- Email: [email protected]
Corticosteroids for the management of severe intracranial hypertension in meningoencephalitis caused by Cryptococcus gattii: A case report and review
+ Models
MYCMED-648; No. of Pages 4 Journal de Mycologie Médicale (2016) xxx, xxx—xxx
Available online at
ScienceDirect www.sciencedirect.com
CASE REPORT/CAS CLINIQUE
Corticosteroids for the management of severe intracranial hypertension in meningoencephalitis caused by Cryptococcus gattii: A case report and review ´ ve ` re Corticoı¨des pour la gestion de l’hypertension intracranial se ´ par Cryptococcus gattii : ´etude dans meningoencephalitis cause d’un cas et traitement R.-A. Maciel, L.-S. Ferreira, F. Wirth, P.-D. Rosa, M. Aves, E. Turra, L.-Z. Goldani * Section of Infectious Diseases, Hospital de Clı´nicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, Ramiro Barcelos, 2350, 90035-903 Porto Alegre, RS, Brazil Received 22 May 2016; received in revised form 15 September 2016; accepted 16 September 2016
KEYWORDS Cryptococcus gattii; Corticosteroids; Intracranial hypertension; Management
Summary Immune reconstitution inflammatory syndrome in meningitis caused by Cryptococcus gattii in immunocompetent patients after initiation of antifungal therapy appears to be the result of paradoxical antifungal treatment-induced clinical deterioration due to improved local immune responses to cryptococcal organisms. Recent anecdotal reports have suggested a favorable clinical response to corticosteroids in select patients with C. gattii central nervous system (CNS) infections. In this report, we describe a 65-year-old patient with meningoencephalitis caused by C. gattii who developed persistent intracranial hypertension and was successfully managed with antifungal therapy, repeated lumbar puncture and corticosteroids. Our observations suggest a possible benefit of dexamethasone in the management of select cases of C. gattii CNS infection with intracranial hypertension. Further studies are necessary to evaluate the long-term use of steroids in select patients with C. gattii with intracranial hypertension. # 2016 Elsevier Masson SAS. All rights reserved.
* Corresponding author. E-mail address: [email protected] (L.Z. Goldani). http://dx.doi.org/10.1016/j.mycmed.2016.09.003 1156-5233/# 2016 Elsevier Masson SAS. All rights reserved.
Please cite this article in press as: Maciel R-A, et al. Corticosteroids for the management of severe intracranial hypertension in meningoencephalitis caused by Cryptococcus gattii: A case report and review. Journal De Mycologie Médicale (2016), http://dx.doi.org/ 10.1016/j.mycmed.2016.09.003
+ Models
MYCMED-648; No. of Pages 4
2
R.-A. Maciel et al.
MOTS CLÉS Cryptococcus gattii ; Corticoïdes ; Hypertension intracrânienne ; Traitement
Re ´sume ´ Le syndrome inflammatoire de reconstitution immunitaire dans la méningite au Cryptococcus gattii se manifeste fréquemment chez les patients immunocompétents après la mise en place d’un traitement antifongique. Il semble résulter d’un traitement antifongique paradoxal — une détérioration clinique induite liée à l’amélioration des réponses immunitaires locales aux cryptocoques. De récents rapports anecdotiques ont suggéré une réponse clinique favorable aux corticostéroïdes chez certains patients atteints d’une infection du système nerveux central (SNC) par C. gattii. Dans ce rapport, nous décrivons un patient âgé de 65 ans, atteint de méningo-encéphalite à C. gattii, qui a développé une hypertension intracrânienne persistante et a pu être soigné avec succès par un traitement à base d’antifongiques, de ponctions lombaires répétées et de corticostéroïdes. Nos observations suggèrent un bénéfice possible de la dexaméthasone dans la gestion de certains cas d’infection du SNC par C. gattii accompagnée d’hypertension intracrânienne. Des études plus poussées seront nécessaires pour évaluer l’utilisation à long terme de stéroïdes chez certains patients atteints d’hypertension intracrânienne liée au C. gatti. # 2016 Elsevier Masson SAS. Tous droits réservés.
Introduction Cryptococcosis is a fungal disease caused by Cryptococcus neoformans and C. gattii [1,2]. The fungal disease is caused by inhalation and subsequent pulmonary infection and may disseminate to the CNS and cause meningitis or meningoencephalitis. Cryptococcosis due to C. gattii is usually described in immunocompetent patients. Characteristics of C. gattii central nervous infection (CNS) and pulmonary disease include a higher rate of space-occupying lesions and longterm sequelae compared with C. neoformans disease [3]. There is evidence of immune reconstitution inflammatory syndrome in C. gattii infection in immunocompetent patients after initiation of antifungal therapy. This syndrome appears to be the result of paradoxical antifungal treatmentinduced clinical deterioration due to improved local immune responses to cryptococcal organisms [4]. Recent anecdotal reports have suggested a favorable clinical response to corticosteroids in selected patients with C. gattii CNS infection [5—7]. In this report, we describe the management of intracranial hypertension with corticosteroids in a patient with C. gattii meningoencephalitis.
Case report A 65-year-old Brazilian man was referred to a tertiary care hospital for evaluation of headache, fatigue, weight loss, and a progressive hearing deficit. The patient lived in a rural area in southern Brazil and depended on agriculture and related activities for his income. His past medical history was relevant for arterial hypertension, depression and thyroidectomy for nodular thyroid disease. The patient was initially admitted in a local hospital in his hometown and referred to this hospital for management of meningitis. Vital signs included a temperature of 37 8C, a heart rate of 127 beats/min, a respiratory rate of 17 breaths/min, a blood pressure of 118/57 mmHg, and a room air oxygen saturation of 98%. The patient was well-developed but appeared chronically ill. His neck was supple without lymphadenopathy. The oral cavity and pharynx showed normal mucosa and good dental hygiene. Cardiovascular examination revealed tachycardia without murmur, and both lungs were clear to auscultation. The
abdomen was soft, flat and non-tender with no hepatosplenomegaly. The skin was warm and dry. Despite left-side hearing loss, neurological examination revealed intact cranial nerves, motor function (normal tone coordination and muscle strength against resistance) and symmetrical deep tendon reflexes. Laboratory examination revealed that the patient had a white blood cell (WBC) count of 9140/L (4000—10,000/ L) with neutrophil predominance and a hematocrit of 39% (41—50%). An ELISA for HIV was negative, and chest radiography revealed a right upper-lobe lesion. A gadoliniumenhanced MRI scan of the brain revealed multiple enhancing lesions within the cerebral hemispheres, brainstem and cerebellum, consistent with gelatinous pseudocysts. Lumbar puncture revealed an opening pressure of 32.5 cm H2O (normal range 5 to 20 cm H2O) with colorless cerebral spinal fluid (CSF) with a WBC count of 64/mL (0—5/mL) (6% monocytes, 94% lymphocytes), low glucose of 20 mg/dL (40—85 mg/dL), and elevated protein level of 165 mg/dL (15—45 mg/dL). CSF cryptococcal antigen titer was positive (> 1:10,000). Because 5-fluorocytosine is not available in Brazil, the patient was immediately given intravenous amphotericin B deoxycholate (60 mg/day) and fluconazole (800 mg/day). Several days later, C. gattii was observed in CSF culture. Molecular analysis performed as described previously revealed that the C. gattii isolate belonged to genotype VGII, serotype B [8]. The minimum inhibitory concentrations (MICs) using the NCCLS reference indicated that the strain was sensitive to amphotericin B (MIC = 1.0 mg/mL), fluconazole (4 mg/mL), itraconazole (1.0 mg/mL), and voriconazole (0.03 mg/mL). Resistance to antifungal agents was observed for fluconazole ( 64 mg/mL), itraconazole and voriconazole ( 1.0 mg/mL), and amphotericin B ( 2.0 mg/mL). C. gattii was isolated in bronchoalveolar lavage. In addition to antifungal therapy, the patient was managed with multiple lumbar punctures to relieve intracranial hypertension. Despite these interventions, the patient presented persistent headaches and vomiting, and intravenous dexamethasone 4 mg every 6 hours was initiated. As shown in Figs. 1 and 2, the patient presented substantial improvement of brain lesions and intracranial hypertension after starting dexamethasone. After 98 days of hospitalization, the patient was clinically stable and discharged with fluconazole 900 mg/day and prednisone 60 mg/day (with a plan of tapering over time
Please cite this article in press as: Maciel R-A, et al. Corticosteroids for the management of severe intracranial hypertension in meningoencephalitis caused by Cryptococcus gattii: A case report and review. Journal De Mycologie Médicale (2016), http://dx.doi.org/ 10.1016/j.mycmed.2016.09.003
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MYCMED-648; No. of Pages 4
Meningoencephalitis caused by C. gattii and corticosteroids
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Figure 2 Intracranial pressures during hospitalization of the patient with Cryptococcus gattii meningoencephalitis. Period of hospitalization (total of 98 days). Arrow indicates start day of corticosteroids (dexamethasone 16 mg/day). Normal opening pressure (normal range 5 to 20 cm H2O). ˆ niennes pendant l’hospitalisation du paLes pressions intracra ´ ningo. tient avec C. gattii me
68 mg/dL, and a protein level of 48 mg/dL. Culture of the CSF was negative. The patient was started on amphotericin B lipid complex 150 mg/day and fluconazole 400 mg/day and underwent ventriculoperitoneal derivation. Despite negative CSF cultures and controlled intracranial pressure, the patient died of infectious complications related to the surgical procedure and prolonged hospitalization.
Comments
Figure 1 Brain MRI showing improvement of the Cryptococcus gattii brainstem enhancing lesion after starting steroids (arrow). Before dexamethasone (A); after 10 days of dexamethasone (B). ´ re ´ brale montrant une ame ´ lioration du C. gattii brainstem IRM ce ´ e apre ` s le de ´ but des ste ´ roı¨des (fle ` che). Avant la ´ sion rehausse le ´ thasone (A) ; apre ` s 10 jours de dexame ´ thasone (B). dexame
to cease therapy). The patient was neurologically intact except for a continued mild bilateral hearing deficit. Lumbar puncture revealed an opening pressure of 19 cmH2O with colorless CSF containing 23 WBC/mL (100% lymphocytes), glucose of 48 mg/dL, and a protein level of 54 mg/dL. Three weeks later, the patient was admitted to the intensive care unit (ICU) with dizziness, gait disturbance and headaches. The patient was receiving fluconazole 900 mg/day while tapering oral prednisone at 10 mg/day. Lumbar puncture revealed an opening pressure of 32 cmH2O with colorless CSF containing 12 WBC/mL (100% lymphocytes), glucose of
CSF pressure control is a critical determinant of outcome in meningoencephalitis caused by Cryptococcus [9]. In the presence of persistent pressure elevation 25 cmH2O and related symptoms, daily repeated lumbar puncture is recommended until the CSF pressure and symptoms have stabilized [10—12]. Temporary percutaneous lumbar drains or ventriculostomy should be considered for patients who require repeated and prolonged daily lumbar punctures. Corticosteroids have been recommended for CNS inflammation with increased intracranial pressure due to immune reconstitution inflammatory response syndrome. However, this approach is reportedly of no benefit in HIV-infected patients and might increase mortality [9]. Previous reports have shown that corticosteroids may be beneficial in patients with C. gattii CNS infection who are not responding clinically to treatment with an amphotericin B formulation plus 5-fluorocytosine in association with negative CSF culture and the development of new or worsening focal inflammatory brain lesions on follow-up imaging (Table 1) [5,6]. Philips et al. described a favorable clinical outcome in three of four patients with C. gattii CNS infection who received dexamethasone for the treatment of persisting mental status abnormalities and focal lesions on brain scan despite culture-negative CSF and management of intracranial pressure [6]. Interestingly, Seaton et al. reported in a retrospective study that visual deterioration occurred less frequently in patients with C. gattii meningitis receiving varying doses of corticosteroids, mainly 100—250 mg of hydrocortisone daily for the prevention of febrile reactions
Please cite this article in press as: Maciel R-A, et al. Corticosteroids for the management of severe intracranial hypertension in meningoencephalitis caused by Cryptococcus gattii: A case report and review. Journal De Mycologie Médicale (2016), http://dx.doi.org/ 10.1016/j.mycmed.2016.09.003
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MYCMED-648; No. of Pages 4
4
R.-A. Maciel et al. Table 1 Characteristics of the patients with Cryptococcus gattii meningoencephaltis treated with antifungal agents and corticosteroids. ´ s avec des agents anti-fongiques et des corticoste ´ roı ´ ristiques des patients avec C. gattii meningoencephaltis traite ¨des. Caracte Ref.
Age/sex
Brain imaging
Corticosteroids
Response to steroids
Treatment
Outcome
[6]
40/female
Caudate mass
Dexamethasone
46/female
Dexamethasone
[6]
63/male
[6]
62/male
Basal ganglia lesions Posterior fossa lesion Negative
[5]
29/male
[7]
16 patients; 14—39 y (range) Ratio male: female 11:5 65/male
L-AMB-AMB + 5-Flu L-AMB-AMB + 5-Flu L-AMB-AMB + 5-Flu L-AMB-AMB + 5-Flu AMB + 5-Flu; VP shunt AMB + 5-Flu
Alive
[6]
Improved mental lesion size Improved mental lesion size Improved mental lesion size Improved mental
Present
Infarction of the right caudate NA
Cerebral hemisphere brainstem and cerebelum lesions
Dexamethasone Dexamethasone Dexamethasone/ prednisone Low dose hydrocortisone to avoid AMB febrile reactions Dexamethasone/ prednisone
status; status; status; status
Improved lower limb function; headaches Decreased visual deterioration
Improved headaches, lesion size, ICH relapse on tapering steroids
AMB-L + FLZ
Alive Death Alive Alive Alive
Death
ICH: intracranial hypertension; AMB: amphotericin B deoxyxholate; AMB-L: lipid formulation of amphotericin B; FLZ: fluconazole; 5-FLU, 5flucytosine; VP: ventriculoperitoneal.
to amphotericin B, compared to those not receiving corticosteroids [7]. However, risk considerations include the potential adverse effects of systemic corticosteroids. Moreover, corticosteroids should not be substituted as a measure to control increased intracranial pressure where serial lumbar punctures or a CSF shunting procedure may be indicated, particularly in the presence of inflammatory cerebral lesions. Consistent with previous reports, the clinical course, imaging findings, and marked clinical response to corticosteroids of our patient were consistent with an antifungal therapy-induced paradoxical clinical deterioration related to improved local immune responses to C. gattii organisms. Unfortunately, intracranial hypertension recurred in the patient while tapering corticosteroids despite negative CSF cultures for C. gattii. Our observations suggest a possible benefit of dexamethasone in the management of selected cases of C. gattii CNS infection. Further studies are necessary to evaluate the long-term use of steroids in select patients with C. gattii with intracranial hypertension.
Disclosure of interest The authors declare that they have no competing interest.
References [1] Kwon-Chung KJ, Bennett JE. Epidemiologic differences between the two varieties of Cryptococcus neoformans. Am J Epidemiol 1984;120:123—30. [2] Speed B, Dunt D. Clinical and host differences between infections with the two varieties of Cryptococcus neoformans. Clin Infect Dis 1995;21:28—34.
[3] Chen SC, Meyer W, Sorrell TC. Cryptococcus gattii infections. Clin Microbiol Rev 2014;27:980—1024. [4] Einsiedel L, Gordon DL, Dyer JR. Paradoxical inflammatory reaction during treatment of Cryptococcus neoformans var. gattii meningitis in an HIV-seronegative woman. Clin Infect Dis 2004;39:e78—82. [5] Lane M, McBride J, Archer J. Steroid responsive late deterioration in Cryptococcus neoformans variety gattii meningitis. Neurology 2004;63:713—4. [6] Phillips P, Chapman K, Sharp M, Harrison P, Vortel J, Steiner T, et al. Dexamethasone in Cryptococcus gattii central nervous system infection. Clin Infect Dis 2009;49:591—5. [7] Seaton RA, Verma N, Naraqi S, Wembri JP, Warrell DA. The effect of corticosteroids on visual loss in Cryptococcus neoformans var. gattii meningitis. Trans R Soc Trop Med Hyg 1997;91:50—2. [8] Meyer W, Aanensen DM, Boekhout T, Cogliati M, Diaz M, Esposto ME, et al. Consensus multi-locus sequence typing scheme for Cryptococcus neoformans and Cryptococcus gattii. Med Mycol 2009;47:561—70. [9] Graybill JR, Sobel J, Saag M, van Der Horst C, Powderly W, Cloud G, et al. Diagnosis and management of increased intracranial pressure in patients with AIDS and cryptococcal meningitis. The NIAID Mycoses Study Group and AIDS Cooperative Treatment Groups. Clin Infect Dis 2000;30:47—54. [10] Chen SC, Korman TM, Slavin MA, Marriott D, Byth K, Bak N, et al. Australia and New Zealand Mycoses Interest Group (ANZMIG) Cryptococcus Study. Clin Infect Dis 2013;57:543—51. [11] Franco-Paredes C, Womack T, Bohlmeyer T, Sellers B, Hays A, Patel K, et al. Management of Cryptococcus gattii meningoencephalitis. Lancet Infect Dis 2015;15:348—55. [12] 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.
Please cite this article in press as: Maciel R-A, et al. Corticosteroids for the management of severe intracranial hypertension in meningoencephalitis caused by Cryptococcus gattii: A case report and review. Journal De Mycologie Médicale (2016), http://dx.doi.org/ 10.1016/j.mycmed.2016.09.003
MYCMED-648; No. of Pages 4 Journal de Mycologie Médicale (2016) xxx, xxx—xxx
Available online at
ScienceDirect www.sciencedirect.com
CASE REPORT/CAS CLINIQUE
Corticosteroids for the management of severe intracranial hypertension in meningoencephalitis caused by Cryptococcus gattii: A case report and review ´ ve ` re Corticoı¨des pour la gestion de l’hypertension intracranial se ´ par Cryptococcus gattii : ´etude dans meningoencephalitis cause d’un cas et traitement R.-A. Maciel, L.-S. Ferreira, F. Wirth, P.-D. Rosa, M. Aves, E. Turra, L.-Z. Goldani * Section of Infectious Diseases, Hospital de Clı´nicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, Ramiro Barcelos, 2350, 90035-903 Porto Alegre, RS, Brazil Received 22 May 2016; received in revised form 15 September 2016; accepted 16 September 2016
KEYWORDS Cryptococcus gattii; Corticosteroids; Intracranial hypertension; Management
Summary Immune reconstitution inflammatory syndrome in meningitis caused by Cryptococcus gattii in immunocompetent patients after initiation of antifungal therapy appears to be the result of paradoxical antifungal treatment-induced clinical deterioration due to improved local immune responses to cryptococcal organisms. Recent anecdotal reports have suggested a favorable clinical response to corticosteroids in select patients with C. gattii central nervous system (CNS) infections. In this report, we describe a 65-year-old patient with meningoencephalitis caused by C. gattii who developed persistent intracranial hypertension and was successfully managed with antifungal therapy, repeated lumbar puncture and corticosteroids. Our observations suggest a possible benefit of dexamethasone in the management of select cases of C. gattii CNS infection with intracranial hypertension. Further studies are necessary to evaluate the long-term use of steroids in select patients with C. gattii with intracranial hypertension. # 2016 Elsevier Masson SAS. All rights reserved.
* Corresponding author. E-mail address: [email protected] (L.Z. Goldani). http://dx.doi.org/10.1016/j.mycmed.2016.09.003 1156-5233/# 2016 Elsevier Masson SAS. All rights reserved.
Please cite this article in press as: Maciel R-A, et al. Corticosteroids for the management of severe intracranial hypertension in meningoencephalitis caused by Cryptococcus gattii: A case report and review. Journal De Mycologie Médicale (2016), http://dx.doi.org/ 10.1016/j.mycmed.2016.09.003
+ Models
MYCMED-648; No. of Pages 4
2
R.-A. Maciel et al.
MOTS CLÉS Cryptococcus gattii ; Corticoïdes ; Hypertension intracrânienne ; Traitement
Re ´sume ´ Le syndrome inflammatoire de reconstitution immunitaire dans la méningite au Cryptococcus gattii se manifeste fréquemment chez les patients immunocompétents après la mise en place d’un traitement antifongique. Il semble résulter d’un traitement antifongique paradoxal — une détérioration clinique induite liée à l’amélioration des réponses immunitaires locales aux cryptocoques. De récents rapports anecdotiques ont suggéré une réponse clinique favorable aux corticostéroïdes chez certains patients atteints d’une infection du système nerveux central (SNC) par C. gattii. Dans ce rapport, nous décrivons un patient âgé de 65 ans, atteint de méningo-encéphalite à C. gattii, qui a développé une hypertension intracrânienne persistante et a pu être soigné avec succès par un traitement à base d’antifongiques, de ponctions lombaires répétées et de corticostéroïdes. Nos observations suggèrent un bénéfice possible de la dexaméthasone dans la gestion de certains cas d’infection du SNC par C. gattii accompagnée d’hypertension intracrânienne. Des études plus poussées seront nécessaires pour évaluer l’utilisation à long terme de stéroïdes chez certains patients atteints d’hypertension intracrânienne liée au C. gatti. # 2016 Elsevier Masson SAS. Tous droits réservés.
Introduction Cryptococcosis is a fungal disease caused by Cryptococcus neoformans and C. gattii [1,2]. The fungal disease is caused by inhalation and subsequent pulmonary infection and may disseminate to the CNS and cause meningitis or meningoencephalitis. Cryptococcosis due to C. gattii is usually described in immunocompetent patients. Characteristics of C. gattii central nervous infection (CNS) and pulmonary disease include a higher rate of space-occupying lesions and longterm sequelae compared with C. neoformans disease [3]. There is evidence of immune reconstitution inflammatory syndrome in C. gattii infection in immunocompetent patients after initiation of antifungal therapy. This syndrome appears to be the result of paradoxical antifungal treatmentinduced clinical deterioration due to improved local immune responses to cryptococcal organisms [4]. Recent anecdotal reports have suggested a favorable clinical response to corticosteroids in selected patients with C. gattii CNS infection [5—7]. In this report, we describe the management of intracranial hypertension with corticosteroids in a patient with C. gattii meningoencephalitis.
Case report A 65-year-old Brazilian man was referred to a tertiary care hospital for evaluation of headache, fatigue, weight loss, and a progressive hearing deficit. The patient lived in a rural area in southern Brazil and depended on agriculture and related activities for his income. His past medical history was relevant for arterial hypertension, depression and thyroidectomy for nodular thyroid disease. The patient was initially admitted in a local hospital in his hometown and referred to this hospital for management of meningitis. Vital signs included a temperature of 37 8C, a heart rate of 127 beats/min, a respiratory rate of 17 breaths/min, a blood pressure of 118/57 mmHg, and a room air oxygen saturation of 98%. The patient was well-developed but appeared chronically ill. His neck was supple without lymphadenopathy. The oral cavity and pharynx showed normal mucosa and good dental hygiene. Cardiovascular examination revealed tachycardia without murmur, and both lungs were clear to auscultation. The
abdomen was soft, flat and non-tender with no hepatosplenomegaly. The skin was warm and dry. Despite left-side hearing loss, neurological examination revealed intact cranial nerves, motor function (normal tone coordination and muscle strength against resistance) and symmetrical deep tendon reflexes. Laboratory examination revealed that the patient had a white blood cell (WBC) count of 9140/L (4000—10,000/ L) with neutrophil predominance and a hematocrit of 39% (41—50%). An ELISA for HIV was negative, and chest radiography revealed a right upper-lobe lesion. A gadoliniumenhanced MRI scan of the brain revealed multiple enhancing lesions within the cerebral hemispheres, brainstem and cerebellum, consistent with gelatinous pseudocysts. Lumbar puncture revealed an opening pressure of 32.5 cm H2O (normal range 5 to 20 cm H2O) with colorless cerebral spinal fluid (CSF) with a WBC count of 64/mL (0—5/mL) (6% monocytes, 94% lymphocytes), low glucose of 20 mg/dL (40—85 mg/dL), and elevated protein level of 165 mg/dL (15—45 mg/dL). CSF cryptococcal antigen titer was positive (> 1:10,000). Because 5-fluorocytosine is not available in Brazil, the patient was immediately given intravenous amphotericin B deoxycholate (60 mg/day) and fluconazole (800 mg/day). Several days later, C. gattii was observed in CSF culture. Molecular analysis performed as described previously revealed that the C. gattii isolate belonged to genotype VGII, serotype B [8]. The minimum inhibitory concentrations (MICs) using the NCCLS reference indicated that the strain was sensitive to amphotericin B (MIC = 1.0 mg/mL), fluconazole (4 mg/mL), itraconazole (1.0 mg/mL), and voriconazole (0.03 mg/mL). Resistance to antifungal agents was observed for fluconazole ( 64 mg/mL), itraconazole and voriconazole ( 1.0 mg/mL), and amphotericin B ( 2.0 mg/mL). C. gattii was isolated in bronchoalveolar lavage. In addition to antifungal therapy, the patient was managed with multiple lumbar punctures to relieve intracranial hypertension. Despite these interventions, the patient presented persistent headaches and vomiting, and intravenous dexamethasone 4 mg every 6 hours was initiated. As shown in Figs. 1 and 2, the patient presented substantial improvement of brain lesions and intracranial hypertension after starting dexamethasone. After 98 days of hospitalization, the patient was clinically stable and discharged with fluconazole 900 mg/day and prednisone 60 mg/day (with a plan of tapering over time
Please cite this article in press as: Maciel R-A, et al. Corticosteroids for the management of severe intracranial hypertension in meningoencephalitis caused by Cryptococcus gattii: A case report and review. Journal De Mycologie Médicale (2016), http://dx.doi.org/ 10.1016/j.mycmed.2016.09.003
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MYCMED-648; No. of Pages 4
Meningoencephalitis caused by C. gattii and corticosteroids
3
Figure 2 Intracranial pressures during hospitalization of the patient with Cryptococcus gattii meningoencephalitis. Period of hospitalization (total of 98 days). Arrow indicates start day of corticosteroids (dexamethasone 16 mg/day). Normal opening pressure (normal range 5 to 20 cm H2O). ˆ niennes pendant l’hospitalisation du paLes pressions intracra ´ ningo. tient avec C. gattii me
68 mg/dL, and a protein level of 48 mg/dL. Culture of the CSF was negative. The patient was started on amphotericin B lipid complex 150 mg/day and fluconazole 400 mg/day and underwent ventriculoperitoneal derivation. Despite negative CSF cultures and controlled intracranial pressure, the patient died of infectious complications related to the surgical procedure and prolonged hospitalization.
Comments
Figure 1 Brain MRI showing improvement of the Cryptococcus gattii brainstem enhancing lesion after starting steroids (arrow). Before dexamethasone (A); after 10 days of dexamethasone (B). ´ re ´ brale montrant une ame ´ lioration du C. gattii brainstem IRM ce ´ e apre ` s le de ´ but des ste ´ roı¨des (fle ` che). Avant la ´ sion rehausse le ´ thasone (A) ; apre ` s 10 jours de dexame ´ thasone (B). dexame
to cease therapy). The patient was neurologically intact except for a continued mild bilateral hearing deficit. Lumbar puncture revealed an opening pressure of 19 cmH2O with colorless CSF containing 23 WBC/mL (100% lymphocytes), glucose of 48 mg/dL, and a protein level of 54 mg/dL. Three weeks later, the patient was admitted to the intensive care unit (ICU) with dizziness, gait disturbance and headaches. The patient was receiving fluconazole 900 mg/day while tapering oral prednisone at 10 mg/day. Lumbar puncture revealed an opening pressure of 32 cmH2O with colorless CSF containing 12 WBC/mL (100% lymphocytes), glucose of
CSF pressure control is a critical determinant of outcome in meningoencephalitis caused by Cryptococcus [9]. In the presence of persistent pressure elevation 25 cmH2O and related symptoms, daily repeated lumbar puncture is recommended until the CSF pressure and symptoms have stabilized [10—12]. Temporary percutaneous lumbar drains or ventriculostomy should be considered for patients who require repeated and prolonged daily lumbar punctures. Corticosteroids have been recommended for CNS inflammation with increased intracranial pressure due to immune reconstitution inflammatory response syndrome. However, this approach is reportedly of no benefit in HIV-infected patients and might increase mortality [9]. Previous reports have shown that corticosteroids may be beneficial in patients with C. gattii CNS infection who are not responding clinically to treatment with an amphotericin B formulation plus 5-fluorocytosine in association with negative CSF culture and the development of new or worsening focal inflammatory brain lesions on follow-up imaging (Table 1) [5,6]. Philips et al. described a favorable clinical outcome in three of four patients with C. gattii CNS infection who received dexamethasone for the treatment of persisting mental status abnormalities and focal lesions on brain scan despite culture-negative CSF and management of intracranial pressure [6]. Interestingly, Seaton et al. reported in a retrospective study that visual deterioration occurred less frequently in patients with C. gattii meningitis receiving varying doses of corticosteroids, mainly 100—250 mg of hydrocortisone daily for the prevention of febrile reactions
Please cite this article in press as: Maciel R-A, et al. Corticosteroids for the management of severe intracranial hypertension in meningoencephalitis caused by Cryptococcus gattii: A case report and review. Journal De Mycologie Médicale (2016), http://dx.doi.org/ 10.1016/j.mycmed.2016.09.003
+ Models
MYCMED-648; No. of Pages 4
4
R.-A. Maciel et al. Table 1 Characteristics of the patients with Cryptococcus gattii meningoencephaltis treated with antifungal agents and corticosteroids. ´ s avec des agents anti-fongiques et des corticoste ´ roı ´ ristiques des patients avec C. gattii meningoencephaltis traite ¨des. Caracte Ref.
Age/sex
Brain imaging
Corticosteroids
Response to steroids
Treatment
Outcome
[6]
40/female
Caudate mass
Dexamethasone
46/female
Dexamethasone
[6]
63/male
[6]
62/male
Basal ganglia lesions Posterior fossa lesion Negative
[5]
29/male
[7]
16 patients; 14—39 y (range) Ratio male: female 11:5 65/male
L-AMB-AMB + 5-Flu L-AMB-AMB + 5-Flu L-AMB-AMB + 5-Flu L-AMB-AMB + 5-Flu AMB + 5-Flu; VP shunt AMB + 5-Flu
Alive
[6]
Improved mental lesion size Improved mental lesion size Improved mental lesion size Improved mental
Present
Infarction of the right caudate NA
Cerebral hemisphere brainstem and cerebelum lesions
Dexamethasone Dexamethasone Dexamethasone/ prednisone Low dose hydrocortisone to avoid AMB febrile reactions Dexamethasone/ prednisone
status; status; status; status
Improved lower limb function; headaches Decreased visual deterioration
Improved headaches, lesion size, ICH relapse on tapering steroids
AMB-L + FLZ
Alive Death Alive Alive Alive
Death
ICH: intracranial hypertension; AMB: amphotericin B deoxyxholate; AMB-L: lipid formulation of amphotericin B; FLZ: fluconazole; 5-FLU, 5flucytosine; VP: ventriculoperitoneal.
to amphotericin B, compared to those not receiving corticosteroids [7]. However, risk considerations include the potential adverse effects of systemic corticosteroids. Moreover, corticosteroids should not be substituted as a measure to control increased intracranial pressure where serial lumbar punctures or a CSF shunting procedure may be indicated, particularly in the presence of inflammatory cerebral lesions. Consistent with previous reports, the clinical course, imaging findings, and marked clinical response to corticosteroids of our patient were consistent with an antifungal therapy-induced paradoxical clinical deterioration related to improved local immune responses to C. gattii organisms. Unfortunately, intracranial hypertension recurred in the patient while tapering corticosteroids despite negative CSF cultures for C. gattii. Our observations suggest a possible benefit of dexamethasone in the management of selected cases of C. gattii CNS infection. Further studies are necessary to evaluate the long-term use of steroids in select patients with C. gattii with intracranial hypertension.
Disclosure of interest The authors declare that they have no competing interest.
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Please cite this article in press as: Maciel R-A, et al. Corticosteroids for the management of severe intracranial hypertension in meningoencephalitis caused by Cryptococcus gattii: A case report and review. Journal De Mycologie Médicale (2016), http://dx.doi.org/ 10.1016/j.mycmed.2016.09.003