OCULAR COMPLICATIONS CAUSED BY Cryptococcus gattii AFLP4/VGI MENINGITIS IN AN IMMUNOCOMPETENT HOST

Changhua, June 15, 2016

Dear Editor

The Cryptococcus gattii complex has been recognized as an endemic pathogen since the 1990s and has caused multiple outbreaks since then¹. Cryptococcal meningitis (CM) is a globally occurring invasive mycosis associated with significant morbidity and mortality^2,3, including papilledema and visual loss^1,3. We present a case of CM caused by C. gattii sensu stricto (AFLP4/VGI) that was complicated by visual loss under the continuation of antifungal therapy (AFT).

A 45-year-old woman complained of neck stiffness and headaches for two weeks. She was admitted to a community hospital. Her opening intracranial pressure (ICP) was 230 mmH₂O. A cerebrospinal fluid (CSF) study revealed the following values: protein, 53 mg/dL (reference range, 10-45 mg/dL); glucose, 62 mg/dL (45-75 mg/dL); white blood cells (WBCs), 84/mL (<5/mL); lymphocytes, 79% (63-99%); and neutrophils, 17% (0-2%). The Cryptococcus antigen titer in both CSF and serum were positive, at 1:8 and 1:64, respectively. With the impression of a diagnosis of CM, the patient received intravenous amphotericin B (AmB; 0.7 mg/kg/day) with flucytosine (5-FC; 100 mg/kg/day) for two weeks, followed by intravenous AmB (1 mg/kg/day) for another two weeks. Then, a consolidation therapeutic regimen with oral fluconazole (FLC; 450 mg/day orally) was administered for the following three months. She was rehospitalized because of seizures, unfavorable CSF data, and progression of the brain MRI finding. Her opening ICP was 180 mmH₂O. A follow-up CSF study revealed the following values: protein, 140 mg/dL; glucose, 68 mg/dL; WBCs, 468/mL; lymphocytes, 69/mL; and neutrophils, 16/mL. The cryptococcal antigen titer in CSF was 1:128, and staining the CSF with India ink reveled positivity for the pathogen. Hence, CM was still present. We prescribed a combination therapy for reinduction, but she noticed floaters and blurred vision (ou) since the first day of the second admission. Her eye findings were as follows: visual acuity, no light perception (ou), and fungus with: papilledema, subhyaloid hemorrhage, and retinal hemorrhage. Her fundus color photograph and follow-up MRI scan are presented in Figure 1. The cryptococcal isolate 44-6 was identified as C. gattii sensu stricto according to the findings of the culture using canavanine-glycine-bromothymol blue medium. Molecular identification by sequencing the URA5 gene revealed that the isolate was genotype AFLP4/VGI, representing the recently described species C. gattii sensu stricto⁴. She received consolidated oral FLC (450 mg/day) at home in the following years. No new neurological sequelae were found after a follow-up period of 3 years, except for visual loss.

Fig. 1
Timeline of the C. gattii AFLP4/VGI infection, a serial brain magnetic resonance image, and serial fundus color photographs. The magnetic resonance image (A, B, October) and 1-month follow-up magnetic resonance image (C, D, November) were analyzed. The axial, short tau inversion recovery (STIR) image (A, C) and axial, fat-suppressed, post-contrast, T1-weighted image (B, D) demonstrate a faint but increased signal in both the non-expanded optic nerves (A, arrow). Enhancement (B) in the follow-up STIR image (C, arrow) shows progression of the high-signal change and mild atrophy of both the optic nerves. The lesser enhancement (D) is consistent with progression of visual loss. The initial fundus color photograph (E, October) and 1-month follow-up fundus color photograph (F, November) show retinal hemorrhage.

To our knowledge, this is the first case report to describe ocular complications of CM caused by C. gattii AFLP4/VGI under continuation of AFT in Taiwan. In general, C. gattii AFLP4/VGI tends to produce larger and more numerous cryptococcomas in the central nervous system¹. Seaton et al. suggested that the high rate of visual loss in immunocompetent patients with C. gattii AFLP4/VGI infections may reflect immune-mediated optic nerve dysfunction in C. gattii meningitis caused by either compression due to arachnoid adhesions or edema and inflammatory cell-mediated damage⁵. The optic nerve lesion can be due to direct destruction by this pathogen⁵ or indirectly caused by increased intracranial pressure⁶. Our case was treated in accordance with the recommendation in the guidelines³, but her eye condition continued to deteriorate, most likely due to optic nerve damage (Fig. 1). Use of corticosteroids could be recommended for immunocompetent patients with severe C. gattii sensu stricto (AFLP4/VGI) meningitis.

CM due to C. gattii AFLP4/VGI can cause significant neurological morbidities, including ocular complications. We emphasize that physicians should pay attention to the possible complications of CM in patients, even during active AFT.

ACKNOWLEDGEMENTS

The authors thank the Changhua Christian Hospital for the grant support. All authors thank the assistant of the Clinical Microbiology Laboratory of the Changhua Christian Hospital for their assistance in data collection. Authors thank Miss Yi-Chen Tseng and Miss Chi-Lun Chang, who studied at Department of Microbiology, Immunology and Biopharmaceuticals, National Chiayi University, Chiayi City, for the re-identification of the isolate. This research project would not have been possible without the support of many people. The authors wish to express our gratitude to staffs of Division of Infectious Diseases, Division of Neurosurgery, and Division of Critical Care of Changhua Christian Hospital who were abundantly helpful and offered patient care, invaluable assistance, and support.

REFERENCES

• ¹
  Chen SC, Meyer W, Sorrell TC. Cryptococcus gattii infections. Clin Microbiol Rev. 2014;27:980-1024.
• ²
  Tseng HK, Liu CP, Ho MW, Lu PL, Lo HJ, Lin YH, et al. Microbiological, epidemiological, and clinical characteristics and outcomes of patients with cryptococcosis in Taiwan, 1997-2010. PLoS One. 2013;8:e61921.
• ³
  Perfect JR, Dismukes WE, Dromer F, Goldman DL, Graybill JR, Hamill RJ, et al. Clinical practice guidelines for the management of cryptococcal disease: 2010 update by the infectious diseases society of America. Clin Infect Dis. 2010;50:291-322.
• ⁴
  Hagen F, Khayhan K, Theelen B, Kolecka A, Polacheck I, Sionov E, et al. Recognition of seven species in the Cryptococcus gattii/Cryptococcus neoformans species complex. Fungal Genet Biol. 2015;78:16-48.
• ⁵
  Seaton RA, Verma N, Naraqi S, Wembri JP, Warrell DA. Visual loss in immunocompetent patients with Cryptococcus neoformans var. gattii meningitis. Trans R Soc Trop Med Hyg. 1997;91:44-9.
• ⁶
  Keltner JL, Albert DM, Lubow M, Fritsch E, Davey LM. Optic nerve decompression. A clinical pathologic study. Arch Ophthalmol. 1977;95:97-104.

• ETHICS STATEMENTS

  This study was approved by the Changhua Christian Hospital (CCH) Institutional Review Board [CCH IRB No. 131221] for human subjects

• RESEARCH FUNDING/SUPPORT

  Changhua Christian Hospital (CCH grant 104-CCH-IRP-001, CCH rant 105-CCH-IRP-001)

Publication Dates

• Publication in this collection
  2016

History

• Received
  15 June 2016
• Accepted
  15 Sept 2016