Brain Pathology Case of the Month - July 2004

DIAGNOSIS:

Cryptococcal meningitis and focal pneumonitis in a patient with pulmonary sarcoidosis.

DISCUSSION:

Cultures of post mortem lung parenchyma and meninges yielded Cryptococcus neoformans variety neoformans. This patient with stage II sarcoidosis died from cryptococcal meningitis. Sarcoidosis was diagnosed antemortem but cryptococcal meningitis was undiagnosed. His neurological symptoms were attributed to neurosarcoidosis.

Sarcoidosis, a systemic disorder of unknown cause, is characterised by the presence of non-caseating epithelioid granulomata, with Langerhan's giant cells, Schaumann and asteroid bodies 1. Because the lungs and thoracic lymph nodes are almost always involved, most patients present with respiratory symptoms. Lung, bone and skin are the commonest sites affected with neurosarcoid occurring in only 5% of cases 2. In this case the patient presented principally with neurological symptoms but had no evidence of neurosarcoid at autopsy. The investigation of the dry cough and the observation of bilateral hilar lymphadenopathy and pulmonary infiltrates led to the diagnosis of sarcoidosis. It is difficult to determine how long this patient had pulmonary sarcoidosis, but based on the extensive fibrosis in the hilar nodes and lung parenchyma it was long standing 3. Cryptococci were not present in hilar nodes or in the granulomatous lung foci making it highly unlikely that the granulomatous reaction in the lungs was due to cryptococcus.

Pulmonary cryptococcosis is an uncommon and generally benign infection 4 but as an opportunistic T-cell mediated mycosis, is an important disease in patients with supressed immune function. The vast majority of patients who present with fulminant cryptococcal infection are immunocompromised as a result of HIV infection, chemo- and/or radio-therapy or corticosteroids. In this case the steroid therapy did not play a role in the development of cryptococcal meningitis as the headaches were the initial and significant observation. There are rare cases of cryptococcal infection in immunocompetent patients and a small proportion of these are described in patients with supervening sarcoidosis 5-6. Cryptococcus in association with sarcoidosis is thought to occur due to an inversion of the CD4/CD8 ratio, probably because of redistribution of helper T-cells to the lungs and other sites of disease activity. There are two varieties of Cryptococcus neoformans - gattii and neoformans with the latter commonly affecting immunocompromised patients 7.

Patients with C. neoformans in the CSF have a high mortality . Despite being seronegative for HIV, our patient was predisposed to opportunistic infection because of the underlying sarcoidosis. He thus presented a diagnostic challenge to the clinicians. The absence of typical symptoms (hemoptysis, chest pain and pleural effusion) usually seen in pulmonary cryptococcus served to confound the diagnosis. Bronchoscopy was non-diagnostic, initial blood cultures were negative and lumbar puncture was not possible due to raised intracranial pressure. The finding of leptomeningeal enhancement on MR, an uncommon finding in cryptococcal meningitis,8 further confused the issue leading to a diagnosis of neurosarcoid . Therefore a strong index of clinical suspicion is necessary to diagnose this exceedingly rare association of cryptococcus complicating sarcoidosis.

In conclusion, we present a 40 year old, HIV-negative man who presented with the rare association of sarcoidosis and cryptococcal infection. The presence of neurological signs in a patient with pulmonary sarcoid and leptomeningeal enhancement on MR does not necessarily mean that the patient is suffering from neurosarcoid.

REFERENCES:

  1. Newman LS, Rose CS, Maier LA. (1999) Sarcoidosis. New Eng J Med 336:1224-34
  2. Thomas G, Murphy S, Staunton H, O'Neill S, Farrell MA, Brett FM. Pathogen-free granulomatous diseases of the central nervous system (1998) Hum Pathol 29:110-5
  3. Lukacs NW, Hogaboam C, Chensue SW, Blease K, Kunkel SL (2001) Type 1, type 2 cytokine paradigm and the progression of pulmonary fibrosis. Chest 120 (Suppl)5S-8S
  4. Menefee McDonnell J, Hutchins GH (1985) Pulmonary cryptococcosis. Hum Pathol 16:121-8
  5. Botha RJP, Wessels E. Cryptococcal meningitis in an HIV negative patient with systemic sarcoidosis (1999) J Clin Pathol 52:928-930.
  6. Shijubo N, Fujishima T, Ooashi K, Morita S, Shigehara K, Nakata H, Abe S. Pulmonary cryptococcal infection in an untreated patient with sarcoidosis (1995) Sarcoidosis 12:71-74
  7. Mitchell DH, Sorrell TC, Allworth AM, Heath CH, McGregor, AR, Papanaoum K, Richards MJ, Gottleib T (1995) Cryptococcal disease of the CNS in immunocompetent hosts: Influence of cryptococcal variety on clinical manifestations and outcome. CID 20:611-616.
  8. Arnder L, Castilla M, Heinz ER, Scatliff JH, Enterline D. Unusual pattern of enhancement in cryptococcal meningitis: in vivo findings with post mortem correlation (1996) J Comput Assist Tomogr 20; 1023-1026

Contributed by Lane H MB, PhD., Browne L MRCPI; Delanty N MD MRCP; O Neill S FRCP., Thornton J FRCR; Brett FM, MD FRCPath

International Society of Neuropathology