J Neurosurg / June 26, 2009

DOI: 10.3171/2009.6.JNS081176

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L ymphocytic hypophysitis is an uncommon autoim-mune inflammatory disorder of the pituitary gland, most often occurring in women of child-bearing

age, usually late in pregnancy or shortly after childbirth. Patients typically seek medical attention because of in-trasellar mass effects and pituitary hypofunction, with headache, visual deficits, and deficiency in adrenocorti-cotropic hormone secretion being the usual presenting features.11 This condition can also present as pituitary apoplexy.10

Uncommonly, the disorder has also been known to affect men, women past child-bearing age,1,7,8 and chil-dren.3 An equal incidence according to sex was reported in an earlier study performed at our institution.8 Micro-scopically, the gland is infiltrated with lymphocytes, macrophages, and plasma cells, and antipituitary anti-bodies—notably secretogranin II—have been isolated.2 The condition is occasionally associated with a ruptured Rathke cleft cyst,12,15 other autoimmune disorders such

as thyroiditis,9 systemic lupus erythematosus,4 and dac-roadenitis.5 Not infrequently, it can be misdiagnosed as a nonfunctioning pituitary adenoma.6

The therapeutic options for this disease are contro-versial, and include transsphenoidal removal of the intra-sellar mass and administration of corticosteroid therapy; stereotactic radiotherapy has also been used.13 The pos-sibility of late recurrence after transsphenoidal surgery has been reported.16 We report on a case of lymphocytic hypophysitis in which symptoms and signs recurred af-ter transsphenoidal surgery. The patient was eventually treated successfully with GKS.

Case Report

History and Examination. This 37-year-old pregnant woman (para 1, gravida 2) was referred to the Neuroen-docrine Center at the University of Virginia. She under-went evaluation for a large pituitary mass that had been diagnosed 3 weeks previously. At that time, she had ex-perienced sudden-onset diplopia and was found to have a

Gamma Knife surgery for lymphocytic hypophysitis

Case reportDibyenDu Kumar ray, m.D.,1 Chun Po yen, m.D.,1 mary Lee VanCe, m.D.,2 eDwarD r. Laws, m.D.,4 beatriz LoPes, m.D.,3 anD Jason P. sheehan, m.D., Ph.D.1

Departments of 1Neurological Surgery, 2Medicine, and 3Division of Neuropathology, University of Virginia, Charlottesville, Virginia; and 4Department of Neurological Surgery, Brigham and Women’s Hospital, Boston, Massachusetts

Lymphocytic hypophysitis is a relatively uncommon autoimmune inflammatory disorder affecting the pituitary gland. It most frequently occurs in women of child-bearing age. The authors report on their experience with a patient who presented with diplopia and marked enlargement of the pituitary gland. She underwent transsphenoidal surgery, and histopathological analysis confirmed the diagnosis of lymphocytic hypophysitis. The disease proved refractory to resection, and any attempt at withdrawal of corticosteroid therapy resulted in a return of the patient’s symptoms and enlargement of the sellar contents.

The patient underwent Gamma Knife surgery (GKS) to the sella and both cavernous sinuses. After GKS, the patient was able to discontinue steroid therapy without return of her symptoms. Follow-up MR images demonstrated no evidence of recurrence of lymphocytic hypophysitis.

For persistent lymphocytic hypophysitis, GKS is a reasonable treatment option.(DOI: 10.3171/2009.6.JNS081176)

Key worDs      •      lymphocytic hypophysitis      •      Gamma Knife surgery      • radiosurgery      •      pituitary disorder

1

Abbreviation used in this paper: GKS = Gamma Knife surgery.

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right cranial nerve VI nerve palsy. She had no significant medical history, except a normal pregnancy resulting in the delivery of a full-term baby girl 3 years earlier. The patient had done well through her first 18 weeks of preg-nancy. In the 21st week, she experienced acute onset of double vision, which was not accompanied by headache, nausea, or vomiting. The double vision was initially eval-uated by an ophthalmologist, and the patient was found to have normal visual acuity and fields but a right cranial nerve VI palsy. Subsequent noncontrast-enhanced MR images revealed a large sellar and suprasellar mass abut-ting the right carotid artery and extending to involve the right cavernous sinus (Fig. 1A).

During her third trimester, the patient underwent transsphenoidal decompression, removal of intrasellar tissue, and decompression of the right cavernous sinus. Her immediate postoperative course was uneventful apart from the development of transient postoperative diabetes insipidus, which was managed conservatively. The diabe-tes insipidus resolved a few days postoperatively.

Histopathological Analysis. Tissue submitted for pathological analysis was composed of dura mater and pi-tuitary gland fragments. The dura mater showed a dense inflammatory infiltrate composed of mature lymphocytes invading the layers of dense connective tissue (Fig. 2A). Analysis of the pituitary gland sample revealed it to be both anterior and posterior pituitary gland with preserva-tion of the cytoarchitecture and reticulin network (Fig. 2B and C). Although inflammatory cells were seen rarely on H & E staining (Fig. 2B), immunohistochemical stains for leukocyte common antigen (CD45) demonstrated a mild to focally moderate inflammatory (mainly lym-phocytic) infiltrate of the pituitary parenchyma (Fig. 2D). There was no evidence of fibrosis within the gland as seen on stains with H & E and Wilder’s reticulin (Fig. 2B and C). These histopathological findings were consistent with lymphocytic hypophysitis.

Postoperative Course. The patient had relief of her dip lo pia for 2 weeks. However, an MR imaging scan per formed 5 weeks later revealed a right sellar mass ex-tending into the cavernous sinus. One month after the transsphenoidal surgery, she had a low free T4 level and was treated with thyroid hormone. Concerns regarding radiation exposure from any radiosurgical treatment dur-ing pregnancy prompted the treating clinicians to recom-mend steroid (prednisone) therapy, and within 2 weeks of initiation of therapy she became symptom free. She had a successful delivery by cesarean section, and remained symptom-free on steroid therapy. However, each time the steroids were discontinued, her diplopia recurred. Be-cause of the adverse effects of long-term steroid therapy, including the development of Cushing’s syndrome, she was referred for radiosurgery.

Radiosurgery. The patient underwent stereotactic ra-diosurgery at the University of Virginia Gamma Knife Center (Fig. 1B). Stereotactic MR imaging was per-formed and a 3D stereotactic treatment plan was created to treat the sellar and cavernous sinus contents. Sixteen isocenters and 1 dose matrix were used in the treatment.

A volume of 3.5 cm3 was treated with a prescription dose of 15 Gy to the 50% isodose line.

Postradiosurgery Follow-Up. The prednisone dose was tapered beginning 3 weeks after radiosurgery. Four weeks after treatment, she was able to discontinue predni-sone therapy altogether, without recurrence of symptoms. She continues to be asymptomatic without prednisone at > 12 months after GKS. Recent MR images obtained in the patient showed no evidence of a reduction in the size of the sellar contents (Fig. 1C). No new hormone deficits, beyond her hypothyroidism, which predated radiosurgery, have been diagnosed. The patient has normal menses and gonadal function, and is attending regular follow-up with a neurosurgeon, endocrinologist, and a neuroophthalmol-ogist.

DiscussionThe optimal treatment of lymphocytic hypophysi-

tis remains the subject of debate. Initial transsphenoidal surgery to relieve mass effect has been associated with recurrence, more so if there is cavernous sinus involve-ment. Initiation of steroid therapy offers potent medical management of the condition (provided the diagnosis of a nonfunctioning pituitary adenoma has been excluded), but the adverse effects of long-term steroid therapy limit its use as a solution. Success has earlier been reported with the use of stereotactic radiotherapy using a dose of 24 Gy given in 12 treatments of 200 cGy per fraction.13

This is the first reported case of lymphocytic hy-pophysitis successfully treated with stereotactic radio-surgery using the Leksell Gamma Knife. Symptomatic relief was achieved using a prescription dose of 15 Gy. This strategy seems to be a prudent option for patients with lymphocytic hypophysitis whose condition has not responded to conventional surgery and medical therapy. Follow-up to assess for clinical recurrence and delayed hypopituitarism must be performed. At our center, de-layed hypopituitarism after radiosurgery has been ob-

Fig. 1. Coronal MR images obtained in the patient with lymphocytic hypophysitis at presentation (A), the day of GKS (B), and 9 months post-GKS (C).

J Neurosurg / June 26, 2009

Gamma Knife surgery for lymphocytic hypophysitis

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served in ~ 20–30% of patients with pituitary adenoma; hypopituitarism typically occurs within the first 5 years following radiosurgery.14

ConclusionsGamma Knife surgery may be a viable treatment op-

tion for patients with lymphocytic hypophysitis in whom surgical or medical management has failed. Experience with a larger number of such patients will provide more information on this method of treatment.

Disclaimer

The authors report no conflict of interest concerning the mate-rials or methods used in this study or the findings specified in this paper.

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Fig. 2. Photomicrographs. A: Stain of a dura mater biopsy sample showing dense lymphocytic inflammatory infiltrates. H & E, original magnification × 200. B: Anterior pituitary gland tissue staining showing essentially normal cytoarchitecture with pres-ervation of the acinar pattern confirmed by reticulin stain. Reticulin also demonstrates absence of appreciable gland fibrosis. H & E, original magnification × 200. C: Section from the anterior pituitary gland showing essentially normal cytoarchitecture with preservation of the acinar pattern confirmed by reticulin stain. Reticulin also demonstrates absence of appreciable gland fibrosis. Wilder’s reticulin stain, original magnification × 100. D: Sample stained with leukocyte common antigen (LCA, CD45) showing mild lymphocytic inflammatory infiltration of the anterior pituitary gland. Original magnification × 200.

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Manuscript submitted September 17, 2008.Accepted June 3, 2009.Please include this information when citing this paper: published

online June 26, 2009; DOI: 10.3171/2009.6.JNS081176.Address correspondence to: Jason P. Sheehan, M.D., Ph.D.,

De partment of Neurological Surgery, University of Virginia Health Sci ences Center, Box 800212, Charlottesville, Virginia 22902. email: jps2f@virginia.edu.