Lymphocytic Hypophysitis

Greg Dowd, MD and Deepak Awasthi, MD
Department of Neurosurgery; LSU Medical Center; New Orleans, LA

[Introduction | LSU Experience | Discussion | References]

Introduction:
Lymphocytic hypophysitis (LH) is an important cause of pituitary dysfunction in the young female. Multiple reports in the last 15 years have helped to clarify this disorder as an auto immune inflammation of the pituitary gland. This process can lead to both endocrine dysfunction and/ or gland enlargement with compression of visual pathway structures. As treatment strategies for this condition differ from other lesions of the pituitary, recognition of this diagnosis is crucial.

The pathology of LH was first described in 1962 in a young postpartal female who died of shock following an appendectomy (7). She was found to have marked adrenal atrophy in addition to fibrosis and lymphocytic invasion of her piuitary gland. Subsequent autopsy reports in young postpartum females followed suggesting a dismal course for lymphocytic hypophysitis. However, in 1980 an antemortem diagnosis and successful outcome was documented in a patient that under went a trans- sphenoidal resection of a suspected pituitary tumor (9). Since this time, several indicators suggest thst this rarely diagnosed condition is probably much more common than previously suspected.

LSU Experience:
During the period 1993-6, three patients with lymphocytic hypophysitis presented to the neurosurgical service. All three patients were young females in the early post partum period with headaches and visual field deficits. Table 1 provides a summary of their clinical picture at presentation.

TABLE 1
Lymphocytic Hypophysitis
LSU Experience 1993-1996
Age Months
Post-partum
Symptoms Endocrine MRI
26 2 * Headache
* Right homonymous visual field deficit
low TSH
low FTI
* non-aerated cells
* contrast-enhancing
lesion
* suprasellar ext.
27 5 * Headache (1 year)
* Nipple discharge
* Amenorrhea
* Left temporal mon-
ocular anopsia
PRL: 96 * suprasellar ext.
28 5 * Headache normal * 1.5x2.5cm contrast-enhancing lesion
* suprasellar ext with chiasmatic compression

TSH: Thyroid stimulating hormone
FTI: Free Thyroid Index
PRL: Prolactin
ext: extension

Case History:
A.H. is a 26 yo black female who was previously healthy and five months postpartum from a normal vaginal delivery. She had complained of headaches since delivery and persistent amenorrhea despite bottle feeding. She noticed a right temporal visual field deficit one month prior to neurosurgical evaluation. An MRI (Figure 1) demonstrated a 2.0 x 2.5 cm lesion with suprasellar extension and chiasmal compression. This had diffuse enhancement with contrast, including the infundibular area.


Figure 1; left: T1-weighted sagittal MRI scan of the brain after IV contrast reveals diffuse enhancement of the pituitary gland (black arrow). Also note the enlargement of the infundibular stalk (white arrow). right: T1-weighted coronal MRI scan of the brain after IV contrast reveals diffuse enhancement and enlargement of the pituitary gland. Once again note the enlargement and enhancement of the stalk (white arrow).
Download a larger coronal image as seen on the right above.

The patient underwent near total hypophysectomy via the trans-sphenoidal route with decompression of the chiasm. The pituitary tissue was found to be brownish and fibrous. Microscopic evaluation showed fibrous inflammatory tissue surrounding clumps of pituitary tissue. A decadron stress dose and taper over a ten day period was also given. Post-operatively, the patient had transient diabetes insipidus necessitating DDAVP for four days and had resolution of her headaches and visual field deficit. A follow up MRI done two months later showed a normal pituitary gland without enhancement and a decompressed optic chiasm.

Discussion:
The cases presented here serve to illuminate and confirm the most common presentation of lymphocytic hypophysitis. Although described in both sexes (1) and in all age groups from adolescence until old age, young females either during pregnancy or immediately post partum comprise the bulk of the patients.

Pathophysiology:
The occurrence of pituitary inflammation associated with pregnancy is felt to be secondary to the involution of the pituitary gland that takes place during this time (4,7). Under the influence of estrogen during pregnancy, the pituitary gland increases in size up to 400% (6). This rapidly returns to baseline following parturition. Serologic examination of women one week following normal delivery demonstrated that 18% developed anti- pituitary antibodies (5). It was noted that those with antibodies present had a much higher incidence of pituitary insufficiency. This suggests that pregnancy induced reaction against the pituitary gland may affect a potentially large group of women with a range of pathologic changes. It is entirely possible that those women diagnosed with lymphocytic hypophysitis due to a visual defect or gross hormonal change represent only the tip of the iceberg.

In women with the appropriate immune background, an auto immune response is generated. Amongst one group of LH patients, a 24% prevalence of other auto immune disorders was identified (11). Thyroiditis was the most common disorder amongst this group. Several of the cases of LH have not been associated with pregnancy but their was an history of an antecedent viral illness. Possibly an altered immune reaction to the viral antigens cross reacted with the pituitary tissue. This suggests that lymphocytic hypophysitis may be the final common pathway for several combinations of genetic backgrounds and antigen combinations.

Differentiating Pituitary Adenoma from Hypophysitis (Table 2):

TABLE 2
Differentiation of Lymphocytic Hypophysitis and Pituitary Adenoma
Lymphocytic Hypophysitis (LH) Pituitary Adenoma (PA)
Presentation Headaches and visual changes more common infertlity more common
Hormones Prolactin usually <100 pg/ml Prolactin usually >200pg/ml
Radiology (MRI) * Diffusely enhancing gland
* No hypointense areas
* Thickened and contrast-enhancing infundibular stalk
* Parasellar enhancement
* Less likely to enhance (especially microadenoma)- if enhancing, adjacent pituitary is normal
* No parasellar or infundibular enhancement

The initial presentation of headaches and possible visual or endocrine disturbance associated with pregnancy already goes a long way to separate the two. A history of infertility is common in the adenoma (PA) group while nearly all LH patients achieve spontaneous pregnancy. Also, headaches and visual changes are much more common in the LH group. The prominence of visual problems of LH patients may reflect an under diagnosis of those patients without visual deficit.

The type of endocrine change is very important Both lesions may show elevation of prolactin, but that with a prolcatinoma is generally much higher; values in LH rarely go higher than 100pg/ml while PA patients frequently have values greater than 200 pg/ml. Hormonal production is frequently blocked. Since the mechanism for this is compression of the gland in PA and diffuse inflammation in LH, the size of the sellar mass is usually much greater in PA for a given degree of hormonal derangement. Early changes in LH are hypoadrenalism and hypothyroidism while PA often shows gonadotropin and growth hormone reduction. Thus, quantitative hormonal changes and the relation to mass size is quite important.

Radiological characteristics can also be used to distinguish these two entities. Plain films may show reactive sellar bony sclerosis from the inflammatory process. Computed tomography has demonstrated contrast uptake in the sellar bone and sphenoid sinus in LH which is absent in pituitary adenoma. MRI, with its greater characterization of soft tissues, has been invaluable for differentiating these two processes. Pituitary adenomas typically have a contrast enhancing or hypointense area confined to or compressing adjacent normal gland. The picture of LH is quite different; The gland is diffusely and dramatically enhancing (see Figure 1). Also, the presence of a thickened and contrast enhancing infundibular stalk is nearly pathognomonic of the condition (10)- see Figure 1. This enhancement may be either homo- or heterogeneous. Parasellar structures such as dura mater, sphenoid and cavernous sinuses may also enhance with lymphocytic hypophysitis (2).

Management:
Selection of a therapeutic intervention after diagnosis has been made requires an understanding of the natural history of this affliction. Lymphocytic hypophysitis begins with acute inflammation of the pituitary marked by edema. This results in headaches and, if extensive, it can lead to compression of the optic chiasm. Endocrine changes may occur, ranging from undetectable to panhypopituitarism. The acute phase of inflammation subsides over time to yield either a scarred, atrophic sellar space or regression of the gland back towards the normal state. It must be stressed that a high index of suspicion is necessary to diagnose lymphocytic hypophysitis when only the protean signs of mild headache and malaise are present. This is important because at least nine deaths are documented in the literature, most based on delayed pituitary insufficiency. These patients will need careful endocrinologic follow up to avoid such complications (3).

Those patients that present with evidence of intense inflammation as manifest by visual pathway compression will require surgical decompression (4,8). There are many reports of visual improvement following decompression via the trans-nasal, trans- sphenoidal route. A large group of patients will have only headache and radiologic evidence of lymphocytic hypophysitis. There have been multiple reports of these patients improving with glucocorticoid administration alone (3,4,11). An exact dosage necessary for treatment has not been determined. However, investigators report sucessful results with dosing in the range of 60 mg prednisone/ day for a period of one month to a year followed by a gradual tapering with concurrent monitoring for relapse of symptomatology (3,4,8). Glucocorticoids have a diagnostic as well as therapeutic role (prolactinoma size should not change with steroids). This will allow further differentiation of these two entities.

Using this treatment paradigm, surgery would be reserved for patients with (i) the progression of clinical signs of mass effect, (ii) failure to improve on follow up MRI scanning or (iii) recrudescence of symptoms upon cessation of glucocorticoids.

References:

  1. Abe T, Matsumoto K, Sanno N, Osamura Y: Lymphocytic hypophysitis: Case report. Neurosurgery 36:1016-1019, 1995.
  2. Ahmadi J, Meyers GS, Segall HD, Sharma OP, Hinton DR: Lymphocytic adenohypophysitis: Contrast enhancing MR imaging in five cases. Radiology 195:30-34, 1995.
  3. Beressi N, Cohen R, Beressi J-P, Dumas J-L, Legrand M, Iba-Zizen M-T, Modigliani E: Pseudotumoral lymphocytic hypophysitis successfully treated by corticosteroid alone: First case report. Neurosurgery 505-508, 1994.
  4. Cosman F, Post KD, Holub DA, Wardlaw SL: Lymphocytic Hypophysitis: Report of 3 new cases and review of the literature. Medicine 68:240-256, 1989.
  5. Engleberth O, Jezkova Z: Autoantibodies in Sheehan's syndrome. Lancet 1: 1075, 1965.
  6. Gonzalez JG, Elizondo G, Saldivar D, Nanez H, Todd LE, Villarreal JZ: Pituitary gland during normal pregnancy: An in-vivo study using MRI. Am J Med 85:217-220, 1988.
  7. Goudie RB, Pinkerton PH: Anterior hypophysitis and Hashimoto's disease in a young woman. J Path Bact 83: 584-585, 1962.
  8. Leiba S,Schindel B, Weinstein R, Lidor I, Friedman S, Matz S: Spontaneous postpartum regression of pituitary mass with return of function. JAMA 255 (2):230-232, Jan10,1986.
  9. Mayfield RK, Levine JH, Gordon L, Powers J, Galbraith RM, Rawe SE: Lymphoid adenohypophysitis presenting as a pituitary tumor. Am J Med 69:619-623, 1980.
  10. Powrie JK, Powell M, Ayers AB, Lowy C, Sonksen PH: Lymphocytic adenohypophysitis: Magnetic resonance imaging features of two new cases and a review of the literature. Clin Endo 42:315-322, 1995.
  11. Pressman EK, Zeidman SM, Reddy UM, Epstein JI, Brem H: Differentiating lymphocytic hypophysitis from pituitary adenoma in the peripartum patient. J Rep Med 40:251-259, 1995.