Documenta, Ophthalmologica 44,1 : 49-56, 1977 CRYPTOCOCCAL EYE DISEASE P.I. CONDON, S.I. TERRY & H. FALCONER
(Waterford, Ireland/Jamaica, W. Indies)
ABSTRACT A survey is given of the clinical picture of an infection with Cryptococcus neoformans. The symptoms and therapy are reviewed and the case history of a 13 year old boy suffering from this fungus infection is discussed. Cryptococcus neoformans is a saprophytic yeast found in soil, milk from infected herds and pigeon droppings. Because pigeons are themselves immune to cryptococcus, their faeces offer an ideal medium for the propagation of this fungus in nature. Cryptococcus is transmitted to humans mainly by inhalation through the respiratory tract resulting in pulmonary lesions, but entry through the skin or gastro-intestinal system by direct contact or ingestion respectively can occur. The resulting condition is called cryptococcosis, torulosis or Busse-Buschke's disease. Predisposing factors to the development of this disease are immunologically deficient states such as exist in patients on immunosuppressive and steroid therapy, and in patients with chronic illnesses such as leukaemia, Hodgkin's disease or sarcoidosis. Involvement of the lungs with haematogenous spread to the brain and meninges occurs frequently but cutaneous and bony lesions also occur. 40% of patients with cryptococcal meningitis develop eye signs (Gonyea & Heilman, 1972). EYE INVOLVEMENT Exogenous cryptococcal eye disease from an infected anterior segment wound or after intra-ocular surgery is unusual, and most reports in the literature deal with endogenous infections from a haematogenous source or directly by leptomeningeal spread down the optic nerves from an associated meningitis. (a) Anterior Uveitis (Friedenwald et al., 1952; DeBuen et al., 1954; Wager & Calhoun, 1954; Sciortino et al., 1958; Weiss et al., 1948; Hiles & Font, 1968; Grieco & Freilich, 1971; Ehrhorn et al., 1976) can be severe enough to have an hypopian or secondary glaucoma. (b) Posterior Uveitis can take several forms.
49
A single white elevated mass varying in size from 1-10 disc diameters (D.D.) can occur (Friedenwald et al., 1952; Khoudadoust & Payne, 1969; Ehrhorn et al., 1976), but multiple small focal choroiditis type lesions due to foci in the choriocapillaris and resembling miliary tuberculosis, can also occur (Beck et al., 1955; Turner, 1959; Hiles & Font, 1968). (c) Retinitis is usually a complication of posterior uveitis but retinal haemorrhages .and exudates varying in size from small dots to l DD in size (Hiles & Font, 1968) can also occur and blindness from retinal detachment has also been reported (Heath, 1950; Heinsius, 1949; Wager & Calhoun, 1954). (d) Optic atrophy was reported by Heinsius (1950). (e) papiUoedema can be associated with an active choroiditis but is generally associated with raised intracranial pressure or direct spread via the leptomeninges secondary to a meningitis (Cohen, 1944; Heinsius, 1950; Friedenwald et al., 1952; Turner, 1959; Okun & Butler, 1964; Hiles & Font, 1968). (f) Neuro-ophthalmic involvement can manifest itself as III, IV or VI nerve palsies with diplopia, ptosis, pupillary abnormalities, and nystagmus (Okun & Butler, 1964) or as a internuclear or supranuclear ophthalmoplegia (Watkins et al., 1969; Goyea & Heilman, 1972). (g) Orbital involvement was reported by Gill, (1934) and Krainer et al., (1846). DIAGNOSIS Isolation of the cryptococcal organism from an exogenous eye infection involves doing a paracentesis of the anterior chamber or a vitreous tap. The organism can be readily demonstrated by various staining techniques such as Indian Ink and Giemsa stains on a glass slide but culture in Sabourauds Dextrose Broth and in Litmann's solid oxgall medium should be carried out. Tests for pathogenicity are a useful back-up and intracerebral injection of 0'.02-0.04 ml of a suspension of the organism in saline into Swiss White Mice is lethal within 4 0 - 7 3 days. Isolation of the organism in the endogenous type of eye disease is however much more difficult, the aqueous tap usually being sterile and search from wounds, abscesses, blood and urine should be carried out. Because of the high incidence of brain and meningeal involvement with eye disease, cerebro-spinal fluid examination should be carried out. Complement-fixation tests on serum and spinal fluid in the form of the Latex slide and whole cell agglutination tests can be highly specific for cryptococcal antibodies and the use of hypertonic sucrose media may enhance the results (Grieco & Freilich, 1971). 50
TREATMENT
Amphotericin B This toxic drug is a fungicidal and fungistatic agent acting against a wide range of fungi including cryptococcus neoformans. It acts directly on the fungal cell membrane allowing K-ions and other intracellular contents to leak out. Unfortunately it can also have the same effect on the mammalian cell especially those of the renal tubules and bone marrow resulting sometimes in renal tubular disease and bone marrow depression. 80% of patients on this drug can develop renal disease. For exogenous infections, Amphotericin B can be given topically in 0.1% or 0.2% concentration disolved in distilled water without preservatives or 5% dextrose in water. Subconjunctival injection of up to 500 microgrms/ 0.5 mls of 5% dextrose in water have been given without adverse effects and should be proceeded by injection of lignocaine to counteract painful side-effects. Foster et al. (1960) reported good effects from intracameral injection but as there was a real danger of iritis and lens opacities this would seem to exclude it from routine practice. Amphotericin B is given by intravenous route in a 5% dextrose in water solution for endogenous infections. The dose is 0.25 ml grms per Kilogram Body Weight and given over a 6 - 8 hour period. The dose is increased gradually on alternate days to 1 grm per Kilogram Body Weight up to a maximum dose of 1 - 4 grins given over a week or month. Routine assessment of blood urea and white cell count will prevent the general medical complications of this drug.
Flucytosine (Ancobon) This halogenated pyrimidine is specific against cryptococcus neoformans and candida albicans and has no effect against any of the other fungi. Its action depends on the deammination of 5-fluorocytosine to 5-fluorouracil by the fungal enzyme cystine deaminase. This product interferes with nucleic acid synthesis of the fungus but has no effect on mammalian nuclear acid production, hence its relatively low toxicity to humans as compared to Amphotericin B. F o r exogenous eye infections it can be used topically as a 1% solution and intracameral injections have been shown by Dikstein (1969) to have low endothelial toxicity. Endogenous infections can be treated with an oral dose of 5 0 - 1 5 0 ml grms per Kilogram Body Weight. Penetration of the drug across the blood aqueous and blood brain barriers are excellent. A dose of 100 ml grms per Kilogram Body Weight ( 2 - 9 grms daily) results in a blood
51
level of 16.8+7.8 micro grms per ml. 6 4 - 8 8 % Flucytosine reaches the C.S.F. as distinct from 2.5% with Amphotericin B. Richards et al. (1969) report serum levels of 50 micro grins per ml and aqueous levels of 10 micro grms per ml with oral dose of 200 mt grms per Kilogram Body Weight. F o r resistant cryptococcal infections, use of both Amphotericin B and Flucytosine in combination can be life saving and should be considered in the treatment of endogenous eye disease.
CLINICAL CASE The following case illustrates the difficulties encountered in the diagnosis of cryptococcal eye disease. A 13 year old schoolboy from Kingston, Jamaica, West Indies was admitted to the University Hospital of the West Indies, Jamaica with a history of frontal headaches for 4 weeks. He had had a grand mal fit 2 weeks previously. By the time of admission his headaches were accompanied by vomiting, his fight vision was impaired and he was drowsy. Examination revealed a depressed, drowsy, sometimes irritable boy with a mild pyrexia and a temperature of 100 ~ F. Examination of the effected eye showed the visual acuity to be less than 6/60, the vision in the other eye being quite normal. The anterior segment appeared to be quite normal but examination of the vitreous showed the presence of haziness due to excessive accumulation of white cells. At the posterior pole in this eye there was a large raised whitish area temporal to the optic disc and involving the macular area and extending out along the superior and inferior retinal vessels for a distance of 5 - 6 d diameters. A diagnosis of choroiditis was made. Repeated lumbar punctures showed mean values of WBC 126/cumin (Lymphocytes 64% and neutrophils 36%), cerebro-spinal fluid glucose was 2.7 mMol/litre, protein 562 mg/litre, but microscopy and culture was unhelpful. Treatment for Tuberculous meningitis was started pending culture reports. Isoniazid 100 mg three times daily with rifampicin 300 mg twice daily and streptomycin 0.75 G intra-muscularly were given together with dexamethasone 5 mg daily for his choroiditis. Because there was no improvement, diethylcarbamazine was given on the assumption that he might have toxocariasis. During his fifth week of hospitalisation he suddenly developed a right hemiparesis. F o u r days later Cryptococcus antigen was positive 1:8 Latex Fixation test in both serum and C.S.F. and he was started on flucytosine 200 rag/ Kg/day by m o u t h in divided doses. His pyrexia continued and the dose of flucytosine was increased to 250 mg/Kg/day. 52
Fig. 1. Composite fundus fluorescein angiogram of right posterior poler area in a 13 year old Jamaican male with cryptococcal meningitis. The affected area measuring 5 disc diameters in length by 2 ~ disc diameters in width and involving the macular area has sharply demarcated borders and leaks fluorescein dye subretinally through a defective permanently damaged pigment epithelium.
Flucytosine therapy was continued for 24 weeks, by which time his C.S.F. had returned to normal. At 6 weeks repeat Latex Fixation Titres were serum antigen positive 1 : 64, C.S.F. antigen positive t : 8. At 19 weeks both antigen and antibody were absent from serus and C.S.F. His progress was uneventful and although he has a very mild residual right hemiparesis at the moment he has returned to school and is off therapy. The appearance of the lesion at the posterior pole of the right eye is unchanged and fluorescein angiograms confirmed the presence of normal retinal arterioles with gross leakage from the choroid through a defective pigment epithelium in the late stages of dye transit in the area of the white lesion (Fig. 1).
DISCUSSION The similarity of cryptococcal meningitis to tuberculous meningitis and the difficulties encountered in its diagnosis, as illustrated in this case report, are weU documented (Wilson et al., 1970). Similar difficulties can also be encountered in the diagnosis of cryptococcal eye disease. Grieco & Freilich (1971) described a very similar case to ours and highlighted the usefulness of the Latex Fixation tests with cryptococcal antigen on both serum and spinal fluid. They suggested that C.S.F. examination be routinely carried out in the evaluation of any patient with persistent uveitis of undetermined aetiology, specially if progressive deterioration occurs despite cortico steroid therapy. The high effectivity of Flucytosine for the treatment of cryptococcal meningitis is also illustrated by this case report. Unnecessary delay in the diagnosis as occurred in this case, unfortunately lead to irreversible posterior polar chorio-retinal damage and a blind eye which might have been prevented had the diagnosis been made sooner. The specificity of flucytosine for cryptococcal infections, its low toxicity in humans and the enhanced effects when combined with Amphotericin B make it adamant that a diagnosis of a cryptococcosis, if present, be made as soon as possible in all cases of uveitis or meningitis.
ACKNOWLEDGEMENTS We wish to thank Dr. Graham Serjeant M.D., M.R.C.P., for use of the retinal fluorescein photographic facilities at the M.R.C. Laboratories, University of the West Indies, Kingston, Jamaica and Miss Dolores Firth for secretarial assistance. 54
REFERENCES Beck, A. et al. Infection with Cryptococcus neoformans in man. Lancet I: 535 (1955). Cohen, M. Binocular papilledema in a case of torulosis associated with Hodgkin's disease. Arch. Ophthal. 3 2 : 4 7 7 (1944). DeBuen, S., L.E. Zimmerman & H.C. Foerster. Patologia ocular en la cryptococcosis. Rev. Inst. Salubr. Enferm. Trop. (M~x.) 1 4 : 1 6 3 (1954). Dikstein, S. Antifungal drugs for oculumycosis. III. In vitro measurement of corneal endothelial toxicity of certain antifungal drugs. Trans. OphthaL Soc. U.K. 8 9 : 8 4 5 (1969). Ehrhorn, J. et al. Intraokular Cryptococcose. Klin. Mbl. Augenheilk. 1 6 8 : 5 7 7 (1976). Foster, J.B.T. et al. Some intraocular and conjunctival effects of Amphotericin B in man and in the rabbit. Arch. OphthaL 6 0 : 5 5 5 (1960). Friedenwald, J.S. et al. Ophthalmic pathology: an atlas and textbook. Philadelphia, Saunders (1952). Gill, W.D. Torula mycosis in man with special reference to involvement of the upper respiratory tract. Trans. Amer. Laryng. Rhin. Otol. Soe. 4 0 : 2 4 7 (1934). Gonyea, E.F. & K.M. Heilman. Neuro-ophthalmic aspects of central nervous system cryptococcosis. Arch. OphthaL 8 7 : 1 6 4 (1972). Grieco, H.M. & D.B. Freilich. Diagnosis of cryptococcal uveitis with hypertonic media. Amer. J. Ophthal. 72:171 (1971). Heath, P. Massive separation of the retina in full term infants and juveniles. J. Amer. Med. Ass. 144:1148 (1950). Heinsius, E. Augenbeteiligung bei Blastomykose. Ber. Deutsche OphthaL Gesellseh. 55: 358 (1949). Hiles, D.A. & R.L. Font. Bilateral intraocular cryptococcosis with unilateral spontaneous regression. Report of a case and review of the literature. Amer. J. OphthaL 6 7 : 7 4 5 (1969). Krainer, L. et al. A case of systemic torula infection with tumor formation in the meninges. J. Neurol. Neurosurg. Psychiat. 9 : 1 5 8 (1946). Okun, E. & W.T. Butler. Ophthalmologic complications of cryptococcal meningitis. Arch. Ophthal. 7 1 : 5 2 (1964). Richards, A.B. et al. Corneal and intra-ocular infection by Candida albicans treated with 5-fluorocytosine. Trans. Ophthal. Soc. U.K. 8 9 : 8 6 7 (1969). Sciortino, A.L. et al. Cryptococcosis. Arch. Intern. Med. 102:450 (1958). Speller, D.C.E. et al. Cryptococcal meningitis complicating systemic lupus erythematosis. Two patients treated with flucytosine and Amphotericine-B. J. Clin. Path. 30: 254 (1977). Turner, P.P. A case of cryptococcosis with choroidal torulomata. East Afr. reed. J. 3 6 : 2 2 0 (1959). Water, H.E. & F.P. Calhoun. Torula uveitis. Trans. Amer. Acad. Ophthal. Otolaryng. 5 8 : 6 1 (1954). Watkins, J.S. et al. Two cases of cryptococcal meningitis, one treated with 5-fluorocytosine. Brit. med. J. 3 : 2 9 (1969). Weiss, C., I.H. Perry & M.C. Shevky. Infection of the human eye with Cryptococcus neoformans (Torula histolytica; Cryptococcus hominis). Arch. OphthaL 3 9 : 7 3 9 (1948). Wilson, T.S. et al. Cryptococcus meningitis associated with steroid therapy. J. Clin. Path. 2 3 : 6 5 7 (1970).
55
Authors' addresses: P.I. Condon Regional Eye Department Ardkeen Hospital Waterford Ireland S.I. Terry & H. Falconer Dept of Medicine University Hospital of the West Indies Kingston, Jamaica West Indies
56
(Waterford, Ireland/Jamaica, W. Indies)
ABSTRACT A survey is given of the clinical picture of an infection with Cryptococcus neoformans. The symptoms and therapy are reviewed and the case history of a 13 year old boy suffering from this fungus infection is discussed. Cryptococcus neoformans is a saprophytic yeast found in soil, milk from infected herds and pigeon droppings. Because pigeons are themselves immune to cryptococcus, their faeces offer an ideal medium for the propagation of this fungus in nature. Cryptococcus is transmitted to humans mainly by inhalation through the respiratory tract resulting in pulmonary lesions, but entry through the skin or gastro-intestinal system by direct contact or ingestion respectively can occur. The resulting condition is called cryptococcosis, torulosis or Busse-Buschke's disease. Predisposing factors to the development of this disease are immunologically deficient states such as exist in patients on immunosuppressive and steroid therapy, and in patients with chronic illnesses such as leukaemia, Hodgkin's disease or sarcoidosis. Involvement of the lungs with haematogenous spread to the brain and meninges occurs frequently but cutaneous and bony lesions also occur. 40% of patients with cryptococcal meningitis develop eye signs (Gonyea & Heilman, 1972). EYE INVOLVEMENT Exogenous cryptococcal eye disease from an infected anterior segment wound or after intra-ocular surgery is unusual, and most reports in the literature deal with endogenous infections from a haematogenous source or directly by leptomeningeal spread down the optic nerves from an associated meningitis. (a) Anterior Uveitis (Friedenwald et al., 1952; DeBuen et al., 1954; Wager & Calhoun, 1954; Sciortino et al., 1958; Weiss et al., 1948; Hiles & Font, 1968; Grieco & Freilich, 1971; Ehrhorn et al., 1976) can be severe enough to have an hypopian or secondary glaucoma. (b) Posterior Uveitis can take several forms.
49
A single white elevated mass varying in size from 1-10 disc diameters (D.D.) can occur (Friedenwald et al., 1952; Khoudadoust & Payne, 1969; Ehrhorn et al., 1976), but multiple small focal choroiditis type lesions due to foci in the choriocapillaris and resembling miliary tuberculosis, can also occur (Beck et al., 1955; Turner, 1959; Hiles & Font, 1968). (c) Retinitis is usually a complication of posterior uveitis but retinal haemorrhages .and exudates varying in size from small dots to l DD in size (Hiles & Font, 1968) can also occur and blindness from retinal detachment has also been reported (Heath, 1950; Heinsius, 1949; Wager & Calhoun, 1954). (d) Optic atrophy was reported by Heinsius (1950). (e) papiUoedema can be associated with an active choroiditis but is generally associated with raised intracranial pressure or direct spread via the leptomeninges secondary to a meningitis (Cohen, 1944; Heinsius, 1950; Friedenwald et al., 1952; Turner, 1959; Okun & Butler, 1964; Hiles & Font, 1968). (f) Neuro-ophthalmic involvement can manifest itself as III, IV or VI nerve palsies with diplopia, ptosis, pupillary abnormalities, and nystagmus (Okun & Butler, 1964) or as a internuclear or supranuclear ophthalmoplegia (Watkins et al., 1969; Goyea & Heilman, 1972). (g) Orbital involvement was reported by Gill, (1934) and Krainer et al., (1846). DIAGNOSIS Isolation of the cryptococcal organism from an exogenous eye infection involves doing a paracentesis of the anterior chamber or a vitreous tap. The organism can be readily demonstrated by various staining techniques such as Indian Ink and Giemsa stains on a glass slide but culture in Sabourauds Dextrose Broth and in Litmann's solid oxgall medium should be carried out. Tests for pathogenicity are a useful back-up and intracerebral injection of 0'.02-0.04 ml of a suspension of the organism in saline into Swiss White Mice is lethal within 4 0 - 7 3 days. Isolation of the organism in the endogenous type of eye disease is however much more difficult, the aqueous tap usually being sterile and search from wounds, abscesses, blood and urine should be carried out. Because of the high incidence of brain and meningeal involvement with eye disease, cerebro-spinal fluid examination should be carried out. Complement-fixation tests on serum and spinal fluid in the form of the Latex slide and whole cell agglutination tests can be highly specific for cryptococcal antibodies and the use of hypertonic sucrose media may enhance the results (Grieco & Freilich, 1971). 50
TREATMENT
Amphotericin B This toxic drug is a fungicidal and fungistatic agent acting against a wide range of fungi including cryptococcus neoformans. It acts directly on the fungal cell membrane allowing K-ions and other intracellular contents to leak out. Unfortunately it can also have the same effect on the mammalian cell especially those of the renal tubules and bone marrow resulting sometimes in renal tubular disease and bone marrow depression. 80% of patients on this drug can develop renal disease. For exogenous infections, Amphotericin B can be given topically in 0.1% or 0.2% concentration disolved in distilled water without preservatives or 5% dextrose in water. Subconjunctival injection of up to 500 microgrms/ 0.5 mls of 5% dextrose in water have been given without adverse effects and should be proceeded by injection of lignocaine to counteract painful side-effects. Foster et al. (1960) reported good effects from intracameral injection but as there was a real danger of iritis and lens opacities this would seem to exclude it from routine practice. Amphotericin B is given by intravenous route in a 5% dextrose in water solution for endogenous infections. The dose is 0.25 ml grms per Kilogram Body Weight and given over a 6 - 8 hour period. The dose is increased gradually on alternate days to 1 grm per Kilogram Body Weight up to a maximum dose of 1 - 4 grins given over a week or month. Routine assessment of blood urea and white cell count will prevent the general medical complications of this drug.
Flucytosine (Ancobon) This halogenated pyrimidine is specific against cryptococcus neoformans and candida albicans and has no effect against any of the other fungi. Its action depends on the deammination of 5-fluorocytosine to 5-fluorouracil by the fungal enzyme cystine deaminase. This product interferes with nucleic acid synthesis of the fungus but has no effect on mammalian nuclear acid production, hence its relatively low toxicity to humans as compared to Amphotericin B. F o r exogenous eye infections it can be used topically as a 1% solution and intracameral injections have been shown by Dikstein (1969) to have low endothelial toxicity. Endogenous infections can be treated with an oral dose of 5 0 - 1 5 0 ml grms per Kilogram Body Weight. Penetration of the drug across the blood aqueous and blood brain barriers are excellent. A dose of 100 ml grms per Kilogram Body Weight ( 2 - 9 grms daily) results in a blood
51
level of 16.8+7.8 micro grms per ml. 6 4 - 8 8 % Flucytosine reaches the C.S.F. as distinct from 2.5% with Amphotericin B. Richards et al. (1969) report serum levels of 50 micro grins per ml and aqueous levels of 10 micro grms per ml with oral dose of 200 mt grms per Kilogram Body Weight. F o r resistant cryptococcal infections, use of both Amphotericin B and Flucytosine in combination can be life saving and should be considered in the treatment of endogenous eye disease.
CLINICAL CASE The following case illustrates the difficulties encountered in the diagnosis of cryptococcal eye disease. A 13 year old schoolboy from Kingston, Jamaica, West Indies was admitted to the University Hospital of the West Indies, Jamaica with a history of frontal headaches for 4 weeks. He had had a grand mal fit 2 weeks previously. By the time of admission his headaches were accompanied by vomiting, his fight vision was impaired and he was drowsy. Examination revealed a depressed, drowsy, sometimes irritable boy with a mild pyrexia and a temperature of 100 ~ F. Examination of the effected eye showed the visual acuity to be less than 6/60, the vision in the other eye being quite normal. The anterior segment appeared to be quite normal but examination of the vitreous showed the presence of haziness due to excessive accumulation of white cells. At the posterior pole in this eye there was a large raised whitish area temporal to the optic disc and involving the macular area and extending out along the superior and inferior retinal vessels for a distance of 5 - 6 d diameters. A diagnosis of choroiditis was made. Repeated lumbar punctures showed mean values of WBC 126/cumin (Lymphocytes 64% and neutrophils 36%), cerebro-spinal fluid glucose was 2.7 mMol/litre, protein 562 mg/litre, but microscopy and culture was unhelpful. Treatment for Tuberculous meningitis was started pending culture reports. Isoniazid 100 mg three times daily with rifampicin 300 mg twice daily and streptomycin 0.75 G intra-muscularly were given together with dexamethasone 5 mg daily for his choroiditis. Because there was no improvement, diethylcarbamazine was given on the assumption that he might have toxocariasis. During his fifth week of hospitalisation he suddenly developed a right hemiparesis. F o u r days later Cryptococcus antigen was positive 1:8 Latex Fixation test in both serum and C.S.F. and he was started on flucytosine 200 rag/ Kg/day by m o u t h in divided doses. His pyrexia continued and the dose of flucytosine was increased to 250 mg/Kg/day. 52
Fig. 1. Composite fundus fluorescein angiogram of right posterior poler area in a 13 year old Jamaican male with cryptococcal meningitis. The affected area measuring 5 disc diameters in length by 2 ~ disc diameters in width and involving the macular area has sharply demarcated borders and leaks fluorescein dye subretinally through a defective permanently damaged pigment epithelium.
Flucytosine therapy was continued for 24 weeks, by which time his C.S.F. had returned to normal. At 6 weeks repeat Latex Fixation Titres were serum antigen positive 1 : 64, C.S.F. antigen positive t : 8. At 19 weeks both antigen and antibody were absent from serus and C.S.F. His progress was uneventful and although he has a very mild residual right hemiparesis at the moment he has returned to school and is off therapy. The appearance of the lesion at the posterior pole of the right eye is unchanged and fluorescein angiograms confirmed the presence of normal retinal arterioles with gross leakage from the choroid through a defective pigment epithelium in the late stages of dye transit in the area of the white lesion (Fig. 1).
DISCUSSION The similarity of cryptococcal meningitis to tuberculous meningitis and the difficulties encountered in its diagnosis, as illustrated in this case report, are weU documented (Wilson et al., 1970). Similar difficulties can also be encountered in the diagnosis of cryptococcal eye disease. Grieco & Freilich (1971) described a very similar case to ours and highlighted the usefulness of the Latex Fixation tests with cryptococcal antigen on both serum and spinal fluid. They suggested that C.S.F. examination be routinely carried out in the evaluation of any patient with persistent uveitis of undetermined aetiology, specially if progressive deterioration occurs despite cortico steroid therapy. The high effectivity of Flucytosine for the treatment of cryptococcal meningitis is also illustrated by this case report. Unnecessary delay in the diagnosis as occurred in this case, unfortunately lead to irreversible posterior polar chorio-retinal damage and a blind eye which might have been prevented had the diagnosis been made sooner. The specificity of flucytosine for cryptococcal infections, its low toxicity in humans and the enhanced effects when combined with Amphotericin B make it adamant that a diagnosis of a cryptococcosis, if present, be made as soon as possible in all cases of uveitis or meningitis.
ACKNOWLEDGEMENTS We wish to thank Dr. Graham Serjeant M.D., M.R.C.P., for use of the retinal fluorescein photographic facilities at the M.R.C. Laboratories, University of the West Indies, Kingston, Jamaica and Miss Dolores Firth for secretarial assistance. 54
REFERENCES Beck, A. et al. Infection with Cryptococcus neoformans in man. Lancet I: 535 (1955). Cohen, M. Binocular papilledema in a case of torulosis associated with Hodgkin's disease. Arch. Ophthal. 3 2 : 4 7 7 (1944). DeBuen, S., L.E. Zimmerman & H.C. Foerster. Patologia ocular en la cryptococcosis. Rev. Inst. Salubr. Enferm. Trop. (M~x.) 1 4 : 1 6 3 (1954). Dikstein, S. Antifungal drugs for oculumycosis. III. In vitro measurement of corneal endothelial toxicity of certain antifungal drugs. Trans. OphthaL Soc. U.K. 8 9 : 8 4 5 (1969). Ehrhorn, J. et al. Intraokular Cryptococcose. Klin. Mbl. Augenheilk. 1 6 8 : 5 7 7 (1976). Foster, J.B.T. et al. Some intraocular and conjunctival effects of Amphotericin B in man and in the rabbit. Arch. OphthaL 6 0 : 5 5 5 (1960). Friedenwald, J.S. et al. Ophthalmic pathology: an atlas and textbook. Philadelphia, Saunders (1952). Gill, W.D. Torula mycosis in man with special reference to involvement of the upper respiratory tract. Trans. Amer. Laryng. Rhin. Otol. Soe. 4 0 : 2 4 7 (1934). Gonyea, E.F. & K.M. Heilman. Neuro-ophthalmic aspects of central nervous system cryptococcosis. Arch. OphthaL 8 7 : 1 6 4 (1972). Grieco, H.M. & D.B. Freilich. Diagnosis of cryptococcal uveitis with hypertonic media. Amer. J. Ophthal. 72:171 (1971). Heath, P. Massive separation of the retina in full term infants and juveniles. J. Amer. Med. Ass. 144:1148 (1950). Heinsius, E. Augenbeteiligung bei Blastomykose. Ber. Deutsche OphthaL Gesellseh. 55: 358 (1949). Hiles, D.A. & R.L. Font. Bilateral intraocular cryptococcosis with unilateral spontaneous regression. Report of a case and review of the literature. Amer. J. OphthaL 6 7 : 7 4 5 (1969). Krainer, L. et al. A case of systemic torula infection with tumor formation in the meninges. J. Neurol. Neurosurg. Psychiat. 9 : 1 5 8 (1946). Okun, E. & W.T. Butler. Ophthalmologic complications of cryptococcal meningitis. Arch. Ophthal. 7 1 : 5 2 (1964). Richards, A.B. et al. Corneal and intra-ocular infection by Candida albicans treated with 5-fluorocytosine. Trans. Ophthal. Soc. U.K. 8 9 : 8 6 7 (1969). Sciortino, A.L. et al. Cryptococcosis. Arch. Intern. Med. 102:450 (1958). Speller, D.C.E. et al. Cryptococcal meningitis complicating systemic lupus erythematosis. Two patients treated with flucytosine and Amphotericine-B. J. Clin. Path. 30: 254 (1977). Turner, P.P. A case of cryptococcosis with choroidal torulomata. East Afr. reed. J. 3 6 : 2 2 0 (1959). Water, H.E. & F.P. Calhoun. Torula uveitis. Trans. Amer. Acad. Ophthal. Otolaryng. 5 8 : 6 1 (1954). Watkins, J.S. et al. Two cases of cryptococcal meningitis, one treated with 5-fluorocytosine. Brit. med. J. 3 : 2 9 (1969). Weiss, C., I.H. Perry & M.C. Shevky. Infection of the human eye with Cryptococcus neoformans (Torula histolytica; Cryptococcus hominis). Arch. OphthaL 3 9 : 7 3 9 (1948). Wilson, T.S. et al. Cryptococcus meningitis associated with steroid therapy. J. Clin. Path. 2 3 : 6 5 7 (1970).
55
Authors' addresses: P.I. Condon Regional Eye Department Ardkeen Hospital Waterford Ireland S.I. Terry & H. Falconer Dept of Medicine University Hospital of the West Indies Kingston, Jamaica West Indies
56
