Pituitary apoplexy

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Pituitary apoplexy

Pituitary apoplexy

Pituitary apoplexy also known as pituitary infarction is a rare vision and life threatening disorder where bleeding occurs in the pituitary gland and/or blood flow to the pituitary gland is blocked 1, 2, 3, 4, 5, 6, 7. Apoplexy means “sudden death” usually caused by bleeding into an organ or loss of blood flow to an organ 7. The term pituitary apoplexy refers to the “sudden death” of the pituitary gland, usually caused by an acute ischemic infarction or hemorrhage. 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 2. Pituitary apoplexy is commonly caused by bleeding inside a benign (non-cancerous) tumor of the pituitary called pituitary adenoma or pituitary neuroendocrine tumor 4, 5, 6. Pituitary adenomas are very common with more than 10,000 pituitary tumors being diagnosed each year in the United States and are often not diagnosed because these tumors are small and never cause any symptoms or health problems 8. When examining people who have died or who have had imaging tests (like MRI scans) of their head for other health problems, doctors have found that as many as 1 in 4 people may have a pituitary adenoma without knowing it 8. Pituitary tumors can occur in people of any age including in children, but they are most often found in older adults 8. The pituitary is damaged when the tumor suddenly enlarges. It either bleeds into the pituitary or blocks blood supply to the pituitary. The larger the tumor, the higher the risk for future pituitary apoplexy. When pituitary bleeding occurs in a woman during or right after childbirth, it is called Sheehan syndrome. This is a very rare condition.

Pituitary apoplexy is a rare event 6. According to recent epidemiological studies, the prevalence of pituitary apoplexy is about 6.2 cases per 100,000 in Banbury Oxfordshire, United Kingdom 9 and its incidence 0.17 episodes per 100,000 per year in Northern Finland 10. Between 2% and 12% of patients with all types of pituitary adenoma experience apoplexy and the diagnosis of pituitary tumor was unknown at time of apoplexy in more than 3 out of 4 cases 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36. If the nonfunctioning pituitary adenomas (often incidentalomas) were already known and that a decision was made to manage them conservatively, the risk of pituitary apoplexy was calculated to be between 0.2 and 0.6 events per 100 person-years in 2 metaanalyses 37, 38.

Pituitary apoplexy is characterized by a sudden onset of headache, visual symptoms and vomiting (Apoplexy Triad) with altered mental status, and hormonal dysfunction due to acute hemorrhage or infarction of a pituitary gland 2. An existing pituitary adenoma usually is present. Sudden-onset headache located behind the eyes is the most common symptom 39, 40. Several mechanisms have been theorized to explain the headache in pituitary apoplexy and include involvement of the superior division of the trigeminal nerve inside the cavernous sinus, meningeal irritation, dura-mater compression, or enlargement of sellar walls. Other symptoms include visual acuity impairment and visual field impairment from involvement of the optic nerve or chiasm, hemianopia, diplopia, ptosis, nausea and vomiting, altered mental status, and hormonal dysfunction 41, 42, 40, 43, 44, 45. Many patients complain of double vision, which is caused by extrinsic compression of one or several of the extraocular nerves traversing the cavernous sinus. The oculomotor is the nerve most commonly affected 46. Patients will have ptosis and lateral eye deviation, sometimes accompanied by pupillary dilation of the affected eye.

Pituitary apoplexy diagnosis is based on history, examination, and neuro-imaging. Radiographic features of pituitary apoplexy include enlargement of the pituitary gland, with or without bleeding 47. Macroscopic hemorrhage is common and occurs in about 85%. It shows peripheral enhancement around a non-enhancing infarcted center 47. Surrounding edema may be seen in the optic tracts and chiasm.

Pituitary apoplexy treatment can vary between conservative management to prompt resuscitation, including administration of intravenous corticosteroids to avoid Addisonian crisis and neurosurgical intervention, which generally is by the trans-sphenoidal route 3.

For patients presenting with neurological changes from pituitary tumor apoplexy, urgent surgical intervention is commonly performed for tumor resection, and optic apparatus decompression 48. Pituitary apoplexy treatment aims are to improve symptoms and relieve compression of local structures. For this purposes, surgical decompression is the most rapid way for achieving them 49, 48. It has been reported that the surgical outcomes of patients with pituitary apoplexy may be quite poor when compared to the surgical outcomes of patients operated for a pituitary tumor without pituitary apoplexy 50. Accordingly, a complete recovery of oculomotor nerve (the third cranial nerve) palsies has been described in 31–57% of patients presenting pituitary apoplexy after surgery 48, 51, 52, normalization of visual acuity in about 50% of the cases 51, 52, anterior pituitary function normalization in more than 50% of cases and complete tumor resection in most of the patients 53, 54.

Acute pituitary apoplexy can be life-threatening if its not diagnosed or treated in a timely manner. The prognosis (outlook) is good for people who is diagnosed and treated in a timely manner. When appropriately managed, visual symptoms often improve, but long-term (chronic) pituitary deficiency may remain 55.

Figure 1. Pituitary apoplexy

Pituitary apoplexy

Footnotes: 30 year old male with one month blurred vision and increasing headache. A 19 x 23 x 25 mm ovoid mass lesion is seen in the pituitary fossa with suprasellar extension (necrotic pituitary macroadenoma). The mass is not clearly separate from the anterior portion of the pituitary, which cannot be identified. A solid component is located anterolaterally (towards the left) and this component enhances. The optic chiasm is markedly compressed, draped over the superior aspect of the mass lesion. The mass is T1 and T2 hyperintense centrally with no significant enhancement post contrast. There are a few fine internal septations. No restricted diffusion within the mass. No calcifications. The remaining imaged brain, including posterior fossa structures, are normal. The white matter in the peri trigonal regions is thinned with undulation of the lateral margins of the lateral ventricles. This patient went on to have transphenoidal surgery. Final diagnosis is pituitary tumor (non-functioning gonadotroph cell adenoma).

[Source 56 ]

Figure 2. Pituitary Ring Sign

pituitary ring sign

Footnotes: A 55-year-old man presented with acute onset of severe headache, diplopia, nausea, and vomiting. The neuro-ophthalmologic examination showed a visual acuity with correction at the bedside of 20/50 (right eye), 20/70 (left eye), with normal color vision and confrontational visual fields. Pupils were normal without a relative afferent pupillary defect. Ocular motility, slit-lamp, and ophthalmoscopic examinations were normal. Post-contrast sagittal T1-weighted scan shows sphenoid sinus roof mucosal thickening. The horizontal arrow shows the “pituitary ring sign”; the vertical arrow shows sphenoid sinus roof mucosal thickening.

[Source 57 ]
When to see a doctor

See your doctor if you have any symptoms of chronic pituitary insufficiency.

Go to the emergency room or call your local emergency number if you have symptoms of acute pituitary apoplexy, including:

  • Eye muscle weakness or vision loss
  • Sudden, severe headache
  • Low blood pressure (which can cause fainting)
  • Nausea
  • Vomiting

If you develop these symptoms and you have already been diagnosed with a pituitary tumor, seek medical help right away.

What is the pituitary gland?

The pituitary is a small gland at the base of the skull, just below the brain and above the nasal passages and the fleshy back part of the roof of the mouth (known as the soft palate). The pituitary sits in a tiny bony space called the sella turcica. The nerves that connect the eyes to the brain, called the optic nerves, pass just above it. The pituitary is connected directly to part of the brain called the hypothalamus. This provides a key link between the brain and the endocrine system, a collection of glands and organs in the body that make hormones. Hormones are substances released into the blood that control how other organs work. The hypothalamus releases hormones into tiny blood vessels connected to the pituitary gland. These then cause the pituitary to make its own hormones. The pituitary is considered the “master control gland” because it makes the hormones that control the levels of other hormones made by most of the endocrine glands in the body.

The pituitary gland has 2 parts, the anterior pituitary and the posterior pituitary. Each part has distinct functions.

Figure 3. The pituitary gland location

pituitary gland

Figure 4. Pituitary gland

location of the pituitary gland

Figure 5. The hypothalamus and pituitary gland (anterior and posterior) endocrine pathways and target organs

Hypothalamus hormones
[Source 58 ]

The anterior pituitary

Most pituitary tumors start in the larger, front part of the pituitary gland known as the anterior pituitary. This part of the gland makes several hormones:

  • Growth hormone (GH, also known as somatotropin) promotes body growth during childhood. If a child or teen’s body makes too much growth hormone, they will grow very tall (a condition called gigantism). If an adult’s body makes too much growth hormone, the bones of the hands, feet, and face can grow larger than normal, distorting their features. This condition is called acromegaly.
    Thyroid-stimulating hormone (TSH, also called thyrotropin) stimulates the thyroid gland to release thyroid hormones, which regulate body metabolism. Too much of these hormones makes you hyperactive and shaky, and too little makes you sluggish. If a pituitary tumor makes too much TSH, it can cause hyperthyroidism (an overactive thyroid gland).
  • Adrenocorticotropic hormone (ACTH, also known as corticotropin) causes the adrenal glands to make steroid hormones (such as cortisol). Too much ACTH from a pituitary tumor causes Cushing’s disease, the symptoms of which can include rapid weight gain and the build-up of fat in certain parts of the body, as well as high blood pressure and diabetes.
  • Luteinizing hormone (LH) and follicle-stimulating hormone (FSH) are also called gonadotropins. In women their main effects are on the ovaries, where they control ovulation (the release of eggs) and the production of the hormones estrogen and progesterone. In men, LH and FSH control testosterone and sperm production in the testicles.
  • Prolactin causes milk production in the female breast. Its function in men is not known. Pituitary tumors that make prolactin can cause reproductive problems, as well as milk production in both women and men.

The posterior pituitary

The smaller, back part of the pituitary gland is really an extension of brain tissue from the hypothalamus. The posterior pituitary stores and releases hormones made by the hypothalamus (vasopressin and oxytocin) into the bloodstream.

  • Vasopressin (also called antidiuretic hormone, or ADH) causes the kidneys to keep water in the body, rather than losing it all in the urine. When vasopressin levels are low, a person urinates too much and becomes dehydrated. This condition is called diabetes insipidus. Vasopressin also can raise blood pressure by constricting blood vessels. It might have other functions as well.
  • Oxytocin causes the uterus to contract in women during childbirth and the breasts to release milk when a woman breastfeed her baby. It might also have other functions in both men and women.

Tumors rarely start in the posterior pituitary.

Pituitary apoplexy causes

A pre-existing pituitary adenoma is usually found in cases of pituitary apoplexy 3. In the majority of the cases, the patients are unaware of the pituitary tumor 24.

Several predisposing or contributing factors for pituitary apoplexy include 59, 3:

  • endocrine stimulation tests 60
  • head trauma
  • bromocriptine or cabergoline treatment 61, 62
  • gonadotropin-releasing hormone treatment 63
  • lumbar fusion in the prone position 64, 65
  • pregnancy 66, 67
  • pituitary irradiation 68
  • anticoagulation 59
  • thrombocytopenia (low platelet level) 69, 70
  • erectile dysfunction medications 71

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. Sheehan syndrome occurs in postpartum women in which there is necrosis of the pituitary gland secondary to ischemia after significant bleeding during childbirth. It will present with adrenal insufficiency, hypothyroidism, and hypopituitarism, but rarely with visual changes. Most of the time, this entity is not included as a pituitary apoplexy as the gland did not have a pre-existing tumor, and visual symptoms are extremely rare. Sheehan syndrome is regarded as a neurologic emergency and is potentially lethal.

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.

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” 57.

Pituitary 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.

Okuda reported one woman with a giant pituitary adenoma who underwent triple bolus stimulation test with luteinizing hormone-releasing hormone, thyrotropin-releasing hormone (TRH), and insulin 72. 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 72.

Some scientists associate pituitary apoplexy with administration of gonadotropin hormone-releasing hormone (GnRH). Corticotropin-releasing hormone (CRH) 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 resulting in internal carotid artery occlusion has been reported due to the mass compressing the bilateral cavernous sinuses, resulting in obliteration of the cavernous portion of the right internal carotid artery 73.

Pituitary apoplexy during induction chemotherapy for acute myeloid leukemia has been reported by Silberstein and colleagues 74.

Pituitary apoplexy has been reported after cardiac bypass surgery by Thurtell and colleagues 75.

Brar and Garg reported a case of pituitary apoplexy in a young man who ascended to high altitude gradually, even after proper acclimatization 76.

Pituitary apoplexy has been reported in a patient with dengue fever and thrombocytopenia 77. Kruljac et al reported a patient with pituitary metastasis presenting as ischemic pituitary apoplexy after heparin-induced thrombocytopenia 78.

Weisberg warns that radiotherapy is potentially hazardous in pituitary tumors with prior hemorrhagic, necrotic, or cystic changes 79.

Some believe that pituitary 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 80. Both may result in brain ischemia.

Pituitary apoplexy risk factors

Pituitary apoplexy risk factors include 1, 81:

  • Pituitary Tumor
  • Non-functioning pituitary macroadenoma
  • Certain functional tumors
  • Hypertension and/or hypotension
  • Surgery
  • Cardiac surgery (heart lung bypass; coronary artery grafts)
  • Cerebral angiography
  • Major orthopedic procedures
  • Drugs
  • Endocrine stimulation tests (thyrotropin releasing hormone stimulation; insulin tolerance test)
  • Anticoagulation therapy
  • Estrogen
  • Head Trauma
  • Changes in intracranial pressure
  • Pregnancy and Delivery (Sheehan syndrome)
  • Infections
  • Dengue fever
  • Hypophyisitis
  • Radiation therapy
  • Medical treatment of a prolactinoma (especially with bromocriptine) 82.

Pituitary apoplexy pathophysiology

Pituitary apoplexy pathophysiology is not fully understood, but it is noteworthy that most cases involve patients with pituitary adenomas or, less commonly, in a nonadenomatous gland from infarction or hemorrhage 83, 84, 17, 22, 85.

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 86.

Some theorized that a gradually enlarging pituitary tumor becomes impacted at the diaphragmatic notch, compressing and distorting the hypophyseal stalk and its vascular supply 87. 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 87. This explanation is doubtful, since most tumors that undergo apoplexy are slow growing.

Nevertheless, pituitary adenomas are prone to bleed and undergo infarction and necrosis, possibly because pituitary gland has this unique rich vascular structure and/or because pituitary tumors which have a high-energy requirement may outgrow their blood supply or because ischemia (and thus infarction) occurs after compression of infundibular or superior hypophyseal vessels against the sellar diaphragm by the expanding tumor mass with intrinsically poor vascularity 85, 88, 89.

Moreover, as recently demonstrated, pituitary tumor cells are particularly sensitive to glucose deprivation 90. In this setting, all clinical situations that acutely decrease systemic blood pressure, such as cardiac, vascular, or orthopedic surgery may decrease blood supply to the pituitary adenoma and precipitate pituitary apoplexy 87. Dynamic tests or hypoglycemia that acutely increase the metabolic needs of the tumor may also precipitate pituitary apoplexy, as well as severe vomiting/diarrhea with concomitant increased Valsalva pressure.

The inherent fragility of pituitary tumor blood vessels may also explain the hemorrhagic tendency 91. The blood vessels of pituitary adenomas show signs of incomplete maturation and poor fenestration, and their basal membranes are often ruptured 41, 92, 93. Immunohistochemical expression of vascular endothelial growth factor was found to correlate positively with the risk of pituitary hemorrhage 94. Pituitary tumor-transforming gene (PTTG), which is correlated to vascularization and expression of vascular endothelial growth factor 95, is also overexpressed in pituitary adenomas 96, 97. Fetal liver kinase 1, a vascular marker, is also expressed, particularly in nonfunctioning pituitary adenomas, particularly in older subjects 98, as is nestin, another vascular marker 99.

Whatever the mechanism, the extent of hemorrhage and necrosis will produce an increase in intrasellar pressure 17, 41, 100, 101, 102, which in turn leads to more or less pronounced compression of neighboring structures, thus explaining the broad clinical spectrum, from “classical” acute pituitary apoplexy to totally silent necrotic and/or hemorrhagic pituitary adenomas found only on pathological examination.

Pituitary apoplexy symptoms

Pituitary apoplexy usually has a short period of symptoms (acute), which can be life threatening. 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.

Pituitary apoplexy symptoms during the acute phase of apoplexy often include 1, 103:

  • Severe headache (worst of your life) (95%). Sudden-onset headache located behind the eyes is the most common symptom 39, 40. Several mechanisms have been theorized to explain the headache in pituitary apoplexy and include involvement of the superior division of the trigeminal nerve inside the cavernous sinus, meningeal irritation, dura-mater compression, or enlargement of sellar walls. Other symptoms include decreased visual acuity, hemianopia, diplopia, ptosis, nausea and vomiting, altered mental status, and hormonal dysfunction.[2][28][29][30][31] Many patients complain of double vision, which is caused by extrinsic compression of one or several of the extraocular nerves. The oculomotor is the nerve most commonly affected.[23] Patients will have ptosis and lateral eye deviation, sometimes accompanied by pupillary dilation of the affected eye.
  • Paralysis of the eye muscles, causing double vision (ophthalmoplegia) or problems opening an eyelid (78%)
  • Loss of peripheral vision (52%) or loss of all vision in one or both eyes (64%)
  • Low blood pressure (hypotension) (95%), nausea, loss of appetite, and vomiting (70%) from acute adrenal insufficiency
  • Personality changes due to sudden narrowing or spasm of one of the arteries in the brain (anterior cerebral artery)
  • Hemiplegia rare
  • Meningismus rare
  • There is one case report of stubborn hiccups in association with pituitary apoplexy 104

Less commonly, pituitary dysfunction may appear more slowly. In Sheehan syndrome, for example, the first symptom may be a failure to produce milk caused by a lack of the hormone prolactin after delivery.

As the hemorrhagic infarct resolves, over time problems with other pituitary hormones may develop, causing hypopituitarism symptoms 103:

  • Growth hormone deficiency
  • Adrenal insufficiency (if not already present or treated)
  • Hypogonadism (body’s sex glands produce little or no hormones)
  • Hypothyroidism (thyroid gland does not make enough thyroid hormone)

In rare cases, when the posterior (back part) of the pituitary is involved, symptoms may include 103:

  • Failure of the uterus to contract to give birth to a baby (in women)
  • Failure to produce breast milk (in women)
  • Frequent urination and severe thirst (diabetes insipidus)

Pituitary apoplexy complications

Complications of untreated pituitary apoplexy can include:

  • Adrenal crisis also called Addisonian crisis (condition that occurs when there is not enough cortisol, a hormone produced by the adrenal glands)
  • Vision loss
  • Frontal lobe herniation and chiasmal herniation have been reported 105

If other missing hormones are not replaced, symptoms of hypothyroidism and hypogonadism may develop, including infertility.

In pituitary apoplexy, the most impacting clinical problem is the lack of secretion of adrenocorticotropic hormone (ACTH), which occurs in more than two-thirds of the patients with pituitary apoplexy 3. The lack of secretion causes a cessation of cortisol secretion by the adrenal gland, which produces a variety of symptoms called “adrenal crisis” 42, 39. The patient may have nausea and vomiting, abdominal pain, bradycardia and hypotension, hypothermia, lethargy, and sometimes coma.

Pituitary apoplexy diagnosis

Your doctor will perform a physical exam and ask about your symptoms.

Tests that may be ordered include:

  • Eye exams
  • Magnetic resonance imaging (MRI) or computed tomographic (CT) scan of your brain

Neuroimaging

Magnetic resonance imaging (MRI) scan, as seen in Figure 1 above is the most sensitive imaging study for evaluating the pituitary gland, possibly visualizing hemorrhage not seen on CT scan 42, 46. 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 (see Figure 2) 57. Vaphiades retrospectively reviewed the cranial MRIs of 3 patients with ischemic (nonhemorrhagic) pituitary apoplexy; all 3 patients displayed the “pituitary ring sign” 57. The term “pituitary ring sign” is used to describe an enlarged pituitary gland bulging under the optic chiasm, with peripheral enhancement surrounding a hypointense gland 57. This MRI appearance was first noted in 1995 by Lavallée et al. in a patient with Sheehan syndrome on a contrast-enhanced computed tomography (CT) scan and on a T1-weighted contrast-enhanced MRI scan and thought to be unique to ischaemic apoplexy in patients with Sheehan syndrome 106. However, the ring sign is not specific for pituitary infarction, because it can be seen in association craniopharyngioma 107 in addition to lymphocytic hypophysitis, pituitary abscess, and pituitary adenoma that has not undergone apoplexy 108. Lymphocytic hypophysitis is a rare inflammatory disorder of the pituitary gland, commonly manifesting late in pregnancy or during the postpartum period. It can mimic pituitary adenoma. In the majority of cases, the lymphocytic hypophysitis diagnosis is made after pituitary surgery for suspected pituitary adenoma 109.

Sphenoid sinus mucosal thickening, occurring in the setting of pituitary apoplexy, was first described by Arita et al. in 2001 110. 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 obtained within 7 days after the onset of apoplectic symptoms 110. Controls consisted of MR images obtained in 100 consecutive patients with pituitary adenomas but without apoplectic symptoms. Included in this group were 58 functioning and 42 non-functioning pituitary adenomas. Fifteen patients experienced thickening of the sphenoid sinus mucosa, including five with some apparent pansinusitis. The incidence of mucosal thickening of the sphenoid sinus in the patients with apoplexy was significantly greater than that in the patients without apoplexy 110. On histopathological specimens in the apoplexy patients, the thickened sphenoid sinus mucosa demonstrates a swollen sub-epithelial layer presumably responsible for the rim of MRI gadolinium enhancement 110. In 2006, Liu et al. 19 performed a retrospective review of 28 patients with pituitary apoplexy. Thickening of sphenoid sinus mucosa was present in 22 (79%) of these patients. They also noted that patients with thickened sphenoid sinus mucosa had larger tumours, 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 with those patients without thickened mucosa 19. In 2012, Agrawal et al. 111 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. Each sign, “pituitary ring sign” and “sphenoid sinus mucosal thickening”, alone may exist in patients with or without pituitary apoplexy, yet presence of both signs together in the appropriate clinical context is a strong predictor of pituitary apoplexy 57. This is important because timely diagnosis treatment of pituitary apoplexy may be vision- and life-saving 57 .

Kaplun and colleagues reported the MRI evolution of pituitary changes in 2 patients with Sheehan syndrome 112. The first case initially had the pituitary ring sign, although MRI later showed an empty sella with shrinkage of 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 subarachnoid hemorrhage (SAH). CT scanning can help to exclude subarachnoid hemorrhage (SAH) from an aneurysm by showing an intrasellar mass with hemorrhagic components, seen in 80% of pituitary apoplexy cases 39.

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 113.

Liu et al 114 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).

Blood tests

Pituitary hormonal evaluation is required, as nearly 80% of patients present with a deficiency of at least one of the anterior pituitary hormones 4. The most common deficiencies are growth hormone deficit in 90% of the patients and ACTH (adrenocorticotropic hormone) deficit in 70% of them 42, 39, 115.

Blood tests will be done to check levels of:

  • ACTH (adrenocorticotropic hormone)
  • Cortisol
  • FSH (follicle-stimulating hormone)
  • Growth hormone
  • LH (luteinizing hormone)
  • Prolactin
  • TSH (thyroid-stimulating hormone)
  • Insulin-like growth factor-1 (IGF-1)
  • Sodium
  • Osmolarity in blood and urine

Histologic findings

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 84. By immunostaining criteria, null-cell adenomas were the most frequent tumor type found.

Pituitary apoplexy differential diagnosis

Several conditions have to be excluded as they can present with similar visual, ophthalmoplegic, and headache symptoms that occur in pituitary apoplexy. Some of the conditions will only require medical treatment, while in others, the surgical treatment is completely different.

  • Rathke’s cleft cyst 116, 117, 118
  • Temporal arteritis 119
  • Aneurysm
  • Craniopharyngioma
  • Subarachnoid hemorrhage (SAH) 120
  • Meningitis 121 or encephalitis
  • Cavernous venous sinus thrombosis
  • Basilar artery infarct
  • Hypertensive encephalopathy
  • Ophthalmoplegic migraine 122
  • Retrobulbar neuritis

Pituitary apoplexy treatment

Pituitary apoplexy treatment should be individualized for each patient. Acute pituitary apoplexy may require surgery to relieve pressure on the pituitary and improve vision symptoms. Severe cases need emergency surgery. If vision is not affected, surgery is often not necessary. Surgical intervention, when necessary, should be undertaken early and the majority of the patients will have residual hormonal deficits requiring hormone replacement 86.

Immediate treatment with adrenal replacement hormones (glucocorticoids) may be needed. These hormones are often given through the vein (IV). Other hormones may eventually be replaced, including:

  • Growth hormone
  • Sex hormones (estrogen/testosterone)
  • Thyroid hormone
  • Vasopressin (ADH)

Management of the mass is controversial as some advocate early transsphenoidal surgical decompression in all patients, whereas others adopt a conservative approach for those patients without visual acuity or field defects and with normal consciousness 3. Emergency surgery should be reserved for patients with progressive deterioration of consciousness, hypothalamic involvement, and progressive visual worsening 3. It has been demonstrated that a significant postoperative clinical improvement is a consequence of a surgical procedure performed as soon as possible 46. Decompressive surgery can be delayed but performed within 1 week when visual acuity defects appear stable. If ophthalmoplegia is improving or stable, a conservative strategy could be considered 123, 124. Microscopic endonasal or sublabial transsphenoidal surgery is commonly used. For very large tumors and those extending over the chiasm or laterally to the temporal fossa, a craniotomy should be used to achieve complete resection. Endoscopic endonasal approaches for pituitary apoplexy are effective 44, 125, 126. Patients operated using the endoscopic approach have a similar visual outcome, but a better endocrinological outcome as the viable tumoral component can be removed from restricted areas like the cavernous sinus 127. Sometimes, an endoscopic approach can prove difficult to perform if required at late night hours as it needs the collaboration of an otolaryngologist with the neurosurgeon.

Immediate medical management

Immediate medical management of patients with pituitary apoplexy includes a careful assessment of fluids and electrolyte balance, ensure hemodynamic stability, and replacement with corticosteroids 115.

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 128.

All patients should receive corticosteroids even if they do not present symptoms of adrenal crisis 3. The recommended dose is an intravenous 100–200 mg bolus of hydrocortisone. Additional administration of 50-100 mg every 6 hours should be continued. Alternatively, a continuous intravenous infusion of 2-4 mg/hour can be started after the initial bolus 39.

Surgical care

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) 39. Children with pituitary tumor apoplexy has a more aggressive natural history in comparison to adults, and early surgery may reduce its occurrence and improve outcomes 129, 130.

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 39, 131, 132.

Shepard et al 133 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 133. 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 133.

Cavalli et al 134 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 134.

Pituitary apoplexy prognosis

Acute pituitary apoplexy can be life-threatening if its not diagnosed or treated in a timely manner. The prognosis (outlook) is good for people who is diagnosed and treated in a timely manner. The overall mortality is 1.6% to 1.9% 3. Visual acuity, visual field defects, and ophthalmoplegia improve in the majority of the patients after both conservative and surgical decompression 55. After surgery, such improvement can be observed in the immediate postoperative period and often continues for several weeks after surgery. Visual recovery has been reported to be less likely in patients presenting with monocular or binocular blindness 3. Although visual outcome appears to be better with early intervention as compared to late 135, others found that visual deficits, resolution of oculomotor palsy, recovery from hypopituitarism, or non-neuroendocrine signs and symptoms such as headache and encephalopathy do not depend on the timing of surgery 136. A complete restoration of the oculomotor palsy usually needs 3 months, while abducens nerve palsy usually needs 6 months 46. Overall, visual improvement is seen in 75 to 85% of patients, recovery of normal vision in 38% of patients, and rectification of preoperative oculomotor palsies in 81% of patients 44.

Gross total resection and short duration of preoperative headaches are predictors for improvement in postoperative headaches 137. Hormonal replacement therapy is needed in 80% of the patients 4, 21, 136. In some cases that are treated conservatively, spontaneous remission of the tumor has occurred, and surgery is not required 138, 139. This may be caused by ischemic necrosis of the tumoral tissue 3.

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