JAMA CLINICAL CHALLENGE

Frontal Headache
A

Figure 1. Left, Cranial computed tomography showing discrete obliteration of the sulci. Right, Fluid-attenuated inversion recovery magnetic resonance imaging showing hyperintensity in the frontal, temporal, and occipital lobes (figure reprinted from Arch Neurol. 2010;67[12]:1516-15201).

Huan J. Chang, MD, MPH Gianna Zuccotti, MD 47-YEAR-OLD BRAZILIAN WOMAN PRESENTED TO A WALK-IN CLINIC REPORTing a headache of 8 days duration that started in the frontal area and evolved into a holocranial headache. The intensity progressively worsened, and she developed vomiting 2 days earlier. She denied having a fever. Past medical history was significant only for systemic arterial hypertension. There was no history of diabetes mellitus or other comorbidities. She did not drink alcohol. Physical examination revealed mild neck stiffness and a nonfocal neurological examination. Funduscopy findings were normal. The patient had no lymphadenopathy, fever, or skin alterations. An emergency cranial computed tomographic scan showed discrete sulcus obliteration (FIGURE 1, left). Magnetic resonance imaging (MRI) showed hyperintensity in the frontal, temporal, and occipital lobes (Figure 1, right).

What Would You Do Next? A. Admit the patient to the hospital and start intravenous acyclovir B. Admit the patient to the hospital to obtain a cerebrospinal fluid sample C. Obtain a neurosurgical evaluation for a brain biopsy D. Order an emergency magnetic resonance angiogram (MRA) of the brain See www.jama.com for online Clinical Challenge.

Author Affiliation: Dr Chang (tina.chang@jama-archives.org) and Dr Zuccotti are both Contributing Editors, JAMA. Dr Zuccotti is also with Partners Healthcare, Boston, Massachusetts. JAMA Clinical Challenge Section Editor: Huan J. Chang, MD, Contributing Editor. We encourage authors to submit papers for consideration as a JAMA Clinical Challenge. Please contact Dr Chang at tina.chang@jama-archives.org.

2011 American Medical Association. All rights reserved.

JAMA, July 20, 2011Vol 306, No. 3 317

JAMA CLINICAL CHALLENGE

Diagnosis Granulomatous amoebic encephalitis (caused by Balamuthia mandrillaris) What to Do Next B. Admit the patient to the hospital to obtain a cerebrospinal fluid (CSF) sample The key clinical feature in this case is to know the appropriate workup for a person with a frontal lobe headache and abnormal imaging results. Regardless of the final diagnosis, the next step in diagnosing this patients problems should be obtaining a CSF sample via lumbar puncture or ventriculostomy. Comment Granulomatous amoebic encephalitis (GAE) is a rare and sporadic central nervous system infection caused by freeliving amoebae. Infection is characterized by a subacute or chronic, slowly progressive meningoencephalitis. Disease can occur in both immunocompetent and immunocompromised individuals. The involvement of free-living amoebae in human diseases was only recognized after 1965, when the first fatal cases of meningoencephalitis were described in Australia and the United States.2 Free-living amoeba species causing central nervous system involvement include Naegleria fowleri, Acanthamoeba species, and B mandrillaris.3,4 Infection with B mandrillaris is thought to be acquired via direct skin inoculation or inhalation of cysts present in soil. The diagnosis of GAE is difficult because there are no pathognomonic symptoms.5,6 Available methods for laboratory diagnosis include histologic analysis of hematoxylin-eosinstained specimens and detection of amoebae in tissue samples and serum antibodies using indirectimmunofluorescence.Cellculture, polymerase chain reaction, and cerebrospinal fluid analysis3 may also be done. Most cases are identified in retrospective postmortem studies.3,6 Computed tomography and MRI generally show 1 or more contrast-enhanced lesions that are nonspecific and can be seen in other conditions such as fungal or bacterial infections, tuberculoma, toxoplasmosis,
318 JAMA, July 20, 2011Vol 306, No. 3

Figure 2. Histopathologic examination of the cerebellum showing a vessel completely filled with trophozoites (hematoxylin-eosin, original magnification 400) (figure reprinted from Arch Neurol. 2010;67[12]:1516-15201).

or neoplasms.6 Magnetic resonance imaging reveals hyperintense multifocal lesions on T2-weighted images that show a heterogeneous or ringlike enhancement. Lesions are preferentially located in the diencephalon, brainstem, and structures of the posterior cranial fossa.7 A brain biopsy is important for the diagnosis of GAE.8 MRA would be used to rule out central nervous system vasculitis. Although the majority of cases of GAE are fatal attempts to treat with combination therapy, regimens including pentamidine, fluconazole, sulfadiazine, flucytosine, azithromycin, and clarithromycin have been administered to 3 patients who successfully recovered.9,10 The differential diagnosis in this patient includes primary angiitis of the central nervous system, vasculitis, giant cell arteritis, and infection by a broad range of viruses, fungi, Mycobacterium tuberculosis, and other protozoa. On admission, lumbar puncture showed an elevated openingpressure(44cmH2O),proteinlevel of 131 mg/dL, glucose level of 57 mg/dL, and39nucleatedcells(69%lymphocytes, 12%neutrophils,15%monocytes,and4% plasma cells). Results of Gram staining, acid-fast staining, and oncotic cytologic analysis were negative. The VDRL test results were nonreactive. Cultures for fungi and M tuberculosis were negative. After lumbar puncture, this patient was treated for presumed herpes encephalitis with intravenous acyclovir without resolution. The patient died 15 days after hospital admission.Histopathologicanalysisrevealed

extensive areas of necrosis and hemorrhage in the cerebellum, fibrinoid necrotizing panarteritis, some thrombosis, granulomatous lymphoplasmacytic inflammatoryinfiltrate,foamymacrophages, isolated multinucleated giant cells, and incipientformationofperivasculargranulomas. Different structures (isolated or forming small clusters) with the morphological characteristics of amoeba trophozoites were identified in the vascular wall and in areas with and without an inflammatory reaction (FIGURE 2). The patient had no skin lesions; the probable route of invasion of the pathogen might have been the respiratory tract, followed by hematogenic dissemination to the central nervous system.
Conflict of Interest Disclosures: Both authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported. Additional Information: This JAMA Clinical Challenge is based on a previously published article (Silva RA, Araujo SA, Avellar IF, et al. Granulomatous amoebic me ningoencephalitis in an immunocompetent patient. Arch Neurol. 2010;67[12]:1516-1520).

REFERENCES 1. Silva RA, Araujo SA, Avellar IF, Pittella JE, Oliveira JT, Christo PP. Granulomatous amoebic meningoencephalitis in an immunocompetent patient. Arch Neurol. 2010;67(12):1516-1520. 2. Foronda AS. Infeccoes por Amebas de Vida Livre: Tratado de Infectologia. 3rd ed. Vol 2. Sao Paulo, Bra zil: Editora Atheneu; 2005:1461-1470. 3. Cuevas P M, Smoje P G, Jofre M L, et al. Granulo matous amoebic meningoencephalitis by Balamuthia mandrillaris: case report and literature review [in Spanish]. Rev Chilena Infectol. 2006;23(3):237242. 4. Oddo B D, Ciani A S, Vial C P. Granulomatous ame bic encephalitis caused by Balamuthia mandrillaris: first case diagnosed in Chile [in Spanish]. Rev Chilena Infectol. 2006;23(3):232-236. 5. Balamuthia amebic encephalitis California, 1999-2007. JAMA. 2008;300(21):2477-2479. doi: 10.1001/jama.300.21.2477. 6. Deol I, Robledo L, Meza A, Visvesvara GS, Andrews RJ. Encephalitis due to a free-living amoeba (Balamuthia mandrillaris): case report with literature review. Surg Neurol. 2000;53(6):611-616. 7. Singh P, Kochhar R, Vashishta RK, et al. Amebic meningoencephalitis: spectrum of imaging findings. AJNR Am J Neuroradiol. 2006;27(6):1217-1221. 8. Guarner J, Bartlett J, Shieh WJ, Paddock CD, Visvesvara GS, Zaki SR. Histopathologic spectrum and immunohistochemical diagnosis of amebic meningoencephalitis. Mod Pathol. 2007;20(12): 1230-1237. 9. Deetz TR, Sawyer MH, Billman G, Schuster FL, Visvesvara GS. Successful treatment of Balamuthia amoebic encephalitis: presentation of 2 cases. Clin Infect Dis. 2003;37(10):1304-1312. 10. Jung S, Schelper RL, Visvesvara GS, Chang HT. Balamuthia mandrillaris meningoencephalitis in an immunocompetent patient: an unusual clinical course and a favorable outcome. Arch Pathol Lab Med. 2004; 128(4):466-468.

2011 American Medical Association. All rights reserved.