British Journal of Ophthalmology, 1988, 72, 171-175

Fatal disseminated cryptococcosis followingintraocular involvementJOEL A SCHULMAN,' CHRISTOPHER LEVEQUE,2 MARION COATS,'LINDA LAWRENCE,' AND JOHN C BARBER'

From the Departments of 'Ophthalmology and 'Pathology, University of Texas Medical Branch, Galveston,Texas 77550, USA

SUMMARY A 33-year-old man was treated with systemic steroids for a retinal inflammatory lesionbefore the diagnosis of cryptococcal retinitis and meningitis was suspected. He died from centralnervous system disease despite treatment with parenteral antifungals. Histopathological studiesdemonstrated ocular and disseminated systemic infection with Cryptococcus neoformans. Directcryptococcal involvement of the eye is rare and is usually associated with disseminated disease.Systemic steroids must be used with caution, and patients who take these drugs require frequentmonitoring.

Cryptococcosis is a mycosis caused by a non-mycelialyeast-like fungus, Cryptococcus neoformans. Theorganism is worldwide in distribution and endemic inthe human population in the Mississippi Valley. Theprimary lesion is usually in the lung, with dissemina-tion most frequently to the meninges and brain orspinal cord. Other reported sites of cryptococcusinclude the skin, bones, and liver.'2 Direct crypto-coccal involvement of the eye is rare and usuallyassociated with disseminated disease.3We present a patient treated with systemic steroids

for a non-pigmented retinal inflammatory lesionbefore the diagnosis of cryptococcal retinitis andmeningitis was established. The patient died from thecentral nervous system disease despite treatmentwith parenteral antifungals.

Case report

The patient was a 33-year-old male in good healthuntil September 1984, when he developed decreasedvision, pain, and photophobia in his left eye. Thepatient lived in a wooded area where he raised dogsas a hobby, and was exposed to pigeons. Two monthsprior to ophthalmological examination he reportedaccidental eye contact with parvo and leptospirosisvaccine while inoculating his dogs. His past medicalhistory included the consumption of one pint to onequart (600-1200 ml) of spirits per day over theCorrespondence to Joel A Schulman, MD, 2849 Dominique,Galveston, Texas 77550, USA.

previous year. He admitted to homosexual activitywhich stopped three years before initial presentationto an ophthalmologist. He denied parenteral use ofillicit drugs.He was first examined by a local ophthalmologist

on 11 January 1984, at which time his best correctedvisual acuity was 20/20 in the right eye and 20/40 inthe left eye. The right eye was completely normal.The left eye had a cellular reaction in both theanterior chamber and vitreous cavity. A slightlyelevated yellowish retinal lesion approximately 31/2by 5 disc diameters in size involving the temporalmacula (Fig. 1) was observed. The patient wasdiagnosed as having an unspecified infectiouschorioretinitis. Homatropine 5% four times dailyand prednisolone acetate 1% every two hours wereprescribed for the left eye.

Tests for acquired immune deficiency disorderwere negative. Additional test results included anegative rapid plasmin reagent test for syphilis(RPR) and a negative hepatitis B surface antigen. Atest of leptospira titre was negative; histoplasmosis(mycelial) and histoplasmosis (yeast) titres were bothless than 1:8 and toxoplasmosis titre was less than1:16. The cytomegalovirus titre was 1:128 and thecomplete blood cell count and differential wereunremarkable except for a mildly increased whiteblood cell count of 9-4x 109/l.

Re-examination on 7 March showed that thepatient could barely count fingers with the left eye.The vitreous contained a large number of non-

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JoelA Schulman, Christopher Leveque, Marion Coats, Linda Lawrence, andJohn C Barber

Fig. 1 Fundus photograph ofthe left eye showingaslightlyelevated retinal lesion involving the temporalportion ofthemacula and inferior arcade. Retinal haemorrhages are

present over the lesion. The overlying retinal vessels appearto be involved in the inflammatory process.

pigmented cells, and the retinal lesion had enlarged(Fig. 2). Oral prednisone 100 mg daily was initiatedand tapered to 60 mg after three days. Best correctedvision in the left eye one week later improved to20/200 and the patient reported decreased ocularpain. On 21 March the fundus lesion was smaller, andthe oral prednisone was decreased to 40 mg daily.The patient went to an emergency room on 6 April

1984 with a six-day history of fever up to 39 4°C,nausea (without vomiting), anorexia, confusion,neck stiffness, headaches in the occipital and nuchalregion, and photophobia and blurred vision of theleft eye. The oral prednisone had been tapered to

...............................I

Fig. 2 Left eye approximately two months later. The lesionhas enlarged and now extends beyond the temporal macula.The inferior aspect appears lobulated. A preretinalmembrane extendsfrom the retinal lesion to the optic disc.Retinal vessels appear to be constricted and disappear withinthe lesion.

20 mg daily. The patient was transferred to theUniversity of Texas Medical Branch (UTMB) atGalveston after receiving intravenous fluids fordehydration.When admitted to UTMB, Galveston, the

patient's temperature was 39-50C, blood pressure136/80 mmHg, pulse 100/min, and respiration 20/min. The patient appeared lethargic and confused.Physical examination was normal except for a fewenlarged cervical lymph nodes, inappropriate affect,and execution of commands in an opposite manner tothe directive about 50% of the time.

Visual acuity in the right eye was 20/20 and findingswere normal. In the left eye the visual acuity was20/400, and examination revealed numerous vitreouscells and a yellowish retinal lesion temporal to theoptic disc associated with an overlying vitreousinfiltrate.The opening pressure on lumbar puncture was 333

mm H20 with a closing pressure of 160 mm H20. AnIndia ink preparation of cerebrospinal fluid (CSF)demonstrated organisms resembling Cryptococcusneoformans. The cryptococcal latex agglutinationtest was positive for cryptococcal antigen in a dilutionof 1:64 when performed on both blood and CSF.Cultures of CSF failed to isolate any organisms.A diagnosis of cryptococcal meningitis, retinitis,

and possible endophthalmitis was made, and thepatient was started on intravenous amphotericin Band oral 5-flucytosine. His neurological statusdeteriorated despite therapy. A third nerve palsydeveloped on the second day of admission and hedeveloped apnoeic spells four days later. A CT scanthe following day showed posterior fossa infarcts andhydrocephalus.Four days later a right frontal indwelling ventricu-

lar reservoir system (Omaya reservoir) for intra-thecal amphotericin B administration was placed.The patient continued on a downhill course andrequired intubation and tracheostomy. He becamecomatose and died on day 30 in hospital.

PATHOILOGICAL EXAMINATIONThe necropsy showed disseminated cryptococcosiswith cryptococcal granulomata present in the centralnervous system, liver, adrenal glands, and bothkidneys. Microscopic examination of the left eyerevealed numerous cryptococcal organisms infiltrat-ing the retina (Fig. 3). Choroidal and optic nerveinvolvement was not observed.

Discussion

Cryptococcosis is caused by Cryptococcusneoformans, an encapsulated saprophytic yeast-likefungus which grows best at 37°C. The organism is

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Fatal disseminated cryptococcosisfollowing intraocular involvement

Fig. 3 Tangential microscopic section (left eye) through theretina revealing a cluster ofcryptococcal organisms withinthe layer ofrods and cones. Thepigment epithelium isattached. Gomorimethenamine silver.

found in high concentrations in soil that containspigeon faeces, though the birds are not naturallyinfected. The organism has also been recovered fromvarious animals (including dogs, cats, and cows),fresh vegetable skins, and fruits. 24

Human infection is acquired by inhalation ofcontaminated particles. The primary pulmonaryinfection may be asymptomatic but be followed byhaematogenous spread to other areas of the body.2The organism has a predilection for the CNS. Directanimal-to-man transmission has not been docu-mented,' and only one case of direct person-to-person transmission has been reported. A case ofexogenous intraocular cryptococcal endophthalmitisfollowed corneal transplantation with donor materialfrom a patient with disseminated cryptococcosis.5New cases of the disease are rare, approximately 300being reported annually in the United States.' Thissuggests a strong natural resistance to the organism.Although 50% of the cases of cryptococcosis occur inotherwise healthy individuals, a three-fold increaseof this infection exists among patients with sarcoido-sis, lymphoreticular malignancies, or steroidalimmunosuppression. 4 Cryptococcosis also occursmore frequently in patients with acquired immunedeficiency' or diabetes.'4 Therapy with steroids or

immunosuppressives appears to increase individualsusceptibility to cryptococcosis and dissemination ofdormant primary lesions.'4 Cirrhosis of the liver isassociated with an extremely fulminant form of thedisease.2

Cryptococcus neoformans is the most commonfungus causing CNS infections, usually meningoen-cephalitis or meningitis. In rare instances patientswith CNS involvement may be afebrile and display noneurological signs or symptoms.6

Cryptococcus neoformans rarely causes primaryocular disease. The organism may invade the eyeeither as a result of direct extension along the opticnerve or its meningeal sheath or by haematogenousdissemination.3 Histological studies show that endo-genous ocular cryptococcosis is primarily a choroidaldisease, with secondary invasion of the sensory retinaand other intraocular structures.7. Cryptococcusneoforms has also been reported to cause endo-phthalmitis, uveitis, and retinitis.3 The histologicalreaction caused by the organism in the choroid andretina can range from minimal to no inflammatoryreaction or necrosis to granulomatous changes.7

Secondary involvement of the eye as a conse-quence of CNS involvement is more common.Approximately 40% of individuals with crypto-coccal meningitis have eye signs or symptoms.Papilloedema, optic atrophy, and extraocular muscleparesis were the most common ophthalmic signs in aseries of 36 cases of cryptococcal meningitis reportedby Okun and Butler.8 Decreased visual acuity withCNS involvement appears in many patients to becaused by direct invasion of the visual pathways bythe cryptococcal organism.8The differential diagnosis of a posterior, slightly

elevated, amelanotic choroidal, retinal, or chorio-retinal lesion includes melanoma, metastaticcarcinoma, or other neoplastic ocular diseases suchas leukaemia, haemangioma, toxocariasis, osteoma,chorioretinal fungal abscess, cryptococcal chorio-retinitis or retinitis, and serous or disciform extra-macular or macular detachment. Syphilis andtuberculosis must also be ruled out.

Several other infectious agents includingcytomegalovirus, Candida albicans, Toxoplasmagondii, and herpes hominis virus usually present as aretinitis with varying degrees of secondary choroidalinvolvement. Affected patients have areas ofopacified retina with overlying vitreous cells. Incontrast the initial lesion in cryptococcal chorio-retinitis develops in the choroid with secondaryretinal involvement.79 Vitreous overlying thechorioretinal lesions usually remains clear.6

Funduscopic examination by indirect ophthalmo-scopy, a fundus contact lens examination, and the useof adjunct diagnostic tests including quantitativeultrasonography and fluorescein angiography areuseful in differentiating along the several conditionspresenting as moderately elevated posterior chorio-retinal or retinal masses.

Special serological tests such as detection of IgGantibodies against Toxoplasma gondii"' or the ELISAtest (enzyme-linked immunosorbent assay) insuspected ocular toxocariasis" may help confirm asuspected diagnosis. A clinical diagnosis of a retinitiscaused by herpes hominis or cytomegalovirus may be

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JoelA Schulman, Christopher Leveque, Marion Coats, Linda Lawrence, andJohn C Barber

supported by demonstrating rising serum antibodytitres to the virus or recovery of the virus from blood,urine, aqueous, or the throat.9The diagnosis in a patient with a suspected crypto-

coccal chorioretinal or retinal lesion is complicatedby the frequent association between direct intra-ocular cryptococcal involvement and the dissemi-nated form of the infection, which frequentlyinvolves the central nervous system. 12 Routinelaboratory tests such as complete blood count andsedimentation rate usually give normal results.Identification of the encapsulated organism incerebrospinal fluid stained with India ink is sufficientfor making a presumptive diagnosis and initiatingtreatment pending culture results.4 India ink prepara-tions are negative in 50% of cases involving thecentral nervous system.' In suspected cases the urine,CSF, blood, and sputum should be cultured even inthe absence of evidence suggesting genitourinary orpulmonary infection.

Cryptococcus neoformans grows well on bothblood agar and Sabouraud's medium. 3 Cyclo-heximide, which is added to most fungal media toinhibit non-pathogens, also inhibits C. neoformansand should not be present in the agar.' Severalserological tests for cryptococcus have beendeveloped including complement fixation, tubeagglutination, immunodiffusion, and an indirectimmunofluorescence test. ' The latex agglutinationtest for detection of antigen on the cryptococcalpolysaccharide capsule is the most commonly usedcommercially available test. A titre greater than 1:8 isan indication for treatment.8 The presence of antigenshould be tested in blood, urine, and CSF if thediagnosis is suspected but not proved.When tests of serum, sputum, CSF, and blood are

negative and a high index of suspicion still exists, adiagnostic vitreous tap,9 vitrectomy,7 or eye wallbiopsy'5 can be performed to obtain tissue specimenssuitable for histological examination and culture.Morphological characteristics of the organism whichallow identification are apparent with periodic acidSchiff (PAS) or methenamine silver stains. Mayer'smucicarmine will stain the polysaccharide capsulered, which differentiates Cryptococcus neoformansfrom other organisms and artefacts. '

Before the introduction of the antifungal agentamphotericin B disseminated cryptococcal infectionswere invariably fatal, and most cases with directocular involvement were positively diagnosed eitherat necropsy or following enucleation.'2 Parenteralamphotericin B alone89 " or in combination with5-flucytosine39 has been used successfully in thetreatment of some cases of intraocular crypto-coccosis. Miconazole, which has been reported to beeffective in a case of central nervous system crypto-

coccosis unresponsive to amphotericin B and 5-flucytosine,3 is an alternative form of therapy formyotic intraocular infections. Intravitreal injectionof amphotericin B, which is used to treat otherintraocular fungal infections,'6 may also have a role inthe treatment of cryptococcal eye disease.

Systemic steroids were used in the patient reportedhere to treat an unknown intraocular infection. Thediagnosis was not established until late in the courseof the disease. The ocular lesion initially appeared torespond well to oral and topical steroids, butfulminant systemic disease eventually appeared.

Systemic steroids must be used with caution, andpatients who take these drugs require frequentmonitoring. Fujikawa and associates'7 reportedhyperosmolar hyperglycaemic non-ketotic coma inthree patients who received systemic steroid therapyfor ocular disorders. Two of these patients died.

This case demonstrates the diagnostic difficultiesthat may be encountered in a patient presenting withan apparently inflammatory retinal lesion with over-lying vitreous involvement. Cryptococcusneoformans must be considered in the assessment ofsuch a lesion, or a delay in diagnosis and treatmentmay occur.

References

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14 Wolf PL. Immunofluorescence as a diagnostic aid in cryptococcal 16 Perraut LE Jr, Perraut LE, Bleiman B, Lyons J. Successfulmeningitis and other fungal infections. Am J Pathol 1975; 78: treatment of Candida albicans endophthalmitis with intravitreal17a. amphotericin B. Arch Ophthalmol 1981; 99: 1565-7.

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Accepted for publication 22 December 1986.