CLINICAL STUDIES

The Primary Empty Sella Syndrome Analysis of the Clinical Characteristics, Radiographic Features, Pituitary Function and Cerebrospinal Fluid Adenohypophysial Hormone Concentrations

RICHARD M. JORDAN, M.D.* JOHN W. KENDALL, M.D. CHARLES W. KERBER, M.D. Portiaml, Oregon

From the Medical Research, Veterans Administration Hospital and the Deparhnents of Medicine and Radiology, University of Oregon Health Sciences Center, Portland, Oregon. This study was supported by grants from the Portland Veterans Administration Hospital (MRIS 4737 and 4883). Request for reprints should be addressed to Dr. Richard M. Jordan. Manuscript accepted July 21, 1976. Present address: Division of Endocrinology, Wilford Hall USAF Medical Center (AFSC), Lackland Air Force Base, Texas 78236. l

Twelve cases of the primary empty seiia syndrome were analyzed in regard to clinical findings, roentgenographic features, pituitary function and cerebrospinai fluid adenohypophysiai hormone concentration. The findings were compared with those in 247 cases of the primary empty seiia syndrome reviewed from the literature in order to determine the major characteristics of this disorder. The majority of patients are obese, multiparous women with normal pituitary reserve, normal visual fields and undetectable adenohypophysiai hormone concentrations in cerebrospinai fluid. in addition, occasional patients will have hypertension, pseudotumor cerebri and cerebrospinai fluid rhinorrhea. Patients who present with the typical features of the primary empty seiia syndrome should be evaluated periodictiiiy with pituitary function testing, visual field examinations and cerebrospinai fluid adenohypophysiai hormone determinations. if these parameters remain normal during careful follow-up studies, the patient is likely to have an empty seiia, and pneumoencephaiographic and angiographic studies can be avoided. The empty sella syndrome results from an extension of the subarachnoid space into an intrasellar position with subsequent remodeling of the sella turcica and flattening of the pituitary gland [ 1,2]. The sella turcica is usually enlarged, but this feature is not invariably present [ 11. This anomaly causes the greatest diagnostic difficulty when physicians attempt to distinguish it from a pituitary tumor. Without a pneumoencephalogram to outline the parasellar anatomy, uncertainty exists as to whether the enlarged sella turcica is secondary to an expanding intrasellar tumor or to an empty sella. Recognition of the primary empty sella syndrome has become common with more than 240 cases reported [l-47]. Autopsy studies indicate an incidence of 5.5 to 23.5 per cent [49-511. Because the primary empty sella syndrome is seemingly very prevalent, and because untoward complications of pneumoencephalography are not rare [48], we have attempted to determine characteristics of this disorder which would allow identification prior to pneumoencephalography and angiography. Twelve patients seen over a period of three years have been evaluated in a prospective fashion with regard to

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TABLE I

Case No.

1 2 3 4 5 6 7 8 9 10 11 12

SELLA

SYNDROME-JORDAN

ET AL.

Clinical Featuresof the Primary Empty Sella Syndrome Sex and

Age(yr) F, F, F, F, F, F, F, F, F, F, F, M,

58 29 59 77 33 69 63 46 62 49 57 51

Height 5’5” 5’5” 5’6” 5’1” 5’2” 5’5” 5’6” 5’5” 5’2” 5’0” 5’3” 5’9”

Weight (lb) 232 185 240 135 118 195 207 180 150 380 250 195

Blood Pressure (mm Hg) 160/105 140/100 160/l 05 120150 116180 200/120 190/105 130185 150/l 05 130185 170/120 1 OOJ64

clinical features, roentgenographic studies, endocrine function tests and measurement of adenohypophysial hormone in cerebrospinal fluid. Our findings and those reviewed from the reports of other investigators suggest that many patients with the primary empty sella syndrome can be reliably identified without pneumoencephalography. MATERIALS AND METHODS Patients. Twelve patients, 11 women and one man, were referred for pneumoencephalography because of an enlarged sella turcica. In 11 patients the diagnosis of a primary empty sella was made at pneumoencephalography and in one at surgery. None of the patients had a previous history of pituitary radiation or pituitary surgery. Informed consent in accordance with the Helsinki conference was obtained in all patients who received thyrotropin releasing hormone (TRH) and gonadotropin releasing hormone (LRH). Adenohypophyslal Hormone Measurement. All cerebrospinal fluid specimens were obtained as a byproduct of a pneumoencephalographic examination. Samples studied were clear and colorless. On microscopic examination, cerebrospinal fluid specimens from all patients were found to be virtually free of red blood cells. Both cerebrospinal fluid and blood specimens were immediately chilled in an ice bath. The blood was centrifuged at 4OC within 1 hour of collection; the plasma was separated, and both plasma and cerebrospinal fluid were frozen until the time of radioimmunoassay. Corticotropin (ACTH), growth hormone (GH), prolactin (PRL), thyrotropin (TSH), luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels were determined by radioimmunoassay. The method of ACTH determination has been described previously [52]. The sensitivity limit of this assay was 10 pg/ml. GH was determined with a double antibody system modified from the method of Roth et al. [53]. The sensitivity limit was 0.2 ng/ml. TSH was determined using a double antibody system modified from the method of Well et al. [54]. The sensitivity limit was 0.25 pU/ml. PRL was measured by the double antibody method of Sinha et al. [55].

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The sensitivity limit was 2 ng/ml. LH was measured by the double antibody radioimmunoassay of Morgan and Lazarow as adapted by Midgely for LH [56]. The sensitivity limit was 3.0 mlU/ml. FSH was measured utilizing the radioimmunoassay technic of Midgely [57]. The sensitivity limit was 3 mlU/ml. Recovery of all adenohypophysial hormones when added to cerebrospinal fluid was virtually 100 per cent and has been previously reported [58]. Thyroxine was assessed by a competitive protein binding technic and normal values range from 5 to 13 pg/lOO ml. Triiodothyronine (Ts) resin uptake was determined in accordance with the method of Sisson [59], with normal values of 25 to 35 per cent. Plasma cortisol was determined by a competitive protein binding technic, normal values are 6 to 20 pg/lOO ml. Urinary 17hydroxycorticosteroids were measured according to the method of Silber and Porter [ 601. Visual Field Examination. Visual fields were evaluated by perimetry and/or tangent screen. Pneumoencephalography. All but one patient were placed in a brow-up position. Air was confirmed to have entered the sella turcica by performing two plane thin section laminography. RESULTS Features. Clinical features of the 12 patients are shown. in Table I. Eleven of the patients were women. The age range was 29 to 77 years with a mean age of 54.42 f 3.99 years. All but one of the patients were overweight, exceeding his or her ideal body weight by at least 10 per cent as determined by standards of the Metropolitan Life Insurance Company. Eight of the women were multiparous and one was primiparous. The number of pregnancies ranged from one to nine. Hypertension, defined as a mean diastolic blood pressure in excess of 95 mm Hg, was present in seven. Ten patients had severe headaches, and in nine it was the presenting complaint. Headaches had been present for six days to 12 years prior to the initial evaluation. No characteristic pain pattern or area of localization was evident. Other presenting complaints included galactorrhea-amenorrhea (one patient), hypothyroidism with loss of visual acuity (one patient) and cerebrospinal fluid rhinorrhea (one patient). The patient with galactorrhea-amenorrhea had a pituitary tumor; at surgery, a coexisting partially empty sella was found. Two patients had adult onset diabetes mellitus. Chronic congestive heart failure was present in one patient who required treatment with digitalis and diuretics. Roentgenographic Studies. All 12 patients demonstrated enlargement of the sella turcica as determined from skull roentgenograms and pneumoencephalography. Enlargement was defined as an anteroposterior measurement of 17 mm or greater or a depth of 14 mm or greater. Several patterns of sellar deformity were seen. A “globular” sella, defined as sellar enlargement maintaining the regular smooth contour of the dorsum sella (Figure lA), was observed in six patients. Deep-

Clinical

PRIMARY EMPTY SELLA SYNDROME--JORDAN

ET AL.

Figure 1. Plain films of the sella turcica. A, a globular or symmetrically enlarged sella. B, a deep sella. C, posterior displacement of the dorsum sellae. The open arrows (9) outline the dorsum and the clivus is outlined by closed arrows (t).

Figure 2, Lateral views of the sella turcica showing marked demineralization of the posterior floor and dorsum. A, on the plain film sellar outlines are very indistinct. 6, thin section laminography shows that the cortical margin is absent posterior to the cortex of the sphenoid sinus (arrow). This area is the most sensitive detector of sellar demineralization.

Figure 3. A, lateral plain film of the sella turcica showing a “‘double floor. ” The open arrows (9) outline the higher floor and the closed arrows (t ) show the lower floor. B, frontal thin section tomogram through the sellar fkwr. The arrows outline the unequal and asymmetrical bony cortices.

a brow-up

a known a “double a prolactin-producing

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ET AL.

Anterior

Air

gland

ir

Figure 4. Pneumoencephalograms and corresponding line drawings of patients with the primary empty sella syndrome. The pituitary gland is most commonly flattened in an inferoposterior position.

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PRIMARY EMPTY SELLA SYNDROME-JORDAN

TABLE Case

No.

ET AL.

Endocrine Function in the Primary Empty Sella Syndrome

II

Growth Hormone (nglml)

Cortisol (pug/100 ml)

2

1 O-20”

19’

8-18”

235”

3 6

11

3,500 + 65

ACTH (pglml)

Urinary 17-OHCS (mg/24 hr)

(rg$OO ml)

4.4 to 43 a

9.1

28

4.0

7.4

10.1 8tol90

8* IO’ 8-16%

26 18

.

9

70+

18

150+

10

12+

21

570+

FSH

(mlU/ ml)

Comments

34

72

28

12

15

7.0 1 .8

40 21

25 21

50 61

4.6

24

3

8

8&6§ 4.7

6.5 9.8 13.7

28 24 23

29 47

48 43

Multinodular goiter, adult onset drabetes mellitus Normal pregnancy 2 mo prior to diagnosis Cerebrospinal flurd rhinorrhea Vrsual field deficit 24 hour iodine uptake was 3 per cent Plasma TSH was 4.4 IU/ml; plasma PRL was 2,000 ng/ml, normal pregnancy after removal of PRL-producing tumor Normal prolactin response to TRH

5.5

2.9

22

31

42

7.7

27

42

30

8

6 7 8

LH T RU (mlU/ i%) ml)

650 +

11 to355

On estrogens following oophorohysterectomy; plasma 11 -desoxycortisol increased to 8 ug/dl after 3 g of oral metyrapone Normal response of PR L, TSH. LH and FSH to TRH and LRH; plasma TSH was 77 @U/ml; adult onset drabetes mellitus Visual field defictt; normal response of PRL, TSH, LH and FSH to TRH and LRH

NOTE: Two patients (Cases 6 and IO) have high base line plasma ACTH values because the specimens were obtained after pneumoencepalography. Growth hormone reserve was considered adequate if values increased to 7 ng/ml or greater. Plasma ACTH was considered normal if values exceeded 140 pg/ml. Cortisol values represent 8 A.M. values unless otherwise noted. Postmenopausal values for LH and FSH normally are 25 mlU/ml or greater. Urinary 17-hydroxycorticosteroids (17-OHCS) should demonstrate a twofold increment. TSH and prolactin should show an increase of 6 flu/ml or greater and 20 nglml or greater, respectively. after the administration mal response to LRH was defined as an increase in LH and FSH of 15 mlU/ml or greater. “Maximum response to insulin hypoglycemia. +Maximum values obtained with pneumoencephalographic stress. TMaximum response to the administration of 500 mg of L-DOPA. 5 Response to the administration of 750 mg of metyrapone, given orally every 4 hours for six doses.

of TRH.

Nor-

she was given maintainance therapy with estrogens after undergoing oophorohysterectomy. A premenopausal woman had normally cycling menstrual periods. One patient (Case 4) had an elevated plasma FSH level but LH levels were in the premenopausal range. Thus, eight of nine patients had evidence of normal gonadotropin function. Cerebrospinal Fluid Hormone Concentrations. Plasma and cerebrospinal fluid specimens were obtained simultaneously and the concentrations of adenohypophysial hormones were measured in seven patients with the primary empty sella syndrome and in two patients with a “secondary” empty sella. Of the patients with a secondary empty sella, one had received pituitary radiation for acromegaly and the other had had previous surgery for removal of a craniopharyngioma. Levels of ACTH, TSH, LH, FSH, PRL and GH in cerebrospinal fluid were at the limits of detectability in all instances (Figure 5). Adenohypophysial hormone concentrations in cerebrospinal fluid were low despite markedly elevated levels in plasma. The high levels in

had unequivocal evidence of anterior pituitary deficiency. This patient had hypothyroidism with a normal plasma TSH concentration. In addition, she had had amenorrhea for 16 years. Menstrual periods returned, and pregnancy was established after removal of the tumor, suggesting normal gonadotropin function. ACTH reserve was evaluated in eight patients by insulin hypoglycemia, metyrapone stimulation or measurement of plasma ACTH during the stress of pneumoencephalography; it was considered normal in all. GH reserve, evaluated by insulin hypoglycemia, 500 mg of oral L-DOPA or pneumoencephalographic stress, was normal in the six patients tested. One patient (Case 4) had an isolated GH level of 6 ng/ml. Blood levels of thyroid hormone were low in two patients in addition to the patient (Case 5) already described. In these, primary hypothyroidism was suggested by a low 13’1 uptake (Case 4) and increased plasma TSH (Case 10). Six postmenopausal patients had elevated plasma gonadotropin levels. In another postmenopausal patient, the plasma gonadotropin level was not elevated; however,

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ET AL.

loo -

0 b 0 .

_

l

_

loo

Plasma

CSF

Plasma

CSF

Plasma

CSF

Plasma

CSF

FSH

Plasma

CSF

Figure 5. A comparison of plasma and cerebrospinal fluid (CSF) adenohypophysial hormones in patients with an empty se/la. Plasma hormone determinations were not performed on all patients. 0 -primary empty sella, A -secondary empty sella. Corticotropin (ACTH), thyroid-stimulating hormone (TSH), growth hormone (GH), prolactin (PRL), luteinizing hormone (LH), follicle-stimulating hormone (FSH).

plasma were produced by pneumoencephalographic stress, a postmenopausal state, thyrotropin-releasing hormone (TRH) or gonadotropin-releasing hormone (LRH). In addition, plasma and cerebrospinal fluid specimens were obtained simultaneously at 15 to 30 minute intervals during pneumoencephalography in three patients who were given TRH (500 pg intravenously) and LRH (100 pg intravenously) immediately after a base line cerebrospinal fluid sample was acquired (Figure 6). In one of the patients, TSH, LH and FSH were not measured. The expected rise of plasma hormone levels was not accompanied by any change in cerebrospinal fluid hormone concentrations which remained undetectable to the end of the collection period. In addition, in several patients plasma adenohypophysial hormone levels had presumably been elevated over extended periods. One patient with a 16 year history of acromegaly had a plasma GH level of 65 ng/ml, another with primary hypothyroidism had a plasma TSH of 77 pU/ml, and six postmenopausal women had high plasma concentrations of gonadotropins. Thus, despite marked and prolonged increases in plasma adenohypophysial hormone concentrations, cerebrospinal fluid levels remain undetectable in the empty sella syndrome.

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COMMENTS The term “primary empty sella” should be used when this anomaly occurs in patients who have not received prior pituitary radiation or pituitary surgery [3-51. Empty sellas discovered after such procedures are usually classified as secondary cases [3]. All patients discussed here, unless otherwise indicated, have the primary empty sella syndrome. The primary empty sella occurs most commonly in women. The incidence of female predominance as well as other commonly associated findings are shown in Table Ill. In addition to obesity, hypertension and pseudotumor cerebri, hydrocephalus [2,7,8,18,25, 30,361 and congestive heart failure [ 1,431 sometimes occur with a primary empty sella. All can be associated with an increase in cerebrospinal fluid pressure. Increased cerebrospinal fluid pressure transmitted through a patulous diaphragma sella is postulated as the most common mechanism by which an empty sella develops [ 1,611. An increased cerebrospinal fluid pressure could be responsible for the high incidence of cerebrospinal fluid rhinorrhea that occurs with the primary empty sella. Other possible etiologies, such as pituitary infarction [ 19,25,34], rupture of an intrasellar

62

PRIMARY

EMPTY

SELLA

SYNDROME-JORDAN

ET AL.

----.-

0 A

A

CSF

1 Patient Potiont Patiwd Plasma CSF

PRL W-

ng/ml

20-

100 60 80 50

LH

GH 4oI

mIU/ml

ng/ml

‘lo -

30 20

6o-

20 -

1

10t

o-

,i 80 600 F 60 -

500 -

ACTH 4oo P9/ml 3W_

FSH mIU/ml

200-

4O-

20 -

100 O-

O-

0

15

30

Minutes

6o

90

Figure 6. Simultaneo~ plasma and cerebrospinal fluid (CSF) akwohypophysial hormone concentrations after the intravenous administration thyrotropin+ekasing hormone (lRH) and gona&tropin-reieasing hormone (LRH) during pneumoencephaiography. One patient (Case 6) did not have TSH, LH and FSH measurements performed. Corticotropin (ACTH), thyroid-stimulating hormone (TSH), growth hormone (GH), prolactin (PRL), luteinking hormone (LH) and follicle-stimulating hormone (FSH).

cyst [62-641 and hypotrophy following pregnancy [64], seem less likely to be responsible in most patients. Any association of an empty sella with disorders such as mucopolysaccharidosis [36], virilization [20] and renal tubular acidosis [24] are almost certainly coincidental. Although headaches were present in 10 of our patients,

it is difficult to be certain if they are part of the syndrome. No characteristic pattern or area of localization was apparent, and it is possible that headaches simply lead to a skull film and that an empty sella is discovered fortuitously. Visual field abnormalities, although not uncommon

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IO 9 6

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TABLE III

ET AL.

Commonly Associated Features with the Primary Empty Sella Syndrome

Features Female predominance* Obesity* Hypertension* Pseudotumor cerebrit Cerebrospinal fluid rhinorrheaf

Cases Incidence (no.) (%) 2051245 1271162 501164 261247 241247

83.7 78.4 30.5 10.5 9.7

References [ 1,2,4-4446,471 [ 1,2,4-2446,471 [1,2,4-8,10,11,14-20,22-3346,471 [2,5,7-10.45461 [1,6-9,11-13,16,18,23,25,45,461

“Statistics were taken only from reports which contained adequate clinical information. tit was assumed that all investigators would mention pseudotumor cerebri or cerebrospinal fluid rhinorrhea if these entities were present.

with a secondary empty sella [4,65] are said to be rare in patients with the primary empty sella syndrome [4,5,8]. Two of our patients, however, had generalized peripheral field constrictions without evidence of increased intracranial pressure. Peripheral field constriction with the primary empty sella syndrome has been previously reported [21,31]. In addition, four cases of primary empty sella with bitemporal hemianopsia or quadrantanopsia have been reported [ 25,471. This suggests that, although infrequent, visual field abnormalities can occur in the primary empty sella syndrome. Roentgenographically the empty sella presents a diverse picture and is best evaluated by tomography. The most characteristic feature is the symmetrically enlarged sella [7] (Figure 1A). Here enlargement is present, and there is usually erosion of the lamina dura. The dorsum sella, however, retains its normal curvature, and there is approximation of the anterior and posterior clinoids. All degrees of sellar deformity can occur, including posterior displacement and demineralization of the dorsum sellae (Figure lC), marked erosion of the entire sella turcica (Figure 2) and a double contour of the sella floor (Figure 3). Progressive sellar enlargement has also been reported with the primary empty sella [ 171. Roentgenologically, the primary empty sella can be indistinguishable from a pituitary tumor. The pneumoencephalographic appearance of the empty sella is shown in Figure 4. The sella need not be completely filled by air, but there should be remodeling of the sella turcica with flattening of the pituitary gland. Air was not demonstrated intrasellarly in one of our patients. This patient, with a suspected pituitary tumor, was not placed in a brow-up position. Such positioning, with the head hyperextended, is essential for air to fill an empty sella turcica. Because an empty sella can harbor a pituitary tumor [ 1,5-7,17,19,29,35,46], all positioning maneuvers should be performed to exclude an empty sella. Knowledge that an empty sella is present will aid the neurosurgeon to avoid a tear of the arachnoid membrane when performing transsphenoidal

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microdissection. Such a complication occurred in one of our patients with acromegaly and a secondary empty sella. Cerebrospinal fluid rhinorrhea followed by Proteus mirabilis meningitis developed, and the patient died from her infection. The patient was not placed in a brow-up position, and an empty sella was not suspected before surgery. Endocrine testing of our patients demonstrated normal pituitary function except when other predisposing factors existed (a pituitary tumor). Our findings are in agreement with the majority of reports that pituitary function is usually normal in patients with the primary empty sella syndrome [5,8,39,42]. Normal TSH and PRL reserve after the intravenous administration of TRH was found by Snyder et al. [42] and Ridgeway et al. [39] in almost all patients tested. Faglia and colleagues [37] found a normal TSH response to the administration of TRH in six of eight patients evaluated, although in two, the response was delayed. Plasma gonadotropins increased normally after the administration of LRH in four of their patients. GH reserve has been reported as normal [5]; however, disagreement exists [8,10,33]. The defects of GH secretion observed could be related to obesity since obesity can blunt GH responses to stimulatory testing [66]. With few exceptions [33], ACTH reserve has been normal when carefully examined [5,8,14]. Posterior pituitary function has also been normal except for one reported instance of diabetes insipidus [32]. Isolated cases of hypopituitarism with the primary empty sella syndrome, however, do occur [ 1,7,11,25,31,34,38]. It is possible that these patients represent a small subgroup in which spontaneous infarction of the pituitary gland or a pituitary tumor is responsible for the empty sella. Although most patients with the primary empty sella syndrome have normal pituitary function, this is not true of patients with pituitary tumors in whom there is usually some abnormality of pituitary hormone secretion [42,67,68]. Measurement of blood PRL concentration is especially important in the evaluation of a patient with an enlarged sella. An increased value will be present

PRIMARY EMPTY SELLA SYNDROME--JORDAN

ET AL.

T

NORMAL

erns Diaphr Setloe

F&e 7. hbrmal relationship of the meninges to the humanpituikxy gland (f&). The arachnoidsurrounds the aparture through which the pituitary stalk passes. The pituitary gland is boundedsuperiorly by reflections of dura which form the diaphragma sellae. The pia extends dawn the pitui&y stalk to just abovethe pituiWy gland where it is reflected and blends with the d&phragma sellae. In the empty sella syndrome (rt$ht) the arachnoid membrane herniates through an incompetent diaphragmasellae.

in approximately 35 per cent of patients with a pituitary tumor [58,68]. Thus, careful pituitary testing can be of value in distinguishing the patient with a primary empty sella from one with a pituitary tumor. The human pituitary gland lies in close proximity to the subarachnoid space [69] (Figure 7). In the empty sella syndrome only the arachnoid membrane separates the surface of the pituitary gland from cerebrospinal fluid [ 11. This relationship prompted us to measure concentrations of adenohypophysial hormones in the cerebrospinal fluid of patients with an empty sella. In all nine patients evaluated, adenohypophysial hormone levels in cerebrospinal fluid were at the lower limits of detectability. This was true even when plasma adenohypophysial hormone levels had been elevated for prolonged periods, suggesting that a “pituitary-cerebrospinal fluid” barrier for adenohypophysial hormones exists in the empty sella syndrome. Our previous studies have shown that 27 patients with various neurologic disorders and 27 patients with pituitary tumors but without suprasellar extension also have low adenohypophysial hormone concentrations in cerebrospinal fluid [58]. However, in 21 of 22 patients with suprasellar extension of a pituitary tumor, one or more adenohypophysial hormones were readily detected in cerebrospinal fluid. Several lines of evidence suggest the hormones reach cerebrospinal fluid by direct secretion from the pituitary tumor which has expanded into the basilar cisterns [58,70] rather than by transport from blood through a break in the “blood-cerebrospinal fluid”

barrier. The absence of adenohypophysial hormones in cerebrospinal fluid, although not excluding the presence of a pituitary tumor, provides strong evidence against suprasellar extension. Thus, the lack of adenohypophysial hormones in the cerebrospinal fluid of a patient with an enlarged sella is not diagnostic of an empty sella; however, it provides valuable information regarding the expansile nature of a possible pituitary tumor. A recent claim has been advanced that PRL appears in the cerebrospinal fluid of patients with hyperprolactinemia without suprasellar extension of a pituitary tumor [ 7 11. This finding could be explained because pregnant patients and neonates were studied. The pituitary gland is known to enlarge two to three times normal size during pregnancy, primarily from an increase of PRL-secreting cells [72], and occasionally results in visual field defects [73]. This could result in “physiologic” suprasellar extension with release of hormones directly into cerebrospinal fluid. Interestingly, the only false-positive increase in cerebrospinal fluid PRL we observed was in a pregnant patient [58]. In neonates, the permeability of the blood-cerebrospinal fluid barrier is increased as evidenced by the higher protein concentration in cerebrospinal fluid [74,75]. In addition, studies from four additional laboratories support the findings that adenohypophysial hormones are normally found only in low concentration in cerebrospinal fluid despite increased plasma values [76791.

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PRlMAdl

It

sella

EMPTY

SELLA

SYNDROME-JORDAN

is clear that no single feature syndrome

is sufficiently

ET AL.

of the primary

specific

empty

to distinguish

it

from a pituitary tumor. If, however, all clinical features are considered as a composite, a typical presentation emerges. Patients are likely to be middle-aged, obese, hypertensive and female. Pituitary function and visual fields will be normal in most patients, and cerebrospinal fluid adenohypophysial hormone levels will be low. It is possible that a pituitary tumor could present in a similar fashion [80]; however, the last 50 patients with documented pituitary tumors who were evaluated at the University of Oregon have had either pituitary hormone abnormalities (hypersecretion or hyposecretion), visual field defects or increased cerebrospinal fluid adenohypophysial concentrations [58]. This suggests that few pituitary tumors will be misdiagnosed as an empty sella, and certain ‘patients with features characteristic of an empty sella can be identified and followed periodically with pituitary function studies, visual field examinations and cerebrospinal fluid adenohypophysial hormone measurements. If the results of these studies remain normal, it would appear likely that such patients have an empty sella and could be spared the expensive, painful and dangerous procedures of pneumoencephalography and arteriography. Patients with atypical clinical features, pituitary function or visual field abnormalities, or elevated cerebrospinal fluid adenohypophysial hormone levels would require the full complement of roentgenologic studies. Applying this criteria to our series, one patient (Case 5) with hyperprolactinemia and amenorrhea, two patients (Cases 4 and 10) with visual field defects, one

patient (Case 12) atypical because of sex, and another patient (Case 2) atypical because of age would all require air contrast studies regardless of the results of additional testing. Normal results in the remainder would allow them to be followed. Although we believe such an approach is useful, it is essential that close follow-up be obtained since some pituitary tumors are slow growing, and an occasional pituitary tumor will coexist in an empty sella. If follow-up is doubtful, pneumoencephalography should be performed even in a “classic” patient. A simplified means of evaluating the relatively inaccessible sella turcica is greatly needed. Future refinements of computerized axial tomography could provide such a diagnostic tool. The present generation of instruments, however, is relatively insensitive to detecting intrasellar abnormalities even with enhancement technics, although suprasellar extension of 1 cm can be visualized [8 11. Pneumoencephalography remains, however, more sensitive in the detection of juxtasellar lesions [82]. ACKNOWLEDGMENT We express our gratitude to the National Pituitary Agency, Bethesda, Maryland, for kindly providing prolactin antigen and antibody; Ayerst Laboratories for generously donating gonadotropin-releasing hormone; and to Drs. Larry Brice, George Donahower, Huldrick Kammer and John Berland for allowing us to study their patients. We gratefully acknowledge the technical assistance of Miss Donna Gaudette.

REFERENCES 1.

6. 7.

8.

9.

10.

579

Kaufman B: The “empty” sella syndrome-a manifestation of the intrasellar subarachnoid space. Radiology 90: 931, 1968. El Gamma1 T, Allen MD Jr: The intrasellar subarachnoid recess. Acta Radio1 13: 401, 1972. Weiss SR, Raskin R: Non-neoplastic intrasellar cysts. Int Surg 51: 282, 1969. Hodgson SF, Randall RV, Holman CB, et al.: Empty sella syndrome. Med Clin North Am 56: 897, 1972. Neelon FA, Goree JA, Lebovitz HE: The primary empty sella: clinical and radiographic and endocrine function. Medicine (Baltimore) 52: 73, 1973. Zatz RM, Janlon EA, Newton TH: The enlarged sella and the intrasellar cistern. Radiology 93: 1085, 1969. Kaufman B, Pearson OH, Chamberlin WB: Radiographic features of intrasellar masses and progressive, asymmetrical, nontumorous enlargements of the sella turciCa, the ‘empty’ sella. Diagnosis and Treatment of Pituitary Tumors (Ross GT, Kohler PO, eds), Amsterdam, Exerpta Medica, 1973, p 100. Brisman R, Hughes JO, Holub DA: Endocrine function in nineteen patients with empty sella syndrome. J Clin Endocrinol Metab 34: 570, 1972. Weisberg LA, Housepian EM, Saur DP: The empty sella syndrome as a complication of benign intracranial hypertension. J Neurosurg 43: 177. 1975. Foley KM, Posner JP: Does pseudotumor cerebri cause the

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11. 12.

13.

14. 15. 16. 17. 18. 19. 20.

21. 22.

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