Clinical presentation, evaluation and case management of primary empty sella syndrome: a retrospective analysis of 10-year single-center patient data

Empty Sella (ES) is a rare pituitary condition often characterized by the herniated appearance of the pituitary, making it appear flattened with partial or complete filling of the sella turcica space by cerebrospinal fluid. Although the term is referred to as ‘empty’, the pituitary may still function normally. The severity of the syndrome depends on the absence of one or more pituitary hormones due to the extent of involvement of pituitary stalk. The empty sella has been categorized as primary empty sella or secondary empty sella based on the etiology, which is mostly unclear while many hypotheses have been proposed. The congenital absence of diaphragm sellae is the only established etiology for PES, while other causes may include relative changes in intracranial pressure from the cerebrospinal fluid (CSF). And secondary empty sella may result from secondary causes like traumatic factors, side effects of radiotherapy and drugs, infections and necrosis, pituitary tumors or even autoimmune-related [1]. Although the term was first coined by Busch in 1951, Schaeffer, in 1924 first observed the sellae in 125 patients and described the radiological variations from dense to a small peripheral rim of the sellar space [2]. In general, the aetiology of empty sell is not clear and many hypotheses have been studied. The cause of empty sella is either primary (idiopathic) and most likely related to congenital defect in diaphragmatic sella or secondary (acquired) due to pituitary surgery, radiation and pituitary apoplexy. The most common clinical presentation of empty sella syndrome is persistent headache and hormonal deficiencies are rare as clinical presentation for that reason in our paper as in others the diagnosis of empty sella is incidental finding during the work up of neurological symptoms. Since hormonal deficiencies are rare and most likely acquired, the growth and the sexual development less likely to be affected.

Once considered a rare disorder, diagnosis of ES has been increasing since it is primarily regarded as an incidental finding on brain imaging scans like Magnetic Resonance Imaging (MRI) predominantly, Computed Tomography (CT), or rarely plain X-ray. However, very often the patient may present with various symptoms which are attributed to PES in the absence of any other likely causation. The clinical significance related to the incidental finding is ambiguous and some studies elucidate it to more than a mere incidental finding [3]. Several isolated case reports and case series have been published over the last three decades [4] and statistics collectively from single-centerr or multicenter retrospective studies have reported prevalence as low as 2.3% [1] to as high as 38% [5] in autopsy studies with large predominance in the female gender.

Studies from the Saudi Arabian region are scanty except a report from the western region documenting a brief description of 537 patients with PES without exploring further details on clinical significance, the symptoms and hormonal assessments Moreover, no specific guidelines or recommendations exist in the diagnosis and management of PES, resulting in the majority of the cases being managed without a referral to an endocrinologist. However, experts in the field have advised endocrine assessment of even the asymptomatic cases and a multi-disciplinary approach in the management of PES [6]. The objective of the present study is to report a 10-year retrospective review of primary empty sella from a single-center registry, aiming to determine the epidemiology, clinical presentation and management of PES, and to identify the differences in investigations and diagnosis of PES between endocrinologists and non endocrinologists in a tertiary care setting.”

Ten-year retrospective data of PES cases was extracted and analysed from the radiology and imaging unit of the tertiary care referral hospital.

Data extraction: The study population comprised of patients who underwent MRI of brain at the radiology unit from 1st July 2007 to 30th June 2017. The keyword ‘Primary Empty Sella’ was used to extract the data. A total of 26,218 patients had undergone MRI in this period and 765 patients were diagnosed to have PES. The most common indications for MRI of the brain included headache, traumatic brain injury, neurological symptoms like stroke and Transient Ischemic Attack. Diagnosis of PES was made if there was i) enlargement of the sella turcica, ii) filling of the sella turcica with CSF and iii) compression and flattening of the pituitary gland against the sella floor. The medical identification number of the PES patients was retrieved to include further details of clinical presentation, hormone profiles and whether the diagnosis was an incidental finding. Upon an incidental finding, the cases were subjected to confirmation by biochemical investigations.

To define hormonal deficiency for each axis, the case would be termed ‘affected’ if: gonadal hormonal deficiency was based on low testosterone in male or estradiol in female with low or inappropriately normal LH and FSH level, the thyrotrophic axis deficiency was defined based on low free T4 and low or low normal TSH level, for corticotroph axis to be considered affected if morning plasma cortisol is less than 100 nmol/l and confirmed by failure to respond to ACTH stimulation by short synacthin test, somatotroph axis was considered affected if IGF-1 level is low for the age-adjusted range in the presence of 3 or more affected axes. The description of each hormonal deficiency is tabulated accordingly;

The results of the assays are entered in the centralized electronic health record system of the hospital that can be accessed by all those physicians and healthworkers who are authenticated to its use. Patients who had deficiencies in hormonal profile were referred to as ‘affected. Those who had no evidence of hormonal deficiency despite proven to have PES radiologically were termed as ‘not affected’. Only some cases were referred to the endocrinologists for complete hormonal evaluation.

Ethics approval: The study approval was obtained by the Institution’s Review Board (IRB), College of Medicine, with a reference number of 19/067/IRB-CM. No disclosure of patient identity was made and the data collected was meant solely for the purpose of research.

The registry had enrolled 765 patients with PES in the 10-year period since 2007. Higher female preponderance was noted with 607 females and 158 males. The clinical presentation of PES patients is shown in Table 1. The mean age at diagnosis of the study patients was 48.4 ± 14.8 years and the men showed a lower mean age than women. Occurrence of PES was more common in both male and female patients older than 50 years. Younger males aged less than 29 years showed a higher prevalence of PES than females of the same age. Although it did not reach statistical significance, women presented with symptoms more often than men. While 79% of the cases were diagnosed as incidental findings during MRI scans, only 20% were referred to and seen by the endocrinologists. Further analysis showed that almost 42% of the incidental cases were symptomatic. The most common symptoms reported were headache, visual disturbance including diplopia, nystagmus, fatigue, galactorrhea, infertility and menstrual-related problems. Men had significantly higher gonadal disorders like infertility and diminished libido. Other reported non-specific symptoms include tinnitus, nausea, lack of growth, dizziness or vertigo, seizures, weakness/numbness of head and neck or extremities or body sides, acute behavioral changes, ataxia and dysarthria, delusion, memory loss and myalgia.

Table 2 shows the details of evaluation and clinical management of the patients. The general physicians handled 80% of the cases, and of them, more than 90% were not assessed for gonadal, growth and adrenal hormones. Furthermore, the details of those affected by the hormonal deficiencies are also displayed. Although the endocrinologists had only 20% of the total PES cases, hormonal assessment was still markedly under-evaluated. In addition, the affected among those assessed are summarized in decreasing order of prevalence in Fig. 1.

Table 3 provides the general biochemical profile of the PES patients under hormone replacement therapy. Table 4 illustrates the distribution of pituitary hormone levels in PES patients, in addition to the assessment statistics of individual hormones. The categorization of values as low, normal and high is based on reference range, where low and high values are referred to as abnormal. Pituitary dysfunction is referred to two to three hormonal deficiencies (multi-hormonal deficiency) or three or more hormonal deficiencies (panhypopituitarism) as presented graphically in Fig. 2. Males showed higher levels of pituitary dysfunction than females. Hypogonadism was the most frequent disorder observed, followed by hypothyroidism and hypocortisolism.

Other related disorders: Behcet syndrome was found in four patients and two patients were diagnosed with Woodhouse-Sakati syndrome. There were two cases with high levels of prolactin indicating a diagnosis of prolactinoma.

The present study analyzed the clinical presentation and management of the PES patients. The clinical picture of patients with PES is quite intricate due to the involvement of the extent of hormones from none to all. Since the causation mechanism is not established, it is not clear if the symptoms are due to PES or coincidental. There is extreme variation in the prevalence of endocrine abnormalities reported with PES ranging from normal pituitary function to certain grades of pituitary dysfunction depending on the pituitary stalk compression by CSF or intracranial hypertension. Except for few comprehensive reviews reporting the clinical diagnosis and management, there are no standard guidelines available for the diagnosis and management of PES, which has resulted in case-handling by non-endocrinologists and under-evaluation of hormones [6]. Primary empty sella syndrome (PES) is considered one of the causes of hypopituitarism. Structural causes of hypopituitarism like pituitary adenoma, pituitary abscess, apoplexy, and traumatic brain injury are associated with sequential pattern of hormonal deficiencies starts with Usually, the development of hypopituitarism occurs in a sequence of loss of function of the somatotrophic axis, subsequently followed by gonadotrophin, thyrotrophic, and finally corticotrophic axis, due to the anatomical location of the somatotropic, gonadotropic, thyrotropic, and corticotropic cells, respectively. Whether this sequence is respected in empty sella or not is uncertain. Usually, low IGF-1 levels are the first sign of hypopituitarism, but normal levels should not exclude the presence of dysfunctions in other axes, particularly in patients with empty sella, for which the patterns of hormonal dysfunctions, if any, remains to be characterized [7]. Hormonal deficiencies in PES can follow similar pattern if underlying causes of PES are related to the mentioned structural pathology before the time of the diagnosis of PES. Hormonal deficiency can be isolated single hormone or multiple hormonal deficiencies affecting all the hypothalamic-pituitary axeses. Symptomatic hyperprolactinemia in PES is rare in general but some patients might present with symptoms related to high prolactin. Hormonal alteration in PES is an area of controversy and it is not clear cut in most of the studies and accurate biochemical diagnosis is advocated. The most important part in hormonal assessment is to do basal hormonal assessment and dynamic testing only if it is indicated.

The findings may point towards poor case referrals to endocrinologists and sub-optimal assessment of hormonal profile. Evidence suggests that PES can mostly be an incidental finding without any symptoms [8]. In our experience, PES was mostly, also, an incidental finding diagnosed during radiological imaging of brain studies and hence not all patients had undergone endocrine evaluation. Gross under-evaluation of hormonal assessment is one of the significant findings of the present research, although almost 42% of the patients were symptomatic and presented with variable clinical features. This, however, precludes the possibility of overlooking PES as an incidental finding and demonstrates the role of endocrinologists being the cornerstone in the assessment and management of hormonal deficiencies.

In addition, the challenges of the diagnoses of central hormonal deficit since the central hormones may either be inappropriately normal, or mildy below the lower normal range may also lead to underdiagnosis of empty sella-related hormonal dysfunctions.

The findings of the study denote PES to be more than an incidental finding since high prevalence of co-existing endocrine abnormalities were found. Most of the cases are not properly evaluated by non-endocrinologists due to lack of appropriate loop feedback from the primary gland to the pituitary which is part of normal physiological response to the absence of primary gland function and make it difficult and challenging to non-endocrinologist to recognize the above abnormalities in different axes based on the available normal range values of the hormones. Lack of referral to endocrinologists and gross under-evaluation of hormonal assessment pointed towards poor clinical management and risk of being not replaced for the deficit hormones. This is our main concern with considerable clinical implications.