Ocular Findings of Cryptococcal Meningitis in Previously Healthy Adults

Patients with cryptococcal meningitis (CM) often have ocular manifestations; although data are describing these findings in nonimmunosuppressed, previously healthy individuals are scarce.

Original Contribution Section Editors: Clare Fraser, MD Susan Mollan, MD Ocular Findings of Cryptococcal Meningitis in Previously Healthy Adults Chinwenwa U. Okeagu, MD, Seher H. Anjum, MD, Susan Vitale, PhD, MHS, Jing Wang, MS, Deven Singh, BA, Lindsey B. Rosen, BS, M. Teresa Magone, MD, Edmond J. Fitzgibbon, MD, Peter R. Williamson, MD, PhD Background: Patients with cryptococcal meningitis (CM) often have ocular manifestations; although data are describing these findings in nonimmunosuppressed, previously healthy individuals are scarce. Methods: A retrospective chart review was performed for previously healthy patients with CM who underwent a complete ophthalmological examination within a 5-year period at the National Institutes of Health. Demographics, CSF parameters, findings on initial ophthalmological examination, and MRI abnormalities were analyzed. Results: Forty-four patients within a median of 12 weeks after CM diagnosis were included in our study; 27 patients (61%) reported abnormal vision on presentation. Seventy-one percent of patients were not shunted at the time of their initial eye examination. The most common ocular abnormalities were visual field defects in 21 (66%), decreased visual acuity in 14 (38%), and papilledema in 8 (26%) patients. Intraocular pressure was within normal range in all patients. Cranial nerve defects were identified in 5 patients and optic neuropathy in 2 patients. Patients who had hydrocephalus or did not receive a ventriculoperitoneal shunt were not noted to have worse ocular abnormalities. Conclusions: The most common ocular findings in our cohort of nontransplant, non-HIV cryptococcal meningitis Consult Services Section (CO, SV, MTM, EF), National Eye Institute (NEI), National Institutes of Health, Bethesda, Maryland; Laboratory of Clinical Immunology and Microbiology(LCIM) (SHA, LBR, PRW), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health, Bethesda, Maryland; Clinical Monitoring Research Program Directorate (JW), Frederick National Laboratory for Cancer Research, Frederick, Maryland; and Rutgers University (DS), New Brunswick, New Jersey. Supported in part by the Intramural Research Program of the National Institutes of Health [AI001123 and AI001124] and by the Division of Intramural Research of the National Eye Institute. The authors report no conflicts of interest. C. Okeagu and S. H. Anjum contributed equally to this work. Address correspondence to Seher H. Anjum, MD, 9000 Rockville Pike, Building 10, Room 11C209, Bethesda, MD 20892; E-mail: seher. [e-mail] 214 patients were visual field defects, decreased visual acuity, and papilledema. Our results emphasize the need for a comprehensive eye examination in patients with CM who may not always report a change in vision on presentation. Journal of Neuro-Ophthalmology 2023;43:214–219 doi: 10.1097/WNO.0000000000001713 © 2022 by North American Neuro-Ophthalmology Society C ryptococcosis is a prominent cause of fungal meningoencephalitis with a significant disease burden globally (1). Although this infection is more often an opportunistic consequence of HIV/AIDS infection, it has also been reported in apparently immunocompetent populations (2). Currently, it is reported that approximately 20% of cases occur in clinically nonimmunocompromised patients (3,4), and the disease course in these patients has been associated with poorer cerebro-spinal fluid (CSF) inflammatory responses and mortality rates (5). Cryptococcal meningitis (CM) most frequently manifests in patients as headaches, fever, nausea, vomiting, and visual impairment. When the eye is involved, patients may experience photophobia, diplopia, ptosis, nystagmus, and ophthalmoplegia (6). Isolated ocular cryptococcus with no neurological involvement has been reported (7). In previously healthy adults with CM, ocular manifestations include optic neuropathy, cranial nerve VI palsies, chorioretinitis, vitritis, posterior uveitis, and papilledema (8,9). Although there are several case reports in the literature describing ocular findings in previously patients with healthy CM, rare reports exist depicting these findings in a substantial cohort. In this study of 44 previously healthy patients with CM, we identify abnormal ocular examination findings, attempt to detect an association with key CSF markers, and MRI findings. Okeagu et al: J Neuro-Ophthalmol 2023; 43: 214-219 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution METHODS Ethics Statement All patients were seen at the National Institutes of Health Clinical Center, Bethesda, MD, and informed consent was obtained under an institutional review board–approved protocol (ID: 93-I-0106). Participants and Patient Clinical Data To characterize the type and severity of vision health in CM, a retrospective study was performed involving previously healthy patients with CM who underwent a comprehensive ophthalmological examination between January 2010 and August 2016 at the NIH clinical center. A diagnosis of CM was defined as a positive cryptococcal antigen in CSF and/or the isolation of Cryptococcus from CSF cultures. All participants in this study were diagnosed with CM at another facility and subsequently referred to the NIH for immunogenetic testing or because of deterioration in the clinical status after receiving antifungals. Before arrival at NIH, all patients had received standard induction therapy with parenteral amphotericin B and flucytosine for at least 4 weeks or 2 weeks after CSF fungal cultures became negative. Patients were excluded if they were HIV positive, transplant recipients, on immunosuppressants or recently diagnosed with a malignancy. Available cryptococcal isolates were shipped to the NIH and speciated as part of the protocol. Demographic and clinical data including symptoms, results of CSF analysis, and radiological impressions on MRI brain were recorded on admission to the NIH. MRI findings were assessed in a blinded fashion to visual loss, focusing on ventriculomegaly, hydrocephalus, and meningeal enhancement on postgadolinium fluid-attenuated inversion recovery images. Details of the initial ophthalmologic evaluation were noted, of interest were visual acuity (VA), presence of an afferent pupillary defect, color vision deficits, applanation tonometry (IOP), cup-to-disc ratio (C/D), grading of disc edema according to the Frisen scale, optical coherence tomography retinal nerve fiber layer (RNFL) thickness, and automated visual field (HVF) 30-2. Ocular coherence tomography (OCT) RNFL thickness was obtained for patients who presented after 2014 when it became part of the initial examination. Among the variables assessed on initial ophthalmological examination, data were missing for w30% of the patients for the Ishihara test (color vision), presence of cataract, and degree of papilledema, and these parameters were, therefore, excluded for analysis. In patients who presented with altered mental status, a complete ophthalmological examination could not be performed at the time of presentation and was completed at a later date after clinical improvement. The best corrected VA was measured for both eyes using the Snellen chart and pinhole vision. RNFL thickness was measured by Cirrus-OCT and considered normal for values Okeagu et al: J Neuro-Ophthalmol 2023; 43: 214-219 ranging from 75–115 mm. The HVF result was categorized as normal if the mean deviation (MD) was #22 and abnormal if greater than this value. Snellen VA was converted to logMAR vision for statistical analysis, and vision below 20/40 was considered decreased vision. Statistical Analysis Data were stored and analyzed on the SAS version 9.4 software, R version 4.0.2., and GraphPad prism version 8.0. Left and right ocular variables that are continuous were summarized for mean or geometric mean (10). Median values were computed for RNFL, HVF mean deviation, tonometry, Ishihara color testing, and C/D; geometric mean was computed for pinhole and Snellen vision results after conversion to logMAR vision. Associations between categorical variables were evaluated with either the chi-square test or Fisher exact test; associations of categorical variables with continuous variables were evaluated using the Wilcoxon rank-sum test; correlations between continuous variables were assessed using Spearman rank correlation coefficients. RESULTS Study Subjects Forty-four patients admitted with cryptococcal meningitis between January 2010 and August 2016 who had comprehensive ophthalmological examinations were included in this study; 15 (34%) were female. Five (11%) patients had an underlying history of diabetes and 22 (50%) had hypertension; there was no known history of cirrhosis in any patient. Importantly, 31 (70%) patients had not been shunted at the time their eye examination was performed. Additional demographic details are presented in Table 1. Clinical Findings The most common symptoms at CM diagnosis included headache (91%), vision change (61%), hearing loss (48%), and nausea and vomiting (57%) (Table 1). On transfer to NIH, a lumbar puncture (LP) was performed within a median of 9 weeks (interquartile range [IQR] 4–25) after CM diagnosis. The median opening pressure was 20 cm CSF (IQR 15–28, n = 43), and the median CSF cryptococcal antigen titer was 1:64 (IQR 1:1–1:256; Table 1). MRI brain scans were performed for all patients at a median of 12 weeks from diagnosis (IQR 6–22), results of which showed leptomeningeal enhancement in 32 (73%), ventriculomegaly in 19 (43%), and hydrocephalus in 6 (14%) patients. Ocular Findings Each patient received a complete, dilated eye examination within a median of 12 weeks (IQR 5–21) after CM diagnosis. Data describing ocular findings are summarized in Table 2. The median RNFL thickness was 98 mm (IQR 215 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution TABLE 1. Demographic details, symptoms at presentation, and CSF parameters for all patients who underwent an eye examination Demographic Characteristics N = 44 (%) Gender, females Median age in years at the first eye examination (IQR) Ethnicity Asian African American Caucasian Hispanic Biracial Location Midwest United States NE United States SE United States W Coast United States Species (n = 39) neoformans gattii GMCSF auto Ab (n = 34) Median CD4 count (IQR) Underlying conditions Diabetes Hypertension No. shunted at the time of eye examination Time in weeks from CM diagnosis to eye examination (IQR) Disease presentation Fever Headache Worsening mental status Hearing loss Vision change Nausea and vomiting Falls Dizziness Gait instability 15 (34) 56 (44–64) CSF Parameters Median (IQR) Cryptococcal antigen titer (n = 44) Opening pressure (cm CSF) (n = 43) Glucose (mg/dL) (n = 44) Protein (mg/dL) (n = 43) WBC (/mm3) (n = 42) 4 (9) 2 (4.5) 35 (80) 2 (4.5) 1 (2) 1 (2) 16 (36) 17 (39) 10 (23) 29 (74) 10 (26) 6 (18) 452 (304–769) 5 (11) 22 (50) 13 12 (5–21) 13 (30) 40 (91) 16 (36) 21 (48) 27 (61) 25 (57) 4 (9) 11 (25) 9 (20) 1:64 (1:1–1:256) 20 (15–28) 47 (29–56) 84 (57–199) 39 (14–91) 86–141, n = 31) with 8 (26%) patient measurements being .115 mm, suggestive of papilledema and 2 (6%) patients having a measurement of ,75 mm, indicating optic nerve atrophy. Five of 8 patients with papilledema had an elevated opening pressure (.25 cm H2O) on initial LP. 216 The median mean deviation (MD) on HVF testing was 25.2 dB (IQR 21.25 to 211.6, n = 33) with 22 (67%) patients having a value of ,22 db. The most common HVF defects were superior (47%) followed by enlarged blind spots (22%), central scotomas (19%), heminanopsias (6%), and generalized depression (6%). HVF and RNFL thickness maps of a 27-year-old and 58-year-old patient with severe visual field defects and papilledema are shown in Figures 1 and 2, respectively. The geometric median calculated for best-corrected VA by logMAR vision was 0.6 (20/80 Snellen vision; IQR 0.28–0.8, n = 37); 14 (38%) patients had a decreased VA (,20/40). The median intraocular pressure (IOP) was 14 mm Hg (IQR 12–16, n = 41), and all patients had an IOP within normal limits (,23 mm Hg). All patients without papilledema in whom a C/D was measured had values ,0.5. The presence of an afferent pupillary defect was noted in 2 (6%) of the 31 patients who had a pupil examination; both patients had abnormal MD on HVF testing (25 and 212, respectively), and 1 patient had a compromised VA of 20/80. Cranial neuropathy was identified in 5 patients, of which 3 had cranial nerve VI palsy and 2 had cranial nerve III and IV palsy, respectively. Three patients had severe optic neuropathy (1 unilateral and 2 bilateral) and presented with severely reduced VA which was noted to be irreversible on subsequent examinations. No retinal defects were identified. Among the 44 participants, 13 (30%) underwent ventriculoperitoneal shunt insertion before their first eye examination, 9 (20%) were shunted after their first examination, and 22 (50%) did not receive a shunt. When CSF and ocular findings were compared between those that were shunted and not shunted, the median CSF protein was more elevated in the shunted population (226 mg/dL compared with 69 mg/dL in nonshunted patients, P = 0.01), but there was no difference in ocular findings between both groups. For radiographic abnormalities, patients who had hydrocephalus were not noted to have worse ocular abnormalities. DISCUSSION In this study of 44 nonimmunosuppressed patients with CM, we report for the first time OCT RNFL and HVF findings and their correlation to key CSF markers and radiographic findings in a sizeable cohort, which may help predict a poor prognosis for vision. The most common ocular abnormalities noted were visual field defects in 21 (66%), decreased VA in 14 (38%), and papilledema in 8 (26%) patients. Intraocular pressure measured within a median of 12 weeks after CM diagnosis was within normal range in all patients. Cranial nerve defects were identified in 5 patients and optic neuropathy in 2 patients. Overall, 29% of the population examined was shunted, and there were no differences in ocular examination findings compared with the nonshunted group. In a previous report of 82 previously healthy patients in Papua New Guinea diagnosed with CM and vision loss, 60% Okeagu et al: J Neuro-Ophthalmol 2023; 43: 214-219 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution TABLE 2. Ocular findings in previously healthy adults with cryptococcal meningitis Ocular Measurements RNFL thickness (mm) Visual field deficit (mean deviation in dB) Pinhole visual acuity (logMAR) Visual acuity (logMAR) Intraocular pressure (mm Hg) Cup-to-disc ratio Number (%) Tested Median (IQR) Normal Range 31 (70) 32 (73) 30 (68) 37 (84) 41 (93) 35 (80) 98 (86 to 141) 25.2 (21 to 212) 0.85* (0.63 to 1) 0.63* (0.28 to 0.8) 14 (12 to 16) 0.3 (0.1 to 0.3) 75 to 115 0 to 22 10 to 23 ,0.5 *Geometric median calculated for the visual acuity. dB, decibels; logMAR= logarithm of the minimum angle of resolution. of cases were noted to have optic atrophy as a result of optic disc swelling (11). In another report, 31% of 29 previously healthy patients with CM treated with standard antifungal therapy were blind at the time of discharge (12). On comparison of ocular findings in the literature available for immunosuppressed patients, the disease course seems to be similar; in a retrospective study conducted in 18 Peruvian HIV-CM adults, half had decreased VA and 2 had diplopia. In another case series, most had decreased VA and diplopia, followed by papilledema and cranial nerve palsies. Abnormal pupillary reactions and microvasculopathy were rare. Another prospective study from South Africa reported early onset (within 2–4 weeks of CM diagnosis) decreased VA in 46.5% patients and abnormal visual fields by HVF in 76% patients (13), figures slightly higher than percentages found in our study. We also found fewer cases of optic atrophy (6%) and a low incidence of complete blindness in our study compared with prior literature. In our cohort, 61% patients reported visual symptoms, but the timeline for symptom progression is unknown because most patients were transferred from other referral centers approximately 6 weeks after the diagnosis was made. A previous study suggested an association between the timing of vision loss and the underlying mechanism. Patients with acute-onset vision loss were found to have optic neuropathy attributed to fungal infiltration of the optic nerve, whereas those with gradual vision loss were found to have papilledema with slow loss of optic nerve axons (14). Twenty-six percent of patients in our study still had papilledema on presentation, suggestive of elevated intracranial pressure during the initial course of the disease as the most likely underlying mechanism for the observed findings. This further highlights the necessity FIG. 1. Right (A) and left (B) HVF, corresponding the RNFL thickness map (C) for a 20 y/o male with severe visual field defects and papilledema. HVF indicates automated visual field; RNFL, retinal nerve fiber layer; C/D, cup to disk ratio. FIG. 2. Right (A) and left (B) HVF, corresponding the RNFL thickness map (C) for a 58 y/o male with enlarged blind spots. HVF indicates automated visual field; RNFL, retinal nerve fiber layer; C/D, cup to disk ratio. Okeagu et al: J Neuro-Ophthalmol 2023; 43: 214-219 217 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution FIG. 3. Scatter plot demonstrating a positive correlation between the geometric mean of logMAR vision and visual field deficit (1 = 0.53, P . 0.05). MD indicates mean deviation (HVF). of controlling intracranial pressures early in the course of the illness, a measure proven to both decrease mortality and prevent vision loss (15). Our results also demonstrated a positive correlation between the geometric mean of logMAR vision and visual field deficit mean deviation and a larger visual field defect correlated with poorer vision (Fig. 3, r = 0.53, P . 0.05), suggesting that in patients with CM with decreased vision, a visual field defect is likely present as well. In this study, it was difficult to confirm that the observed findings were due to the cryptococcal organism as opposed to an associated postinfectious inflammatory state because of the timing of the eye examinations and limited data available regarding the timing of CSF fungal cultures converting to negative. Ophthalmological abnormalities in CM have been attributed to an excessive inflammatory response in both HIV and non-HIV hosts in earlier studies (16). Postinfectious inflammatory syndrome (PIIRS) in previously healthy adults is characterized by worsening VA despite normal opening pressures and CSF fungal cultures turning negative with antifungal therapy and is responsive to corticosteroids (17). Previously, we reported visual field defects and papilledema as the most common ocular defects in a case series of 15 previously healthy patients with CM and PIIRS (18). We did not find any correlation noted between elevated opening pressures (.25 cm H2O) and increased RNFL thickness although 63% of patients with papilledema did have raised intracranial pressure. This is consistent with results noted by Graybill and colleagues in a cohort of 221 AIDSassociated patients with CM in which papilledema was noted more frequently in those with an elevated intracranial pressure (19). The underlying mechanism for papilledema is the accumulation of CSF in the optic nerve sheath causing axoplasmic stasis in the optic nerve head leading to optic disc edema. The findings in this study may have been due to the eye examination being performed at a median of 3 weeks after the LP by which time intracranial pressures may have normalized in some patients. In addition, exposure to papilledema for a prolonged period before examination may have resulted in 218 axonal loss and resultant decreased RNFL thickness in some patients. The lesson learned is that the absence of papilledema on ocular examination is not necessarily predictive of normal intracranial pressure, particularly in the acute setting. In 6 (18%) of our patients, the presence of granulocytemacrophage colony stimulating factor (GM-CSF) auto antibodies in the serum was detected. Four had C. gatti isolated from CSF cultures, 1 had Cryptococcus neoformans, and for 1 patient, speciation data were not available. This corroborates findings reported previously which suggested that the presence of these antibodies may play a major role in compromised host immunity, specifically in response to Cryptococcus gattii infection (20). However, we did not find any differences in eye findings within patients with or without GM-CSF auto antibodies. Auto antibodies to GM-CSF may suppress important immunological pathways mediated by pulmonary macrophages, phagocytes, and dendritic cells, thereby increasing host susceptibility to the fungus. Moreover, Cryptococcus independently is known to inhibit T-cell–induced production of GMCSF and tumor necrosis factor alpha (TNF-a), a chemokine required for the maturation of dendritic cells which are crucial in recognition of the fungus once it enters the lungs (20). A limitation of this study is referral bias because most patients admitted to the NIH had refractory disease, and the severity and frequency of ocular abnormalities may differ in the general population compared with that reported in our group. In addition, the timing of the ocular examination (median of 12 weeks following CM diagnosis) does not exclude the possibility that visual defects may have been present earlier in the course of the disease. Finally, there are missing data for ocular parameters that could not be assessed at bedside for a few patients who presented with a significant alteration in their mental status, precluding a comprehensive eye examination. In summary, our results emphasize the need for a comprehensive eye examination including visual field testing and OCT of the optic nerves in patients with CM who may not always report a change in vision on presentation. Because papilledema may have detrimental effects on vision, it is imperative to control intracranial pressure along with concomitant antifungal therapy. STATEMENT OF AUTHORSHIP Conception and design: C. Okeagu, S. Anjum, P. Williamson; Acquisition of data: S. Vitale, C. Okeagu, S. Anjum, D. Singh; Analysis and interpretation of data: J. Wang, S. Anjum. Drafting the manuscript: C. Okeagu, S. Anjum, P. R. Williamson, D. Singh, T. Magone, E. Fitzgibbon; Revising the manuscript for intellectual content: T. Magone, E. Fitzgibbon. Final approval of the completed manuscript: T. Magone, E. Fitzgibbon. REFERENCES 1. Rajasingham R, Smith RM, Park BJ, Jarvis JN, Govender NP, Chiller TM, Denning DW, Loyse A, Boulware DR. Global burden of disease of HIV-associated cryptococcal Okeagu et al: J Neuro-Ophthalmol 2023; 43: 214-219 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution meningitis: an updated analysis. 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