorrhagic infarction of the tumor and the adjacent pituitary tissue. It should be recognized that the pathologic process may be relatively circumscribed, producing a sudden, albeit restricted, increase in the volume of the tumor. Under these circumstances the accompanying clinical symptoms may be minimal (e.g., a transient episode of headache or diplopia) or may even be absent. On the other hand, a massive hemorrhagic infarction of a large pituitary tumor may present as an acute medical catastrophe.

Incidence

Cysts, many containing old or recent haemorrhages, within pituitary tumors examined pathologically are relatively common. In Henderson's review of Cushing's series of 338 pituitary tumors, 17 percent of 260 chromophobe adenomas and 6 percent of 67 eosinophilic adenomas were largely cystic. Lopez, in 1970, collected cases of pituitary tumor from the literature and estimated that they included 135 instances of pituitary apoplexy, an incidence of about 6 percent. Wakai and colleagues, reviewing their own series of 560 verified pituitary tumors in 1981, found the incidence of pituitary apoplexy to be unexpectedly high, 93 cases (16.6 percent); a major attack was documented in 6.8 percent of cases, a minor attack in 2.3 percent, and asymptomatic haemorrhages in 7.5 percent of proven cases. Mϋller-Jensen and Lϋdecke reported an incidence of extended cystic necrotic areas, frequently containing a hemorrhagic component, in 72 cases (12.3 percent) of 586 pituitary tumors operated on by the transnasal route. In only 10 instances (1.7 percent of the entire series) had the hemorrhagic area ruptured through the tumor capsule into the chiasmatic cistern, producing meningeal irritation. These authors postulated that the incidence of pituitary apoplexy was highest in hormonally inactive adenomas, although they included prolactinomas in this category. Other authors have suggested that patients harbouring endocrinologically active adenomas (e.g., those associated with acromegaly and Cushing's disease) are at increased risk for the development of pituitary apoplexy.

Predisposing Factors

In most instances, the syndrome of pituitary apoplexy occurs de novo without any identifiable precipitating factor. In many patients the apoplectiform attack may represent the first definite indication that either a pituitary tumor or an endocrinopathy is present. Mohanty and colleagues have suggested that the incidence of intra­tumoral hemorrhage is directly related to the size and vascularity of the pituitary tumor. This correlation has not been corroborated in other series.

On the other hand, a variety of potential insults have been associated with documented instances of pituitary apoplexy. The common denominator is the pre-existence of naturally occurring conditions, artificial agents, or manipulations that can result in rapid tumor expansion, usually accompanied by ischemia or hemorrhage. Instances of pituitary apoplexy have been associated with pregnancy, endocrinologic manipulations such as estrogen administration, bromocriptine medication, head injury, chronic coughing and sneezing, anticoagulant drugs, cerebral angiography, and radiation therapy of a pituitary tumor.

Symptoms and Signs

There are many reports of surgically verified but clinically asymptomatic cases of pituitary apoplexy. In these instances, obvious hemorrhage, relatively acute or chronic, or the residua of old hemorrhage and/or infarction (cysts containing xanthrochromic fluid, an empty sella, etc.) are found at operation, yet the patient cannot recall any clinical event to match up with the pathologic data.

The symptoms and corresponding signs are consistent with precipitous enlargement of and/or hemorrhage within the pituitary tumor. Sudden headache, nausea, vomiting, diplopia, and visual impairment are all concomitants of rapid expansion of a turn or, first laterally, with compression of the cranial nerves in one or both cavernous sinuses, then by superior extension of the tumor, with compression of the visual apparatus. Paresis of the oculomotor nerve followed by abducens weakness and in some instances trigeminal impairment and proptosis are the signs of cavernous sinus compression. These may occur unilaterally or bilaterally. Compression of the visual apparatus by suprasellar tumor expansion results in diminished visual acuity on one or both sides, progressing occasionally to blindness. Scotomas and/or field defects are produced by direct pressure on or ischemia of the optic nerves, chiasm, or rarely, the optic tracts. In some series, ophthalmoplegias were the major sign of visual system impairment, while in others loss of vision predominated.

Other symptoms of an abrupt and potentially catastrophic intracranial ictus, possibly secondary to acutely increased intracranial pressure and/or hypothalamic involvement, are lethargy, stupor, and coma. Meningeal irritation with neck stiffness and photophobia, accompanied by bloody cerebrospinal fluid (CSF), occurs when an acute hemorrhage in a pituitary tumor breaks through the tumor capsule into the neighbouring chiasmatic cistern.

Symptoms and signs of a pre-existing endocrinopathy may be present: acromegaly, Cushing's syndrome, or the amenorrhea­galactorrhea syndrome of a prolactinoma. On the other hand, the tumor that is presenting as a neurological catastrophe may be a nonfunctioning adenoma that has produced pressure on normal pituitary tissue and resulted in hypopituitarism. Occasionally, acute but restricted necrosis of a functioning adenoma may have a salutary effect on a pre-existing endocrinopathy, resulting in improvement of pituitary hormone hypersecretion with or without the development of hypopituitarism. In many instances, the apoplectiform insult constitutes the first conclusive evidence that a pituitary tumor is present.

Possible Pathophysiologic Mechanisms in Pituitary Apoplexy

It is possible for any tumor, especially at times of rapid growth, to outstrip its blood supply with resultant ischemia, necrosis, and hemorrhage-the more so if the tumor is confined within a bony or membranous space such as the sella turcica, where turn or expansion is limited by relatively unyielding structures. An additional factor that may render a pituitary tumor peculiarly vulnerable to ischemic necrosis is its somewhat tenuous blood supply.

The anterior lobe of the pituitary gland (pars distalis) is supplied exclusively by a hypophyseal-portal system of vessels consisting of a capillary network originating from branches of the internal carotid which terminate in the neural lobe of the pituitary gland and infundibular stem. It has been hypothesized that an expanding pituitary tumor may squeeze its way through the diaphragmatic notch, distorting and compressing the infundibular stem between the tumor and the firm, fibrous walls of the diaphragma sellae. If this occurs, the afferent blood supply to the tumor and surrounding pituitary tissue may be severely compromised at the infundibulum, resulting in acute necrosis and infarction of the anterior lobe of the pituitary. Cardoso and Peterson are skeptical of the role of tumor ischemia in the pathogenesis of pituitary apoplexy, however.

Clinical and Laboratory Diagnosis

Sudden excruciating headache, nausea, vomiting, or meningismus, accompanied by a decreased state of consciousness with visual impairment and ophthalmoplegia, suggests an acute process localized primarily at the base of the brain around the chiasmal­hypophyseal region. The differential diagnosis includes ruptured cerebral aneurysm, meningitis, mesencephalic infarction and/or hemorrhage, chiasmal apoplexy, and transtentorial uncal herniation secondary to a cerebral mass lesion. The possibility of pituitary apoplexy is not usually entertained unless the patient's previous history or general physical examination suggests the presence of a pituitary tumor.

In patients in whom apoplexy constitutes the initial definite indication of a pituitary disorder- a not unappreciable number­plain roentgenograms of the skull invariably provide the key diagnostic clue. A large eroded sella turcica, thinning or erosion of the dorsum sellae, undercutting of the clinoid processes, a double floor to the sella, and occasionally a soft tissue mass projecting into the sphenoid sinus are all highly suggestive of a pituitary tumor. These radiographic changes, which are seen more clearly with tomographic techniques, are not specific for the apoplectiform event but are characteristic of a pituitary mass, usually an adenoma.

The next diagnostic step should be computed tomography (CT) or magnetic resonance imaging (MRI), without and with contrast enhancement, supplemented with thin slices centered around the sella turcica. In instances of acute hemorrhage, provided the CT examination is performed shortly after the insult, a high-density, nonenhancing area should be seen, consisting of a portion of a soft tissue mass that occupies an expanded sella and often extends into the suprasellar cistern. On occasion, the hemorrhage may occupy virtually the entire tumor mass. In instances where infarction or necrosis of a pituitary tumor rather than acute hemorrhage has taken place or in which the apoplectiform insult occurred days to weeks before CT scanning, the mass in and above the sella may be of normal to low density and be surrounded by a complete or fragmented ring of contrast enhancement. The latter is consistent with a necrotic or cystic area in a pituitary tumor, the enhancing ring being the result of increased vascularity or increased permeability. With large suprasellar masses or extreme hemorrhagic insults, hydrocephalus may be present.

Recently, MRI without and with contrast enhancement has facilitated the diagnosis and preoperative assessment of these patients. This technique provides data in axial, sagittal, and coronal projections, delineating clearly the size, location, and probable age of a hemorrhage within a pituitary tumor, in addition to demonstrating displacement of adjacent structures such as the optic chiasm and third ventricle. Hydrocephalus, if present, is clearly seen. Magnetic resonance angiography may further clarify the location and integrity of important adjacent vascular structures, eliminating or substantially reducing the necessity for supplementary angiography.

Since the advent of CT and MRI, the role of angiography in the diagnostic workup of patients with pituitary tumors, including those with apoplexy, has changed substantially. The angiographic features of pituitary apoplexy are not dissimilar to those of pituitary tumors: displacement of vessels consistent with an expanding intrasellar tumor having a variable degree of suprasellar extension and occasionally associated with hydrocephalus. Extreme narrowing of the supraclinoid portion of the internal carotid artery and anterior cerebral vessels has been reported with this syndrome, a consequence both of rapid tumor expansion and of sudden pressure on contiguous vessels. Vasospasm caused by blood breaking through into the basal cisterns may also contribute to the narrowed cerebral vasculature.

In general, the diagnosis of pituitary apoplexy can be established by CT or MRI with cerebral angiography used on rare occasions to rule out a ruptured or associated aneurysm, especially a giant intrasellar aneurysm. Angiography and MR angiography may also be helpful in delineating the course and configuration of the intracavernous carotid vessels prior to transsphenoidal surgery.

The correct diagnosis should be established on clinical and radiographic grounds; routine lumbar puncture is neither necessary nor advisable. Lumbar puncture may be performed when the patient presents with a sudden devastating headache, rapid deterioration of consciousness, fever, and severe meningismus. In these circumstances the possibility of meningitis must be entertained, especially in those rare instances in which the sella turcica is normal or only slightly enlarged. With pituitary apoplexy, the CSF may be grossly bloody, xanthrochromic, or occasionally clear. Elevated CSF pressure and protein levels have been encountered.

Management and Treatment

The treatment of pituitary apoplexy is no different from the management of any rapidly enlarging pituitary tumor. Bleeding or infarction within a pituitary tumor invariably compromises the secretion of endogenous pituitary hormones as well as of the hypothalamic factors that regulate the release of pituitary hormones. Prompt administration of corticosteroids is necessary. along with rapid laboratory investigation of the patient's endocrinologic status. The latter survey requires determination of serum prolactin, growth hormone, follicle-stimulating hormone, luteinizing hormone, and cortisol levels; assessment of thyroid status; and. occasionally, provocative tests to evaluate the functional integrity of the hypothalamic-hypophyseal axis.

Whether a patient with pituitary apoplexy should be managed solely with corticosteroids or should undergo prompt surgical decompression depends almost exclusively on the status of and impending threat to the visual apparatus. Patients with severe and or rapid deterioration in visual acuity or with constricted visual fields require prompt decompression of a swollen, necrotic, or hemorrhagic pituitary tumor, usually via a transsphenoidal approach. Corticosteroids must be given before and during surgery and in the postoperative period. The primary goal of the operation is to decompress the optic nerves and chiasm, as well as those lateral expansions of pituitary tumor compressing the cavernous sinuses. It may be neither necessary nor desirable to remove all the pituitary tumor, but sufficient pathologic tissue must be evacuated to provide a thorough decompression of the visual apparatus. Adequate transsphenoidal decompression of an acutely swollen pituitary tumor will usually relieve acute hydrocephalus, the result of large or sudden suprasellar tumor extension. On occasion, supplemental ventricular drainage or a shunting procedure may be required.

Prompt and adequate transsphenoidal decompression is usually followed by resolution of pre-existing ophthalmoplegia. Generally there is also an improvement or at least a stabilization of visual deficits, but this depends largely on the degree of irreversible neuropathy that existed before surgery. It should be emphasized that the transsphenoidal route for evacuation of an acutely swollen pituitary tumor is usually the surgical procedure of choice; but on occasion (e.g., where pituitary apoplexy occurs in a patient with a normal or non aerated sella turcica), technical considerations might favour the transfrontal approach to the pituitary.

Those patients in whom the apoplectiform attack does not pose an immediate threat either to vision or to consciousness may be followed closely and treated expectantly. Sudden, albeit restricted, pituitary hemorrhage or infarction may occur in patients with pituitary tumors more often than is generally believed. In many of these cases, the apoplectic event is recalled only retrospectively, e.g., when the surgeon who has removed a cystic or necrotic pituitary tumor reviews the history in detail with the patient. Sudden headache, with or without meningismus, with minimal impairment of visual acuity and fields in an alert patient who has a pituitary tumor verified by CT or MRI may be treated medically with corticosteroids, at least over the short term, unless it is apparent that vision is threatened. After the apoplectiform event has been successfully managed medically, with resolution of headache and ophthalmoplegia, the long-term management of these patients is the same as that of the usual patient with a pituitary tumor. The primary treatment options, used singly or in combination, are medical management of any endocrinopathy, surgery with tumor removal, stereotactic aspiration of the pituitary hemorrhage, radiation therapy, and pharmacologic manipulation (e.g., bromocriptine administration). Since cases of pituitary apoplexy are known to have developed during or after radiation treatment of a pituitary tumor, it has been suggested that this modality not be used for patients known to have had an attack of pituitary apoplexy with recovery. No data supporting this conclusion are available, and radiation therapy of pituitary tumors has been successfully used in patients who have previously recovered from apoplexy.