Successful Treatment of Meningoencephalitis due to Cryptococcus gattii with Ommaya Reservoir and Intrathecal Injection of Amphotericin B – a Case Report

Overview

Cryptococcal meningitis (CM) is a potentially fatal disease. We report successful treatment with the Ommaya reservoir and intrathecal injection of amphotericin B for the control of refractory cerebral cryptococcosis due to Cryptococcus gattii AFLP4/ VGI. A 63-year-old male patient presented with a 2-week history of fever and headache, and was he diagnosed with CM. Combined amphotericin B and 5-flucytosine treatment was initiated and followed by fluconazole therapy. After 7 months, he was refractory to traditional CM treatment and received salvage therapy with an Ommaya reservoir and intrathecal injection of amphotericin B. His neurological symptoms recovered gradually with no evidence of relapse during 12-month follow-up. The isolate was re-identified by culturing in canavanine-glycine-bromothymol Blue media and by molecular typing using URA5 as Cryptococcus gattii AFLP4/ VGI. The Ommaya reservoir could serve as an alternative treatment for Cryptococcus gattii AFLP4/ VGI-induced CM, which responds poorly to standard regimens.

Key words:
Ommaya reservoir – intrathecal injection of amphotericin B – Cryptococcus gattii AFLP4/VGI – meningoencephalitis – cryptococcoma

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Chinese summary - 摘要

使用Ommaya reservoir和鞘內注射 amphotericin B成功治療隱球菌性腦膜炎- 案例報告

陳昶華¹, 王紹鴻²,顏華正³, 王文甫^4,5,陳威良⁶, 楊詠仁⁵,陳昱旻⁷, 黃介辰⁸

隱球菌性腦膜炎，是一種會致命的疾病，我們報告一個案例，成功使用Ommaya reservoir和鞘內注射(intrathecal injection)amphotericin B，治療對標準治療配方的反應不佳的隱球菌性腦膜炎病患。這名63歲男性患者，起初有2週的發燒和頭痛，並被診斷出隱球菌性腦膜炎。給與標準治療配方amphotericin B 與 5-flucytosine治療後，再給予fluconazole治療。7個月後，病患對標準治療配方，反應不佳，出現神經症狀逐漸惡化 ; 病患接受Ommaya reservoir和鞘內注射 amphotericin B，病患的神經症狀逐漸恢復，並且病患在追蹤的12個月期間，沒有隱球菌性腦膜炎復發的跡象。此菌株經過重新鑑定，在canavanine-glycine-bromothymol培養基培養，和運用URA5進行分子分型鑑定等等後，此菌株鑑定為Cryptococcus gattii AFLP4/ VGI。我們建議在治療Cryptococcus gattii AFLP4/ VGI引起的隱球菌性腦膜炎並且病患對標準治療配方的反應不佳時候，Ommaya reservoir可以考慮作為隱球菌性腦膜炎的替代治療。

Introduction

Cryptococcal meningitis (CM) is a potential­ly fatal disease caused by infection with Cryptococcus spp. Cryptococcus neoformans (C. neoformans) and Cryptococcus gattii (C. gattii) are the most com­monly isolated pathogenic Cryptococcus species, and the taxonomy of their species complexes has been revised [1,2]. CM is a global invasive mycosis as­sociated with significant morbidity and mortality [3,4] from neurological complications [4– 6]. C. gattii, formerly known as C. neoformans var. gattii, has been recognized as an endemic pathogen since the 1990s [5– 7]. Those infected with C. gattii tend to be younger patients with meningitis but without underly­ing conditions [8,9]. Wheth­­er the im­mune function of the host or dif­ferent C. gattii subtypes contribute more to poor prognoses, pathogenesis is still be­ing debated [10,11].

Intensive induction therapy with amphotericin B (AmB) and 5-flucytosine (5-FC) is a standard practice to improve the outcome of the central nervous system (CNS) infections caused by C. gattii [4,5,12,13]. However, response to this typical combination regimen varies and high mortality is seen in treated patients with complicated CM [4]. Ow­ing to the low permeability of the blood-brain bar­rier to the majority of antifungal agents, these parenteral treatments are not always ef­fective, result­ing in treatment-refractory CM. Although the majority of CM treatment guidelines discouraged or rarely considered the use of adjunctive intrathecal or intraventricular administration of antifungal agents, this approach may be an option for patients with poor treatment response. The Om­maya reservoir, original­ly invented in 1963 by Pakistani neurosurgeon A. K. Om­maya, facilitates delivery of intrathecal medication (e. g. antibio­tics, chemotherapy) [14].

Here, we present a case of a 63-year-old male patient with cerebral cryptococcosis caused by C. gattii (genotype AFLP4/ VGI), acute severe hydrocephalus, and cryptococcoma, who failed to respond to conventional parenteral treatments.

Case report

A previously healthy 63-year-old male patient developed a fever and headache that persisted for 3 weeks. Prior to his first hospitalisation at Changhua Christian Hospital, he had received treatment for 2 weeks, without a definite dia­gnosis. Upon his ar­rival at the emergency room, physical and neurological examinations revealed a fever (39°C), severe headache, neck stif­fnes­s, and a positive Brudzinski’s sign. He reported no history of blur­red vision, double vision, neck pain, or change in consciousnes­s.We performed computed tomography (CT) of the brain and a subsequent lumbar puncture. India ink-positive yeast was identified in the cerebrospinal fluid (CSF; Tab. 1) and CM was dia­gnosed. Later, magnetic resonance imag­ing (MRI) of the brain showed enhanced cortical nodules and mild hydrocephalus (Fig. 1A). We also investigated potential risk factors for CM by as­ses­s­ing im­munity parameters and test­ing for human imunnodeficiency virus (HIV) and other systemic or malignant diseases. All find­ings were negative. He was then hospitalized and treated with intravenous AmB (0.7 mg/ kg//day) and 5-FC (100 mg/ kg per day, 4-times a day). His clinical symp­toms subsided 4 weeks later and a consolidation therapy regimen with oral fluconazole (FLC) (450 mg per day oral­ly) was administered for 3 months fol­low­ing discharge. Ow­ing to seizure attacks, he was re-hospitalized. Fol­low-up CSF analysis indicated that the cryptococcal infection was still present. We prescribed intravenous AmB (0.7 mg/ kg/ day) and oral 5-FC (100 mg/ kg/ day) for 2 weeks, fol­lowed by 6 weeks of treatment with intravenous FLC (6 mg/ kg/ day). He was then discharged, as the signs of clinical infection appeared to be under control. Oral FLC (450 mg/ day) was prescribed for consolidation therapy.

He was re-admitted 4 months after his second hospitalization ow­ing to general weaknes­s, changes in consciousnes­s, and unfavorable CSF data (Tab. 1). Fol­low-up MRI showed multiple new nodules and exacerbated hydrocephalus (Fig. 1C). No evidence of cryptococcal infection in the peripheral system was found. Ow­ing to his deteriorated clinical condition, persistent unfavorable CSF data, and MRI results indicat­ing disease progres­sion, his family agreed to treatment with intraventricular AmB. He was treated with intraventricular AmB (0.25 mg/ dose, 6 doses/ week) administered by Om­maya reservoir (Model number 44111, Medtronic PS Medical Inc.) and intravenous AmB (0.7 mg/ kg/ day) for 8 weeks. For each injection, we withdrew 10 mL of CSF from the Om­maya reservoir, slowly infused a combination of 0.5 mL distil­led water and 0.25 mg AmB into the Om­maya reservoir, and flushed with 1 mL CSF us­ing the previously with­drawn CSF. The total dose of AmB delivered intraventricularly and that delivered intravenously was 12 mg and 3,000 mg, resp. His response to treatment was fair and he was final­ly discharged after 71 days of hospitalization. Dur­ing the fol­low-up of 2 years, he received consolidated oral FLC (600 mg/ day) treatment at home and was clinical­ly stable as confirmed by fol­low-up CSF analysis and MRI (Fig. 1D).

Six months later, CSF isolate was re-identified and cultured on canavanine-glycine-bromothymol blue (CGB) medium and the isolate was identified C. gattii sensu stricto. Molecular taxonomy via sequenc­ing of the URA5 gene revealed that the isolate was genotype AFLP4/ VGI, represent­ing the recently described C. gattii sensu stricto [2]. Antifungal susceptibility obtained by a com­mercial­ly prepared, dried colorimetric microdilution panel (Sensititre YeastOne, Thermo-Fisher Scientific, West Sus­sex, UK) showed 0.5 mg/ mL for AmB, 8 mg/ mL for 5-FC, and 8 mg/ mL for FLC.

Discus­sion

This is the first case report describ­ing administration of adjunctive intra-ventricular amphotericin B via the Om­maya reservoir to treat neurological complications of C. gattii AFLP4/ VGI-induced CM. The present report demonstrated that adjunctive intra-ventricular AmB delivered via Om­maya reservoir could represent an alternative treatment for patients with C. gattii AFLP4/ VGI-induced CM who fail to respond adequately to conventional interventions. As intra-ventricular antifungal treatment via an Om­maya implant has been rarely utilized to treat CNS cryptococcosis, we conducted a literature review to support our course of treatment (sum­marized in Tab. 2). On analyz­ing the reports, we found that Om­maya reservoirs were frequently applied in the treatment of refractory CM, notably in im­munocompromised or fragile populations. Consider­ing the disease course characteristics and poor response from our patient, the few case studies describ­ing treatment of CM with an Om­maya reservoir suggested a potential alternative treatment for our patient. Our intervention led to eradication of C. gattii sensu stricto and resolution of clinical manifestations. We believe that intraventricular administration of AmB in our patient enabled more of the drug to pass through the blood-brain bar­rier, result­ing in higher brain concentrations than with the conventional approach. The intraventricular approach also yielded practical secondary benefits, since intracranial pres­sure could be directly monitored and simultaneously man­aged at high pres­sure, without any further adverse ef­fects. Although intraventricular administration of antifungal agents and decompres­sion of intracranial pres­sure through an Om­maya reservoir was not the standard approach, and was even discouraged in accordance with CM treatment guidelines, we believe this intervention could be reserved as a last resort for similar clinical cases. However, there are potential disadvantages of intraventricular antifungal injection via an Om­maya reservoir, includ­ing device-as­sociated infections [15], over-drainage of the CSF [16], tentorial/ tonsil­lar herniation [17] and subdural hematoma [18].

We emphasize that physicians should pay attention to the pos­sible complications of cryptococcal infection in patients, even dur­ing active therapy. We also stress the importance of discriminat­ing between C. gattii and C. neoformans, us­ing CGB medium in clinical situations, as it is neces­sary to achieve a positive outcome. Im­muno­com­petent individuals are also susceptible to CM infection.

In conclusion, intraventricular administration of antifungal agents via an Om­maya reservoir could represent an alternative choice for treat­ing patients with C. gattii AFLP4/ VGI-induced CM, who respond inadequately to typical interventions. How­ever, we recom­mend that it should only be used after attempt­ing all other treatment options.

All acknowledgements

The authors thank the Changhua Christian Hospital for the grant support (CCH grant 104-CCH-IRP-001, CCH grant 105-CCH-IRP-001). 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 study 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.

Chen Chang-Hua, MD

Division of Infectious Diseases

Department of Internal Medicine

Changhua Christian Hospital

135 Nanhsiao Street

Changhua 500

Taiwan

e-mail: 76590@cch.org.tw

Accepted for review: 25. 8. 2016

Accepted for print: 2. 1. 2017