Keywords
Chagas disease - central nervous system diseases - heart transplantation - immunosuppression
therapy
Palavras-chave
doença de Chagas - doenças do sistema nervoso central - transplante de coração - imunossupressão
Introduction
Chagas disease (CD) or American trypanosomiasis is a zoonosis caused by the protozoan
Trypanosoma cruzi. It is an important public health problem in Latin American countries, affecting
∼ 6 million people within the region.[1] This disease presents an acute phase that is usually asymptomatic or oligosymptomatic
and, in the absence of specific treatment, lasts 8 to 12 weeks. Once the host's immune
response is able to reduce the replication of the parasite, the patient enters the
chronic phase, which persists for his entire life. The chronic form of the disease
comprises an asymptomatic latency period that can last for several years. The symptomatic
chronic manifestation occurs in ∼ 20 to 30% of those infected, with heart and gastrointestinal
disease being its most common forms.[2]
The heart is the most affected organ in the chronic symptomatic phase of CD.[3] In patients with the chronic form and some type of immunosuppression, reactivation
of the acute form may occur with manifestations involving various organs, such as
the heart, skin, and the central nervous system. In advanced cases of Chagasic cardiomyopathy,
heart transplantation is the chosen procedure, and these patients are at risk of reactivation
as a result of the immunosuppressant therapy.
Three cases of patients who have undergone heart transplantation due to Chagasic cardiomyopathy
and evolved with neurological symptoms are described. They underwent brain biopsy,
and the result was compatible with cerebral CD. Furthermore, a literature review was
performed through the PUBMED database searching for articles in English, Portuguese,
and Spanish, with no date limit. The descriptors used were: Chagas disease, American trypanosomiasis, central nervous system, cardiac transplant and immunosuppression.
Case Reports
Case 1
A 47-year-old male patient was admitted to the emergency room after his first generalized
tonic-clonic seizure. He was alert, oriented, afebrile, without focal neurological
deficits and without neck stiffness. The patient had undergone a heart transplant
7 months prior to admission due to Chagasic cardiomyopathy. He reported daily headache
that started after the transplant, with a worsening in intensity in the last 3 days,
associated with apathy and behavioral changes. In addition, he had chronic renal failure
and cataracts. The patient was taking the following medications: cyclosporine 200 mg/day,
mycophenolate mofetil 2 g /day, tacrolimus 4 mg/day, prednisone 10 mg/day, diltiazem
10 mg/day, simvastatin 20 mg/day, metformin 500 mg/day, alendronate 70 mg/week, calcium
carbonate 1,000 mg/day, and sulfamethoxazole-trimethoprim 400/80 mg/day.
The computed tomography (CT) scan without contrast showed left frontal hypodensity
associated with perilesional edema. The magnetic resonance imaging (MRI) showed an
expansive left frontal lesion with hyposignal in T1, heterogeneous enhancement by
gadolinium, perilesional edema, and absence of restriction to diffusion ([Fig. 1]). The patient underwent a lumbar puncture that showed an opening pressure of 23 cmH2O,
and the other results of biochemistry, cytology, and microbiology were normal. Serological
tests for toxoplasmosis and human immunodeficiency virus (HIV) tests were negative.
Fig. 1 Brain magnetic resonance imaging (MRI) of the case 1. (A) T1-weighted MRI with gadolinium.
Note the heterogeneous contrast enhancement. (B) T2-weighted MRI shows heterogeneous
lesion with intense perilesional edema. (C) Diffusion-weighted imaging MRI showing
absence of restriction on diffusion.
Due to the atypical lesion in an immunosuppressed patient with a history of CD, a
brain open biopsy was chosen. Concomitantly, empirical treatment with benznidazole
300 mg/day was started. Histology showed neutrophilic and histiocytic inflammatory
infiltrate, mainly perivascular, associated with amastigotes nests, compatible with
CD ([Fig. 2A]). Immunohistochemistry confirmed the diagnosis ([Fig. 2B]). The patient was treated with benznidazole for 60 days and showed complete improvement.
He had no new neurological symptoms after 3 years of follow-up.
Fig. 2 (A) Hematoxylin-eosin stain with inflammatory infiltrate and amastigotes nests (arrows).
(B) Immunohistochemistry analysis positive for the presence of T. cruzi (arrows).
Case 2
A 48-year-old female patient was admitted to the emergency department with left fasciobraquiocrural
hemiparesis and dysarthria initiated in the last hours. There was a report of progressive
headache of about 4 months of evolution and chronic hepatitis B being treated with
entecavir. She underwent a heart transplant 4 months before admission as a result
of Chagasic cardiomyopathy. The immunosuppression regimen was performed with cyclosporine
200 mg/day, prednisone 10 mg/day, and mycophenolate mofetil 2 g/day.
Image propaedeutic showed an extensive lesion in the right temporo-parietal region
with the predominantly annular enhancement by gadolinium ([Fig. 3]). Serological tests for toxoplasmosis and HIV tests were negative. We opted for
an open biopsy of the lesion. In the hematoxylin-eosin stain, numerous parasites were
observed forming amastigotes nests ([Fig. 4]). Immunohistochemistry confirmed the diagnosis of reactivation of CD. After diagnosis,
treatment with benznidazole was started. After completing 60 days of treatment and
partial improvement, the patient presented a further worsening of the deficit. Magnetic
resonance imaging examination showed worsening of the lesions. The patient underwent
a new benznidazole cycle with improvement of the condition but maintained a sequel
motor deficit and dependence for basic activities.
Fig. 3 (A) Magnetic resonance imaging of the brain in axial section in T1-weighted sequence
with the presence of an expansive lesion with hyposignal and predominantly annular
enhancement by gadolinium. (B) Computed tomography of the skull in axial section at
the same level. Note non-specific hypodensity associated with intralesional bleeding.
Fig. 4 Hematoxylin-eosin stain showing several nests of amastigotes (arrows) associated
with inflammatory infiltrate.
Case 3
A female patient, 67 years-old, presented with a sudden onset of aphasia. She had
undergone a heart transplant 4 months before admission due to Chagasic cardiomyopathy
and used prednisone 5 mg/day, cyclosporine 150 mg/day, mycophenolate mofetil 1 g/day,
and prophylaxis for neurotoxoplasmosis with trimethoprim sulfamethoxazole. Propaedeutics
demonstrated a heterogeneous right frontal-temporal lesion with enhancement by paramagnetic
contrast ([Fig. 5]). Cerebrospinal fluid was not positive for research of T. cruzi, and biochemistry as well as cytology were normal. Serological tests for toxoplasmosis
and HIV tests were negative. Cerebral open biopsy showed necrotizing encephalitis
with the presence of amastigotes, and immunohistochemistry was positive for CD ([Fig. 6]). The patient underwent treatment with benznidazole and maintained motor aphasia
after 6 months of follow-up.
Fig. 5 Magnetic resonance imaging of brain in axial (A) and sagittal (B) section in T1-weighted
sequence with presence of expansive lesion with hyposignal and heterogeneous enhancement
by gadolinium.
Fig. 6 (A) Hematoxylin-eosin stain with intracellular amastigotes (arrows) adjacent to an
area of hemorrhagic necrosis. (B) Positive immunohistochemistry for T. cruzi.
Discussion
In Latin America, Chagasic cardiomyopathy is the third most common cause of indication
for heart transplantation.[4] Posttransplant immunosuppressive therapy increases the risk of T. cruzi infection reactivation, whose incidence after transplantation varies from 8 to 90%.
This event is defined as an increase in parasitemia that can be detected by direct
parasitological techniques or polymerase chain reaction (PCR), even in the absence
of symptoms.[1]
[5]
[6]
Reactivation of CD is associated with immunodeficiency states, such as those caused
by the acquired immunodeficiency syndrome (AIDS), hematological neoplasms, corticosteroid
therapy, and other immunosuppressants, including in the context of solid organ transplantation.[7] General clinical manifestations observed include fever, myocarditis, symptoms suggestive
of rejection or dermatological manifestations, including inflammatory panniculitis
and skin nodules.[4] When the central nervous system is involved, the most common manifestations include
headache, vomiting, seizures, and focal neurological deficits. The involvement of
the central nervous system in reactivation is well described for patients with AIDS,
accounting for up to 80% of cases.[8] In these patients, the most common form of presentation is meningoencephalitis,
which may also present itself as tumor-like expansive lesions similar to abscesses,
described by some authors as cerebral chagoma.[7]
[8] Cerebral chagoma is characterized by the presence of single or multiple nodular
lesions with necrotic-hemorrhagic tissue, which are little and defined, but can evolve
and reach bigger dimensions. These lesions are usually located in the white matter
of the brain lobes, but they also affect the brainstem. Histologically, there is inflammatory
infiltrate in the nervous and perivascular tissue, in addition to abundant intracellular
amastigotes.[8] Magnetic resonance imaging reveals an expansive lesion with mass effect with T1
hyposignal, T2 hypersignal, and irregular or annular gadolinium enhancement, as shown
in the cases described.
The first report of the brain tumor-like form reactivation of CD was made in 1973,
by Queiroz,[6] in a patient with cutaneous T-cell lymphoma (mycosis fungoides). Since then, there
have been several reports of cerebral chagoma in AIDS patients.[7]
[8]
[9]
[10]
[11]
[12]
[13]
[14]
[15]
[16]
[17] The cases of cerebral chagoma non-related to AIDS found in our review are summarized
in [Table 1]. Among patients immunosuppressed for causes other than AIDS, the following was found:
1 patient using methotrexate due to rheumatoid arthritis;[18] 2 patients with leukemia;[19]
[20] 2 patients undergoing kidney transplantation;[21]
[22] and only 1 reported case of a patient who underwent a heart transplantation,[4] similar to our case. Such a complication in heart transplant patients is very rare.
In a series of 107 heart transplantations over 25 years, it occurred to only 1 patient,[23] the same case described by Marchiori et al.[4] We present 3 transplanted and biopsied cases in the same hospital with an interval
of 5 years between them. Like the case described by Marchiori et al. (2007), the reactivation
in the 3 cases of our sample occurred in the first 7 months after transplantation.
Table 1
Tumor-like Chagas disease reactivation cases non-related to acquired immunodeficiency
syndrome
|
Author, year
|
Sex
|
Age
(years)
|
Base disease
|
Symptoms
|
Site of lesion
|
Treatment
|
|
Queiroz,[6] 1973
|
M
|
62
|
T-cells lymphoma
|
−
|
−
|
No
|
|
Salgado,[19] 1996
|
M
|
76
|
Lymphocytic leukemia
|
Intracranial hypertension
|
Right Parieto-occipital
|
Benznidazole 5 mg/kg/day
|
|
Marchiori,[3] 2007
|
M
|
46
|
Cardiac transplant, 7m
|
Left hemiparesis, dysarthria, dysphagia
|
Right fronto-parietal
|
No
|
|
Cohen,[20] 2010
|
F
|
15
|
Lymphoblastic leukemia
|
Headache, fever
|
Left occipital
|
Benznidazole 7 mg/kg/day
|
|
Cicora,[21] 2014
|
M
|
27
|
Kidney transplant, 6y
|
Intense headache
|
Right frontal
|
Benznidazole 7 mg/kg/day
|
|
Montero,[22] 2018
|
M
|
62
|
Kidney transplant, 3y
|
Left arm paresis, bradypsychia
|
Corpus callosum
|
Benznidazole
15 mg/kg/day
|
|
Kaushal,[18] 2019
|
F
|
88
|
Rheumatoid arthritis
|
Right-sided weakness, slurred speech
|
Bilateral frontoparietal
|
No
|
The best treatment for CD in immunocompromised patients is still uncertain, since
the available data are limited to observational studies. Two medications are described
as effective in reactivation treatment, benznidazole and nifurtimox. In all 3 cases
described in this report, treatment with benznidazole at a dose of 5 mg/kg/day for
60 days was used.[25]
[26] The mortality rate in cases of CD reactivation in patients with HIV is ∼ 79%, with
an average survival time of 21 days.[7] On the other hand, in reactivation after heart transplantation, the behavior is
apparently more indolent, since all patients described in our series are alive and
only one patient has severe neurological sequelae.
Conclusion
Heart transplantation is considered the gold standard for the treatment of severe
Chagas cardiomyopathy. Although more common in patients with AIDS-related immunosuppression,
tumor-like reactivation in the central nervous system may happen in heart-transplant
patients. Therefore, due the multiple differential diagnoses in this context, we believe
that brain biopsy should be considered when feasible.
