Factors Determining the Clinical Significance of an Empty Sella Turcica

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1 Neuroradiology/Head and Neck Imaging Original Research Saindane et al. MRI of Empty Sella Turcica Neuroradiology/Head and Neck Imaging Original Research Amit M. Saindane 1 Paolo P. Lim 1 Ashley Aiken 1 Zhengjia Chen 2 Patricia A. Hudgins 1 Saindane AM, Lim PP, Aiken A, Chen Z, Hudgins PA Keywords: empty sella turcica, idiopathic intracranial hypertension, MRI DOI: /AJR Received April 3, 2012; accepted after revision May 13, Presented at the 2011 annual meeting of the American Society of Neuroradiology, Seattle, WA. 1 Department of Radiology and Imaging Sciences, Emory University Hospital, 1364 Clifton Rd NE, BG22, Atlanta, GA Address correspondence to A. M. Saindane (asainda@emory.edu). 2 Department of Biostatistics & Bioinformatics, Emory University School of Medicine, Atlanta, GA. AJR 2013; 200: X/13/ American Roentgen Ray Society Factors Determining the Clinical Significance of an Empty Sella Turcica OBJECTIVE. Although often incidental, the empty sella turcica can reflect chronically elevated intracranial pressure (ICP). It is particularly common in the setting of idiopathic intracranial hypertension (IIH). This study evaluated which clinical and MRI findings could be used to differentiate patients with chronically elevated ICP from those with incidental empty sella turcica. MATERIALS AND METHODS. Forty-five patients with definite IIH and 92 patients with empty sella reported on brain MRI were evaluated. Measurements of the sella turcica, diaphragm sella, pituitary gland, infundibulum, and scalp and neck soft tissues were made on MR images. These measurements, age, sex, clinical symptoms, and frequency of previously reported orbital findings of IIH were compared between the IIH and incidental empty sella turcica groups. Measurements on MRI were correlated with patient age in each group. RESULTS. The IIH and incidental empty sella turcica groups had statistically similar sellar, pituitary, and infundibular measurements. The patients with IIH were significantly younger than the patients with incidental empty sella turcica (mean age, 36.1 vs 54.3 years, respectively; p < 0.05); were more likely to report headache (93.3% vs 32.6%; p < 0.05) and visual complaints (66.2% vs 28.3%; p < 0.05); showed greater mean scalp thickness (9.0 vs 6.4 mm; p < 0.05) and neck soft-tissue thickness (19.5 vs 13.8 mm; p < 0.05); and were more likely to have an orbital finding suggestive of IIH (93% vs 14%). Age modestly correlated with the width of the diaphragm sella (r = 0.53) in the IIH group only. CONCLUSION. The significance of the MRI finding of an empty sella turcica can be determined using a combination of clinical and imaging findings. T he empty sella turcica is characterized by intrasellar herniation of suprasellar arachnoid and subarachnoid space CSF, resulting in flattening of the pituitary gland. Chronically transmitted CSF pulsations from the herniated subarachnoid space often lead to bony expansion and remodeling of the sella turcica. The empty sella turcica has been associated with elevated intracranial pressure (ICP); posteriorly placed optic chiasm; and a reduction in pituitary gland volume due to menopause, multiparity, pituitary gland infarction, diabetes, or bromocriptine treatment [1 5]. In most cases, however, the empty sella turcica is considered an incidental finding and is considered a normal variant related to a deficiency in the diaphragm sella [6 9]. In the absence of surgery, radiation therapy, or medical therapy for an intrasellar tumor, this entity has been termed a primary empty sella turcica [6]. Idiopathic intracranial hypertension (IIH), also known as pseudotumor cerebri, is a syndrome of unknown cause that results in elevated ICP without an intracranial mass lesion or hydrocephalus [10, 11]. Most patients with IIH have headaches, tinnitus, diplopia, and transient visual obscurations associated with papilledema [12, 13]. Symptoms can be improved with a reduction of CSF pressure through pharmacologic therapy or CSF diversion procedures. If untreated, chronically elevated ICP may lead to permanent vision loss [14, 15]. Although the diagnosis of IIH is based on clinical findings and elevated CSF pressure on lumbar puncture in the setting of normal neuroimaging findings [10, 11], orbital findings on CT and MRI are commonly seen in patients with IIH. These CT and MRI findings include flattening of the posterior sclera, distention of the perioptic nerve subarachnoid CSF space, vertical tortuosity AJR:200, May

2 Saindane et al. of the optic nerve sheath complex, and protrusion or enhancement of the prelaminar optic nerve [16]. However, these imaging findings lack sufficient sensitivity or specificity to be diagnostic of the cause of elevated ICP, such as IIH [17]. The empty sella turcica is the most commonly described imaging sign in the setting of IIH and presumably is an imaging correlate of chronically elevated ICP [17 20]. On MRI, the empty sella turcica is shown by varying degrees of flattening of the superior surface of the pituitary gland and by CSF-intensity signal in the sellar confines and is often associated with enlargement and remodeling of bony sella turcica. An anatomic defect in the diaphragm sella has been shown in up to 50% of adults [21, A C D Fig. 1 Techniques for measuring sella turcica, infundibulum, optic chiasm, scalp fat, and neck fat on MRI. A, Magnified midsagittal T1-weighted image through sellar region shows anteroposterior distance of diaphragm sella (1), anteroposterior distance of infundibulum along diaphragm sella (2), and maximum anteroposterior dimension of sella (3). B, Magnified midsagittal T1-weighted image through sellar region shows maximum craniocaudal dimension of sella (4) and craniocaudal distance of optic chiasm above diaphragm sella (5). C, Midsagittal contrast-enhanced T1-weighted image shows scalp fat at level of coronal suture (6). D, Midsagittal contrast-enhanced T1-weighted image shows neck fat at C2 C3 interspace level (7). 22], and the overall incidence of an empty sella turcica on imaging has been estimated at 12% [23]. In contrast, the incidence of IIH is relatively rare, estimated at approximately 1 case per 100,000 [24] individuals. Therefore, most patients showing an empty sella turcica on imaging will not have IIH and should not require further diagnostic evaluation for the condition. The purpose of this study was to determine whether a patient with an imaging finding of an empty sella turcica can be confidently classified as a case of incidental empty sella turcica or as a case of empty sella turcica associated with IIH using a combination of patient demographics; presenting clinical symptoms; measurements of the pituitary gland, infundibulum, and sella turcica; orbital findings; and measurements of subcutaneous B fat thickness (as a correlate of obesity, which is common in IIH) [25, 26]. Materials and Methods Patient Selection Institutional review board approval was obtained, and informed patient consent was not required for the retrospective review of the medical records and imaging studies for this study. The electronic medical records were searched from January 2008 through August 2010 for MRI reports containing the terms idiopathic intracranial hypertension, pseudotumor cerebri, IIH, or benign intracranial hypertension. This search yielded 71 patients; of those cases, 26 did not meet the inclusion criteria of having both a clinical diagnosis of IIH based on Dandy criteria [11] documented in the medical record and sagittal T1-weighted images available for review. Thus, the remaining 45 patients were included in the IIH group. A search of MRI reports from January 2008 through August 2010 for the terms empty sella, empty sella turcica, partially empty sella, partially-empty sella, CSF filled sella, CSF-filled sella, flattened pituitary, flattening of pituitary, flattening of the pituitary, intrasellar arachnoid cyst, sellar arachnoid cyst, or arachnoid cyst of the sella yielded 657 reports. We excluded patients without an otherwise normal MRI examination (any intracranial abnormality present), patients with a history of pituitary surgery or a known diagnosis of a pituitary tumor, patients whose records lacked sagittal T1-weighted images for review, and patients who had a documented diagnosis of IIH or who were under evaluation for IIH; this yielded 92 patients for inclusion in the incidental empty sella turcica group. The indication for brain MRI in the group with incidental empty sella turcica was headaches (n = 17), metastatic workup for known non-cns malignancy (n = 9), dizziness (n = 7), mental status change (n = 7), seizure disorder (n = 7), dementia (n = 6), paresthesias or numbness (n = 6), hearing loss (n = 5), ataxia (n = 3), tinnitus (n = 3), weakness (n = 3), tremor (n = 1), disorder of smell or taste (n = 1), and nystagmus (n = 1). There were seven patients with endocrinologic indications for the MRI examination: hyperprolactinemia (n = 4), hyperglycemia (n = 2), and infertility (n = 1); however, none of these patients had evidence of pituitary tumor on MRI. Nine patients with incidental empty sella turcica had visual symptoms that were the primary indications for MRI: diplopia (n = 2), blurry vision (n = 3), optic atrophy (n = 2), and pseudopapilledema (n = 2). All nine of these patients were referred by a neuroophthalmologist who had documented the absence of papilledema on funduscopic examination AJR:200, May 2013

3 MRI of Empty Sella Turcica MRI Technique and Data Analysis MRI was performed at either 3 T (Trio, Siemens Healthcare) or 1.5 T (Avanto, Siemens Healthcare; or Signa, GE Healthcare) using a standard head coil. Although the imaging protocol varied, all patients in both groups had sagittal T1-weighted images for review, as well as axial T1- and T2-weighted images. Sixty-four patients in the incidental empty sella turcica group and 37 patients in the IIH group had contrast-enhanced sequences after a standard dose (0.1 mmol/kg) of IV contrast material (gadobenate dimeglumine [MultiHance, Bracco Diagnostics]). Images were reviewed in consensus by an experienced neuroradiologist and a neuroradiology fellow. The following measurements were recorded on the midsagittal T1-weighted images (Fig. 1): estimated anterior-posterior (anteroposterior) length of the diaphragm sella (in millimeters), maximum anteroposterior dimension of the sella (in millimeters), maximum craniocaudal dimension of the sella (in millimeters), anteroposterior distance from the anterior diaphragm sella to the pituitary stalk (in millimeters), and craniocaudal distance of the optic chiasm from the diaphragm sella. Pituitary A D B E Fig. 2 Midsagittal T1-weighted images through sella turcica show categories of pituitary tissue height based on system proposed by Yuh et al. [20]. A, Category I, normal. B, Category II, mild superior concavity (less than one third height of sella). C, Category III, moderate concavity (between one third and two thirds of height of sella). D, Category IV, severe concavity (more than two thirds of height of sella). E, Category V, no visible pituitary tissue. tissue height on the sagittal T1-weighted images was classified into one of five categories using the system of Yuh et al. [20]: I, normal; II, mild superior concavity (less than one third of the height of the sella); III, moderate concavity (between one third and two thirds of the height of the sella); IV, severe concavity (more than two thirds of the height of the sella); and V, no visible pituitary tissue. Examples of each of these categories are depicted in Figure 2. Subcutaneous fat thickness was measured orthogonal to the coronal suture and posteriorly at the level of C2 C3. Reviewers were blinded to the clinical indication for imaging and the diagnosis of IIH. They evaluated each patient s full set of images for the following imaging findings: increased perioptic nerve CSF, flattening of the posterior sclera, protrusion of the optic disc, and vertical tortuosity of the intraorbital optic nerve. The electronic medical records were reviewed and the presence or absence of the following was recorded: headache, visual symptoms (including transient visual obscurations and double vision), clinical evidence of papilledema or secondary optic atrophy, and known pituitary-related endocrine dysfunction (laboratory results indicating hypofunction or hyperfunction). Statistical Analysis The chi-square or Fisher exact test was used to compare the following characteristics of the IIH and incidental empty sella turcica groups: sex; frequency of presenting clinical symptoms of headache, visual complaints, known papilledema, and known pituitary-related endocrine dysfunction; and frequency of orbital findings. Age and MRI measurements of the sella and infundibulum were compared between the two groups using a Student t test, and pituitary grade was compared between the two groups using the Wilcoxon rank sum test. MR measurements of the sella, infundibulum, and scalp and neck fat thicknesses were correlated with patient age for the two groups using a Pearson coefficient, and pituitary grade was correlated with patient age for each group using a Spearman coefficient. Results Nearly all patients in the IIH group (96%) and all patients in the incidental empty sella turcica group (by definition) showed some C AJR:200, May

4 Saindane et al. TABLE 1: Differences in Clinical Presentation and MRI Findings Between Patients With Idiopathic Intracranial Hypertension (IIH) and Patients With Incidental Empty Sella Turcica degree of empty sella turcica on MRI, as defined by a pituitary grade of II, III, IV, or V. Comparisons of age, sex, sellar measurements, and scalp and neck fat measurements and frequencies of orbital findings and clinical symptoms of the two groups are summarized in Table 1. The mean age of the IIH group (36.1 years [SD, 11.7]; range, years) was significantly lower (p < ) than that of the incidental empty sella group (54.3 years [SD, 14.3]; range, years). Both groups were predominantly female (IIH vs empty sella, 44/45 [97.8%] vs 78/92 [84.8%]), but there was a significantly greater percentage of females in the incidental empty sella turcica group (p = 0.02). IIH patients were significantly more likely to have headache and visual complaints than the patients with incidental empty sella turcica. All the patients in the IIH group had documented papilledema, whereas review of the medical records did not reveal papilledema in any of the patients in the incidental empty sella turcica group. Both groups had extremely low reported rates of pituitary-related endocrine dysfunction in the medical record that did not differ significantly. The infundibulum was reliably seen on sagittal images of all patients, allowing the measurements described. All of the MRI measurements related to the sella and infundibulum (estimated anteroposterior width of the diaphragm sella, maximum anteroposterior dimension of the sella, maximum craniocaudal dimension of the sella, anteroposterior position of the infundibulum relative to the diaphragm sella, and craniocaudal distance of the optic chiasm from the diaphragm sella) did not significantly differ between the two groups. The pituitary grade, however, was significantly higher in the incidental empty sella turcica group than the IIH group (p < ). Incidental Empty Sella Turcica (n = 92) IIH (n = 45) p a Demographic and clinical parameters Age (y), mean (SD) 54.3 (14.3) 36.1 (11.7) < Sex, % of female patients b Presence of headache, % of patients < c Presence of pituitary dysfunction, % of patients c Presence of visual complaints, % of patients b Presence of papilledema or secondary optic atrophy, % of patients < MRI measurements (mm) Anteroposterior length of diaphragm sella, mean (SD) (2.3) (2.6) 0.91 Maximum anteroposterior dimension of sella, mean (SD) (3.1) (2.3) 0.30 Maximum craniocaudal dimension of sella, mean (SD) (3.4) (2.5) 0.86 Anteroposterior distance of infundibulum along diaphragm sella, mean (SD) 9.46 (2.0) 9.22 (2.1) 0.53 Craniocaudal distance of optic chiasm from diaphragm, mean (SD) 1.70 (1.3) 1.93 (1.2) 0.74 Pituitary grade, mean (range) IV (II V) IV (I V) < d Fat measurements (mm), mean (SD) Scalp fat 6.35 (2.5) 9.00 (2.5) < Neck fat (4.9) (5.3) < MRI orbital findings, % of patients Increased perioptic nerve CSF < c Flattened posterior sclera < b Protrusion of optic disc < c Vertical tortuosity of optic nerve c a Statistical analysis was performed using a Student t test except when noted otherwise. Boldface indicates difference between groups was statistically significant. b Chi-square test. c Fisher exact test. d Wilcoxon rank sum test. Patients with IIH showed significantly greater scalp fat thickness at the level of the coronal suture and greater neck fat thickness than the incidental empty sella turcica group (both, p < ). Figure 3 depicts scalp and neck fat measurements in representative patients from both groups. Correlations of the MRI measurements with age for both groups are listed in Table 2. The estimated anteroposterior dimension of the diaphragm sella, maximum anteroposterior dimension of the sella, maximum craniocaudal dimension of the sella, anteroposterior position of the infundibulum relative to the diaphragm sella, and pituitary grade showed significant age-related increases in the IIH group but not in the incidental empty sella turcica group. Figure 4 shows a plot of the anteroposterior dimension of the diaphragm sella versus age in both groups. The optic chiasm height did not show an age-related corre AJR:200, May 2013

5 MRI of Empty Sella Turcica lation in either group. Scalp fat exhibited an age-related correlation (Pearson correlation coefficient, 0.27; p = 0.01) in the incidental empty sella turcica group but not in the IIH group. There were no correlations between neck fat thickness and age in either group. A Discussion The empty sella is a term used to describe a spectrum of findings related to the bony sella turcica and pituitary gland, ranging from mild superior concavity of the pituitary gland to apparent absence of the gland and CSF expansion of the bony confines of the sella turcica. Milder appearances without bony expansion and lesser degrees of pituitary compression are often referred to as a partially empty sella. Frequently during the course of interpreting a brain MRI study, some degree of an empty sella turcica is observed. Because the finding may be seen incidentally (incidental empty sella turcica) or pathologically as a manifestation of IIH, it would be helpful to advise clinicians about which patients should be evaluated further for IIH, including funduscopic evaluation and lumbar puncture with CSF pressure measurement, and which patients might not need further workup for elevated ICP. In this study, we evaluated patients with an MRI finding of an empty sella turcica but no known diagnosis of IIH (i.e., incidental empty sella turcica) and patients with an MRI finding of an empty sella turcica and a clinical diagnosis of IIH. Not surprisingly, the most important features that suggested the diagnosis of IIH were clinical findings including younger patient age; increased scalp thickness and neck fat thickness; and presence of headache, visual symptoms, papilledema, and orbital findings suggestive of IIH. Although none of these factors alone can distinguish between patients with IIH and those with incidental empty sella turcica, taking into account the presence or absence of each B Fig. 3 Scalp and neck fat measurements in patient with incidental empty sella turcica and patient with idiopathic intracranial hypertension (IIH). A, Midsagittal T1-weighted image of 52-year-old woman with incidental empty sella turcica (category IV empty sella turcica) shows relatively little scalp fat at level of coronal suture (short arrow) and at posterior neck at C2 C3 level (long arrow). B, Midsagittal contrast-enhanced T1-weighted image of 37-year-old woman with IIH (category IV empty sella turcica) shows abundant scalp fat at level of coronal suture (short arrow) and at posterior neck at C2 C3 level (long arrow). Sella turcica and pituitary gland appear similar in both patients. TABLE 2: Correlation of MRI Measurements With Age for Patients With Idiopathic Intracranial Hypertension (IIH) and Patients With Incidental Empty Sella Turcica MRI Measurements Incidental Empty Sella Turcica (n = 92) IIH (n = 45) r a p b r a p b Anteroposterior length of diaphragm sella Maximum anteroposterior dimension of sella Maximum craniocaudal dimension of sella Anteroposterior distance of infundibulum along diaphragm sella Craniocaudal distance of optic chiasm from diaphragm Scalp fat Neck fat Pituitary grade 0.19 c c a Pearson correlation coefficients unless noted otherwise. b Boldface indicates difference between groups was statistically significant. c Spearman correlation coefficient. of these features in the setting of an empty sella turcica can improve confidence in proposing the diagnosis and workup for IIH or dismissing the finding as an incidental empty sella turcica. In this study, no difference was found in the measurements of the sella between the IIH patients and the incidental empty sella turcica patients. This finding suggests that the effect of elevated ICP on the sella turcica and pituitary gland in IIH is not unique and that the appearance itself is nonspecific. Varying appearances of empty sella turcica have been described with IIH [20]. A scatterplot of the size of the diaphragm sella versus age (Fig. 3) shows that the diaphragm sella may actually widen more over time in the IIH group as a result of the elevated ICP, whereas the lack of a correlation in the incidental empty sella turcica group suggests that size is a function of a preexisting defect in the diaphragm sella that may not increase AJR:200, May

6 Saindane et al. Anteroposterior Width of Diaphragm Sella (mm) IIH Incidental empty sella turcica significantly or that may increase more slowly over the age range listed under conditions of normal ICP. The significant difference in pituitary grade between the two groups may be related to this age dependence in the IIH group, because these patients were significantly younger than patients in the incidental empty sella turcica group. The absence of significant differences in any of the specific measurements of the sella argues that the extent of the empty sella should not be used to decide whether or not the patient is symptomatic from the finding. The IIH group was more likely than the incidental empty sella turcica group to have one or more orbital finding of increased perioptic nerve CSF, flattening of the posterior sclera, protrusion of the optic disc, and vertical tortuosity of the intraorbital optic nerve. These orbital findings have been significantly associated with IIH [19, 27]; however, according to Agid and Farb [17] and Agid et al. [28] et al., posterior globe flattening is the only sign that strongly suggests the diagnosis of IIH (specificity, 100%; sensitivity, 43.5%; positive likelihood ratio, 49.7). Because patients with an incidental empty sella turcica do not have elevated ICP, MRI correlates of papilledema should not be present. The most common orbital finding in the incidental empty sella turcica group was increased CSF surrounding the optic nerve intraorbital segment. The results of this study show, as previously described in Age (y) Fig. 4 Scatterplot shows age-related correlation of anteroposterior width of diaphragm sella in patients with idiopathic intracranial hypertension (IIH) and patients with incidental empty sella turcica. Solid black line depicts linear trend line for IIH group (r = 0.53; p = ), whereas dotted line represents linear trend line for incidental empty sella turcica group (r = 0.13; p = 0.21 [not significant]). the literature [17, 28], that this finding is a relatively nonspecific sign for chronically elevated ICP. Rohr et al. [29] found that a combination of at least two imaging signs including optic nerve sheath hydrops, reduction in pituitary height, and venous outflow obstruction discriminated between patients with elevated ICP from a variety of causes and age-matched control subjects. Scalp and neck subcutaneous fat thicknesses were significantly greater in the IIH group than in the incidental empty sella turcica group. These findings have not been previously reported, but as a potential crude imaging marker of body mass index (BMI), subcutaneous fat thickness would be expected to be associated with IIH because IIH is a disease predominantly of obese patients [30 33]. Normal BMI and age greater than 50 years are rare or atypical for patients with IIH, and this atypical subset of patients is more likely to have visual complaints [33]. Both groups were predominantly female, as has been previously described [3]; however, the incidental empty sella turcica group did have a significantly higher percentage of males. Patients in the IIH group were more likely to present with headache than those in the incidental empty sella turcica group. Previous studies have shown that the most common presenting symptom for IIH is headache, occurring in more than 90% of cases in most series [11, 26]. Although headache is common in the general population and is a frequent indication for brain imaging, most patients with incidental empty sella turcica did not have the symptom of headache described in their clinical records or as an indication for imaging. The patients with IIH were more likely to present with visual symptoms than the patients with incidental empty sella. Previous studies have shown that visual symptoms including transient visual obscurations, blurred vision, photophobia, and double vision occur in 40 70% of patients with IIH [26]. These symptoms should not occur in patients with incidental empty sella turcica. Finally, pituitary symptoms and laboratory evidence of pituitary hypofunction or hyperfunction have been described in patients with incidental empty sella turcica [34]. It is possible that there were subclinical or laboratory abnormalities in these patients that were not mentioned in the medical records. There are several limitations to this study. A major limitation is that the clinical symptoms and diagnosis were based on retrospective review of electronic records. It is possible that some of the cases of incidental empty sella turcica were not appropriately diagnosed as IIH. Although funduscopic examination was not performed in all of the incidental empty sella turcica patients, it was performed in the nine patients presenting with visual complaints as the indication for MRI and did not show papilledema. Most of the remaining patients did not have headache or other typical symptoms suggestive of IIH, again making it less likely that these patients had subclinically elevated ICP. Second, there is likely some inaccuracy in the measurements of the diaphragm sella and sella because the diaphragm sella is not always clearly visible but must be inferred and because differences in slice position for sagittal images could affect the size of the sella turcica. These errors would, however, be systematic errors that would not be expected to differentially affect one group over the other. Finally, there was variability in the imaging protocols used, and it is possible that patients presenting with visual complaints were more likely to have dedicated orbital images on which orbital findings were easier to detect and that the orbital findings were underestimated in the incidental empty sella turcica group on that basis. The imaging findings related to pituitary compression and bony sellar expansion in an empty sella turcica alone are nonspecific. Using a combination of the available clinical information of patient age and sex, headache, visual symptoms, and papilledema and imag AJR:200, May 2013

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