Increased awareness of chronic inflammatory lesions

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1 Skull base Lymphocytic Infundibulo- Neurohypophysitis with Hypothalamic and Optic Pathway Involvement: Report of a Case and Review of the Literature J.R. Ouma, M.D., and V.J.R. Farrell, M.D. Department of Neurological Surgery, Johannesburg Hospital, and the University of the Witwatersrand, Johannesburg, South Africa Ouma JR, Farrell VJR. Lymphocytic infundibulo-neurohypophysitis with hypothalamic and optic pathway involvement: report of a case and review of the literature. Surg Neurol. BACKGROUND Lymphocytic adenohypohysitis and lymphocytic infundibulo-neurohypophysitis are rare auto-immune mediated diseases of the anterior and posterior pituitary, respectively. The former usually manifests as insufficiency of anterior pituitary hormone secretion, associated in many patients with disturbances of vision. The latter presents as diabetes insipidus of central origin. They present most commonly in pregnant or postpartum females. There have been infrequent reports in females with no association with pregnancy, and in males. CASE DESCRIPTION We present a nulliparous female with central diabetes insipidus, pan-hypopituitarism, and severely impaired vision. Magnetic resonance imaging demonstrated a large mass involving the hypothalamus, infundibulum, optic nerves, chiasm, and tracts. At operation, the optic pathways were found to be grossly involved in the inflammatory mass. Histological examination of a biopsy demonstrated a nonspecific, mixed inflammatory infiltrate, composed predominantly of lymphocytes and plasma cells. She responded dramatically to treatment with dexamethasone, with disappearance of the mass on serial imaging studies and improvement in vision. In addition, she received hormone replacement therapy. CONCLUSION We present a case of lymphocytic infundibuloneurohypophysitis unique in the degree of optic pathway inflammatory involvement, with a documented response to steroids by Elsevier Science Inc. Address reprint requests to: Dr. John Ouma, University of the Witwatersrand, Department of Neurosurgery, 7 York Road, Parktown, 2193, Johannesburg, South Africa. Received February 14, 2001; accepted July 25, KEY WORDS Lymphocytic infundibulo-neurohypophysitis, optic chiasm, nerves, tract. Increased awareness of chronic inflammatory lesions involving the pituitary gland and neighboring structures, and the availability of magnetic resonance imaging (MRI), have led to a growing number of reports of these conditions in the literature [15]. Though lymphocytic adenohypophysitis and infundibulo-neurohypophysitis are the commonest of these conditions [15], they remain relatively uncommon and poorly understood. Their importance lies in the possible association with serious complications such as panhypopituitarism, central diabetes insipidus, and visual impairment which, if unrecognized or treated too cautiously, can lead to significant morbidity and mortality. Case Report A 23-year-old, nulliparous female clerk presented with a 4-year history of amennorhoea, a 4-month history of polyuria and polydipsia, and sudden loss of vision in the left eye 2 months before referral to our unit. She denied any history of inexplicable fatigue, heat or cold intolerance, recent unexplained changes in body weight or size of clothing, or disturbances in libido. A diagnosis of hypothyroidism was made by the family practitioner and levothyroxine sodium was prescribed 2 months before referral to our unit by Elsevier Science Inc /02/$ see front matter 655 Avenue of the Americas, New York, NY PII S (01)

2 50 Surg Neurol Ouma and Farrell 1 Serum Hormone Assay Results HORMONE LEVEL REFERENCE RANGE Prolactin 63.7 mcg/lt mcg/lt Growth hormone 1.6 mu/lt 1 10 mu/lt Adrenocorticotrophic 10 ng/lt 46 ng/lt hormone (ACTH) Cortisol 21 nmol/lt nmol/lt Thyroid stimulating 0.04 miu/lt miu/lt hormone (TSH) T pmol/lt pmol/lt T pmol/lt pmol/lt Luteinizing hormone 0.1 IU/lt IU/lt (LH) Follicle stimulating hormone (FSH) 0.3 IU/lt IU/lt During the course of endocrine investigations an MRI scan of the brain was conducted, leading to the referral. She was of slender build, normotensive and apyrexial. She lacked axillary and pubic hair. The remainder of the general examination was unremarkable. She was alert and correctly oriented, with intact speech, memory, and higher functions. The left pupil was dilated and unreactive to direct light, but reacted normally consensually. There was severe optic atrophy, with vision restricted to counting of fingers at 50 cm. The right pupil was of normal size and reacted to direct light, with no consensual reaction. There was marked optic atrophy, with visual acuity of 6/60, and a macular sparing temporal field loss. The remainder of the neurological examination was normal. Laboratory investigations revealed a hypernatremia of 156 mmol/lt, and the serum hormone assay results were as illustrated in Table 1. MRI scan showed a mm strongly enhancing mass involving the hypothalamus, optic nerves, chiasm, and tracts as well as the infundibulum. The adenohypophysis was not involved, and the usual enhancement of the posterior pituitary was preserved (Figure 1). Initial treatment consisted of cortisone and des- Initial gadolinium MRI brain scans, demonstrating the 20 mm 40 mm 40 mm strongly enhancing mass involving 1 the hypothalamus, optic nerves, chiasm and optic tracts as well as the infundibulum, but sparing the adenohypophysitis. (A: axial; B: sagittal).

3 Lymphocytic Infundibulo-Neurohypophysitis Surg Neurol 51 MRI 6 weeks later, after the first biopsy, showing 2 worsening of the radiological appearance, including striking involvement of the optic tracts. mopressin nasal drops, with levothyroxine sodium re-introduced once the serum cortisol level had been corrected. In addition, she was placed on a contraceptive pill (Demulen, Searle) by our endocrinologists. Once her metabolic and endocrine parameters were satisfactory, a right pterional craniotomy was performed. A firm mass, pinkish grey in color with gross enlargement of the distal optic nerves, chiasm, and proximal tracts, was encountered. A biopsy was taken from the inferior part of the expanded chiasm. Histological examination revealed extensive inflammation with lymphocyte and plasma cell infiltrate. Occasional neutrophils and foci of haemorrhage were present. There were no features of granuloma or neoplasia. Owing to concern about the accuracy of the biopsy, associated with worsening of the radiological picture (Figure 2), the procedure was repeated after 2 months. Once again, the histology showed inflammatory infiltration with lymphocytes and plasma cells. Treatment with dexamethasone was begun and hormone replacement therapy continued. Gadolinium MRI scans of the brain, after 4 months of 3 dexamethasone therapy. Note the significant resolution of the mass compared to the previous images. Over the next 4 months, there was a dramatic reduction in size (Figure 3) and, finally, disappearance of the mass (Figure 4), with improvement in the vision of her right eye to an acuity of 6/18, though with persistence of the macular sparing temporal field loss. The vision in the left eye remained unchanged. This improvement persisted after the dexamethasone was gradually withdrawn. She remains on cortisone, levothyroxine sodium, and desmopressin nasal drops, and is followed by the Endocrine as well as Neurosurgical outpatient departments. Discussion Lymphocytic adenohypophysitis and lymphocytic infundibulo-neurohypophysitis are two distinct conditions [19]. Both are believed to be autoimmune diseases [16], and are regarded as part of the spectrum of autoimmune diseases such as autoimmune thyroiditis [7], pernicious anaemia [10], organ specific antibodies including anti-pituitary an-

4 52 Surg Neurol Ouma and Farrell 4 Comparable contrast CT scan axial cuts, contrasting the radiological appearance shortly after commencing dexamethasone therapy (A), with that two years later, (B), in which the mass is no longer visible. tibodies [13], anti-mitochondrial [2], anti-parietal [14], and antinuclear antibodies [8]. They occur predominantly in females in pregnancy or the postpartum period. Six cases in males have been reported [12], as have thirteen in females unrelated to pregnancy [3,6,18,19,20]. Lymphocytic adenohypophysitis usually presents as a large mass with visual impairment and hormonal disturbances, while lymphocytic infundibulo-neurohypophysitis presents as a small mass with no visual impairment [9,18]. The histological features of these lesions are characterized by lymphocytic infiltration, destruction of the normal organoid pattern, and replacement by fibrosis [15,19]. Lymphocytic adenohypophysitis may cause hypopituitarism and visual impairment. Diabetes insipidus is uncommon, the neurohypophysis reported to being normal in most cases [4,15]. By contrast, lymphocytic infundibulo-neurohypophysitis, is known to be a cause of central diabetes insipidus [18], with inflammation restricted to the neurohypophysis and infundibulum [9], the adenohypophysis usually being spared on MRI imaging and histological examination [11]. The natural course is progression from inflammatory enlargement of the pituitary stalk or posterior pituitary gland to fibrosis and atrophy of these structures. No cases of spontaneous recovery have been reported [19]. Necrosis is not a feature of lymphocytic hypophysitis, but has been reported in two cases of lymphocytic infundibulo-hypophysitis. These have been labeled as necrotizing infundibulo-hypophysitis [1]. Compared to the majority of reported cases, our patient appears to differ in certain respects. There was no association with pregnancy [3,6,20]. She presented with both pan hypopituitarism and diabetes of central origin. In this regard she differs from the commonly described clinical picture in which partial or complete hypopituitarism accompanies lymphocytic adenohypophysitis, while lymphocytic infundibulo-hypophysitis is associated with central diabetes insipidus [15]. In addition, a large mass was present with profound visual impairment, as opposed to the usual small mass

5 Lymphocytic Infundibulo-Neurohypophysitis Surg Neurol 53 without visual impairment described as being typical findings in lymphocytic infundibuloneurohypophysitis [9,18]. The visual impairment appears to have been because of direct inflammatory involvement of the optic nerves, chiasm and tracts rather than compression of these structures. Visual impairment in this condition has hitherto been regarded as being because of compression of the optic pathways by the inflammatory mass [4,15]. As far as we are aware, actual direct involvement of the optic pathways noted on neuroimaging and confirmed at operation has not been described before. Biopsy or chiasmal decompression in the presence of impaired vision, accompanied by appropriate pre- and postoperative hormone replacement, is usually advised [5]. It has been recommended, though, that at least for some cases especially those related to pregnancy, with consistent clinical findings, supportive laboratory results, and nonresponse to bromocriptine where appropriate, a presumptive, noninvasive diagnosis may be made and corticosteroid therapy instituted along with appropriate hormone replacement, provided there is no visual compromise necessitating decompression [4,15]. This patient responded very well to a course of dexamethasone, suggesting that steroid treatment is as effective in the treatment of lymphocytic infundibulo-neurohypophysitis as it is in the more common lymphocytic adenohypophysitis [19]. REFERENCES 1. Ahmed SR, Aiello DP, Page R, Hopper K, Towfighi J, Santen RJ. Necrotizing infundibulo-hypophysitis: a unique syndrome of diabetes insipidus and hypopituitarism. Journ Clin Endoc Metab 76;6: Asa SL, Bilbao JM, Kovacs K, Josse RG, Kreines K. Lymphocytic hypophysitis of pregnancy resulting in hypopituitarism: a distinct clinico-pathological entity. Ann Int Med 1981;95: Cebelin MS, Velasco ME, De las Mulas JM, Druet RL. Galactorrhoea associated with lymphocytic adenohypophysitis. Brit Journ Obstet Gynae 1981;88: Cosman F, Post KD, Holub DA, Wardlaw SL. Lymphocytic hypophysitis: report of three new cases and review of the literature. Medicine 1989;68: Feigenbaum SL, Martin MC, Wilson CB, Jafee RB. Lymphocytic adenohypophysitis; A pituitary mass lesion occurring in pregnancy: proposal for medical treatment. Am J Obstet Gynecol 1991;164: Godart J, Jacquet G, Angonin PH, Klofenstein A, Bonneville JF, Czorny A. Adeno hypophysite lymphocytaire: a propos d un nouveau cas. Neurochirurgie 1994;40: Goudie RB, Pinkerton PH. Anterior hypophysitis and Hashimoto s disease in a young woman. Journ Pathol Bact 1962;83: Guay AT, Agnello V, Tronic BC, Gresham DG, Freidberg SR. Lymphocytic hypophysitis in a man. J Clin Endocrinol Metab 1987;64: Hoshimaru M, Hashimoto N, Kikuchi H. Central diabetes insipidous resulting from a non-neoplastic tiny mass lesion localized in the neurohypophyseal system. Surg Neurol 1992;38: Hume R, Roberts GH. Hypophysitis and hypopituitarism: report of a case. Brit Med J,i, 1976; Kojima H, Nojima T, Nagashima K, Ono Y, Kudo M, Ishikura M. Diabetes insipidus caused by lymphocytic infundibulo-neurohypophysitis. Arch Pathol Lab Med 1989;113: Lee JH, Laws ER, Guthrie BL, Dina TS, Nochomovitz LE. Lymphocytic hypophysitis: occurrence in two men. Neurosurgery 1994;34: Mayfield RK, Levine JH, Gordon L, Powers J, Galbraith RM, Raw SE. Lymphoid adenohypophysitis presenting as a pituitary tumour. Amer J Med 1980;69: Mazzone T, Kelly W, Ensink J. Lymphocytic hypophysitis associated with antiparietal cell antibodies and vitamin B12 deficiency. Arch Int Med 1983;143: Nishioka H, Akada K, Miki T, Ito H. A case of lymphocytic hypophysitis with massive fibrosis and the role of surgical intervention. Surg Neurol 1994;42: Pestell RG, Best JD, Alford FP. Lymphocytic hypophysitis. The clinical spectrum of the disorder and evidence for an autoimmune pathogenesis. Clin Endoc 1990;33: Prasad A, Madan VS, Sethi PK, Prasad ML, Buxi TB, Kanwar CK. Lymphocytic hypophysitis: can open exploration of the sella be avoided? Br J Neurosurgery 1991;5: Tmura H, Nakao K, Shimatsu A, Ogawa Y, Sando T, Fujisawa I, Yamabe H. Lymphocytic infundibuloneurohypophysitis as a cause of central diabetes insipidus. N Engl J Med 1993;329: van Havenbergh T, Robberecht W, Wilms G, van Calenbergh F, Goffin J, Dom R, Bouillon R, Plets C. Lymphocytic infundibulo-hypophysitis presenting in the postpartum period: Case report. Surg Neurol 1996;46: Venneste JAL, Kemphorst W. Lymphocytic hypophysitis. Surg Neurol 1987;28: COMMENTARY Lymphocytic adenohypophysitis is a rare idiopathic lymphocytic inflammatory condition confined to the pituitary gland (lymphocytic hypophysitis). The process can involve the pituitaryhypothalamic axis. It occurs predominantly in women, usually during pregnancy or postpartum [1,2,5]. The pituitary gland is infiltrated with lymphocytes and plasma cells, with scattered eosinophils and histiocytes [4]. In most cases, the lymphocytes are mostly CD4 cells [4], and there is evidence of panhypopituitarism. Diabetes insipidus can be caused by lymphocytic infundibuloneurohypophysitis. In most cases of lymphocytic hypophysitis, there is evidence of hypopituitarism. Amenorrhea is the most common initial symptom [4,5]. In

6 54 Surg Neurol Ouma and Farrell some women the disorder first becomes evident during pregnancy [5]. CT and MR imaging often show marked uniform contrast enhancement of an enlarged pituitary gland, resembling a macroadenoma [5]. There may be only enlargement of the infundibulum or infundibulo-hypothalamic axis. Imura et al [4] have reported 17 patients with idiopathic diabetes insipidus. In all patients, the normal hyperintense signal of the neurohypophysitis on T1-weighted images was not seen. In addition, 9 of 17 patients had thickening of the pituitary stalk, enlargement and enhancement of the neurohypophysis, or both on MR imaging. Imura et al called this entity lymphocytic infundibuloneurohypophysitis. The natural course of the disease suggested a self-limited process. They concluded that lymphocytic infundibuloneurohypophysitis is a common cause of what was previously considered to be idiopathic (autoimmune) diabetes insipidus. Antibodies against magnicellular neurons of the hypothalamus have been detected in some patients with secondary diabetes insipidus, leading to speculation that it is an autoimmune disorder [4,5]. They also stated that this entity is probably not a variant of lymphocytic hypophysitis. It is, however, possible that the two entities are related, with one affecting the anterior pituitary and the other having the posterior as the principal site of inflammation. Other causes of a thickened infundibulum and hypothalamus associated with contrast enhancement on CT and MRI include sarcoidosis, tuberculosis, lymphoma, Langerhans cell histiocytosis, intracranial plasma cell granuloma, germinoma, granular cell tumor (granular myoblastoma), and metastasis. Ouma et al report an excellent case of a lymphocytic infundibuloneurohypophysitis with hypothalamic and optic pathway involvement. It is important to realize that the CT and MRI appearance of sarcoidosis, Langerhans histiocytosis, and lymphoma may be identical to lymphocytic adenohypophysitis with involvement of the hypothalamus and optic pathways as well. It is also important to remember that occasionally meningiomas may contain plasma cell and lymphocytic components [3] that may cause a diagnostic problem. Mahmood F. Mafee, M.D. Department of Radiology University of Illinois at Chicago Chicago, Illinois REFERENCES 1. Asa SL, Bilbao JM, Kovas K, Josse RG, Kreines K. Lymphocytic hypophysitis of pregnancy resulting in hypopituitarism: a distinct clinicopathologic entity. Ann Intern Med 1981;95: Elster AD. Imaging of the sella: anatomy and pathology. Semin Ultrasound CT MRI 1993;14: Horten BC, Urich H, Stefoski D. Meningiomas with conspicuous plasma cell-lymphocytic components: a report of five cases. Cancer 1979;43: Imura H, Nakao K, Shimatsu A, Ogawa Y, Sando T, Fujisawa I, Yamabe H. Lymphocytic infundibuloneurohypophysitis as a cause of central diabetes insipidus. N Engl J Med 1993;329: Mafee MF, Smirniotopolous JG, Goodwin J. Imaging of chiasmal and juxtasellar regions. Ophthalmol Clin North Am 1994;7: Lymphocytic adenohypophysitis and lymphocytic infundibuloneurohypophysitis, although rare entities, are usually evaluated and treated by the endocrinologists. These entities are even less commonly seen by the neurosurgeon as in this case, when the clinical problem has been progressive loss of vision and the diagnosis is in question (i.e., tumor versus inflammatory etiology). John C. VanGilder, M.D. Division of Neurosurgery University of Iowa Iowa City, Iowa The policy of being too cautious is the greatest risk of all. Jawaharlal Nehru