Pituitary 5: 37–44, 2002

C© 2003 Kluwer Academic Publishers. Manufactured in The Netherlands.

A Relapsing Remitting Lymphocytic HypophysitisM.P. Matta1, M. Kany2, M.B. Delisle3,J. Lagarrigue2, and P.H. Caron1

1Service d’Endocrinologie et Maladies Metaboliques,CHU Rangueil, Toulouse, France; 2Service de neuroradiologie,CHU Rangueil, Toulouse, France; 3Service d’anatomopathologie,CHU Rangueil, Toulouse, France

Abstract. Lymphocytic Hypophysitis is a rare autoimmune

disease of the pituitary presenting mainly with features of

a mass lesion and loss of pituitary function. Its cousre is

quite unpredictable and its treatment is still controversial

as experience in the field remains scarce.

We describe a 45 year-old woman with a history of re-

current fever and meningeal symptoms who was referred

3 years later to our department for pituitary insuffi-

ciency Hormonal studies revealed an anterior pituitary de-

ficiency and autoimmune thyroiditis. Pituitary hypertro-

phy as evidenced by magnetic resonance imaging showed

complete regression upon hydrocortisone substitution

therapy.

Two years later, fever and meningeal symptoms recurred

as well as pituitary hypertrophy. Cerebrospinal fluid anal-

ysis revealed an aseptic lymphocytic meningitis. Pituitary

biopsy confirmed the diagnosis of LH. The patient was

started on prednisone 70 mg per day. She improved clinically

and radiologically and remained free of symptoms there-

after. At a recent follow up the MRI showed an empty sella

turcica. Hereby we illustrate a yet unreported pattern of

LH presenting as a recurrent aseptic meningitis. We also

describe one of the long-term course of the disease which is

still unpredictable.

Key Words. lymphocytic hypophysitis, autoimmune disease,

corticosteroids, primary hypophysitis

Introduction

Lymphocytic Hypophysitis (LH) is a rare autoimmunedisease of the pituitary occuring mainly in women in theperipartum period. Although several reports underlinedits occurence in men [1,2], the female to male prepon-derance remains a striking finding [3].

Commonly LH presents with features of a mass lesionsuch as headache and visual impairement with variableloss of anterior pituitary function and rarely posteriorinvolvement. Clinical and neuroradiologic patterns maysuggest this condition but histopathology remains thegold standard in confirming the diagnosis.

Since long term course of LH is unpredictable asspontaneous remision, relapses, as well as pituitary de-ficiencies have been reported, its treatment with corti-costeroids or surgery remains controversial.

Hereby, we report a peculiar case of a recurrent LHmimicking aseptic meningitis in a non pregnant female

followed for about 9 years illustrating one of the long-term courses of the disease.

Case Study

A forty five year-old female was referred in 1995 for apituitary insufficiency. Her past medical history con-sisted in 2 uneventful pregnancies in 1971 and 1979.She had been well until three years earlier when shewas hospitalized for aseptic meningitis in 1992 and 1993manifested as fever, headache, photophobia, neck stiff-ness and abnormal visual field. In both episodes, CSFanalysis disclosed a lymphocytic meningitis (Table 1).MRI of the brain demonstrated a pituitary mass withsuprasellar extension (Fig. 1). She was started on antibi-otics (tetracycline and amoxicillin) along with cortico-steroids (methylprednisolone 40 mg thrice daily). On thefifth day the fever and the visual symptoms disappearedcompletely. A regression of the pituitary lesion was ob-served on the MRI (Fig. 2). The patient refused any fur-ther work up and she was lost to follow up thereafter.

Two years later when first seen in our departmentof endocrinology, she was complaining of cold intoler-ance, fatigue, amenorrhea of 6 months duration withoutany galactorrhea, polyuria, polydypsia or headache. Shewas afebrile, the physical and neurological exams werewithin the normal limits except for sparse axillary hair,a palpable heterogenous thyroid and early graying of thehair.

Hormonal studies revealed an anterior pituitary in-sufficiency and autoimmune thyroiditis (Table 2). MRIshowed a heterogenous hypertrophy of the pituitarywithout evidence of chiasmatic compression (Fig. 3)The clinical evolution and the neuroradiologic findingssuggested that the pituitary insufficiency is strongly as-cribed to an underlying LH. The patient was dischargedon hormonal replacement therapy with Hydrocortisone30 mg/d, levothyroxin 75 µg/d and ovarian substitu-tion with oestroprogestatives. A follow up MRI done3 months later noted a decrease in the intrasellar mass(Fig. 4).

Address correspondence to: Philippe Caron, Service d’Endocri-nologie et Maladies Metaboliques, Hopital de Rangueil, 1, avenueJean-Poulhes, 31403 Toulouse cedex 4, France. Tel: +11-33-5-61 3223 44; Fax: +11-33-5-61 32 20 55; E-mail: caron.p@chu-toulouse.fr

38 Matta et al.

Fig. 1. MRI of the head (T1 sagittal view with gadolinium contrast) shows intra and suprasellar heterogenous enhancing mass lesion

with marked meningeal enhancement.

Fig. 2. MRI of the head (T1 sagittal view with gadolinium contrast) shows a fifty percent decrease in the size of the pituitary mass

with disappearance of the meningeal enhancement.

Lymphocytic Hypophysitis 39

Fig. 3. (a and b) Coronal and sagittal MRI views with gadolinium contrast revealing necrotic mass lesion in the pituitary fossa with

meningeal enhancement.

40 Matta et al.

Fig. 4. MRI of the head (T1 sagittal view with gadolinium contrast) showing 60% decrease in the size of the pituitary mass and

disappearance of the meningeal enhancement.

In 1997 (2 years later) fever and meningeal symp-toms recurred. CSF analysis revealed once again a lym-phocytic meningitis (Table 1). The MRI showed a recur-rence of the pituitary lesion (Fig. 5). Total body Gallium67 nuclear medicine scan revealed an abnormal uptakeat the level of the sella turcica. Infectious and systemicinflammatory diseases have been ruled out (Table 3).

Table 1. CSF analysis

1993 1997

RBC (/mm3) 10 1WBC (/mm3) 203 300

Lymphocytes (%) 75 80PMN (%) 12 10Macrophages (%) 13 10

Protein (g/l) 1.36 0.9Glucose (g/l) 0.5 0.42

Results of CSF analysis in a patient with lymphocytic hypophysitis mani-

festing with fever and headache.

A pituitary biopsy was done showing an inflammatoryexudate consisting mainly of lymphocytes with smallarea of necrosis and fibrosis, there were no evidenceof a histiocytic infiltrate or granuloma formation andno lymphoid follicles were present (Fig. 6). Prednisonewas started at 70 mg/d with a spectacular improvement.It was tapered progressively over 6 months thereafterand replaced by hydrocortisone 30 mg/d.

Since that time, no relapse was noted by the patient.At a recent follow up, she was doing well on hormonalreplacement therapy. The last MRI, 9 years later, showsa small pituitary gland with evidence of a partial emptysella turcica (Fig. 7).

Discussion

LH is a rarely diagnosed disease. Approximately 100cases have been reported so far with a female prepon-derance (8.5:1), affecting female mainly in the peripar-tum period [3]. However its incidence and the frequencywith which it is not clinically recognized remains to

Lymphocytic Hypophysitis 41

Fig. 5. MRI of the head (T1 sagittal view with gadolinium contrast) shows recurrence of the mass lesion of the pituitary with

meningeal enhancement.

be shown. The cause of LH is unknown, but autoim-mune etiology was strongly suggested, as associationwith other autoimmune diseases such as thyroiditis [4],adrenalitis, atrophic gastritis lymphocytic parathyroidi-tis and type 1 diabetes were noted [3,5,6]. Lately an im-munoblotting test has been developed for the detectionof antipituitary autoantibodies and was used to iden-tify two target auto antigens 49 and 40 KDa cytosolicproteins in 50 to 70% of biopsy proven lymphocytic hy-pophysitis [6].

Usually the clinical manifestations of LH are dueto an expansive sellar mass such as visual field de-fect, headache, nausea and vomiting [7]. Variable pi-tuitary deficiencies have been reported including cor-ticotropin, thyrotropin, gonadotropin, and vasopressin[8] either alone or in combination [1]. Hyperprolactine-mia was noted in half of the patients [3]. Meningealsymptoms and fever were signaled in only two reports[6–9] making recurrent episodes of aseptic meningi-tis over a 5 year period in our patient an exceptionalfinding.

Although the diagnosis may be suspected in theperipartum-female with typical clinical features, its con-firmation in otherwise older women or men remainsproblematic. In fact, the diagnosis in our patient wasstrongly suspected in front of the clinical and neurora-diologic evolution of pituitary insufficiency and its as-sociation with an autoimmune thyroiditis revealed bypositive anti-thyroperoxidase antibodies.

Cohen et al. described some MRI characteristics ofLH [10] such as, large pituitary mass with symmetricalextension in triangular shape toward the chiasma andhomogenous enhancement with thickened diaphragmasella after Gadolinium infusion.

As there are no definite serological or radiologicalmarkers, the diagnosis of LH is often made based onhistopathological examination which reveals lympho-plasmocytic infiltrates occasionnally forming lymphoidfollicles and accompanied by varying number of neu-trophils, eosinophils and macrophages, associated withfocal and diffuse parenchymal destruction [3]. Differ-ential diagnosis include other primary or idiopathic

42 Matta et al.

Fig. 6. Histological appearance of lymphocytic hypophysitis showing lymphocytic infiltrate with destruction of the underlying

pituitary parenchyma.

hypophysitis such as granulomatous and xanthomatoushypophysitis [11]. The presence of histiocytes and mult-inucleated giant cells in the former and lipid rich foamyhistiocytes in the latter generally distinguishes theseconditions from LH.

Long term course of LH is quite unpredictable. Manyreports showed spontaneous recovery of the anterior pi-tuitary function [12,13] leading some authors to suggestsimple observation and others surgery [2]. Although LHis a chronic inflammatory-process the role of cortico-

Table 2. Hormonal studies at different stages of the patient’s

course

Normal1993 1995 1997 2000 range

FT4 ( pg/ml) 3.2 2.8 2 9.5∗∗∗ 6–15TSH (µu/ml) 1.1 3 4.7 0.174∗∗∗ 2–4Anti TPO Ab (U/ml) NR 580 2090 184 <100Cortisol (µg/dl) 8 4∗/24 4∗/11 NR 5–25Estradiol (ng/dl) 0.7 0.6 0.6 NR 1.8–2.5LH (mU/ml) 0.4 1.2∗∗/0.6 2∗∗/1.8 0.7 1–11FSH (mU/ml) 1.4 2.7∗∗/3.9 2.8∗∗/2.3 2.2 0.8–1.6PRL (ng/ml) 17 4.6 6.5 4.3 <20IGF1 (ng/ml) NR 76 100 167 132–228

Results of hormonal assays in a patient with lymphocytic hypophysitis.

NR, not recorded.

Anti TPO, anti thyroperoxydase antibodies.∗Cortisol at baseline/30 minutes after 250 µg of ACTH.∗∗LH and FSH at baseline/25 minutes after 100 µg of GHRH.∗∗∗Patient was on levothyroxine replacement therapy.

steroids in its treatment remains ill defined. As sev-eral anecdotal cases responded well to a doses of pred-nisolone ranging from 13 to 60 mg/d [5–14], others toa replacement dose of Hydrocrtisone (30 mg/d) [15,16],

Table 3. Biochemical and immunological investigations of the

patient with LH

Results

SerologyHIV1 and 2 NegativeHepatitis B NegativeHepatitis C Negative

ADN detection by PCR in CSF ofCMV NegativeEBV NegativeEnterovirus Negative

Body fluid cultures for mycobactrium TB NegativeTPHA NegativeSerum ACE 64 U/LCSF ACE 1 U/LAutoantibodies

Antiadrenal NegativeAntismooth muscle NegativeANA NegativeAnti TPO 2090Antiparietal cell Weakly positive

PCR, Polymerase chain reaction, CSF, cerebrospinal fluid, CMV, cy-

tomegalovirus, EBV, Epstein Barr virus, TB, tuberculosis, TPHA, treponema

pallidum hemmaglutination test, ACE, angiotensin converting enzyme, ANA,

anti-nuclear antibodies.

Normal ranges are serum ACE 60–120 U/L, anti TPO <100.

Lymphocytic Hypophysitis 43

Fig. 7. T1 sagittal view showing a partial empty sella turcica.

many cases showed spontaneous recovery of the pitu-itary function and radiological regression of the mass.The results of the first prospective trial of High dosemethylprednisolone pulse therapy (HDMPT 120 mg/dfor 2 weeks) conducted in only nine patients showedimprovement of the adenopituitary function in 44% ofthe cases and was more favourable in those with shortstanding disease (less than 6 months), whereas improve-ment of the MRI findings occured in 88% of the patientswithin 6 weeks to 6 months after HDMPT [17]. It remainsdoubtful whether the results of HDMPT are definitivebecause follow up in this trial was relatively short. Ourpatient did show a decrease in its pituitary mass on highdose methylprednisolone during the first episode of LHbut responded as well clinically and radiologically toa substitution therapy with 30 mg/d of hydrocortisoneduring a subsequent episode. This raises several ques-tions: is there a real benefit in using corticosteroids inLH and, if so, at what dose? Is empty sella turcica aninevitable outcome of LH? Therefore the role of corti-costeroids are yet to be clearly defined, and it seemsreasonable to manage these patients expectantly when

the symptoms develop in the classic setting and surgeryshould be warranted only when mandated by the pres-ence of potentially irreversible neurological signs nonresponsive to steroids.

References

1. Jenkins PJ, Chew SL, Lowe DG, Afshar F, Charlesworth M,Besser GM, Wass JAH. Lymphocytic hypophysitis: Unusual fea-tures of a rare disorder. Clin Encrinol 1995;42:529–534.

2. Abe T, Matsumoto K, Sanno N, Osamura Y. Lymphocytic hy-pophysitis: Case report. Neurosurgery 1995;36(5):1016–1019.

3. Thodou E, Asa SL, Kontogeorgos K, Kovacs K, Horvath E, EzzatS. Clinical case seminar: Lymphocytic hypophysitis: Clinico-pathological findings. J Clin Endocrinol Metab 1995;80:2302–2311.

4. Barbaro D, Loni G. Lymphocytic hypophysitis and autoimmunethyroid disease. J Endocrinol Invest 2000;23:339–340.

5. Pestell RG, Best JD, Alford FP. Lymphocytic hypophysitis. Theclinical spectrum of the disorder and evidence for an autoim-mune pathogenesis. Clin Endocrinol 1990;33:457–466.

6. Crock P. Cytosolic autoantigens in lymphocytic hypophysitis.J Clin Endocrinol Metab 1998;83:609–618.

44 Matta et al.

7. Naik RG, Ammini A, Shah P, Sarkar C, Mehta VS, BerryM. Lymphocytic hypophysitis. Case report. J Neurosurg

1994;80(5):925–927.8. Honegger J, Fahlbush R, Bornemann A, Hensen J, Buchfelder

M, Muller M, Nomikos P. Lymphocytic and granulomatoushypophysitis: Experience with nine cases. Neurosurgery

1999;44:426–427.9. Vanneste JAL, Kamphorst W. Lymphocytic hypophysitis. Surg

Neurol 1987;28:145–149.10. Cohen R, Beressi N, Modigliani E. Lymphocytic hypophysitis.

Clin Endocrinol 1995;43:769.11. Cheung CC, Ezzat S, Smyth HS, Asa SL. The spectrum and

significance of primary hypophysitis. J Clin Endocrinol Metab

2001;86:1048–1053.12. Nihioka H, Fukushima C. Reccurrent lymphocytic hypophisi-

tis: Case report. Neurosurgery 1997;41(3):684–686.13. Noto H, Tsukamoto K, Hayashi S, Fujita T, Kimura S.

Spontaneous recovery from hypopituitarism in a man with lym-phocytic hypophysitis: A case report. Endocr J 2001;48:483–486.

14. Beressi N, Cohen R, Beressi JP, Dumas JL, Legrand M, Iba-ZizenMT, Modigliani E. Pseudotumoral lymphocytic hypophysitissuccessfully treated by corticosteroids alone: First case report.Neurosurgery 1994;35:505–508.

15. Hayes FJ, Mckenna TJ. The occurrence of lymphocytic hy-pophysitis in a first but not subsequent pregnancy. J Clin

Endocrinol Metab 1996;81:3131–3132.16. Gagneja H, Arafah B, Taylor HC. Histologically proven

lymphocytic hypophysitis: Spontaneous resolution and sub-sequent pregnancy. Mayo Clin Proc 1999;74:150–154.

17. Kristof R, Van Roost D, Klingmuller D, Springer W, Schramm J.Lymphocytic hypophysitis: Non invasive diagnosis and treat-ment by high dose methylprednisolone pulse therapy? J Neurol

Neurosurg Psychiatry 1999;67:398–402.