- Email: [email protected]
Cerebral Trypanosomiasis in an Immunocompromised Patient: Case Report and Review of the Literature
Case Report
Cerebral Trypanosomiasis in an Immunocompromised Patient: Case Report and Review of the Literature Mayank Kaushal1, Saman Shabani1, Elizabeth J. Cochran2, Hasan Samra2, Nathan T. Zwagerman1
Key words Benznidazole - Chagas disease - Kinetoplasts - Trypanosoma cruzi -
Abbreviations and Acronyms CNS: Central nervous system CSF: Cerebrospinal fluid CT: Computed tomography ED: Emergency Department HIV: Human immunodeficiency virus MRI: Magnetic resonance imaging MTX: Methotrexate From the Departments of 1Neurosurgery and 2Pathology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA To whom correspondence should be addressed: Nathan T. Zwagerman, M.D. [E-mail: [email protected]]
- BACKGROUND:
We document a case of central nervous system infection with Trypanosoma cruzi.
- CASE
DESCRIPTION: An 88-year-old woman presented with altered mental status, right-sided weakness, and slurred speech. Her medical history was significant for methotrexate intake for rheumatoid arthritis, and she tested negative for human immunodeficiency virus. Magnetic resonance imaging of the brain showed bilateral thick and peripherally enhancing white matter lesions in the frontoparietal region with extensive surrounding vasogenic edema. A lumbar puncture revealed increased protein and lymphocytic pleocytosis, and needle biopsy highlighted brain necrosis, chronic inflammation, and numerous intracellular organisms suggestive of T. cruzi amastigotes. Despite treatment with benznidazole, the patient expired soon after presentation.
- CONCLUSION:
Chagas disease should be included in the differential diagnosis of an immunocompromised patient presenting with a central nervous system mass, meningoencephalitis, or focal neurologic signs.
Citation: World Neurosurg. (2019) 129:225-231. https://doi.org/10.1016/j.wneu.2019.05.260 Journal homepage: www.journals.elsevier.com/worldneurosurgery Available online: www.sciencedirect.com 1878-8750/$ - see front matter ª 2019 Elsevier Inc. All rights reserved.
INTRODUCTION An association between opportunistic parasitic infections and compromised immunity, presumably due to disease reactivation, is commonly observed.1,2 Chagas disease, also known as American trypanosomiasis, is one such infection, caused by Trypanosoma cruzi, a flagellate protozoan endemic to Latin America. There are few reported cases of T. cruzi meningoencephalitis from North America published in the literature. The rare occurrence of this infection in the clinical setting in the United States and the similarity of presenting symptoms to toxoplasmosis (caused by Toxoplasma gondii) often lead to delays in correct diagnosis and initiation of specific treatment. Consequently, even though drugs to treat T. cruzi infection are available, Chagas disease is associated with a high mortality rate.3,4 This underscores the importance of including T. cruzi infection in the differential diagnosis in patients with a
compromised immune system who present with a clinical syndrome resembling central nervous system (CNS) toxoplasmosis. Here we report a patient with immunosuppression and review the published cases of Chagas disease. To our knowledge, this is the first reported case of a patient presenting with meningoencephalitis most likely caused by reactivation of Chagas disease. The number of clinical investigations performed to determine the correct diagnosis in this patient highlights the challenge of diagnosing Chagas disease in a timely manner and the consequences associated with delayed initiation of treatment for Chagas disease. CASE REPORT An 88-year-old female with a previous medical history of rheumatoid arthritis treated with methotrexate (MTX), transient ischemic attack, hypertension, fungal otitis, and history of travel to Oklahoma and Texas presented to our hospital with altered mental status, rightsided weakness, and slurred speech. She had been seen 3 days before this Emergency Department (ED) visit, with altered
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mental status and right-sided weakness. Imaging had been negative for stroke, and brain magnetic resonance imaging (MRI) was obtained, which was concerning for MTX toxicity (Figure 1). Her MTX was discontinued at that ED visit. Repeat MRI was obtained at the current ED visit (Figure 2), which showed bilateral thick and peripherally enhancing white matter lesions in the frontoparietal region with extensive surrounding vasogenic edema. The edema and mass effect had progressed compared with the previous MRI despite the low serum MTX level obtained at the second presentation to the ED. She was admitted and placed on continuous electroencephalography, which was negative for seizure activity. Magnetic resonance spectroscopy was nondiagnostic owing to significant motion artifact. Lumbar puncture was performed, which showed increased protein and lymphocytic pleocytosis; however, flow cytometry results were negative. She underwent needle biopsy, which showed brain necrosis, chronic inflammation, and numerous intracellular organisms suggestive of T. cruzi amastigotes (Figure 3). Kinetoplasts were
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Figure 1. Brain magnetic resonance imaging without contrast showing bilateral signal abnormalities involving frontal and parietal white matter with minimal mass effect.
CEREBRAL TRYPANOSOMIASIS IN AN IMMUNOCOMPROMISED PATIENT
identified within the organisms (Figure 4). Multitarget real-time polymerase chain reaction for T. cruzi performed according to Centers for Disease Control and Prevention recommendations was positive for T. cruzi. Treatment with nenznidazole was started in accordance with the Centers for Disease Control and Prevention recommendation. CD4 and CD8 panels to assess for occult immunodeficiency demonstrated very low CD4 (34 cells/mm3) and CD8 (12 cells/mm3) cell counts in the setting of human immunodeficiency virus (HIV) negativity. Shortly after diagnosis, the patient became hypoxic to 87% on room air and hypotensive to 69/56 mmHg. She was transferred to the intensive care unit. A chest radiograph showed significant interstitial and patchy opacifies concerning for aspiration pneumonia. After
Figure 2. Repeat brain magnetic resonance imaging (MRI) with contrast showing bilateral thick peripherally enhancing white matter lesions centered within the frontoparietal regions (A) with extensive surrounding vasogenic edema as seen on T2-weighted fluid-attenuated inversion recovery (B, D). The edema and mass effect had progressed compared with the previous MRI (Figure 1). Some restriction signal is noted on the diffusion weighted imaging (C).
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discussion with the family, the decision was made to withdraw treatment. DISCUSSION Clinical Presentation This literature review focuses on the CNS manifestations of Chagas disease (American trypanosomiasis). We searched individual case reports, case series, and reviews pertaining to CNS presentation in Chagas disease. The involvement of CNS in Chagas disease can be classified as acute disease, chronic disease, or reactivated acute nervous form in the intermediate or chronic stage. In addition, some patients demonstrate cerebral changes due to ischemia from chronic chagasic cardiopathy, which, although not associated with direct infection of the CNS, produces clinical sequelae in the nervous system. The clinical manifestations of Chagas disease vary widely. Factors theorized as responsible include the quantity of parasites, size of inoculum of T. cruzi in the initial infection, host immune response, and lineage of T. cruzi.5-7 Depending on the combination of some of the mentioned factors, the initial acute disease can range from a mild infection with few or no symptoms to a severe presentation of chagasic encephalitis.6,8 Of note, only a small number of patients infected with T. cruzi go on to develop encephalitis, the majority of whom are 2 years old or younger.9 In a subset of cases, reactivation of acute nervous form of Chagas disease is seen in previously asymptomatic patients, most if not all of whom share the common underlying finding of immunosuppression (Table 1). The immunocompromised state can be due to various causes, such as organ transplantation, use of such drugs as immunosuppressants and corticosteroids, and, most significantly and frequently, HIV infection.6,51 CNS involvement in the reactivated form of Chagas disease is characterized by fever, headache, seizures, and focal neurologic signs.6,51 Involvement of the CNS in chronic Chagas disease infection is controversial, with rare accounts of such findings as dementia, confusion, chronic encephalopathy, and sensorial and motor deficits.52 Macroscopic and Histopathological Findings The macroscopic picture in Chagas disease varies with the phase of disease
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macrophages, lymphocytes, and plasma cells.6 The chronic nervous form is characterized by presence of a few small, hypocellular, thinly distributed inflammatory nodules associated with few parasites, raising the possibility of these nodules representing sequelae of acute inflammatory lesions of a residual nature.9
Figure 3. T. cruzi amastigotes (circles) in a background of necrotic brain tissue and mixed inflammatory cells (hematoxylin and eosin stain; original magnification 500).
presentation. In the acute nervous form of Chagas disease, edema, congestion, and scattered petechial hemorrhages are frequently encountered. On histopathological examination, encephalitis involving multiple locations throughout the CNS is observed, comprising multiple cell types such as microglia, macrophages, neutrophils, and astrocytes in a nodular arrangement, with the amastigote form of parasite residing within astrocytes.6,8 The inflammatory foci are always associated with lymphomonocytic leptomeningitis and also may be associated with degenerative
changes to nerve cells located in the vicinity. In cases of CNS involvement due to disease reactivation, the encephalitic lesions are not clearly demarcated and are associated with the development of a necrotizing component and the presence of a large number of amastigotes.9 In some of these patients, a characteristic tumoral or pseudotumoral form (brain “chagoma”), comprising necrotic-hemorrhagic nodular lesions commonly located in brain white matter, is observed. These lesions show histological findings of necrosis, hemorrhage, microglial nodules, and exudates of
Figure 4. T. cruzi amastigote (arrow) with the identified kinetoplast (hematoxylin and eosin stain; original magnification 1000).
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Radiologic Findings Radiologic investigations performed in suspected cases of Chagas disease include computed tomography (CT) scans and MRI. The most frequent nonspecific findings seen on CT are single or multiple hypodense lesions, which can be associated with ring enhancement patterns.21 In some instances, CT scans show a nodular lesion. MRI findings may include hypointense lesions that show gadolinium enhancement on T1-weighted images or hyperintense lesions on T2-weighted images. Supratentorial white matter is the most commonly reported location for the nodular “chagoma” or cerebral mass lesion surrounded by extensive areas of edema.26 These findings do not follow a typical neuroimaging pattern, supporting the inclusion of toxoplasmosis and primary CNS lymphoma in the differential diagnosis.30 Diagnostic Studies In acute disease, direct detection of motile flagellated parasites consistent with trypomastigote forms in wet preparations of anticoagulated blood allows for early and conclusive testing in suspected cases of acute Chagas disease.53 Although not done routinely, lumbar puncture should be performed in patients with signs and symptoms of meningoencephalitis. Cerebrospinal fluid (CSF) examination can identify inflammatory changes such as lymphocytosis, elevated protein, and low glucose, as well as the presence of motile trypomastigote forms.52 Similar to acute nervous disease, acute Chagas disease reactivation requires detection of the parasite via parasitologic studies involving blood and/or CSF smears.29 The examination of CSF under a microscope might identify trypomastigotes but warrants caution, given the high percentage of false-negative results.26,54 Serologic testing is frequently used in the diagnosis of T. cruzi infection but is of limited value, because a negative result
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Table 1. Published Cases of Chagas Disease T. cruzi Author, Year 10
Del Castillo et al., 1990 11
Gallo et al., 1992
Age (years)/Sex
CD4 T-Cell Count (/mm3)
Serology
Blood
CSF
Treatment
Survival
19/male
NR
þ
NR
NR
Nifurtimox
>3 months
26/female
NR
þ
NR
-
Benznidazole
2 months
Gluckstein et al., 1992
32/male
45
þ
-
NR
-
2 weeks
Rosemberg et al., 199213
40/male
NR
þ
NR
þ
-
3 days
31/male
35
þ
NR
NR
Benznidazole
>6 months
52/male
NR
þ
NR
NR
-
NR
12
14
Oddo et al., 1992
Solari et al., 199315 Rocha et al., 199316
33/male
382
þ
þ
þ
Benznidazole
3 months
Metze et al., 199318
48/female
NR
þ
þ
þ
Benznidazole
18 days
19
Nishioka et al., 1993
17
50/female
104
þ
þ
-
Benznidazole
>4 months
Salgado et al., 199620
73/male
NR
þ
NR
þ
Benznidazole
>5 months
Di Lorenzo et al., 199621
32/male
NR
þ
NR
NR
Benznidazole
NR
32/male
NR
þ
NR
NR
Nifurtimox
NR
9/male
NR
NR
NR
NR
Nifurtimox
70 days
Pimentel et al., 199622
47/male
NR
þ
-
þ
Benznidazole
17 days
Ferreira et al., 199723
27/male
NR
NR
þ
NR
Benznidazole
>50 day
48/male
264
þ
þ
NR
Benznidazole
72 hours
Cohen et al., 1998
30/male
NR
NR
þ
NR
Nifurtimox
8 days
Silva et al., 19993
36/male
23
-
þ
þ
Benznidazole
20 days
29/male
46
þ
þ
þ
Benznidazole
34 days
Sartori et al., 1995
24
25/male
NR
þ
-
þ
Benznidazole
1 year
24/female
NR
þ
þ
þ
Benznidazole
6 days
25/male
185
þ
þ
þ
Benznidazole
10 days
47/male
NR
NR
NR
NR
-
20 days
32
NR
þ
NR
NR
Benznidazole
>1 year
33
NR
þ
NR
NR
Nifurtimox
NR
21
NR
NR
NR
NR
Nifurtimox
NR
25
NR
NR
NR
NR
Benznidazole
NR
28
NR
NR
NR
þ
Benznidazole
NR
25
NR
NR
NR
NR
Benznidazole
NR
50
NR
NR
NR
NR
Benznidazole
NR
42
NR
NR
NR
NR
Benznidazole
NR
37
NR
NR
NR
NR
Benznidazole
NR
29
NR
NR
NR
þ
Benznidazole; Nifurtimox
NR
26/male
NR
þ
NR
þ
NR
36 hours
Lages-Silva et al., 2002
63/male
67
þ
þ
þ
Benznidazole
>2 months
Antunes et al., 200229
36/female
8
þ
NR
þ
Benznidazole
6 weeks
22/male
77
þ
þ
þ
Nifurtimox
>3 weeks
dos Santos Sde et al., 199925 Pagano et al., 199926
de Oliveira Santos et al., 200227 28
30
Yoo et al., 2004
Continues
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Table 1. Continued T. cruzi Age (years)/Sex
CD4 T-Cell Count (/mm3)
Serology
Madalosso et al., 2004
52/male
NR
þ
Lury et al., 200532
56/male
50
þ
29/male
22
þ
32/male
42
þ
56/male
37
þ
Author, Year 31
Burgos et al., 2005
33
Corti et al., 200634 35
Lambert et al., 2006
Blood
CSF
Treatment
Survival
þ
þ
Benznidazole
24 hours
NR
NR
Nifurtimox
>3 days
-
NR
Benznidazole
>30 months
-
þ
Benznidazole
>3 years
NR
NR
Nifurtimox
>10 days
Marchiori et al., 2007
46/male
NR
-
-
þ
NR
NR
Nijjar et al., 200737
40/male
40
NR
NR
NR
Benznidazole
>1 week
Sica et al., 200838
28/male
70
-
-
NR
Benznidazole
>50 days
36
51/male
46
þ
-
-
NR
>4 days
35/male
551
þ
þ
NR
Benznidazole
>14 months
Burgos et al., 200839
41/male
61
þ
NR
NR
Benznidazole
2 days
Verdu et al., 200940
35/male
NR
þ
þ
NR
NR
>2 weeks
26/female
NR
þ
NR
þ
Benznidazole
>5 years
38/female
104
þ
NR
NR
Nifurtimox
>54 days
48/male
NR
þ
NR
NR
NR
NR
Bisio et al., 2013
33/male
NR
þ
NR
þ
Benznidazole
>7 years
Cicora et al., 201445
27/male
NR
þ
NR
NR
Benznidazole
>45 days
38/male
<200
NR
NR
þ
Nifurtimox
10 days
DiazGranados et al., 200941 Campo et al., 2010
42
Bernabeu et al., 201343 44
Rossi Spadafora et al., 201446 Yasukawa et al., 2014
49/female
38
þ
NR
þ
Benznidazole
>5 months
Buccheri et al., 201548
42/female
318
þ
-
þ
Benznidazole
>1.5 years
47
49
Alyemni et al., 2017
47/male
18
-
-
-
Benznidazole
50 days
Fernandes et al., 201750
57/male
480
NR
NR
þ
Benznidazole
39 days
CSF, Cerebrospinal fluid; NR, not reported.
does not rule out the possibility of CNS infection, as demonstrated in published accounts of confirmed CNS infection in patients with negative serology for T. cruzi.26,54 If a conclusive diagnosis still proves elusive, brain biopsy should be considered.51 In contrast to acute and reactivated acute disease, the diagnosis of chronic disease requires serologic testing to detect immunoglobulin G antibodies due to the rare demonstration of parasites on direct visualization. Treatment Treatment in the acute phase should begin as soon as possible. Between 30% and 80% of patients have negative test results from the fifth day of treatment. Options include nifurtimox (8e10mg/kg/day) or
benznidazole (5e7 mg/kg/day) orally twice daily, continued for at least 60e90 days. Higher doses are used in severe cases, generally without success.26 In most patients, excluding those with a severe form, symptoms disappear even without specific treatment, although treatment is always recommended to avoid the chronic phase of the disease. Literature Review In our review of cases reported in the literature (Table 1), the patients ranged in age from 9 to 63 years, with a median age of 35 years. In most cases, the CD4 cell counts were not reported; however, in the few cases with reported CD4 counts, the counts ranged from 8 to 480 cells/mm3, with a mean CD4 count of 72 cells/mm3.
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The duration of survival ranged from 24 hours to 7 years, with a mean survival of 1.3 months. It is unclear whether the lag time from diagnosis to administration of antiparasitic medication was longer in patients with shorter survival. In 75% of the cases (45 of 60), results from serologic testing were reported, with positive serology noted in 91% of these reported cases (41 of 45). However, the presence of T. cruzi in blood and CSF were positive in only 60% (15 of 25) and 86% (25 of 29) of the reported cases, respectively. In the present case, the patient most likely had occult immunodeficiency as well as use of MTX, supporting the inclusion of Chagas disease in the differential diagnosis, especially in immunocompromised patients presenting with a CNS mass,
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meningoencephalitis, or focal neurologic signs.23,54,55 This is important, because reactivation of acute Chagas disease is largely restricted to patients with compromised immunity, and a timely diagnosis is imperative owing to the high mortality associated with T. cruzi infection. Moreover, HIV infection is the predominant cause of immunodeficiency in patients with acute Chagas disease reactivation, complicating the diagnosis because several etiologies can present with a CNS mass or masses, a common finding in reactivation. In conclusion, successful treatment of the clinical sequelae of Chagas disease requires strong clinical suspicion to prevent misdiagnosis and start specific therapy, and this disease remains associated with high mortality. CONCLUSIONS Chagas disease should be included in the differential diagnosis when an immunocompromised patient presents with a CNS mass, meningoencephalitis, or focal neurologic signs. Successful treatment of Chagas disease requires a high index of suspicion for timely diagnosis owing to the high mortality associated with T. cruzi infection. REFERENCES 1. Harms G, Feldmeier H. The impact of HIV infection on tropical diseases. Infect Dis Clin North Am. 2005;19:121-135. ix. 2. Karp CL, Auwaerter PG. Coinfection with HIV and tropical infectious diseases, I: protozoal pathogens. Clin Infect Dis. 2007;45:1208-1213. 3. Silva N, O’Bryan L, Medeiros E, et al. Trypanosoma cruzi meningoencephalitis in HIV-infected patients. J Acquir Immune Defic Syndr Hum Retrovirol. 1999;20:342-349. 4. Cordova E, Boschi A, Ambrosioni J, Cudos C, Corti M. Reactivation of Chagas disease with central nervous system involvement in HIVinfected patients in Argentina, 1992-2007. Int J Infect Dis. 2008;12:587-592. 5. Coura JR. Chagas disease: what is known and what is needed: a background article. Mem Inst Oswaldo Cruz. 2007;102(suppl 1):113-122. 6. Pittella JE. Central nervous system involvement in Chagas disease: a hundred-year-old history. Trans R Soc Trop Med Hyg. 2009;103:973-978. 7. Coura JR, Borges-Pereira J. Chagas disease: 100 years after its discovery. A systemic review. Acta Trop. 2010;115:5-13.
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after heart transplantation of chagasic myocardiopathy. J Heart Lung Transplant. 2007;26:1091-1096. 37. Nijjar SS, Del Bigio MR. Cerebral trypanosomiasis in an incarcerated man. CMAJ. 2007;176:448. 38. Sica RE, Gargiullo G, Papayanis C. Tumour-like chagasic encephalitis in AIDS patients: an atypical presentation in one of them and outcome in a small series of cases. Arq Neuropsiquiatr. 2008;66: 881-884. 39. Burgos JM, Begher S, Silva HM, et al. Molecular identification of Trypanosoma cruzi I tropism for central nervous system in Chagas reactivation due to AIDS. Am J Trop Med Hyg. 2008; 78:294-297. 40. Verdú J, De Paz F, Castaño V, Torrús D, Reus S. Reactivation of Chagas disease with central nervous system involvement: peripheral blood smear evidence. Int J Infect Dis. 2009;13: e527-e528.
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44. Bisio M, Altcheh J, Lattner J, et al. Benznidazole treatment of chagasic encephalitis in pregnant woman with AIDS. Emerg Infect Dis. 2013;19: 1490-1492. 45. Cicora F, Escurra V, Bibolini J, Petroni J, González I, Roberti J. Cerebral trypanosomiasis in a renal transplant recipient. Transpl Infect Dis. 2014; 16:813-817.
patient without known immunosuppression. Am J Trop Med Hyg. 2017;96:292-294. 51. Ferreira MS, Borges AS. Some aspects of protozoan infections in immunocompromised patients: a review. Mem Inst Oswaldo Cruz. 2002;97:443-457. 52. Córdova E, Maiolo E, Corti M, Orduña T. Neurological manifestations of Chagas disease. Neurol Res. 2010;32:238-244.
46. Rossi Spadafora MS, Céspedes G, Romero S, et al. Trypanosoma cruzi necrotizing meningoencephalitis in a Venezuelan HIVþ AIDS patient: pathological diagnosis confirmed by PCR using formalin-fixed and paraffinembedded tissues. Anal Cell Pathol (Amst). 2014;2014:124795.
53. Hoff R, Teixeira RS, Carvalho JS, Mott KE. Trypanosoma cruzi in the cerebrospinal fluid during the acute stage of Chagas’ disease. N Engl J Med. 1978; 298:604-606.
47. Yasukawa K, Patel SM, Flash CA, Stager CE, Goodman JC, Woc-Colburn L. Trypanosoma cruzi meningoencephalitis in a patient with acquired immunodeficiency syndrome. Am J Trop Med Hyg. 2014;91:84-85.
55. Vaidian AK, Weiss LM, Tanowitz HB. Chagas’ disease and AIDS. Kinetoplastid Biol Dis. 2004;3:2.
54. Corti M. AIDS and Chagas’ disease. AIDS Patient Care STDS. 2000;14:581-588.
41. Diazgranados CA, Saavedra-Trujillo CH, Mantilla M, Valderrama SL, Alquichire C, FrancoParedes C. Chagasic encephalitis in HIV patients: common presentation of an evolving epidemiological and clinical association. Lancet Infect Dis. 2009;9:324-330.
48. Buccheri R, Kassab MJ, Freitas VL, et al. Chagasic meningoencephalitis in an HIV infected patient with moderate immunosuppression: prolonged survival and challenges in the HAART era. Rev Inst Med Trop Sao Paulo. 2015;57:531-535.
Conflict of interest statement: The authors declare that the article content was composed in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
42. Campo M, Phung MK, Ahmed R, et al. A woman with HIV infection, brain abscesses, and eosinophilia. Clin Infect Dis. 2010;50:239-240, 276-277.
49. Alyemni D, Miller AF, Couto P, et al. Histopathologic identification of Trypanosoma cruzi (Chagas’) encephalitis in an AIDS patient. Hum Pathol. 2017; 7:23-26.
Citation: World Neurosurg. (2019) 129:225-231. https://doi.org/10.1016/j.wneu.2019.05.260
43. Bernabeu A, Alcaraz-Mateos E, Lopez-Celada S. Usefulness of magnetic resonance spectroscopy in the assessment of brain Chagas disease: a case report. J Neurol Res. 2013;3:150-154.
50. Fernandes HJ, Barbosa LO, Machado TS, Campos JP, Moura AS. Meningoencephalitis caused by reactivation of Chagas disease in
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Received 2 May 2019; accepted 30 May 2019
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Cerebral Trypanosomiasis in an Immunocompromised Patient: Case Report and Review of the Literature Mayank Kaushal1, Saman Shabani1, Elizabeth J. Cochran2, Hasan Samra2, Nathan T. Zwagerman1
Key words Benznidazole - Chagas disease - Kinetoplasts - Trypanosoma cruzi -
Abbreviations and Acronyms CNS: Central nervous system CSF: Cerebrospinal fluid CT: Computed tomography ED: Emergency Department HIV: Human immunodeficiency virus MRI: Magnetic resonance imaging MTX: Methotrexate From the Departments of 1Neurosurgery and 2Pathology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA To whom correspondence should be addressed: Nathan T. Zwagerman, M.D. [E-mail: [email protected]]
- BACKGROUND:
We document a case of central nervous system infection with Trypanosoma cruzi.
- CASE
DESCRIPTION: An 88-year-old woman presented with altered mental status, right-sided weakness, and slurred speech. Her medical history was significant for methotrexate intake for rheumatoid arthritis, and she tested negative for human immunodeficiency virus. Magnetic resonance imaging of the brain showed bilateral thick and peripherally enhancing white matter lesions in the frontoparietal region with extensive surrounding vasogenic edema. A lumbar puncture revealed increased protein and lymphocytic pleocytosis, and needle biopsy highlighted brain necrosis, chronic inflammation, and numerous intracellular organisms suggestive of T. cruzi amastigotes. Despite treatment with benznidazole, the patient expired soon after presentation.
- CONCLUSION:
Chagas disease should be included in the differential diagnosis of an immunocompromised patient presenting with a central nervous system mass, meningoencephalitis, or focal neurologic signs.
Citation: World Neurosurg. (2019) 129:225-231. https://doi.org/10.1016/j.wneu.2019.05.260 Journal homepage: www.journals.elsevier.com/worldneurosurgery Available online: www.sciencedirect.com 1878-8750/$ - see front matter ª 2019 Elsevier Inc. All rights reserved.
INTRODUCTION An association between opportunistic parasitic infections and compromised immunity, presumably due to disease reactivation, is commonly observed.1,2 Chagas disease, also known as American trypanosomiasis, is one such infection, caused by Trypanosoma cruzi, a flagellate protozoan endemic to Latin America. There are few reported cases of T. cruzi meningoencephalitis from North America published in the literature. The rare occurrence of this infection in the clinical setting in the United States and the similarity of presenting symptoms to toxoplasmosis (caused by Toxoplasma gondii) often lead to delays in correct diagnosis and initiation of specific treatment. Consequently, even though drugs to treat T. cruzi infection are available, Chagas disease is associated with a high mortality rate.3,4 This underscores the importance of including T. cruzi infection in the differential diagnosis in patients with a
compromised immune system who present with a clinical syndrome resembling central nervous system (CNS) toxoplasmosis. Here we report a patient with immunosuppression and review the published cases of Chagas disease. To our knowledge, this is the first reported case of a patient presenting with meningoencephalitis most likely caused by reactivation of Chagas disease. The number of clinical investigations performed to determine the correct diagnosis in this patient highlights the challenge of diagnosing Chagas disease in a timely manner and the consequences associated with delayed initiation of treatment for Chagas disease. CASE REPORT An 88-year-old female with a previous medical history of rheumatoid arthritis treated with methotrexate (MTX), transient ischemic attack, hypertension, fungal otitis, and history of travel to Oklahoma and Texas presented to our hospital with altered mental status, rightsided weakness, and slurred speech. She had been seen 3 days before this Emergency Department (ED) visit, with altered
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mental status and right-sided weakness. Imaging had been negative for stroke, and brain magnetic resonance imaging (MRI) was obtained, which was concerning for MTX toxicity (Figure 1). Her MTX was discontinued at that ED visit. Repeat MRI was obtained at the current ED visit (Figure 2), which showed bilateral thick and peripherally enhancing white matter lesions in the frontoparietal region with extensive surrounding vasogenic edema. The edema and mass effect had progressed compared with the previous MRI despite the low serum MTX level obtained at the second presentation to the ED. She was admitted and placed on continuous electroencephalography, which was negative for seizure activity. Magnetic resonance spectroscopy was nondiagnostic owing to significant motion artifact. Lumbar puncture was performed, which showed increased protein and lymphocytic pleocytosis; however, flow cytometry results were negative. She underwent needle biopsy, which showed brain necrosis, chronic inflammation, and numerous intracellular organisms suggestive of T. cruzi amastigotes (Figure 3). Kinetoplasts were
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Figure 1. Brain magnetic resonance imaging without contrast showing bilateral signal abnormalities involving frontal and parietal white matter with minimal mass effect.
CEREBRAL TRYPANOSOMIASIS IN AN IMMUNOCOMPROMISED PATIENT
identified within the organisms (Figure 4). Multitarget real-time polymerase chain reaction for T. cruzi performed according to Centers for Disease Control and Prevention recommendations was positive for T. cruzi. Treatment with nenznidazole was started in accordance with the Centers for Disease Control and Prevention recommendation. CD4 and CD8 panels to assess for occult immunodeficiency demonstrated very low CD4 (34 cells/mm3) and CD8 (12 cells/mm3) cell counts in the setting of human immunodeficiency virus (HIV) negativity. Shortly after diagnosis, the patient became hypoxic to 87% on room air and hypotensive to 69/56 mmHg. She was transferred to the intensive care unit. A chest radiograph showed significant interstitial and patchy opacifies concerning for aspiration pneumonia. After
Figure 2. Repeat brain magnetic resonance imaging (MRI) with contrast showing bilateral thick peripherally enhancing white matter lesions centered within the frontoparietal regions (A) with extensive surrounding vasogenic edema as seen on T2-weighted fluid-attenuated inversion recovery (B, D). The edema and mass effect had progressed compared with the previous MRI (Figure 1). Some restriction signal is noted on the diffusion weighted imaging (C).
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discussion with the family, the decision was made to withdraw treatment. DISCUSSION Clinical Presentation This literature review focuses on the CNS manifestations of Chagas disease (American trypanosomiasis). We searched individual case reports, case series, and reviews pertaining to CNS presentation in Chagas disease. The involvement of CNS in Chagas disease can be classified as acute disease, chronic disease, or reactivated acute nervous form in the intermediate or chronic stage. In addition, some patients demonstrate cerebral changes due to ischemia from chronic chagasic cardiopathy, which, although not associated with direct infection of the CNS, produces clinical sequelae in the nervous system. The clinical manifestations of Chagas disease vary widely. Factors theorized as responsible include the quantity of parasites, size of inoculum of T. cruzi in the initial infection, host immune response, and lineage of T. cruzi.5-7 Depending on the combination of some of the mentioned factors, the initial acute disease can range from a mild infection with few or no symptoms to a severe presentation of chagasic encephalitis.6,8 Of note, only a small number of patients infected with T. cruzi go on to develop encephalitis, the majority of whom are 2 years old or younger.9 In a subset of cases, reactivation of acute nervous form of Chagas disease is seen in previously asymptomatic patients, most if not all of whom share the common underlying finding of immunosuppression (Table 1). The immunocompromised state can be due to various causes, such as organ transplantation, use of such drugs as immunosuppressants and corticosteroids, and, most significantly and frequently, HIV infection.6,51 CNS involvement in the reactivated form of Chagas disease is characterized by fever, headache, seizures, and focal neurologic signs.6,51 Involvement of the CNS in chronic Chagas disease infection is controversial, with rare accounts of such findings as dementia, confusion, chronic encephalopathy, and sensorial and motor deficits.52 Macroscopic and Histopathological Findings The macroscopic picture in Chagas disease varies with the phase of disease
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macrophages, lymphocytes, and plasma cells.6 The chronic nervous form is characterized by presence of a few small, hypocellular, thinly distributed inflammatory nodules associated with few parasites, raising the possibility of these nodules representing sequelae of acute inflammatory lesions of a residual nature.9
Figure 3. T. cruzi amastigotes (circles) in a background of necrotic brain tissue and mixed inflammatory cells (hematoxylin and eosin stain; original magnification 500).
presentation. In the acute nervous form of Chagas disease, edema, congestion, and scattered petechial hemorrhages are frequently encountered. On histopathological examination, encephalitis involving multiple locations throughout the CNS is observed, comprising multiple cell types such as microglia, macrophages, neutrophils, and astrocytes in a nodular arrangement, with the amastigote form of parasite residing within astrocytes.6,8 The inflammatory foci are always associated with lymphomonocytic leptomeningitis and also may be associated with degenerative
changes to nerve cells located in the vicinity. In cases of CNS involvement due to disease reactivation, the encephalitic lesions are not clearly demarcated and are associated with the development of a necrotizing component and the presence of a large number of amastigotes.9 In some of these patients, a characteristic tumoral or pseudotumoral form (brain “chagoma”), comprising necrotic-hemorrhagic nodular lesions commonly located in brain white matter, is observed. These lesions show histological findings of necrosis, hemorrhage, microglial nodules, and exudates of
Figure 4. T. cruzi amastigote (arrow) with the identified kinetoplast (hematoxylin and eosin stain; original magnification 1000).
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Radiologic Findings Radiologic investigations performed in suspected cases of Chagas disease include computed tomography (CT) scans and MRI. The most frequent nonspecific findings seen on CT are single or multiple hypodense lesions, which can be associated with ring enhancement patterns.21 In some instances, CT scans show a nodular lesion. MRI findings may include hypointense lesions that show gadolinium enhancement on T1-weighted images or hyperintense lesions on T2-weighted images. Supratentorial white matter is the most commonly reported location for the nodular “chagoma” or cerebral mass lesion surrounded by extensive areas of edema.26 These findings do not follow a typical neuroimaging pattern, supporting the inclusion of toxoplasmosis and primary CNS lymphoma in the differential diagnosis.30 Diagnostic Studies In acute disease, direct detection of motile flagellated parasites consistent with trypomastigote forms in wet preparations of anticoagulated blood allows for early and conclusive testing in suspected cases of acute Chagas disease.53 Although not done routinely, lumbar puncture should be performed in patients with signs and symptoms of meningoencephalitis. Cerebrospinal fluid (CSF) examination can identify inflammatory changes such as lymphocytosis, elevated protein, and low glucose, as well as the presence of motile trypomastigote forms.52 Similar to acute nervous disease, acute Chagas disease reactivation requires detection of the parasite via parasitologic studies involving blood and/or CSF smears.29 The examination of CSF under a microscope might identify trypomastigotes but warrants caution, given the high percentage of false-negative results.26,54 Serologic testing is frequently used in the diagnosis of T. cruzi infection but is of limited value, because a negative result
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Table 1. Published Cases of Chagas Disease T. cruzi Author, Year 10
Del Castillo et al., 1990 11
Gallo et al., 1992
Age (years)/Sex
CD4 T-Cell Count (/mm3)
Serology
Blood
CSF
Treatment
Survival
19/male
NR
þ
NR
NR
Nifurtimox
>3 months
26/female
NR
þ
NR
-
Benznidazole
2 months
Gluckstein et al., 1992
32/male
45
þ
-
NR
-
2 weeks
Rosemberg et al., 199213
40/male
NR
þ
NR
þ
-
3 days
31/male
35
þ
NR
NR
Benznidazole
>6 months
52/male
NR
þ
NR
NR
-
NR
12
14
Oddo et al., 1992
Solari et al., 199315 Rocha et al., 199316
33/male
382
þ
þ
þ
Benznidazole
3 months
Metze et al., 199318
48/female
NR
þ
þ
þ
Benznidazole
18 days
19
Nishioka et al., 1993
17
50/female
104
þ
þ
-
Benznidazole
>4 months
Salgado et al., 199620
73/male
NR
þ
NR
þ
Benznidazole
>5 months
Di Lorenzo et al., 199621
32/male
NR
þ
NR
NR
Benznidazole
NR
32/male
NR
þ
NR
NR
Nifurtimox
NR
9/male
NR
NR
NR
NR
Nifurtimox
70 days
Pimentel et al., 199622
47/male
NR
þ
-
þ
Benznidazole
17 days
Ferreira et al., 199723
27/male
NR
NR
þ
NR
Benznidazole
>50 day
48/male
264
þ
þ
NR
Benznidazole
72 hours
Cohen et al., 1998
30/male
NR
NR
þ
NR
Nifurtimox
8 days
Silva et al., 19993
36/male
23
-
þ
þ
Benznidazole
20 days
29/male
46
þ
þ
þ
Benznidazole
34 days
Sartori et al., 1995
24
25/male
NR
þ
-
þ
Benznidazole
1 year
24/female
NR
þ
þ
þ
Benznidazole
6 days
25/male
185
þ
þ
þ
Benznidazole
10 days
47/male
NR
NR
NR
NR
-
20 days
32
NR
þ
NR
NR
Benznidazole
>1 year
33
NR
þ
NR
NR
Nifurtimox
NR
21
NR
NR
NR
NR
Nifurtimox
NR
25
NR
NR
NR
NR
Benznidazole
NR
28
NR
NR
NR
þ
Benznidazole
NR
25
NR
NR
NR
NR
Benznidazole
NR
50
NR
NR
NR
NR
Benznidazole
NR
42
NR
NR
NR
NR
Benznidazole
NR
37
NR
NR
NR
NR
Benznidazole
NR
29
NR
NR
NR
þ
Benznidazole; Nifurtimox
NR
26/male
NR
þ
NR
þ
NR
36 hours
Lages-Silva et al., 2002
63/male
67
þ
þ
þ
Benznidazole
>2 months
Antunes et al., 200229
36/female
8
þ
NR
þ
Benznidazole
6 weeks
22/male
77
þ
þ
þ
Nifurtimox
>3 weeks
dos Santos Sde et al., 199925 Pagano et al., 199926
de Oliveira Santos et al., 200227 28
30
Yoo et al., 2004
Continues
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Table 1. Continued T. cruzi Age (years)/Sex
CD4 T-Cell Count (/mm3)
Serology
Madalosso et al., 2004
52/male
NR
þ
Lury et al., 200532
56/male
50
þ
29/male
22
þ
32/male
42
þ
56/male
37
þ
Author, Year 31
Burgos et al., 2005
33
Corti et al., 200634 35
Lambert et al., 2006
Blood
CSF
Treatment
Survival
þ
þ
Benznidazole
24 hours
NR
NR
Nifurtimox
>3 days
-
NR
Benznidazole
>30 months
-
þ
Benznidazole
>3 years
NR
NR
Nifurtimox
>10 days
Marchiori et al., 2007
46/male
NR
-
-
þ
NR
NR
Nijjar et al., 200737
40/male
40
NR
NR
NR
Benznidazole
>1 week
Sica et al., 200838
28/male
70
-
-
NR
Benznidazole
>50 days
36
51/male
46
þ
-
-
NR
>4 days
35/male
551
þ
þ
NR
Benznidazole
>14 months
Burgos et al., 200839
41/male
61
þ
NR
NR
Benznidazole
2 days
Verdu et al., 200940
35/male
NR
þ
þ
NR
NR
>2 weeks
26/female
NR
þ
NR
þ
Benznidazole
>5 years
38/female
104
þ
NR
NR
Nifurtimox
>54 days
48/male
NR
þ
NR
NR
NR
NR
Bisio et al., 2013
33/male
NR
þ
NR
þ
Benznidazole
>7 years
Cicora et al., 201445
27/male
NR
þ
NR
NR
Benznidazole
>45 days
38/male
<200
NR
NR
þ
Nifurtimox
10 days
DiazGranados et al., 200941 Campo et al., 2010
42
Bernabeu et al., 201343 44
Rossi Spadafora et al., 201446 Yasukawa et al., 2014
49/female
38
þ
NR
þ
Benznidazole
>5 months
Buccheri et al., 201548
42/female
318
þ
-
þ
Benznidazole
>1.5 years
47
49
Alyemni et al., 2017
47/male
18
-
-
-
Benznidazole
50 days
Fernandes et al., 201750
57/male
480
NR
NR
þ
Benznidazole
39 days
CSF, Cerebrospinal fluid; NR, not reported.
does not rule out the possibility of CNS infection, as demonstrated in published accounts of confirmed CNS infection in patients with negative serology for T. cruzi.26,54 If a conclusive diagnosis still proves elusive, brain biopsy should be considered.51 In contrast to acute and reactivated acute disease, the diagnosis of chronic disease requires serologic testing to detect immunoglobulin G antibodies due to the rare demonstration of parasites on direct visualization. Treatment Treatment in the acute phase should begin as soon as possible. Between 30% and 80% of patients have negative test results from the fifth day of treatment. Options include nifurtimox (8e10mg/kg/day) or
benznidazole (5e7 mg/kg/day) orally twice daily, continued for at least 60e90 days. Higher doses are used in severe cases, generally without success.26 In most patients, excluding those with a severe form, symptoms disappear even without specific treatment, although treatment is always recommended to avoid the chronic phase of the disease. Literature Review In our review of cases reported in the literature (Table 1), the patients ranged in age from 9 to 63 years, with a median age of 35 years. In most cases, the CD4 cell counts were not reported; however, in the few cases with reported CD4 counts, the counts ranged from 8 to 480 cells/mm3, with a mean CD4 count of 72 cells/mm3.
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The duration of survival ranged from 24 hours to 7 years, with a mean survival of 1.3 months. It is unclear whether the lag time from diagnosis to administration of antiparasitic medication was longer in patients with shorter survival. In 75% of the cases (45 of 60), results from serologic testing were reported, with positive serology noted in 91% of these reported cases (41 of 45). However, the presence of T. cruzi in blood and CSF were positive in only 60% (15 of 25) and 86% (25 of 29) of the reported cases, respectively. In the present case, the patient most likely had occult immunodeficiency as well as use of MTX, supporting the inclusion of Chagas disease in the differential diagnosis, especially in immunocompromised patients presenting with a CNS mass,
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meningoencephalitis, or focal neurologic signs.23,54,55 This is important, because reactivation of acute Chagas disease is largely restricted to patients with compromised immunity, and a timely diagnosis is imperative owing to the high mortality associated with T. cruzi infection. Moreover, HIV infection is the predominant cause of immunodeficiency in patients with acute Chagas disease reactivation, complicating the diagnosis because several etiologies can present with a CNS mass or masses, a common finding in reactivation. In conclusion, successful treatment of the clinical sequelae of Chagas disease requires strong clinical suspicion to prevent misdiagnosis and start specific therapy, and this disease remains associated with high mortality. CONCLUSIONS Chagas disease should be included in the differential diagnosis when an immunocompromised patient presents with a CNS mass, meningoencephalitis, or focal neurologic signs. Successful treatment of Chagas disease requires a high index of suspicion for timely diagnosis owing to the high mortality associated with T. cruzi infection. REFERENCES 1. Harms G, Feldmeier H. The impact of HIV infection on tropical diseases. Infect Dis Clin North Am. 2005;19:121-135. ix. 2. Karp CL, Auwaerter PG. Coinfection with HIV and tropical infectious diseases, I: protozoal pathogens. Clin Infect Dis. 2007;45:1208-1213. 3. Silva N, O’Bryan L, Medeiros E, et al. Trypanosoma cruzi meningoencephalitis in HIV-infected patients. J Acquir Immune Defic Syndr Hum Retrovirol. 1999;20:342-349. 4. Cordova E, Boschi A, Ambrosioni J, Cudos C, Corti M. Reactivation of Chagas disease with central nervous system involvement in HIVinfected patients in Argentina, 1992-2007. Int J Infect Dis. 2008;12:587-592. 5. Coura JR. Chagas disease: what is known and what is needed: a background article. Mem Inst Oswaldo Cruz. 2007;102(suppl 1):113-122. 6. Pittella JE. Central nervous system involvement in Chagas disease: a hundred-year-old history. Trans R Soc Trop Med Hyg. 2009;103:973-978. 7. Coura JR, Borges-Pereira J. Chagas disease: 100 years after its discovery. A systemic review. Acta Trop. 2010;115:5-13.
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Conflict of interest statement: The authors declare that the article content was composed in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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