Primary Hypophysitis: Idiopathic Inflammatory Disorders of the Pituitary Gland

Neurosurgery Quarterly 12(3):197 215 2002 Lippincott Williams & Wilkins, Inc., Philadelphia Primary Hypophysitis: Idiopathic Inflammatory Disorders of the Pituitary Gland M. Necmettin Pami. r and Koray Özduman Department of Neurosurgery, Marmara University Faculty of Medicine, Istanbul, Turkey Summary: Primary hypophysitis is a rare but significant cause of sellar spaceoccupying lesions. Three forms have been described: granulomatous, lymphocytic, and xanthomatous hypophysitis. Current methods cannot diagnose or distinguish these entities before surgery with sufficient certainty. The disease most commonly presents with sellar space-occupying symptoms as a result of pituitary enlargement and hormonal abnormalities such as potentially lethal pituitary insufficiency or hyperprolactinemia. Pituitary insufficiency almost always ensues, with progressive inflammatory destruction of the pituitary tissue. All three disorders clinically and radiologically mimic pituitary adenomas, and the diagnosis is usually made after surgery. Idiopathic giant cell granulomatous hypophysitis is a cryptogenic inflammatory lesion. The diagnosis rests on eliminating secondary causes. Lymphocytic hypophysitis is a chronic autoimmune disorder of the anterior and, rarely, posterior pituitary. Although it is most commonly seen in peripartum women, it may be encountered in either sex and may be associated with other autoimmune diseases. Surgical removal, biopsy, and medical are the three options of. Response to medical is unpredictable, but remissions are reported with steroids. A consensus regarding drug choice timing, duration, and dosage of is lacking, but in preoperatively suspected cases, a therapeutic trial is justified. Surgery results in cure at the expense of potentially viable pituitary tissue. The natural course of these rare disorders is currently unknown, the prognosis is unpredictable, and the choice of effective is yet to be established. Key Words: Granulomatous hypophysitis Lymphocytic hypophysitis Xanthomatous hypophysitis Giant cell hypophysitis Pituitary surgery Pituitary adenoma. Inflammatory processes compose a small but significant proportion of sellar pathologic findings. 1,2 Since the popularization of pituitary surgery at the beginning of the 20th century, these rare entities have become more commonly recognized, and their management has challenged even skillful neurosurgeons. 3 After the description of granulomatous hypophysitis in 1911 4 and lymphocytic hypophysitis in 1962, 5 only a limited number of cases have been reported. Although their causes are still obscure, the epidemiology and characteristics of these rare disorders are roughly established. 1 Address correspondence and reprint requests to M. Necmettin Pami. r, MD, Department of Neurosurgery, Marmara University Hospital, Tophanelioğlu caddesi,. 13/15 Altunizade, Istanbul, 81190 Turkey. E-mail: ozduman@superonline.com Three forms of primary hypophysitis have been described: granulomatous, lymphocytic, and xanthomatous hypophysitis. 6 All three are considered in the differential diagnosis of sellar space-occupying lesions, and their distinction from pituitary adenomas poses great diagnostic difficulties. 6 8 Currently, a noninvasive means of distinguishing these entities before surgery is nonexistent. 6,9,10 All cases of biopsy-verified idiopathic giant cell granulomatous hypophysitis reported in the literature are listed in Table 1. The first report of giant cell granulomatous hypophysitis was in 1911 by Geurgeot and Gy, 4 followed by a report by Simmonds in 1917. 11 In 1949, Sheehan and Summers 12 hypothesized that this lesion may be the presentation of a distinct specific disease of 197 DOI: 10.1097/01.WNQ.0000023274.57247.F9

198 M. PAMİR AND K. ÖZDUMAN TABLE 1. Biopsy-verified idiopathic giant cell granulomatous hypophysitis Reference (year) Patient age (years)/ gender Presentation Endocrine status Radiologic findings Steroid / Operation performed/ intraoperative findings Taylon and Duff 78 (1980) Del Pozo et al. 79 (1980) Hassoun et al. 55 (1985) Scanarini et al. 14 (1989) Siquieiria et al. 80 (1989) Yoshioka et al. 65 (1992) Higuchi et al. 81 (1993) Pamir et al. 54 (1993) Brisman et al. 17 (1996) Honegger et al. 24 (1997) Vasile et al. 8 (1997) Kristof et al. 53 (1999) Gazioglu et al. 80 (2000) 50/M H/A, CN III palsy details given available; intrasellar mass and right cavernous sinus involvement on CT 28/F H/A, amenorrhea PH available; enlargement of the sella on radiography; upward displacement of the sella on pneumoencephalography 65/F N/V, weight loss PH available; intrasellar mass and no increase in volume of the sella on CT 20/F H/A, galactorrhea PRL, DI, PH available; ring-enhancing low-density intrasellar mass on CT 19/F Galactorrhea, amenorrhea 57/M H/A, CN III palsy, impotence PRL PH available; ring-enhancing low-density intrasellar mass on CT available; slightly enhancing intrasellar mass expanding into the right parasellar area and sphenoid sinus on CT 58/M PH PH preoperative available; uniformly enhancing isodense mass enlarging the sella on CT 37/M H/A, CN III palsy, CN VI palsy PH available; intrasellar mass and with hyperdense areas on CT; no abnormalities on cerebral angiography 76/F Visual sterile meningitis PH Intrasellar mass and 46/F Visual symptoms PRL, PH available; intrasellar mass an with thickened infundibulum on CT 55/F DI DI Intrasellar mass, and homogeneous enhancement with thickened infundibulum 55/M Visual symptoms PH Intrasellar mass, and homogeneous enhancement with thickened infundibulum 41/F PRL Intrasellar mass, and homogeneous enhancement with irregular hyperintensities ; calcifications on CT 36/F PRL Intrasellar mass, and homogeneous enhancement 72/F H/A, vomiting, visual adrenal insufficiency PH Intrasellar mass, homogeneous enhancement, and enlarged stalk 16/F Sterile meningitis PH, DI, PRL Intrasellar mass, homoenous contrast enhancement, nonenhancing center, and thickened stalk 48/F H/A PH, DI, PRL Intrasellar mass, and thickened stalk with sphenoid mucosal thickening 40/F H/A, sterile meningitis, DI 16/F DI, hypogonadism, dwarfism 32/F DI, visual menstrual irregularity DI, PH GH, LH/ FSH, DI Mild hypocortisolemia Intrasellar mass, heterogenous enhancement, and dural enhancement with no posterior gland signal, sphenoid mucosal thickening, or abnormal sphenoid bone marrow Atrophic pituitary and enlarged stalk Intrasellar mass, dumbbell suprasellar extension, chiasmal compression, sphenoid mucosal thickening, and stalk unidentifiable 33/F H/A, N/V PRL Intrasellar mass, isointense on T1, heterogenous on T2, and nonenhancing center Before surgery, reversed CN palsies Methylprednisone pulse, no surgery/ edematous gland surgery/ close resemblance to a fibrous adenoma surgery/ surgery/ cyst containing thick whitish fluid surgery/ cyst containing creamy grayish yellow fluid surgery/ solid with a firm capsule surgery/ fibrous encapsulated mass surgery/ surgery/ surgery/ calcified mass surgery/ fibrous mass surgery/ fibrous mass surgery/ encapsulated grayish yellow surgery/ encapsulated grayish yellow surgery/ yellow adherent to arachnoid and cavernous sinus Transcranial surgery (frontotemporal approach)/firm capsule with creamy content Transcranial surgery (frontotemporal approach)/ surgery/ firm whitish mass adherent to dura mater Transcranial stalk biopsy (subfrontal approach)/ thickened but otherwise normalappearing stalk surgery/ surgery/ Neurosurgery Quarterly, Vol. 12,. 3, 2002

PRIMARY HYPOPHYSITIS 199 TABLE 1. (Continued) Reference (year) Patient age (years)/ gender Presentation Endocrine status Radiologic findings Steroid / Operation performed/ intraoperative findings Cheung et al. 6 (2001) Buxton and Robertson 58 (2000) Arsava et al. 59 (2001) 50/M H/A PH but normal PRL 39/F H/A, N/V, weight loss, hot and cold flashes 32/F H/A, amenorrhea, visual symptoms PRL, hypocortisolism Intrasellar mass, isotense on T1, heterogenous on T2, and nonenhancing center Intrasellar mass and At recurrence, yes surgery/ surgery/ PH Pituitary mass, no details given details given surgery/ 38/F PH, visual symptoms PH, DI Pituitary mass, no details given details given surgery/ 45/F Diplopia, bilateral CN VI palsy, PH Pituitary mass, no details given details given surgery/ visual symptoms 46/F H/A, amenorrhea PH Intrasellar mass and details given surgery/ 53/F Amenorrhea, ptosis, diplopia PH Intrasellar mass Associated optic neuritis responsive to methylprednisolone surgery/ firm fibrotic yellowish mass PH, pan; PRL, hyperprolactinemia; H/A, headache; N/V, nausea-vomiting; CN, cranial nerve; DI, diabetes insipidus;, magnetic resonance imaging; GH, growth hormone; LH/FSH, luteinizing hormone/follicle-stimulating hormone; CT, computed tomography. unknown origin. In 1954, Rickards and Harvey 13 reported 115 cases of granulomatous hypophysitis and identified a group of 23 idiopathic cases in which evidence of systemic granulomatous disease was lacking. Since its first description, several other causes leading to secondary granulomatous hypophysitis have been described, but idiopathic giant cell granulomatous hypophysitis has emerged as a separate entity. 14 It is characterized by varying degrees of lymphocytic infiltration in the pituitary parenchyma and by the presence of noncaseating granulomas with epithelioid histiocytes and multinucleated giant cells. 14,15 In secondary granulomatous hypophysitis, anterior pituitary tissue is primarily affected, but the neurohypophysis, the pituitary stalk, and even the hypothalamus may also be involved. 6 Patients may present with headache, nausea, vomiting, visual, hyperprolactinemia, diabetes insipidus (DI), or cranial nerve palsies. 16,17 All cases of biopsy-verified lymphocytic hypophysitis reported in the literature are listed in Table 2. Lymphocytic hypophysitis was first described by Goudie and Pinkerton in 1962. 5 The first report was that of the postmortem examination of a young postpartum woman who had pituitary lymphoid infiltration, adrenal atrophy, and Hashimoto thyroiditis. Initial reports were mainly focused on peripartum women, but the range has been broadened to encompass a diverse population, including men and postmenopausal women, and the disease s causal relation with pregnancy has been questioned. 6,9,18,19 Autoimmunity is the most plausible pathogenetic mechanism for the selective inflammation of the pituitary gland in lymphocytic hypophysitis. 6,20,21 Recently, a third form of primary hypophysitis has been introduced to the literature by Folkerth et al. 22 Xanthomatous hypophysitis, first described in 1998, is the least common form of primary hypophysitis. The process histopathologically resembles that of xanthomatous inflammations encountered in other parts of the body such as the genitourinary and biliary tracts in to chronic bacterial infection. 6,22 PATHOGENESIS It has been suggested that the three forms of primary hypophysitis, namely, granulomatous, lymphocytic, and xanthomatous hypophysitis, may be different stages or various presentations of a single disease. 6,10,23,24 Evidence supporting this hypothesis is currently lacking. 6,22 Preoperative diagnostic methods usually cannot differentiate between these three entities in spite of the fact that there are considerable differences in the epidemiology of these three conditions. 6,7,10 Whether they are related has yet to be investigated. 6 Giant Cell Granulomatous Hypophysitis Occurrence of granulomatous hypophysitis is attributable to systemic granulomatous diseases and infections such as tuberculosis, 14,25 27 syphilis, 14 sarcoidosis, 14 histiocytosis X, 14 Wegener granulomatosis, 28 pyoderma Neurosurgery Quarterly, Vol. 12,. 3, 2002

200 M. PAMİR AND K. ÖZDUMAN TABLE 2. Biopsy-verified lymphocytic hypophysitis cases Reference (year) Age (years)/ gender Association with pregnancy Presentation Radiologic findings Immunosuppressive / Mode of diagnosis/intraoperative findings Associated autoimmune disease Goudie and Pinkerton 5 (1962) Hume and Roberts 83 (1967) Egloff et al. 84 (1969) Kiaer and rgaard 85 (1969) 22 F Hypopituitarism, amenorrhea N/A Necropsy/atrophic Hashimoto thyroiditis 74/F Hypopitutarism N/A Necropsy/atrophic Pernicious anemia 29/F Postpartum Hypopituitarism, amenorrhea 74/F Hypopituitarism, H/A N/A Necropsy/enlarged N/A Necropsy/N/A Lack 86 (1975) 42/F Hypopituitarism N/A Necropsy/not enlarged Parathyroiditis, adrenalitis Gleason et al. 87 60/F Hypopituitarism N/A Necropsy/enlarged (1978) Quencer 88 25/F Postpartum Amenorrhea, Enhancing intrasellar (1980) galactorrhea mass on CT Richtsmeier et al. 38 (1980) 32/F Postpartum Adrenal insufficiency N/A Necropsy/thickened capsule Mayfield et al. 47 (1980) Asa et al. 58 (1981) Portocarrero et al. 62 (1981) Cebelin et al. 89 (1981) Hungerford et al. 90 (1982) Baskin et al. 3 (1982) McKeel 91 (1983) Mazzone et al. 56 (1983) Ludmerer and Kissane 50 (1984) Madsen et al. 92 (1985) Sobrinho-Simoes et al. 52 (1985) Okamoto et al. 93 (1986) Gal et al. 94 (1986) 23/F Postpartum Hypopituitarism, H/A, fever, CN VI palsy 28/F Antepartum Amenorrhea, visual 29/F Postpartum Amenorrhea, 25/F Postpartum Amenorrhea, H/A, galactorrhea Enlarged sella and intrasellar mass on CT Lobulated intrasellar mass with asymmetric on CT 50 mg/d prednisone/ CN VI palsy resolved surgery/gritty nonencapsulated mass Intrasellar mass on CT Diffuse enhancement of the pituitary, but no on CT 22/F H/A, galactorrhea N/A Necropsy 27/F Antepartum Visual 33/F Antepartum Visual Uniformly enhancing intrasellar mass and on CT Uniformly enhancing intrasellar mass, and bone erosion on CT 28/F Postpartum Visual symptoms Uniformly enhancing intrasellar mass, and bone erosion on CT surgery/firm white mass surgery/firm yellow mass 30/F Hypopituitarism N/A Necropsy 37/F Postpartum Hypopituitarism, H/A Sellar enlargement and intrasellar mass on CT 33/F Amenorrhea, H/A, 29/F Amenorrhea, 24/F Amenorrhea, H/A, 28/F Postpartum Visual H/A, 29/F Visual coma, surgery/fibrotic tissue adherent to the surrounding structures abnormalities on CT surgery/atrophic Hashimoto thyroiditis, adrenalitis, pancreatitis Pernicious anemia N/A Necropsy rmal skull radiograph Necropsy Round contrast-enhancing intrasellar mass on CT N/A Necropsy/enlarged Neurosurgery Quarterly, Vol. 12,. 3, 2002

PRIMARY HYPOPHYSITIS 201 TABLE 2. (Continued) Reference (year) Age (years)/ gender Association with pregnancy Presentation Radiologic findings Immunosuppressive / Mode of diagnosis/intraoperative findings Associated autoimmune disease Moriyama et al. 95 (1986) Kurisaka et al. 96 (1986) Jensen et al. 35 (1986) Wild and Kepley 61 (1986) Meichner et al. 46 (1987) 28/F Antepartum Visual Intrasellar mass and enlarged sella on CT 30/F Antepartum Visual Enlarged sella and intrasellar mass on CT 32/F Antepartum Amenorrhea, H/A, Intrasellar enhancing PRL mass on CT 31/F Amenorrhea Enlarged sella on CT surgery/not enlarged 24/F Postpartum Visual H/A Guay et al. 18 52/M Male Impotence, H/A, McGrail et al. 71 29/F Antepartum Visual (1987) H/A, N/V, Fever, Vanneste and Kamphorst 64 (1987) Parent et al. 97 (1988) Levine et al. 66 (1988) 29/F PH, galactorrhea, H/A, fever 21/F Postpartum Amenorrhea, visual H/A, 29/F Postpartum Amenorrhea, galactorrhea, H/A, visual 18/F Postpartum H/A, visual McDermott et al. 98 31/F Antepartum H/A, visual 45/F H/A, visual PH, amenorrhea Castle et al. 99 37/F Postpartum Visual Cosman et al. 100 29/F Postpartum Amenorrhea, visual H/A, 34/F Postpartum Amenorrhea, H/A, Intrsellar enhancing mass and suprasellar extension on CT Intrasellar enhancing mass on CT Intrasellar enhancing mass and suprasellar extension on CT Intrasellar enhancing mass and suprasellar Transcranial surgery (subfrotal approach)/enlarged extension on CT Enlarged sella on CT Enlarged sella on CT Homogeneous isointense intrasellar mass but no suprasellar extension Enlarged sella on CT Enlarged sella on CT Enlarged sella on CT Intrasellar mass, and chiasmal compression Intrasellar mass and on CT 38/F Postpartum H/A, Intrasellar mass, and left parietal arachnoid cyst on Miura et al. 101 45/F Visual PH, DI Pestell et al. 102 (1990) McConnon et al. 30 (1991) Bitton et al. 103 (1991) Hashimoto et al. 104 (1991) 24/F H/A, amenorrhea, Diffuse pituitary enlargement and absent posterior gland high signal Diffuse pituitary enlargement and absent posterior gland high signal 22/F Antepartum Visual H/A, PRL Enlarged sella on CT Yes/positive 61/M Male Hypopituitarism Enlarged sella on CT Yes/positive 22/F Amenorrhea, H/A, Coincidental intrasellar galactorrhea, PRL adenoma 22/F Antepartum H/A, visual Enlarged sella on CT hypothyroidism 39/F Postpartum Visual, DI Intrasellar mass and Neurosurgery Quarterly, Vol. 12,. 3, 2002

202 M. PAMİR AND K. ÖZDUMAN TABLE 2. (Continued) Reference (year) Age (years)/ gender Association with pregnancy Presentation Radiologic findings Immunosuppressive / Mode of diagnosis/intraoperative findings Associated autoimmune disease Hayashi et al. 105 (1991) Nussbaum et al. 24 (1991) McCutcheon and Oldfield 106 (1991) Stelmach and O Day 107 23/F Postpartum Visual H/A, 40/M Male Bilateral CN VI palsy,, DI Intrasellar mass on CT Mildly enlarged pituitary with homogeneous enhancement on CT, isotense mass and cavernous sinus involvement surgery/avascular gray fibrous tissue 34/F Postpartum H/A, amenorrhea, DI Intrasellar mass 29/F H/A, PRL Enlarged pituitary on CT 21/F H/A, visual PRL (1991) Prasad et al. 108 44/F H/A, visual Feigenbaum et al. 109 (1991) Supler and Mickle 110 (1992) Reusch et al. 72 (1992) Ahmed et al. 42 (19930 Intrasellar mass and Intrasellar mass on CT 26/F H/A, fever, Intrasellar mass on CT 56/M Male H/A, Intrasellar mass and cavernous sinus involvement 29/F Antepartum Visual symptoms Intrasellar mass, and chiasmal compression 33/M Male DI, HP Enlarged pituitary and strong homogeneous enhancement in 39/M Male DI Enlarged pituitary and strong homogeneous enhancement Nishioka et 33/F Postpartum H/A, visual al. 111 Koshiyama et al. 112 (1994) Yamagushi et al. 113 (1994) Homogeneously enhancing intrasellar mass and suprasellar extension 50/F H/A, DI Homogeneously enlarged pituitary, loss of posterior gland high signal, and thickened stalk 44/F H/A, fever,, DI Homogeneously enhancing isointense intrasellar mass, and loss of posterior pituitary signal no Lee et al. 9 (1994) 47/M Male H/A, decreased libido Intrasellar mass, and chiasmal compression Paja et al. 114 (1994) Magner and West 115 (1994) 27/M Male H/A, impotence Intrasellar mas, suprasellar extension, and chiasmal compression on mri 25/F Amenorrhea, fever,, DI Intrasellar mass, and thickened stalk on 30/F Postpartum H/A, visual symptoms Enhancing intrasellar mass, suprasellar extension, and chiasmal compression Dexamethasone positive Yes/positive Dexamethasone/no effect 60 mg/d prednisolone/ clinical and radiologic surgery/gritty capsule, creamy content, panhypophysitis surgery/necrotic tissue surgery/firm white mass Pulmonary and eye sarcoidosis Pustulosis palmaris et plantaris with eosinophilia Neurosurgery Quarterly, Vol. 12,. 3, 2002

PRIMARY HYPOPHYSITIS 203 TABLE 2. (Continued) Reference (year) Age (years)/ gender Association with pregnancy Presentation Radiologic findings Immunosuppressive / Mode of diagnosis/intraoperative findings Associated autoimmune disease Beressi et al. 44 (1994) Naik et al. 75 (1994) Ahmadi et al. 7 (1995) Abe et al. 116 (1995) McDonald et al. 117 (1995) Thodou et al. 15 (1995) 27/F H/A, visual amenorrhea,, galactorrhea, PRL 34/F Postpartum H/A, N/V, amenorrhea, 40/M Male H/A, visual Diffusely enhancing intrasellar mass with and thickened stalk Pure intrasellar homogeneously enhancing mass on CT Intrasellar slightly hyperintense mass, diffuse enhancement and suprasellar extension 15/F H/A, diplopia Intrasellar slightly hyperintense mass, diffuse enhancement, cavernous sinus involvement, and dural enhancement on 33/F H/A, Intrasellar slightly hyperintense mass, diffuse enhancement, and dural enhancement 38/F H/A, visual 52/M Male Impotence,, DI 34/F Postpartum H/A,, PRL Pure intrasellar mass and dural enhancement Intrasellar mass, loss of posterior gland high signal, and ehickened stalk on Cystic heterogenous intrasellar mass and 60 mg/d prednisolone/positive N/A N/A N/A N/A surgery/not enlarged 52/M N/A H/A, DI Intrasellar lesion on CT 27/F Visual rmal sella and stalk PRL, DI lesion on CT surgery/stalk lesion?/f Postpartum Hyperthyroidism N/A 38/F PH N/A Necropsy 34/F Postpartum PH N/A Necropsy 32/M Male Hypopituitarism Intrasellar mass and suprasellar and cavernous sinus involvement on CT 31/F Antepartum H/A, visual loss Intrasellar mass, and cystic degeneration on CT 41/F Postpartum H/A Intrasellar mass, and cavernous sinus involvement Dexamethasone/no 24/F Amenorrhea N/A 29/F Antepartum PRL, visual Intrasellar mass and symptoms 29/F Visual loss, PRL, DI Stalk lesion, suprasellar extension, and optic atrophy High-dose steroids/no Thyroiditis Neurosurgery Quarterly, Vol. 12,. 3, 2002

204 M. PAMİR AND K. ÖZDUMAN TABLE 2. (Continued) Reference (year) Age (years)/ gender Association with pregnancy Presentation Radiologic findings Immunosuppressive / Mode of diagnosis/intraoperative findings Associated autoimmune disease Hughes et al. 118 (1995) Nishioka et al. 73 (1997) Jabre et al. 16 (1997) Honegger et al. 23 (1997) Tsujii et al. 39 (1997) Sato et al. 40 (1998) 33/F PH Intrasellar mass, and homogeneous enhancement 53/F DI Intrasellar poorly enhancing mass and loss of posterior gland high signal on 25/M Male H/A, N/V Ring-enhancing mass and suprasellar extension with chiasmal compression 35/M Male H/A, PRL Enlarged pituitary and thickened stalk on 42/F DI, PRL Enlarged pituitary and thickened stalk on 18/F DI, PRL Enlarged pituitary, thickened stalk, and sphenoid sinus mucosal swelling on Yes/resolution of symptoms surgery/stalk lesion 28/F PRL Intrasellar mass 38/F PH, PRI, DI Intrasellar rings Desamethasone/ enhancing mass and positive thickened stalk on 40/M Male Hypopituitarism, PRL Intrasellar triangular-shaped enhancing lesion, thickened stalk, and sphenoid mucosal thickening 52/F PH, PRL Intasellar ring-enhancing mass, thickened stalk, and sphenoid mucosal thickening 56/M Male DI Mass in the posterior pituitary and loss of posterior pituitary high signal 31/M N/A PH, DI Enlarged pituitary and loss of posterior pituitary high signal on mri 53/M Male Decreased libido Enlarged pituitary and loss of posterior pituitary high signal Crock 21 (1998) 57/F Apoplexy, PH Enlarged pituitary and 43/F Hypopituitarism Enlarged pituitary and 51/M Male PH Enlarged pituitary on 25/F Hypopituitarism Enlarged pituitary and 52/F PH Enlarged pituitary and 32/F Meningoencephalitis Enlarged pituitary and ring enhancement on Desamethasone/ positive with recurrence surgery/soft mass in the neurohypophysis surgery surgery surgery surgery IDDM, Graves disease, psoriasis IDDM, pernicious anemia Neurosurgery Quarterly, Vol. 12,. 3, 2002

PRIMARY HYPOPHYSITIS 205 TABLE 2. (Continued) Reference (year) Age (years)/ gender Association with pregnancy Presentation Radiologic findings Immunosuppressive / Mode of diagnosis/intraoperative findings Associated autoimmune disease Kristof et al. 10 (1999) Li et al. 48 (1999) Alexiadou- Rudolph et al. 119 (2000) Cheung et al. 6 (2001) Buxton and Robertson 51 (2001) Fujiwara et al. 63 (2001) 60/M Male PH, DI Stalk mass surgery 23/M Male PH Enlarged pituitary, Methylprednisolone pulse/none thickened stalk, and enhancing diaphragm 29/F Antepartum H/A, visual PH Enlarged pituitary, and enhancing stalk 36/F Oligomenorrhea, PH Enlarged pituitary, and enhancing but normal-sized stalk on 73/M Male Sjögren syndrome, DI Mildly enlarged pituitary, extension into hypothalamus and cavernous sinus, thickened stalk, enhancing tentorium and adjacent dura, and loss of posterior pituitary high signal 24/F Antepartum H/A, visual disturbances 24/F Postpartum H/A, galactorrhae, oligomenorrhae 26/F Antepartum H/A, visual Intrasellar homogeneously enhancing mass and available; diffuse sellar enlargement on CT Pituitary mass but no further information on oligomenorrhea 47/F PH, DI, PRL Suprasellar mass and empty sella 72/F PH Enlarged pituitary and thickened infundibulum on mri Methylprednisolone pulse/complete, shrinkage to empty sella Methylprednisolone pulse/none Methylprednisolone pulse/complete surgery/whitish firm mass Transphenoidal surgery/whitish firm mass surgery/reddish firm mass surgery/ surgery/ surgery/sticky yellowish surgery Sjögren syndrome, hypertrophic cranial pachymeningitis Transcranial surgery/panhypophysitis empty sella t reported Tubridy et al. 67 (2001) 46/M Male DI, PH, unilateral CN IV palsy Thickened enhancing stalk and left cavernous sinus mass Prednisolone + methotrexate/ complete biopsy/posterior hypophysitis PH, pan; PRI, hyperprolactinemia; DI, diabetes insipidus; H/A, headache; N/V, nausea-vomiting; CN, cranial nerve; N/A, data not available;, magnetic resonance imaging; IDDM, insulin-dependent diabetes mellitus. gangrenosum, 29 or Crohn disease. 6 Foreign body reactions to adenomas, 30,31 ruptured Rathke cleft cysts, 32 34 mucoceles, 14 and even previous surgery (personal experience) have all been reported to cause granulomatous hypophysitis. After exclusion of all systemic disorders, there remains a small but distinct group with a cryptogenic etiology, 14 commonly known as giant cell granulomatous hypophysitis. Some authors claim that pituitary granulomas attributable to systemic granulomatous diseases have become exceedingly rare in the postantibiotic era. 23 associations with any known autoimmune disease have been reported, except for cases secondary to pyoderma gangrenosum 29 or Crohn disease. 6 There are three reports of granulomatous hypophysitis caused by ruptured intrasellar Rathke cleft cysts. 32 34 All reported patients were women who presented with headache and amenorrhea. On magnetic resonance imaging (), all patients had masses with suprasellar extension, each with a cystic area. of these cases was associated with pregnancy, and in none of these cases was a preoperative diagnosis of hypophysitis suspected. The histologic examination was identical to that Neurosurgery Quarterly, Vol. 12,. 3, 2002

206 M. PAMİR AND K. ÖZDUMAN of idiopathic cases, except for the demonstration of a Rathke cleft cyst. Mucin staining identified the cyst material as the cause of the sterile granulomatous reaction in one of the reports. 33 A granulomatous foreign body reaction to leakage of cyst contents was proposed as the cause of hypophysitis in these patients. 32,33 Because of their close resemblance to giant cell granulomatous hypophysitis, Roncaroli et al. 33 hypothesized that at least some of the cases of idiopathic granulomatous hypophysitis were caused by nondemonstrated ruptured Rathke cleft cysts, but this has never been proven. Lymphocytic Hypophysitis Autoimmunity was suspected from the first case reported, 5 and this hypothesis still continues to be the most plausible pathogenetic mechanism. 6 The presence of lymphoid follicles and activated immune cells, 1,35 interdigitation of lymphocytes with pituitary cells on electron microscopy, 1,35 presence of antipituitary antibodies 20,36,37 in several cases, and association with several other autoimmune pathologic findings 15 support this notion. The immunologic picture, however, is quite nonspecific, and it is not known whether the humoral or cell-mediated arm is primarily active. 35 In most cases, only the adenohypophysis is affected. 6 This inflammation is assumed to be caused by antibodies directed at pituitary cells. 6,21 Autoimmunity against a single population of hormone-producing cells has been reported. 35,38 The disease process less frequently affects the neurohypophysis, but disease restricted to the neurohypophysis and pituitary stalk may still be seen. 24,39 41 Immura et al. 41 suggested that at least some cases of idiopathic DI might be caused by lymphocytic hypophysitis. Some authors claimed that infundibuloneurohypophysitis was a distinct entity but that the coexistence of inflammatory infiltrates in both the adenohypophysis and neurohypophysis favors a common etiology. 39 The disease process is reported to be self-limiting, and remissions such as those seen in lymphocytic hypophysitis may occur. 1 Selective inflammation of the neurohypophysis without any change in hormone production in the anterior pituitary may occur. A necrotizing form of infundibuloneurohypophysitis is reported to be associated with DI. 42 Experimental autoimmune hypophysitis models in mice and rabbits were created by injecting laboratory animals with autologous or homologous pituitary tissue homogenates in combination with Freund adjuvant. 18,43 Interestingly, in the rat model of hypophysitis, inflammation was found to be more severe in pregnant or lactating rats. 4 Antipituitary antibodies were present in several cases, although none were detectable in others. 20,36,37 Bottazzo et al. 20 were the first to describe autoantibodies directed toward prolactin-producing pituitary cells. Several other studies have investigated antipituitary antibodies with incidences reaching 18% in postpartum women. 44 46 specificity could be shown, and it was hypothesized that their presence might be a result of nonspecific pituitary damage. 37 Bottazzo et al. 20 reported that corticotrophic cells of the pituitary exhibited a nonspecific affinity for the human immunoglobulin Fc site in immunofluorescence assays. Earlier reports on pituitary antibodies thus should be cautiously interpreted. 21 Newer tests such as immunoblotting are not hampered by this phenomenon. 21 Nishiki et al. 36 detected serum antibodies to 68-, 49-, and 43-kd anterior pituitary antigens by immune electrophoresis in 5 of 13 cases with lymphocytic hypophysitis, 1 of 12 cases of infundibuloneurohypophysitis, and 0 of 4 cases with isolated adrenocorticotropic hormone (corticotropin) deficiency. The authors conclusion was that these antigens were specific but infrequent. Crock 21 speculated that the 49-kd autoantigen might be related to selective corticotrophin loss occurring in association with lymphocytic hypophysitis or in isolation, but his findings were not supported by Nishiki et al. 36 The absence of any detectable antipituitary antibody does not exclude an immune pathogenesis that may take place early in the pathologic process, and the lack of antibodies in the rat and rabbit models supports this notion. 18,24,43 Guay et al. 18 reported the disappearance of pituitary antibodies in a case treated by transsphenoidal surgery. Pituitary antibodies are also found in empty sella syndrome, 36 Sheehan syndrome, 37 idiopathic growth hormone deficiency, 15 Cushing syndrome, 45 and several other endocrinopathies without hypophysitis. 15 Their significance is debatable. 15 Only a few investigators reported an association with human leukocyte antigens (HLAs). 1,39,47 49 In one of these cases, the patient carried HLA-B8, which the authors reported to be associated with immunologic hyperresponsiveness in normal persons and several autoimmune diseases. 18 An association with several HLAs was reported in hypophysitis cases, but none was common to all. 1,39,47 49 It has been suggested that aberrant expression of HLA D-related antigens and the capacity of epithelial cells to present autoantigens to T lymphocytes may be of importance in the formation of endocrine autoimmunity. 15 It is most likely that the HLAs are not responsible, per se, but only closely related. 1 McCutcheon et al. 49 failed to demonstrate major histocompatibility complex class II antigens on pituitary cells from patients with hypophysitis. Neurosurgery Quarterly, Vol. 12,. 3, 2002

PRIMARY HYPOPHYSITIS 207 An association has been reported with several autoimmune diseases in as many as 30% of cases. 6,10,23 Primary thyroiditis is the most common associated endocrinopathy. Others include Graves disease, 35,50 dacroadenitis, 51 idiopathic retroperitoneal fibrosis, 51,52 adrenalitis, 38 atrophic gastritis and pernicious anemia, 21,52 diabetes mellitus, 21 pancreatitis, 38,51 Sjögren syndrome, 48 and lymphocytic parathyroiditis. 52 Xanthomatous Hypophysitis Only a few cases of xanthomatous hypophysitis have been reported. Because of its close histopathologic resemblance to other infectious xanthomatous findings elsewhere in the body, an infectious etiology is suspected but remains unproven. 22 PATHOLOGIC FINDINGS Histopathologic findings in both diseases vary according to the stage of the inflammation. The acute inflammatory process is followed by progressive scarring, eventually leading to complete replacement of the pituitary tissue by a fibrous scar. 12,31,53,54 Macroscopically, hypophysitis may be solid 3,8,10,23,47,55 or cystic, 14,23,42 and it may appear whitish, 3,8,10,14, yellowish, 3,14,54 or reddish tan. 10,61 Its consistency may range from soft 6,39 to fibrous and gritty. 3,10,47,56 Cysts are often surrounded by a thick capsule. Ultrastructurally, giant cell granulomatous hypophysitis and lymphocytic hypophysitis resemble each other. 55 The adenohypophysis is primarily affected. 23 Extension within the posterior pituitary or stalk may be seen. 39 Giant cell granulomatous hypophysitis is characterized by noncaseating granulomas of epithelioid histiocytes and multinucleated giant cells. 53,54 Lymphocyte collections of varying degree also may be noted. 54 Schaumann and asteroid bodies characteristic of sarcoidosis as well as caseating necrosis, which is a hallmark of tuberculosis, are lacking. 54 Lymphocytic hypophysitis is thought to start as an acute inflammation with symmetric and diffuse enlargement of the gland. 15 The severity of the infiltrate varies from minimal and focal to diffuse and destructive. 35,38 Interstitial fibrosis may be noted and becomes most prominent with prolonged disease. 9 The disease process eventually leads to total replacement of the pituitary tissue by fibrosis and the development of empty sella syndrome. 57 Lymphoplasmacytic infiltration of the anterior pituitary with occasional lymphoid follicles with pale germinal centers is the hallmark of the disease. 1 Varying numbers of neutrophils, eosinophils, and macrophages may be demonstrated. 1 The pituitary parenchyma is diffusely damaged. 1 Selective loss of pituitary cell populations is also reported. 15,35 This selective loss is claimed to be a result of immune attack. In cases presenting with isolated corticotropin deficiency, 21,47,52 no corticotrophic cells were demonstrated by immunohistochemistry or electron microscopy. 42 Occasional islands of preserved cells are seen and may be demonstrated by immunohistochemistry for cytokeratins and hormones. 1 Neurohypophyseal tissue may be demonstrated by vasopressin, neurophysins, neurofilaments, S-100, and glial fibrillary acidic protein. 1 As shown by immunohistochemistry, the infiltrate consists of a mixed population of T and B cells, with T cells being more common. 17 The T4-to-T8 ratio is reported to be 2:1. 35 The B cells tend to form follicles. 35 FIG. 1. Granulomatous hypophysitis. (A) Diffuse, symmetrical enlargement of the pituitary is noted on T1W nonenhanced coronal. te the granular enhancement of the gland and the symmetrical sellar floor. (B)The enlarged pituitary gland appears hypointense on T2W MR images. (C) Thickening of the pituitary stalk is noted with contrast enhancement of the sellar diagphram. Neurosurgery Quarterly, Vol. 12,. 3, 2002

208 M. PAMİR AND K. ÖZDUMAN FIG. 2. Lymphocytic hypophysitis. (A) Diffuse, symmetrical, triangle-shaped enlargement of the pituitary gland with and compression of the optic apparatus is noted on T1W nonenhanced coronal. The gland appears heterogeneous and slightly hypointense. (B) Diffuse, rather homogeneous enhancement is noted after intravenous gadolinium injection. te the enhancing sellar diaphragm and sphenoid mucosa. asymmetry on the sellar floor is seen. (C) T2W coronal image showing the enlarged and hyperintense pituitary gland. (D) Sellar plain x-ray showing ballooning of the sella, erosion of the dorsum, and posterior clinoids. (E) Enlarged pituitary with is noted in the sagital contrast enhance image. te the loss of posterior gland high signal and the thickened sphenoid mucosa. Electron microscopic examination reveals that the infiltrating cells are mainly plasma cells and lymphocytes. 1,35,58 Degenerative changes are noted in pituitary cells, and the number is reduced. 35 A scant number of secretory granules are noted. 1 Oncocytic changes in secretory cells and crinophagy may be noted. 1 Interdigitation of activated cytotoxic lymphocytes with pituitary cells is reported, which favors an autoimmune etiology. 23 immune complex deposits have been noted. 58 Mixed forms of lymphocytic and granulomatous hypophysitis are reported. 23 Xanthomatous hypophysitis is characterized by variable degrees of lymphocyte infiltration as well by lipidladen foamy histiocytes in a well-preserved pituitary gland. 20 The lesions tend to be cystic on both and surgery. 6 INCIDENCE Granulomatous hypophysitis is rare, accounting for less than 1% of all pituitary lesions approached via the transsphenoidal route, 14,54 but rates up to 1.4% have been reported. An annual incidence of 1 in 1 million has been reported. 6 According to Cheung et al., 6 the mean age at diagnosis is 21.5 years for women and 50 years for men, but patient age ranges from 16 years to 76 years. Lymphocytic hypophysitis makes up 0.38% to 1.1% Neurosurgery Quarterly, Vol. 12,. 3, 2002

PRIMARY HYPOPHYSITIS 209 of all cases operated on for sellar pathologic findings. 1 A strong female predilection with a ratio of as much as 8.5:1 was reported 1 ; however, the disease has been reported in a diverse patient population, including men and postmenopausal women. 6,9,18,19 It is now widely accepted that hypophysitis unrelated to pregnancy is more frequent than previously thought. 6 The typical patient is a young woman during late pregnancy or in the postpartum period. 6 Forty-seven percent to 62% of patients present in the peripartum period. 10 Despite the strong association of lymphocytic hypophysitis with pregnancy and delivery, no such association is reported with granulomatous hypophysitis. 1 The mean age of presentation in women is 34.5 years. In male patients, the entity presents a decade later, with a mean age of 44.7 years. 10 CLINICAL MANIFESTATIONS As many as 60% of patients present with mass effect. 6 Unlike pituitary adenoma, headache is usually accompanied by nausea and vomiting and is a common symptom. 23 Headache and decreased libido are the most common symptoms in male patients. 16 Chiasmal compression is common. 10 Diplopia has been reported in 6% of the cases and is attributed to cavernous sinus involvement. 10,24,59 Other ocular palsies caused by cavernous sinus involvement have been reported. 24 Ocular palsies in hypophysitis have been shown to be responsive to steroids. 47 Seventy percent of patients present with endocrine abnormalities. 10 Most commonly, a partial or total adenohypophyseal insufficiency is noted, and unlike pituitary adenoma, corticotrophic and thyrotrophic functions are more commonly affected. 10,35,38,60 Most of the early cases were diagnosed after death in patients who were lost as a result of unrecognized adrenal insufficiency. 5,15,38,52 Suggestive cases must be approached with a great deal of suspicion, because if unrecognized and untreated, the disease may result in death as a result of pituitary insufficiency. 6 In pituitary tumors, the size of the tumor is the major determinant of the degree of. In patients with lymphocytic hypophysitis, the degree of insufficiency is out of proportion to the size of the mass, however. 10,23 Even though isolated corticotropin deficiency is rare, it is the most commonly encountered single hormone deficiency in lymphocytic hypophysitis. 15 Isolated thyroid-stimulating hormone deficiency or selective absence of gonadotropins has also been reported. 15 Giant cell granulomatous hypophysitis most frequently presents with pituitary dysfunction. This may range from single hormonal abnormalities, such as hyperprolactinemia, to pan. 14 Hyperprolactinemia is usually of moderate degree and may clinically present as the syndrome of amenorrhea and galactorrhea. 14,54 Markedly elevated levels also may be encountered. 14 Hyperprolactinemia is a frequent finding in lymphocytic hypophysitis and is encountered in 38% of cases. 10,61 It is more common in lymphocytic hypophysitis than in idiopathic giant cell granulomatous hypophysitis. 54 Thodou et al., 31 having documented lactotrophic hyperactivity and hyperplasia with electron microscopy, reported that this may be a normal finding in pregnancy and the postpartum period. Nevertheless, this theory fails to explain the hyperprolactinemia in men and postmenopausal women. Hyperprolactinemia has been attributed to four mechanisms, including stalk compression by the suprasellar mass, 14 direct alteration of dopamine receptors by immune attack, 1 increased hormone production by stimulating antibodies similar to the ones observed in Graves disease, 62 and destruction of the gland and escape of produced hormone to the circulation. 1 Lactation failure as a result of reduced prolactin levels may be seen in the postpartum period and may be easily confused with Sheehan syndrome. 57 Diabetes insipidus with involvement of the neurohypophysis, which is most commonly reported in neurosarcoidosis, is an uncommon feature in hypophysitis but is reported in both granulomatous and lymphocytic hypophysitis. 15,24,63,64 It is reported that as many as 31% of the patients with lymphocytic hypophysitis may present with a sudden onset of DI. 10 Neurohypophyseal dysfunction is reported to result from compression of the posterior pituitary or stalk or by direct invasion of the inflammatory infiltrate. 40 In such cases, granulomatous hypophysitis or infundibuloneurohypophysitis should be strongly suspected. Both lymphocytic and giant cell granulomatous hypophysitis have been reported to cause pleocytosis and meningitis. 23,64,65 Patients may present with classic signs and symptoms of meningitis. Cerebrospinal fluid cultures are always sterile. 23,64,65 A cerebrospinal fluid examination is not reported in every patient in the literature. 23 Increased cerebrospinal fluid cells counts without associated aseptic meningitis may be noted in occasional patients with lymphocytic hypophysitis. 23 Whether pleocytosis is secondary to spillage of inflammatory cells from the inflamed pituitary or whether it is a result of the spread of the immune reaction to the cerebrospinal fluid spaces has not been ascertained. An increased erythrocyte sedimentation rate may also be noted in patients with hypophysitis. 23 Neurosurgery Quarterly, Vol. 12,. 3, 2002

210 M. PAMİR AND K. ÖZDUMAN DIAGNOSIS Preoperative diagnosis of primary hypophysitis is challenging. There are no serologic or biochemical markers. 16 Several cases of lymphocytic hypophysitis with a preoperative diagnosis and steroid management have been reported. 10 In none of the reported cases of primary granulomatous hypophysitis was the diagnosis made before surgery. 7 The diagnosis of giant cell granulomatous hypophysitis is one of exclusion. 53 Imaging Routine radiographic imaging reveals a normal-sized or symmetrically enlarged sella. 23 Erosion of the dorsum or thinning of the sellar floor may be seen. 54 Computed tomography only demonstrates an intrasellar space-occupying lesion and falls short of distinguishing neoplastic disease from inflammation. 9,54 Lesions have been shown to express one of various contrast enhancement patterns, including homogeneous, patchy, and ring-formed patterns, and the degree ranged from sparse to heavy. 8,9,14,54 With its superb soft tissue resolution, is the method of choice for imaging of hypophysitis. 23 Preoperative use of was first reported by Levine at al. 66 for lymphocytic hypophysitis and by Pamir et al. 54 for giant cell granulomatous hypophysitis. A diffusely enlarged pituitary gland as seen is encountered in 83% of cases. 15 Suprasellar extension is a frequent finding. 15 The mass is frequently iso- or hypointense to the brain parenchyma on T1-weighted images and hyperintense on T2-weighted images, and it enhances strongly with contrast, mimicking macroadenomas. 7,23 The pattern of enhancement is granular, however. 54 Lesions may be cystic, and xanthomatous hypophysitis is more likely to be cystic than other forms of hypophysitis. 22 A normal-sized or even shrunken pituitary may also be seen. 10 An empty sella was seen in 7% of cases of granulomatous hypophysitis and in 9% of cases of lymphocytic hypophysitis. In roughly 9% of cases, imaging was unremarkable. 10 Several findings have been shown to be suggestive of hypophysitis. A symmetric enlargement of the sellar content was seen in 66% of cases. 10 Asymmetric enlargement was seen in only 18% of patients. 10 Unlike pituitary adenomas, which cause an early asymmetric depression, the sellar floor is usually plain in hypophysitis. 23 Loss of posterior gland high signal is frequent. 15 Enlargement of the neurohypophysis may be noted. 15 Radiologic involvement of the posterior pituitary is not always correlated with the presence of DI, however. 15 Thickening of the pituitary stalk or infundibulum is a frequent finding in hypophysitis. 8,15,23 Because the pituitary stalk is an extremely rare site for a pituitary adenoma, this finding is highly suggestive of hypophysitis. It may be seen in granulomatous or lymphocytic hypophysitis, primarily or in combination with findings suggestive of anterior hypophysitis. Thickening was noted in 56% of lymphocytic hypophysitis cases and in 66% of granulomatous hypophysitis cases. 10 Usually, both the stalk and enlarged pituitary tissue enhance homogeneously with contrast. 8 A granular pattern may be seen. 54 Grossly, heterogeneous enhancement was seen in 20% and 12% of cases of granulomatous and lymphocytic hypophysitis, respectively. 10 Enhancement of the diaphragma sella and/or adjacent dura 7,8 or tongue-like extensions along the basal hypothalamus 7,10 are suggestive of hypophysitis. Cavernous sinus or hypothalamic involvement was seen in roughly 12% and 8% of lymphocytic and granulomatous hypophysitis cases, respectively. 7,10,23,24,67 Ahmadi et al. 7 reported that cavernous involvement might result in unilateral or bilateral narrowing of the carotid, mimicking the Tolosa-Hunt syndrome. The presence of enhancing nodular aggregates of epithelioid histiocytes in the subarachnoid space is a rare finding. 7 Hypertrophy of the sphenoid sinus mucosa and changes in the sphenoid bone marrow are frequent findings in hypophysitis. 8,23 Submucosal contrast enhancement may be noted. 7 Whether these changes are related to hypophysitis itself or whether they are a coincidence is yet to be determined. 23 The radiologic appearance closely resembles that of a pituitary adenoma; reportedly, most cases were operated on with a misdiagnosis of pituitary adenoma. 3,15,47,54 When combined with clinical suspicion, the presence of suggestive findings may be highly suggestive of hypophysitis. 10 In such cases, a more conservative approach may be favored in comparison to aggressive surgery in the absence of any thread to the visual system. 7,10,23 All the aforementioned findings may be encountered in granulomatous, lymphocytic, and secondary hypophysitis and cannot distinguish between these pathologic entities. 8,53 Honegger et al. 23 reported that an isointense and diffusely enlarged gland with a triangular suprasellar extension and diffuse and homogeneous enhancement accompanied by enhancement of the diaphragma sella is a rare but pathognomonic feature of lymphocytic hypophysitis. Neurosurgery Quarterly, Vol. 12,. 3, 2002

PRIMARY HYPOPHYSITIS 211 Differential Diagnosis The most common pituitary mass is adenoma. 6 With few exceptions, most cases of inflammatory pituitary disorders were operated on with a preoperative diagnosis of pituitary adenoma. 7 Other neoplastic pathologic entities such as germinoma, craniopharyngioma, dermoid tumor, and metastasis must also be included in the differential diagnosis. 6,50 Inflammatory pathologic findings of the pituitary are rare. 1,23 Despite their rarity, these entities are of great diagnostic importance, because conservative management may be more rewarding than aggressive surgery. 6 A wide variety of causes may result in hypophysitis. Secondary hypophysitis may be caused by bacterial, 2,6,25 27 fungal, or viral pathogens 50 as well as by systemic inflammatory diseases such as sarcoidosis 68 70 and histiocytosis X. 5 Systemic diseases such as Wegener granulomatosis, 28 Takayasu disease, 6 pyoderma gangranosum, 29 and Crohn disease 6 have rarely been shown to result in secondary granulomatous hypophysitis in single case reports. Hypophyseal involvement is an exceedingly rare complication of tuberculosis. 27 It is shown to induce hypophysitis either primarily or secondarily from extension of diffuse basal meningitis. 27 The disease mainly causes caseating granulomas, but as in miliary tuberculosis, caseation necrosis and the demonstration of acid-fast bacilli may not always be possible. 26 The radiologic appearance is usually indistinguishable from that of other causes of hypophysitis with an intrasellar mass and thickened pituitary stalk. 27 Other systemic foci are usually lacking in 71% of these patients, but systemic markers of tuberculosis such as an increased erythrocyte sedimentation rate and a positive purified protein derivative test may be found. 27 Pituitary apoplexy caused by hypophysitis may be falsely interpreted as Sheehan syndrome. 1 In patients with Sheehan syndrome who lack a clear history of postpartum hemorrhage or sepsis, lymphocytic hypophysitis should be suspected. 57,71 Empty sella, a common finding in Sheehan syndrome, is reported to be rare in inflammatory hypophysitis. 53,57 Diabetes insipidus is an uncommon finding in Sheehan syndrome. 57 TREATMENT Medical Therapy Because of possible lethal consequences, hormone replacement should be promptly instituted as indicated. 1,10 Adrenal and thyroid functions are the main concerns. An early morning serum cortisol level below 5 g/dl suggests secondary adrenal insufficiency and a level above 11 g/dl excludes it. 60 A cosyntropin test should be performed if the level is 5 g/dl to 11 g/dl. A low serum free thyroxin level suggests secondary hypothyroidism. 60 Replacement should be started by correcting adrenal insufficiency, because levothyroxine may exacerbate adrenal insufficiency. 60 Therapy should be continued as long as the insufficiency lasts. Although the disease is largely accepted to be of autoimmune origin, anti-inflammatory therapies are not commonly reported. 10 Use of corticosteroids is reported, with variable therapeutic regimens and results to date. 10 According to Kristof et al., 10 lasting improvements occurred in 15% of cases and transient improvements occurred in 62% of cases. Patients should be maintained on steroid over a long period. 23 Relapses were seen days to months after discontinuation of, 10 and cases unresponsive to steroid have been reported. 69 Probably because of the rarity of the entity and the lack of reliable diagnostic parameters, no prospective controlled trials have been reported. Kristof et al. 10 reported the only trial of high-dose methylprednisolone pulse. A pulse was chosen to reduce long-term sequelae caused by steroid and to differentiate therapeutic effect from the natural course. The authors reported a normalization or improvement of findings in 88% of their cases. The results appeared within 6 weeks in 7 of 15 patients and within 6 months in 8 of 15 patients. Improvement in adenohypophyseal function was seen in 44% of these patients. relapses or spontaneous recoveries were detected in the series. Total recovery of hypophyseal function occurred in none of these patients. Despite its encouraging results, the study lacks long-term follow-up, and definitive conclusions cannot be made. Reusch et al. 72 reported a 5-day trial of 4 mg/d dexamethasone in a pregnant woman without any. The patient underwent decompressive surgery at 27 weeks. The authors stressed the fact that steroids do cross the placental barrier to result in earlier lung maturation. Tubridy et al. 67 reported the successful use of a combination of prednisolone and methotrexate after histologic confirmation of lymphocytic hypophysitis. The patient had complete symptomatic and radiologic resolution as confirmed by 9 months after. Steroid has been used in giant cell granulomatous hypophysitis as well. Kristof et al. 53 reported a case unresponsive to a trial of 4 days of 120 mg/kg prednisolone tapered over the next 7 weeks. Nevertheless, the authors noted that the fibrosis of the entire Neurosurgery Quarterly, Vol. 12,. 3, 2002