British Journal of Ophthalmology, 1988, 72, 167-170

Cryptococcal meningitis presenting as uveitisS P STONE,' J BENDIG,2 J HAKIM,3 P E KINNEAR,3 B S AZADIAN,2 ANDF CLIFFORD-ROSE'

'From the Departments of 'Neurology, 2Microbiology, and 3Ophthalmology, Charing Cross Hospital,London W6

SUMMARY A patient presented with a posterior uveitis. An inferior plaque of retinal exudationwas seen. Full investigation failed to establish a cause until six weeks later, when cryptococcalmeningitis developed. The patient was immunocompetent. Exudation in relation to retinal vesselsis unusual in idiopathic posterior uveitis, and cryptococcosis should be considered in thedifferential. Diagnosis is by lumbar puncture or vitreous aspiration.

Cryptococcosis is a well recognised infection ofimmunocompromised patients. It usually presentswith meningitis. Uveitis is a secondary complication.We report an immunocompetent patient who pre-sented with posterior uveitis of unknown cause sixweeks prior to developing cryptococcal meningitis. Alocalised exudate in relation to retinal vessels isunusual in idiopathic posterior uveitis and shouldalert the clinician to the possibility of cryptococcosis.

Case report

A 39-year-old, previously well, Tanzanian Indian,who had not left the UK for 12 years, presented to hislocal hospital with disturbance of vision in his righteye. Best corrected visual acuities were 6/18 OD, 6/6OS. Refraction was -0-25 (both eyes). He had auveitis and chorioretinitis which was treated withtopical steroid (dexamethasone) but did not im-prove. He consulted an ophthalmologist directly,who confirmed posterior uveitis, noted a focalplaque, and investigated fully. After four weeks thepatient presented to another hospital with right eyepain and mild biparietal headache. Visual acuitieswere 6/18 OD, 6/5 OS. Refraction was -0-25 botheyes. Anterior and posterior uveitis was present inthe right eye with macular oedema, vitreous cells andretinal exudate (an inferior plaque). The left eye wasnormal. There was no evidence elsewhere of sarco-idosis, tuberculosis, inflammatory bowel disease, orseronegative arthritis. The erythrocyte sedimenta-Correspondence to Dr S P Stone, Department of Neurology, StBartholomews Hospital, West Smithfield, London EClA 7BE.

tion rate was 51 mm in the first hour, but chest x-rayand full blood count were normal; syphilis serology,autoantibodies, acute and convalescent serology(toxoplasma, cytomegalovirus, herpes simplex, andEpstein-Barr) were negative. On this basis idiopathicposterior uveitis was diagnosed. Treatment with60 mg prednisolone daily was begun. Vision im-proved over five days to 6/9 OD, with resolution ofmacular oedema.

Fig. 1 Rightfundusshowingan inferiorplaque ofretinalexudation.

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S P Stone, J Bendig, JHakim, P E Kinnear, B SAzadian, andF Clifford-Rose

Fig. 2 CTbrain scan: both cutstaken at thesame level through ththalamus and internal capsule. Tpatient has been injected withcontrastmedium before the righthandscan was done, which reveameningeal enhancementseen as t.brighter white outline ofthe sulci.

Two weeks later he presented to another hospitalcomplaining of three days' violent headache, photo-phobia, and vomiting. There was a pyrexia of 39-50Cwithout meningism or focal neurological signs. Theright vitreous was cloudy. Retinal exudate was seen(Figure I). Tuberculous meningitis was suspectedbecause he was Indian and on steroids. He wasreferred to the Regional Neurosciences Centre atCharing Cross Hospital. A CT scan showed menin-geal enhancement (Figure II). Examination of thecerebrospinal fluid (CSF) revealed white cells 396/m3(70% lymphocytes, raised protein (0-72 g/l, normal0-1-0-5 g/l) and low glucose (1.4 mmol/l, normal2-8-4-7 mmol/l).

Fig. .3 Indian inkstain ofcerebrospinalftuidsmearshowingCryptococcus neoformans with negative staining capsules.

Gram stain and Indian ink (Figure III) showedmoderate numbers of encapsulated yeasts. Crypto-coccus neoformans was isolated on blood, chocolate,and Sabouraud's agar after 48 hours' incubation at370C and subsequently confirmed as serotype A bythe Mycological Reference Laboratory. The latexagglutination test for C. neoformans capsular antigenwas positive with a titre of 200 in the CSF and 64 inthe serum.

Chest x-ray, midstream urine, full blood count(lymphocytes 2-1 x 109/1), glucose, and liver functiontests were normal. There was no clinical evidence ofmalignant disease or reticulosis and he was not at riskofAIDS. HTLV-III antibody and hepatitis B antigenwere negative. The Th/Ts ratio was normal. Directquestioning revealed that he was regularly exposed tolarge amounts of pigeon faeces (the main environ-mental source of Cryptococcus neoformans) when herearranged the electrical wiring on the roof of hislocal Hindu temple. Culture of faeces from the roofgrew a Cryptococcus species, but not C. neoformans.He was treated with intravenous amphotericin

0-5 mg/kg and flucytosine 250 mg four times daily forsix weeks. Repeat lumbar puncture at two and fiveweeks showed a progressive fall in the antigen titre toless than 1:2. His headache resolved, his acuityreturned to 6/6, 6/5, but exudates remained when hewas discharged. Three months later both CSF andophthalmological examination were normal. Heremained well six months later.

Discussion

Although human beings frequently come into contactwith Cryptococcus neoformans, clinical disease israre, but subclinical infection may be common. Themain source of the organism is pigeon droppings,'which it colonises; 0-1 g of dried pigeon droppingsfrom a sidewalk under a New York City fire escapecontained 50 million cryptococci.2 The organism isdisseminated by wind currents, and in one notable

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Cryptococcal meningitis presenting as uveitis

experiment conducted in the tower of a church belfrycontaminated by pigeon manure was recovered fromair, being carried in particles small enough to enter analveolous.3 It thus enters the lung as an infectiousinhalant dust and then spreads to meninges, bone,kidney, and other organs. The pulmonary and neuro-logical manifestations are well documented,"4 withinfection of the central nervous system most com-monly presenting as meningitis, but occasionally ashydrocephalus or an intracranial mass.7A third of over 100 known respiratory cases were

asymptomatic,5 so that subclinical disease is com-mon. There are 500-15 000 estimated cases of sub-clinical lung disease per annum in New York Cityalone," and there is immunological evidence of sub-clinical disease in pigeon breeders9 "' as well asnecropsy evidence of unsuspected cryptococcallesions in patients dying of unrelated disease."Subclinical or chronic meningitis can culminate inhydrocephalus or give rise to transient neurologicalsymptoms. 12-14The AIDS outbreak has focused Western attention

on cryptococcosis as a disease of the immunosup-pressed.'5 In the UK in 1985 28 out of 31 cases wereimmunocompromised, nine by AIDS (Mackenzie D,personal communication). In the Orient, however,86-89% are immunocompetent, as shown by seriesfrom Singapore,'6 Malaysia,'7"" South Africa(blacks),'9 and Australia (aborigines).20 The mostrecent of these reports7 counsels a high index ofsuspicion in otherwise healthy orientals. It has beensuggested that these apparently immunocompetentindividuals may be 'genetic hyporesponders' on thebasis of immunological studies showing that survivingcryptococcosis patients have a selective failure oflymphocyte responses to C. neoformans2'22 and along-lasting inability to produce antibodies to theorganism.23

Recent exposure to a large amount of pigeonexcreta may predipose to infection, and our patientrecalls kicking a pile of droppings into the air andnoting the offensive odour a few weeks prior to onsetof his ocular disease. Despite circumstantial evid-ence2425 only two cases have been reported of theisolation of the organism from the suspectedsource.2627 In one of these a doctor who contractedcryptococcal meningitis had spent much time in ahospital library near an air conditioner laden withpigeon droppings, culture of which yielded a heavygrowth of C. neoformans.2" Recent work suggeststhat not all cryptococcosis originates from pigeondroppings.2"The combination of chorioretinitis and exudation

in relation to retinal vessels is extremely unusual inidiopathic posterior uveitis but has been described incryptococcal eye disease,12132932 where focal and

miliary lesions may also be seen.2933 Diagnosis is bylumbar puncture'429 or by vitreous aspiration.?"Ocular disease usually complicates meningitis bydirect or haematogenous spread.35 It is rare in theimmunocompetent3' and rarer still in the absence ofother organ disease,3" though it is common in crypto-coccosis for the primary site of infection (usually thelung) to be asymptomatic" or even heal37 whiledisease in a secondary site (usually the meninges)progresses. Eye infection has been known to regressspontaneously.32 33

Uveitis usually follows neurological disease.121332There is only one previous case report of uveitispreceding cryptococcal meningitis,'4 when anterioruveitis developed into a posterior uveitis whichprogressed over 12 months while the patient was onsteroids. Transient vertigo and ataxia resolved, butCSF taken when the patient was neurologicallynormal had detectable antigen and eventually grewC. neoformans.The likely sequence of events in our patient was

as follows. An oriental, possibly a 'genetic hypo-responder,' was exposed to a large dose of C. neo-formans which entered the lung, produced sub-clinical meningitis,'2 14 and then involved the eye,becoming clinically apparent as a uveitis. At the timesteroids were prescribed a mild headache had begun,possibly the first symptom of meningitis, which underthe influence of steroids became fulminant.This case emphasises that cryptococcosis can affect

the immunocompetent, especially orientals," inwhom the major differential diagnosis is oftentuberculosis.?3"3 It may present as a uveitis and shouldbe considered by the clinician whenever the com-bination of chorioretinitis and exudation in relationto retinal vessels occurs, or when a patient with'idiopathic' uveitis develops even mild or transientneurological symptoms.

We thank Ms L Churchill for secretarial help.

References

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S P Stone, J Bendig, J Hakim, P E Kinnear, B S Azadian, and F Clifford-Rose

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Acceptedforpublication 16 October 1986.

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