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Chronic Meningitis and Hydrocephalus due to Sporothrix brasiliensis in Immunocompetent Adults: A Challenging Entity

Chronic Meningitis and Hydrocephalus due to Sporothrix brasiliensis in Immunocompetent Adults: A... Downloaded from https://academic.oup.com/ofid/article-abstract/5/5/ofy081/4989858 by Ed 'DeepDyve' Gillespie user on 18 October 2019 Open Forum Infectious Diseases BRIEF REPORT nonimmunocompromised adults and highlight the challenges Chronic Meningitis and Hydrocephalus in diagnosing and managing these cases. due to Sporothrix brasiliensis CASE 1 in Immunocompetent Adults: A previously healthy 46-year-old male presented in January A Challenging Entity 2016 with a 1-month history of headaches, retro-orbital pain, 1,2 3,4 5 Rafael Mialski, João Nóbrega de Oliveira Jr., Larissa Honorato da Silva, 6 7 8 episodes of confusion, and gait impairment. His previous med- Adriana Kono, Rosangela Lameira Pinheiro, Manoel Jacobsen Teixeira, 9 2 10 Renata Rodrigues Gomes, Flávio de Queiroz-Telles, Fernando Gomes Pinto, and ical history was unremarkable, and he denied alcohol use. The Gil Benard patient was from the countryside of Paraná Sate, where he was 1 2 Ônix Hospital, Paraná State Health Department, Curitiba, Brazil; Infectology Sector, Clinics 3 a quarry worker. Initial investigation showed a cerebrospinal Hospital, Federal University of Paraná, Curitiba, Brazil; Central Laboratory Division, LIM-03, Clinics Hospital, São Paulo University, São Paulo, Brazil; Laboratory of Medical Mycology, LIM-53, Clinics fluid (CSF) with very mild mononuclear pleocytosis (7 cells/ Hospital and Tropical Medicine Institute, São Paulo University, São Paulo, Brazil; Microbiology 3 mm ), low glucose (12 mg/dL), and elevated protein (148 mg/ Sector, Bom Jesus Laboratory, Curitiba, Brazil; Infectious Diseases Division, Clinics Hospital, São Paulo University, São Paulo, Brazil; Micology Laboratory, Clinics Hospital, Federal University of dL), but negative microbiological analyses. Magnetic resonance Paraná, Curitiba, Brazil; Neurology Department, Clinics Hospital, São Paulo University, São Paulo, imaging (MRI) revealed basal meningitis (Figure 1A). Because 9 10 Brazil; Microbiology Laboratory, Federal University of Paraná, Curitiba, Brazil; Neurosurgery tuberculosis is highly endemic in Brazil, he was empirically Department, Clinics Hospital, Medical School, São Paulo University, São Paulo, Brazil treated for tuberculous meningitis with the standard regimen Chronic meningitis caused by Sporothrix sp. is occasionally for 4 months, without showing signs of improvement. described in immunosuppressed patients. We report the chal- On readmission, the patient was wheelchair bound due to lenges in diagnosing and managing 2 nonimmunocompro- motor weakness and lack of balance and was confused and mised patients with hydrocephalus and chronic meningitis disoriented. MRI showed hydrocephalus, and a ventriculoper- caused by Sporothrix brasiliensis. This more virulent species itoneal shunt (VPS) placement was indicated. This procedure appears to contribute more atypical and severe cases than other resulted in partial neurological improvement. The patient was related species. discharged from the hospital but kept on antituberculosis ther- Keywords. Sporotrichosis; Sporothrix brasiliensis; chronic apy. HIV serology was negative. The patient presented relapses meningitis; hydrocephalus; virulence; CNS of the central nervous system (CNS) manifestations that were caused by obstruction of the CSF pathway secondary to for- mation of a pseudocyst around the peritoneal tip of the shunt, Chronic meningitis caused by Sporothrix spp. has occasionally which accumulated large volumes of CSF. The CSF pathway was been described in patients with immunosuppression from al- reestablished each time via a surgical procedure; 3 consecutive cohol abuse, cirrhosis, transplantation, diabetes, and Hodgkin’s CSF samples were collected and showed mild mononuclear ple- disease. It has recently been increasingly reported in AIDS ocytosis, low glucose, and elevated protein; all were negative on patients as part of a cat-associated epidemic of sporotrichosis direct mycological exam (DME), but 2 yielded Sporothrix sp. in Rio de Janeiro State, Brazil [1, 2]. Sporotrichosis has there- e i Th solate was subsequently identified as S.  brasilien- fore been suggested as a differential diagnosis of chronic men- sis by DNA sequencing of the calmodulin gene (GenBank ingitis in immunosuppressed patients living in endemic or MG869808). The patient was treated with amphotericin deox- hyperendemic sporotrichosis areas [3]. The clinical outcomes of ycholate (accumulated dose 2  g), with good clinical response. chronic meningitis due to Sporothrix sp. in immunosuppressed As neither itraconazole nor serum level monitoring was avail- patients are poor, with an overall 50% mortality rate [1]. We able [4], he was treated with fluconazole (800 mg/d), scheduled present 2 cases of hydrocephalus due to unsuspected chronic for 1  year; no relapses were recorded at the time of writing. meningoencephalitis caused by Sporothrix brasiliensis in However, the patient presented neurological sequelae (ataxia Received 13 March 2018; editorial decision 9 April 2018; accepted 13 April 2018. and extrinsic ocular motor paresis related to basal meningitis), Correspondence: G. Benard, MD, PhD, Av Dr Eneas de Carvalho Aguiar 470, CEP 05403-000, which are slowly improving. São Paulo, Brasil (bengil60@gmail.com). Open Forum Infectious Diseases CASE 2 © The Author(s) 2018. Published by Oxford University Press on behalf of Infectious Diseases Society of America. This is an Open Access article distributed under the terms of the Creative Case 2 was a previously healthy 40-year-old male with progres- 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 sive weight loss and lethargy dating from October 2016. He was medium, provided the original work is not altered or transformed in any way, and that the work a farmer in the countryside of Bahia State. He had been treated is properly cited. For commercial re-use, please contact journals.permissions@oup.com DOI: 10.1093/ofid/ofy081 for “depression,” but his symptoms evolved, with headaches, BRIEF REPORT • OFID • 1 Downloaded from https://academic.oup.com/ofid/article-abstract/5/5/ofy081/4989858 by Ed 'DeepDyve' Gillespie user on 18 October 2019 A B C Figure 1. Magnetic resonance imaging (MRI) and computed tomography (CT) scan of the brain and direct mycological exam of cerebrospinal fluid (CSF). A, Pretreatment (March 2016) brain T1-weighted MRI of patient 1 showing hydrocephalus and skull base meningeal contrast enhancement. B, Pretreatment (May 2017) CT scan of the brain of patient 2 showing communicating hydrocephalus and transependymal edema without anomalous intraparenchymal contrast enhancement or intraparenchymal lesions. C, Upper image: baseline CSF direct mycological exam (August 2017) of patient 2 showing yeast cells suggestive of Sporothrix sp. free (thin arrows) or engulfed by macrophages (thick arrows). Lower image: calcofluor white staining of patient 2’s CSF sample collected on August 2017, showing a yeast aggregate surrounded by extracellular matrix suggestive of a biofilm-like structure. D, fibrin sheath on the tip of the ventriculoperitoneal shunt removed (August 2017) from patient 2: culture of the material from the tip yielded Sporothrix sp., subsequently identified by molecular method as S. brasiliensis. vomiting, and confusion. He was HIV-negative and denied al- were negative) was made. This led to empirical treatment with cohol abuse. In April 2017, a cranial computed tomography vancomycin and ceftazidime; abdominal symptoms improved scan showed hydrocephalus and signs suggestive of mild men- significantly. CSF analysis at this time showed 12 mono- ingeal enhancement in some areas (posterior fossa) (Figure 1B). nuclear cells, glucose 53  mg/dL, and protein 43  mg/dL; how- CSF analysis revealed glucose 40 mg/dL, protein 48 mg/dL, and ever, DME yielded yeast forms, and culture revealed Sporothrix mild pleocytosis (8 mononuclear cells/mm ); microbiology tests sp. (Figure  1C). The peritoneal tip of the VPS showed a fibrin were negative. The patient received a provisional diagnosis of sheath (Figure  1D), which was also positive for Sporothrix sp. idiopathic hydrocephalus and received a VPS. Hydrocephalus on culture. Molecular identification revealed the species S. bra- improved, and the patient was discharged but required a subse- siliensis (GenBank MG867724), as in case 1.  e c Th atheter was quent neurosurgical procedure to reestablish the CSF pathway. removed, and a new VPS was positioned. A qualitative immu- He was referred to our service in August 2017 because of nolectrophoresis test for anti-Sporothrix antibodies yielded obstruction of the VPS and abdominal discomfort and distension. positive results in serum and CSF. As with patient 1, a peritoneal pseudocyst with 1500 mL of However, the patient’s follow-up was complicated. Subsequent CSF was found, and a clinical hypothesis of peritonitis due to episodes of obstruction accompanied by recrudescence of hydro- secondary bacterial infection (although cultures for bacteria cephalus required successive neurosurgical procedures, including 2 • OFID • BRIEF REPORT Downloaded from https://academic.oup.com/ofid/article-abstract/5/5/ofy081/4989858 by Ed 'DeepDyve' Gillespie user on 18 October 2019 a neuro-endoscopic ventricular septostomy and, ultimately, a ven- been described [1, 6]. The patients in this report followed this triculoatrial shunt with 2 proximal catheters with a Y-connector. pattern, with case 1 presenting more prominent CSF alterations e p Th atient was started on amphotericin deoxycholate, but attempts than case 2.  Brain imaging, when reported, was either normal to move to itraconazole failed because of the development of severe or showed meningeal enhancement; in a few patients there were pharmacodermy. The patient remains hospitalized, receiving lipo- signs of vasculitis and infarcts. Parenchymal lesions were occa- somal amphotericin and monitoring of hydrocephalus. All subse- sionally described, mostly in immunosuppressed, HIV-infected quent CSF analyses were negative for Sporothrix but still presented patients [1, 7]. mild biochemical and cellular abnormalities, with the exception of In light of the lack of awareness of Sporothrix sp. as a cause the most recent (December 2017), which was normal. of chronic meningitis and the difficulties in obtaining positive fungal cultures from CSF in meningeal sporotrichosis, Scott DISCUSSION et  al. [6] recommended, 30  years ago, systematic serological testing of the CSF for antibodies to Sporothrix sp. when inves- The presented cases highlight the challenges in diagnosing and tigating chronic meningitis cases with difficult etiological diag- managing chronic meningitis caused by Sporothrix brasiliensis. noses. In Brazil, serological testing is restricted to a few research Although currently unusual, this issue will likely be of growing laboratories. Our laboratory (LIM-53) developed a qualitative importance due to the continuous expansion of the sporotrich- immunoelectropheresis test for detecting anti-Sporothrix sp. osis epidemic in Brazil, which is causing atypical and more se- serum antibodies in the 1980s, which will now be included in vere cases [5]. The diagnosis was delayed in both patients; they the screening panel for deep mycoses (histoplasmosis, asper- neither presented clinico-laboratorial evidence of immunosup- gillosis paracoccidioidomycosis). This test was performed in pression nor were from municipalities where cases of human or patient 2, yielding positive results in serum and CSF. However, feline sporotrichosis had been previously reported, according to despite its high specificity, it still has low sensitivity (≤40%) and the local health authorities. However, a case of cutaneous sporo- needs improvement. The importance of serological diagnosis trichosis was documented in patient 1’s municipality several was recently demonstrated by a case report, which could only months after the presented case, likely transmitted by a cat with be diagnosed through CSF antibody detection [7]. an illness typical of sporotrichosis. Unfortunately, the animal e co Th nditions of both patients were and still are difficult could not be located for confirmation. In neither case was CNS to manage. Although they presented very mild CSF pleocyto- involvement preceded by manifestations of cutaneous-lymphatic sis, they evolved with hydrocephalus and required ventricular sportrichosis or associated disseminated disease. In immuno- shunts. Moderate hydrocephalus was also present in several suppressed patients, CNS involvement is commonly part of a of the patients described in the literature [1], but placement constellation of manifestations suggestive of hematogenous dis- of VPS was not frequently reported, except in Scott et al.’s case semination [2, 3]. Therefore, case 1 was empirically treated for series, where 5 of the 7 patients underwent VPS; only 1 of these tuberculosis for more than 4 months, whereas case 2 was diag- patients died, a patient with a 6-month-delayed diagnosis who nosed as idiopathic hydrocephalus 8  months before Sporothrix could only be treated with a small amount of amphotericin brasiliensis was isolated from CSF. These 2 cases are similar to B [6]. More recently, Freitas et  al. [2] reported that 2 of the 4 those previously described in the literature with regards to both HIV-infected patients from the hyperendemic area of Rio de the difficulty in recovering the agent from the CSF [1, 2, 6, 7] Janeiro died of hydrocephalus complications; however, it was and the delay in starting appropriate treatment, likely worsening not mentioned whether these patients underwent VPS. In the the prognosis. Published cases refer to several weeks to many patients in this study, the ventricular shunts were very difficult months from initial symptom presentation to identification of to manage due to frequent obstructions, requiring successive the fungus [1]. The usual scenario is that of a patient present- surgical interventions to restore the CSF pathway, indicating the ing the clinical syndrome of chronic meningitis, manifested presence of a significant and persistent local inflammatory reac- initially by headache that progressed to lethargy, confusion, or tion. Both patients responded to treatment; however, patient 1 other less frequent manifestations such as vomiting, seizures, developed ataxia and extrinsic ocular motor paresis secondary gait disturbances, and other neurological deficits. It is note- to basal meningitis, from which he has yet to recover. Patient 2 worthy, like in the cases reported here, that fever was not always remains hospitalized on antifungal therapy and in the process of present. Preceding or associated cutaneous-lymphatic sporo- neurological rehabilitation. trichosis was also not always present, particularly in nonimmu- It is not known how Sporothrix sp. reaches the CNS. In im- nocompromised patients. Moreover, most patients, like these, munosuppressed patients, it is speculated that it is caused by did not report a history of unusual environmental exposure to hematogenic spread in the setting of a disseminated disease [1– Sporothrix sp. CSF analysis is also indistinguishable from that 3]. However, this would not apply to nonimmunocompromised of chronic meningitis caused by other agents: elevated protein patients without disseminated disease. An attractive yet specula- and low glucose levels were generally described, as well as low tive hypothesis relies on the recent discovery that the CNS has a to moderate pleocytosis, although cases with 0 cells have already BRIEF REPORT • OFID • 3 Downloaded from https://academic.oup.com/ofid/article-abstract/5/5/ofy081/4989858 by Ed 'DeepDyve' Gillespie user on 18 October 2019 Potential coni fl cts of interest. G.B. is a senior researcher from CNPq. functional lymphatic system connected to the body’s lymphatic All authors: no reported conflicts of interest. All authors have submitted the system through deep cervical lymph nodes [8]. It is thus possible ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that that our patients acquired the infection through either the respira- the editors consider relevant to the content of the manuscript have been tory route or an unnoticed traumatic skin inoculation, and cells disclosed. from the initial local inflammatory response (eg, macrophages) that phagocytosed yeast cells would have migrated to the lymph- References 1. Galhardo MC, Silva MT, Lima MA, et al. Sporothrix schenckii meningitis in AIDS atic circulation and eventually reached the CNS through this during immune reconstitution syndrome. J Neurol Neurosurg Psychiatry 2010; pathway. Indeed, Figure 1C shows some CSF macrophages engulf- 81:696–9. 2. Freitas DF, Lima MA, de Almeida-Paes R, et al. Sporotrichosis in the central ner- ing yeast cells in patient 2. In addition, it has been suggested that, vous system caused by Sporothrix brasiliensis. Clin Infect Dis 2015; 61:663–4. at least in experimental models, S. brasiliensis is more virulent in 3. Moreira JAS, Freitas DFS, Lamas CC. The impact of sporotrichosis in HIV‐ vivo than the other species [9]. In vitro, it has also been shown that infected patients: a systematic review. Infection 2015; 43:267–76. 4. Kauffman CA, Bustamante B, Chapman SW, Pappas PG; Infectious Diseases Sporothrix brasiliensis has a greater ability to disarm murine mac- Society of America. Clinical practice guidelines for the management of sporo- rophages, promoting its survival within macrophages (L. Rossato, trichosis: 2007 update by the Infectious Diseases Society of America. Clin Infect Dis 2007; 45:1255–65. PhD, S. A. Almeida, PhD, 2017, unpublished data), and to form 5. Almeida-Paes R, de Oliveira MM, Freitas DF, et  al. Sporotrichosis in Rio de biolm fi s [10]. In fact, biolm-li fi ke structures were observed in pa- Janeiro, Brazil: Sporothrix brasiliensis is associated with atypical clinical presenta- tions. PLoS Negl Trop Dis 2014; 8:e3094. tient 2’s CSF (Figure 1C), which may help to explain the recurrent 6. Scott EN, Kaufman L, Brown AC, Muchmore HG. Serologic studies in the diag- hydrocephalus shunt catheter obstructions. nosis and management of meningitis due to Sporothrix schenckii. N Engl J Med 1987; 317:935–40. es Th e cases carry some potentially important messages: that 7. Hessler C, Kauffman CA, Chow FC. The upside of bias: a case of chronic menin- the Brazilian epidemic, due to the more virulent Sporothrix gitis due to Sporothrix schenckii in an immunocompetent host. Neurohospitalist brasiliensis, contributes more to atypical and unexpectedly 2017; 7:30–4. 8. Louveau A, Smirnov I, Keyes TJ, et al. Structural and functional features of central aggressive cases, even in nonimmunocompromised individuals nervous system lymphatic vessels. Nature 2015; 523:337–41. without a clear-cut epidemiological link, compared with pre- 9. Arrillaga-Moncrieff I, Capilla J, Mayayo E, et al. Different virulence levels of the species of Sporothrix in a murine model. Clin Microbiol Infect 2009; 15:651–5. vious outbreaks due to Sporothrix schenckii [11–14]; that sporo- 10. Brilhante RSN, de Aguiar FRM, da Silva MLQ, et al. Antifungal susceptibility of trichosis should come to mind in cases of chronic meningitis Sporothrix schenckii complex biofilms. Med Mycol. 2018; 56:297–306. 11. Govender NP, Maphanga TG, Zulu TG, et al. An outbreak of lymphocutaneous with complex etiological diagnosis; and that serological tests Sporotrichosis among mine-workers in South Africa. PLoS Negl Trop Dis 2015; should urgently be made widely available to enable earlier diag- 9:e0004096. 12. McGuinness SL, Boyd R, Kidd S, et al. Epidemiological investigation of an out- nosis, prevent severe CNS damage, and reduce mortality rates. break of cutaneous sporotrichosis, Northern Territory, Australia. BMC Infect Dis 2016; 16:16. Acknowledgments 13. Leads from the MMWR. Multistate outbreak of sporotrichosis in seedling han- We thank Gilda M.  B. Del Negro for the assistance in fungal gene dlers, 1988. JAMA 1988; 260:2806, 2811. sequencing, Mônica S. M. Vidal for the immunolectrophoresis assay, Daniel 14. Pappas PG, Tellez I, Deep AE, et al. Sporotrichosis in Peru: description of an area Ciampi for critical advices, and Justin H. Axel-Berg for English review. of hyperendemicity. Clin Infect Dis 2000; 30:65–70. 4 • OFID • BRIEF REPORT http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Open Forum Infectious Diseases Oxford University Press

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Abstract

Downloaded from https://academic.oup.com/ofid/article-abstract/5/5/ofy081/4989858 by Ed 'DeepDyve' Gillespie user on 18 October 2019 Open Forum Infectious Diseases BRIEF REPORT nonimmunocompromised adults and highlight the challenges Chronic Meningitis and Hydrocephalus in diagnosing and managing these cases. due to Sporothrix brasiliensis CASE 1 in Immunocompetent Adults: A previously healthy 46-year-old male presented in January A Challenging Entity 2016 with a 1-month history of headaches, retro-orbital pain, 1,2 3,4 5 Rafael Mialski, João Nóbrega de Oliveira Jr., Larissa Honorato da Silva, 6 7 8 episodes of confusion, and gait impairment. His previous med- Adriana Kono, Rosangela Lameira Pinheiro, Manoel Jacobsen Teixeira, 9 2 10 Renata Rodrigues Gomes, Flávio de Queiroz-Telles, Fernando Gomes Pinto, and ical history was unremarkable, and he denied alcohol use. The Gil Benard patient was from the countryside of Paraná Sate, where he was 1 2 Ônix Hospital, Paraná State Health Department, Curitiba, Brazil; Infectology Sector, Clinics 3 a quarry worker. Initial investigation showed a cerebrospinal Hospital, Federal University of Paraná, Curitiba, Brazil; Central Laboratory Division, LIM-03, Clinics Hospital, São Paulo University, São Paulo, Brazil; Laboratory of Medical Mycology, LIM-53, Clinics fluid (CSF) with very mild mononuclear pleocytosis (7 cells/ Hospital and Tropical Medicine Institute, São Paulo University, São Paulo, Brazil; Microbiology 3 mm ), low glucose (12 mg/dL), and elevated protein (148 mg/ Sector, Bom Jesus Laboratory, Curitiba, Brazil; Infectious Diseases Division, Clinics Hospital, São Paulo University, São Paulo, Brazil; Micology Laboratory, Clinics Hospital, Federal University of dL), but negative microbiological analyses. Magnetic resonance Paraná, Curitiba, Brazil; Neurology Department, Clinics Hospital, São Paulo University, São Paulo, imaging (MRI) revealed basal meningitis (Figure 1A). Because 9 10 Brazil; Microbiology Laboratory, Federal University of Paraná, Curitiba, Brazil; Neurosurgery tuberculosis is highly endemic in Brazil, he was empirically Department, Clinics Hospital, Medical School, São Paulo University, São Paulo, Brazil treated for tuberculous meningitis with the standard regimen Chronic meningitis caused by Sporothrix sp. is occasionally for 4 months, without showing signs of improvement. described in immunosuppressed patients. We report the chal- On readmission, the patient was wheelchair bound due to lenges in diagnosing and managing 2 nonimmunocompro- motor weakness and lack of balance and was confused and mised patients with hydrocephalus and chronic meningitis disoriented. MRI showed hydrocephalus, and a ventriculoper- caused by Sporothrix brasiliensis. This more virulent species itoneal shunt (VPS) placement was indicated. This procedure appears to contribute more atypical and severe cases than other resulted in partial neurological improvement. The patient was related species. discharged from the hospital but kept on antituberculosis ther- Keywords. Sporotrichosis; Sporothrix brasiliensis; chronic apy. HIV serology was negative. The patient presented relapses meningitis; hydrocephalus; virulence; CNS of the central nervous system (CNS) manifestations that were caused by obstruction of the CSF pathway secondary to for- mation of a pseudocyst around the peritoneal tip of the shunt, Chronic meningitis caused by Sporothrix spp. has occasionally which accumulated large volumes of CSF. The CSF pathway was been described in patients with immunosuppression from al- reestablished each time via a surgical procedure; 3 consecutive cohol abuse, cirrhosis, transplantation, diabetes, and Hodgkin’s CSF samples were collected and showed mild mononuclear ple- disease. It has recently been increasingly reported in AIDS ocytosis, low glucose, and elevated protein; all were negative on patients as part of a cat-associated epidemic of sporotrichosis direct mycological exam (DME), but 2 yielded Sporothrix sp. in Rio de Janeiro State, Brazil [1, 2]. Sporotrichosis has there- e i Th solate was subsequently identified as S.  brasilien- fore been suggested as a differential diagnosis of chronic men- sis by DNA sequencing of the calmodulin gene (GenBank ingitis in immunosuppressed patients living in endemic or MG869808). The patient was treated with amphotericin deox- hyperendemic sporotrichosis areas [3]. The clinical outcomes of ycholate (accumulated dose 2  g), with good clinical response. chronic meningitis due to Sporothrix sp. in immunosuppressed As neither itraconazole nor serum level monitoring was avail- patients are poor, with an overall 50% mortality rate [1]. We able [4], he was treated with fluconazole (800 mg/d), scheduled present 2 cases of hydrocephalus due to unsuspected chronic for 1  year; no relapses were recorded at the time of writing. meningoencephalitis caused by Sporothrix brasiliensis in However, the patient presented neurological sequelae (ataxia Received 13 March 2018; editorial decision 9 April 2018; accepted 13 April 2018. and extrinsic ocular motor paresis related to basal meningitis), Correspondence: G. Benard, MD, PhD, Av Dr Eneas de Carvalho Aguiar 470, CEP 05403-000, which are slowly improving. São Paulo, Brasil (bengil60@gmail.com). Open Forum Infectious Diseases CASE 2 © The Author(s) 2018. Published by Oxford University Press on behalf of Infectious Diseases Society of America. This is an Open Access article distributed under the terms of the Creative Case 2 was a previously healthy 40-year-old male with progres- 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 sive weight loss and lethargy dating from October 2016. He was medium, provided the original work is not altered or transformed in any way, and that the work a farmer in the countryside of Bahia State. He had been treated is properly cited. For commercial re-use, please contact journals.permissions@oup.com DOI: 10.1093/ofid/ofy081 for “depression,” but his symptoms evolved, with headaches, BRIEF REPORT • OFID • 1 Downloaded from https://academic.oup.com/ofid/article-abstract/5/5/ofy081/4989858 by Ed 'DeepDyve' Gillespie user on 18 October 2019 A B C Figure 1. Magnetic resonance imaging (MRI) and computed tomography (CT) scan of the brain and direct mycological exam of cerebrospinal fluid (CSF). A, Pretreatment (March 2016) brain T1-weighted MRI of patient 1 showing hydrocephalus and skull base meningeal contrast enhancement. B, Pretreatment (May 2017) CT scan of the brain of patient 2 showing communicating hydrocephalus and transependymal edema without anomalous intraparenchymal contrast enhancement or intraparenchymal lesions. C, Upper image: baseline CSF direct mycological exam (August 2017) of patient 2 showing yeast cells suggestive of Sporothrix sp. free (thin arrows) or engulfed by macrophages (thick arrows). Lower image: calcofluor white staining of patient 2’s CSF sample collected on August 2017, showing a yeast aggregate surrounded by extracellular matrix suggestive of a biofilm-like structure. D, fibrin sheath on the tip of the ventriculoperitoneal shunt removed (August 2017) from patient 2: culture of the material from the tip yielded Sporothrix sp., subsequently identified by molecular method as S. brasiliensis. vomiting, and confusion. He was HIV-negative and denied al- were negative) was made. This led to empirical treatment with cohol abuse. In April 2017, a cranial computed tomography vancomycin and ceftazidime; abdominal symptoms improved scan showed hydrocephalus and signs suggestive of mild men- significantly. CSF analysis at this time showed 12 mono- ingeal enhancement in some areas (posterior fossa) (Figure 1B). nuclear cells, glucose 53  mg/dL, and protein 43  mg/dL; how- CSF analysis revealed glucose 40 mg/dL, protein 48 mg/dL, and ever, DME yielded yeast forms, and culture revealed Sporothrix mild pleocytosis (8 mononuclear cells/mm ); microbiology tests sp. (Figure  1C). The peritoneal tip of the VPS showed a fibrin were negative. The patient received a provisional diagnosis of sheath (Figure  1D), which was also positive for Sporothrix sp. idiopathic hydrocephalus and received a VPS. Hydrocephalus on culture. Molecular identification revealed the species S. bra- improved, and the patient was discharged but required a subse- siliensis (GenBank MG867724), as in case 1.  e c Th atheter was quent neurosurgical procedure to reestablish the CSF pathway. removed, and a new VPS was positioned. A qualitative immu- He was referred to our service in August 2017 because of nolectrophoresis test for anti-Sporothrix antibodies yielded obstruction of the VPS and abdominal discomfort and distension. positive results in serum and CSF. As with patient 1, a peritoneal pseudocyst with 1500 mL of However, the patient’s follow-up was complicated. Subsequent CSF was found, and a clinical hypothesis of peritonitis due to episodes of obstruction accompanied by recrudescence of hydro- secondary bacterial infection (although cultures for bacteria cephalus required successive neurosurgical procedures, including 2 • OFID • BRIEF REPORT Downloaded from https://academic.oup.com/ofid/article-abstract/5/5/ofy081/4989858 by Ed 'DeepDyve' Gillespie user on 18 October 2019 a neuro-endoscopic ventricular septostomy and, ultimately, a ven- been described [1, 6]. The patients in this report followed this triculoatrial shunt with 2 proximal catheters with a Y-connector. pattern, with case 1 presenting more prominent CSF alterations e p Th atient was started on amphotericin deoxycholate, but attempts than case 2.  Brain imaging, when reported, was either normal to move to itraconazole failed because of the development of severe or showed meningeal enhancement; in a few patients there were pharmacodermy. The patient remains hospitalized, receiving lipo- signs of vasculitis and infarcts. Parenchymal lesions were occa- somal amphotericin and monitoring of hydrocephalus. All subse- sionally described, mostly in immunosuppressed, HIV-infected quent CSF analyses were negative for Sporothrix but still presented patients [1, 7]. mild biochemical and cellular abnormalities, with the exception of In light of the lack of awareness of Sporothrix sp. as a cause the most recent (December 2017), which was normal. of chronic meningitis and the difficulties in obtaining positive fungal cultures from CSF in meningeal sporotrichosis, Scott DISCUSSION et  al. [6] recommended, 30  years ago, systematic serological testing of the CSF for antibodies to Sporothrix sp. when inves- The presented cases highlight the challenges in diagnosing and tigating chronic meningitis cases with difficult etiological diag- managing chronic meningitis caused by Sporothrix brasiliensis. noses. In Brazil, serological testing is restricted to a few research Although currently unusual, this issue will likely be of growing laboratories. Our laboratory (LIM-53) developed a qualitative importance due to the continuous expansion of the sporotrich- immunoelectropheresis test for detecting anti-Sporothrix sp. osis epidemic in Brazil, which is causing atypical and more se- serum antibodies in the 1980s, which will now be included in vere cases [5]. The diagnosis was delayed in both patients; they the screening panel for deep mycoses (histoplasmosis, asper- neither presented clinico-laboratorial evidence of immunosup- gillosis paracoccidioidomycosis). This test was performed in pression nor were from municipalities where cases of human or patient 2, yielding positive results in serum and CSF. However, feline sporotrichosis had been previously reported, according to despite its high specificity, it still has low sensitivity (≤40%) and the local health authorities. However, a case of cutaneous sporo- needs improvement. The importance of serological diagnosis trichosis was documented in patient 1’s municipality several was recently demonstrated by a case report, which could only months after the presented case, likely transmitted by a cat with be diagnosed through CSF antibody detection [7]. an illness typical of sporotrichosis. Unfortunately, the animal e co Th nditions of both patients were and still are difficult could not be located for confirmation. In neither case was CNS to manage. Although they presented very mild CSF pleocyto- involvement preceded by manifestations of cutaneous-lymphatic sis, they evolved with hydrocephalus and required ventricular sportrichosis or associated disseminated disease. In immuno- shunts. Moderate hydrocephalus was also present in several suppressed patients, CNS involvement is commonly part of a of the patients described in the literature [1], but placement constellation of manifestations suggestive of hematogenous dis- of VPS was not frequently reported, except in Scott et al.’s case semination [2, 3]. Therefore, case 1 was empirically treated for series, where 5 of the 7 patients underwent VPS; only 1 of these tuberculosis for more than 4 months, whereas case 2 was diag- patients died, a patient with a 6-month-delayed diagnosis who nosed as idiopathic hydrocephalus 8  months before Sporothrix could only be treated with a small amount of amphotericin brasiliensis was isolated from CSF. These 2 cases are similar to B [6]. More recently, Freitas et  al. [2] reported that 2 of the 4 those previously described in the literature with regards to both HIV-infected patients from the hyperendemic area of Rio de the difficulty in recovering the agent from the CSF [1, 2, 6, 7] Janeiro died of hydrocephalus complications; however, it was and the delay in starting appropriate treatment, likely worsening not mentioned whether these patients underwent VPS. In the the prognosis. Published cases refer to several weeks to many patients in this study, the ventricular shunts were very difficult months from initial symptom presentation to identification of to manage due to frequent obstructions, requiring successive the fungus [1]. The usual scenario is that of a patient present- surgical interventions to restore the CSF pathway, indicating the ing the clinical syndrome of chronic meningitis, manifested presence of a significant and persistent local inflammatory reac- initially by headache that progressed to lethargy, confusion, or tion. Both patients responded to treatment; however, patient 1 other less frequent manifestations such as vomiting, seizures, developed ataxia and extrinsic ocular motor paresis secondary gait disturbances, and other neurological deficits. It is note- to basal meningitis, from which he has yet to recover. Patient 2 worthy, like in the cases reported here, that fever was not always remains hospitalized on antifungal therapy and in the process of present. Preceding or associated cutaneous-lymphatic sporo- neurological rehabilitation. trichosis was also not always present, particularly in nonimmu- It is not known how Sporothrix sp. reaches the CNS. In im- nocompromised patients. Moreover, most patients, like these, munosuppressed patients, it is speculated that it is caused by did not report a history of unusual environmental exposure to hematogenic spread in the setting of a disseminated disease [1– Sporothrix sp. CSF analysis is also indistinguishable from that 3]. However, this would not apply to nonimmunocompromised of chronic meningitis caused by other agents: elevated protein patients without disseminated disease. An attractive yet specula- and low glucose levels were generally described, as well as low tive hypothesis relies on the recent discovery that the CNS has a to moderate pleocytosis, although cases with 0 cells have already BRIEF REPORT • OFID • 3 Downloaded from https://academic.oup.com/ofid/article-abstract/5/5/ofy081/4989858 by Ed 'DeepDyve' Gillespie user on 18 October 2019 Potential coni fl cts of interest. G.B. is a senior researcher from CNPq. functional lymphatic system connected to the body’s lymphatic All authors: no reported conflicts of interest. All authors have submitted the system through deep cervical lymph nodes [8]. It is thus possible ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that that our patients acquired the infection through either the respira- the editors consider relevant to the content of the manuscript have been tory route or an unnoticed traumatic skin inoculation, and cells disclosed. from the initial local inflammatory response (eg, macrophages) that phagocytosed yeast cells would have migrated to the lymph- References 1. Galhardo MC, Silva MT, Lima MA, et al. Sporothrix schenckii meningitis in AIDS atic circulation and eventually reached the CNS through this during immune reconstitution syndrome. J Neurol Neurosurg Psychiatry 2010; pathway. Indeed, Figure 1C shows some CSF macrophages engulf- 81:696–9. 2. Freitas DF, Lima MA, de Almeida-Paes R, et al. Sporotrichosis in the central ner- ing yeast cells in patient 2. In addition, it has been suggested that, vous system caused by Sporothrix brasiliensis. Clin Infect Dis 2015; 61:663–4. at least in experimental models, S. brasiliensis is more virulent in 3. Moreira JAS, Freitas DFS, Lamas CC. The impact of sporotrichosis in HIV‐ vivo than the other species [9]. In vitro, it has also been shown that infected patients: a systematic review. Infection 2015; 43:267–76. 4. Kauffman CA, Bustamante B, Chapman SW, Pappas PG; Infectious Diseases Sporothrix brasiliensis has a greater ability to disarm murine mac- Society of America. Clinical practice guidelines for the management of sporo- rophages, promoting its survival within macrophages (L. Rossato, trichosis: 2007 update by the Infectious Diseases Society of America. Clin Infect Dis 2007; 45:1255–65. PhD, S. A. Almeida, PhD, 2017, unpublished data), and to form 5. Almeida-Paes R, de Oliveira MM, Freitas DF, et  al. Sporotrichosis in Rio de biolm fi s [10]. In fact, biolm-li fi ke structures were observed in pa- Janeiro, Brazil: Sporothrix brasiliensis is associated with atypical clinical presenta- tions. PLoS Negl Trop Dis 2014; 8:e3094. tient 2’s CSF (Figure 1C), which may help to explain the recurrent 6. Scott EN, Kaufman L, Brown AC, Muchmore HG. Serologic studies in the diag- hydrocephalus shunt catheter obstructions. nosis and management of meningitis due to Sporothrix schenckii. N Engl J Med 1987; 317:935–40. es Th e cases carry some potentially important messages: that 7. Hessler C, Kauffman CA, Chow FC. The upside of bias: a case of chronic menin- the Brazilian epidemic, due to the more virulent Sporothrix gitis due to Sporothrix schenckii in an immunocompetent host. Neurohospitalist brasiliensis, contributes more to atypical and unexpectedly 2017; 7:30–4. 8. Louveau A, Smirnov I, Keyes TJ, et al. Structural and functional features of central aggressive cases, even in nonimmunocompromised individuals nervous system lymphatic vessels. Nature 2015; 523:337–41. without a clear-cut epidemiological link, compared with pre- 9. Arrillaga-Moncrieff I, Capilla J, Mayayo E, et al. Different virulence levels of the species of Sporothrix in a murine model. Clin Microbiol Infect 2009; 15:651–5. vious outbreaks due to Sporothrix schenckii [11–14]; that sporo- 10. Brilhante RSN, de Aguiar FRM, da Silva MLQ, et al. Antifungal susceptibility of trichosis should come to mind in cases of chronic meningitis Sporothrix schenckii complex biofilms. Med Mycol. 2018; 56:297–306. 11. Govender NP, Maphanga TG, Zulu TG, et al. An outbreak of lymphocutaneous with complex etiological diagnosis; and that serological tests Sporotrichosis among mine-workers in South Africa. PLoS Negl Trop Dis 2015; should urgently be made widely available to enable earlier diag- 9:e0004096. 12. McGuinness SL, Boyd R, Kidd S, et al. Epidemiological investigation of an out- nosis, prevent severe CNS damage, and reduce mortality rates. break of cutaneous sporotrichosis, Northern Territory, Australia. BMC Infect Dis 2016; 16:16. Acknowledgments 13. Leads from the MMWR. Multistate outbreak of sporotrichosis in seedling han- We thank Gilda M.  B. Del Negro for the assistance in fungal gene dlers, 1988. JAMA 1988; 260:2806, 2811. sequencing, Mônica S. M. Vidal for the immunolectrophoresis assay, Daniel 14. Pappas PG, Tellez I, Deep AE, et al. Sporotrichosis in Peru: description of an area Ciampi for critical advices, and Justin H. Axel-Berg for English review. of hyperendemicity. Clin Infect Dis 2000; 30:65–70. 4 • OFID • BRIEF REPORT

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Published: May 1, 2018

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