granulomatous amebic encephalitis due to balamuthia mandriliaris

Am. J. Trop. Med. Hyg., 56(6), 1997, pp. 603—607 Copyright C 1997 by The American Society of Tropical Medicine and Hygiene

GRANULOMATOUS AMEBIC (LEPTOMYXIIDAE):

ENCEPHALITIS DUE TO BALAMUTHIA MANDRILIARIS REPORT OF FOUR CASES FROM MEXICO

JUAN M. RIESTRA-CASTANEDA, ROBERTO RIESTRA-CASTANEDA, ANDRES A. GONZALEZ-GARRIDO, PATRICIO PENA MORENO, A. JULIO MARTINEZ, GOVINDA S. VISVESVARA, FLORENTINO JARDON CAREAGA, JOSE L. OROPEZA

DE ALBA,

AND SALVADOR

GONZALEZ

CORNEJO

Laboratorio de Microcirugia de Base de Craneo, Departamento de Neurologia y Neurocirugia, Hospital Civil de Guadalajara, Guadalajara, Mexico; Departamento de Patologia, Centro Medico de Occidente, Instituto Mexicano del Seguro Social, Guadalajara, Mexico; Division of Neuropathology, Presbyterian University Hospital, Pittsburgh, Pennsylvania; Division of Parasitic Diseases, Centerfor Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia; Departamento de Neurocirugia, Hospital del Cannen, Guadalajara, Mexico

Abstract. (Leptomyxid

In this report, we describe ameba)

in four

previously

four cases of granulomatous healthy

Mexican

patients.

amebic

All four

cases

encephalitis were

caused

characterized

by Balamuthia by focal

neuro

logic signs, increased intracranial pressure, and cerebral hyperdense lesions in computed tomography scans of the head. These patients underwent craniotomies for evaluation of mass lesions for possible brain tumors. Granulomatous chronic inflammatory reaction and amebic trophozoites were found in brain biopsies. At autopsy, areas of hemorrhagic encephalomalacia were located in both basal frontal lobes, right parieto-occipital lobes, and, less often, in the brain stem and cerebellum. Angiitis, necrotizing granulomatous encephalitis, and large numbers of amebic trophozoites in perivascular spaces were present. Amebic trophozoites were seen in the left adrenal gland in one of the cases. The amebas in all four cases were identified as Balamuthia mandrillaris (Leptomyxiidae) based on their reactivity with the anti-Balamuthia (Leptomyxiidae) serum in an test. Granulomatous amebic encephalitis (GAE) is a clinico pathologic entity produced by several species of Acantham oeba. ‘-@ Recently, however, several cases of GAE have been identified caused by a new type of free-living ameba that belongs to the order Leptomyxida.5 6 Most of the re ported cases of GAE have occurred in association with chronic debilitating diseases with mm)4 Granulomatous amebic encephalitis has an insidious onset and progresses to a subacute or chronic infection eventually leading to death. Focal neurologic deficits and signs of in tracranial hypertension are usually present. Neuroimaging studies disclose space-occupying masses in the brain. The penetration into the central nervous system (CNS) is prob ably from hematogenous spread from a primary focus in the upper respiratory tract or skin. Also, the amebic tro phozoites or cysts can reach the CNS directly through the olfactory neuroepithelium. Granulomatous amebic enceph alitis should be differentiated from primary amebic menin goencephalitis (PAM) produced by Naegleria fowleri. Pri mary amebic memngoencephalitis has a different clinical course, characterized by an acute and fulminant neurologic disease in healthy individuals with a recent history of water sport-related activities.' Granulomatous amebic encephali tis should also be differentiated from brain abscesses pro duced by Entamoeba histolytica, which may come from hepatic or pulmonary foci. As of October 1995, more than 200 cases of PAM due to N. fowleri and as many as 100

cases of GAE due to Acanthamoeba

spp. lens

es.

have

than

200

cases

Patient clinical data and other pertinent information are given in Table 1. The patients were clinically evaluated in the Neurosurgery Department of the Centro Medico de Oc cidente (Guadalajara, Mexico). The GAE histopathologic di agnosis was made in our hospital, and the serologic diag nosis was made at the Centers for Disease Control and Pre vention (Atlanta, GA). In all patients, a complete blood count with differential and platelet counts and tests for glu cose, blood urea nitrogen, creatinine, liver function (total protein, albumin, globulin, albumin:globulin ratio, aspartate aminotransferase, alanine aminotransferase, lactate dehydro genase, gamma-glutamyl transpeptidase, total bilirubin, total cholesterol, alkaline phosphatase), and human immunodefi ciency virus (HIV) were performed. In addition, in pediatric patients, physical growth was evaluated using percentiles)° Ethical review and informed consent issues were addressed through normal hospital procedures. Indirect immunofluorescent test (HF). Naegleriafowleri does not produce cysts in the CNS tissue of PAM patients. However, both Acanthamoeba and Balamuthia are known to produce cysts in the CNS sections of GAE cases. Amebic cysts were seen in brain sections of all four patients. How ever, based on the staining and morphologic characteristics of the cysts at the light microscopic level (scanning electron microscopy was not done), it was not possible to identify the actual species of ameba involved. Indirect immunofluo rescence tests using rabbit antisera made against a number of different species of Acanthamoeba as well as Balamuthia

spp. and leptomyxid

amebas have been reported worldwide. Acanthamoeba can also produce keratitis in persons wearing contact More

PATIENTS AND METHODS

of Acanthamoeba

keratitis

mandrillaris

(leptomyxid

ameba)

were

performed

with

the

ameba-containing tissue sections.5 6 These tests were done by the Centers for Disease Control and Prevention (Atlanta, GA).

been reported during recent years.'4 In Mexico, however, only a few cases of cerebral infection due to free-living amebas (PAM and GAE) have been reported.79 We now report four new cases of GAE due to Balamuthia mandril laris (leptomyxid arneba) with a clinical manifestation of space-occupying mass lesions.

RESULTS

The clinical pictures of these four cases were basically similar and were characterized by the presence of space 603

604

RIESTRA-CASTANEDA

AND OTHERS

TABLE

1

Data on patients ClinicalCase no.Age (years)Sexcourse scans133M>6Headaches,

history and associated illnessPathology'Computed

(days)Clinical

nausea, vomiting, fever, meningismCh,

lobes29M>30Headache,

tomography

GR, Infi, Troph, CystsHigh

vomiting, visual

GR, Infi,

disturbances, papilledema, fever, left hemiparesis, meningismCh, vomiting, sei zures, dysphagias, nystag mus, papilledema, Babin

parietotemporal314M>90Headaches,

frontotemporal43M>30Headaches,

density frontal

lesion, base

density lesion, right

Troph, CystsHigh

GR, Infi, Troph, CystsHypodense

lesion, left

ski+Ch, vomiting, Ch

=

chronic;

OR = granulomatous

reaction; Infi = inflammation:

identified

as being

due to B. mandrillaris

described

pathogenic

(leptomyxid

ame

ameba.5 6

DISCUSSION

In Latin America, the term amebiasis is usually applied to E. histolytica traintestinal

GR, Infi,

lesion, left

Troph, CystsHypodense

Troph = trophozoites.

occupying masses in the CNS (Figures 1 and 2). None of the patients had a predisposing or underlying disease or any known state of immunosuppression. Test results for HIV were negative and other routine laboratory tests results were within normal ranges, showing no anemia or hepatic dys function in the pediathc cases. The adult patient had mild anemia (hemoglobin level = 1 1.2 g/dL; normal range = 13.5—18.0 g/dL). Quantitation of immunoglobulin levels was not determined. There were some epidemiologic features in the patients we studied. They all lived in poor suburban areas of the city and had a low socioeconomic level, and we pos tulate that they had poor hygienic habits. The adult patient was a worker at the city's sewer system. On admission, pediatric patients had low (ranging be tween 5 and 10) growth percentiles, which is not uncommon for children from this socioeconomic level. However, it is not known if this finding was because of their illness. The histopathologic features of these cases were those of a chron ic inflammatory encephalitis with the presence of granuloma, amebic trophozoites, and cysts within the lesions (Figure 3). Case no. 3, in particular, showed a profuse lymphoplasma cytic infiltrate and astrocytosis. The amebic organisms failed to show any reactivity in the HF test with antisera against several species of Acantham oeba, but they reacted with the anti-Balamuthia (leptomyxid ameba) serum. These four new Mexican cases were therefore ba), a recently

sei

zures, nystagmusCh,

frontotemporala

infection, which manifests as intestinal or cx infection, with the latter affecting liver (hepatic),

pulmonary, and very rarely skin, genital, or brain tissue. In Mexico, as well as in other Latin American countries, ame bic disease due to E. histolytica is a common public health problem, mainly because of socioeconomic, ecologic, and climatologic factors.― Recently, however, a few cases of in fection with free-living amebas have been reported,@ and it is believed that many more cases may exist. Granulomatous amebic encephalitis has been reported from all continents. One of the etiologic agents, Acantham

oeba, is a ubiquitous ameba that has been isolated from a variety of sources in nature including soil, water, sewage, thermal effluents, heating, ventilation and air-conditioning units, toxic waste dump sites, ocean sediments, vegetables, contact lens paraphernalia, and secretions from the respira tory tract of apparently healthy individuals, as well as bac tenal, fungal, and mammalian cell ul'2 Character istically,

GAE

has

been

described

in

patients

who

have

chronic, debilitating diseases or who are immunosuppressed. Occasionally, it has been described in patients without known intercurrent or associated as9t3-23 There are some similarities between the cases of GAE produced by Acanthamoeba sp. and those produced by B. mandrillaris. In our cases, none of the patients appeared to have a predisposing or underlying disease or any known state of immunosuppression. However, it is possible that some of these patients did have an underlying, unknown inherited immunodeficiency state that was not detected be cause immunologic evaluation was not performed. The spon taneous GAE in these patients may be related to malnutrition (our pediatric cases scored on the lower percentiles) or to a more aggressive or virulent nature of Balamuthia amebas, which might produce disease in individuals with an as yet poorly understood minor immunologic deficiencies. The amebic organisms failed to show any reactivity with antisera against several species of Acanthamoeba and N. fowleri but they reacted with the anti-Balamuthia serum. So far, no characteristic clinical symptoms, laboratory findings, or radiologic indicators have been found to be di agnostic

for GAE.

The

neuroimaging

findings

show

hetero

geneous, hyperdense, nonenhancing, space-occupying le sions. Whether single or multiple, they involve mainly the cerebral cortex and subcortical white matter. These findings suggest a CNS neoplasm, tuberculoma, or septic (bacterial or fungal) inf2 In these cases, a tentative diagnosis based on the CT scan could be a meningioma or a malignant glial neoplasm, or even a primitive neuroectodermal tumor of the early infancy. Brain biopsy could be a method for confirming the diag nosis. Frozen sections should provide the definitive diagno sis in patients

phozoites be easily

in which

GAE

is suspected.

The

amebic

tro

and cysts, even if present in small numbers, can identified because of their characteristic nuclear

AMEBICENCEPHALITISDUE TO BALAMUTHIA IN MEXICO

605

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a I@ 4'.

A

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B FIGURE

1.

A,

Computed

tomography

scan

of

the

head

of patient

1 . There

is a midline

hyperdense

lesion

(arrow)

at the

base

of the

lobes with contrast enhancement. B, Autopsy material from the same patient showing a mass lesion (arrow) at the same location.

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F@ouan2. Computed tomography scan of the head of patient 2 with contrast material. A high-contrast enhancement is observed over the right parieto-temporal areas (arrow).

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FIGuRE 3. Autopsy material of a central nervous (arrow) (hematoxylin and eosin stained, magnification

. S

.

system section X 250).

from patient

,I'

.

2 showing

a perivascular

cuffing

by amebic

trophozoites

AMEBIC

morphology. identify

ENCEPHALITIS

DUE

the etiologic

agent as Acanthamoeba

or Balamuthia

tions because cysts of both Acanthamoeba sp. and Balamu thia are characterized by a double wall with an outer rippled or wrinkled wall under light 18-23However, immunofluorescence or immunoperoxidase techniques using selected antisera may be helpful in distinguishing the organ isms. The frequency of GAE should be studied, taking into ac count the distribution and ecologic factors of different areas as well as the virulence of the strain. The factors related to the immunologic integrity of the host and the environment should also be evaluated. There is no known effective treatment for GAE. A Ni gerian patient with Acanthamoeba infection reportedly ira proved with sulfamethazine therapy but was subsequently lost to follow-up.'@ Two Indian patients apparently recov ered from an Acanthamoeba infection after treatment with ch1oramphenicol'@ and cotrimoxazole.24 In those cases, Acanthamoeba

trophozoites

were

isolated

in culture

from

the

cerebrospinal fluid. In vitro assays indicate that ketocona zole, propamidine isethionate, clotrimazole, and certain big uanides@ have amebicidal activity. Acknowledgments:

We thank Drs. Magdicarla

de Alba, Raul Duran,

Jorge A. Torres, and Francisco Esparragoza for helpful cooperation

and assistance. Financial support: This work was partially supported by Radio Imagenes de Occidente S.C. (RIO). Authors' addresses: Juan M. Riestra Castaneda, Roberto Riestra Castaneda,

Andres

A. Gonzalez

Garrido,

Jose L. Oropeza

de Alba,

and Salvador Gonzalez Cornejo, Laboratorio de Microcirugia de Base de Craneo, Departamento de Neurologia y Neurocirugia, Hos pital Civil de Guadalajara, Calle Hospital 278, Torre de Especiali

dades, 8vo. Piso, Guadalajara, Jalisco, Codigo Postal 44280, Mcxi co. Patricio Pena Moreno and Florentino Jardon Careaga, Departa mento de Patologia, Centro Medico de Occidente, Biblioteca, Insti flito Mexicano del Seguro Social, Apartado Postal No. 2-784, Guadalajara, Jalisco, Cidigo Postal 44280, Mexico. A. Julio Mar

tinez and Govinda S. Visvesvara, Parasitic Diseases Branch, Mail stop F13, Division of Parasitic Diseases, National Center for Infec tious Diseases, Centers for Disease Control and Prevention, 4770 Buford Highway NE, Atlanta, GA 30341-3724.

Is Acanthamoeba

encephalitis

an opportu

mstic infection? Neurology 30: 567—574. 3. Martinez AJ, Garcia CA, Halks-Miller M, Arce-Vela R, 1980. Granulomatous amebic encephalitis presenting as a cerebral mass lesion. Acta Neuropathol (Berl) 55: 85—91.

4. Visvesvara GS, Stehr-Grenn JK, 1990. Epidemiology of free living ameba infections. J Protozool 37: 255—335.

5. Visvesvara GS, Martinez AJ, Shutter FL, Leitch GJ, Wallace SV, Sawyer TK, Anderson M, 1990. Leptomyxid ameba, a new agent of amebic meningoencephalitis in humans and an imals.

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