2/16/2018

Case

 ID: 74 year old Chinese woman with past medical history of rheumatoid RAIN Clinicopathologic arthritis, who presents with fevers and altered mental status.  HPI. Conference 2018  2 weeks prior to presentation – had L vision loss.  Diagnosed with endophthalmitis, unknown cause, treated with intravitreal vancomycin, ceftazidime, and voriconazole x 2.

 CT chest noted incidental LLL cavitary lesion

Dr. Chris McGraw, MD, PhD  Started empiric treatment for Toxo (systemic pyrimethamine and sulfadiazine) due to Department of Neurology elevated serum Toxo IgM. Dr. Melike Pekmezci, MD  1 week prior to presentation – had AMS with neck tenderness. Department of Pathology  Diagnosed with multifocal strokes and had full stroke work-up Dr. Felicia Chow, MD  Cardiac monitor with pAFib. Negative TTE. Department of Neurology  Started warfarin for secondary stroke prevention  Started prednisone taper for unclear reasons (?concern for vasculitis) University of California San Francisco  Day of presentation (2 days following discharge from prior admission) – obtunded 2/16/2018  Presented to TB clinic for scheduled outpatient evaluation.  Transferred to ED, promptly intubated, admitted to ICU

Case Case Comatose, GCS 6/15  PMH. RA, HTN, R glaucoma, L endophthalmitis, ?strokes. Trip to Guangzhou, China  Medication. Warfarin, Sulfadiazine, Pyrimethamine, leucovorin, Prednisone 20mg. Hydroxychloroquine 200, Metoprolol, Timolol. MRI brain multifocal infarcts  SH. Moved from China 8 years ago. Last visit 4 mos ago. Independent ADLs at baseline. Loss of vision L eye  FH. No history of malignancy, autoimmune or neurologic Lung cavitary lesion disease.  Physical exam. Altered mental status  Gen. Fever 103°F, tachycardic 111, normotensive 120s

 Neuro. GCS 6(E1,Vt,M5). L pupil 6mm fixed. Intact cornea, #1 #2 #3 #4 VOR. Weak gag/cough.  Labs. 3 months 013 23 28293234  CBC. WBC 11.6 (80% PMNs, 11% Lymphs, 5% monos, 2.2% eos) prior  Unremarkable BMP, LFTs. HIV negative. Days since onset of illness

1 2/16/2018

Initial thoughts? MRI Brain on admission  Dr. Felicia Chow T2 FLAIR

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MRI Brain on admission MRI Brain on admission T2 TRACE T1 PRE + POST

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2 2/16/2018

Routine Labs Microbiology Basic metabolic panel Na 146, K 4.8, CL 118, CO2 22, BUN 40, Creat Cerebrospinal fluid (CSF) Hospital course – initial treatment 0.99, EGFR 55 #1 Appearance, cell Clear, WBC 347H (57% PMN, Complete blood count WBC 17.0 (90% neut, 5% lymph, 2.5% monos, count, diff, glucose, 11%Mono, 31% Lympho, 3% eos), 0.3% eos). Hb 9.2, MCV 89.5, Plts 165.  protein RBC 13, glc 30L, protein 71H. Initial work-up concerning for toxoplasmosis vs Ammonia 72 H Gram stain. Many PMNs, no organisms. nocardia abscesses > TB meningoencephalitis TSH 0.08 (uU/mL) L Bacterial/fungal/AFB Negative Free T4 0.30 (ng/dL) L Cryptococcal Ag Negative Empiric antibiotics covering toxo + nocardia: Rheumatological (CrAg) Toxo PCR Negative  Ampicillin 2g q6 ANA 1:640 H Rheumatoid Factor 429 H CSF VDRL Non reactive  Cefepime 2g Q12 CRP 151.2 H CSF VZV PCR/IgG/IgM Negative  Metronidazole 500 q8 Microbiology #2 Appearance, cell Clear, WBC 123H (50% PMN, 17% (HD#9) count, diff, glucose, mono, 30% lympho, 3% eos). RBC  Vancomycin Serum Blood cultures (multiple) No growth protein 2. Glc 36L, protein 210H HIV Ab Negative Mixed inflammatory infiltrate, no  Sulfadiazine/Pyrimethamine Cytology malignant cells Toxo PCR/IgM/IgG Negative #3 Appearance, cell Xanthochromic, WBC 123 (50% Steroids tapered off Coccidioides IgM/IgG Negative (HD#13) count, diff, glucose, PMN, 17% mono, 30% lympho, 3% AFB smear Negative x 3 protein eos). RBC 2, glc 36L, prot 210H. RPR Non reactive Diagnostic imaging Trach No organisms, no Gram stain/Culture Chest CT (OSH) LLL cavitary lesion aspirate growth. Transthoracic Negative No e/o valvular disease MTB PCR Echocardiogram Urine Histoplasma Ag Negative CT Angio No flow limiting stenoses

Hospital course – response to treatment Repeat MRI Brain on Day 10 of hospitalization T2 FLAIR

 Patient continued to decline rapidly over the 1st 10 days of hospitalization HD#1  Intermittently febrile despite antibiotics  GCS declining. Initially 6  4 (E1, VT, M3)  2 (E1, VT, M1). Unreactive pupils. Breathing spontaneously.  Brain biopsy #1 was obtained on HD#4 – unimpressive.  Repeat MRI brain on HD#10.

HD#10

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Repeat MRI Brain on Day 10 of hospitalization Additional thoughts?

T1 POST  Dr. Felicia Chow

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Hospital course – treatment change Hospital course – response to treatment change

 Given clinical and radiographic deterioration,  Worsening hemodynamic stability empiric treatment for toxo was discontinued, and  Worsening mass effect of lesions causing empiric treatment for TB / cocci was started on communicating hydrocephalus HD#10-11.  Extraventricular drain (EVD) is placed for CSF diversion  Rifampin, Isoniazid, Pyrazinamide, Ethambutol HD#13, with elevated ICPs noted  Moxifloxacin  Methylprednisone to reduce swelling  Amphotericin  Worsening exam.  Repeat brain biopsy was obtained on HD#11  No cough/gag.  Patient transitioned to comfort care and expires HD#17.

4 2/16/2018

Additional thoughts? Additional diagnostic studies

 Dr. Felicia Chow  Two brain biopsies were obtained  CSF was sent for next generation sequencing

Pathology Biopsy #1 (day 4)  Dr. Melike Pekmezci • Clinical • Klebsiella (urine) • Toxoplasmosis IgM+ • Cavitary lung lesion (TB?) • Embolism per initial imaging (? Bacterial source) • Imaging (multiple lesions with reduced diffusion and central enhancement) • Toxoplasmosis • Nocardia • Cryptococcus • PML • Lymphoma/metastasis

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Diagnosis: Mild white matter gliosis

• No inflammatory component or other features to suggest an infectious process • The findings are mild and nonspecific • Unclear whether the biopsy material is representative of the radiographic abnormality

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Biopsy #2 (day 11) • Clinical • Klebsiella (urine) • Toxoplasmosis IgM+ • Cavitary lung lesion (TB?) • Embolism per initial imaging (? Bacterial source) • Imaging (multiple lesions with reduced diffusion and central enhancement) • Toxoplasmosis • Nocardia • Cryptococcus • PML • Lymphoma/metastasis

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CD20 CD3 Prebiopsy differential diagnosis

• Clinical • Klebsiella (urine) • Toxoplasmosis IgM+ • Cavitary lung lesion (TB?) • Embolism per initial imaging (? Bacterial source) • Imaging (multiple lesions with reduced diffusion and central enhancement) • Toxoplasmosis • Nocardia • Cryptococcus • PML • Lymphoma/metastasis

8 2/16/2018

Vasculitis – Fibrinoid necrosis Vasculitis – Fibrinoid necrosis Lymphocytes, eosinophils, neutrophils Lymphocytes, eosinophils, neutrophils

• Primary CNS vasculitis • Primary CNS vasculitis • Primary angiitis of CNS • Systemic diseases • Aβ-related angiitis • PAN, eosinophilic granulomatous polyangiitis • Systemic Lupus Erythematosis • Rheumatoid arthritis

Necrotizing vasculitis- SLE Vasculitis – Fibrinoid necrosis Lymphocytes, eosinophils, neutrophils

• Primary CNS vasculitis • Systemic diseases • Infectious • Bacterial: Treponema (syphilis), Borrelia (lyme) • Viral: VZV, HCV, HIV • Fungal: Aspergillus, Mucor, Candida, Coccidioides

9 2/16/2018

Vasculitis – Fibrinoid necrosis Aspergillus Lymphocytes, eosinophils, neutrophils

• Primary CNS vasculitis • Systemic diseases • Infectious • Bacterial: Treponema (syphilis), Borrelia (lyme) • Viral: VZV, HCV, HIV • Fungal: Aspergillus, Mucor, Candida, Coccidioides • Protozoal: Toxoplasmosis, Trypanosomiasis, Amebiasis

Vasculitis – Fibrinoid necrosis Toxoplasmosis Lymphocytes, eosinophils, neutrophils

• Primary CNS vasculitis • Systemic diseases • Infectious • Bacterial: Treponema (syphilis), Borrelia (lyme) • Viral: VZV, HCV, HIV • Fungal: Aspergillus, Mucor, Candida, Coccidioides • Protozoal: Toxoplasmosis, Trypanosomiasis, Amebiasis • Nematodes: Toxocariasis • Trematodes: Schistosomiasis • Cestodes: Neurocysticercosis- cerebrovascular form

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Infectious disease stains Diagnosis: Necrotizing vasculitis • PAS and GMS stains are negative for fungal organisms • Gram stain is negative for gram-positive bacteria • Stains for infectious organisms are negative • Steiner stain is negative for spirochete organisms • There is no evidence of lymphoma • • Immunohistochemistry for toxoplasmosis is negative Correlation with serologic / rheumatologic findings

Metagenomic Deep Sequencing Now what? (CSF from day 9)

BIOINFORMATICS

Nextgendiagnostics.ucsf.edu

Wilson MR, et al. Ann Neurol. 2015;78(5):722-30. PMID: 26290222

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Bioinformatics of MDS Re-review of pathology

19,642,946 reads 5.2 gigabases

Align to reference human genome

33,093 candidate non- human reads 0.000412%Additional of filteringall reads for human sequences and 0.54% of knownnon-human contaminants reads 15,021 non-human reads

Align with known pathogen genes in library 81 reads map to Balamuthia mandrillaris

Diagnosis: Amebic encephalitis Confirming the diagnosis- Multiplex PCR

Qvarnstrom Y, J Clin Microbiol. 2006;44(10):3589-95.

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Classifying the Organism -DPH Classifying the Organism - DPH

Section of brain with cluster of Balamuthia amebas (green) and few red blood cells.

Classifying the Organism - CDC Amebic CNS infections Primary amebic “Granulomatous” Cerebral “Sappina” Meningo- amebic Amebiasis encephalitis encephalitis encephalitis • Local meningitis • Fulminant acute • Vasculitis • Necrotic • Cerebral abscess meningo-encephalitis • Focal necrosis hemorrhagic brain • Rapid • neutrophils • Mixed inflammation lesion progression • Predominantly • Delayed CNS • Large trophozoites • Fatal in 72 hours meninges infection (few with two nuclei • Frontal lobe orbital months) attached to each surface • Fatal within 1wk- other • 95% fatal in 1-14 days 6mo (1mo) • No eosinophils or granulomas

A. castellani Entamoeba Naegleria fowleri A. polyphaga Sappina diploidea histolytica B. mandrillaris

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Amebic meningoencephalitis Balamuthia mandrillaris  free-living ameba (single-celled living organism) found naturally in the environment  Unclear environmental niche  Isolated from soil and dust, possibly also water-borne  Exposure may be common, but disease caused by Balamuthia is rare  Infection occurs by inhalation of airborne cysts or direct skin inoculation  Causes granulomatous amebic encephalitis (GAE) when organisms travel from lower respiratory tract/sinuses or skin via hematogenous route to the meninges and brain.  First described in 1989 – since then 200 cases have been reported worldwide  During 1974-2014 in the US, 94 Balamuthia cases reported to CDC  More deaths from Balamuthia than Rabies since 1990  Both immunocompentent and immunocompromised hosts  Disproportionate involvement of patients with Hispanic ethnicitity among US cases (33%, n= 29/88)

Guarner J, et al. Mod Pathol. 2007;20(12):1230-7. PMID: 17932496

Clinical features of Balamuthia GAE Diagnosis of Balamuthia GAE

 Incubation period – unknown  Imaging  In disseminated infections with preceding cutaneous involvement, few weeks to ~2 years may elapse between initial skin lesions  CNS involvement  MRI. Early. One or a few ring-enhancing lesions with mass effect +/- hemorrhage.  Exposure via solid organ transplant more quickly – few days to weeks (range 12-24 days) Late. Increasing size (up to 3-4cm) and number, involving  Symptoms cerebral hemispheres, cerebellum, brainstem, and thalamus.  Gradual, progress over weeks to months  Laboratory testing  Early symptoms of GAE   Personality and mental status changes (can occur in isolation) CSF. Elevated WBC (usually <500, lymphocytic predominant), Glucose normal to low, elevated protein (may be mild in early disease, but later >1000  Meningitic symptoms (headache, stiff neck, photophobia) mg/dL).  Nausea, vomiting, lethargy, fever.  Organisms only rarely seen.  Diplopia, impaired speech, ataxia, or other focal neurologic deficits  Organism-specific testing – if concerned, call CDC.  Seizures  Most often fatal as multifocal brain lesions compromise brain function  Real-time PCR testing (CDC only)  Antecedent findings  IHC/IIF on tissue sections with antibody specific for B. mandrillaris  rhinitis with sinus infections, otitis media,  Serology – not routine (seropositivity observed in healthy persons)  skin lesions  Culture. Axenic cultures with eukaryotic cells (specific for B.  Single >> multiple. Location = face (nose, cheeks), oral cavity (soft palate) > torso or limbs mandrillaris)  Chronic, granulomatous, erythematous plate-like areas enlarging over time  Experimental – next generation sequencing.  Painless, but can ulcerate Lorenzo-Morales et al 2013 Trends in Parasitol

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Treatment of Balamuthia GAE Conclusions  Only ~10 of 200 reported cases have survived  Balamuthia mandrillaris is a free-living ameba  In some cases, survivors had complete return to normal function without reported sequelae associated with granulomatous amebic encephalitis  Early diagnosis and treatment may increase odds of survival (GAE)  CDC recommends combination therapy with:  Affects immunocompetent patients 1. Pentamidine 4mg/kg qD  more cases than rabies in the last 10 years! 2. Sulfadiazine 1.5g q6h (adults), 200mg/kg/day (peds) 3. Flucytosine 37.5 mg/kg q6h  Diagnosis requires specialized testing 4. Fluconazole 12 mg/kg/day  Should contact CDC if suspicion is high (multifocal 5. Azithromycin 20 mg/kg/day encephalitis with negative studies) 6. Miltefosine 150mg daily (in US, only available through IND filed by CDC)  Usually fatal, but 5% of patients have survived  Duration of treatment. Several weeks to several  Treatment requires aggressive combination therapy months/years.

Thank you to all involved in this very challenging References  Baig AM. Pathogenesis of amoebic encephalitis: Are the amoebae being • Onyango CO, et al. Evaluation of a TaqMan Array Card for Detection of Central credited to an 'inside job' done by the host immune response? Acta Trop. Nervous System Infections. J Clin Microbiol. 2017;55(7):2035-2044. PMID: case 2015;148:72-6. PMID: 25930186 28404679  CDC. Investigational drug available directly from CDC for the treatment of • Qvarnstrom Y, et al. Multiplex real-time PCR assay for simultaneous detection of infections with free-living amebae. MMWR (2013) 62;33:666 Acanthamoeba spp., Balamuthia mandrillaris, and Naegleria fowleri. J Clin   Detering H, et al. First Draft Genome Sequence of Balamuthia mandrillaris, Microbiol. 2006;44(10):3589-95. PMID: 17021087 Dr. Barbara Haller – SFGH Microbiology the Causative Agent of Amoebic Encephalitis. Genome Announc. 2015 • Schuster FL. Cultivation of pathogenic and opportunistic free-living amebas. Clin 24;3(5). PMID: 26404594 Microbiol Rev. 2002;15(3):342-54. Review. PMID: 12097243  Dr. Andrew Bollen – UCSF Neuropath  Greninger AL, et al. Clinical metagenomic identification of Balamuthia • Schuster FL, et al. Balamuthia amebic encephalitis risk, Hispanic Americans. mandrillaris encephalitis and assembly of the draft genome: the continuing Emerg Infect Dis. 2004;10(8):1510-2. PMID: 15503402 case for reference genome sequencing. Genome Med. 2015;7:113. PMID: • Schuster FL, et al. Under the radar: balamuthia amebic encephalitis. Clin Infect  Dr. Matt Wood – UCSF Neuropath 26620704 Dis. 2009;48(7):879-87. PMID: 19236272  Guarner J, et al. Histopathologic spectrum and immunohistochemical • Schuster FL, et al. Balamuthia mandrillaris, agent of amebic encephalitis: diagnosis of amebic meningoencephalitis. Mod Pathol. 2007;20(12):1230-7. detection of serum antibodies and antigenic similarity of isolates by enzyme  Dr. Mike Reid – UCSF Infectious Disease PMID: 17932496 immunoassay. J Eukaryot Microbiol. 2008;55(4):313-20. PMID: 18681845  Itoh K, et al. An autopsy case of Balamuthia mandrillaris amoebic • Tavares M, et al. Diagnosis of first case of Balamuthia amoebic encephalitis in  Dr. Niraj Shanbhag – UCSF Neurology encephalitis, a rare emerging infectious disease, with a brief review of the Portugal by immunofluorescence and PCR. J Clin Microbiol. 2006;44(7):2660-3. cases reported in Japan. Neuropathology. 2015;35(1):64-9. PMID: 25186798 PMID: 16825409  Khurana S, et al. Emergence of Balamuthia mandrillaris • van der Beek NA, et al. Fatal Balamuthia mandrillaris Meningoencephalitis in the  Dr. Mike Wilson – Derisi Lab meningoencephalitis in India. Indian J Med Microbiol. 2015;33(2):298-300. Netherlands after Travel to The Gambia. Emerg Infect Dis. 2015;21(5):896-8. PMID: 25865989 PMID: 25897644  Kiderlen AF, et al. Assessment of Balamuthia mandrillaris-specific serum • Visvesvara GS, et al. Leptomyxid ameba, a new agent of amebic  Dr. Carole Glaser – DPH antibody concentrations by flow cytometry. Parasitol Res. 2009;104(3):663- meningoencephalitis in humans and animals. J Clin Microbiol. 1990 28(12):2750- 70. PMID: 19039606 6. Review. PMID: 2280005  Many many others  Kodet R, et al. Amebic encephalitis caused by Balamuthia mandrillaris in a • Wilson MR, et al. Diagnosing Balamuthia mandrillaris Encephalitis With Czech child: description of the first case from Europe. Pathol Res Pract. Metagenomic Deep Sequencing. Ann Neurol. 2015;78(5):722-30. PMID: 1998;194(6):423-9. PMID: 9689651 26290222.  Latifi AR, et al. Presence of Balamuthia mandrillaris in hot springs from • Yagi S, et al. Detection of Balamuthia mitochondrial 16S rRNA gene DNA in Mazandaran province, northern Iran. Epidemiol Infect. 2016;144(11):2456- clinical specimens by PCR. J Clin Microbiol. 2005;43(7):3192-7. PMID: 16000434 For more information related to metagenomic deep sequencing, 61. PMID: 27086943  Martínez AJ. Granulomatous amebic encephalitis: a review and report of a please visit: http://nextgendiagnostics.ucsf.edu spontaneous case from Venezuela. Acta Neuropathol. 1994;87(4):430-4. PMID: 8017178.

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Infectious Workup

 Toxoplasma IgM: positive Confirmation at Palo Alto Toxoplasma Serology Lab: -Vitreous fluid Toxo PCR -Serum Toxo IgM Elisa -Serum Toxo IgG Avidity Negative -Serum Toxo IgG Dye test

 Neurocysticercosis  Bacteria cultures (?septic emboli from endocarditis)  Disseminated drug-resistant Klebsiella  TB meningitis  Nocardial abscess  HIV Negative  Cryptococcus  Coccidioidomycosis  Histoplasma

Parasites MRI Brain on admission

Metazoa Protozoa  Innumerable (>20) contrast- enhancing reduced diffusion Platyhelmin lesions throughout the supra Nematodes Ciliates Flagellates ths and infratentorial brain  Many lesions demonstrate Balantidum coli Giardia central nodular enhancement  Minimal vasogenic edema Coccidia Amebas associated with these lesions

Toxoplasma Entameba Balamuthia gondii histolytica

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Repeat MRI Brain Day 10 of hospitalization Parasites • Marked interval progression of enhancing and non- enhancing supra and infra tentotorial intraparenchymal Protozoa Metazoa lesions. (helminths) • majority of lesions Flagellates Coccidia Nematodes Platyhelminths demonstrate central nodular Eg. Toxoplasma gondii Eg. Giardia lamblia (roundworms) (flatworms) and rim-enhancement with Eg. Ascaris lumbricoides associated reduced diffusion. Ciliates Amebas Eg. Balantidium coli Eg. Entamoeba histolytica, • Development of extensive BalamuthiaBalamuthia mandrillaris Cestodes Trematodes basal meningoencephalitis (tapeworms) (flukes) Eg. Taenia solium and leptomeningeal Eg. Schistosoma spp enhancement (cysticercosis)

Background: Free-Living Amebas References

1. Lobo SA, Patil K, Jain S et al. Diagnostic challenges in Balamuthia mandrillaris infections. Parasitol Res (2013) 112:4015-  Ameba = “to change” 4019  2 forms: 2. Centers for Disease Control and Prevention, www.cdc.gov 3. CDC. Investigational drug available directly from CDC for the treatment of infections with free-living amebae. MMWR -Cyst = nonmotile, resting stage, -Trophozoite = motile, feeding (2013) 62;33:666

resistant to environment stage, “to nourish” 4. CDC. Transplant-transmitted Balamuthia mandrillaris. Arizona, 2010. MMWR (2010) 59:1182

5. Jayasekera S, Matin A, Sissons J et al. Balamuthia mandrillaris stimulates interleukin-6 release in primary human brain microvascular endothelial cells via a phosphatidylinositol 3-kinase-dependent pathway. Micr and Infect (2005) 7:1345- 1351

6. Kiderlen AF, Tata PS, Ozel M et al. Cytopathogenicity of Balamuthia mandrillaris , an opprtunistic causative agent of granulomatous amebic encephalitis. J Euk Micro (2006) 53;6: 456-463

7. LaFleur M, Joyner D, Schlakman B et al. Balamuthia mandrillaris meningoencephalitis associated with solid organ transplantation – review of cases. Radiology Case (2013) 7;9:9-18

8. Lorenzo-Morales J, Cabello-Vilchez AM, Martin-Navarro CM et al. Is Balamuthia mandrillaris a public health concern worldwide? Trends in Parasitol (2013) 29;10:483-488

9. Parija SC, Dinoop KP, Venugopal H. Management of granulomatous amebic encephalitis: laboratory diagnosis and  Four genera known to infect humans: treatment. Trop Parasitol (2015) 5;1:23-28 1) Naegleria fowleri – acute primary amebic meningoencephalitis (PAM) 10. Siddiqui R and Khan NA. Balamuthia amoebic encephalitis: An emerging disease with fatal consequences. Microbial Pathogen (2008) 44: 89-97

2) Acanthamoeba – lung/skin infections, ulcerative keratitis, subacute-to- 11. Siddiqui R and Khan NA. Balamuthia mandrillaris: Morphology, biology, and virulence. Trop Parasitol (2015) 5;1:15-22

12. Trabelsi H, Dendana F, Sellami A et al. Pathogenic free-living amoebae: epidemiology and clinical review. Pathol Biol chronic granulomatous amebic encephalitis (GAE) (2012) 60:399-405 Parija SC et al 2015 Trop Parasitol 3) Balamuthia mandrillaris – skin infections, BAE 13. Visvesvara GS. Infections with free-living amebae. Handbook Clin Neurol (2013) 114, chp 10 Trabelsi H et al 2012 Pathol Biol 4) Sappinia Visvesvara 2013 Handbook Clin Neurol

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Repeat MRI Brain on Day 10 of hospitalization 123456789 /0123456789 2/ 82 T2 FLAIR 8

Repeat MRI Brain on Day 10 of hospitalization Repeat MRI Brain on Day 10 of hospitalization

T2 FLAIR T2 TRACE

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Repeat MRI Brain on Day 10 of hospitalization Repeat MRI Brain on Day 10 of hospitalization

T1 T1 POST

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Clinical Presentation1

N=10

Sex Age # days Ethnicity Risk factors CSF WCC CSF Protein beore Presenting hospit al symptoms M 1.5 30 Hispanic Ataxia NA 153 122

M 3 10 Hispanic Seizures, emesis Contact with 540 122 fever flowerpots M 7 Na Hispanic Headache, NA seizures M 7 2 Hispanic Headache, Steroid therapy 78 nml seizures, lethargy M 12 7 Hispanic Headache, emesis, ATV in desert 230 305 Presentation AMS M 19 14 Hispanic AMS, weight loss, IVDU 11 64 • 70% lethargy fever M 35 NA Hispanic Seziures Occ soil exposure 300 647 • 60% headache M 43 14 Caucasian Fever, headache Contact with soil 128 643 • 40% generalizedCN palsy seizures M 72 1 Pacific Headache, fever, Gardening, yard work 188 114 • 40% cranialIslander nervebehavior changespalsies M 64 4 Hispanic Headache, Landscape gardener, 188 114 nausea, AMS alcoholism 1. Schuster, CID, 2009

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RAIN 2018: Clinicopathologic Conference No disclosures

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Turn on the LITES

• Localization 74-year-old woman with rheumatoid • Immune status of the patient arthritis who presents with fevers,

• Tempo of clinical presentation altered mental status, neck tenderness

• Exposure history

• Systemic (extra-neurological) disease

L IT E S Localization

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L I T E S L I T E S

Localization Localization Localization Localization

• Meningitis: inflammation of the meninges • Meningitis: HSV-2, VZV, enteroviruses, LCMV, Mumps, pyogenic • Fever bacteria, Listeria, Brucella, TB, Lyme, Leptospira, Candida, Cryptococcus, • Neck stiffness Cocci, Histoplasmosis, Sporothrix, Angiostrongylus • Decreased level of arousal/change in mental status • Headache • Encephalitis/meningoencephalitis HSV-1, VZV, CMV (+/- • Encephalitis: inflammation of the brain ventriculitis), enterovirus, EBV, JCV, HHV-6, WNV and other flaviviruses, parenchyma Listeria, Bartonella, TB, Whipple’s, Cocci, Histoplasmosis, Naegleria, • Alteration of consciousness or personality change Acanthameba, Balamuthia, Baylisascaris • Fever • Seizures • Focal neurological deficits • Rhombencephalitis: JCV, enterovirus, EBV, WNV and other flaviviruses, Listeria, TB, Brucella • Encephalitis+ • Meningoencephalitis • Encephalomyelitis • Myelitis: HSV 1/2, VZV, CMV, enteroviruses, WNV, HTLV, HIV, syphilis, • Encephalitis + space-occupying lesions Brucella, Schistosoma • Myelitis, myeloradiculitis

• Radiculitis: HSV-2, VZV, CMV, EBV, WNV, Lyme, Brucella,

IndianJMedMicrobiol_2015_33_2_298_154887_u1.jpg Gnathostoma

Immune status of the patient

• Age 74-year-old woman with rheumatoid arthritis who presents with fevers, • History of rheumatoid arthritis

altered mental status, neck tenderness • Hydroxychloroquine

• Prior immunosuppressing medications

L IT E S

Immune status L I T E S

Immune Status

2 2/16/2018

Infectious causes of encephalitis Tempo of clinical presentation IMMUNOCOMPETENT IMMUNOCOMPROMISED • 2 weeks of waxing and waning

• HSV 1/2 • JCV mental status changes, fevers, • VZV • CMV progressive visual loss OS • West Nile • HHV-6 • Actinomyces • EBV • Neurosyphilis • Nocardia • 1 week later: ongoing decline in • Listeria • Listeria • Tuberculosis • Tuberculosis mental status, not recognizing • Brucella • Aspergillus family members; neck pain • Bartonella • Mucor • Coxiella • Fusarium • Cryptococcus • Candida • Coccidioidomycosis • Cryptococcus • 2 days after discharge: wheelchair- • Histoplasmosis • Toxoplasmosis bound, mute, minimally responsive • Sporotrichosis • Acanthameba • Cysticercosis • Balamuthia • Balamuthia L IT E S

L I T E S Tempo

Immune Status Noun Project: Chanut Is Industries

L I T E S

N. meningitidis Fulminant CNS infections Tempo S. pneumoniae H. influenza Staph aureus E coli Gradually Severe, fulminant, Klebsiella Naegleria fowleri ACUTE progressive, rapidly progressive, Enterovirus Influenza steady decline precipitous decline Rickettsia Pseudomonas HSV 1 HSV 2 Leptospirosis VZV EBV P. acnes Listeria WNV Aspergillus Naegleria Coagulase Nocardia Mucor VZV, HSV-2 JCV Balamuthia negative Lyme HHV-6 LCMV Gnathostoma Actinomyces Toxoplasmosis HSV-1 Acanthameba Staph spp Neurosyphilis Acanthameba Cryptococcus Angiostrongylus HHV-6 West Nile N. meningitidis Coccidiodomycosis Rabies CHRONIC Cysticercosis SSPE M. tuberculosis Histoplasmosis CMV T. pallidum Rabies Baylisascaris Echinococcus Blastomycosis JCV Schistosoma Sporotrichosis Brucella, Bartonella, Coxiella S. pneumoniae, H. influenza Tuberculosis Toxoplasmosis Trypanosoma Listeria Nocardia Brucella Bartonella Cysticercosis Candida Actinomyces Balamuthia Coxiella Baylisascaris Aspergillus T. Whipplei Angiostrongylus Gnathostoma Fusarium Mucorales C. neoformans or gattii L I T E S SUBACUTE Coccidioidomycosis, histoplasmosis, blastomycosis, sporotrichosis Tempo

3 2/16/2018

Exposure history / Epidemiologic risk factors • Travel history (within US and international)

• Activities during international travel (rural vs urban)

• Sick contacts Japanese encephalitis, Rabies, Tuberculosis, • Animal and insect exposures Histoplasma, Sporothrix, Talaromyces marneffei, Cysticercosis, • Fresh water swimming Schistosomiasis

• Dietary history (unpasteurized dairy, raw seafood)

• Health-related behaviors: Substance use (IVDU), sexual history Dengue Chikungunya L IT E S

Exposures L I T E S

Exposures https://www.cdc.gov/travel-static/yellowbook/2018/map_4-12.pdf

• Listeria • T. whipplei Endophthalmitis: Inflammation of internal structures Systemic disease • CMV • Enterovirus of eye (vitreous, aqueous, uvea, retina) Bacterial • N. meningitidis • Staph + Strep spp • Nocardia spp • P. acnes • Rickettsia (RMSF) • Other pyogenic bacteria • Leptospirosis • Lyme Fungal • Syphilis • Candida spp • Bartonella • Aspergillus spp • EBV, VZV, HSV-2, • Pyogenic bacteria • Cryptococcus spp WNV, Zika, Measles • Nocardia spp • Mucorales spp • Endemic mycoses • Tuberculosis • Fusarium spp • Cryptococcus • Endemic mycoses • Sporotrichosis • Sporothrix • Cryptoccoccus spp • Endemic mycoses • Balamuthia • Aspergillus spp • Acanthameba spp • Mucorales spp Other • Toxoplasmosis • Tuberculosis • Brucella, Bartonella • Herpesviruses L IT E S • Syphilis L I T E S Systemic disease • Baylisascaris, Toxocara All icons from the Noun Project (clockwise from top left): BomSymbols, Julia Amadeo, Arthur Shlain, Hermine Blanquart Systemic disease https://www.cehjournal.org/article/postoperative-endophthalmitis/

4 2/16/2018

“T2 hyperintensity in the pons concerning for L T infarct….Small areas of restricted diffusion in multiple I E S vascular territories consistent with infarcts”

• Localization: Meningoencephalitis • Meningitis and/or encephalitis + strokes Considerations: • Viral: VZV Viral: • Immune status of the patient: • Bacteria: Pyogenic bacteria, TB, syphilis Immunocompetent *VZV • Fungal: Aspergillus, Mucor, Cryptococcus, Endemic mycoses Bacterial/Mycobacterial: • Parasites/ameba: Gnathostoma • Tempo of clinical presentation: *Tuberculosis Subacute with fulminant decline *Listeria *Nocardia *Syphilis • Encephalitis + space occupying lesions • Exposure history: *Syphilis *Bartonella, Brucella • Bacteria: Nocardia, Actinomyces, pyogenic bacteria, TB Immigrant from China • Fungal: Aspergillus, Mucor, Cryptococcus, Endemic mycoses Fungal: • Systemic (extra-neurological) disease: *Cryptococcus • Parasites/ameba: Toxoplasma, Cysticercosis, Acanthameba, Ocular involvement *Coccidioidomycosis and Balamuthia other endemic mycoses • Other data: Infarcts on MRI

Gradual versus fulminant CNS infection L IT E S

Gradually Severe, fulminant, progressive, rapidly progressive, Leading diagnoses steady decline precipitous decline *Tuberculosis Naegleria VZV, HSV-2 JCV Balamuthia Actinomyces Toxoplasmosis HSV-1 Acanthameba *Cryptococcus HHV-6 West Nile N. meningitidis SSPE M. tuberculosis T. pallidum Rabies Baylisascaris *Free living ameba: Balamuthia Brucella, Bartonella, Coxiella S. pneumoniae, H. influenza

Cysticercosis Candida Listeria Nocardia Gnathostoma Angiostrongylus Aspergillus Fusarium Mucorales C. neoformans or gattii

Coccidioidomycosis, histoplasmosis, blastomycosis, sporotrichosis

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