Clin Drug Investig (2013) 33 (Suppl 1):S27–S31 DOI 10.1007/s40261-012-0016-2
CASE REPORT
Fungal meningoencephalitis caused by Alternaria: a clinical case Cı´cero J. C. Silveira • Joana Amaral • Rodrigo P. Gorayeb Jose´ Cabral • Teresa Pacheco
•
Ó Springer International Publishing Switzerland 2013
Abstract Cerebral phaeohyphomycosis is an infrequent infectious condition associated with a high mortality rate. The authors describe a very rare case that occurred in an immunocompetent 18-year-old man who developed severe meningoencephalitis and arachnoiditis caused by Alternaria alternata, which were diagnosed in the context of difficult-to-treat hydrocephalus. Etiological diagnosis was made based on fungal culture and histopathologic examination. Empirical treatment consisted of an early aggressive antifungal combination therapy consisting of intravenous liposomal amphotericin B (5 mg/kg per day) and voriconazole (4 mg/kg every 12 h), which initially induced a favorable response. Following the fungus identification, the choice for the combination of posaconazole (400 mg every 12 h) plus flucytosine (4000 mg/day) proved to be effective in the suppression of the signs and symptoms of this uncommon cerebral mycosis. At a
C. J. C. Silveira (&) R. P. Gorayeb J. Cabral Neurosurgery Service, Hospital Egas Moniz - Centro Hospitalar de Lisboa Ocidental, EPE, Lisbon, Portugal e-mail:
[email protected] R. P. Gorayeb e-mail:
[email protected] J. Cabral e-mail:
[email protected] J. Amaral Pharmacy Service, Hospital Egas Moniz - Centro Hospitalar de Lisboa Ocidental, EPE, Lisbon, Portugal e-mail:
[email protected]
12-month follow-up visit no recurrence had occurred and posaconazole was then stopped.
1 Introduction We describe a very rare case of meningoencephalitis and arachnoiditis caused by Alternaria alternata, a fungus of the Phaeohyphomyces family, diagnosed in the context of difficult-to-treat hydrocephalus. The term ‘‘phaeohyphomycosis’’ was introduced by Ajello et al. [1] in 1974, to refer to human infections caused by pigmented filamentous fungi (presence of melanin in the cell wall). These mycoses have been attributed to over 100 different species of fungi, with great variability in the clinical syndromes. The majority of the species are opportunistic agents, although some are considered true pathogens [2]. Cerebral phaeohyphomycosis is a rare fungal infection of the brain; it has gained a bad reputation as one of the most dangerous clinical presentations of this type of mycosis. Over the past decades, many of the etiological agents of these cerebral mycoses have been identified and new emerging pathogens continue to be discovered [3]. The term Alternaria encompasses a genus of opportunistic pigmented filamentous fungi that cause infections in humans, generally in immunosuppressed individuals [4]. The case reported here is probably the second case of cerebral alternariosis ever reported from Portugal [5] and the first with a favorable clinical outcome.
2 Case Report T. Pacheco Pathology Service, Hospital Egas Moniz - Centro Hospitalar de Lisboa Ocidental, EPE, Lisbon, Portugal e-mail:
[email protected]
An 18-year-old male patient had a history of hydrocephalus associated with stenosis of the Sylvian aqueduct since
S28
C. J. C. Silveira et al.
Fig. 1 Cranial CT scan, axial and sagittal planes: postoperative period following ventriculostomy with bilateral implantation of an EVD (sagittal). The axial image represents the test performed at admission
childhood. During this period, the patient underwent several procedures to manage this condition, such as implantation of a ventriculoperitoneal shunt (VPS) and two endoscopic ventriculostomies. The last intervention was in 1998, when his VPS was replaced. He did not present with earlier cognitive deficits and was autonomous with regard to daily life activities. In October 2008, he was admitted to our hospital with a worsening of his consciousness level (Glasgow coma scale [GCS] 12); he was hyporeactive and his gaze deviated to the right. The cerebral computed tomography (CT) scan revealed acute hydrocephalus. He underwent a surgical intervention to check and replace the VPS. The postoperative course was good, with no abnormal images and he was discharged from hospital with a GCS score of 15. He was monitored on an outpatient basis, with no neurological involvement. On August 2009, he was readmitted to the emergency room for progressive and marked deterioration in his level of consciousness, evolving to coma (GCS 4), with bilateral papilloedema. The cerebral CT scan showed signs of acute hydrocephalus caused by VPS dysfunction. The VPS was removed and an external ventricular drain (EVD) was placed. As there were suspicious inflammatory signs in the cranial skin wound, empirical antibiotic treatment was
started for meningitis/ventriculitis of the central nervous system (CNS). Cerebrospinal fluid (CSF) cultures were performed with a negative result. There were no other laboratory signs of infection and the chest X-ray was normal. In the immediate postoperative period, the patient maintained a GCS 3, with active hydrocephalus visible on the cerebral CT scan (Fig. 1), and with a trapped lateral ventricle. In view of this situation, a second contralateral EVD was placed, with improved neurological score (GCS 6). Despite prolonged empirical antibiotic therapy for several weeks, the patient did not show any consistent clinical or neurological improvement. In November 2009, as a result of a lack of clinical improvement, still with negative CSF cultures, febrile/ subfebrile peaks, rigidity of the neck and spastic tetraparesis alternating with flaccid tetraparesis, during one of the EVD replacements, intraventricular endoscopy was performed in an attempt to clarify the origin of the situation. The preoperative cerebral CT scan, i.e. before this endoscopic ventriculostomy, showed persistence of a residual hydrocephalus with ventricles of slightly diminished dimensions and a dilated third ventricle. During the endoscopic procedure, multiple adhesions inside the lateral ventricles were observed, with total occlusion of Monro’s
Fungal Meningoencephalitis
foramen on the right and partial occlusion on the left. A septostomy was performed to free the adhesions in the left Monro’s foramen. The right frontal EVD was the only one kept in situ during the postoperative period. After this intervention, the patient had a GCS 10 and flaccid tetraparesis, which persisted for the next 4 weeks. Nuclear magnetic resonance imaging (MRI) of the entire neuroaxis was performed and displayed persistent hydrocephalus, diffuse arachnoiditis that included the spinal cord and a predominantly right-sided frontotemporal cerebral atrophy. The electroencephalogram did not reveal significant alterations and excluded severe viral encephalitis. The next cerebral CT scan showed areas of de novo calcification in the pachymeninges, suggestive of a painless inflammatory process. All cytochemical and microbiologic tests of the CSF were normal. In the absence of clinical improvement and lacking microbiologic confirmation, he underwent a new ventriculostomy in combination with a cerebral biopsy via frontal craniotomy and subsequent implantation of a single VPS. Histologic examination of the frontal brain tissue revealed a diffuse glial inflammatory reaction of undetermined characteristics. Microbiologically a filamentous fungus was detected in the culture of material obtained from the encephalic parenchyma (frontal cortex/subcortex). Later this organism was identified as A. alternata. As the patient had signs and symptoms of severe meningoencephalitis, early aggressive antifungal therapy was started before the final results of the cultures were available. The empirical treatment consisted of a combination of intravenous liposomal amphotericin B at a dose of 5 mg/kg per day and intravenous voriconazole at a dose of 4 mg/kg every 12 h. During the following weeks, the consciousness level of the patient gradually improved up to GCS 11 after 3 weeks of antifungal treatment (see Fig. 2a, b). The identification of renal dysfunction by exclusion as a result of the prolonged use of antifungal drugs and the graduating better neurological score (speech, motor and feeding conditions) prompted a change in therapy. Amphotericin B and voriconazole were replaced by a combination of posaconazole at a dose of 400 mg every 12 h and flucytosine at a dose of 4,000 mg/day, supplemented by epoetin beta. In theory, this change also allowed a better penetration in the CSF and decreased renal complications. In the course of this therapeutic regimen, the patient’s condition gradually improved with a good neurological response (GCS 15) and recovery of intellectual functions. After 4 weeks of treatment, the patient still had spastic tetraparesis, despite the use of baclofen. Flucytosine was discontinued after 42 days because of a lack of clinical experience with its use over longer periods
S29
Fig. 2 a Direct examination of the culture (Agar Sabouraud Dextrose): typically brown conidia, clavate, ovate and ellipsoid, forming long chains with short cylindrical tips, with up to eight transversal septa and some oblique. b Culture in Agar Sabouraud Dextrose medium: diffuse brown colonies
of time, while posaconazole was maintained as a single agent. The patient was discharged from hospital after 105 days of treatment with posaconazole and was followed up every 3 months. At a 12-month follow-up visit no recurrence had occurred and posaconazole was stopped. In 2011, this patient presented with independent gait (mild spasticity), was admitted to university, with mild dysfunction in speech.
3 Discussion and Conclusion Although cerebral phaeohyphomycosis was described decades ago it is still an infrequent infection. On the other hand, these organisms still carry a very high mortality rate. In a review analysing 101 cases of primary phaeohyphomycosis infection in the CNS published in the literature, the mortality rate was 73% despite the fact that most patients had undergone surgery and treatment with antifungal drugs. Surprisingly, the authors determined that the majority of patients were immunocompetent and had no apparent pre-existing morbidity. The authors also concluded that the complete excision of the cerebral lesions, which present as a brain abscess in 87% of cases, can lead to better results than partial excision or simple aspiration [6]. The main clinical manifestations of this disease are general symptoms such as headaches, fever, sensory variations, behavioural alterations, seizures and focal CNS signs, usually hemiparesis [3]. It is noteworthy that the clinical development of the patient in the present report showed little relation to alterations in the CSF pressure. There is great variation in the radiologic presentation. It varies from no abnormalities to focal hypodense areas in the brain parenchyma and to lesions with variable contrast medium uptake, which are more common in
S30
Fig. 3 Cerebral MRI WT1Gd?, coronal. Postoperative period following endoscopic ventriculostomy and frontal cerebral biopsy (although not visible in the image, the EVD is maintained)
immunosuppressed patients and in patients with lesions that are characteristic of brain abscess formation [3]. Our patient was a young immunocompetent patient who, however, had an active hydrocephalus, which necessitated various surgical procedures for CSF shunting over many years. Because of the difficulty in diagnosis, it is not possible to say at what time the CNS got infected with this fungus. A series of subsequent imaging tests (cerebral CT scan and MRI) displayed no features that were indicative of a specific diagnosis. The cerebral CT scan and MRI (Fig. 3) did not reveal lesions with the uptake of contrast medium, but showed a signal alteration (T1W) in the CSF of the ventricular system. During the acute phase of the infection the patient had an enhanced lymphatic drainage in the CSF, and normal levels were only achieved after antifungal therapy was started. The predominant Alternaria species in the majority of clinical syndromes are A. alternata and Alternaria infectoria. The use of molecular biology techniques facilitates their identification [4]. In this case, all limitations inherent to the laboratory identification of A. alternata were applicable and therefore the diagnosis was based solely on morphologic criteria (Fig. 2). Considering the rarity of these mycoses, some authors report that it is reasonable to combine data from isolated cases to determine the best medical and surgical treatment strategy [6].The switch in therapy to the flucytosine– posaconazole combination was based on the following arguments: the alternative combination of an echinocandin with an azole did not prove effective in the only reported case of brain abscess caused by Alternaria [5].On the other hand, a review on cerebral phaeohyphomycosis mentions the use of flucytosine in combinations as one of the options that produced favorable results [3]. Flucytosine is, indeed, one of the few antifungal agents with an excellent penetration of the CSF, which could explain its activity in vivo. Its potential against pigmented filamentous fungi is supported
C. J. C. Silveira et al.
by in-vitro studies and animal models of systemic and cerebral phaeohyphomycosis [6]. Furthermore, some authors have concluded that therapeutic regimens containing flucytosine were life-saving in some of the cases analysed [7]. Another reason to select flucytosine plus an azole was the observation that azoles can increase intracellular penetration of flucytosine in the fungal cell, which would boost the action of flucytosine as an inhibitor of the synthesis of DNA and RNA of the fungus [3]. The choice of posaconazole as the preferred azole seems questionable but some authors report that posaconazole is a promising therapeutic option considering the results obtained in animal models [8, 9]. Furthermore, posaconazole is the most active triazole in vitro against filamentous fungi [10]. Despite its low penetration in the CSF, the cases reported suggest that it effectively penetrates the CNS when an infection is present, and has been associated with an overall success rate of 80% for phaeohyphomycosis, albeit in a relatively favorable group of patients because critically ill patients who are candidates for intravenous therapy were excluded [11]. In addition, in another report a case of cerebral phaeohyphomycosis caused by Ramichloridium Mackenziei was described, in which the patient was treated successfully with posaconazole, despite an alleged mortality rate of 100% [12]. The high mortality as reported in the literature is attributed to several different factors, which include a failure of the antifungal agents, a delay of clinical diagnosis and late surgery in cases in which a surgical indication exists [7]. Cerebral phaeohyphomycosis can have a favorable outcome if diagnosed early and treated aggressively, starting treatment as early as possible with combined antifungal agents, surgical debriding and immunological intervention [3]. In this case, early aggressive initial therapy with amphotericin B and voriconazole showed a favorable response. Following the identification of the fungus, the choice of the combination of posaconazole with flucytosine also proved to be effective to suppress the signs and symptoms of this uncommon cerebral mycosis. The excellent clinical result that we obtained in the present case leads to the conclusion that in the future it is necessary to continue the exploration of new therapeutic options to improve the outcome of these frequently fatal infections. Disclosures This manuscript has been published in a journal supplement that was created with an unrestricted educational grant from Gilead Portugal. The authors have no conflicts of interest to declare.
References 1. Ajello L. Phaeohyphomycosis: Definition and Etiology. Scientific publication 304. Washington, DC: Pan American Health Organization; 1974.
Fungal Meningoencephalitis 2. Revankar SG, Patterson J, Sutton DA, Pullen R, Rinaldi MG. Disseminated phaeohyphomycosis: review of an emerging mycosis. Clin Infect Dis. 2002;34:467–76. 3. Li D, Hoog GS. Cerebral phaeohyphomycosis—a cure at what lengths? Lancet Infect Dis. 2009;9:376–83. 4. Pastor FJ, Guarro J. Alternaria infections: laboratory diagnosis and relevant clinical features. Clin Microbiol Infect. 2008;14: 734–46. 5. Faria E, Alves A, Hoog GS, et al. Alternaria infectoria brain abscess in a child with chronic granulomatous disease. Eur J Clin Microbiol Infect Dis. 2009;28:377–80. 6. Revankar SG, Sutton DA, Rinaldi MG. Primary central nervous system phaeohyphomycosis: a review of 101 cases. Clin Infect Dis. 2004;38:206–16. 7. Jayakeerthi SR, Dias M, Nagarathna S, Anandh B, Mahadevan A, Chandramuki A. Brain abscess due to Cladophialophora bantiana. Indian J Med Microbiol. 2004;22:193–5.
S31 8. Al Abdely HM, Najvar L, Bocanegra R, et al. SCH 56592, amphotericin B, or itraconazole therapy of experimental murine cerebral phaeohyphomycosis due to Ramichloridium obovoideum (‘‘Ramichloridium Mackenziei’’). Antimicrob Agent Chemother. 2000;44:1159–62. 9. Graybill J, Najvar L, Johnson E, Bocanegra R, Loebenberg D. Posaconazole therapy of disseminated phaeohyphomycosis in a murine model. Antimicrob Agent Chemother. 2004;48:2288–91. 10. Keating GM. Posaconazole. Drugs. 2005;65:1553–67. 11. Torres H, Hachem R, Chemaly R, Kontoyiannis D, Raad I. Posaconazole: a broad-spectrum triazole antifungal. Lancet Infect Dis. 2005;5:775–85. 12. Abdely HM, Alkhunaizi AM, Tawfi JA, et al. Successful therapy of cerebral phaeohyphomycosis due to Ramichloridium Mackenziei with the new triazoleposaconazole. Med Mycol. 2005;43: 91–5.
