Open Forum Infectious Diseases BRIEF REPORT She was started on liposomal amphotericin-B and renally Rapid Reversal of Complete adjusted flucytosine; mycophenolate was discontinued, and Binocular Blindness With High-Dose tacrolimus dose decreased, aiming at a trough level of 4 ng/mL. Corticosteroids and Lumbar Drain in a Both blood and CSF cultures were negative by day 6 (day 3 of antifungal treatment). Solid Organ Transplant Recipient With She continued to have elevated OP, receiving sequential LP Cryptococcal Meningitis and Immune (Figure 1). All post-LP OP were <20 cm H O. Funduscopic Reconstitution Syndrome: First Case examination did not show papilledema. On hospital day 12 (day 9 of treatment), she developed right-sided vision loss Study and Literature Review with no light perception, right aer ff ent pupillary defect (APD), 1 2 3 4 Zoe Weiss, Nihaal Mehta, Su Nandar Aung, Michael Migliori, and decreased left-sided visual acuity with diminished color percep- Dimitrios Farmakiotis tion, and bilateral conjunctival chemosis. Computed tomogra- Department of Internal Medicine, Warren Alpert Medical School of Brown University, Providence, Rhode Island; Warren Alpert Medical School of Brown University, Providence, phy angiography of the brain and contrast magnetic resonance Rhode Island; Division of Infectious Disease, Warren Alpert Medical School of Brown 4 imaging of the orbits were unremarkable. On day 15, despite University, Providence, Rhode Island; Division of Ophthalmology, Rhode Island Hospital, Warren Alpert Medical School of Brown University, Providence, Rhode Island; Division of repeated LP, she had bilateral complete loss of vision with no Infectious Disease, Rhode Island Hospital, Warren Alpert Medical School of Brown University, light perception and grade I papilledema. An epidural drain was Providence, Rhode Island placed to allow for continuous CSF drainage without improve- ment. Prednisone 80 mg twice daily was started on day 16 for Blindness is a rare, devastating, usually permanent complica- presumed early immune reconstitution inflammatory syn- tion of cryptococcal meningitis (CM). We present the first case of complete vision loss in a solid organ transplant recipient with drome (IRIS). She recovered light perception aer t ft he first 3 CM treated with placement of a lumbar drain who had a dra- doses. e l Th umbar drain was removed the following day. Her matic visual recovery that started aer ft 3 doses of high-dose vision returned to baseline in both eyes by day 25 (Figure 1). steroids. Prednisone was tapered to 10 mg over 4 weeks. She had no Keywords. cryptococcal meningitis; immune reconstitu- further eye complaints. She completed 4 weeks of induction tion inflammatory syndrome; CM-IRIS; vision loss. for cryptococcal meningitis, followed by 6 weeks of eradica- tion treatment, and now receives renally adjusted maintenance CASE PRESENTATION uco fl nazole. A 62-year-old woman with history of renal transplantation 18 years earlier presented with headache, photophobia, and METHODS right facial droop. Her immunosuppressive regimen included We performed a literature search in the National Center for mycophenolate, tacrolimus, and prednisone in the setting of Biotechnology Information’s PubMed database using the term chronic rejection. Brain MRI, MRA, and MRV were negative “cryptococcal meningitis,” in conjunction with “immune recon- for stroke. Laboratory results on admission are summarized stitution syndrome,” “immune reconstitution inflammatory in Table 1. She underwent a lumbar puncture (LP) on day 3 syndrome,” “IRIS,” “CM-IRS,” “CM-IRIS”, “ocular,” “optic,” with opening pressure (OP) of 28 cm H O; her cerebrospinal “ophthalmic,” “ophthalmologic,” “blindness,” “visual loss,” and fluid (CSF) had 208 nucleated cells (88% lymphocytes), glucose “visual.” After publications were identified, their references 51 mg/dL, and protein 222 mg/dL; Gram stain revealed yeast were reviewed. For the purposes of this analysis, we included forms, and culture was positive for Cryptococcus neoformans. cases of visual impairment independent of suspected etiology (eg, increased intracranial pressure, inflammatory optic neu- ropathy, direct infection of the optic nerve). Received 12 November 2017; editorial decision 22 December 2017; accepted 5 January 2018. Correspondence: Z. Weiss, MD, 593 Eddy St, Providence, RI 02906 (firstname.lastname@example.org, email@example.com). RESULTS AND DISCUSSION Open Forum Infectious Diseases © The Author(s) 2018. Published by Oxford University Press on behalf of Infectious Diseases CM is a highly morbid opportunistic fungal infection result- Society of America. This is an Open Access article distributed under the terms of the Creative ing in elevated intracranial pressure (ICP) and neurologic Commons Attribution-NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/ by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any symptoms. Though classically described in the setting of HIV medium, provided the original work is not altered or transformed in any way, and that the work infection, CM is nowadays recognized at least as frequently in is properly cited. For commercial re-use, please contact firstname.lastname@example.org patients with other forms of immunosuppression, including DOI: 10.1093/ofid/ofy007 BRIEF REPORT • OFID • 1 Downloaded from https://academic.oup.com/ofid/article-abstract/5/2/ofy007/4793116 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Table 1. Pertinent Initial Laboratory Results and Reference Ranges solid organ transplant (SOT) and occasionally in immunocom- petent hosts [1, 2]. Visual symptoms occur in approximately Laborator y Test Value Reference Range 35% , and, in some regions, 10% will suffer irreversible blind- WBC 14.3 × 10^9/L 3.5–11.0 × 10^9/L ness . Treatment involves antifungal therapy and control of Creatinine 2.6 mg/dL (baseline) 0.44–1.03 mg/dL ICP [1,5]. CSF Multiple pathophysiologic mechanisms of visual loss in CM Nucleated cells 208 0–5 cells/µL have been described. The predominant mechanism is optic Lymphocyte % 88% 63%–99% nerve damage due to elevated ICP, as a result of obstruction of Glucose 51 mg/dL 38–85 mg/dL Protein 222 mg/dL 15–45 mg/dL CSF outflow by cryptococcal polysaccharide capsules or fungal Bacterial and fungal culture +Cryptococcus organisms [3, 6]. Vision impairment secondary to elevated ICP neoformans. progresses over weeks and may be accompanied by persistent, Cryptococcal antigen titer >1:256 significant papilledema [7 ], which our patient did not have. In Blood culture +Cryptococcus neoformans. some cases, early and aggressive control of increased ICP—such HIV 1/2 antibody/antigen Negative as through serial lumbar punctures, optic nerve sheath fenes- Abreviations: CSF, cerebrospinal fluid; WBC, white blood cell. tration, or CSF shunting—allowed for reversal of vision loss Day 01 23 45 67 89 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 Opening Pressure (cmH O) CSF Nucleated Cells (cells/μL) CSF Protein (mg/dL) ++ –– –– –– –– – CSF Cultures High Dose Prednisone Lumbar Drain 20 20 20 20 20 20 Visual Acuity 20 20 Right NLP NLP NLP NLP CF LP 60 25 400 100 25 40 25 40 20 20 20 20 20 20 20 20 20 20 20 Left NLP NLP NLP 60 400 800 400 200 200 70 100 100 70 Funduscopic Exam Day 9 Day 20 OD OS BD Figure 1. Timeline of opening pressure and CSF results, visual acuity, medical interventions, funduscopic exam, and eye images. Funduscopic exam on day 9 (A, B) demonstrates grade 1 papilledema with disc hyperemia, diminished cup size, marginal polar disc blurring and early nerve fiber bundle definitions (arrow A), and increased vessel tortuosity (arrow B). On day 20 (C, D), there is stable grade 1 papilledema, disc hyperemia, persistent polar disc blurring (arrow C), and vessel tortuosity (arrow D), no significant optic nerve ischemia, and improved nerve fiber bundle definition. Abbreviations: CSF, cerebrospinal fluid; LP, light perception; NLP, no light perception; OD, right eye; OS, Left eye. 2 • OFID • BRIEF REPORT Downloaded from https://academic.oup.com/ofid/article-abstract/5/2/ofy007/4793116 by Ed 'DeepDyve' Gillespie user on 16 March 2018 mg/dL Number of Cells cmH20 . For patients in whom elevated ICP is not the driving mech- inflammatory conditions, which also resolved aer hig ft h-dose anism of vision loss, proposed alternative mechanisms include steroids. optic nerve inflammation, direct fungal infiltration of the optic Our literature review identified 8 additional patients with nerve, other pathogen-mediated mechanisms (exotoxins, deb- CM, presumed IRIS, and vision loss, all of whom were HIV pos- ris from killing, vasculopathy with interstitial edema), optic itive. Four patients had elevated ICP and prominent optic disc nerve sheath compartment syndrome, and restrictive arach- edema . The remaining 4 were felt to have inflammatory noiditis (limited vascular supply to the optic nerve) [4, 7, 8]. optic neuropathy with either normal or mildly elevated ICP, An infiltrative or inflammatory process results in rapid visual and minimal papilledema. Three of these patients were treated symptoms (within hours to days) and can occur both inde- with steroids and had rapid improvement within 1–5 days [8, pendently or in conjunction with elevated ICP [9, 10]. 9, 17, 18]. To our knowledge, ours is the first reported case of Our patient developed rapid bilateral blindness, APD, and steroid-responsive inflammatory optic neuropathy in an SOT grade I papilledema despite almost 2 weeks of appropriate anti- recipient, presumably due to CM-IRIS. fungal therapy with persistently negative fungal cultures. Her Although steroids are indicated for the management of funduscopic exam showed no evidence of uveitis, retinitis, reti- patients with intracranial hypertension and cerebral edema in nal hemorrhages, exudates, vascular occlusion, vascular sheath- pneumococcal and tuberculous meningitis, their role in CM ing, optic disc atrophy, or ischemia (Figure 1). These findings has been controversial . In HIV-infected patients, the pro- were less consistent with vasculopathy (from pathogen-me- cess leading to blindness in CM is presumably one of pauci-im- diated mechanisms, such as Cryptococcus infiltration or fun- mune inflammation [3, 20]. u Th s, use of corticosteroids has gal debris) than with optic nerve inflammation. Furthermore, been associated with higher morbidity and mortality [10, 20]. lack of improvement with serial LP and only mild papilledema Beardsley et al. conducted a randomized controlled trial assess- suggest that her symptoms were unlikely driven by ICP alone. ing the effect of adjunctive high-dose dexamethasone in 451 Rapid visual loss and marked improvement shortly aer ft initi- HIV-infected patients initiating therapy for CM. The study was ation of steroids were most consistent with an inflammatory stopped when preliminary results showed higher mortality and optic neuropathy in the setting of IRIS. slower fungal clearance with corticosteroids, compared with IRIS is a paradoxical inflammatory response caused by patients receiving placebo . However, these findings may immune recovery, initially described during treatment of an not apply to patients treated with steroids aer dem ft onstrated opportunistic infection and initiation of antiretroviral ther- fungal clearance or in those without HIV, that is, patients who apy in HIV-infected patients. However, IRIS also occurs with can probably mount a strong immune host response. reduction of immunosuppressive therapy and host response to Indeed, HIV-negative patients seem to have a more robust, treatment of opportunistic infections in SOT recipients, and it and potentially steroid-responsive, inflammatory response to is an underrecognized complication in the SOT patient pop- CM . One study of 16 non-HIV immunocompetent patients ulation, most commonly associated with cryptococcosis . showed a 10-fold reduction in blindness among patients with Discontinuation of the calcineurin inhibitor (CNI), but not CM receiving low-dose steroids . Current Infectious decrease in CNI dose or discontinuation of mycophenolate or Diseases Society of America guidelines recommend steroid use azathioprine, has been identified as a risk factor for adverse only in patients with CM who develop either acute respiratory clinical outcomes in SOT recipients with CM [11, 12]. This distress syndrome or IRIS . These patients, like ours, should observation may be due to the antifungal activity of CNI [13, have documented negative CSF cultures [5, 19]. 14] although the development of IRIS may be a contributing Our case study has limitations. We cannot exclude the factor . In SOT recipients with CM, IRIS usually occurs at possibility that our patient experienced visual recovery as a a median of 6 weeks aer ini ft tiation of antifungal treatment, delayed response to placement of a lumbar drain. However, but onset as early as 2 weeks has been described , similar this is less likely given rapid onset and reversal of her symp- to our case. toms with steroid administration and minimal papilledema. Proposed diagnostic criteria for CM-IRIS are worsening Other pathogen-induced mechanisms may have played a clinical features, CSF pleocytosis and increased ICP, or radio- role, although funduscopic findings, negative cultures, and graphic findings in the setting of appropriate antifungal ther - rapid response to corticosteroids make these less likely, as apy and persistently negative cultures [11, 15]. Vision loss has detailed above. not been previously described as a defining feature of IRIS. In conclusion, this is the fourth reported case of blindness Our patient’s clinical decline manifested as blindness associ- in a patient with CM who rapidly improved with steroids, pre- ated with CSF pleocytosis and elevated ICP aer ini ft tiation of sumably due to CM-IRIS, and the first in an SOT recipient. antifungal therapy, reduction of immunosuppression, and with Corticosteroids should not be part of the standard treatment fungal clearance in blood and CSF. Furthermore, our patient for CM. However, clinicians should consider using high-dose had significant conjunctival chemosis, oen s ft een in ocular steroids in patients with suspected CM-IRIS, including those BRIEF REPORT • OFID • 3 Downloaded from https://academic.oup.com/ofid/article-abstract/5/2/ofy007/4793116 by Ed 'DeepDyve' Gillespie user on 16 March 2018 9. De Socio GV, Bernini L, Menduno P, et al. Monolateral visual loss due to crypto- with sudden visual loss late in the course of treatment, docu- coccal meningitis. J Int Assoc Physicians AIDS Care (Chic) 2011; 10:76–8. mented clearance of CSF cultures, and no clinical response to 10. Rex JH, Larsen RA, Dismukes WE, et al. Catastrophic visual loss due to Cryptococcus neoformans meningitis. Medicine (Baltimore) 1993; 72:207–24. CSF drainage. 11. Sun HY, Alexander BD, Huprikar S, et al. Predictors of immune reconstitution syndrome in organ transplant recipients with cryptococcosis: implications for the Acknowledgments management of immunosuppression. Clin Infect Dis 2015; 60:36–44. 12. Singh N, Alexander BD, Lortholary O, et al; Cryptococcal Collaborative Transplant We acknowledge the assistance of Dr. Allan Tunkel in editing this Study Group. Cryptococcus neoformans in organ transplant recipients: impact of manuscript. calcineurin-inhibitor agents on mortality. J Infect Dis 2007; 195:756–64. Financial support. Publication of this work was supported by a Rhode 13. Kontoyiannis DP, Lewis RE, Alexander BD, et al. Calcineurin inhibitor agents Island Foundation medical research grant to D.F. interact synergistically with antifungal agents in vitro against Cryptococcus Potential conifl cts of interest. D.F. received research support from neoformans isolates: correlation with outcome in solid organ transplant recipients Astellas and consultant fees from Viracor. All remaining authors: no with cryptococcosis. Antimicrob Agents Chemother 2008; 52:735–8. reported conflicts of interest. All authors have submitted the ICMJE form 14. Davis JA, Horn DL, Marr KA, Fishman JA. Central nervous system involvement for Disclosure of Potential Conflicts of Interest. in cryptococcal infection in individuals after solid organ transplantation or with AIDS. Transpl Infect Dis 2009; 11:432–7. 15. Singh N, Perfect JR. Immune reconstitution syndrome associated with opportun- References istic mycoses. Lancet Infect Dis 2007; 7:395–401. 1. Perfect JR, Dismukes WE, Dromer F, et al. Clinical practice guidelines for the 16. Khurana RN, Javaheri M, Rao N. Ophthalmic manifestations of immune recon- management of cryptococcal disease: 2010 update by the Infectious Diseases stitution inflammatory syndrome associated with Cryptococcus neoformans. Ocul Society of America. Clin Infect Dis 2010; 50:291–322. Immunol Inflamm 2008; 16:185–90. 2. George IA, Spec A, Powderly WG, Santos CAQ. Comparative epidemiology and 17. Werner AC, Vuong LN, Hedges TR, Baumal CR. Immune reconstitution inflam- outcomes of HIV, non-HIV Non-transplant and organ transplant associated matory syndrome causing progressive optic nerve edema in cryptococcal menin- cryptococcosis: a population-based study. Clin Infect Dis. In press. gitis. Retin Cases Brief Rep. In press. 3. Moodley A, Rae W, Bhigjee A. Visual loss in HIV-associated cryptococcal meningitis: 18. De Schacht C, Smets RM, Callens S, Colebunders R. Bilateral blindness after a case series and review of the mechanisms involved. South Afr J HIV Med 2015; 16:9. starting highly active antiretroviral treatment in a patient with HIV infection and 4. Duggan J, Walls HM. Ocular complications of cryptococcal meningitis in patients cryptococcal meningitis. Acta Clin Belg 2005; 60:10–2. with HIV: report of two cases and review of the literature. J Int Assoc Physicians 19. Beardsley J, Wolbers M, Kibengo FM, et al; CryptoDex Investigators. Adjunctive AIDS Care (Chic) 2012; 11:283–8. dexamethasone in HIV-associated cryptococcal meningitis. N Engl J Med 2016; 5. The Southern African HIV Clinicians Society. Guideline for the prevention, diag- 374:542–54. nosis and management of cryptococcal meningitis among HIV-infected persons: 20. Graybill JR, Sobel J, Saag M, et al. Diagnosis and management of increased intrac- 2013 update. South Afr J HIV Med 2013; 14(2). ranial pressure in patients with AIDS and cryptococcal meningitis. The NIAID 6. Rex JH, Larsen RA, Dismukes WE, et al. Catastrophic visual loss due to Mycoses Study Group and AIDS Cooperative Treatment Groups. Clin Infect Dis Cryptococcus neoformans meningitis. Medicine (Baltimore) 1993; 72:207–24. 2000; 30:47–54. 7. Moodley A, Rae W, Bhigjee A. Visual loss in HIV-associated cryptococcal menin- 21. Robertson EJ, Najjuka G, Rolfes MA, et al. Cryptococcus neoformans ex vivo cap- gitis: a case series and review of the mechanisms involved. South Afr J HIV Med sule size is associated with intracranial pressure and host immune response in 2015; 16:9. HIV-associated cryptococcal meningitis. J Infect Dis 2014; 209:74–82. 8. Ghatalia PA, Vick A, Vattoth S, et al. Reversible blindness in cryptococcal men- 22. Seaton RA, Verma N, Naraqi S, et al. The effect of corticosteroids on visual loss in ingitis with normal intracranial pressure: case report and review of the literature. Cryptococcus neoformans var. gattii meningitis. Trans R Soc Trop Med Hyg 1997; Clin Infect Dis 2014; 59:310–3. 91:50–2. 4 • OFID • BRIEF REPORT Downloaded from https://academic.oup.com/ofid/article-abstract/5/2/ofy007/4793116 by Ed 'DeepDyve' Gillespie user on 16 March 2018
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