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RAIN Clinicopathologic Conference 2018

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RAIN Clinicopathologic Conference 2018 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 1/282/283/284/285/286/287/288/289/2810/2811/2812/2813/2814/2815/2816/2817/2818/2819/2820/2821/2822/2823/2824/2825/2826/2827/2828/28 MRI Brain on admission MRI Brain on admission T2 TRACE T1 PRE + POST 1/692/693/694/695/696/697/698/699/6910/6911/6912/6913/6914/6915/6916/6917/6918/6919/6920/6921/6922/6923/6924/6925/6926/6927/6928/6929/6930/6931/6932/6933/6934/6935/6936/6937/6938/6939/6940/6941/6942/6943/6944/6945/6946/6947/6948/6949/6950/6951/6952/6953/6954/6955/6956/6957/6958/6959/6960/6961/6962/6963/6964/6965/6966/6967/6968/6969/69 1/252/253/254/255/256/257/258/259/2510/2511/2512/2513/2514/2515/2516/2517/2518/2519/2520/2521/2522/2523/2524/2525/25 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 3 2/16/2018 Repeat MRI Brain on Day 10 of hospitalization Additional thoughts? T1 POST Dr. Felicia Chow 1/272/273/274/275/276/277/278/279/2710/2711/2712/2713/2714/2715/2716/2717/2718/2719/2720/2721/2722/2723/2724/2725/2726/2727/27 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 5 2/16/2018 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 6 2/16/2018 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 7 2/16/2018 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 10 2/16/2018 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 11 2/16/2018 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
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