A Relapsing Remitting Lymphocytic Hypophysitis

Transcription

1 Pituitary 5: 37 44, 2002 C 2003 Kluwer Academic Publishers. Manufactured in The Netherlands. A Relapsing Remitting Lymphocytic Hypophysitis M.P. Matta 1, M. Kany 2, M.B. Delisle 3, J. Lagarrigue 2, and P.H. Caron 1 1 Service d Endocrinologie et Maladies Metaboliques, CHU Rangueil, Toulouse, France; 2 Service de neuroradiologie, CHU Rangueil, Toulouse, France; 3 Service 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 recurrent fever and meningeal symptoms who was referred 3 years later to our department for pituitary insufficiency Hormonal studies revealed an anterior pituitary deficiency and autoimmune thyroiditis. Pituitary hypertrophy 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 analysis 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 thereafter. 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 autoimmune disease of the pituitary occuring mainly in women in the peripartum period. Although several reports underlined its occurence in men [1,2], the female to male preponderance remains a striking finding [3]. Commonly LH presents with features of a mass lesion such as headache and visual impairement with variable loss of anterior pituitary function and rarely posterior involvement. Clinical and neuroradiologic patterns may suggest this condition but histopathology remains the gold standard in confirming the diagnosis. Since long term course of LH is unpredictable as spontaneous remision, relapses, as well as pituitary deficiencies have been reported, its treatment with corticosteroids or surgery remains controversial. Hereby, we report a peculiar case of a recurrent LH mimicking aseptic meningitis in a non pregnant female followed for about 9 years illustrating one of the longterm courses of the disease. Case Study A forty five year-old female was referred in 1995 for a pituitary insufficiency. Her past medical history consisted in 2 uneventful pregnancies in 1971 and She had been well until three years earlier when she was hospitalized for aseptic meningitis in 1992 and 1993 manifested as fever, headache, photophobia, neck stiffness and abnormal visual field. In both episodes, CSF analysis disclosed a lymphocytic meningitis (Table 1). MRI of the brain demonstrated a pituitary mass with suprasellar extension (Fig. 1). She was started on antibiotics (tetracycline and amoxicillin) along with corticosteroids (methylprednisolone 40 mg thrice daily). On the fifth day the fever and the visual symptoms disappeared completely. A regression of the pituitary lesion was observed on the MRI (Fig. 2). The patient refused any further work up and she was lost to follow up thereafter. Two years later when first seen in our department of endocrinology, she was complaining of cold intolerance, fatigue, amenorrhea of 6 months duration without any galactorrhea, polyuria, polydypsia or headache. She was afebrile, the physical and neurological exams were within the normal limits except for sparse axillary hair, a palpable heterogenous thyroid and early graying of the hair. Hormonal studies revealed an anterior pituitary insufficiency and autoimmune thyroiditis (Table 2). MRI showed a heterogenous hypertrophy of the pituitary without evidence of chiasmatic compression (Fig. 3) The clinical evolution and the neuroradiologic findings suggested that the pituitary insufficiency is strongly ascribed to an underlying LH. The patient was discharged on hormonal replacement therapy with Hydrocortisone 30 mg/d, levothyroxin 75 µg/d and ovarian substitution with oestroprogestatives. A follow up MRI done 3 months later noted a decrease in the intrasellar mass (Fig. 4). Address correspondence to: Philippe Caron, Service d Endocrinologie et Maladies Metaboliques, Hôpital de Rangueil, 1, avenue Jean-Poulhes, Toulouse cedex 4, France. Tel: ; Fax: ; caron.p@chu-toulouse.fr

2 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.

3 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.

4 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 symptoms recurred. CSF analysis revealed once again a lymphocytic meningitis (Table 1). The MRI showed a recurrence of the pituitary lesion (Fig. 5). Total body Gallium 67 nuclear medicine scan revealed an abnormal uptake at the level of the sella turcica. Infectious and systemic inflammatory diseases have been ruled out (Table 3). Table 1. CSF analysis RBC (/mm 3 ) 10 1 WBC (/mm 3 ) Lymphocytes (%) PMN (%) Macrophages (%) Protein (g/l) Glucose (g/l) Results of CSF analysis in a patient with lymphocytic hypophysitis manifesting with fever and headache. A pituitary biopsy was done showing an inflammatory exudate consisting mainly of lymphocytes with small area of necrosis and fibrosis, there were no evidence of a histiocytic infiltrate or granuloma formation and no lymphoid follicles were present (Fig. 6). Prednisone was started at 70 mg/d with a spectacular improvement. It was tapered progressively over 6 months thereafter and 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 hormonal replacement therapy. The last MRI, 9 years later, shows a small pituitary gland with evidence of a partial empty sella turcica (Fig. 7). Discussion LH is a rarely diagnosed disease. Approximately 100 cases have been reported so far with a female preponderance (8.5:1), affecting female mainly in the peripartum period [3]. However its incidence and the frequency with which it is not clinically recognized remains to

5 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 autoimmune etiology was strongly suggested, as association with other autoimmune diseases such as thyroiditis [4], adrenalitis, atrophic gastritis lymphocytic parathyroiditis and type 1 diabetes were noted [3,5,6]. Lately an immunoblotting test has been developed for the detection of antipituitary autoantibodies and was used to identify two target auto antigens 49 and 40 KDa cytosolic proteins in 50 to 70% of biopsy proven lymphocytic hypophysitis [6]. Usually the clinical manifestations of LH are due to an expansive sellar mass such as visual field defect, headache, nausea and vomiting [7]. Variable pituitary deficiencies have been reported including corticotropin, thyrotropin, gonadotropin, and vasopressin [8] either alone or in combination [1]. Hyperprolactinemia was noted in half of the patients [3]. Meningeal symptoms and fever were signaled in only two reports [6 9] making recurrent episodes of aseptic meningitis over a 5 year period in our patient an exceptional finding. Although the diagnosis may be suspected in the peripartum-female with typical clinical features, its confirmation in otherwise older women or men remains problematic. In fact, the diagnosis in our patient was strongly suspected in front of the clinical and neuroradiologic evolution of pituitary insufficiency and its association with an autoimmune thyroiditis revealed by positive anti-thyroperoxidase antibodies. Cohen et al. described some MRI characteristics of LH [10] such as, large pituitary mass with symmetrical extension in triangular shape toward the chiasma and homogenous enhancement with thickened diaphragma sella after Gadolinium infusion. As there are no definite serological or radiological markers, the diagnosis of LH is often made based on histopathological examination which reveals lymphoplasmocytic infiltrates occasionnally forming lymphoid follicles and accompanied by varying number of neutrophils, eosinophils and macrophages, associated with focal and diffuse parenchymal destruction [3]. Differential diagnosis include other primary or idiopathic

6 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 xanthomatous hypophysitis [11]. The presence of histiocytes and multinucleated giant cells in the former and lipid rich foamy histiocytes in the latter generally distinguishes these conditions from LH. Long term course of LH is quite unpredictable. Many reports showed spontaneous recovery of the anterior pituitary function [12,13] leading some authors to suggest simple observation and others surgery [2]. Although LH is a chronic inflammatory-process the role of cortico- Table 2. Hormonal studies at different stages of the patient s course Normal range FT4 ( pg/ml) TSH (µu/ml) Anti TPO Ab (U/ml) NR <100 Cortisol (µg/dl) 8 4 /24 4 /11 NR 5 25 Estradiol (ng/dl) NR LH (mu/ml) /0.6 2 / FSH (mu/ml) / / PRL (ng/ml) <20 IGF1 (ng/ml) NR 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 several anecdotal cases responded well to a doses of prednisolone ranging from 13 to 60 mg/d [5 14], others to a replacement dose of Hydrocrtisone (30 mg/d) [15,16], Table 3. Biochemical and immunological investigations of the patient with LH Results Serology HIV1 and 2 Hepatitis B Hepatitis C ADN detection by PCR in CSF of CMV EBV Enterovirus Body fluid cultures for mycobactrium TB TPHA Serum ACE 64 U/L CSF ACE 1 U/L Autoantibodies Antiadrenal Antismooth muscle ANA Anti TPO 2090 Antiparietal cell Weakly positive PCR, Polymerase chain reaction, CSF, cerebrospinal fluid, CMV, cytomegalovirus, EBV, Epstein Barr virus, TB, tuberculosis, TPHA, treponema pallidum hemmaglutination test, ACE, angiotensin converting enzyme, ANA, anti-nuclear antibodies. Normal ranges are serum ACE U/L, anti TPO <100.

7 Lymphocytic Hypophysitis 43 Fig. 7. T1 sagittal view showing a partial empty sella turcica. many cases showed spontaneous recovery of the pituitary function and radiological regression of the mass. The results of the first prospective trial of High dose methylprednisolone pulse therapy (HDMPT 120 mg/d for 2 weeks) conducted in only nine patients showed improvement of the adenopituitary function in 44% of the cases and was more favourable in those with short standing disease (less than 6 months), whereas improvement of the MRI findings occured in 88% of the patients within 6 weeks to 6 months after HDMPT [17]. It remains doubtful whether the results of HDMPT are definitive because follow up in this trial was relatively short. Our patient did show a decrease in its pituitary mass on high dose methylprednisolone during the first episode of LH but responded as well clinically and radiologically to a substitution therapy with 30 mg/d of hydrocortisone during a subsequent episode. This raises several questions: is there a real benefit in using corticosteroids in LH and, if so, at what dose? Is empty sella turcica an inevitable outcome of LH? Therefore the role of corticosteroids are yet to be clearly defined, and it seems reasonable to manage these patients expectantly when the symptoms develop in the classic setting and surgery should be warranted only when mandated by the presence of potentially irreversible neurological signs non responsive to steroids. References 1. Jenkins PJ, Chew SL, Lowe DG, Afshar F, Charlesworth M, Besser GM, Wass JAH. Lymphocytic hypophysitis: Unusual features of a rare disorder. Clin Encrinol 1995;42: Abe T, Matsumoto K, Sanno N, Osamura Y. Lymphocytic hypophysitis: Case report. Neurosurgery 1995;36(5): Thodou E, Asa SL, Kontogeorgos K, Kovacs K, Horvath E, Ezzat S. Clinical case seminar: Lymphocytic hypophysitis: Clinicopathological findings. J Clin Endocrinol Metab 1995;80: Barbaro D, Loni G. Lymphocytic hypophysitis and autoimmune thyroid disease. J Endocrinol Invest 2000;23: Pestell RG, Best JD, Alford FP. Lymphocytic hypophysitis. The clinical spectrum of the disorder and evidence for an autoimmune pathogenesis. Clin Endocrinol 1990;33: Crock P. Cytosolic autoantigens in lymphocytic hypophysitis. J Clin Endocrinol Metab 1998;83:

8 44 Matta et al. 7. Naik RG, Ammini A, Shah P, Sarkar C, Mehta VS, Berry M. Lymphocytic hypophysitis. Case report. J Neurosurg 1994;80(5): Honegger J, Fahlbush R, Bornemann A, Hensen J, Buchfelder M, Muller M, Nomikos P. Lymphocytic and granulomatous hypophysitis: Experience with nine cases. Neurosurgery 1999;44: Vanneste JAL, Kamphorst W. Lymphocytic hypophysitis. Surg Neurol 1987;28: Cohen R, Beressi N, Modigliani E. Lymphocytic hypophysitis. Clin Endocrinol 1995;43: Cheung CC, Ezzat S, Smyth HS, Asa SL. The spectrum and significance of primary hypophysitis. J Clin Endocrinol Metab 2001;86: Nihioka H, Fukushima C. Reccurrent lymphocytic hypophisitis: Case report. Neurosurgery 1997;41(3): Noto H, Tsukamoto K, Hayashi S, Fujita T, Kimura S. Spontaneous recovery from hypopituitarism in a man with lymphocytic hypophysitis: A case report. Endocr J 2001;48: Beressi N, Cohen R, Beressi JP, Dumas JL, Legrand M, Iba-Zizen MT, Modigliani E. Pseudotumoral lymphocytic hypophysitis successfully treated by corticosteroids alone: First case report. Neurosurgery 1994;35: Hayes FJ, Mckenna TJ. The occurrence of lymphocytic hypophysitis in a first but not subsequent pregnancy. J Clin Endocrinol Metab 1996;81: Gagneja H, Arafah B, Taylor HC. Histologically proven lymphocytic hypophysitis: Spontaneous resolution and subsequent pregnancy. Mayo Clin Proc 1999;74: Kristof R, Van Roost D, Klingmuller D, Springer W, Schramm J. Lymphocytic hypophysitis: Non invasive diagnosis and treatment by high dose methylprednisolone pulse therapy? J Neurol Neurosurg Psychiatry 1999;67: