Table 1.
Reports of infectious encephalitis diagnosed by metagenomic next generation sequencing (mNGS) meeting inclusion criteria.
| Study | Case No. | Age (yrs) | Immunosuppressed? | Specimen Type | Pathogen Identified | Confirmatory testing of metagenomics result | Final Diagnosis | Type of pathogen | Treatment | Outcome |
|---|---|---|---|---|---|---|---|---|---|---|
| Palacios et al. (2008)26 | 1 | 63 | Yes (post solid organ transplantation) | Pooled RNA from brain, cerebrospinal fluid, serum, kidney, and liver | Arenavirus | Viral culture, EM, immunohistochemistry and serology. Donor IgM and IgG positive | Arenavirus Encephalitis | Novel organism | None | Died |
| 2 | 64 | Yes (post solid organ transplantation) | Pooled RNA from brain, cerebrospinal fluid, serum, kidney, and liver | Arenavirus | Viral culture, EM, immunohistochemistry and serology. Seroconversion | Arenavirus Encephalitis | Novel organism | None | Died | |
| 3 | 44 | Yes (post solid organ transplantation) | Pooled RNA from brain, cerebrospinal fluid, serum, kidney, and liver | Arenavirus | Viral culture, EM, immunohistochemistry and serology. | Arenavirus Encephalitis | Novel organism | None | Died | |
| Quan et al. (2010)27 | 4 | 15 | Yes (primary immunodeficiency disorder caused by mutations in the Btk gene, which results in absence of B lymphocytes and serum immunoglobulins) | Brain biopsy | Astrovirus VA1/HMO-C | PCR and antigen detection (IHC) | Astrovirus encephalitis | Novel organism | None | Died |
| Benjamin et al. (2011)28 | 5 | 2 | NR | CSF | Parvovirus 4 | Serum Parvovirus IgM positive, serum and CSF Parvovirus PCR positive. | Parvovirus 4 Encephalitis | Novel cause of encephalitis (known organism) | None | Discharged against medical advice on day 18 after admission |
| 6 | 3 | NR | CSF | Parvovirus 4 | CSF Parvovirus PCR positive | Parvovirus 4 Encephalitis | Novel cause of encephalitis (known organism) | None | Recovered | |
| Tan et al. (2013)29 | 7 | 31 | NR | DNAse treated CSF supernatant | Cyclovirus | PCR | None (unclear association) | Novel organism | None | Recovered |
| 8 | 1 | NR | DNAse treated CSF supernatant | Cyclovirus | PCR | None (unclear association) | Novel organism | None | Recovered | |
| Chan et al. (2014)30 | 9 | NR | NR | Brain Biopsy | Measles virus | PCR and neuropathology | Measles SSPE | Known cause of encephalitis | None | Died |
| 10 | NR | NR | Brain Biopsy | Measles virus | PCR and neuropathology | Measles SSPE | Known cause of encephalitis | None | Died | |
| 11 | NR | NR | Brain Biopsy | HSV1 | PCR and neuropathology | HSV1 Encephalitis | Known cause of encephalitis | None | Died | |
| 12 | NR | NR | Brain Biopsy | HSV1 | PCR and neuropathology | HSV1 Encephalitis | Known cause of encephalitis | None | Died | |
| 14 | NR | NR | Brain Biopsy | HSV1 | PCR and neuropathology | HSV1 Encephalitis | Known cause of encephalitis | None | Died | |
| Wilson et al. (2014)24 | 16 | 14 | Yes ((SCID); partial immune reconstitution after two BMT). | CSF and serum; DNAse treated and untreated | Leptospira santarosai | PCR | Leptospira Meningoencephalitis | Rare | High-dose intravenous penicillin G (13 million units daily). | Recovered |
| Brown et al. (2015)31 | 17 | 1 | Yes (cartilage hair hypoplasia and associated immunodeficiency due to RMRP mutations, peripheral blood stem cell transplant) | Brain Biopsy | Astrovirus VA1/HMO-C | Pan-astrovirus hemi-nested PCR, real-time PCR, IHC and EM in brain biopsy. Real-time PCR in CSF, stool, serum | Astrovirus Encephalitis | Novel organism (emerging cause of encephalitis) | None | Died |
| Frémond et al. (2015)32 | 18 | 14 | Yes (primary immunodeficiency disorder caused by mutations in the Btk gene, which results in absence of B lymphocytes and serum immunoglobulins) | Brain Biopsy | Astrovirus VA1/HMO-C | PCR positive brain (CSF negative) | Astrovirus Encephalitis | Novel organism (emerging cause of encephalitis) | IVIG, ribavirin and PEG-IFN | Some clinical improvement following tailored therapy |
| Greninger et al. (2015)33 | 19 | 15 | No (Type 1 diabetes mellitus and celiac disease) | Brain Biopsy | Balamuthia mandrillaris | PCR and histopathology | Balamuthia mandrillaris Encephalitis | Rare | None (miltefosine was requested but the patient died awaiting treatment) | Died |
| Hoffmann et al. (2015)34 | 20 | 63 | No | Brain Biopsy | Variegated Squirrel Bornavirus | Immunohistochemistry, PCR and neuropathology and serology | Bornavirus Encephalitis | Novel organism | None | Died |
| 21 | 62 | No | Brain Biopsy | Variegated Squirrel Bornavirus | Immunohistochemistry, PCR and neuropathology | Bornavirus Encephalitis | Novel organism | None | Died | |
| 22 | 72 | No | Brain Biopsy | Variegated Squirrel Bornavirus | Immunohistochemistry, PCR and neuropathology | Bornavirus Encephalitis | Novel organism | None | Died | |
| Naccache et al. (2015)35 | 23 | 42 | Yes (CLL with BMT) | Brain Biopsy and CSF (DNAse treated and untreated) | Astrovirus VA1/HMO-C | PCR and immunohistochemistry. | Astrovirus Encephalitis | Novel organism (emerging cause of encephalitis) | Ribavirin and Immunoglobulin | Died |
| Perlejewski et al. (2015)36 | 24 | 60 | No | CSF | HSV1 | PCR and seroconversion | HSV1 Encephalitis | Known cause of encephalitis | Acyclovir | Recovered |
| Phan et al. (2015)37 | 25 | NR | NR | CSF supernatant | Cyclovirus | PCR | None (unclear association) | Novel organism | Not reported | Not reported |
| 26 | NR | NR | CSF supernatant | Gemycircularvirus | PCR | None (unclear association) | Novel organism | Not reported | Not reported | |
| 27 | NR | NR | CSF supernatant | Gemycircularvirus | PCR | None (unclear association) | Novel organism | Not reported | Not reported | |
| 28 | NR | NR | CSF supernatant | Gemycircularvirus | PCR | None (unclear association) | Novel organism | Not reported | Not reported | |
| Wilson et al. (2015)38 | 29 | 74 | Yes (hydroxychloroquine for rheumatoid arthritis) | CSF | Balamuthia mandrillaris | 18S PCR positive CSF, brain biopsy and vitreous fluid; immunohistochemistry and borderline positive serology | Balamuthia mandrillaris Encephalitis | Rare | None | Died |
| Christopeit et al. (2016)39 | 30 | 65 | Yes (chemotherapy, radiotherapy, BMT) | CSF | Fungi – candida tropicalis and fusarium | Candida confirmed by PCR. Fusarium not confirmed. | Fungal encephalitis | Rare | Antifungals (caspofungin, voriconazole, amphotericin) | Died |
| Guan et al. (2016)40 | 31 | NR | NR | CSF | HSV1 | PCR | HSV 1 Encephalitis | Known cause of encephalitis | Acyclovir | Recovered |
| 32 | NR | NR | CSF | HSV1 | PCR | HSV 1 Encephalitis | Known cause of encephalitis | Acyclovir | Recovered | |
| 33 | NR | NR | CSF | HSV2 | PCR | HSV 2 Encephalitis | Known cause of encephalitis | Acyclovir | Recovered | |
| 34 | NR | NR | CSF | VZV | PCR | VZV Encephalitis | Known cause of encephalitis | Acyclovir | Recovered | |
| Kawada et al. (2016)41 | 35 | <1 | NR | CSF | Coxsachievirus A9 | PCR | Coxsachievirus A9 encephalitis | Known cause of encephalitis | Not reported | Not reported |
| 36 | 7 | NR | CSF | Coxsachievirus A9 | PCR | Coxsachievirus A9 encephalitis | Known cause of encephalitis | Not reported | Not reported | |
| 37 | 3 | NR | CSF | Mumps | PCR | Mumps encephalitis | Known cause of encephalitis | Not reported | Not reported | |
| Lum et al. (2016)42 | 38 | <1 | Yes (AML 120 days post-BMT) | FFPE Brain Biopsy | Astrovirus VA1/HMO-C | PCR | Astrovirus VA1/HMO-C encephalitis | Novel organism (emerging cause of encephalitis) | Immunosuppression reduced. | Died |
| Morfopoulou et al. (2016)43 | 39 | <1 | Yes (SCID) | Brain Biopsy | Coronavirus OC43 | PCR and immunohistochemistry. | Coronavirus OC43 Encephalitis | Novel cause of encephalitis (known organism) | Unconditioned cord-blood transplantation, which resulted in T-cell engraftment. | Died |
| Phan et al. (2016)44 | 40 | 6 | NR | Filtered CSF supernatant DNAse treated | Densovirus | PCR, including in CSF re-extracted in different lab | NMDA Encephalitis. Unclear association with densovirus. | Novel organism | High dose IV steroids and rituximab. | Recovered |
| Salzberg et al. (2016)45 | 41 | 16 | NR | Brain Biopsy | JC polyomavirus | Immunohistochemistry and neuropathology | JC encephalitis | Known cause of encephalitis | Not stated. | Not reported |
| 42 | 67 | NR | Brain Biopsy | Mycobacterium tuberculosis | Not confirmed by conventional microbiology (AFB negative) but had necrotising granulomas and responded rapidly to treatment | M. tuberculosis encephalopathy | Known cause of encephalitis | Anti-TB therapy | Recovered | |
| 43 | 44 | Yes (post solid organ transplant) | FFPE Brain Biopsy | EBV | RNA in-situ hybridisation | EBV encephalopathy | Known cause of encephalitis | Immunotherapy modulated | Not reported | |
| Sato et al. (2016)46 | 44 | 4 | Yes (congenital aplastic anaemia since birth and previous cord blood cell transplant and chronic pulmonary graft-versus host disease on immunosuppressants). | CSF | Astrovirus-MLB1 | PCR but only in stool, throat and urine. CSF and serum were PCR negative (suggest due to low viral load) | Astrovirus-MLB1 Encephalitis | Novel cause of encephalitis (known organism) | None | Recovered |
| Mongkolrattanothai et al. (2016)47 | 45 | 11 | No | CSF | Brucella melitensis | PCR and serology. 16S PCR was negative | Neurobrucellosis | Rare | Treated | Recovered |
| Morfopoulou et al. (2017)48 | 46 | 1 | Yes (SCID); BMT | Brain biopsy | Mumps vaccine strain | PCR and immunohistochemistry | Vaccine derived mumps encephalitis | Novel cause of encephalitis (known organism) | None | Died |
NR, not reported; CSF, cerebrospinal fluid; FFPE, formalin fixed paraffin embedded; SCID, severe combined immunodeficiency; BMT, bone marrow transplant; AML, acute myeloid leukaemia; CLL, chronic lymphocytic leukaemia.