Neurol Med Chir (Tokyo) 48, 314¿317, 2008

Neurosarcoidosis Manifesting as Tremor of the Extremities and Severe —Case Report—

Yoshikazu OGAWA,TeijiTOMINAGA*,andHidetoshiIKEDA**

Department of , Kohnan Hospital, Sendai, Miyagi; *Department of Neurosurgery, Tohoku Graduate School of Medicine, Sendai, Miyagi; **Department of Neurosurgery, Ohara Medical Center, Fukushima

Abstract A 48-year-old woman initially presented with significant tremor of the extremities and subsequent severe hypopituitarism. Magnetic resonance imaging showed hyperintense areas in bilateral caudate heads and putamina, and a pituitary mass. L-dopa and corticosteroid were given and the tremor was reduced. Serum markers including autoimmune diseases were negative. Computed tomography and positron emission tomography detected no abnormalities except for pituitary lesion. Transsphenoidal revealed a noncaseating including giant cells with destroyed . The diagnosis was . Diagnosis of isolated neurosarcoidosis is definitely difficult. Biopsy may be essential to establish the diagnosis in such a case. Corticosteroid administration is strongly recom- mended to avoid irreversible damage to the normal tissues even if histological confirmation was not achieved.

Key words: basal ganglia, hypopituitarism, neurosarcoidosis, tremor

Introduction Case Presentation

Neurosarcoidosis accounts for about 5% of cases of A 48-year-old woman suffering from severe tremor systemic sarcoidosis.2) The major types of clinical of the extremities was introduced to Kohnan manifestations are peripheral nerve palsy, basal Hospital in August 2005. She first suffered resting , and granuloma. Peripheral nerve palsy tremor in her fingers and bradykinesia in October has a generally indolent prognosis because cor- 2004, and began to suffer frequent . ticosteroid is often effective.7,8) Granuloma usually was detected at a local hospital in spreads from the basal leptomeninges through the February 2005 and levothyroxine was administered. Virchow-Robin spaces,3) and manifests as focal signs However, the symptoms became aggravated. She and , and corticosteroid therapy is less effec- had moderate fever and severe fatigability. Head MR tive.5) The endocrine system is also sometimes af- imaging revealed abnormal areas in whole of the fected, most commonly resulting in hyperprolactine- bilateral caudate heads and putamina appearing as 7,8) mia due to hypothalamic involvement, and diabe- hyperintense on T2-weighted imaging (Fig. 1). The tes insipidus.5) Isolated effects of the pituitary gland pituitary gland was slightly expanded and showed are extremely rare.2) significant but mottled enhancement by gadolinium We treated a middle-aged female who presented (Fig. 2). She was transferred to the neurological with severe hypopituitarism and significant tremor department, where hyponatremia (119 mIU/ml) and of the extremities, identified as the first manifesta- hypopituitarism were identified (Table 1). In addi- tion of neurosarcoidosis with atypical magnetic tion to resting tremor, mild positional tremor and resonance (MR) imaging findings. rigidity in her left hand were detected. She was given daily administration of 0.5 mg dexamethasone and 300 mg of l-dopa, and introduced to our depart- Received October 11, 2007; Accepted February 26, ment. 2008 On admission she suffered significant tremor of

314 Neurosarcoidosis With Frequent Tremor and Hypopituitarism 315

Fig. 1 Axial (A) and coronal (B) T2-weighted mag- netic resonance images showing localized hyperintense areas in the whole of the bilateral caudate heads and putamina.

Fig. 3 Positron emission tomography using fluoro- deoxyglucose showing accumulation only in the sellar lesion in the whole body with stan- dardized uptake value 2.37.

the extremities, walked and spoke very slowly be- cause of the bradykinesia. The moderate fever con- tinued all day. No signs of ophthalmological abnor- mality were found. Routine laboratory investiga- Fig. 2 T1-weighted magnetic resonance image with tions, pituitary, , and adrenal functions were contrast medium revealing a sellar mass ex- evaluated. Although Wilson disease and mitochon- panding to the suprasellar area with sig- drial abnormality were suspected as differential di- nificant and mottled enhancement. agnoses, all the markers of such diseases were with- in the normal ranges. Chest and abdominal com- Table 1 Basal value of pituitary, thyroidal, and puted tomography showed no abnormal findings. adrenal Positron emission tomography using fluorodeoxy- LH (mIU/ml) º0.10 æ glucose (FDG-PET) showed accumulation only in the FSH (mIU/ml) 1.57 sellar lesion in the whole body with standardized up- ACTH (pg/ml) º5.0 æ take value 2.37, which suggested less possibility of Serum (mg/dl) º1.0 æ malignancy (Fig. 3). PRL (ng/ml) 46.81 Shewastreatedwithsamedoseofdexametha- GH (ng/ml) 0.08 æ sone, levothyroxine, and l-dopa as she was in- IGF-1 (ng/ml) 64 troduced. Eight months later the tremor had im- TSH (mU/ml) 0.009 æ proved, and only l-dopa was gradually reduced and Free T3 (pg/ml) 2.82 finally discontinued. Resting tremor has not Free T4 (ng/ml) 1.52 recurred, but bradykinesia and easy fatigability con- 17-KS (mg/day) º0.2 æ 17-OHCS (mg/day) 1.3 æ tinued. Follow-up examination showed no improve- Urinary free cortisol (mg/day) º19.0 æ ment in pituitary hormones and MR imaging. There- ADH (pg/ml) 0.6 fore, transsphenoidal biopsy was performed in BNP (pg/ml) 5.5 August 2006. The pale and tough tissue and bran-like denatured pituitary were randomly distributed. æ indicates below normal range. ACTH: adrenocor- Small amounts of normal pituitary tissue were iden- ticotropic , ADH: antidiuretic hormone, tified among these abnormal tissues. BNP: brain natriuretic peptide, FSH: follicle-stimulat- ing hormone, GH: growth hormone, IGF-1: insulin- Histological examination showed that the normal like growth factor-1, 17-KS: 17-ketosteroid, LH: lu- pituitary had been destroyed with massive infiltra- teinizing hormone, 17-OHCS: 17-hydroxycorticoster- tion of and formation of lymph folli- oid, PRL: prolactin, TSH: thyroid-stimulating hor- cles. Immunohistochemistry demonstrated UCLH-1- mone. positive cells infiltrating around the granuloma as a

Neurol Med Chir (Tokyo) 48, July, 2008 316 Y. Ogawa et al.

heads and putamina, suggesting that edema was less possible and another mechanism including immu- nological system was involved. More specific diag- nostic tests may include serum angiotensin-convert- ing enzyme with 55–60% sensitivity and 25% specif- icity for sarcoidosis, and soluble interleukin-2 re- ceptor with similar sensitivity and 83% specificity.2) In our case, both markers were within the normal ranges. Our patient had electrolyte abnormality at the initial manifestation. Since hyponatremia had never occurred after corticosteroid supplementa- tion, this abnormal electrolyte concentration was due to hypocortisolemia. Hyponatremia is known to be associated with neuroendocrinological disor- ders.6) Fig. 4 Photomicrographs of the surgical specimen Although corticosteroid administration is the fun- showing a noncaseating granuloma, (A) damental treatment, various adjuvant immunosup- hematoxylin and eosin staining, (B) UCLH- pressants have been proposed to minimize the 1, (C) L26 immunohistochemistry (original steroid dose including cyclosporine, , magnification ×80). Significant infiltration and .1,5) Pulse of UCLH-1 and L26-positive cells around the therapy has also been recommended.2,5) However, granuloma was observed. such adjuvant therapies may result in higher re- mission rate than only corticosteroids, so are still controversial. In our case the disease was stable, so marker to B-cell lymphocytes and L26-positive cells the patient was treated only with 0.5 mg/day of infiltrating massively around the granuloma as a dexamethasone, and careful follow up has been marker to T-cell lymphocytes indicating not ne- continued with MR imaging, angiotensin-convert- oplasm but inflammation. Giant cells were seen in- ing enzyme, and soluble interleukin-2 receptor cluding asteroid-like bodies in some nodules. These monitoring.Inadditionrecentpapersreportthat nodules were noncaseating granuloma. Therefore, FDG-PET is quite characteristic for systemic sarcoi- the diagnosis was established as hypophysitis dosis, and can be more sensitive to predict therapy caused by sarcoidosis (Fig. 4). response early in the course of therapy and disease Immediately after the operation insipidus condition.2,9) Inonecaseofsystemicsarcoidosis,the occurred, so daily administration of desmopressin FDG foci disappeared after the corticosteroid ther- acetate was necessary. The clinical course was apy.2) We intend to follow up our patient with this otherwise uneventful. She discharged on foot with examination in the future. daily medication consisting of 0.5 mg of dexametha- The present patient with isolated neurosarcoido- sone, 100 mg of levothyroxine, and desmopressin sis initially presented with severe hypopituitarism acetate. She remained in stable condition with the and significant tremor of the extremities. Hypopitui- same dose of dexamethasone and levothyroxine tarism was thought to be caused by destruction of without the need for l-dopa administration in the pituitary gland, and tremor by lesions in the November 2007. bilateralbasalganglia,whichimprovedwithl-dopa administration. Discussion References The diagnosis of isolated neurosarcoidosis poses great difficulties. The most sensitive test for neu- 1) Agbogu BN, Stern BJ, Sewell C, Yang G: Therapeutic rosarcoidosis is MR imaging, with the most frequent considerations in patients with refractory neurosar- abnormal findings of periventricular lesion and lep- coidosis. Arch Neurol 52: 875–879, 1995 tomeningeal enhancement.2) Apreviouscaseofin- 2) Aide N, Benayoun M, Kerrou K, Khalil A, Cadranel J, 18 18 flammatory pseudotumor revealed symmetrical hy- Talbot JN: Impact of [ F]-fluorodeoxyglucose ([ F]- FDG) imaging in sarcoidosis: unsuspected neurosar- perintense areas in the anterior horns of the lateral coidosis discovered by [18F]-FDG PET and early meta- ventricles on T -weighted imaging, suggesting that 2 bolic response to corticosteroid therapy. Br J Radiol 4) edema was the cause. In our case, the hyperintense 80: 67–71, 2007 areas corresponded just to the bilateral caudate

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3) Bullmann C, Faust M, Hoffmann A, Heppner C, Jock- manifesting as hyponatremia. Neurol Med Chir enhovel F, Muller-Wieland D, Krone W: Five cases (Tokyo) 47: 58–64, 2007 with central and hypogonadism as 8) Sharma OP, Sharma AM: Sarcoidosis of the nervous first presentation of neurosarcoidosis. Eur J En- system. Arch Intern Med 151: 1317–1321, 1991 docrinol 142: 365–372, 2000 9) Zhuang H, Alavi A: 18-fluorodeoxyglucose positron 4) Gizzi MS, Lidov M, Rosenbaum D: Neurosarcoidosis emission tomographic imaging in the detection and presenting as a tumour of the basal ganglia and brain- monitoring of infection and inflammation. Semin Nucl stem: sequential MRI. Neurol Res 15: 93–96, 1993 Med 32: 47–59, 2002 5) Hansen I, Petrossians P, Thiry A, Flandroy P, Gaillard RC, Kovacs K, Ckaes F, Stevenaert A, Piguet P, Beck- ers A: Extensive inflammatory pseudotumor of the pituitary. J Clin Endocrinol Metab 86: 4603–4610, 1986 Address reprint requests to: Yoshikazu Ogawa, M.D., 6) Lower EE, Broderick JP, Brott TG, Boughman RP: Department of Neurosurgery, Kohnan Hospital, Diagnosis and management of neurological sarcoido- 4–20–1 Nagamachi–minami, Taihaku–ku, Sendai, sis. Arch Intern Med 157: 1864–1868, 1997 Miyagi 982–8523, Japan. 7) Ogawa Y, Tominaga T, Ikeda H: Clinicopathological e-mail:yogawa＠kohnan-sendai.or.jp and endocrinological study of Rathke's cleft cyst

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