A 65-year-old beef-cattle farmer with a 9-year history of sarcoidosis presented with a 2-year history of depressed mood with cognitive decline, weight loss and vomiting. Treatment with three antidepressant medications had proved ineffectual. After bronchoscopic diagnosis, his sarcoidosis had been treated for the ensuing 9 years with prednisolone (initially 30 mg/day and slowly reduced to 2 mg/day). At the time of initial diagnosis, three sputum samples had stained positive for acid-fast bacilli, and the patient was placed on conventional antituberculous therapy. This was ceased after 3 months, following negative mycobacterial cultures of sputa and bronchoscopic specimens. His family history was unremarkable.
On examination, the patient appeared cachectic and older than his stated age. He was vague, with slow speech. Bedside cognitive testing revealed severe memory impairment, with moderate impairment in attention, visuo-constructional ability and executive function. The result of a mini-mental state examination (MMSE) was 17/30. Neurological examination revealed ataxia, brisk tendon reflexes, bilateral habituating palmomental reflexes and proximal weakness. There were no other physical abnormalities.
Magnetic resonance imaging (MRI) scans of the brain showed ventricular enlargement, supratentorial white-matter hyperintensities, and extensive leptomeningeal enhancement in the posterior fossa, brain stem and basal cisterns, with extension along the cranial nerves (Figure 1). The MRI results were reported as consistent with neurosarcoidosis. A SPECT (single-photon emission computed tomography) scan, undertaken to differentiate possible causes of dementia, demonstrated global hypoperfusion (Figure 2).
Cerebrospinal fluid (CSF) analysis revealed a raised protein level (3.02 g/L; reference range, 0.15–0.45 g/L) and an opening pressure within the normal range. Cryptococcal antigen was detected in the CSF at a titre of 1 : 4. Although India-ink staining for Cryptococcus was negative, Cryptococcus neoformans var. neoformans was isolated on culture. Serum cultures were negative for fungae. Notably, no malignant cells or bacteria (including acid-fast bacilli) were identified from stained smears. Mycobacterial cultures showed no growth after 8 weeks.
A number of measurements showed that the patient’s sarcoidosis was stable: serum angiotensin-converting enzyme and 24-hour urine calcium levels were normal; respiratory function testing showed moderate air flow obstruction and gas transfer, with no change from previous measurements; and a chest x-ray (Figure 3) showed no new changes.
The patient was diagnosed with cryptococcal meningitis and secondary hydrocephalus. He was initially given antifungal therapy for 4 weeks (intravenous amphotericin B 40 mg a day and oral 5-flucytosine 1.5 g four times a day, followed by intravenous ambisome 200 mg a day when he developed renal impairment with toxic accumulation of 5-flucytosine). Twelve months’ oral fluconazole therapy (400 mg a day) was planned, and a ventriculoperitoneal shunt was inserted. The patient’s mental state had improved when he was re-examined 2 weeks after commencement of therapy (MMSE result, 23/30), and cryptococcal antigen titres fell to levels below detection.
The patient’s longer-term course was complicated by worsening confusion, with chronic subdural haematoma and bilateral posterior cranial fossa infarcts seen on MRI scans done at intervals of several weeks. To ensure that inadequately treated cryptococcosis was not contributing to his cognitive decline, treatment with amphotericin B and 5-flucytosine was reinstituted for 3 weeks. Three months after discharge, the patient was well, with moderate cognitive impairment.