Pituitary Apoplexy

The word apoplexy is defined as a sudden neurologic impairment, usually due to a vascular process. Pituitary apoplexy is characterized by a sudden onset of headache, visual symptoms, altered mental status, and hormonal dysfunction due to acute hemorrhage or infarction of a pituitary gland. An existing pituitary adenoma usually is present. The visual symptoms may include both visual acuity impairment and visual field impairment from involvement of the optic nerve or chiasm, and also may include ocular motility dysfunction from involvement of the cranial nerves traversing the cavernous sinus.[1] It is important to note that pituitary apoplexy may be divided into hemorrhagic or ischemic, each with unique neuroimaging findings, and some patients have elements of both.

Pituitary apoplexy stems from an acute expansion of a pituitary adenoma or, less commonly, in a nonadenomatous gland from infarction or hemorrhage. The anterior pituitary gland is perfused by its portal venous system, which passes down the hypophyseal stalk. This unusual vascular supply likely contributes to frequency of pituitary apoplexy. It is more common in macroadenomas and nonfunctioning adenomas, and it rarely has been reported in microadenomas.[2]  

Some postulate that a gradually enlarging pituitary tumor becomes impacted at the diaphragmatic notch, compressing and distorting the hypophyseal stalk and its vascular supply. This deprives the anterior pituitary gland and the tumor itself of its vascular supply, apoplectically causing ischemia and subsequent necrosis.

Another theory stipulates that rapid expansion of the tumor outstrips its vascular supply, resulting in ischemia and necrosis. This explanation is doubtful, since most tumors that undergo apoplexy are slow growing.

Frequency

International

Pituitary apoplexy results in an estimated 1.5-27.7% of cases of pituitary adenoma, although the figure is probably closer to 10%.  

Mohr and Hardy reviewed hospital records of 664 patients who had surgery for pituitary adenomas.[3]  Typical symptomatic pituitary apoplexy occurred in only 0.6% of patients with significant hemorrhagic and necrotic changes in 9.5% of surgical specimens.

Frequency of intratumoral hemorrhage increases to 26% if using only MRI criteria without clinical evidence of apoplexy. However, hemorrhagic pituitary apoplexy may be fatal. Kurisu et al described a 68-year-old man who developed pituitary apoplexy resulting in massive intracerebral hemorrhage and death 1 month later.[4]

Sex

Pituitary apoplexy has a male-to-female ratio of 2:1.

Age

The usual age range is 37-57 years. Pediatric pituitary apoplexy has been described.[5]

Pituitary apoplexy can be a life-threatening condition, and it is not easily diagnosed or treated. When appropriately managed, visual symptoms often improve, but endocrinologic function may remain compromised.[6]

Educate patients about the disorder and the complications that can arise from its treatment.

Patients with pituitary apoplexy may present with the following complaints[7] :

• Headache (often sudden and severe)
• Nausea and vomiting
• Diplopia
• Changes in vision or visual field
• Ptosis

There is one case report of recalcitrant hiccups in association with pituitary apoplexy.[8]

Clinical presentation is marked by headache in 95% of cases. The headache is sudden and postulated to result from stretching and irritation of the dura mater in the walls of the sella supplied by the meningeal branches of cranial nerve V. The headache also may result from irritation of the trigeminal nerve from the expanding mass. Frequently, it is retro-orbital in location and may be unilateral at onset, then becomes generalized.

Vomiting occurs in 69% of patients and often accompanies the headache. The mechanism is unclear but may be due to meningeal irritation or increased intracranial pressure.

Visual acuity defects (52%) and visual field defects (64%) result from upward expansion of the tumor, which compresses the optic chiasm, optic tracts, or optic nerve. The classic visual field defect is a bitemporal superior quadrantic defect. Optic tract involvement from a prefixed chiasm is less common and results in a contralateral homonymous hemianopia. Optic nerve compression from a postfixed chiasm is rare and may mimic optic neuritis with pain on eye movement, monocular visual acuity loss, and a central scotoma on visual field testing. 

Ocular paresis (78%) results from compression of the cavernous sinus, which makes cranial nerves III, IV, and VI vulnerable to compression. If consciousness is maintained, diplopia may be present. Of the cranial nerves, the oculomotor nerve (cranial nerve III) is involved most commonly, resulting in a unilateral dilated pupil, ptosis, and a globe that is deviated inferiorly and laterally.[9]

Less commonly, cranial nerve IV is involved. A fourth cranial nerve palsy typically manifests as vertical diplopia that worsens when the patient gazes in a direction opposite or tilts the head toward the direction of the hypertropic (affected) eye. It also is worsened by downgaze.

Cranial nerve VI is least commonly involved, perhaps because, in the cavernous sinus, it is more sheltered from the pituitary expansion than are cranial nerves III and IV. Abducens involvement produces horizontal diplopia owing to the inability to abduct the involved eye.

Trigeminal nerve (cranial nerve V) involvement may produce facial pain or sensory loss.

Horner syndrome may develop from damage to the sympathetic fibers. Hemispheric deficits may also develop.

The carotid siphon may be compressed against the anterior clinoid process, leading to stroke and vasospasm from subarachnoid blood.

Leakage of blood and necrotic tissue into the subarachnoid space may lead to meningismus, stupor, and coma.

The cerebrospinal fluid frequently is marked by increased pressure and pleocytosis (even in the absence of hemorrhage), increased numbers of red blood cells, and xanthochromia.

Involvement of the hypothalamus may alter thermal regulation. Destruction of adenohypophyseal tissue may lead to endocrinologic deficiencies.

Rarely, pituitary apoplexy can occur in ectopic sites. Hori examined normal adult brains at autopsy and found ectopic pituitary cells in the leptomeninges of the peri-infundibular region in 75%.[10] He postulated that these cells may produce an ectopic pituitary adenoma. Ectopic pituitary adenomas commonly present late because they displace rather than invade vital nervous structures. They may be discovered only after the patient has pituitary apoplexy. Only one case of an ectopic pituitary adenoma that underwent apoplexy has been reported.

Predisposing factors of pituitary apoplexy include endocrine stimulation tests, bromocriptine treatment, head trauma, pregnancy, pituitary irradiation, and, perhaps, anticoagulation.[11]

Okuda reported one woman with a giant pituitary adenoma who underwent triple bolus stimulation test with luteinizing hormone-releasing hormone, thyrotropin-releasing hormone (THR), and insulin.[12] The patient became stuporous, and computerized tomography (CT) scan revealed pituitary and subarachnoid hemorrhage (SAH). The investigators theorized that TRH-induced vasospasm may be a causative factor.

Some associate apoplexy with administration of gonadotrophin-releasing hormone. Corticotropin-releasing hormone administration was associated with pituitary apoplexy in a patient with Cushing syndrome. In one study, bromocriptine therapy was associated with high T1 signal in the pituitary tumor on magnetic resonance imaging (MRI), but none of the patients studied had clinical evidence of pituitary apoplexy. Others associate pituitary apoplexy with long-term bromocriptine therapy.

Pituitary apoplexy can occur after head trauma. This probably results from shear forces applied to the pituitary stalk with contusion, hemorrhage, and infarction of the adenoma.

Pituitary apoplexy during induction chemotherapy for acute myeloid leukemia has been reported by Silberstein and colleagues.[13]

Apoplexy has been reported after cardiac bypass surgery by Thurtell and colleagues.[14]

Brar and Garg reported a case of pituitary apoplexy in a young man who ascended to high altitude gradually, even after proper acclimatization.[15]

Pituitary apoplexy has been reported in a patient with dengue fever and thrombocytopenia.[16] Kruljac et al reported a patient with pituitary metastasis presenting as ischemic pituitary apoplexy after heparin-induced thrombocytopenia.[17]

Apoplexy may occur during pregnancy. Normally, the pituitary gland hypertrophies in pregnancy because of diffuse nodular hyperplasia of the prolactin secreting cells. This hypertrophy, combined with locally released factors, mediates vascular spasm and renders the pituitary more susceptible to infarction from compromised blood flow.

Sheehan syndrome refers to pituitary apoplexy of a nontumorous gland, presumably due to postpartum arterial spasm of arterioles supplying the anterior pituitary and its stalk. In 1937, Sheehan reported 11 cases of women who died in the puerperium, all of whom had necrosis of the anterior pituitary gland (adenohypophysis). Nine of the 11 cases had severe hemorrhage at delivery. The other 2 cases had no hemorrhage but were gravely ill prior to delivery. Usually, at least 1-2 liters of blood loss and hypovolemic shock are associated with a retained placenta. Sheehan syndrome occurs in 1-2% of women suffering significant postpartum hemorrhage.

The clinical presentation of acute pituitary apoplexy has only been reported in the literature in a minority of patients with Sheehan syndrome. The more commonly reported scenario is a woman who develops amenorrhea years later, with a diagnosis of Sheehan syndrome being made retrospectively. Notwithstanding, Sheehan syndrome is regarded as a neurologic emergency and is potentially lethal.

In Sheehan syndrome, lactation failure may occur as a result of prolactin deficiency, and there may be amenorrhea due to gonadotrophin deficiency. In addition, in the postpartum period, shaved pubic or axillary hair fails to regrow, and waxy skin depigmentation develops.

Signs of hypothyroidism and hypoadrenalism may develop, and posterior pituitary (neurohypophysis) involvement with diabetes insipidus may occur. The less frequent involvement of the neurohypophysis probably stems from a difference in the anatomy of the vascular supply. The neurohypophysis contains an anastomotic ring of blood vessels that the adenohypophysis lacks.

The neuroimaging characteristics of Sheehan syndrome are distinctive. On MRI, the normal pituitary gland is largest in the immediate postpartum period, measuring up to 11.8 mm in height and convex in appearance. The anterior pituitary is usually hyperintense on T1-weighted images in pregnant and postpartum women when compared with controls. After delivery, the size of the pituitary gland rapidly returns to normal beyond the first week postpartum. The characteristic MRI finding in Sheehan syndrome is an enlarged pituitary gland bulging under the optic chiasm with peripheral enhancement surrounding an isointense gland; this characteristic MRI finding is called the "pituitary ring sign" (see Imaging Studies).[18]

Weisberg warns that radiotherapy is potentially hazardous in pituitary tumors with prior hemorrhagic, necrotic, or cystic changes.[19] Apoplexy may be precipitated in these cases.

Some believe that apoplexy is more prevalent in patients who produce excess pituitary hormones (eg, acromegaly, Cushing syndrome), perhaps because the tumor is fueled by the hormones. Others report that most pituitary tumors that undergo apoplexy are endocrinologically silent.

Ahmed and Semple reviewed the potential complications of pituitary apoplexy, one being mechanical occlusion of the internal carotid arteries in the cavernous sinus, and the other being vasospasm.[20] Both may result in brain ischemia.

Complications include optic neuritis, acute ophthalmoplegia, increased intracranial pressure, extraocular muscle paralysis, and ptosis.

Frontal lobe herniation and chiasmal herniation have been reported.[21]

Pituitary apoplexy can present in a variery of different ways, and if one is not familiar with the diagnosis, it can be missed with devastating consequences. Thus, laboratory studies and neuro-imaging are key to the diagnosis.

At least one anterior pituitary deficiency always is present at the onset of pituitary apoplexy, with corticotropic deficiency being the most common and most life-threatening, affecting 60%-80% of patients.[26] Electrolytes, glucose, pituitary hormones, and plasma/urine osmolality should be evaluated.

CT scanning and MRI are radiologic tests used to evaluate the pituitary.

CT scanning generally is the initial imaging study of choice in the emergency department for patients who present with sudden-onset severe headache, visual loss, and/or ophthalmoplegia suggestive of SAH. CT scanning can help to exclude SAH from an aneurysm by showing an intrasellar mass with hemorrhagic components, seen in 80% of pituitary apoplexy cases.[26]

Binning and colleagues reported 6 patients with Rathke cleft cyst apoplexy presenting with the clinical and imaging features of both hemorrhagic and nonhemorrhagic pituitary apoplexy.[27]

Kaplun and colleagues reported the MRI evolution of pituitary changes in 2 patients with Sheehan syndrome.[28] The first case initially had the pituitary ring sign, although MRI later showed an empty sella with shrinkage of the pituitary.

Liu et al reported spontaneous partial or complete radiological disappearance of adenoma following pituitary apoplexy without the use of dopaminergic agonists (which may result in regression of pituitary adenoma).[29]

MRI, as seen in the images below, is the most sensitive imaging study for evaluating the pituitary gland, possibly visualizing hemorrhage not seen on CT scan.

In the first 3-5 days, hemorrhage within the sella is isointense or hypointense on T1-weighted images. On T2-weighted sequences, the blood appears hypointense.

A characteristic MRI finding in ischemic (nonhemorrhagic) pituitary apoplexy is an enlarged pituitary gland bulging under the optic chiasm with peripheral enhancement surrounding a hypointense gland. Vaphiades coined the phrase "pituitary ring sign" to denote this MRI appearance.[18] Vaphiades retrospectively reviewed the cranial MRIs of 3 patients with ischemic (nonhemorrhagic) pituitary apoplexy; all 3 patients displayed the "pituitary ring sign."[18]

This MRI appearance of the “pituitary ring” was first noted in 1995 by Lavalee et al in a patient with Sheehan syndrome on a contrast-enhanced CT scan and on a T1-weighted contrast-enhanced MRI and thought to be unique to ischemic apoplexy in patients with Sheehan syndrome.[30]

In 1998, Kleinschmidt-Demasters and Lillehei reported the pathological and MRI features of 15 patients with pituitary adenomas presenting with apoplexy. On T1-weighted contrast-enhanced MRI, they observed a peripheral rim of enhancement with gadolinium in 10 cases.[31]

Subsequent reports corroborated this MRI finding in patients with ischemic pituitary apoplexy.[32, 33]

The presumed etiology of the hypointense center in the pituitary gland is necrosis, which does not enhance with gadolinium on T1-weighted MRI. The enhancing part of the tumor is the outer-most portion of the infarcted pituitary or its “skin.” This was found to correspond to the presence of granulation tissue and lymphocytosis at histologic examination.[31]

Sphenoid sinus mucosal thickening in the setting of pituitary apoplexy was first described by Arita et al in 2001. They retrospectively evaluated 14 patients with pituitary apoplexy. The mucosa of the sphenoid sinus on MRI had thickened the compartment just beneath the sella turcica in 9 of 11 patients when performed within 7 days after the onset of apoplectic symptoms. Controls consisted of MRIs obtained in 100 consecutive patients with pituitary adenomas but without apoplectic symptoms. Included in this group were 58 functioning and 42 nonfunctioning pituitary adenomas. Fifteen patients experienced thickening of the sphenoid sinus mucosa, including 5 with some apparent pansinusitis. The incidence of mucosal thickening of the sphenoid sinus in patients with apoplexy was significantly greater than that in the patients without apoplexy.[34] On histopathological specimens in patents with apoplexy, the thickened sphenoid sinus mucosa demonstrates a swollen subepithelial layer presumably responsible for the rim of MRI gadolinium enhancement.[34]

In 2006, Liu et al performed a retrospective review of 28 patients with pituitary apoplexy. Thickening of sphenoid sinus mucosa was found in 22 (79%) of these patients. They also noted that patients with thickened sphenoid sinus mucosa had larger tumors, a higher rate of cranial nerve deficits at presentation than those without mucosal thickening, and a higher rate of hypopituitarism and subsequent long-term hormone replacement therapy compared to patients without thickened mucosa.[35]

In 2011, Agrawal et al concluded that there is a temporal association with the radiographic finding of sphenoid sinus mucosal thickening and pituitary apoplexy and that sphenoid sinus mucosal thickening may precede an apoplectic event.[36]

In 2017, Vaphiades reviewed twelve cases of ischemic pituitary apoplexy, all of which showed both the "pituitary ring sign" and "sphenoid sinus mucosal thickening" signs on MRI. The twelve cases were composed of ten cases from the literature (3 of which were published by this author) and two cases recently evaluated in the author’s hospital. Thus, five of the twelve cases were evaluated by this author. Five of the twelve patients had both headache and visual loss, five had headache alone, and two had no initial symptoms (nonfunctioning pituitary adenomas were incidentally found on MRI). These findings indicate that each sign ("pituitary ring sign" and "sphenoid sinus mucosal thickening") may exist alone with or without pituitary apoplexy, yet both signs together in the appropriate clinical context is a strong predictor of pituitary apoplexy. This is important because timely diagnosis treatment of pituitary apoplexy may be vision- and life-saving in this disorder.[37]  

Histologically, many of these tumors display hemorrhagic necrosis in their substance. This has been postulated to result from unrecognized episodes of focal hemorrhage. Bills reviewed histories of 37 patients with symptomatic pituitary apoplexy.[38] By immunostaining criteria, null-cell adenomas were the most frequent tumor type found.

Treatment should be individualized for each patient. Surgical intervention, when necessary, should be undertaken early and the majority of the patients will have residual hormonal deficits requiring hormone replacement.[2]

The management of pituitary apoplexy is controversial in that some advocate early transsphenoidal surgical decompression in all patients, whereas others adopt a conservative approach for selected patients (without visual acuity or field defects and with normal consciousness).[26]

Medical treatment consists of the following:

• Medically stabilize the patient.
• Immediately evaluate electrolytes, glucose, and pituitary hormones.
• Administer high-dose corticosteroids (most patients have hypopituitarism).
• Administer appropriate endocrinologic replacement therapy alone or combined with transsphenoidal surgical decompression of the tumor.
• Avoid the "head down" position, when possible. ^[39]

 

Evacuation of the tumor by a neurosurgeon should be planned once the patient is medically stable, especially in the setting of altered consciousness, visual acuity, and visual field loss.[26, 40, 41]

Shepard et al identified 64 patients with pituitary apoplexy, 47 (73.4%) underwent intended conservative management, while 17 (26.6%) had early surgery. Tumor volumes were greater in the early surgical cohort. Among those with visual acuity and field deficits, visual outcomes were similar between both groups. Conservative management failed in 7 patients (14.9%) and they required surgery. Younger age, female sex, and patients with field deficits or chiasmal compression were more likely to experience unsuccessful conservative management. The authors concluded that the majority of patients with pituitary apoplexy can be successfully managed without surgical intervention assuming close neurosurgical, radiologic, and ophthalmologic follow-up is available.[42]

Cavalli et al retrospectively reviewed 30 patients with pituitary apoplexy; they found that 86.7% of patients presented with visual disturbances (70% acuity, 50% field, 50% diploplia), 10 (33%) patients underwent emergency surgery, and 8 underwent delayed elective surgery. At early and late follow-up, the outcome was not significantly different between groups. The authors concluded that good results are possible with conservative management in selected cases. Emergency surgery provides better visual outcomes and a tumor vertical diameter >35 mm should tip the balance in favor of surgical management in presence of visual deficit.[43]

Consultations to consider include the following:

• Neurosurgery for potential surgical therapy

• Medicine for general medical management

• Endocrinology for hormonal management

• Ophthalmology for documentation of visual acuity, perimetry, and motility

In a prospective study in 152 consecutive patients undergoing transsphenoidal removal of pituitary tumors, not necessarily apoplexy, various immediate postoperative complications were noted including CSF leaks, meningitis, diabetes insipidus, dyselectrolytemia, deterioration of visual acuity of field ot new cranial nerve deficit or palsy, postoperative intracranial bleeding/hematoma at operation site, and hydrocephalus.[44]

 

Most patients experience improvement in their visual exam varying from partial improvement to complete recovery, with no difference between the conservative and surgically treated group.[2, 45]

There is a small risk for recurrent apoplexy in patients with residual tumors, and there is also a small risk for tumor recurrence following apoplexy; thus all patients should undergo surveillance examinations and repeat neuroimaging.[2]  

Monitor metabolic status, visual acuity, visual fields, and ocular motility.

There are scoring systems that can aid in the treatment of pituitary apoplexy.[2, 45, 46]  Giritharan et al proposed a scoring system called the Pituitary Apoplexy Score (PAS), which ranges fron 0 to 10 and includes the level of consciousness, visual acuity, visual fields, and ocular paresis.[45]  Jho et al proposed another scoring system that stratifies into the following 5 grades: 

Grade 1: patients are asymptomatic with typical radiologic findings of pituitary apoplexy (subclinical);                                                                  Grade 2: patients have endocrinopathy with appropriate MRI findings with no other clinical symptoms;                                                                  Grade 3: patients with headache;                                                                                                                                                                              Grade 4: patients with ocular palsies; and                                                                                                                                                                           Grade 5: patients with visual deficits or altered sensorium.[2, 46]

As reported in the previous grading system, there was a trend toward surgical management in higher grade patients rather than lower grade patients. Both scoring systems, however, are not perfect.

As corticotropic deficiency is present in most patients with pituitary apoplexy and may be life-threatening,[26] the goals of pharmacotherapy are to correct the corticosteroid deficiency, to reduce morbidity, and to prevent complications.  

In one study, 84% of patients developed one or more anterior pituitary hormone deficiency, 74% were diagnosed with severe growth hormone deficiency, and 68% required long-term steroid replacement. Sixty-five percent were deficient in both thyroxine and also gonadotrophin. No patients had long-term diabetes insipidus. Overall, the rates of hypopituitarism at follow-up were similar between the emergency surgical, elective surgical, and the conservative treatment groups[45] .

Class Summary

Corticosteroids replenish the cortisol that would normally be produced under this type of physiologic stressful situation.

Hydrocortisone (Hydrocortone, Cortef, Solu-Cortef)

Hydrocortisone decreases inflammation by suppressing migration of polymorphonuclear leukocytes and reversing increased capillary permeability.