Granulomatous Amoebic Encephalitis Mimicking Neuromyelitis Optica Spectrum Disorder

Clinical Correspondence Section Editors: Robert Avery, DO Karl C. Golnik, MD Caroline Froment, MD, PhD An-Guor Wang, MD Granulomatous Amoebic Encephalitis Mimicking Neuromyelitis Optica Spectrum Disorder Christina E. Douglas, MD, Matthew L. Haynie, MD, Geoffrey A. Weinberg, MD, Mahlon D. Johnson, MD, PhD, Rajnish Bharadwaj, MBBS, PhD, Zoë R. Williams, MD N euromyelitis optica spectrum disorder (NMOSD) is rare and can be difficult to diagnose. Typically, it presents with optic neuritis, characteristic MRI findings, and often seropositivity for aquaporin-4 (AQP4) or myelin oligodendrocyte (MOG) antibodies. Several clinical mimickers of NMOSD have been reported—ADEM, MS, and metabolic conditions such as biotinidase deficiency (1,2). Here, we report a case of granulomatous amoebic encephalitis (GAE) caused by Balamuthia mandrillaris in a healthy 6-year-old girl, which presented clinically as NMOSD. A 6-year-old girl presented to the emergency department for new esotropia, ataxia, dizziness, emesis, and headaches. She was born in Puerto Rico, moved to New York at 15 months old, and had not traveled outside NY state since. She lived at home with her parents, sister, and 2 dogs. She had a history of pruritic skin rash on her face and arms, which was diagnosed as scabies. Dermatologic evaluation was consistent with postinflammatory hypopigmentation and xerosis. She subsequently was admitted to an outside hospital for headaches, anorexia, emesis, and fever. Noncontrast MRI of the brain was normal. An abdominal x-ray showed moderate stool burden, and she was treated for delayed gastric emptying. One week before admission to our hospital, pediatric ophthalmologic evaluation demonstrated minimal refractive error, normal ocular motility and alignment, gaze-evoked nystagmus, and normal fundus examination. Initial neuro-ophthalmologic evaluation on admission to UR Golisano Children’s Hospital demonstrated decreased visual acuity bilaterally (20/50 in the right Department of Ophthalmology (CD, MH, ZRW), University of Rochester Medical Center, Flaum Eye Institute, Rochester, New York; Department of Pediatrics (GAW), University of Rochester Medical Center, University of Rochester Golisano Children’s Hospital, Rochester, New York; Department of Pathology and Laboratory Medicine (MDJ, RB), University of Rochester Medical Center, Rochester, New York; Department of Neurosurgery (ZRW), University of Rochester Medical Center, Strong Memorial Hospital, Rochester, New York; and Department of Neurology (ZRW), University of Rochester Medical Center, Strong Memorial Hospital, Rochester, New York. The authors report no conflicts of interest. Address correspondence to Zoë R. Williams, MD, Department of Neurosurgery, Flaum Eye Institute, University of Rochester Medical Center, 210 Crittenden Boulevard, Rochester, NY 14642; E-mail: [e-mail] Douglas et al: J Neuro-Ophthalmol 2022; 42: e473-e475 eye, 20/30 in the left eye), an esotropia that worsened on right gaze, gaze-evoked nystagmus, and decreased right facial sensation in CN V1-3 distribution. There was no relative afferent pupillary defect (RAPD), and fundus examination was normal. Contrast MRI brain revealed an infiltrative nodular enhancement along the walls of the third and fourth ventricles as well as diffuse leptomeningeal enhancement (Fig. 1A). Her neuroimaging was believed to be most suggestive of the central nervous system (CNS) germinoma. Cerebrospinal fluid analysis demonstrated elevated protein (95 mg/dL), decreased glucose (33 mg/dL), and 200 nucleated cells with lymphocytic predominance (76%). Gram stain and bacterial/fungal/acid fast bacillus cultures were negative. Flow cytometry was negative for lymphoma. Inflammatory markers, including sedimentation rate and c-reactive protein, were normal. Biopsy of the fourth ventricular mass demonstrated chronic inflammation with lymphocytes, plasma cells, histiocytes, and giant cells associated with necrosis. Stains for mycobacteria, bacteria, fungi, and encysted amoeba were negative. HSV-1 and HSV-2, varicella-zoster, Epstein–Barr virus, and Toxoplasma immunoreactivity were also negative. She was not treated empirically with antibiotics or corticosteroids before biopsy. Given her negative infectious workup, NMOSD was considered, and NMO/AQP4 antibody was ordered (resulted as negative 12 days later). Repeat MRI brain and orbits 1 week later demonstrated interval development of diffuse enhancement of the prechiasmal optic nerves extending to the optic chiasm and tracts (Fig. 1B). She was treated with methylprednisolone followed by plasma exchange. After a few days of improvement, she rapidly decompensated. Interval evaluation demonstrated new left partial CN III paresis and a right gaze palsy as well as new trace right RAPD and temporal pallor of the right optic disc. Interval MRI brain demonstrated new ring-enhancing lesions, with hemorrhage in several of the lesions. She developed cerebral edema, which was refractory to treatment, and died 25 days after hospital admission. Autopsy revealed widespread CNS necrosis with numerous leptomeningeal and parenchymal amoebic forms, which were confirmed to be B. mandrillaris by DNA polymerase chain reaction (PCR) (Fig. 2). e473 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Correspondence FIG. 1. A. Sagittal fat-suppressed T1-weighted MRI with contrast (left) and axial T1-weighted MRI with contrast (right) at presentation demonstrating infiltrative nodular enhancement along the walls of the third ventricle (solid circle), cerebral aqueduct (long arrow), fourth ventricle (dashed circle), and foramen of Luschka (short arrow) and Magendie (arrowhead). B. Axial T1–weighted fat-suppressed MRI with contrast 1 week after presentation demonstrating interval development of diffuse enhancement of the prechiasmal optic nerves (dashed circle, left image) extending to the optic chiasm (dashed circle, right image) and tracts (more prominently on left side) (long arrow). Short arrows depict regions of infiltrative nodular enhancement in the midbrain. GAE is a rare, life-threatening CNS infection caused by primarily 2 types of free-living amoeba, Acanthamoeba and Balamuthia. B.alamuthia mandrillaris is found in soil and freshwater with a global distribution of cases. Epidemiologic studies show predominance in men, patients of Hispanic ethnicity, and in the southwestern United States (3,4). Amoebic encephalitis is typically associated with an immunocompromised state and afflicts patients of all ages. Infections in immunocompetent children are increasingly reported because of greater awareness of the disease and the use of immunofluorescence staining and molecular detection techniques. Portals of entry for the amoeba include nasal mucosa, skin, and lungs with hematogenous dissemination to the CNS. Patients often report exposure to soil (85%); however, in many cases, there is no readily apparent source of infection (3). Pruritic midface or upper extremity rash can be an important indicator of the infectious etiology. Clinical presentation of GAE varies but is often insidious and can simulate tumor or granulomatous disease. Common neurologic features with GAE are mental status changes, seizures, weakness, ataxia, and hemiparesis (3). Nonspecific symptoms such as fever and headache are frequent. Cranial nerve palsies, especially CN III–VI, are common. Neuroimaging characteristically shows either ringenhancing lesions or peripheral contrast enhancement in 75% of cases (5). Other “typical” neuroimaging characteristics in GAE lesions are hypodensity on CT scan (48%), hypointensity on T1-weighted (34%), and hyperintensity on T2-weighted (45%) MRI (5). Intralesional hemorrhage on CT, gradient echo, or other MRI sequences is also fairly common. Edema and mass effect are commonly reported, 62% and 48%, respectively (5). The neuroimaging features are nonspecific and require a high level of clinical suspicion for amoebic encephalitis. Clinicians must distinguish between antibody-negative NMSOD and other conditions mimicking NMSOD. Cerebrospinal fluid of patients with Balamuthia GAE often shows pleocytosis with lymphocytic predominance and elevated protein similar to NMOSD. Balamuthia is rarely isolated in CSF by PCR, and brain tissue is usually necessary to achieve a diagnosis (3). However, as in this case, special stains of brain tissue for amoeba can be negative. The gold standard for diagnosis of GAE due to Balamuthia is FIG. 2. Hematoxylin and eosin (H&E)-stained brain tissue from autopsy specimen demonstrating angiocentric inflammation at lower magnification (left). Higher magnification of the same slide demonstrating B. mandrillaris (arrow) and additional amoeba at 6 o’clock (asterisk) (right). e474 Douglas et al: J Neuro-Ophthalmol 2022; 42: e473-e475 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Correspondence immunofluorescent staining of brain tissue (available through the Centers for Disease Control and Prevention). The mortality rate is over 90% with antemortem diagnosis made in less than one-third of cases (2). Survivors have been treated with a combination of macrolide antibiotic (azithromycin or clarithromycin), flucytosine, sulfadiazine, pentamidine, fluconazole, and miltefosine because they have shown amebicidal activity in vitro (3). Encephalitis constitutes a significant cause of morbidity and mortality in the United States and often poses a diagnostic challenge with fewer than half of cases having an identifiable etiology. Balamuthia should be considered early in the differential diagnosis of patients with encephalitis of unknown origin and remains a possible etiology unless ruled out by negative molecular diagnosis. Awareness of Balamuthia and early initiation of antimicrobial therapy is crucial for better clinical outcomes. STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: C. E. Douglas, G. A. Weinberg, and Z. R. Williams; b. Acquisition of data: M. L. Haynie, Z. R. Williams, G. A. Weinberg, R. Bharadwaj, and M. D. Johnson; c. Analysis and interpretation of data: Z. R. Williams, G. A. Weinberg, R. Douglas et al: J Neuro-Ophthalmol 2022; 42: e473-e475 Bharadwaj, and M. D. Johnson. Category 2: a. Drafting the manuscript: C. E. Douglas, M. L. Haynie, Z. R. Williams, and G. A. Weinberg; b. Revising it for intellectual content: Z. R. Williams, G. A. Weinberg, R. Bharadwaj, and M. D. Johnson. Category 3: a. Final approval of the completed manuscript: C. E. Douglas, M. L. Haynie, G. A. Weinberg, R. Bharadwaj, M. D. Johnson, and Z. R. Williams. REFERENCES 1. Kim SM, Kim SJ, Lee HJ, Kuroda H, Palace J, Fujihara K. Differential diagnosis of neuromyelitis optica spectrum disorders. Ther Adv Neurol Disord. 2017;10:265–289. 2. Dutra BG, da Rocha AJ, Nunes RH, Maia ACM Jr. Neuromyelitis optica spectrum disorders: spectrum of MR imaging findings and their differential diagnosis. Radiographics. 2018 JanFeb;38(1):169-193. Erratum in. Radiographics. 2018;38:662. 3. Cope JR, Landa J, Nethercut H, Collier SA, Glaser C, Moser M, Puttagunta R, Yoder JS, Ali IK, Roy SL. The epidemiology and clinical features of Balamuthia mandrillaris disease in the United States, 1974-2016. Clin Infect Dis. 2019; 68:1815– 1822. 4. Centers for Disease Control and Prevention. Balamuthia amoebic encephalitis—California 1999-2007. MMWR Morb Mort Wkly Rep. 2008;57:768–771. 5. Lukies MW, Watanabe Y, Maeda T, Kusakabe S, Arita H, Tomiyama N. Amoebic encephalitis: case report and literature review of neuroimaging findings. BJR Case Rep. 2016;2:20150499. e475 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.