Cryptococcal Meningitis Presenting as Endophthalmitis in an Otherwise Asymptomatic Patient

Abstract

Purpose:

Cryptococcus neoformans is a budding yeast that has a tropism for the central nervous system where it may cause meningitis, which has a high mortality rate. Endophthalmitis is rare and typically occurs in the setting of meningitis and disseminated disease. This report describes an atypical presentation of cryptococcal endophthalmitis and outlines the appropriate workup and management for this disease.

Methods:

A case report is presented.

Results:

A 66-year-old man on chemotherapy who presented with blurry vision without any extraocular symptoms was diagnosed with cryptococcal endophthalmitis and found to have underlying bloodstream and central nervous system infection on subsequent workup. He was treated with intravenous and intravitreal antifungals and remained systemically well, although a large subretinal mass lesion remained stable at 2-month follow-up.

Conclusions:

Cryptococcal endophthalmitis may be the initial presentation of disseminated cryptococcal disease. If vitreous cultures grow Cryptococcus, clinicians should presume that meningitis is present, regardless of symptoms, until proven otherwise.

Introduction

Cryptococcus neoformans is an encapsulated yeast commonly found in soil and bird excrement. Infection may develop in humans via inhalation and affect almost any organ, most commonly the lungs or central nervous system (CNS). Immunosuppression increases susceptibility, but immunocompetent patients can be affected as well. CNS involvement is associated with a high mortality rate and requires intensive and long-term antifungal treatment. ¹

Ocular involvement is extremely rare and may be the result of extension of the infection from the CNS or hematogenous seeding. ^2,3 Ocular cryptococcosis may present with a variety of findings, and diagnosis is difficult and often delayed. ⁴ Ophthalmic involvement typically occurs in patients with known disseminated infection. ³ We present a case of endophthalmitis as the initial manifestation of cryptococcal meningitis and disseminated disease, which allowed for early initiation of potentially life-saving therapy.

Methods

Case Report

A 66-year-old man presented to his ophthalmologist with blurry vision in the right eye for 1 month. He was referred to the Wills Eye Hospital (Philadelphia, Pennsylvania) emergency department out of concern for endophthalmitis. His medical history was significant for myasthenia gravis, which was treated with chronic prednisone therapy of 20 mg/d, and metastatic thymic carcinoma, which was treated with carboplatin and paclitaxel (the most recent infusion was 9 days prior to presentation). He denied fever, chills, or headache, and the review of systems had negative findings except for a 2-month history of hearing loss that his otolaryngologist had attributed to his chemotherapy.

Examination revealed a generally well-appearing man with normal vital signs. Ocular examination showed visual acuities (VAs) of 20/400 –1 in the right eye and 20/50 in the left eye, bilateral nuclear sclerotic cataracts, and an otherwise normal anterior segment in both eyes. The right eye had 2+ vitritis and a dense, 4 × 6-mm, thickened, yellow subretinal lesion superior to the optic nerve (Figure 1A). B-scan ultrasonography, indocyanine green angiography, and optical coherence tomography showed vitreous haze and confirmed the subretinal location of the lesion (Figure 2). Fluorescein angiography (FA) did not show significant vascularity or enhancement of the lesion. The fundus examination in the left eye was within normal limits.

Figure 1.

Fundus photographs of the right eye. (A) Shortly after presentation: There is vitreous haze with a large, yellow, dome-like, dense, elevated, well-demarcated chorioretinal lesion. (B) At 2-month follow-up: Notice the more well-demarcated appearance in the chorioretinal lesion as well as the interval decrease in size and thickness. Vitritis has also improved.

Figure 2.

Optical coherence tomography of the right eye demonstrating vitreous haze and a lobular, subretinal lesion superior to the optic nerve.

The patient underwent needle vitreous aspiration, and the sample was sent for Gram stain and cultures. Intravitreal vancomycin 1 mg/0.1 mL, ceftazidime 2 mg/0.1 mL, and voriconazole 0.05 mg/0.1 mL were injected. The patient was admitted for infectious disease consultation. He was started on intravenous cefepime, vancomycin, and oral voriconazole as well as prednisolone acetate 1% eye drops every 2 hours, ofloxacin 0.3% eye drops every 2 hours, and atropine 1% eye drops twice daily in the right eye.

The systemic workup was significant for a white blood cell count of 4.4 × 10⁹ cells/L, 2 sets of blood cultures that had negative results, no signs of infection on thoracic and lumbar spinal radiographs, and a normal computed tomography of the head. He remained afebrile and hemodynamically stable without any extraocular complaints throughout this time.

Gram stain of the vitreous was positive for yeast, but vitreous cultures had negative findings at 3 days. The primary source remained unidentified, but transient fungemia caused by gastrointestinal translocation related to chemotherapy was suspected. The bedside ocular examination remained unchanged. On the fourth day after biopsy, budding yeast consistent with Cryptococcus was identified on culture.

Lumbar puncture, performed after Cryptococcus was identified in the vitreal cultures, showed a white blood cell count of 58 cells/mm³ (2 neutrophils, 62 lymphocytes, and 36 monocytes), red blood cell count of 4 cells/mm³, protein level of 239 mg/dL, glucose level of 21 mg/dL, positive growth of C neoformans, and reactive cryptococcal antigen at titer of 1:1280 in the cerebrospinal fluid (CSF). Cryptococcal antigen was reactive in the blood. HIV testing results were negative and urinalysis did not show evidence of infection. Review of magnetic resonance imaging (MRI) of the brain from 3 months prior, which was performed as screening for metastasis, showed leptomeningeal enhancement in the right temporal lobe and ependymal enhancement in the right frontal horn and left occipital horn of the lateral ventricles (Figure 3, arrow). On neuroimaging consultation, it was felt that this area represented undiagnosed meningitis. Another MRI was not performed during this hospitalization because of the stability of the neurologic examination and ability to diagnose CNS involvement via lumbar puncture.

Figure 3.

Axial fluid-attenuated inversion recovery magnetic resonance imaging of the brain performed 3 months prior to the diagnosis of endophthalmitis. The arrow shows leptomeningeal enhancement of the right temporal lobe that could reflect underlying meningitis.

Results

Systemic therapy was transitioned to intravenous amphotericin-B 5 mg/kg every 24 hours and flucytosine 1750 mg by mouth every 6 hours for treatment of cryptococcal meningitis and endophthalmitis. The prednisone was tapered from 20 to 10 mg daily to minimize immunosuppression while still controlling the underlying myasthenia gravis. Two weeks later, a second lumbar puncture showed negative CSF fungal cultures and reactive cryptococcal antigen at titer of 1:640. The patient was discharged on fluconazole 800 mg daily and prednisolone acetate 1% eye drops 4 times daily. One month from presentation, he remained afebrile without any localizing signs of meningitis or disseminated infection.

Throughout the patient’s hospitalization, he received twice-weekly intravitreal injections of amphotericin 5 μg/0.1 mL for 3 weeks beginning 4 days after his initial presentation. His VA improved from 20/400 –1 to 20/60 at his most recent follow-up, which was 5 months after diagnosis. The vitritis improved somewhat, but the single subretinal lesion remained stable after initial improvement with sharper margins and less elevation and density. Figure 1 compares fundus appearance at presentation (Figure 1A) and 2-month follow-up (Figure 1B). Surgical drainage of the lesion was discussed but deferred because of the patient’s overall weakness from the myasthenia gravis. He remained on oral fluconazole and topical prednisolone acetate at 5 months after presentation.

Conclusions

Approximately 5% of endophthalmitis cases are endogenous, of which 50% to 62% are fungal. ^5,6 Candida followed by Aspergillus are the most common pathogens. ⁷ Endogenous cryptococcal endophthalmitis is a rarely encountered entity with a limited number of confirmed cases reported in the literature. ^3,4,8 Additionally, its variable clinical manifestations both ophthalmologically and systemically can make the diagnosis difficult. Because findings from blood cultures are often negative, the diagnosis typically requires lumbar puncture for CSF cultures. This report describes an unusual case of endophthalmitis in an otherwise asymptomatic patient in whom the diagnosis of cryptococcal endophthalmitis and disseminated infection was made initially based on the results of a vitreous culture.

Although Cryptococcus may infect any organ, meningitis is the most common manifestation. ⁹ It is most commonly found in patients with AIDS, but any type of systemic immunosuppression increases susceptibility. However, 10% to 40% of patients with cryptococcal meningitis have no known immunosuppressive risk factors. ¹⁰ The majority of patients are systemically ill, most commonly with fever, headache, and altered sensorium, although up to 43% of patients with cryptococcal meningitis are asymptomatic at the time of diagnosis. ¹⁰ It is likely that our patient had been harboring CNS cryptococcosis for at least 3 months, as the leptomeningeal enhancement on MRI from 3 months prior likely reflected cryptococcal meningitis on review by a neuroradiologist. Immunosuppression, especially decreased T-cell function, has been shown to be associated with asymptomatic or atypical meningitis. ¹¹ Chemotherapy and chronic oral steroid use could explain the blunted immune response and lack of symptoms in our patient.

There are several reports of cryptococcal choroiditis or retinitis preceding the onset of systemic disease. ^4,12,13 Hiss et al described a 63-year-old man with a large vitreoretinal abscess due to C neoformans that was attributed to long-term use of systemic corticosteroids for polyarteritis nodosa. ¹² As in our case, the patient had no neurologic or systemic symptoms referable to cryptococcal infection at the time of ocular diagnosis and had positive results from CSF cultures and cryptococcal antigen. Cryptococcal antigen was not found in the blood of that patient, but the authors postulated that blood-borne dissemination resulted both in ocular and CNS infections with subsequent resolution of the cryptococcemia and cited experimental results in cats that have shown that while optic nerve meningitis develops by extension from the CNS, intraocular cryptococcal infection is of hematologic origin. ¹⁴

We believe that cryptococcal endophthalmitis begins as a choroiditis, extends anteriorly into the retina, and then passes into the vitreous cavity unless treated; thus, the clinical manifestations depend on the duration of the infection and the host’s immune factors. However, bilateral cryptococcal endophthalmitis was reported by Amphornphruet et al ¹³ to be in an immunocompetent patient more than 10 years after craniotomy with ventriculoperitoneal shunt for a brain tumor, in whom the initial presentation was a multifocal choroiditis on 1 eye but only severe vitritis in the other. The source of the cryptococcosis was not identified.

In a review of 72 patients diagnosed with cryptococcal meningitis, 18% experienced visual disturbances. ² These symptoms were most commonly caused by papilledema or optic neuritis and were a result of direct spread from the CNS. ² Intraocular findings were quite rare. In contrast, the largest review of patients with cryptococcal endophthalmitis included 27 patients and reported choroiditis, often with vitritis, as the most common manifestation. ⁴ Vitreoretinal masses, retinal detachments, and anterior uveitis were also reported. ⁴ All patients noted blurry vision, but pain was reported in only 11% and photophobia in only 4% of patients. ⁴ Endophthalmitis is the result of hematogenous spread, and as such, should lead to presumptive diagnosis of cyptococcemia. ⁸

The subretinal lesion in our patient was resistant to both systemic and repeated intravitreal antifungal therapy. This may be referred to as a cryptococcoma, a term used to describe the discrete, encapsulated lesions harboring pathogen and immune infiltrates that may be found in the brain or lungs of patients infected with Cryptococcus. ¹⁵ Subretinal mass lesions have been previously reported twice, and both of those patients underwent vitrectomy and surgical debridement of the cryptococcomas. ¹⁶ That was the first known case for which long-term medical therapy was used to treat an intraocular cryptococcoma, and it demonstrated that those lesions were unlikely to clear completely in the absence of surgical intervention.

However, that case also demonstrated that good VA may be achieved with medical therapy if the lesion is extramacular. Our patient’s VA of 20/60 at 5 months after diagnosis was similar to the uninvolved eye, which may be attributed to cataract, and subjectively he reported the vision to be only slightly blurred with prominent floaters. Thus, it appeared that medical therapy may stabilize, but not cure, intraocular cryptococcomas. There is also the potential for clinical worsening if oral fluconazole and/or topical prednisolone acetate were to be discontinued.

The differential diagnosis for cryptococcal endophthalmitis includes candidiasis, toxoplasmic retinitis, aspergillosis, histoplasmosis, cytomegalovirus retinitis, and metastatic bacterial endophthalmitis, among others. Identifying the organism is critical for proper intraocular and systemic treatment, as 1 review found that 76% of patients with cryptococcal endophthalmitis had concomitant meningitis. ³ FA was important in demonstrating that this was not a vascular lesion, as would be seen in metastasis, and the indocyanine green angiography’s findings supported its subretinal location. Vision loss in the setting of cryptococcal endophthalmitis may also have been from CNS spread to the optic nerve; however, there was no retinal nerve fiber layer thickening on optical coherence tomography nor disc abnormalities on FA. Additionally, there was no disc edema acutely or disc pallor chronically, no afferent pupillary defect, and opening pressure was normal on lumbar puncture.

Previous studies have shown that positive cryptococcal blood titers may appear prior to symptom onset and are a predictor of disease and mortality. ¹⁰ Significant improvements in mortality were achieved by treating asymptomatic HIV patients with positive cryptococcal blood titers in one large study. ¹⁷ Further, increasing titers are associated with increased mortality, and our patient’s titer of 1:1280 would place him at high risk of mortality. ⁹ This evidence indicates that positive blood and CSF cryptococcal titers in the absence of disease should be regarded as early evidence of impending disseminated disease and/or meningitis.

The Infectious Diseases Society of America recommends induction therapy with amphotericin-B plus flucytosine for 4 to 6 weeks, followed by consolidation with fluconazole for 8 weeks, then maintenance for 6 to 12 months for cryptococcal CNS disease or cryptococcemia. ¹⁸ However, the relapse or therapeutic failure rate may be as high as 33% on this regimen in patients with cryptococcal endophthalmitis. ^{19 -21} Several reports have described patients with cryptococcal meningitis or endophthalmitis as responsive to voriconazole after failing amphotericin and flucytosine treatment, which has been proposed to be related to superior intravitreal penetration. ⁷ Voriconazole administered orally reaches intravitreal concentrations of 1.0 to 1.5 µg/mL, which are well above the minimum inhibitory concentration and have no significant toxicity in concentrations up to 250 µg/mL. ²² We recommended systemic treatment per the Infectious Diseases Society of America’s guidelines in conjunction with serial biweekly intravitreal amphotericin or voriconazole until clinical improvement is noted for a minimum of 6 intravitreal injections. Our strong preference would have been for surgical management of the cryptococcoma as described by Wykoff et al, ¹⁶ but the patient declined.

The literature and this case support that even in the absence of extraocular symptoms, cryptococcal endophthalmitis has a high likelihood of associated disseminated disease, including meningitis. Vision changes, especially in an immunocompromised patient, should not be overlooked. Identification of the causative organism in fungal endophthalmitis is crucial, especially in populations prone to opportunistic infections, so that appropriate therapeutic intervention can be initiated. In this case, a life-threatening diagnosis was made by intraocular vitreous culture, which allowed for timely therapeutic intervention.

Optimal treatment of cryptococcal endophthalmitis involves long-term systemic antifungal therapy with amphotericin, flucytosine, and/or fluconazole or voriconazole in addition to intravitreal antifungal therapy. Intraocular cryptococcomas or subretinal mass lesions may be stabilized by medical therapy but require surgical intervention to achieve resolution. If the lesion is located outside the macula, the patient may achieve relatively good VA on medical management alone, as seen in this case. This infection has a high mortality rate and poor ocular and systemic prognosis. Prompt diagnosis and treatment is essential to life-saving and vision-saving interventions.