Continuing Education Activity

Empty sella syndrome (ESS), also known as arachnoidocele, is a radiologic finding in which the sella turcica appears empty due to cerebral spinal fluid (CSF) within the subarachnoid space herniating into the sella turcica. Subsequently, the pituitary gland contained in the sella turcica is compressed and flattened, and the pituitary stalk is stretched by the CSF, which fills the space. Over the years, radiologists noticed a similar phenomenon in CT and MRI brain imaging, further refining the term empty sella. ESS is the condition associated with this finding that may present with symptoms including headache and visual changes. ESS is commonly classified into 2 etiologic categories: primary empty sella (PES), which has no identified underlying cause, and secondary empty sella (SES), which has an identifiable etiology (eg, cerebral trauma and postpartum pituitary necrosis). ESS can be further subdivided into complete and partial types, with the latter referring to the sella turcica being less than 50% filled with CSF and the former being more than 50% filled with CSF.

Due to advances in radiologic technology, the incidence of empty sella has recently increased. Although empty sella has historically been considered an incidental finding without clinical significance, recent evidence suggests that patients may have associated symptoms, otherwise known as ESS, more frequently than previously believed. Consequently, most experts recommend a thorough evaluation in all patients initially found to have empty sella; reevaluation in asymptomatic patients may be reasonable also. Symptomatic patients with ESS should be managed supportively; the type of treatment indicated can vary from pharmacologic (eg, growth hormone replacement) to surgical (eg, lumbar peritoneal shunt) therapies. Because this condition is being identified more frequently and may be associated with more symptoms than previously believed, clinicians should be familiar with this finding and the variety of potential presentations. This activity will enhance the healthcare professional's competence in diagnosing and managing empty sella syndrome and highlight the critical need for collaboration among multidisciplinary team members such as ophthalmology, neurology, and endocrinology clinicians to improve patient outcomes. 

Objectives:

• Differentiate between primary and secondary empty sella syndrome and recognize underlying causes.
• Identify the clinical signs and symptoms of empty sella syndrome to facilitate early diagnosis and intervention.
• Select appropriate imaging modalities to confirm and evaluate Empty Sella Syndrome.
• Coordinate long-term follow-up and treatment adjustments for patients with this condition.

Introduction

Empty sella, also known as arachnoidocele, is a radiologic finding in which the sella turcica appears empty due to cerebral spinal fluid (CSF) within the subarachnoid space herniating into the sella turcica. Subsequently, the pituitary gland contained in the sella turcica is compressed and flattened, and the pituitary stalk is stretched by the CSF, which fills the space.[1][2] Over the years, the term empty sella was adapted further by radiologists incidentally observing a similar phenomenon in CT and MRI brain imaging. 

Due to advances in radiologic technology, the incidence of empty sella has recently increased. Although empty sella has historically been considered an incidental finding without clinical significance, recent evidence suggests that patients may have associated symptoms, otherwise known as ESS, more frequently than previously believed.[3][4] Consequently, most experts recommend a thorough evaluation in all patients initially found to have empty sella; reevaluation in asymptomatic patients may be reasonable also. Symptomatic patients with ESS should be managed supportively; the type of treatment indicated can vary from pharmacologic (eg, growth hormone replacement) to surgical (eg, lumbar peritoneal shunt) therapies.[3][5][1][2]

Because this condition is being identified more frequently and may be associated with more symptoms than previously believed, clinicians should be familiar with this finding and the variety of potential presentations. This activity enhances the healthcare professional's competence in the diagnosis and management of ESS and highlights the critical need for collaboration among multidisciplinary team members such as ophthalmology, neurology, and endocrinology clinicians to improve patient outcomes. 

Etiology

Empty sella is a radiologic finding most often seen incidentally caused by the incompetence of the diaphragm sellae and the resultant herniation of CSF into the sella turcica.[2] ESS is the condition associated with this finding that may present with symptoms including headache and visual changes. ESS is commonly classified into 2 etiologic categories: primary empty sella (PES), which has no identified underlying cause, and secondary empty sella (SES), which has an identifiable etiology (eg, cerebral trauma and postpartum pituitary necrosis). ESS can be further subdivided into complete and partial types, with the latter referring to the sella turcica being less than 50% filled with CSF and the former being more than 50% filled with CSF.[3][5]

The etiology of PES is primarily considered idiopathic; however, there may be some genetic association in individuals with defects resulting in an incompetent diaphragm sellae. In contrast, SES etiologies include surgery, trauma, radiation, hemorrhage, infection, or infarction of the pituitary gland and can occur at any time in an individual's life.[2]

Epidemiology

Empty sella was historically considered a rare entity. The incidence has recently increased, most likely due to advances in imaging studies.[4] Still, the reported incidence is present in 6% to 20% of autopsy cases and is also estimated to be present in around 38% of patients undergoing neuroimaging, more often on MRI than CT.[3] Empty sella occurs more than 5 times more frequently in women. Furthermore, ESS is also more common in obese patients and individuals aged 40 to 60.[6][7] The incidence of ESS, with associated hormonal abnormalities, is estimated to occur in 40% of patients.[3]

Pathophysiology

ESS falls into 2 categories: PES and SES. PES is the less common of the 2 entities. Currently, its cause is not entirely understood. Still, researchers have proposed several mechanisms, including incompetence or complete absence of the diaphragm sellae, chronic intracranial hypertension, small vessel disease, and temporary expansion followed by regression of the pituitary gland.[4] Congenital incompetent diaphragm sellae is thought to be a potential pathophysiologic cause of PES, with the anomalous diaphragm sellae allowing the accumulation of CSF into the sella turcica, causing remodeling and enlargement of the sella turcica and flattening of the pituitary gland.[3]

Intracranial hypertension is also thought to increase the likelihood of herniation of CSF into the sella turcica, especially if the diaphragm sellae is already compromised. The most common neuroimaging finding in patients with idiopathic intracranial hypertension, known as pseudotumor cerebri, is empty sella.[8] Many pathologies causing increased CSF pressures correlate with PES, including brain tumors, idiopathic pseudotumor cerebri, intracranial thrombosis, and hydrocephalus. The resolution of empty sella on imaging after treatment of intracranial hypertension illustrates further evidence that intracranial hypertension can cause empty sella.[9]

Another proposed pathophysiologic mechanism causing empty sella involves an initial enlargement of the pituitary gland followed by a later decrease in gland size, creating a space where CSF can accumulate.[10] Examples include an expected increase in pituitary volume during pregnancy and lactation, followed by spontaneous regression during menopause in women. However, SES, which is more common than PES, can result from various conditions affecting the pituitary gland, including treatment of a pituitary adenoma with medications, surgery, or radiotherapy; spontaneous regression of the pituitary gland; postpartum pituitary necrosis; or lymphocytic hypophysitis.[7]

History and Physical

Although empty sella is often identified incidentally on diagnostic imaging performed for issues not involving the pituitary, patients are frequently diagnosed with visual, neurologic, or hormonal conditions, though the clinical association remains unclear. For instance, ESS has been identified in approximately 40% of individuals with hormonal abnormalities and in up to 94% of patients with intracranial hypertension.[2][3] Therefore, most experts recommend a comprehensive evaluation, even in asymptomatic patients.

In any patient, a thorough clinical history and physical should be obtained. A complete medical history, including obstetric and surgical history, is essential as a clinician may find an underlying etiology for SES (eg, pituitary surgery, recent pregnancy, traumatic head injury, or radiation treatment). History and physical exam findings are typically normal in patients with asymptomatic empty sella because the endocrine function is usually intact. However, in patients with ESS, common symptoms include headache and visual disturbances (eg, diplopia and decreased acuity). Other reported symptoms include dizziness, syncope, amenorrhea, galactorrhea, erectile dysfunction, polydipsia, and polyuria.[3][2] Spontaneous CSF rhinorrhea is also possible, though rare.[11] In recent case reports, rare patients have had unusual signs and symptoms such as hyponatremia and cognitive impairment (eg, dementia).[12][13] 

Physical exam findings of ESS can be normal or include features such as hypertension, endocrine abnormalities (eg, gynecomastia, acromegaly, and signs of hypogonadism), and papilledema. Findings associated with obesity are frequently present, including sleep apnea and increased BMI.[2][3]

Evaluation

Imaging Studies

Clinicians can diagnose empty sella when characteristic findings are seen on diagnostic imaging, typically a head CT or MRI. Diagnostic findings on imaging consist of CSF filling the sellar space, and the remaining pituitary gland is flattened against the sellar floor (see Image. Empty Sella on MRI). The total pituitary volume is often reduced to less than 611.21 mm³. The bony structure of the sella also often appears enlarged. Partial empty sella refers to a sella turcica filled less than 50% with CSF, and complete empty sella refers to a sella filled to more than 50% with CSF; the thickness of the remnant pituitary tissue is ≤2 mm.[2][3]

Laboratory Studies

Testing the entire pituitary axis is appropriate and highly recommended in patients with ESS after diagnosis; however, society-based guidelines are currently lacking.[14][1][15] The pituitary function can be normal despite the abnormal appearance of the pituitary gland. However,  A recent study found that up to half of individuals with PES have some level of pituitary insufficiency.[16] Hyperprolactinemia and growth hormone deficiency appear to be the 2 most common laboratory findings in patients with empty sella.[7][5]

Hyperprolactinemia is present in 10% to 17% of cases resulting from a microprolactinoma or functional hyperprolactinemia.[6][5] Growth hormone deficiency is identified in 4% to 60% of patients, but the clinical significance in adults is unclear.[6][14] Furthermore, gonadotropin deficiency is seen in 2% to 32% of patients, while adrenocorticotropin, thyroid-stimulating hormone, and antidiuretic hormone deficiencies are seen in about 1% of individuals with empty sella.[14] Therefore, most experts recommend that diagnostic studies be obtained to assess for endocrine dysfunction. The laboratory studies suggested for the evaluation of pituitary function in any patient found to have empty sella include:[3]

• Adrenal axis: Early morning fasting cortisol levels are a screening option for adrenocorticotropin (ACTH) deficiency, and overtly low cortisol levels <3.0 mcg/dL are consistent with adrenal insufficiency.[17] Morning cortisol levels >11.0 mcg/dL, though some authors suggest 14.0 mcg/dL, make adrenal insufficiency very unlikely; morning cortisol levels of 3.1 to 11.0 mcg/dL are indeterminant and can warrant further testing, such as ACTH stimulation testing. If the morning cortisol level is low, an ACTH level should be obtained and correlated to the low morning cortisol level to help differentiate primary from secondary adrenal insufficiency. Metyrapone testing can also assist in this diagnosis. If corticosteroid excess is suspected, an ACTH level again must be correlated with cortisol level, and a workup for Cushing disease should be the next step.[2][5]
• Thyroid axis: Morning levels of thyroid-stimulating hormone with free thyroxine (T4) should be evaluated simultaneously.[5]
• Reproductive axis: In premenopausal women with regular menses, gonadotropin and estradiol levels are unnecessary. Women with irregular or absent menses should have follicle-stimulating hormone and luteinizing hormone with estradiol levels assessed; postmenopausal women most likely do not. A testosterone level with simultaneous luteinizing hormone and follicle-stimulating hormone levels should be obtained in men.[5]
• Prolactin: Prolactin levels should be evaluated as prolactin abnormalities are prevalent, with hyperprolactinemia found more than Prolactin deficiency. Prolactin elevations can also be seen in many conditions unrelated to ESS (eg, medications and pregnancy). Therefore, abnormalities must be correlated with the entire clinical presentation.
• Growth hormone, excess or deficiency: Growth hormone has a short half-life and is pulsatile throughout the day, so measuring serum levels is not a common practice. Insulin-like growth factor 1 can be used instead as a screening measure. However, normal insulin-like growth factor 1 levels do not rule out growth hormone deficiency. Some experts recommend stimulation testing to rule out the possibility of growth hormone deficiency.[14] The gold standard testing for growth hormone deficiency is the insulin tolerance test. Additional testing options include the growth hormone-releasing hormone plus arginine test, the glucagon stimulation test, and the macimorelin test.[18]
• Antidiuretic hormone: Antidiuretic hormone levels are not typically measured, but the clinician should inquire about the frequency of urination, including nocturia, to rule out the possibility of diabetes insipidus. If suspicious of diabetes insipidus, serum sodium, serum osmolality, and urine osmolality should be obtained. In rare case reports, hyponatremia was the presenting sign of empty sella.[12]

Treatment / Management

While no established guidelines for managing ESS exist, most experts advise providing supportive care for symptomatic individuals. If hormone imbalances are identified, treatment is tailored to address these specific issues. For example, individuals with hypopituitary impairment may receive cortisol replacement therapy, while those with hyperprolactinemia could benefit from dopamine agonist treatment.[3][1][2][19] Treatment options for intracranial hypertension in patients include pharmacologic therapies like oral acetazolamide (250-500 mg daily) or escin (100-250 mg daily) and surgical placement of a ventricular-peritoneal shunt. The choice among these options depends on clinical indications and guideline recommendations. Additionally, ongoing follow-up is essential to monitor any underlying conditions.[5][3]

For asymptomatic individuals without hormone abnormalities, there is limited evidence of clinically significant progression.[16][3] Recommendations for managing such cases are scarce, but some sources suggest periodic clinical assessments and diagnostic studies every 2 to 3 years or as needed.[5][3]

Differential Diagnosis

Empty sella is a radiologic finding and diagnosis. Some differential diagnoses include:

• Pituitary tumors
• Idiopathic pseudotumor cerebri
• Intracranial thrombosis
• Hydrocephalus
• Pituitary cystic lesions
• Congenital pituitary abnormalities
• cystic prolactinomas 
• Craniopharyngioma
• Arachnoid cyst [20][2][5][9]

Prognosis

EES, usually benign, does not impact life expectancy. The prognosis depends on the specific hormone imbalance if present. Based on current evidence, asymptomatic individuals without hormone abnormalities typically show minimal clinical progression.[16][3]

Complications

As mentioned earlier, potential empty sella complications include partial or complete hypopituitarism or hormone overactivity. Furthermore, patients with primary empty sella (eg, Cushing disease) and radiographic disruption of the pituitary stalk may experience worse outcomes following pituitary surgery.[21][22]

Deterrence and Patient Education

Patients cannot take specific actions to prevent this occurrence, but they should understand the importance of assessing their hormone levels at the initial diagnosis. Additionally, asymptomatic individuals without signs of hormone abnormalities should be informed that there is limited evidence of significant clinical progression. However, they should seek periodic clinical evaluations and diagnostic studies if clinically indicated.[16][3][5]

Enhancing Healthcare Team Outcomes

ESS is a rare condition typically discovered by chance during brain imaging when evaluating complaints like headaches. Although only a small number of these patients have hormone deficiencies, performing a comprehensive pituitary hormone assessment upon diagnosis and referring patients to an endocrinologist are essential.

The best approach to managing ESS involves an interprofessional team of specialized and primary care clinicians who provide ongoing follow-up, educate patients and their families, and coordinate care. This collaborative effort should also include technicians responsible for imaging and laboratory tests. Given the increasing incidence and various presentations of ESS, healthcare professionals should continue to work together across disciplines, such as ophthalmology, neurology, and endocrinology, to diagnose and assess ESS patients accurately, ultimately improving their outcomes.

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References

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Disclosure: Peter Ucciferro declares no relevant financial relationships with ineligible companies.

Disclosure: Catherine Anastasopoulou declares no relevant financial relationships with ineligible companies.