Pituitary Apoplexy

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Diagnosis and reasoning

This 57 year-old man has presented with almost a textbook 'thunderclap' headache, in association with visual disturbances and confusion; this is a highly concerning presentation which mandates urgent evaluation. Key etiologies to consider in this respect include subarachnoid hemorrhage, cerebral venous sinus thrombosis and cervical artery dissection, all of which are life-threatening conditions. Examination in turn reveals bilateral papilledema, suggesting at intracranial hypertension; it also reveals reduced visual acuity in the right eye, and most interestingly, bitemporal hemianopsia, which is most often a sequela of compression of the optic chiasm. In this context, the optic chiasm compression might be secondary to tumoral lesions such as pituitary adenomas, craniopharyngiomas or meningiomas, or vascular etiologies such as aneurysms of the carotid siphon or anterior communicating artery. The hypothesis of a lesion located in the sellar or parasellar region is compatible with the signs and symptoms described thus far; following this line of thought, the severe hyponatremia seen in the electrolyte profile would likely be due to disturbances in pituitary function. Urgent brain imaging is a mandatory next step; this reveals a compressive mass lesion in the sella and suprasellar area, which is hyperintense on T1 weighted images, and shows areas of hypointensity on T2 weighted images; gadolinium contrast reveals peripheral rim enhancement of the pituitary gland. The aforementioned imaging findings can be seen in craniopharyngioma, Rathke's cleft cysts and hemorrhagic pituitary apoplexy; however, thickening of the sphenoid sinus mucosa is very specific for the last of these, thus clinching the diagnosis. A complete biochemical profile is also a must, along with evaluation of pituitary functions; in the latter, note the marked response to ACTH stimulation, suggesting at a pituitary deficit in secretion. Note also the normal serum prolactin levels. Diagnostic lumbar punctures are of little value here, and are best avoided, given the presence of a mass lesion. Neither is there much justification for performing electroencephalography (EEG). Key elements of his management include prompt correction of the severe hyponatremia, and replacement of pituitary deficits, including the administration of stress dose glucocorticoids (dexamethasone or hydrocortisone). Given the compressive optic neuropathy, early surgical sellar decompression via the transsphenoidal route is also indicated. Note that neither mannitol or phenobarbital play a role in the management of pituitary apoplexy.


Discussion

Pituitary apoplexy (PA) is a rare, life-threatening clinical syndrome resulting from a sudden increase in the volume of the pituitary gland, due to infarction or hemorrhage. While there is limited data on the incidence and prevalence of PA, a community-based, cross-sectional study in the United Kingdom estimated a prevalence of 6.2 cases per 100,000 persons, and incidence of 0.17 cases per 100,000 persons/year. The condition most often occurs in the fifth or sixth decades of life; males are slightly more affected than females, with an estimated gender ratio of 2:1. In 60-80% of cases PA represents the first manifestation of a previously undetected pituitary tumor, typically a macroadenoma (which is often nonfunctioning). While the underlying pathophysiology is still not completely understood, it has been postulated that PA may occur when the enlarging tumor outgrows its blood supply, or when the adenoma compresses the infundibulum and superior pituitary arteries; these theories, however, do not explain all cases. Recent studies also suggest that pituitary adenomas may develop abnormal vascularization, making their vessels more susceptible to hemorrhage; a significant correlation between the intratumoral expression of VEGF and TNF╬▒ and the presence of tumor hemorrhage has been found. Rarely, PA may be secondary to non-adenomatous pituitary lesions, including hypophysitis, pituitary metastasis, craniopharyngioma, Rathke's cleft cyst, and sellar tuberculoma. Most cases of PA appear to be spontaneous; only in 40% of instances can a precipitating factor be identified. These include surgery, radiotherapy, hypertension, coagulopathies, provocative pituitary tests, GnRH or somatostatin analogues therapy, dopamine agonist therapy, pregnancy, diabetes mellitus, sickle cell anemia, lymphocytic leukemia and cranial trauma The signs and symptoms of PA are usually rapid in onset, evolving in hours to days. Headache is the most frequent symptom, and is often described as sudden, severe and retro-orbital in location. The presentation also often includes visual disturbances, such as decreased visual acuity, bitemporal hemianopsia or complete blindness; nausea, vomiting, meningismus, cranial nerve palsies (especially of the third cranial nerve), hypopituitarism, and altered mentation. In the vast majority of patients, there is no history suggestive of a pituitary tumor, rending clinical diagnosis difficult; a high index of suspicion is essential. Where PA is suspected, neuroimaging is key to establishing the diagnosis and ruling out other pathologies with a similar presentation. CT is often the first diagnostic study utilized in the emergency setting; it is primarily of value in the first few hours from onset (i.e. the hyperacute stage), where hemorrhages appear isointense or slightly hypointense on MRI images and are thus easily missed. However, CT has low sensitivity for the detection of non-hemorrhagic PA, and can be inconclusive in the latter stages of hemorrhagic PA, where the hemorrhage becomes progressively less hyperdense, and may thus be misdiagnosed as an abscess or cystic degeneration. MRI imaging is of greater diagnostic value; in hemorrhagic PA, the imaging findings depend on the time interval from the event: - in the acute phase (0-7d), the hemorrhage is isointense or slightly hypointense on noncontrast T1-weighted images (T1WI) and hypointense on T2-weighted images (T2W1); thickening of the sphenoid mucosa is particularly suggestive of PA. Following gadolinium, a thin peripheral rim of enhancement may appear; - in the subacute phase (7-21 days), there is focal or heterogeneous hyperintensity on T1WI with increasing signal in T2WI; - in the chronic phase (>21 days), the hemorrhage shows strong hypointensity on both T1WI and T2WI, and lesions have a heterogeneous aspect due to the presence of blood products in various stages; fluid levels within a pituitary mass are specific radiological findings in this phase. Note that non-hemorrhagic PAs appear hypointense on T1 images and hyperintense on T2 images, with no enhancement following contrast administration. Biochemical and endocrinological evaluation is also mandatory. In particular, pituitary function testing helps diagnose secretory pituitary adenomas as well as anterior pituitary deficiencies. Furthermore, hyponatraemia is observed in up to 40% of cases, secondary to hypopituitarism or, less often, inappropriate ADH secretion (SIADH). A multidisciplinary team including an endocrinologist, neurosurgeon and neuro-ophthalmologist should direct the management of these patients; treatment should mainly be dictated by the clinical presentation and presence of comorbidities, with imaging providing important supportive evidence. The first priorities should be hemodynamic stabilization, correction of electrolyte imbalances, and replacement of any pituitary deficits, if present. The administration of stress dose glucocorticoids is useful in all cases with clinical suspicion of, or confirmed hypoadrenalism - particularly if severe neurological or neuro-ophthalmological signs are also present; this not only covers the hypoadrenalism, but also exerts significant anti-inflammatory and anti-edematous effects on the parasellar structures. Patients with a mild, stable clinical picture, including isolated ocular palsies, can be managed conservatively. Continuous careful monitoring is still mandatory because the clinical evolution can be unpredictable, even where the initial presentation is reassuring. For patients with altered vision or mentation, early surgical decompression via the transsphenoidal route is indicated; in cases with deteriorating visual or neurological signs or further enlargement of the sellar mass on serial imaging, a late elective intervention can be performed. Given the risk of tumor recurrence, long-term follow-up, including periodical evaluation of the sellar structures and endocrinological function, is recommended. MRI imaging is recommended between three to six months after the acute event, followed by annual imaging for five years, and biannual imaging afterwards. Hormonal levels must be assessed four to eight weeks after apoplexy and then reviewed annually. Overall, patients with hemorrhagic PA tend to have a worse prognosis than those with the ischemic type. With proper management, the visual and neurological outcomes are favourable in most cases, although the endocrinological outcome is less so, with many patients requiring replacement therapy. Low prolactin levels on presentation are associated with a better chance of pituitary function recovery.


Take home messages

  1. Pituitary apoplexy (PA) is a rare, life-threatening clinical syndrome where there is a sudden increase in pituitary gland volume secondary to acute ischemia or hemorrhage.
  2. PA is most often caused by a pituitary adenoma, which is previously undetected in 60-80% of cases.
  3. Key signs and symptoms include headache, visual disturbances, nausea, vomiting, meningismus, cranial nerve palsies, hypopituitarism and altered mentation.
  4. Neuroimaging is key to detecting the pituitary lesion and ruling out other pathologies; while MRI is the modality of choice, CT may be superior in the hyperacute stage.
  5. The management includes hemodynamic stabilization, correction of electrolyte unbalances, replacement of pituitary deficits and administration of stress dose glucocorticoids; in cases with altered consciousness or vision, early surgery is indicated.

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  1. BOELLIS A, DI NAPOLI A, ROMANO A, BOZZAO A. Pituitary apoplexy: an update on clinical and imaging features. Insights Imaging [online] 2014 Dec, 5(6):753-62 [viewed 24 December 2016] Available from: http://www.ncbi.nlm.nih.gov/pubmed/25315035
  2. CAPATINA C, INDER W, KARAVITAKI N, WASS JA. Management of endocrine disease: pituitary tumour apoplexy. Eur J Endocrinol [online] 2015 May, 172(5):R179-90 [viewed 24 December 2016] Available from: http://www.ncbi.nlm.nih.gov/pubmed/25452466
  3. GLEZER A, BRONSTEIN MD. Pituitary apoplexy: pathophysiology, diagnosis and management. Arch Endocrinol Metab [online] 2015 Jun, 59(3):259-64 [viewed 24 December 2016] Available from: http://www.ncbi.nlm.nih.gov/pubmed/26154095