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Sarcoidosis is a multisystem granulomatous disorder that can affect the hypothalamus and pituitary glands.1 Three decades ago the mean survival in hypothalamic-pituitary sarcoidosis, in a review of 19 cases, was 45 months.2 We report on two patients still alive after diagnosis 20 years ago.
A man of 34 sought advice in 1981 after 10 months of nausea, weight loss, depression and reduced libido. Severe depression was diagnosed and he was admitted to a psychiatric hospital. On examination, he was noted to have a nasal erythematous rash, sausage shaped fingers, reduced secondary sexual hair and small testes. Plasma sodium was 112 mmol/L. Anterior pituitary hormone stimulation tests (Table 1) and a water deprivation test demonstrated panhypopituitarism. A biopsy specimen of the nasal rash was reported as showing granulomatous inflammation consistent with lupus pernio, and in radiographs of the hands there were translucent cystic lesions likewise consistent with sarcoidosis. On CT the pituitary gland appeared normal. A Kveim test was positive. Cerebrospinal fluid had a raised protein (0.48 g/L) and white cell count (12/μL, all lymphocytes) but angiotensin converting enzyme (ACE) activity was normal. A whole-body gallium scan was normal.
After treatment with prednisolone 60 mg daily and pituitary hormone replacement his symptoms and depression resolved. After 6 months the prednisolone dose was reduced by 5 mg every 2–3 months until stabilized at 7.5 mg daily. In 1995, however, he developed acute ataxia. MRI of the brain showed hydrocephalus and basal meningeal enhancement of the hemisphere and pituitary fossa consistent with leptomeningitis (Figure 1). The prednisolone was increased to 60 mg per day and within three months his ataxia had completely resolved. In 2004, 23 years after diagnosis, he was still well, on a regimen of full pituitary hormone replacement and prednisolone 10 mg daily.
A 59-year-old male farmer was seen in 1988 with a 6-month history of polyuria, polydipsia, dry mouth and weight loss. An oral glucose tolerance test was normal but dynamic pituitary testing revealed anterior and posterior pituitary dysfunction. Bilateral hilar lymphadenopathy was seen on chest radiography and transbronchial biopsy of the nodes showed non-necrotizing granulomas consistent with sarcoidosis. A Kveim test was positive. As in case 1 the cerebrospinal fluid protein (0.51 g/L) and white cell count (34/μL) were raised but ACE was normal. CT of the pituitary showed an infiltrate within the gland. A wholebody gallium scan was normal. He was started on pituitary hormone replacement, together with prednisolone 60 mg daily, tapered to 7.5 mg daily. When last seen, 14 years after diagnosis, he was fit and active, still working on the farm.
The nervous system is affected in 5–16% of patients with sarcoidosis, and presentations range from peripheral or cranial neuropathy to granulomatous meningitis and, as in our two cases, hypothalamic-pituitary dysfunction. Any or all of these can occur without evidence of pulmonary or other systemic features of sarcoidosis.3
Hypothalamic-pituitary sarcoidosis, which occurs in less than 10% of patients with neurosarcoidosis,1 continues to present challenges both in diagnosis and in treatment. Originally the neuroendocrine dysfunction was attributed to a destructive process affecting the pituitary, but pituitary responsiveness to synthetic hypothalamic releasing factors indicates that hypothalamic insufficiency is the major cause for the hypopituitarism.4 The infiltrative process often involves a patchy destruction of the hypothalamic-pituitary tract, resulting in various combinations of anterior and posterior pituitary hormone dysfunction and sometimes isolated dysfunction. Diagnosis is difficult because of the variety of resultant symptoms. Contrast enhanced MRI is the imaging procedure of choice for diagnosis and followup. Gallium scanning and ACE measurement in serum and cerebrospinal fluid may be helpful but lack sensitivity and specificity. The same is true of increased protein and mild pleocytosis (usually lymphocytosis) in the cerebrospinal fluid. Definitive diagnosis of sarcoidosis requires biopsy evidence of non-caseating necrotizing granulomas.5
Hypothalamic-pituitary sarcoidosis is treated with corticosteroids together with anterior and posterior pituitary hormone replacement. Corticosteroids lower the CD4/CD8 lymphocyte ratio, decrease interleukin-2 production, and inhibit collagen synthesis, all of which are abnormal at the sites of active disease within the brain. When the dose of prednisolone is lowered to 20–25 mg daily the symptoms commonly recur. There are few data on other immunomodulatory therapies, but ciclosporin, radiotherapy, azathioprine, chlorambucil and cyclophosphamide have all been used with disappointing results.1 Surgical intervention is indicated in cases of hydrocephalus or when an expanding mass lesion causes an increase in intracranial pressure.
Clearly, treatment of hypothalamic-pituitary sarcoidosis has made great advances since 1971, when the median survival was only 45 months.2 The patients reported here were two of only three diagnosed in our unit over that period. The third, a 26-year-old man, was seen in 1986 with panhypopituitarism. On replacement therapy he remains well 19 years later. Unfortunately the condition can still cause sudden unexpected death.6