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Olie SE, Andersen CØ, van de Beek D, Brouwer MC. Molecular diagnostics in cerebrospinal fluid for the diagnosis of central nervous system infections. Clin Microbiol Rev 2024; 37:e0002124. [PMID: 39404267 PMCID: PMC11629637 DOI: 10.1128/cmr.00021-24] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2024] Open
Abstract
SUMMARYCentral nervous system (CNS) infections can be caused by various pathogens, including bacteria, viruses, fungi, and parasites. Molecular diagnostic methods are pivotal for identifying the different causative pathogens of these infections in clinical settings. The efficacy and specificity of these methods can vary per pathogen involved, and in a substantial part of patients, no pathogen is identified in the cerebrospinal fluid (CSF). Over recent decades, various molecular methodologies have been developed and applied to patients with CNS infections. This review provides an overview of the accuracy of nucleic acid amplification methods in CSF for a diverse range of pathogens, examines the potential value of multiplex PCR panels, and explores the broad-range bacterial and fungal PCR/sequencing panels. In addition, it evaluates innovative molecular approaches to enhance the diagnosis of CNS infections.
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Affiliation(s)
- Sabine E. Olie
- Department of Neurology, Amsterdam UMC, University of Amsterdam, Amsterdam Neuroscience, Amsterdam, the Netherlands
| | - Christian Ø. Andersen
- Statens Serum Institute, Diagnostic Infectious Disease Preparedness, Copenhagen, Denmark
| | - Diederik van de Beek
- Department of Neurology, Amsterdam UMC, University of Amsterdam, Amsterdam Neuroscience, Amsterdam, the Netherlands
| | - Matthijs C. Brouwer
- Department of Neurology, Amsterdam UMC, University of Amsterdam, Amsterdam Neuroscience, Amsterdam, the Netherlands
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2
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Cheawcharnpraparn K, Kanjanaphan T, Lertkovit O, Puripat N, Chavanisakun C, Sirimongkolchaiyakul O, Tangcheewinsirikul S. Epstein-Barr Virus encephalitis associated hemophagocytic lymphohistiocytosis in childhood-onset systemic lupus erythematosus: a case-based review. Pediatr Rheumatol Online J 2024; 22:98. [PMID: 39482670 PMCID: PMC11529320 DOI: 10.1186/s12969-024-01025-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2024] [Accepted: 09/28/2024] [Indexed: 11/03/2024] Open
Abstract
BACKGROUND Hemophagocytic lymphohistiocytosis (HLH) is characterized by immune dysregulation that results in an uncontrolled hyperinflammatory state. HLH is classified into two main categories: primary (familial) HLH and secondary (acquired) HLH. Secondary HLH can result from various underlying, including infection-associated hemophagocytic syndrome (IAHS) and macrophage activation syndrome (MAS) associated with rheumatologic disorders, among others. Epstein-Barr virus (EBV) often causes IAHS, but central nervous system (CNS) involvement is rare among systemic lupus erythematosus (SLE) patients. We report a case of EBV encephalitis associated with HLH in a patient with childhood-onset SLE. CASE PRESENTATION A 12-year-old girl had received a diagnosis of SLE 2 months before presentation. After a period of inactive disease on treatment, fever and seizures, with altered mental status and hallucinations, developed over several weeks. A complete blood cell count (CBC) revealed pancytopenia, accompanied by elevated levels of inflammatory markers: 86 mm/hr erythrocyte sedimentation rate, 8.9 mg/dl c-reactive protein, and 3,966 ng/mL of ferritin. The differential diagnosis included active neuropsychiatric SLE, CNS infection and neurological manifestations in secondary HLH, which could have represented either IAHS or MAS. Meropenem and acyclovir were initially administered for clinical acute encephalitis, followed by pulse methylprednisolone; however, the fever persisted, and another CBC revealed progressive cytopenia. A bone marrow study showed hypocellularity and active hemophagocytic activity, and intravenous immunoglobulin was additionally given due to the diagnosis of HLH. Cerebrospinal fluid (CSF) analysis showed 60/mm3 white blood cells (N 55%, L 45%), 141 mg/dL glucose (0.7 blood-CSF glucose ratio), < 4 mg/dL protein; results of Gram stain and bacterial culture were negative. The viral encephalitis panel from the CSF confirmed EBV infection. Bone marrow immunohistochemistry examination revealed increasing levels of CD8 + T-cell and equivocal positive results for EBV-encoded RNA in situ hybridization; therefore, HLH potentially associated with EBV was diagnosed. After treatment with IVIg, cyclosporin A, and prednisolone, the patient's symptoms gradually improved and she was eventually able to return to school. CONCLUSIONS Our case highlights the importance of a thorough differential diagnosis, including EBV encephalitis associated with HLH, in patients with childhood SLE, particularly in cases of clinical deterioration occurs after initial treatment.
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Affiliation(s)
- Krit Cheawcharnpraparn
- Division of Neurology, Department of Pediatrics, Faculty of Medicine Vajira Hospital, Navamindradhiraj University, Bangkok, Thailand
| | - Thiraporn Kanjanaphan
- Division of Pediatric Infectious, Department of Pediatrics, Faculty of Medicine Vajira Hospital, Navamindradhiraj University, Bangkok, Thailand.
| | - Oranooj Lertkovit
- Division of Hematology and Oncology, Department of Pediatrics, Faculty of Medicine Vajira Hospital, Navamindradhiraj University, Bangkok, Thailand
| | - Napaporn Puripat
- Department of Anatomical Pathology, Faculty of Medicine Vajira Hospital, Navamindradhiraj University, Bangkok, Thailand
| | - Chutima Chavanisakun
- Department of Anatomical Pathology, Faculty of Medicine Vajira Hospital, Navamindradhiraj University, Bangkok, Thailand
| | - Ornatcha Sirimongkolchaiyakul
- Division of Nephrology, Department of Pediatrics, Faculty of Medicine Vajira Hospital, Navamindradhiraj University, Bangkok, Thailand
| | - Sirikarn Tangcheewinsirikul
- Division of Rheumatology, Department of Pediatrics, Faculty of Medicine Vajira Hospital, Navamindradhiraj University, Bangkok, 10300, Thailand.
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3
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Sato K, Watanabe R, Ito I, Imadome KI, Sumi M, Kobayashi H. Successful Treatment of Epstein-Barr Virus Reactivation-associated Transverse Myelitis Following Herpes Zoster with Intravenous Rituximab in a Cord Blood Transplant Recipient. Intern Med 2024; 63:2445-2450. [PMID: 38296479 PMCID: PMC11442935 DOI: 10.2169/internalmedicine.2874-23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2023] [Accepted: 12/04/2023] [Indexed: 09/03/2024] Open
Abstract
The Epstein-Barr virus (EBV) is associated with many malignancies and autoimmune diseases, including multiple sclerosis. In addition, EBV rarely but occasionally causes central nervous system (CNS) complications. We herein report a case of transverse myelitis (TM) associated with systemic EBV reactivation after herpes zoster infection in a cord blood transplant recipient. Identification of EBV-infected peripheral blood cells revealed a predominance of B cells. Notably, intravenous rituximab ameliorated EBV reactivation and TM. Since the CNS infiltration rate of intravenous rituximab is markedly low, the clinical efficacy of rituximab against TM suggests that EBV reactivation may cause TM via immune-mediated mechanisms.
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Affiliation(s)
- Keijiro Sato
- Department of Hematology, Nagano Red Cross Hospital, Japan
| | - Rie Watanabe
- Department of Neurology, Nagano Red Cross Hospital, Japan
| | - Ichiro Ito
- Department of Clinical Pathology, Nagano Red Cross Hospital, Japan
| | - Ken-Ich Imadome
- Department of Advanced Medicine for Virus Infections, National Center for Child Health and Development, Japan
| | - Masahiko Sumi
- Department of Hematology, Nagano Red Cross Hospital, Japan
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Fang M, Li S, Mao Z, Liu X, Wang X, Lu S. A retrospective study on intracranial mixed infection with tuberculous meningitis in Shenzhen, China. Microbiol Spectr 2024; 12:e0374723. [PMID: 38767391 PMCID: PMC11218455 DOI: 10.1128/spectrum.03747-23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2023] [Accepted: 04/24/2024] [Indexed: 05/22/2024] Open
Abstract
Tuberculous meningitis (TBM) is a prevalent global intracranial infection and the most lethal and disabling form of tuberculosis. TBM with mixed intracranial infections is clinically rare but has a higher mortality rate. To investigate the clinical characteristics of TBM with mixed intracranial infections, demographic and clinical data of TBM and pulmonary tuberculosis (PTB) patients admitted to Shenzhen Third People's Hospital between January 2015 and October 2022 were collected anonymously. A total of 207 cases of TBM were diagnosed, of which 16 cases (7.73%) were TBM with mixed intracranial infections. The overall mortality rate of TBM cases was 16.4%, while the mortality rate of TBM cases with mixed intracranial infections was as high as 35.7%. Compared to simple TBM cases, TBM cases with mixed intracranial infections had severer clinical symptoms. The percentage of human immune deficiency virus (HIV)-positive TBM cases with mixed intracranial infections reached up to 68.8%. HIV co-infection, CD4+/CD8+ T-cell counts less than 1, cranial nerve impairment, paralysis, cerebral infarction, PRO less than 450 mg/L, WBC less than 10 × 106 /L, and CL more than 120 mmol/L were risk factors for TBM cases with mixed intracranial infections. Compared to PTB, HIV co-infection, CD4+ T cell less than 550 /uL, and age less than 45 years were risk factors for TBM, and TBM was associated with higher mortality rates. Our study provides additional data to better understand single TBM and TBM with mixed intracranial infections. More than two-thirds of TBM cases with mixed intracranial infections were HIV-positive. Clinicians should consider the possibility of multiple infections in people with TBM/HIV co-infection. IMPORTANCE TBM can cause severe neurological damage and death, and TBM with mixed intracranial infections can exacerbate the damage and poor prognosis of the disease. TBM with mixed intracranial infections is a rare disease, which has led to an incomplete understanding of its clinical features. This study investigated the clinical features of TBM and its associated factors by comparing the characteristics of TBM with mixed intracranial infections, single TBM and pulmonary tuberculosis. This information will help to improve the understanding of TBM, diagnostic accuracy and treatment outcomes.
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Affiliation(s)
- Mutong Fang
- Department of Pulmonary Medicine, Shenzhen Third People’s Hospital, Shenzhen, Guangdong, China
| | - Sinian Li
- Department of Pulmonary Medicine, Shenzhen Third People’s Hospital, Shenzhen, Guangdong, China
| | - Zhi Mao
- Department of Pulmonary Medicine, Shenzhen Third People’s Hospital, Shenzhen, Guangdong, China
| | - Xuhui Liu
- Department of Pulmonary Medicine, Shenzhen Third People’s Hospital, Shenzhen, Guangdong, China
| | - Xiaomin Wang
- National Clinical Research Center for Infectious Diseases, Shenzhen Third People’s Hospital, Shenzhen, Guangdong, China
| | - Shuihua Lu
- Department of Pulmonary Medicine, Shenzhen Third People’s Hospital, Shenzhen, Guangdong, China
- National Clinical Research Center for Infectious Diseases, Shenzhen Third People’s Hospital, Shenzhen, Guangdong, China
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5
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Lu Y, Li S, Su Z, Luo C, Gu M, Yuan D, Qin BE, Dai K, Xia H, Chen Y, Peng F, Jiang Y. Presence of Epstein-Barr virus in cerebrospinal fluid is associated with increased mortality in HIV-negative cryptococcal meningitis. Med Mycol 2024; 62:myae052. [PMID: 38710585 DOI: 10.1093/mmy/myae052] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2023] [Revised: 04/15/2024] [Accepted: 05/05/2024] [Indexed: 05/08/2024] Open
Abstract
Cryptococcus neoformans is the most common cause of fungal meningitis and is associated with a high mortality. The clinical significance of concurrent Epstein-Barr virus (EBV) in the cerebrospinal fluid (CSF) of human immunodeficiency virus (HIV)-negative patients with cryptococcal meningitis (CM) remains unclear. A retrospective cohort study was performed by analyzing CSF samples from 79 HIV-negative Chinese Han patients with confirmed CM. We identified CSF viral DNA in these patients by metagenomic next-generation sequencing (mNGS) and compared 10-week survival rates among those with and without EBV DNA in CSF. Of the 79 CSF samples tested, 44.3% (35/79) had detectable viral DNA in CSF, while 55.7% (44/79) were virus-negative. The most frequent viral pathogen was EBV, which was detected in 22.8% (18/79) patients. The median number of CSF-EBV DNA reads was 4 reads with a range from 1 to 149 reads. The 10-week mortality rates were 22.2% (4/18) in those with positive CSF-EBV and 2.3% (1/44) in those with negative CSF-virus (hazard ratio 8.20, 95% confidence interval [CI] 1.52-81.80; P = 0.014), which remained significant after a multivariate adjustment for the known risk factors of mortality (adjusted hazard ratio 8.15, 95% CI 1.14-92.87; P = 0.037). mNGS can identify viruses that coexist in CSF of HIV-negative patients with CM. EBV DNA is most commonly found together with C. neoformans in CSF and its presence is associated with increased mortality in HIV-negative CM patients.
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Affiliation(s)
- Yi Lu
- Department of Neurology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, PR China
- Department of Neurology, The Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen, Guangdong, PR China
| | - Shubo Li
- Department of Statistics, The Pennsylvania State University, State College, Pennsylvania, USA
| | - Zhihui Su
- Department of Neurology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, PR China
| | - Chongliang Luo
- Division of Public Health Sciences, Washington University School of Medicine in St. Louis, St Louis, Missouri, USA
| | - Meifeng Gu
- Department of Neurology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, PR China
| | - Dasen Yuan
- Department of Neurology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, PR China
| | - Bang-E Qin
- Department of Neurology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, PR China
| | - Kai Dai
- Department of Neurology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, PR China
| | - Han Xia
- Department of Scientific Affairs, Hugobiotech Co, Beijing, PR China
| | - Yong Chen
- Department of Biostatistics, Epidemiology, and Informatics, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Fuhua Peng
- Department of Neurology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, PR China
| | - Ying Jiang
- Department of Neurology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, PR China
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Kuenzli AB, Müller MD, Z`Graggen WJ, Walti LN, Martin Y, Lazarevic V, Schrenzel J, Oberli A. Case report: Chronic Candida albicans meningitis: a rare entity diagnosed by metagenomic next-generation sequencing. Front Cell Infect Microbiol 2024; 14:1322847. [PMID: 38707513 PMCID: PMC11066203 DOI: 10.3389/fcimb.2024.1322847] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2023] [Accepted: 02/07/2024] [Indexed: 05/07/2024] Open
Abstract
The aetiology of chronic aseptic meningitis is difficult to establish. Candida meningitis in particular is often diagnosed late, as cerebrospinal fluid (CSF) work-up and imaging findings are nonspecific. A 35-year-old patient with chronic aseptic meningitis, for which repeated microbiological testing of CSF was unrevealing, was finally diagnosed with Candida albicans (C. albicans) meningitis with cauda equina involvement using metagenomic next-generation sequencing (mNGS). This report highlights the diagnostic challenges and the difficulties of treating shunt-associated fungal meningitis.
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Affiliation(s)
- Andrea B. Kuenzli
- Department of Infectious Diseases, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
- Service d’Infectiologie, Department of Internal Medicine, Neuchâtel Hospital Network, Neuchâtel, Switzerland
| | - Mandy D. Müller
- Department of Neurosurgery, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Werner J. Z`Graggen
- Department of Neurosurgery, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Laura N. Walti
- Department of Infectious Diseases, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Yonas Martin
- Department of Infectious Diseases, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
- Department of General Internal Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Vladimir Lazarevic
- Genomic Research Laboratory, Geneva University Hospitals (HUG) and University of Geneva, Geneva, Switzerland
| | - Jacques Schrenzel
- Genomic Research Laboratory, Geneva University Hospitals (HUG) and University of Geneva, Geneva, Switzerland
| | - Alexander Oberli
- Institute for Infectious Diseases, University of Bern, Bern, Switzerland
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7
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Papantoniou M, Korfias S, Argyrakos T, Aggelidakis P, Tavernarakis A. Primary angiitis of the central nervous system in a patient with transient episodes of headache and aphasia: A case report. Mod Rheumatol Case Rep 2023; 8:117-120. [PMID: 37300559 DOI: 10.1093/mrcr/rxad034] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2023] [Revised: 05/21/2023] [Accepted: 06/08/2023] [Indexed: 06/12/2023]
Abstract
Primary angiitis of the central nervous system (PACNS) refers to a rare form of vasculitis of unknown cause, with a challenging diagnostic work-up. We report the case of a 57-year-old patient who presented with transient episodes of headache and global aphasia. Cerebrospinal fluid (CSF) examination revealed lymphocytic pleocytosis with moderate elevated protein and normal glucose. CSF and serum tests for infections and autoimmune/paraneoplastic antibodies were negative, except CSF polymerase chain reaction testing that detected Epstein-Barr virus (EBV). Magnetic resonance imaging of the brain with intravenous gadolinium showed meningeal enhancement and pachymeningitis. Due to continuous relapsing episodes of aphasia, a leptomeningeal and brain tissue biopsy was performed and revealed lesions of granulomatous necrotising vasculitis of medium-sized leptomeningeal and intracranial vessels, as well as negative in situ hybridism for EBV. A diagnosis of primary granulomatous necrotising angiitis of the central nervous system was made, and the patient was treated with intravenous methylprednisolone and oral cyclophosphamide, showing excellent response to treatment. Diversity in clinical and laboratory features makes it difficult for PACNS to be distinguished by other systemic vasculitides. Laboratory tests and neuroimaging can provide guidance in evaluation of the patients and exclude other possible causes, but tissue biopsy remains the gold standard for a definite diagnosis.
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Affiliation(s)
| | - Stefanos Korfias
- Department of Neurosurgery, Evangelismos General Hospital, Athens, Greece
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Musukuma-Chifulo K, Ghebremichael M, Chilyabanyama ON, Bates M, Munsaka S, Simuyandi M, Chisenga C, Tembo J, Sinkala E, Koralnik IJ, Dang X, Chilengi R, Siddiqi OK. Characterizing Epstein-Barr virus infection of the central nervous system in Zambian adults living with HIV. J Neurovirol 2023; 29:706-712. [PMID: 37902948 DOI: 10.1007/s13365-023-01178-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2023] [Revised: 09/20/2023] [Accepted: 10/12/2023] [Indexed: 11/01/2023]
Abstract
The significance of Epstein-Barr virus (EBV) detection in the cerebrospinal spinal fluid (CSF) in people living with HIV (PLWH) is not entirely understood. The detection of EBV DNA may represent active central nervous system (CNS) infection, reactivation in the setting of another CNS pathogen or due to impaired immunity, or detection of quiescent virus. We screened 470 adult PLWH in Zambia with neurological symptoms for the presence of EBV DNA in the CSF. We performed quantitative EBV PCR on the CSF and blood. We then performed quantitative EBV DNA PCR on the blood of controls with documented HIV viral suppression without CNS symptoms. The prevalence of EBV DNA in the CSF of patients with CNS symptoms was 28.9% (136/470). EBV DNA positivity was associated with younger age, shorter duration of HIV diagnosis, lower CSF glucose levels, higher CSF protein and white blood cell levels, and a positive CSF Mycobacterium tuberculosis result. The median EBV DNA load was 8000 cps/mL in both the CSF and blood with a range of 2000-2,753,000 cps/mL in the CSF and 1000 to 1,871,000 cps/mL in the blood. Molecular screening of CSF for other possible causes of infection identified Mycobacterium tuberculosis in 30.1% and cytomegalovirus (CMV) in 10.5% of samples. EBV DNA load in the blood and CSF was not associated with mortality. Our results suggest that even though EBV DNA was commonly detected in the CSF of our population, it appears to have limited clinical significance regardless of EBV DNA load.
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Affiliation(s)
- Kalo Musukuma-Chifulo
- Department of Biomedical Sciences, School of Health Sciences, The University of Zambia, Lusaka, Zambia.
- Centre for Infectious Diseases Research in Zambia, Lusaka, Zambia.
| | - Musie Ghebremichael
- Harvard Medical School and Ragon Institute of Mass General, MIT and Harvard, Boston, MA, USA
| | | | - Matthew Bates
- HerpeZ, University Teaching Hospital, Lusaka, Zambia
- School of Life & Environmental Sciences, University of Lincoln, Lincoln, UK
| | - Sody Munsaka
- Department of Biomedical Sciences, School of Health Sciences, The University of Zambia, Lusaka, Zambia
| | | | | | - John Tembo
- HerpeZ, University Teaching Hospital, Lusaka, Zambia
| | - Edford Sinkala
- Department of Internal Medicine, University of Zambia School of Medicine, Lusaka, Zambia
| | - Igor J Koralnik
- Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA
| | - Xin Dang
- Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA
| | - Roma Chilengi
- Zambia National Public Health Institute, Ministry of Health, 10101, Lusaka, Zambia
| | - Omar K Siddiqi
- Department of Internal Medicine, University of Zambia School of Medicine, Lusaka, Zambia
- Global Neurology Program, Department of Neurology, Beth Israel Deaconess Medical Center, Boston, MA, USA
- Center for Vaccines and Virology Research, Department of Internal Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA
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Zhang Y, Zheng Y. Leptospirosis-associated meningitis in a patient with sjögren's syndrome: a case report. BMC Infect Dis 2023; 23:778. [PMID: 37946137 PMCID: PMC10636908 DOI: 10.1186/s12879-023-08794-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2023] [Accepted: 11/06/2023] [Indexed: 11/12/2023] Open
Abstract
BACKGROUND Leptospirosis is a zoonotic disease that afflicts both humans and animals. It progresses from flu-like symptoms to more severe hepatic and renal failure, and may also lead to aseptic meningitis. Individuals with autoimmune diseases (ADs) are potentially more susceptible to Leptospirosis. Thus far, limited data has documented the association between Leptospirosis and autoimmune disorders. CASE PRESENTATION The patient had a definitive pathological diagnosis of Sjögren's syndrome (SS). Due to recurrent headaches, the patient sought consultation with a neurologist. Lumbar puncture revealed elevated white blood cells and protein levels in the cerebrospinal fluid, along with decreased glucose. Tuberculous meningitis was suspected. Radiographic imaging exhibited meningeal enhancement, ventricular enlargement, and hydrocephalus. The patient commenced treatment with anti-tuberculosis therapy and corticosteroids. Subsequently, high-throughput sequencing (HTS) of cerebrospinal fluid identified the presence of Leptospira interrogans. The patient was ultimately diagnosed with Leptospiral meningitis, and underwent antimicrobial and immunosuppressive therapy, resulting in stabilization of the condition and gradual symptom recovery. CONCLUSIONS The case highlights the challenges in diagnosing and managing leptospirosis-related meningitis in the presence of ADs and emphasizes the importance of utilizing HTS for accurate pathogen detection. The potential correlation between leptospirosis and SS warrants further investigation, as does the need for multidisciplinary involvement in treatment strategies for such complex cases.
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Affiliation(s)
- Yifan Zhang
- Neurological Center, Shenzhen Baoan People's Hospital, Shenzhen, China
| | - Yong Zheng
- Neurological Center, Shenzhen Baoan People's Hospital, Shenzhen, China.
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10
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He Y, Ma R, Wang HF, Mo XD, Zhang YY, Lyu M, Yan CH, Wang Y, Zhang XH, Xu LP, Liu KY, Sun XJ, Huang YQ. [Clinical significance of Epstein-Barr Virus detection in the cerebrospinal fluid of patients who underwent hematopoietic stem cell transplantation]. ZHONGHUA XUE YE XUE ZA ZHI = ZHONGHUA XUEYEXUE ZAZHI 2023; 44:737-741. [PMID: 38049317 PMCID: PMC10630578 DOI: 10.3760/cma.j.issn.0253-2727.2023.09.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Subscribe] [Scholar Register] [Received: 02/16/2023] [Indexed: 12/06/2023]
Abstract
Objective: To analyze the detection rate, clinical significance, and prognosis of Epstein-Barr virus (EBV) in the cerebrospinal fluid (CSF) of patients following allogeneic hematopoietic stem cell transplantation. Methods: A retrospective analysis was performed on 1100 patients who underwent the CSF virus test after allogeneic hematopoietic stem cell transplantation in Peking University People's Hospital between January 2017 and June 2022. Among them, 19 patients were screened positive for EBV in their CSF, and their clinical characteristics, treatment, and prognosis were analyzed. Results: Among 19 patients with EBV-positive cerebrospinal fluid, 12 were male and 7 were female, with 5 patients aged <18 years and 12 aged ≥18 years, with a median age of 27 (5-58) years old. There were 7 cases of acute myeloid leukemia, 8 of acute lymphocytic leukemia, 2 of aplastic anemia, 1 of Hodgkin's lymphoma, and 1 of hemophagocytic syndrome. All 19 patients underwent haploid hematopoietic stem cell transplantation, including 1 secondary transplant. Nineteen patients had neurological symptoms (headache, dizziness, convulsions, or seizures), of which 13 had fever. Ten cases showed no abnormalities in cranial imaging examination. Among the 19 patients, 6 were diagnosed with EB virus-related central nervous system diseases, with a median diagnosis time of 50 (22-363) days after transplantation. In 9 (47.3%) patients, EBV was detected in their peripheral blood, and they were treated with intravenous infusion of rituximab (including two patients who underwent lumbar puncture and intrathecal injection of rituximab). After treatment, EBV was not detected in seven patients. Among the 19 patients, 2 died from EBV infection and 2 from other causes. Conclusion: In patients who exhibited central nervous system symptoms after allogeneic hematopoietic stem cell transplantation, EBV should be screened as a potential pathogen. EBV detected in the CSF may indicate an infection; however, it does not confirm the diagnosis.
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Affiliation(s)
- Y He
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing 100044, China
| | - R Ma
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing 100044, China
| | - H F Wang
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing 100044, China
| | - X D Mo
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing 100044, China
| | - Y Y Zhang
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing 100044, China
| | - M Lyu
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing 100044, China
| | - C H Yan
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing 100044, China
| | - Y Wang
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing 100044, China
| | - X H Zhang
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing 100044, China
| | - L P Xu
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing 100044, China
| | - K Y Liu
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing 100044, China
| | - X J Sun
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing 100044, China
| | - Y Q Huang
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing 100044, China
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11
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Nguyen ADK, Siu R, Kleinschmidt G, Sood BP, Shandiz EE. Epstein-Barr virus reactivation-related meningoencephalitis with transverse myelitis in pregnancy. Clin Case Rep 2023; 11:e7923. [PMID: 37744622 PMCID: PMC10514378 DOI: 10.1002/ccr3.7923] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2023] [Revised: 08/09/2023] [Accepted: 09/04/2023] [Indexed: 09/26/2023] Open
Abstract
Key Clinical Message Consider the differential of Epstein-Barr virus (EBV) reactivation in pregnant women who develop progressive meningoencephalitis and transverse myelitis. EBV nucleic acid amplification should be considered in immunosuppressed patients. Abstract A 32-year-old G10P6M3K22 pregnant female presented to a regional hospital with progressive severe neurological and behavioral deficits. Magnetic resonance revealed cervical transverse myelitis. Lumbar puncture confirmed Epstein-Barr virus (EBV) DNA on a background of IgG-positive EBV serology. A diagnosis of EBV reactivation-related meningoencephalitis with transverse myelitis in pregnancy was concluded.
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Affiliation(s)
- Andrew Dang Khai Nguyen
- Darling Downs Health Service, Queensland HealthToowoomba HospitalToowoombaQueenslandAustralia
- University of Queensland Rural Clinical SchoolToowoombaQueenslandAustralia
| | - Ronald Siu
- Darling Downs Health Service, Queensland HealthToowoomba HospitalToowoombaQueenslandAustralia
- University of Queensland Rural Clinical SchoolToowoombaQueenslandAustralia
| | - Grant Kleinschmidt
- Darling Downs Health Service, Queensland HealthToowoomba HospitalToowoombaQueenslandAustralia
| | - Bimal Prakash Sood
- Darling Downs Health Service, Queensland HealthToowoomba HospitalToowoombaQueenslandAustralia
- University of Queensland Rural Clinical SchoolToowoombaQueenslandAustralia
| | - Ehsan Esmaili Shandiz
- Darling Downs Health Service, Queensland HealthToowoomba HospitalToowoombaQueenslandAustralia
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12
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Andersen O, Ernberg I, Hedström AK. Treatment Options for Epstein-Barr Virus-Related Disorders of the Central Nervous System. Infect Drug Resist 2023; 16:4599-4620. [PMID: 37465179 PMCID: PMC10351589 DOI: 10.2147/idr.s375624] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2023] [Accepted: 06/28/2023] [Indexed: 07/20/2023] Open
Abstract
Epstein-Barr virus (EBV), a causative agent for several types of lymphomas and mucosal cancers, is a human lymphotropic herpesvirus with the capacity to establish lifelong latent infection. More than 90% of the human population worldwide is infected. The primary infection is usually asymptomatic in childhood, whereas infectious mononucleosis (IM) is common when the infection occurs in adolescence. Primary EBV infection, with or without IM, or reactivation of latent infection in immunocompromised individuals have been associated with a wide range of neurologic conditions, such as encephalitis, meningitis, acute disseminated encephalomyelitis, and cerebellitis. EBV is also involved in malignant lymphomas in the brain. An increasing number of reports on EBV-related disorders of the central nervous system (CNS) including the convincing association with multiple sclerosis (MS) have put in focus EBV-related conditions beyond its established link to malignancies. In this review, we present the clinical manifestations of EBV-related CNS-disorders, put them in the context of known EBV biology and focus on available treatment options and future therapeutic approaches.
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Affiliation(s)
- Oluf Andersen
- Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Ingemar Ernberg
- Department of Microbiology, Tumor and Cell Biology, Biomedicum Q8C, Karolinska Institutet, Stockholm, 171 77, Sweden
| | - Anna Karin Hedström
- Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden
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13
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Abstract
PURPOSE OF REVIEW The most common infectious etiologies of meningitis and encephalitis are viruses. In this review, we will discuss current epidemiology, prevention, diagnosis, and treatment of the most common causes of viral meningitis and encephalitis worldwide. RECENT FINDINGS Viral meningitis and encephalitis are increasingly diagnosed as molecular diagnostic techniques and serologies have become more readily available worldwide but recent progress in novel antiviral therapies remains limited. Emerging and re-emerging viruses that have caused endemic or worldwide outbreaks or epidemics are arboviruses (e.g., West Nile virus, Japanese encephalitis, Tick borne encephalitis, Dengue, Zika, Toscana), enteroviruses (e.g., Enterovirus 71, Enterovirus D68), Parechoviruses, respiratory viruses [e.g., severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), influenza, metapneumoviruses, measles, mumps], and herpes viruses [e.g., herpes simplex virus (HSV) type 1 (HSV-1), HSV-2, human herpes (HV) 6, varicella zoster virus (VZV)]. Future efforts should concentrate in increasing availability for those viruses with effective vaccination [e.g., Japanese encephalitis, Tick borne encephalitis, varicella zoster viruses, SARS-CoV-2, influenza], prompt initiation of those with encephalitis with treatable viruses (e.g., HSV-1, VZV), increasing the diagnostic yield by using novel techniques such as metagenomic sequencing and avoiding unnecessary antibiotics in those with viral meningitis or encephalitis. SUMMARY We review the current epidemiology, clinical presentation, diagnosis, and treatment of the common causative agents of viral meningitis and encephalitis worldwide.
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Affiliation(s)
- Vaishnavi Gundamraj
- Wisconsin Institute of Medical Research, University of Wisconsin-Madison, Madison, Wisconsin
| | - Rodrigo Hasbun
- Professor of Medicine, Section of Infectious Diseases, UT Health McGovern Medical School, Houston, Texas, USA
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14
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Haddad M, Sheybani F, Olfati N, Nahayati MA, Boostani R, Layegh P, Rashid-Nejad A. Central nervous system reactivation of herpesviridae family in patients with COVID-19. J Neurovirol 2023; 29:211-217. [PMID: 37097596 PMCID: PMC10127951 DOI: 10.1007/s13365-023-01132-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2022] [Revised: 03/05/2023] [Accepted: 03/28/2023] [Indexed: 04/26/2023]
Abstract
The objective of this study is to describe our COVID-19 patients with herpesviridae reactivation in the central nervous system (CNS). Four patients were described including two with acute encephalitis and two with acute encephalomyelitis. Three of four patients had abnormal findings on neuroimaging studies. One of four patients died, one survived with major neurological sequelae, and two others fully recovered. Herpesviridae reactivation in the CNS in patients with COVID-19 is a rare but serious coincidence. The optimal therapeutic management has not been investigated and until more information is available, it is prudent to treat these patients with appropriate antivirals with or without anti-inflammatory agents.
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Affiliation(s)
- Mahboubeh Haddad
- Department of Infectious Diseases and Tropical Medicine, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Fereshte Sheybani
- Department of Infectious Diseases and Tropical Medicine, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
| | - Nahid Olfati
- Department of Neurology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mohammad Ali Nahayati
- Department of Neurology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Reza Boostani
- Department of Neurology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Parvaneh Layegh
- Department of Radiology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Azra Rashid-Nejad
- Department of Neurology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
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15
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Kakoullis L, Hentschel C, Colgrove R. Headache, Fever, and Myalgias in an HIV-Positive Male with a History of Tuberculosis: Epstein–Barr Virus Aseptic Meningitis. Trop Med Infect Dis 2023; 8:tropicalmed8040191. [PMID: 37104317 PMCID: PMC10143372 DOI: 10.3390/tropicalmed8040191] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2023] [Revised: 03/17/2023] [Accepted: 03/24/2023] [Indexed: 03/29/2023] Open
Abstract
Background: We describe a case of EBV aseptic meningitis in a patient with HIV with an extensive history of prior infections and exposures. Detailed Case Description: A 35-year-old man with a history of HIV, syphilis, and partially treated tuberculosis presented with headache, fever, and myalgias. He reported recent exposure to dust from a construction site and had sexual contact with a partner with active genital lesions. An initial workup revealed mildly elevated inflammatory markers, significant pulmonary scarring from tuberculosis with a classic “weeping willow sign”, and lumbar puncture findings consistent with aseptic meningitis. An extensive evaluation was conducted to identify causes of bacterial and viral meningitis, including syphilis. Immune reconstitution inflammatory syndrome and isoniazid-induced aseptic meningitis were also considered based on his medications. EBV was ultimately isolated through PCR from the patient’s peripheral blood. The patient’s condition improved, and he was discharged on his home antiretroviral and anti-tuberculous treatment. Conclusion: Central nervous system infections represent unique challenges in patients with HIV. EBV reactivation can present with atypical symptoms and should be considered as a cause of aseptic meningitis in this population.
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Affiliation(s)
- Loukas Kakoullis
- Department of Internal Medicine, Mount Auburn Hospital, Cambridge, MA 02138, USA
- Harvard Medical School, Boston, MA 02138, USA
- Correspondence:
| | - Claudia Hentschel
- Department of Internal Medicine, Mount Auburn Hospital, Cambridge, MA 02138, USA
- Harvard Medical School, Boston, MA 02138, USA
| | - Robert Colgrove
- Harvard Medical School, Boston, MA 02138, USA
- Division of Infectious Diseases, Mount Auburn Hospital, Cambridge, MA 02138, USA
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16
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Dyer Z, Tscharke D, Sutton I, Massey J. From bedside to bench: how existing therapies inform the relationship between Epstein-Barr virus and multiple sclerosis. Clin Transl Immunology 2023; 12:e1437. [PMID: 36844913 PMCID: PMC9947628 DOI: 10.1002/cti2.1437] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2022] [Revised: 01/19/2023] [Accepted: 01/20/2023] [Indexed: 02/25/2023] Open
Abstract
Therapy for relapsing-remitting multiple sclerosis (MS) has advanced dramatically despite incomplete understanding of the cause of the condition. Current treatment involves inducing broad effects on immune cell populations with consequent off-target side effects, and no treatment can completely prevent disability progression. Further therapeutic advancement will require a better understanding of the pathobiology of MS. Interest in the role of Epstein-Barr virus (EBV) in multiple sclerosis has intensified based on strong epidemiological evidence of an association between EBV seroprevalence and MS. Hypotheses proposed to explain the biological relationship between EBV and MS include molecular mimicry, EBV immortalised autoreactive B cells and infection of glial cells by EBV. Examining the interaction between EBV and immunotherapies that have demonstrated efficacy in MS offers clues to the validity of these hypotheses. The efficacy of B cell depleting therapies could be consistent with a hypothesis that EBV-infected B cells drive MS; however, loss of T cell control of B cells does not exacerbate MS. A number of MS therapies invoke change in EBV-specific T cell populations, but pathogenic EBV-specific T cells with cross-reactivity to CNS antigen have not been identified. Immune reconstitution therapies induce EBV viraemia and expansion of EBV-specific T cell clones, but this does not correlate with relapse. Much remains unknown regarding the role of EBV in MS pathogenesis. We discuss future translational research that could fill important knowledge gaps.
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Affiliation(s)
- Zoe Dyer
- Blood Stem Cell and Cancer Research Group, St Vincent's Centre for Applied Medical ResearchDarlinghurstNSWAustralia,St. Vincent's Clinical School, Faculty of MedicineUniversity of New South Wales (UNSW)DarlinghurstNSWAustralia
| | - David Tscharke
- John Curtin School of Medical ResearchAustralian National UniversityCanberraACTAustralia
| | - Ian Sutton
- St. Vincent's Clinical School, Faculty of MedicineUniversity of New South Wales (UNSW)DarlinghurstNSWAustralia,Department of NeurologySt Vincent's ClinicDarlinghurstNSWAustralia
| | - Jennifer Massey
- Blood Stem Cell and Cancer Research Group, St Vincent's Centre for Applied Medical ResearchDarlinghurstNSWAustralia,St. Vincent's Clinical School, Faculty of MedicineUniversity of New South Wales (UNSW)DarlinghurstNSWAustralia,Department of NeurologySt Vincent's ClinicDarlinghurstNSWAustralia,Department of NeurologySt Vincent's HospitalDarlinghurstNSWAustralia
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17
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Shenoy A, Marwaha PK, Worku DA. CD8 Encephalitis in HIV: A Review of This Emerging Entity. J Clin Med 2023; 12:jcm12030770. [PMID: 36769419 PMCID: PMC9917721 DOI: 10.3390/jcm12030770] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2022] [Revised: 01/12/2023] [Accepted: 01/12/2023] [Indexed: 01/20/2023] Open
Abstract
INTRODUCTION Encephalitis is a life-threatening neurological condition with multiple causes in the setting of Human Immunodeficiency Virus (HIV). CD8 Encephalitis (CD8E) is a newly recognised condition which can present in an acute manner, with pertinent features including classical radiological findings with an intense brain parenchymal infiltration of CD8+ T cells. This review attempted to clarify the symptomatology, distribution and determinants of this condition, as well as to examine its vast unknowns. METHODS A literature review was undertaken in July 2022, utilising the PubMed and Google Scholar databases. Papers published between 2006-2022 were reviewed. Eighteen papers, totalling 57 patients, were found and analysed. Statistical analysis was undertaken using Chi-squared and Wilcoxon rank-sum tests as appropriate, with p < 0.05 deemed significant. RESULTS In this review, 57 patients were identified, with a female (61%, 34/56) and Black African (70%, 40/57) preponderance. Females were more likely to present with headache (p = 0.006), and headache was more likely to be present in those who died (p = 0.02). There was no statistically significant association between baseline CD4 count (p = 0.079) and viral load (p = 0.72) with disease outcome. Overall, 77% (41/53) of patients had classical imaging findings, including bilateral gadolinium-enhancing punctate and perivascular white matter lesions. However, many patients (23/57) required a brain biopsy as part of their diagnostic workup. Corticosteroid treatment was commonly prescribed in patients (64%, 35/55) and had a mortality benefit, with an overall survival in this group of 71% (p = 0.0008). In those who died, median survival was 5.5 months. In rare instances, recurrence of the disease was noted, which responded poorly to treatment. DISCUSSION CD8E represents a new and complex condition with few risk factors identified for its occurrence. The presenting symptoms are broad, but headache appears to be more common in females and more significantly associated with death. Though rare, CD8E is likely under-diagnosed, possibly due to overlapping features with other illnesses and lack of physician experience in its recognition and management. Corticosteroids demonstrate a clear mortality benefit, but more studies are required to determine their optimal dosing and duration, as well as the use of steroid-sparing agents. Further reviews should help to better determine the risk factors for the condition, as well as non-invasive biomarkers, to aid in diagnosis and help to predict poor prognosis and disease recurrence.
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Affiliation(s)
- Aniruddh Shenoy
- Haematology, Christie Hospital, Manchester M20 4BX, UK
- Correspondence: (A.S.); (D.A.W.)
| | - Pavan Kaur Marwaha
- Faculty of Medicine, University of Southampton, Southampton SO17 1BJ, UK
| | - Dominic Adam Worku
- Infectious Diseases, Morriston Hospital, Swansea SA6 6NL, UK
- Public Health Wales, Cardiff CF10 4BZ, UK
- Correspondence: (A.S.); (D.A.W.)
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18
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Pangprasertkul S, Sanguansermsri C, Sudjaritruk T. Epstein-Barr virus meningoencephalitis in a young immunocompetent child: A case report. Heliyon 2022; 8:e11150. [PMID: 36299527 PMCID: PMC9589165 DOI: 10.1016/j.heliyon.2022.e11150] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Revised: 08/07/2022] [Accepted: 10/13/2022] [Indexed: 11/06/2022] Open
Abstract
Epstein-Barr virus (EBV) usually causes mild, asymptomatic, and self-recovered infections in young children. Yet, neurological involvement of this virus has been reported. EBV meningoencephalitis is relatively rare in immunocompetent children. Herein, we describe a case of 2-year-old previously healthy girl presented with high-grade fever and exudative tonsillitis. Her neurological examination showed alteration of consciousness and neck stiffness. A history of generalized tonic-clonic seizures was noted. A diagnosis of EBV meningoencephalitis was definitely confirmed by a positive result for serum viral capsid antigen IgM, and a detection of EBV DNA in cerebrospinal fluid. Her neuroimaging studies demonstrated evidence of leptomeningeal enhancements along bilateral parietal cortical sulci and around the brainstem with a hypodense lesion in the left parietal area - the typical findings of EBV meningoencephalitis. This patient was treated with intravenous corticosteroid without antiviral agents. Her clinical symptoms gradually improved. She was discharged from the hospital on the 19th day of hospitalization without neurological sequelae. Although EBV is not a primary causative agent of meningoencephalitis in immunocompetent children, it should always be considered regardless of the presence or absence of classical infectious mononucleosis symptoms. Early recognition and properly treatment are important for a good prognosis.
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Affiliation(s)
- Sipang Pangprasertkul
- Division of Infectious Diseases, Department of Pediatrics, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
| | - Chinnuwat Sanguansermsri
- Division of Neurology, Department of Pediatrics, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
| | - Tavitiya Sudjaritruk
- Division of Infectious Diseases, Department of Pediatrics, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
- Clinical and Molecular Epidemiology of Emerging and Re-emerging Infectious Diseases Research Cluster, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
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19
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Musukuma-Chifulo K, Siddiqi OK, Chilyabanyama ON, Bates M, Chisenga CC, Simuyandi M, Sinkala E, Dang X, Koralnik IJ, Chilengi R, Munsaka S. Epstein-Barr Virus Detection in the Central Nervous System of HIV-Infected Patients. Pathogens 2022; 11:1080. [PMID: 36297137 PMCID: PMC9607430 DOI: 10.3390/pathogens11101080] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2022] [Revised: 07/19/2022] [Accepted: 09/13/2022] [Indexed: 11/01/2023] Open
Abstract
Simply detecting Epstein-Barr virus deoxyribonucleic acid (EBV-DNA) is insufficient to diagnose EBV-associated diseases. The current literature around EBV-DNA detection from cerebrospinal fluid (CSF) in human immunodeficiency virus (HIV)-positive non-lymphoma patients was systematically reviewed and a meta-analysis reporting the estimated pooled prevalence in this population when PCR methods are employed, targeting different sequence segments within the EBV genome, was conducted. Using a combination of three key concepts-Epstein-Barr virus detection, central nervous system disease, and human cerebrospinal fluid-and their MeSH terms, the PubMed database was searched. A total of 273 papers reporting the detection of EBV in CNS were screened, of which 13 met the inclusion criteria. The meta-analysis revealed a pooled prevalence of EBV-DNA in CSF of 20% (CI: 12-31%). The highest pooled prevalence was from studies conducted on the African population at 39% (CI: 27-51%). The investigation of the presence of EBV-DNA in the CSF was also very varied, with several gene targets used. While most patients from the articles included in this review and meta-analysis were symptomatic of CNS disorders, the pathogenicity of EBV in non-lymphoma HIV patients when detected in CSF has still not been determined. The presence of EBV-DNA in the CNS remains a concern, and further research is warranted to understand its significance in causing CNS disorders.
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Affiliation(s)
- Kalo Musukuma-Chifulo
- Department of Biomedical Science, School of Health Sciences, University of Zambia, Lusaka P.O. Box 50110, Zambia
- Department of Research, Centre for Infectious Disease Research in Zambia, Lusaka P.O. Box 34681, Zambia
| | - Omar Khalik Siddiqi
- Global Neurology Program, Department of Neurology, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA
- Department of Internal Medicine, Center for Virology and Vaccines Research, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA
- Department of Internal Medicine, School of Medicine, University of Zambia, Lusaka P.O. Box 50110, Zambia
| | | | - Matthew Bates
- School of Life & Environmental Sciences, University of Lincoln, Lincoln LN6 7TS, UK
- HerpeZ Infection Research and Training, University Teaching Hospital, Lusaka Private Bag RW1X Ridgeway, Lusaka P.O. Box 10101, Zambia
| | | | - Michelo Simuyandi
- Department of Research, Centre for Infectious Disease Research in Zambia, Lusaka P.O. Box 34681, Zambia
| | - Edford Sinkala
- Department of Internal Medicine, School of Medicine, University of Zambia, Lusaka P.O. Box 50110, Zambia
| | - Xin Dang
- Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
| | - Igor Jerome Koralnik
- Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
| | - Roma Chilengi
- Department of Research, Centre for Infectious Disease Research in Zambia, Lusaka P.O. Box 34681, Zambia
| | - Sody Munsaka
- Department of Biomedical Science, School of Health Sciences, University of Zambia, Lusaka P.O. Box 50110, Zambia
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20
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Furuya M, Oji S, Sugimoto K, Kizaki M, Yamashita T, Kaida K. [Epstein-Barr virus-associated subacute sensorimotor neuropathy with multiple cerebellar microbleeding: a case report]. Rinsho Shinkeigaku 2022; 62:609-614. [PMID: 35871562 DOI: 10.5692/clinicalneurol.cn-001726] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/15/2023]
Abstract
We report the case of an 82-year-old male with subacute sensorimotor neuropathy associated with Epstein-Barr virus (EBV) infection, who presented with diplopia followed by gait disturbance due to limb weakness. Pathological findings of a biopsied cervical lymph node showed a high frequency of EBV-positive cells. EBV-DNA was detected in blood. A nerve conduction study suggested a mixture of axonal damage and demyelination. Brain MRI showed multiple microbleeds in cerebellar cortices, but cerebrospinal fluid EBV-PCR was negative, suggesting bleeding due to EBV-related vasculitis. Corticosteroid therapy improved the neurological symptoms and the patient was able to walk independently four months later. The main pathogenesis of the neuropathy in this case is likely to be a mixture of vasculitic neuropathy and immune-mediated demyelinating neuropathy, which are considered to be due to EBV reactivation.
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Affiliation(s)
- Mayumi Furuya
- Department of Neurology, Saitama Medical Center, Saitama Medical University
| | - Satoru Oji
- Department of Neurology, Saitama Medical Center, Saitama Medical University
| | - Kohei Sugimoto
- Department of Neurology, Saitama Medical Center, Saitama Medical University
| | - Masahiro Kizaki
- Department of Hematology, Saitama Medical Center, Saitama Medical University
| | - Takahisa Yamashita
- Department of Pathology, Saitama Medical Center, Saitama Medical University
| | - Kenichi Kaida
- Department of Neurology, Saitama Medical Center, Saitama Medical University
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21
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Lameiras C, Patrocínio de Jesus R, Flor-de-Lima B, Silva J, Pacheco P. A Case of Varicella-Zoster Virus Meningomyelitis in an HIV-1-Infected Patient: Facing the Challenges Related to Its Management and Prognosis. Cureus 2022; 14:e27652. [PMID: 36072168 PMCID: PMC9437380 DOI: 10.7759/cureus.27652] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/02/2022] [Indexed: 12/02/2022] Open
Abstract
Varicella-zoster virus (VZV) myelitis is a rare complication of herpes zoster. Diagnosing and treating this entity may be challenging. Clinical outcomes vary and neurological sequelae may be seen despite treatment. We report a case of a 43-year-old woman with human immunodeficiency virus type 1 (HIV-1) infection (CD4 cell count 191 cells/µL - 14%; undetectable viral load) who was started on antiretroviral treatment eight months before. She presented with VZV meningitis and transverse myelitis and concomitant thoracic vesicular rash at the dermatomal level T6. Neurological examination revealed neck stiffness, paraplegia, sensory level below T4, and autonomic dysfunction. Magnetic resonance imaging (MRI) revealed signs of myelitis from C4 to T10 and VZV DNA by polymerase chain reaction (PCR) was positive (20,00,000 cp/mL) in the cerebrospinal fluid (CSF). The patient completed four weeks of intravenous acyclovir and systemic corticosteroids. Repeat lumbar puncture returned negative for VZV PCR and MRI showed spinal cord improvement. However, only partial neurological improvement was observed after six months. Some features of the present case may be associated with an unfavorable outcome, including high VZV viral load in the CSF and rapid progression of neurological deficits to paraplegia and sphincter dysfunction. Moreover, the recovery of CD4+ cells from 4% to 14% after starting antiretroviral treatment might also have contributed to the extension of myelopathy. Further studies are needed to improve the understanding of VZV myelitis course and optimize its treatment.
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22
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Runge K, Balla A, Fiebich BL, Maier SJ, Pankratz B, Schlump A, Nickel K, Dersch R, Domschke K, Tebartz van Elst L, Endres D. Antibody indices of infectious pathogens from serum and cerebrospinal fluid in patients with schizophrenia spectrum disorders. Fluids Barriers CNS 2022; 19:61. [PMID: 35906648 PMCID: PMC9338642 DOI: 10.1186/s12987-022-00355-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2022] [Accepted: 06/30/2022] [Indexed: 11/10/2022] Open
Abstract
Introduction Infectious and immunological theories of schizophrenia have been discussed for over a century. Contradictory results for infectious agents in association with schizophrenia spectrum disorders (SSDs) were reported. The rationale of this study was to investigate intrathecal antibody synthesis of the most frequently discussed neurotropic pathogens using a pathogen-specific antibody index (AI) in patients with SSD in comparison to controls. Methods In 100 patients with SSD and 39 mentally healthy controls with idiopathic intracranial hypertension (IIH), antibodies against the herpesviruses EBV, CMV, and HSV 1/2 as well as the protozoan Toxoplasma gondii, were measured in paired cerebrospinal fluid (CSF) and serum samples with ELISA-kits. From these antibody concentrations the pathogen-specific AIs were determined with the assumption of intrathecal antibody synthesis at values > 1.5. Results No significant difference was detected in the number of SSD patients with elevated pathogen-specific AI compared to the control group. In a subgroup analysis, a significantly higher EBV AI was observed in the group of patients with chronic SSD compared to patients with first-time SSD diagnosis (p = 0.003). In addition, two identified outlier EBV patients showed evidence for polyspecific immune reactions (with more than one increased AI). Conclusions Evidence for the role of intrathecal EBV antibody synthesis was found in patients with chronic SSD compared to those first diagnosed. Apart from a possible infectious factor in SSD pathophysiology, the evidence for polyspecific immune response in outlier patients may also suggest the involvement of further immunological processes in a small subgroup of SSD patients. Supplementary Information The online version contains supplementary material available at 10.1186/s12987-022-00355-7.
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Affiliation(s)
- Kimon Runge
- Department of Psychiatry and Psychotherapy, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Agnes Balla
- Department of Psychiatry and Psychotherapy, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Bernd L Fiebich
- Department of Psychiatry and Psychotherapy, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Simon J Maier
- Department of Psychiatry and Psychotherapy, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Benjamin Pankratz
- Department of Psychiatry and Psychotherapy, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Andrea Schlump
- Department of Psychiatry and Psychotherapy, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Kathrin Nickel
- Department of Psychiatry and Psychotherapy, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Rick Dersch
- Clinic of Neurology and Neurophysiology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Katharina Domschke
- Department of Psychiatry and Psychotherapy, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.,Center for Basics in Neuromodulation, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Ludger Tebartz van Elst
- Department of Psychiatry and Psychotherapy, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Dominique Endres
- Department of Psychiatry and Psychotherapy, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
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Yang J, Xie S, Li J, Xia H, Liu X. Brain Abscess Caused by Nocardia farcinica and Diagnosed by Metagenomic Next-Generation Sequencing: A Case Report. Front Med (Lausanne) 2022; 9:803554. [PMID: 35252247 PMCID: PMC8890437 DOI: 10.3389/fmed.2022.803554] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2021] [Accepted: 01/10/2022] [Indexed: 11/13/2022] Open
Abstract
Background Brain abscesses caused by Nocardia farcinica are rare and difficult to diagnose. Conventional methods for diagnosing Nocardia species include blood culture, microscopy, and tissue slice, but the performance is not satisfied. We report a case of brain abscess due to N. farcinica diagnosed by metagenomic next-generation sequencing (mNGS). Case Presentation We report a case of a 58-year-old man with brain abscess caused by N. farcinica. The patient had a history of pemphigus and required long-term methylprednisolone administration. No pathogen was detected in blood culture, cerebrospinal fluid (CSF) culture, and fast-acid staining. mNGS identified N. farcinica in the CSF. The symptoms and signs of the patient were significantly improved after changing the antibiotics accordingly to sensitive antibiotics. Conclusion Metagenomic next-generation sequencing (mNGS) is helpful for early diagnosis and subsequent treatment of Nocardia-associated meningitis and encephalitis, avoiding brain surgery. Early and accurate diagnosis and prompt antibiotic treatment reduced its mortality.
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Affiliation(s)
- Jianhua Yang
- Department of Neurology, The Affiliated Ganzhou Hospital of Nanchang University, Ganzhou, China
| | - Shuhua Xie
- Department of Neurology, The Affiliated Ganzhou Hospital of Nanchang University, Ganzhou, China
| | - Junda Li
- Department of Neurology, The Affiliated Ganzhou Hospital of Nanchang University, Ganzhou, China
| | - Han Xia
- Department of Scientific Affairs, Hugobiotech Co., Ltd., Beijing, China
| | - Xianghong Liu
- Department of Neurology, The Affiliated Ganzhou Hospital of Nanchang University, Ganzhou, China
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24
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Optimization of cerebrospinal fluid microbial DNA metagenomic sequencing diagnostics. Sci Rep 2022; 12:3378. [PMID: 35233021 PMCID: PMC8888594 DOI: 10.1038/s41598-022-07260-x] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2021] [Accepted: 02/04/2022] [Indexed: 12/25/2022] Open
Abstract
Infection in the central nervous system is a severe condition associated with high morbidity and mortality. Despite ample testing, the majority of encephalitis and meningitis cases remain undiagnosed. Metagenomic sequencing of cerebrospinal fluid has emerged as an unbiased approach to identify rare microbes and novel pathogens. However, several major hurdles remain, including establishment of individual limits of detection, removal of false positives and implementation of universal controls. Twenty-one cerebrospinal fluid samples, in which a known pathogen had been positively identified by available clinical techniques, were subjected to metagenomic DNA sequencing. Fourteen samples contained minute levels of Epstein-Barr virus. The detection threshold for each sample was calculated by using the total leukocyte content in the sample and environmental contaminants found in the bioinformatic classifiers. Virus sequences were detected in all ten samples, in which more than one read was expected according to the calculations. Conversely, no viral reads were detected in seven out of eight samples, in which less than one read was expected according to the calculations. False positive pathogens of computational or environmental origin were readily identified, by using a commonly available cell control. For bacteria, additional filters including a comparison between classifiers removed the remaining false positives and alleviated pathogen identification. Here we show a generalizable method for identification of pathogen species using DNA metagenomic sequencing. The choice of bioinformatic method mainly affected the efficiency of pathogen identification, but not the sensitivity of detection. Identification of pathogens requires multiple filtering steps including read distribution, sequence diversity and complementary verification of pathogen reads.
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25
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Lagarejos-González E, Gilarranz-Luengo R, Chamizo-López FJ, Díaz-Nicolás S, Redondo-Betancor G, Pena-López MJ. [Infection of the central nervous system by Epstein-Barr virus: clinical manifestations and prognosis]. Rev Neurol 2022; 74:48-54. [PMID: 35014019 PMCID: PMC11500028 DOI: 10.33588/rn.7402.2021406] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Indexed: 11/24/2022]
Abstract
INTRODUCTION The role of Epstein-Barr virus (EBV) in central nervous system (CNS) infections is not fully resolved. We wanted to describe the clinical manifestations of patients with EBV infection in cerebrospinal fluid. PATIENTS AND METHODS We reviewed the clinical records of all adult patients EBV PCR-positive in cerebrospinal fluid, without lymphoproliferative disease, during 2004 to 2020. RESULTS We identified 27 patients, 22 (81.5%) were men, and median age was 54 years. Twenty-three (82.1%) patients were immunosuppressed, 16 HIV-positive. In 15 (55.6%) patients coinfection with another microorganism was diagnosed and in 12 (44.4%) patients it was detected as the only pathogen. Of the 12 patients, three (25%) was immunocompetent patients, one had Guillain Barre syndrome (GBS), another had disseminated multiphasic encephalitis, and another had lymphocytic meningitis; 9 (75%) immunosuppressed, 7 HIV-positive, 4 had encephalitis that resolved without sequelae and 4 had encephalopathy, two HIH-positive had moderate cognitive impairment as a sequela. CONCLUSIONS In our study, EBV produced encephalitis, meningitis, polyradiculomyelitis and GBS, mainly in immunosuppressed patients. In more than half of the cases, it is associated with other pathogens where the role of EBV is unclear. In immunocompetent patient, the infection can be serious and leave sequelae and in HIV-positive patients with encephalopatic involvement without encephalitis, the neurological damage could be greater, so we consider it of interest to carry out studies to evaluate the prognosis as well as the role of antivirals in the evolucion of these clinical pictures.
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Affiliation(s)
- E Lagarejos-González
- Hospital Universitario de Gran Canaria Dr. Negrín, 35020 Las Palmas de Gran Canaria, España
| | - R Gilarranz-Luengo
- Hospital Universitario de Gran Canaria Dr. Negrín, 35020 Las Palmas de Gran Canaria, España
| | - F J Chamizo-López
- Hospital Universitario de Gran Canaria Dr. Negrín, 35020 Las Palmas de Gran Canaria, España
| | - S Díaz-Nicolás
- Hospital Universitario de Gran Canaria Dr. Negrín, 35020 Las Palmas de Gran Canaria, España
| | - G Redondo-Betancor
- Hospital Universitario de Gran Canaria Dr. Negrín, 35020 Las Palmas de Gran Canaria, España
| | - M J Pena-López
- Hospital Universitario de Gran Canaria Dr. Negrín, 35020 Las Palmas de Gran Canaria, España
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26
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Wang Y, Yang J, Wen Y. Lessons from Epstein-Barr virus DNA detection in cerebrospinal fluid as a diagnostic tool for EBV-induced central nervous system dysfunction among HIV-positive patients. Biomed Pharmacother 2021; 145:112392. [PMID: 34781140 DOI: 10.1016/j.biopha.2021.112392] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2021] [Revised: 10/21/2021] [Accepted: 11/02/2021] [Indexed: 12/24/2022] Open
Abstract
Polymerase chain reaction (PCR) analysis of Epstein-Barr virus (EBV) DNA in cerebrospinal fluid (CSF) remains vital for evaluating active EBV infection involving the central nervous system (CNS). CSF EBV DNA was often found in conjunction with other microbial infection affecting the CNS among patients infected with human immunodeficiency virus (HIV). Sometimes CSF EBV DNA is detectable in patients without neurological symptoms. This review focused on the clinical and laboratory features of CNS EBV infection among patients with HIV, and discussed various types of EBV-associated CNS infections, and predominant neoplasms involving CNS such as primary central nervous system lymphoma (PCNSL), CNS-non-Hodgkin's lymphoma, smooth muscle tumors and leiomyosarcomas, EBV encephalitis or myelitis, EBV meningitis and EBV coinfection with other causative agents were also included. Furthermore, the metagenomic next-generation sequencing technique with high sensitivity for the detection of pathogenic coinfection in the CSF were also reviewed. We concluded that CSF EBV-DNA detection with high sensitivity and specificity could be a useful diagnostic tool for CNS lymphoma among HIV patients; however, it is still unknown for other CNS diseases. We further summarized and conclude that positive CSF EBV-DNA detection combined with specific brain focal lesions could be a minimally invasive method to diagnose PCNSL. The occurrence of positive CSF EBV-DNA was influenced by PCR detection limit, PCR methods, immunocompromised status, the possible influence of anti-herpetic therapy and anti-HIV therapy, and the size and location of a tumor mass. Uniform PCR methods as vital diagnostic tools and optimal EBV-DNA load threshold need to be established.
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Affiliation(s)
- Yanli Wang
- Department of Infectious Diseases, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning Province, China
| | - Jun Yang
- Neurology Department, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning Province, China
| | - Ying Wen
- Department of Infectious Diseases, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning Province, China.
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27
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Zhang N, Chen K, Zhu JS, Li H, Shao JB, Jiang H. Sequential infection of Epstein-Barr virus and cryptococcal encephalitis after umbilical cord blood transplantation in a child with X-linked adrenoleukodystrophy. Pediatr Transplant 2021; 25:e13956. [PMID: 33368928 DOI: 10.1111/petr.13956] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2020] [Revised: 11/22/2020] [Accepted: 12/02/2020] [Indexed: 11/29/2022]
Abstract
Dual infection with two pathogens can be found in few cases of encephalitis. Cases of sequential infection with EBV and cryptococcal encephalitis in post-transplant patients are rare. We describe a 5-year-old boy with X-linked adrenoleukodystrophy who presented sequential infection with EBV and cryptococcal encephalitis after umbilical cord blood transplant. The patient showed fever, vomiting and emotional agitation with EBV DNA detected in CSF on day 100. The child underwent 3 doses of intravenous rituximab with a good response. However, the child presented with right facial paralysis, headache, and fever on day 130 after 2 weeks of clinical stability. Brain MRI demonstrated chronic granuloma formed with ring enhancement. FilmArray ME PCR confirmed the existence of Cryptococcus neoformans/gattii in the CSF. The child underwent sequential treatment with amphotericin liposome B and flucytosine. Maintenance treatment with fluconazole was administered for 1 year. Facial paralysis was on longer present on day 260. Cryptococcus neoformans/gattii was not detected on day 310. The biochemistry and cell count of the CSF were completely normal on day 520. Follow-up 2.5 years after presentation, brain MRI changes showed near complete resolution of the lesions. The child survived for 3 years to the last following-up. Invasive cryptococcal encephalitis is rare and life-threatening complication of transplantation. It is important to recognize dual infections, and perform treatment quickly to improve the prognosis of encephalitis after transplantation.
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Affiliation(s)
- Na Zhang
- Department of Hematology and Oncology, Shanghai Children's Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Kai Chen
- Department of Hematology and Oncology, Shanghai Children's Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Jia-Shi Zhu
- Department of Hematology and Oncology, Shanghai Children's Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Hong Li
- Department of Hematology and Oncology, Shanghai Children's Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Jing-Bo Shao
- Department of Hematology and Oncology, Shanghai Children's Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Hui Jiang
- Department of Hematology and Oncology, Shanghai Children's Hospital, Shanghai Jiao Tong University, Shanghai, China
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Tsiatsiou O, Papachristou S, Papadimitriou E, Michailidou E, Chatzidimitriou D, Papa A, Doulioglou V, Karyda S, Antachopoulos C, Roilides E. Epstein-Barr Encephalitis in a Child with Congenital Human Immunodeficiency Virus Infection: A Case Report Calling for No Forgetfulness. Curr HIV Res 2021; 18:63-66. [PMID: 31644409 DOI: 10.2174/1570162x17666191017101223] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2019] [Revised: 09/27/2019] [Accepted: 10/04/2019] [Indexed: 11/22/2022]
Abstract
BACKGROUND In resource-rich settings, the rate of mother-to-child transmission of human immunodeficiency virus (HIV) has dramatically decreased by virtue of a combination of preventive strategies during the last two decades. CASE PRESENTATION We present a case of progressive developmental milestone loss in a toddler with previously unknown congenitally acquired human immunodeficiency virus (HIV) infection, complicated by an Epstein-Barr virus (EBV) coinfection. CONCLUSION Our report underscores the differential diagnosis between HIV encephalopathy and EBV encephalitis and the vertical transmission of the HIV infection, which constitutes an alarming issue in terms of public health.
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Affiliation(s)
- Olga Tsiatsiou
- Pediatric Infectious Diseases Unit, 1st and 3rd Departments of Pediatrics, Faculty of Medicine, Aristotle University School of Health Sciences, Hippokration General Hospital of Thessaloniki, Thessaloniki, Greece.,3rd Department of Pediatrics, Faculty of Medicine, Aristotle University School of Health Sciences, Hippokration General Hospital of Thessaloniki, Thessaloniki, Greece
| | - Savvas Papachristou
- 3rd Department of Pediatrics, Faculty of Medicine, Aristotle University School of Health Sciences, Hippokration General Hospital of Thessaloniki, Thessaloniki, Greece
| | - Eleni Papadimitriou
- Pediatric Infectious Diseases Unit, 1st and 3rd Departments of Pediatrics, Faculty of Medicine, Aristotle University School of Health Sciences, Hippokration General Hospital of Thessaloniki, Thessaloniki, Greece.,1st Department of Pediatrics, Faculty of Medicine, Aristotle University School of Health Sciences, Hippokration General Hospital of Thessaloniki, Thessaloniki, Greece
| | - Elisavet Michailidou
- Pediatric Infectious Diseases Unit, 1st and 3rd Departments of Pediatrics, Faculty of Medicine, Aristotle University School of Health Sciences, Hippokration General Hospital of Thessaloniki, Thessaloniki, Greece.,3rd Department of Pediatrics, Faculty of Medicine, Aristotle University School of Health Sciences, Hippokration General Hospital of Thessaloniki, Thessaloniki, Greece
| | - Dimitrios Chatzidimitriou
- Department of Microbiology, Faculty of Health Sciences, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Anna Papa
- Department of Microbiology, Faculty of Health Sciences, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Vai Doulioglou
- Department of Pediatrics, G. Genimatas General Hospital, Thessaloniki, Thessaloniki, Greece
| | - Stavroula Karyda
- Department of Pediatrics, G. Genimatas General Hospital, Thessaloniki, Thessaloniki, Greece
| | - Charalampos Antachopoulos
- 3rd Department of Pediatrics, Faculty of Medicine, Aristotle University School of Health Sciences, Hippokration General Hospital of Thessaloniki, Thessaloniki, Greece
| | - Emmanuel Roilides
- 3rd Department of Pediatrics, Faculty of Medicine, Aristotle University School of Health Sciences, Hippokration General Hospital of Thessaloniki, Thessaloniki, Greece
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Li J, Wang C, Cao Y, Shi J, Liu H, Zhou M, Liu C, Hu W. Autoimmune glial fibrillary acidic protein astrocytopathy mimicking acute disseminated encephalomyelitis: A case report. Medicine (Baltimore) 2021; 100:e26448. [PMID: 34160439 PMCID: PMC8238277 DOI: 10.1097/md.0000000000026448] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Accepted: 06/07/2021] [Indexed: 01/04/2023] Open
Abstract
INTRODUCTION Autoimmune glial fibrillary acidic protein (GFAP) astrocytopathy is an increasingly recognized type of steroid-responsive autoimmune disease of the nervous system. Defined in 2016, it is associated with the presence of anti-GFAP immunoglobulinG in the serum or cerebrospinal fluid (CSF) of affected patients. PATIENT CHARACTERISTICS Herein, we report a case of acute neurological symptoms, including headache, fever, confusion, and paralysis of the lower extremities. CSF analysis revealed lymphocytic pleocytosis and elevated protein levels, indicating acute disseminated encephalomyelitis, and the patient was given immunotherapy. Cranial magnetic resonance imaging showed multifocal T2/fluid-attenuated inversion recovery hyperintense signal changes in the periventricular white matter, and electromyography testing showed changes consistent with severe sensorimotor neuropathy, indicating the involvement of the brain and peripheral nerves. DIAGNOSES Finally, a diagnosis of autoimmune GFAP astrocytopathy was confirmed due to the presence of GFAP-immunoglobulinG in the patient's CSF. INTERVENTIONS The patient was treated with one course of intravenous immunoglobulin therapy, then followed with intravenous methylprednisolone (1.0 g/d for 3 days) and oral prednisolone. OUTCOMES At 1 week after intravenous immunoglobulin therapy, his level of consciousness improved. However, flaccid paralysis persisted without substantial improvement. CONCLUSION In conclusion, the provision of an accurate early diagnosis and appropriate treatment are crucial for improving the prognosis of patients with autoimmune GFAP astrocytopathy. Further, this case highlights the importance of recognizing the role of peripheral nerve involvement in GFAP autoimmunity.
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30
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Huang L, Zhang X, Fang X. Case Report: Epstein-Barr Virus Encephalitis Complicated With Brain Stem Hemorrhage in an Immune-Competent Adult. Front Immunol 2021; 12:618830. [PMID: 33717113 PMCID: PMC7947888 DOI: 10.3389/fimmu.2021.618830] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2020] [Accepted: 01/04/2021] [Indexed: 11/29/2022] Open
Abstract
Encephalitis caused by Epstein-Barr virus infection is uncommon, but most patients have a good outcome after symptomatic treatment. The infiltration of mononuclear cells in blood vessels and necrosis resulting from the immune response to Epstein-Barr virus infection in a very small number of patients seem to be the main cause of death. We describe a fatal case of Epstein-Barr virus encephalitis diagnosed by next-generation sequencing in an immune-competent adult but progressed to brainstem hemorrhage.
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Affiliation(s)
- Lingtong Huang
- Department of Critical Care Units, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xuan Zhang
- Department of Infectious Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xueling Fang
- Department of Critical Care Units, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
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31
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Abstract
PURPOSE OF REVIEW This article reviews infectious etiologies of spinal cord dysfunction, emphasizing the importance of recognizing common clinicoradiographic syndromes and interpreting them in the context of exposure risk and individual host susceptibilities. RECENT FINDINGS This article discusses the shifting spectrum of neurologic infectious diseases, the growing population of patients who are immunocompromised, and the emergence of effective antiretroviral therapies. In addition, it discusses new molecular and serologic tests that have the potential to enhance our ability to rapidly and accurately diagnose infectious diseases of the spine. SUMMARY When evaluating patients with suspected infectious myelopathies, it is imperative to narrow the range of pathogens under consideration. The geography, seasonality, and clinicoradiographic presentation and immunocompetence status of the patient define the range of potential pathogens and should guide testing and initial management.
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Dickerson F, Katsafanas E, Origoni A, Squire A, Khushalani S, Newman T, Rowe K, Stallings C, Savage CLG, Sweeney K, Nguyen TT, Breier A, Goff D, Ford G, Jones-Brando L, Yolken R. Exposure to Epstein Barr virus and cognitive functioning in individuals with schizophrenia. Schizophr Res 2021; 228:193-197. [PMID: 33450604 PMCID: PMC8023564 DOI: 10.1016/j.schres.2020.12.018] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Revised: 10/19/2020] [Accepted: 12/25/2020] [Indexed: 12/12/2022]
Abstract
Cognitive deficits are a central feature of schizophrenia whose etiology is not fully understood. Epstein Barr Virus (EBV) is a potentially neurotropic infectious agent that can generate persistent infections with immunomodulatory effects. Previous studies have found an association between EBV antibodies and cognitive functioning in different populations, but there has been limited investigation in schizophrenia. In this study, 84 individuals with schizophrenia were administered a comprehensive neuropsychological battery, the MATRICS Consensus Cognitive Battery (MCCB). Participants also provided a blood sample, from which antibodies to the EBV whole virion and specific proteins were measured. Multivariate models were constructed to determine the association between these antibodies and cognitive performance on the MCCB overall and domain scores. Using these models, we found a significant association between the MCCB overall percent composite score and level of antibodies to the EBV Nuclear Antigen-1 (EBNA-1) protein, the Viral Capsid Antigen (VCA) protein, and the EBV whole virion. A significant association was also found for the MCCB social cognition domain with the level of antibodies to the EBV Nuclear Antigen-1 (EBNA-1) protein, the Viral Capsid Antigen (VCA) protein, and the EBV whole virion. In all cases, a higher level of antibodies was associated with a lower level cognitive performance. These findings suggest that exposure to EBV may contribute to cognitive deficits in schizophrenia, a finding which may have implications for new methods of prevention and treatment.
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Affiliation(s)
| | | | | | | | | | | | - Kelly Rowe
- Sheppard Pratt Health System, Baltimore, MD, USA
| | | | | | | | - Tanya T Nguyen
- University of California San Diego, CA, USA; VA San Diego Healthcare System, CA, USA
| | - Alan Breier
- University of Indiana, Indianapolis, IN, USA
| | | | - Glen Ford
- VanPelt Biosciences, Rockville, MD, USA
| | | | - Robert Yolken
- Johns Hopkins School of Medicine, Baltimore, MD, USA
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Lee GH, Kim J, Kim HW, Cho JW. Clinical significance of Epstein-Barr virus in the cerebrospinal fluid of immunocompetent patients. Clin Neurol Neurosurg 2021; 202:106507. [PMID: 33493883 DOI: 10.1016/j.clineuro.2021.106507] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2020] [Revised: 01/13/2021] [Accepted: 01/15/2021] [Indexed: 11/29/2022]
Abstract
INTRODUCTION Polymerase chain reaction (PCR)-based testing of cerebrospinal fluid (CSF) samples has greatly facilitated the diagnosis of central nervous system (CNS) infections. However, the clinical significance of Epstein-Barr virus (EBV) DNA in CSF of individuals with suspected CNS infection remains unclear. We wanted to gain a better understanding of EBV as an infectious agent in immunocompetent patients with CNS disorders. METHODS We identified cases of EBV-associated CNS infections and reviewed their clinical and laboratory characteristics. The study population was drawn from patients with EBV PCR positivity in CSF who visited Pusan National University Hospital between 2010 and 2019. RESULTS Of the 780 CSF samples examined during the 10-year study period, 42 (5.4 %) were positive for EBV DNA; 9 of the patients (21.4 %) were diagnosed with non-CNS infectious diseases, such as optic neuritis, Guillain-Barré syndrome, and idiopathic intracranial hypotension, and the other 33 cases were classified as CNS infections (22 as encephalitis and 11 as meningitis). Intensive care unit admission (13/33 patients, 39.3 %) and presence of severe neurological sequelae at discharge (8/33 patients, 24.2 %) were relatively frequent. In 10 patients (30.3 %), the following pathogens were detected in CSF in addition to EBV: varicella-zoster virus (n = 3), cytomegalovirus (n = 2), herpes simplex virus 1 (n = 1), herpes simplex virus 2 (n = 1), Streptococcus pneumomiae (n = 2), and Enterococcus faecalis (n = 1). The EBV-only group (n = 23) and the co-infection group (n = 10) did not differ in age, gender, laboratory data, results of brain imaging studies, clinical manifestations, or prognosis; however, the co-infected patients had higher CSF protein levels. CONCLUSION EBV DNA in CSF is occasionally found in the immunocompetent population; the virus was commonly associated with encephalitis and poor prognosis, and frequently found together with other microbes in CSF.
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Affiliation(s)
- Gha-Hyun Lee
- Department of Neurology, Biomedical Research Institute, Pusan National University Hospital, Busan, Republic of Korea.
| | - Jiyoung Kim
- Department of Neurology, Biomedical Research Institute, Pusan National University Hospital, Busan, Republic of Korea
| | - Hyun-Woo Kim
- Department of Neurology, Biomedical Research Institute, Pusan National University Hospital, Busan, Republic of Korea; Department of Neurology, Pusan National University Yangsan Hospital, Pusan National University, Yangsan, Republic of Korea
| | - Jae Wook Cho
- Department of Neurology, Biomedical Research Institute, Pusan National University Hospital, Busan, Republic of Korea; Department of Neurology, Pusan National University Yangsan Hospital, Pusan National University, Yangsan, Republic of Korea
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Abstract
BACKGROUND Viral meningoencephalitis is highly heterogeneous, varying by geographic location. The aim of this study was to characterize the etiology and reporting the clinical findings and outcome of viral encephalitis in children in southern Brazil. METHODS A cross-Sectional study was conducted at Hospital Pequeno Príncipe, Curitiba, Brazil, between January 2013 and December 2017. It included patients younger than 18 years, who fulfilled the criteria: altered mental status as a major criteria and 2 or more minor criteria (1) fever, (2) seizures, (3) focal neurologic findings, (4) central system fluid white cell count of ≥5 cells/mm, (5) abnormal brain imaging, and/or (6) electroencephalogram abnormalities. RESULTS Viral meningoencephalitis was diagnosed in 270 children, with median age of 2 years (interquartile range: 0-4), The etiology of viral meningoencephalitis was confirmed in 47% of patients. Enterovirus (18%) was the major cause of encephalitis in Southern Brazilian children, and a high prevalence of Epstein-Barr virus (6%) was demonstrated. Most patients presented with fever (81%), followed by vomiting (50%), focal neurologic findings (46%), seizures (31%) and headache (30%). Few abnormalities were detected on electroencephalograms and brain magnetic resonance images. On discharge from hospital, symptoms resolved completely in 87% of children. Sequelae were mainly observed in patients with focal neurologic symptoms (P<0.001), presence of seizures (P<0.001) and electroencephalogram abnormalities (P=0.024). CONCLUSIONS Enterovirus was the major cause of encephalitis. Etiologic agent of encephalitis seems to be influenced by the local virologic pattern. A poor outcome was identified in patients with seizures, focal neurologic findings and electroencephalogram abnormalities.
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Ohya Y, Nakamura K, Wakisaka Y, Sato H, Wakisaka K, Kumamoto M, Muraya Y, Kuroda J, Nakane H, Yoshimoto G, Kitazono T, Ago T. Epstein-Barr Virus-Associated Encephalopathy Presenting with Nonconvulsive Status Epilepticus in an Immunosuppressive State. Case Rep Neurol 2020; 12:214-221. [PMID: 32774278 PMCID: PMC7383209 DOI: 10.1159/000507976] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2020] [Accepted: 04/16/2020] [Indexed: 11/19/2022] Open
Abstract
Epstein-Barr virus (EBV) infection is occasionally accompanied by central nervous system (CNS) complications, particularly in immunosuppressed patients. However, the symptoms and clinical features of EBV infection in the CNS are rather heterogeneous and remain unknown. We herein describe the first reported adult case manifesting nonconvulsive status epilepticus (NCSE), possibly associated with reactivation of EBV in an immunosuppressive state. A 63-year-old man with a history of acute myeloid leukemia and taking immunosuppressants was admitted due to progressively impaired consciousness without any focal neurological signs, including paralysis or convulsions. Arterial spin labeling magnetic resonance imaging (ASL-MRI) and brain perfusion single-photon emission computed tomography showed hyperperfusion in the right temporal region, despite no morphological abnormalities in other MRI sequences. White blood cell counts, EBV viral load, and virus-capsid antigen IgG in cerebrospinal fluid were elevated. We diagnosed him with EBV-associated encephalopathy presenting with NCSE. Administration of levetiracetam, an antiepileptic, improved the consciousness and the abnormal hyperperfusion. This case suggests a new concept of EBV-associated encephalopathy leading to epilepsy, particularly in immunosuppressed patients.
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Affiliation(s)
- Yuichiro Ohya
- Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Kuniyuki Nakamura
- Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Yoshinobu Wakisaka
- Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Hiroaki Sato
- Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Kayo Wakisaka
- Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Masaya Kumamoto
- Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Yohei Muraya
- Cerebrovascular and Neurology Center, National Hospital Organization Fukuoka-Higashi Medical Center, Koga, Japan
| | - Junya Kuroda
- Cerebrovascular and Neurology Center, National Hospital Organization Fukuoka-Higashi Medical Center, Koga, Japan
| | - Hiroshi Nakane
- Cerebrovascular and Neurology Center, National Hospital Organization Fukuoka-Higashi Medical Center, Koga, Japan
| | - Goichi Yoshimoto
- Department of Medicine and Biosystemic Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Takanari Kitazono
- Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Tetsuro Ago
- Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
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Ramachandran PS, Wilson MR. Metagenomics for neurological infections - expanding our imagination. Nat Rev Neurol 2020; 16:547-556. [PMID: 32661342 PMCID: PMC7356134 DOI: 10.1038/s41582-020-0374-y] [Citation(s) in RCA: 109] [Impact Index Per Article: 21.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/04/2020] [Indexed: 12/11/2022]
Abstract
Over the past two decades, the diagnosis rate for patients with encephalitis has remained poor despite advances in pathogen-specific testing such as PCR and antigen assays. Metagenomic next-generation sequencing (mNGS) of RNA and DNA extracted from cerebrospinal fluid and brain tissue now offers another strategy for diagnosing neurological infections. Given that mNGS simultaneously assays for a wide range of infectious agents in an unbiased manner, it can identify pathogens that were not part of a neurologist’s initial differential diagnosis either because of the rarity of the infection, because the microorganism has not been previously associated with a clinical phenotype or because it is a newly discovered organism. This Review discusses the technical advantages and pitfalls of cerebrospinal fluid mNGS in the context of patients with neuroinflammatory syndromes, including encephalitis, meningitis and myelitis. We also speculate on how mNGS testing potentially fits into current diagnostic testing algorithms given data on mNGS test performance, cost and turnaround time. Finally, the Review highlights future directions for mNGS technology and other hypothesis-free testing methodologies that are in development. This Review discusses the advantages and pitfalls of metagenomic next-generation sequencing (mNGS) in patients with encephalitis, meningitis and myelitis. The authors outline data on mNGS test performance, cost and turnaround time and highlight future directions for mNGS technology.
Meningoencephalitis remains a challenging diagnosis owing to the multitude of possible infectious and autoimmune causes. Meningoencephalitis is associated with a high rate of morbidity and mortality and requires prompt diagnosis and treatment. Metagenomic next-generation sequencing (mNGS) is now a clinically validated test for neuroinfectious diseases that can aid clinicians with a timely diagnosis. mNGS can improve the detection of pathogens that were missed by clinicians or on standard direct testing. mNGS does not perform well when indirect tests are required to make the diagnosis (for example, serology), when infections are compartmentalized and for certain low abundance pathogens. The clinical context of the case is required when interpreting the results of mNGS.
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Affiliation(s)
- Prashanth S Ramachandran
- Weill Institute for Neurosciences, University of California, San Francisco, CA, USA.,Department of Neurology, University of California, San Francisco, CA, USA
| | - Michael R Wilson
- Weill Institute for Neurosciences, University of California, San Francisco, CA, USA. .,Department of Neurology, University of California, San Francisco, CA, USA.
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Jones-Brando L, Dickerson F, Ford G, Stallings C, Origoni A, Katsafanas E, Sweeney K, Squire A, Khushalani S, Yolken R. Atypical immune response to Epstein-Barr virus in major depressive disorder. J Affect Disord 2020; 264:221-226. [PMID: 32056754 PMCID: PMC7025817 DOI: 10.1016/j.jad.2019.11.150] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2019] [Accepted: 11/30/2019] [Indexed: 12/12/2022]
Abstract
BACKGROUND An atypical immune response to Epstein-Barr virus (EBV) infection has been associated with several complex diseases including schizophrenia. The etiology of MDD is unclear; host immune response to EBV infection could play a role. METHODS We utilized solid phase immunoassays and western blots to measure antibodies to EBV virions, specific viral proteins, and 5 other herpesviruses in 87 individuals with MDD and 312 control individuals. RESULTS Individuals with MDD had significantly reduced levels of reactivity to EBV Nuclear Antigen-1. Quantitative levels of antibodies to EBV virions and Viral Capsid Antigen did not differ between groups. Individuals with decreased levels of anti-Nuclear Antigen-1, or elevated levels of anti-virion had increased odds of being in the MDD group. The odds of MDD were elevated in individuals who had the combination of high levels of anti-virion and low levels of anti-Nuclear Antigen-1 (OR =13.6). Western blot analysis corroborated decreased reactivity to Nuclear Antigen-1 in the MDD group and revealed altered levels of antibodies to other EBV proteins. There was a trend towards decreased levels of antibodies to varicella virus in the group of individuals with MDD. LIMITATIONS The MDD sample size was relatively small. There could be unmeasured factors that account for the association between MDD and the immune response to EBV. CONCLUSIONS Individuals with MDD have altered levels and patterns of antibodies to EBV antigens. This atypical response could contribute to the immunopathology of MDD. Therapeutic interventions available for treatment of EBV infection could potentially be of benefit in MDD.
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Affiliation(s)
- Lorraine Jones-Brando
- The Stanley Neurovirology Laboratory, Department of Pediatrics, Johns Hopkins University School of Medicine, 600 N. Wolfe St., Baltimore, MD 21287, United States.
| | - Faith Dickerson
- The Stanley Research Program at Sheppard Pratt, Baltimore, MD.,Joint first-authors
| | | | | | - Andrea Origoni
- The Stanley Research Program at Sheppard Pratt, Baltimore, MD
| | | | - Kevin Sweeney
- The Stanley Research Program at Sheppard Pratt, Baltimore, MD
| | - Amalia Squire
- The Stanley Research Program at Sheppard Pratt, Baltimore, MD
| | | | - Robert Yolken
- The Stanley Neurovirology Laboratory, Department of Pediatrics, Johns Hopkins School of Medicine, Baltimore, MD
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Dickerson F, Jones-Brando L, Ford G, Genovese G, Stallings C, Origoni A, O’Dushlaine C, Katsafanas E, Sweeney K, Khushalani S, Yolken R. Schizophrenia is Associated With an Aberrant Immune Response to Epstein-Barr Virus. Schizophr Bull 2019; 45:1112-1119. [PMID: 30462333 PMCID: PMC6737467 DOI: 10.1093/schbul/sby164] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Epstein-Barr virus (EBV) is a highly prevalent human herpesvirus capable of infecting the central nervous system and establishing persistent infection. METHODS We employed solid phase immunoassay techniques to measure immunoglobulin G (IgG) class antibodies to EBV virions and defined proteins in 432 individuals with schizophrenia and 311 individuals without a history of a psychiatric disorder. Western blot testing was performed to document reactivity to specific EBV proteins. Polygenic risk for schizophrenia was calculated from genome sequencing arrays. Levels of antibodies between the groups were compared by multivariate analyses incorporating clinical, genetic, and demographic measures. RESULTS Individuals with schizophrenia had marked elevations in the levels of antibodies to EBV virions as compared to the control population. Further analyses indicated increased levels of reactivity to EBV-viral capsid antibody (VCA) but not to EBV nuclear antigen-1 (EBNA-1) or to other human herpesviruses. Western blot analysis confirmed increased reactivity to VCA proteins in the group of individuals with schizophrenia and documented a lack of increased levels of antibodies to EBNA-1. Genetic analyses indicated an additive effect of increased levels of antibodies to EBV virions and genetic susceptibility to schizophrenia, with individuals with elevated levels of both type of markers having a greater than 8.5-fold odds of a schizophrenia diagnosis. CONCLUSIONS Individuals with schizophrenia have increased levels of antibodies to some but not all EBV proteins indicating an aberrant response to EBV infection. This aberrant response may contribute to the immunopathology of schizophrenia and related disorders.
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Affiliation(s)
- Faith Dickerson
- The Stanley Research Program at Sheppard Pratt, Baltimore, MD,To whom correspondence should be addressed; Sheppard Pratt, 6501 North Charles St., Baltimore, MD 21204, US; tel: 410-938-4359, fax: 410-938-4364, e-mail:
| | - Lorraine Jones-Brando
- The Stanley Neurovirology Laboratory, Department of Pediatrics, Johns Hopkins School of Medicine, Baltimore, MD
| | | | - Giulio Genovese
- Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA
| | | | - Andrea Origoni
- The Stanley Research Program at Sheppard Pratt, Baltimore, MD
| | - Colm O’Dushlaine
- Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA
| | | | - Kevin Sweeney
- The Stanley Research Program at Sheppard Pratt, Baltimore, MD
| | | | - Robert Yolken
- The Stanley Neurovirology Laboratory, Department of Pediatrics, Johns Hopkins School of Medicine, Baltimore, MD
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Velvet AJJ, Bhutani S, Papachristos S, Dwivedi R, Picton M, Augustine T, Morton M. A single-center experience of post-transplant lymphomas involving the central nervous system with a review of current literature. Oncotarget 2019; 10:437-448. [PMID: 30728897 PMCID: PMC6355190 DOI: 10.18632/oncotarget.26522] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2018] [Accepted: 12/13/2018] [Indexed: 12/13/2022] Open
Abstract
Background Central Nervous System (CNS) lymphoma is a rare presentation of post-transplantation lymphoproliferative disorder (PTLD). Methods This single center retrospective study reviewed presentations, management and outcomes of CNS lymphomas in kidney transplant patients transplanted 1968 to 2015, and reviews relevant current literature. Results We identified 5773 adult kidney transplant recipients of who 90 had a PTLD diagnosis confirmed. CNS disease was diagnosed in 6/90 (7%). Median age at presentation was 60 years and time from transplant 4.5 years. Immunosuppression at diagnosis included mycophenolate mofetil and prednisolone without calcineurin inhibitor in 5/6 patients. Histological analysis diagnosed monomorphic disease in 5/6, and one polymorphic case with tissue positive for Epstein-barr virus (EBV) in 5/6 cases. Despite this 2/4 EBV positive cases had no detectable EBV in peripheral blood or CSF at diagnosis. Treatment strategies included reduction in immunosuppression in all, chemotherapy (n=5), radiotherapy (n=3), Cytotoxic T-Lymphocytes and Craniotomy (n=2). Patient survival was 40% at 1 year with CTL treated patients surviving beyond three years from diagnosis. Conclusion This study supports observational data suggesting MMF treated patients without CNI may have increased risk of disease. Peripheral blood screening for EBV DNAemia does not seem helpful in early identification of those at risk.
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Affiliation(s)
- Anju John John Velvet
- Department of Renal and Pancreas Transplantation, Division of Surgery, Manchester Royal Infirmary, Manchester University Hospitals NHS Foundation Trust, Manchester, UK
| | - Shiv Bhutani
- Department of Renal Medicine and Transplant Nephrology, Manchester Royal Infirmary, Manchester University Hospitals NHS Foundation Trust, Manchester, UK
| | - Stavros Papachristos
- Department of Renal and Pancreas Transplantation, Division of Surgery, Manchester Royal Infirmary, Manchester University Hospitals NHS Foundation Trust, Manchester, UK
| | - Reena Dwivedi
- Department of Radiology, Manchester Royal Infirmary, Manchester University Hospitals NHS Foundation Trust, Manchester, UK
| | - Michael Picton
- Department of Renal Medicine and Transplant Nephrology, Manchester Royal Infirmary, Manchester University Hospitals NHS Foundation Trust, Manchester, UK
| | - Titus Augustine
- Department of Renal and Pancreas Transplantation, Division of Surgery, Manchester Royal Infirmary, Manchester University Hospitals NHS Foundation Trust, Manchester, UK.,Division of Diabetes, Endocrinology and Gastroenterology, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK
| | - Muir Morton
- Department of Renal Medicine and Transplant Nephrology, Manchester Royal Infirmary, Manchester University Hospitals NHS Foundation Trust, Manchester, UK
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Garré J, Sprengers M, Van Melkebeke D, Laureys G. EBV-NMDA double positive encephalitis in an immunocompromised patient. J Neurol Sci 2018; 396:76-77. [PMID: 30419370 DOI: 10.1016/j.jns.2018.11.001] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2018] [Revised: 10/30/2018] [Accepted: 11/01/2018] [Indexed: 10/27/2022]
Affiliation(s)
- Jinte Garré
- Department of Neurology, Ghent University Hospital, Belgium
| | | | | | - Guy Laureys
- Department of Neurology, Ghent University Hospital, Belgium.
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Poorthuis MHF, Battjes S, Dorigo-Zetsma JW, de Kruijk JR. Primary Epstein-Barr virus infection in immunocompetent patients with acute transverse myelitis and a combination of polyradiculitis and anterior horn syndrome as neurological manifestations. BMJ Case Rep 2018; 2018:bcr-2018-225333. [PMID: 30158264 PMCID: PMC6119397 DOI: 10.1136/bcr-2018-225333] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/04/2018] [Indexed: 11/04/2022] Open
Abstract
Neurological manifestations of a primary Epstein-Barr virus (EBV) infection are rare. We describe a case with acute transverse myelitis and another case with a combination of polyradiculitis and anterior horn syndrome as manifestations of a primary EBV infection.The first case is a 50-year-old immunocompetent male diagnosed with acute transverse myelitis, 2 weeks after he was clinically diagnosed with infectious mononucleosis. The second case is an 18-year-old immunocompetent male diagnosed with a combination of polyradiculitis and anterior horn syndrome while he had infectious mononucleosis. The first patient was treated with methylprednisolone. After 1 year, he was able to stop performing clean intermittent self-catheterisation. The second patient completely recovered within 6 weeks without treatment.Primary EBV infection should be considered in immunocompetent patients presenting with acute transverse myelitis and a combination of polyradiculitis and anterior horn syndrome. Antiviral treatment and steroids are controversial, and the prognosis of neurological sequelae is largely unknown.
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Levinson JB, Alvarez MR, Koci K, Feoktistov A, McFarlane IM. Epstein - Barr virus Infection in a Patient with Neuromyelitis Optica Spectrum Disorder and Sjögren's Syndrome: A Case Report and Review of Literature. CLINICAL CASE REPORTS AND REVIEWS 2018; 4. [PMID: 30214826 DOI: 10.15761/ccrr.1000411] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
BACKGROUND The association of Neuromyelitis Optica Spectrum Disorders (NMOSD) with autoimmune disorders including Sjögren's syndrome (SS), is well recognized. Epstein Barr virus (EBV) has been associated to various neurological entities. We describe a case where EBV infection likely preceded NMOSD in a patient with unrecognized SS. The clinical features, work up and management are described. CASE PRESENTATION A 40-year woman with history of stroke and Guillain-Barre Syndrome (GBS) two years prior, presented with progressive lower extremity weakness and pain. Brain MRI revealed hyperintensities in the cerebellar and parietal lobes consistent with old infarcts, high intensity signal in the white matter and enhancing intramedullary lesion at the level of T2 and the conus medullaris. Cerebrospinal fluid (CSF) revealed no oligoclonal bands. Next day, the patient developed right ankle weakness and urinary incontinence. NMOSD was suspected and pulse steroids initiated. Patient's weakness resolved. Antinuclear antibodies (ANA), anti-SSA/SSB and Aquaporin 4 antibodies (AQP4Ab) were positive. CSF was positive for EBV. Parotid gland ultrasound revealed non-homogeneous tissue.Ganciclovir and plasmapheresis were started. The patient's sensation and motor deficits improved and one month after, she had regained motor power and sphincter control. The patient was discharged on oral prednisone and plans for rituximab infusions.On follow-up imaging, Spinal MRI showed areas of myelomalacia and complete resolution at the level of T2 and conus medularis lesions respectively. The patient had no additional flares, but did complain of chronic neuropathic pain. CONCLUSION NMOSD commonly coexist with other autoimmune diseases. The association of SS and NMOSD is well recognized. EBV infections can present with neurological manifestations however, EBV has also been linked to the development of autoimmunity. In our case, EBV was detected in CSF and antiviral therapy was initiated in addition to the treatment modalities for NMOSD which led to a full recovery in our patient.
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Affiliation(s)
- Justin B Levinson
- Department of Medicine, Division of Rheumatology, State University of New York, Downstate Medical Center/Health + Hospitals Kings County Brooklyn, NY 11203 USA
| | - Milena Rodriguez Alvarez
- Department of Medicine, Division of Rheumatology, State University of New York, Downstate Medical Center/Health + Hospitals Kings County Brooklyn, NY 11203 USA
| | - Kristaq Koci
- Department of Medicine, Division of Rheumatology, State University of New York, Downstate Medical Center/Health + Hospitals Kings County Brooklyn, NY 11203 USA
| | - Aleksander Feoktistov
- Department of Medicine, Division of Rheumatology, State University of New York, Downstate Medical Center/Health + Hospitals Kings County Brooklyn, NY 11203 USA
| | - Isabel M McFarlane
- Department of Medicine, Division of Rheumatology, State University of New York, Downstate Medical Center/Health + Hospitals Kings County Brooklyn, NY 11203 USA
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44
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Zarlasht F, Salehi M, Abu-Hishmeh M, Khan M. Encephalitis treatment - a case report with long-term follow-up of EBV PCR in cerebrospinal fluid. Int J Gen Med 2017; 10:371-373. [PMID: 29123419 PMCID: PMC5661833 DOI: 10.2147/ijgm.s143335] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Background Epstein–Barr virus (EBV) has been found to cause infectious mononucleosis multiple times, but has been associated rarely with EBV encephalitis. Also, whenever it is diagnosed, it is always treated symptomatically. Case report A case of confirmed EBV encephalitis is presented, which was treated with antiviral therapy resulting in complete clearance of the virus in cerebrospinal fluid and minimal neurologic symptoms after hospital discharge. Conclusion The Infectious Diseases Society of America guidelines state that intravenous acyclovir is not recommended for EBV-related encephalitis. But we reviewed the literature and found similar cases, and we believe that antiviral therapy should be recommended for EBV encephalitis because it is a potentially fatal disease and if left untreated, can lead to raised intracranial pressure, craniotomy and even death.
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Affiliation(s)
- Fnu Zarlasht
- Department of Medicine, Lourdes Hospital, Binghamton, NY, USA
| | - Mashal Salehi
- Department of Medicine, NYC Health + Hospital/Harlem, Columbia University, NY, USA
| | | | - Muzammil Khan
- Department of Medicine, NYC Health + Hospital/Harlem, Columbia University, NY, USA
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45
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Ke P, Ma X, Bao XB, Liu YJ, Wu XJ, Xue SL, Hu XH, He XF, Wu DP. [Clinical analysis of 7 patients with Epstein-Barr virus encephalitis after allogeneic hematopoietic stem cell transplantation]. ZHONGHUA XUE YE XUE ZA ZHI = ZHONGHUA XUEYEXUE ZAZHI 2017; 38:685-689. [PMID: 28954347 PMCID: PMC7348247 DOI: 10.3760/cma.j.issn.0253-2727.2017.08.007] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/25/2016] [Indexed: 11/05/2022]
Abstract
Objective: To summarize the clinical features, treatment and prognosis of patients with Epstein Barr virus (EBV) encephalitis after allogeneic hematopoietic stem cell transplantation (allo-HSCT) . Methods: The clinical data of 7 patients with EBV encephalitis who had undergone allo-HSCT in the First Affiliated Hospital of Soochow University from January 2012 to December 2015 were reviewed. Results: The incidence of EBV encephalitis was 0.70% (7/998) , and the median time was 63 (10-136) d after allo-HSCT. Seven patients had fever and mental disorder, of whom 4 cases of brain MRI were positive. Two patients received HLA-matched unrelated transplantation, while other 5 ones received haploidentical allo-HSCT. In conditioning regimen process, 7 patients were combined with anti-thymocyte globulin (ATG) to prevent graft versus host disease (GVHD) , of whom 6 patients had grade Ⅱ-Ⅳ acute GVHD. All patients of EBV-DNA were negative in CSF after taking anti-virus agent Rituximab. Until the last follow-up, a total of 3 patients died, 2 died of leukemia recurrence, 1 EBV encephalitis progression. Conclusion: Once suspected EBV encephalitis after allo-HSCT, brain MRI and EBV-DNA in CSF should be detected, which could improve early diagnosis of EBV encephalitis. The usage of Rituximab was effective and well tolerated.
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Affiliation(s)
- P Ke
- First Affiliated Hospital of Soochow University, Jiangsu Institute of Hematology, Key Laboratory of Thrombosis and Hemostasis under Ministry of Health, Collaborative Innovation Center of Hematology, Institute of Blood and Marrow Transplantation, Soochow University, Suzhou 215006, China
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Fillatre P, Crabol Y, Morand P, Piroth L, Honnorat J, Stahl JP, Lecuit M. Infectious encephalitis: Management without etiological diagnosis 48hours after onset. Med Mal Infect 2017; 47:236-251. [PMID: 28314470 PMCID: PMC7131623 DOI: 10.1016/j.medmal.2017.02.004] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2017] [Accepted: 02/22/2017] [Indexed: 12/18/2022]
Abstract
Introduction The etiological diagnosis of infectious encephalitis is often not established 48 hours after onset. We aimed to review existing literature data before providing management guidelines. Method We performed a literature search on PubMed using filters such as “since 01/01/2000”, “human”, “adults”, “English or French”, and “clinical trial/review/guidelines”. We also used the Mesh search terms “encephalitis/therapy” and “encephalitis/diagnosis”. Results With Mesh search terms “encephalitis/therapy” and “encephalitis/diagnosis”, we retrieved 223 and 258 articles, respectively. With search terms “encephalitis and corticosteroid”, we identified 38 articles, and with “encephalitis and doxycycline” without the above-mentioned filters we identified 85 articles. A total of 210 articles were included in the analysis. Discussion Etiological investigations must focus on recent travels, animal exposures, age, immunodeficiency, neurological damage characteristics, and potential extra-neurological signs. The interest of a diagnosis of encephalitis for which there is no specific treatment is also to discontinue any empirical treatments initially prescribed. Physicians must consider and search for autoimmune encephalitis.
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Affiliation(s)
- P Fillatre
- Service de maladies infectieuses et réanimation médicale, CHU Pontchaillou, 35000 Rennes, France
| | - Y Crabol
- Médecine interne, CHBUA site de Vannes, 56017 Vannes, France
| | - P Morand
- Virologie, CHU Grenoble Alpes, 38043 Grenoble cedex 9, France
| | - L Piroth
- Infectiologie, CHU de Dijon, 21000 Dijon, France
| | - J Honnorat
- Inserm U1028, CNRS UMR5292, équipe neuro-oncologie et neuro-inflammation (Oncoflam), centre de recherche en neurosciences (CRNL), université Lyon 1, 69500 Bron, France
| | - J P Stahl
- Service d'infectiologie, CHU de Grenoble, 38043 Grenoble cedex 9, France.
| | - M Lecuit
- Institut Pasteur, Biology of Infection Unit, CNR CCOMS Listeria, Inserm U1117, Paris, France; Paris Descartes University, Sorbonne Paris Cité, Department of Infectious Diseases and Tropical Medicine, Necker-Enfants-Malades University Hospital, Institut Imagine, Assistance Publique-Hôpitaux de Paris, Paris, France
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Bazzino Rubio F, Gonzalez Betlza M, Gonzalez Rabelino G, Bello Pedrosa O. Optic neuritis following Epstein-Barr virus encephalitis in immunocompetent children: A case report. NEUROLOGÍA (ENGLISH EDITION) 2017. [DOI: 10.1016/j.nrleng.2015.03.018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022] Open
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48
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Lupo J, Dos Santos O, Germi R, Baccard-Longère M, Stahl JP, Epaulard O, Morand P. Herpes simplex type 2 encephalitis and methotrexate medication: a fortuitous or causative association in a patient with spondyloarthritis? Antivir Ther 2016; 22:357-359. [PMID: 27879484 DOI: 10.3851/imp3110] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/21/2016] [Indexed: 10/20/2022]
Abstract
It is unclear whether immunosuppression is a risk factor for herpes encephalitis. Herein, we describe a rare case of herpes simplex virus type 2 encephalitis in a patient treated with low-dose methotrexate for HLA-B27-associated spondyloarthritis. The patient was successfully treated with acyclovir but presented sequelae of encephalitis. Here we discuss the possible role of low-dose methotrexate therapy as a risk factor of neurological herpes reactivation and severe disease. The host-related and viral risk factors are also addressed.
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Affiliation(s)
- Julien Lupo
- Laboratory of Virology, University Hospital of Grenoble, Grenoble, France.,Institut de Biologie Structurale, CEA, CNRS, University Grenoble Alpes, Grenoble, France
| | - Ophélie Dos Santos
- Infectious Diseases Department, University Hospital of Grenoble, Grenoble, France
| | - Raphaele Germi
- Laboratory of Virology, University Hospital of Grenoble, Grenoble, France.,Institut de Biologie Structurale, CEA, CNRS, University Grenoble Alpes, Grenoble, France
| | | | - Jean-Paul Stahl
- Infectious Diseases Department, University Hospital of Grenoble, Grenoble, France
| | - Olivier Epaulard
- Infectious Diseases Department, University Hospital of Grenoble, Grenoble, France
| | - Patrice Morand
- Laboratory of Virology, University Hospital of Grenoble, Grenoble, France.,Institut de Biologie Structurale, CEA, CNRS, University Grenoble Alpes, Grenoble, France
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Parisi SG, Basso M, Del Vecchio C, Andreis S, Franchin E, Bello FD, Pagni S, Biasolo MA, Manganelli R, Barzon L, Palù G. Virological testing of cerebrospinal fluid in children aged less than 14 years with a suspected central nervous system infection: A retrospective study on 304 consecutive children from January 2012 to May 2015. Eur J Paediatr Neurol 2016; 20:588-96. [PMID: 27129875 DOI: 10.1016/j.ejpn.2016.04.002] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2015] [Revised: 04/05/2016] [Accepted: 04/06/2016] [Indexed: 01/03/2023]
Abstract
OBJECTIVE The study aimed to describe the prevalence of HSV DNA, VZV DNA, Enterovirus RNA, Parechovirus RNA, CMV DNA, EBV DNA, adenovirus DNA, HHV-6 DNA, HHV-7 DNA, HHV-8 DNA and Parvovirus B19DNA in children aged less 14 years with a suspected viral infection of the central nervous system in a clinical practice setting. METHODS Between January 2012 and May 2015, cerebrospinal fluids from 304 children were tested with an in-house real-time PCR method. RESULTS A positive PCR was detected in 64 subjects (21%): the mean number of tests performed in patients who showed a viral infection was 7.5, significantly higher (p = 0.001) with respect to that reported in negative samples (6.4). Enterovirus is the leading virus detected: 12 out of the 37 positive children reported were newborns (85.7% of all the newborns with a positive result). The second most frequently identified virus was HHV-7 (5 positive PCR out of 105 samples tested, 4.8%, if we excluded a child with a concomitant S. pneumoniae isolated), a prevalence significantly higher with respect to VZV (p = 0.02) and to CMV (p = 0.04). HHV-6 was the third most commonly identified aetiology (4.2%). All children were immunocompetent. SIGNIFICANCE Only a minority of children had a specific viral aetiology identified: the rate of HHV-7 positivity suggests a routine testing of these viruses within the diagnostic algorithm in immunocompetent paediatric patients. This approach could help to define the clinical role of this herpesvirus.
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Affiliation(s)
- Saverio G Parisi
- Department of Molecular Medicine, University of Padova, Via Gabelli 63, 35100 Padova, Italy; Microbiology and Virology Unit, Padova University Hospital, Indirizzo: Via Giustiniani, 2, 35128 Padova, Italy.
| | - Monica Basso
- Department of Molecular Medicine, University of Padova, Via Gabelli 63, 35100 Padova, Italy; Microbiology and Virology Unit, Padova University Hospital, Indirizzo: Via Giustiniani, 2, 35128 Padova, Italy
| | - Claudia Del Vecchio
- Department of Molecular Medicine, University of Padova, Via Gabelli 63, 35100 Padova, Italy; Microbiology and Virology Unit, Padova University Hospital, Indirizzo: Via Giustiniani, 2, 35128 Padova, Italy
| | - Samantha Andreis
- Department of Molecular Medicine, University of Padova, Via Gabelli 63, 35100 Padova, Italy
| | - Elisa Franchin
- Department of Molecular Medicine, University of Padova, Via Gabelli 63, 35100 Padova, Italy; Microbiology and Virology Unit, Padova University Hospital, Indirizzo: Via Giustiniani, 2, 35128 Padova, Italy
| | - Federico Dal Bello
- Department of Molecular Medicine, University of Padova, Via Gabelli 63, 35100 Padova, Italy; Microbiology and Virology Unit, Padova University Hospital, Indirizzo: Via Giustiniani, 2, 35128 Padova, Italy
| | - Silvana Pagni
- Department of Molecular Medicine, University of Padova, Via Gabelli 63, 35100 Padova, Italy; Microbiology and Virology Unit, Padova University Hospital, Indirizzo: Via Giustiniani, 2, 35128 Padova, Italy
| | - Maria Angela Biasolo
- Department of Molecular Medicine, University of Padova, Via Gabelli 63, 35100 Padova, Italy; Microbiology and Virology Unit, Padova University Hospital, Indirizzo: Via Giustiniani, 2, 35128 Padova, Italy
| | - Riccardo Manganelli
- Department of Molecular Medicine, University of Padova, Via Gabelli 63, 35100 Padova, Italy; Microbiology and Virology Unit, Padova University Hospital, Indirizzo: Via Giustiniani, 2, 35128 Padova, Italy
| | - Luisa Barzon
- Department of Molecular Medicine, University of Padova, Via Gabelli 63, 35100 Padova, Italy; Microbiology and Virology Unit, Padova University Hospital, Indirizzo: Via Giustiniani, 2, 35128 Padova, Italy
| | - Giorgio Palù
- Department of Molecular Medicine, University of Padova, Via Gabelli 63, 35100 Padova, Italy; Microbiology and Virology Unit, Padova University Hospital, Indirizzo: Via Giustiniani, 2, 35128 Padova, Italy
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50
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Salzberg SL, Breitwieser FP, Kumar A, Hao H, Burger P, Rodriguez FJ, Lim M, Quiñones-Hinojosa A, Gallia GL, Tornheim JA, Melia MT, Sears CL, Pardo CA. Next-generation sequencing in neuropathologic diagnosis of infections of the nervous system. NEUROLOGY-NEUROIMMUNOLOGY & NEUROINFLAMMATION 2016; 3:e251. [PMID: 27340685 PMCID: PMC4907805 DOI: 10.1212/nxi.0000000000000251] [Citation(s) in RCA: 122] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/04/2016] [Accepted: 05/09/2016] [Indexed: 12/13/2022]
Abstract
Objective: To determine the feasibility of next-generation sequencing (NGS) microbiome approaches in the diagnosis of infectious disorders in brain or spinal cord biopsies in patients with suspected CNS infections. Methods: In a prospective pilot study, we applied NGS in combination with a new computational analysis pipeline to detect the presence of pathogenic microbes in brain or spinal cord biopsies from 10 patients with neurologic problems indicating possible infection but for whom conventional clinical and microbiology studies yielded negative or inconclusive results. Results: Direct DNA and RNA sequencing of brain tissue biopsies generated 8.3 million to 29.1 million sequence reads per sample, which successfully identified with high confidence the infectious agent in 3 patients for whom validation techniques confirmed the pathogens identified by NGS. Although NGS was unable to identify with precision infectious agents in the remaining cases, it contributed to the understanding of neuropathologic processes in 5 others, demonstrating the power of large-scale unbiased sequencing as a novel diagnostic tool. Clinical outcomes were consistent with the findings yielded by NGS on the presence or absence of an infectious pathogenic process in 8 of 10 cases, and were noncontributory in the remaining 2. Conclusions: NGS-guided metagenomic studies of brain, spinal cord, or meningeal biopsies offer the possibility for dramatic improvements in our ability to detect (or rule out) a wide range of CNS pathogens, with potential benefits in speed, sensitivity, and cost. NGS-based microbiome approaches present a major new opportunity to investigate the potential role of infectious pathogens in the pathogenesis of neuroinflammatory disorders.
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Affiliation(s)
- Steven L Salzberg
- Center for Computational Biology, McKusick-Nathans Institute of Genetic Medicine (S.L.S., F.P.B.), Department of Neurology (A.K., C.A.P.), Deep Sequencing and Microarray Core (H.H.), and Departments of Pathology (P.B., F.J.R., C.A.P.), Neurosurgery (M.L., A.Q.-H., G.L.G.), and Medicine (J.A.T., M.T.M., C.L.S.), School of Medicine, and Departments of Biomedical Engineering, Computer Science, and Biostatistics (S.L.S.), Johns Hopkins University, Baltimore, MD
| | - Florian P Breitwieser
- Center for Computational Biology, McKusick-Nathans Institute of Genetic Medicine (S.L.S., F.P.B.), Department of Neurology (A.K., C.A.P.), Deep Sequencing and Microarray Core (H.H.), and Departments of Pathology (P.B., F.J.R., C.A.P.), Neurosurgery (M.L., A.Q.-H., G.L.G.), and Medicine (J.A.T., M.T.M., C.L.S.), School of Medicine, and Departments of Biomedical Engineering, Computer Science, and Biostatistics (S.L.S.), Johns Hopkins University, Baltimore, MD
| | - Anupama Kumar
- Center for Computational Biology, McKusick-Nathans Institute of Genetic Medicine (S.L.S., F.P.B.), Department of Neurology (A.K., C.A.P.), Deep Sequencing and Microarray Core (H.H.), and Departments of Pathology (P.B., F.J.R., C.A.P.), Neurosurgery (M.L., A.Q.-H., G.L.G.), and Medicine (J.A.T., M.T.M., C.L.S.), School of Medicine, and Departments of Biomedical Engineering, Computer Science, and Biostatistics (S.L.S.), Johns Hopkins University, Baltimore, MD
| | - Haiping Hao
- Center for Computational Biology, McKusick-Nathans Institute of Genetic Medicine (S.L.S., F.P.B.), Department of Neurology (A.K., C.A.P.), Deep Sequencing and Microarray Core (H.H.), and Departments of Pathology (P.B., F.J.R., C.A.P.), Neurosurgery (M.L., A.Q.-H., G.L.G.), and Medicine (J.A.T., M.T.M., C.L.S.), School of Medicine, and Departments of Biomedical Engineering, Computer Science, and Biostatistics (S.L.S.), Johns Hopkins University, Baltimore, MD
| | - Peter Burger
- Center for Computational Biology, McKusick-Nathans Institute of Genetic Medicine (S.L.S., F.P.B.), Department of Neurology (A.K., C.A.P.), Deep Sequencing and Microarray Core (H.H.), and Departments of Pathology (P.B., F.J.R., C.A.P.), Neurosurgery (M.L., A.Q.-H., G.L.G.), and Medicine (J.A.T., M.T.M., C.L.S.), School of Medicine, and Departments of Biomedical Engineering, Computer Science, and Biostatistics (S.L.S.), Johns Hopkins University, Baltimore, MD
| | - Fausto J Rodriguez
- Center for Computational Biology, McKusick-Nathans Institute of Genetic Medicine (S.L.S., F.P.B.), Department of Neurology (A.K., C.A.P.), Deep Sequencing and Microarray Core (H.H.), and Departments of Pathology (P.B., F.J.R., C.A.P.), Neurosurgery (M.L., A.Q.-H., G.L.G.), and Medicine (J.A.T., M.T.M., C.L.S.), School of Medicine, and Departments of Biomedical Engineering, Computer Science, and Biostatistics (S.L.S.), Johns Hopkins University, Baltimore, MD
| | - Michael Lim
- Center for Computational Biology, McKusick-Nathans Institute of Genetic Medicine (S.L.S., F.P.B.), Department of Neurology (A.K., C.A.P.), Deep Sequencing and Microarray Core (H.H.), and Departments of Pathology (P.B., F.J.R., C.A.P.), Neurosurgery (M.L., A.Q.-H., G.L.G.), and Medicine (J.A.T., M.T.M., C.L.S.), School of Medicine, and Departments of Biomedical Engineering, Computer Science, and Biostatistics (S.L.S.), Johns Hopkins University, Baltimore, MD
| | - Alfredo Quiñones-Hinojosa
- Center for Computational Biology, McKusick-Nathans Institute of Genetic Medicine (S.L.S., F.P.B.), Department of Neurology (A.K., C.A.P.), Deep Sequencing and Microarray Core (H.H.), and Departments of Pathology (P.B., F.J.R., C.A.P.), Neurosurgery (M.L., A.Q.-H., G.L.G.), and Medicine (J.A.T., M.T.M., C.L.S.), School of Medicine, and Departments of Biomedical Engineering, Computer Science, and Biostatistics (S.L.S.), Johns Hopkins University, Baltimore, MD
| | - Gary L Gallia
- Center for Computational Biology, McKusick-Nathans Institute of Genetic Medicine (S.L.S., F.P.B.), Department of Neurology (A.K., C.A.P.), Deep Sequencing and Microarray Core (H.H.), and Departments of Pathology (P.B., F.J.R., C.A.P.), Neurosurgery (M.L., A.Q.-H., G.L.G.), and Medicine (J.A.T., M.T.M., C.L.S.), School of Medicine, and Departments of Biomedical Engineering, Computer Science, and Biostatistics (S.L.S.), Johns Hopkins University, Baltimore, MD
| | - Jeffrey A Tornheim
- Center for Computational Biology, McKusick-Nathans Institute of Genetic Medicine (S.L.S., F.P.B.), Department of Neurology (A.K., C.A.P.), Deep Sequencing and Microarray Core (H.H.), and Departments of Pathology (P.B., F.J.R., C.A.P.), Neurosurgery (M.L., A.Q.-H., G.L.G.), and Medicine (J.A.T., M.T.M., C.L.S.), School of Medicine, and Departments of Biomedical Engineering, Computer Science, and Biostatistics (S.L.S.), Johns Hopkins University, Baltimore, MD
| | - Michael T Melia
- Center for Computational Biology, McKusick-Nathans Institute of Genetic Medicine (S.L.S., F.P.B.), Department of Neurology (A.K., C.A.P.), Deep Sequencing and Microarray Core (H.H.), and Departments of Pathology (P.B., F.J.R., C.A.P.), Neurosurgery (M.L., A.Q.-H., G.L.G.), and Medicine (J.A.T., M.T.M., C.L.S.), School of Medicine, and Departments of Biomedical Engineering, Computer Science, and Biostatistics (S.L.S.), Johns Hopkins University, Baltimore, MD
| | - Cynthia L Sears
- Center for Computational Biology, McKusick-Nathans Institute of Genetic Medicine (S.L.S., F.P.B.), Department of Neurology (A.K., C.A.P.), Deep Sequencing and Microarray Core (H.H.), and Departments of Pathology (P.B., F.J.R., C.A.P.), Neurosurgery (M.L., A.Q.-H., G.L.G.), and Medicine (J.A.T., M.T.M., C.L.S.), School of Medicine, and Departments of Biomedical Engineering, Computer Science, and Biostatistics (S.L.S.), Johns Hopkins University, Baltimore, MD
| | - Carlos A Pardo
- Center for Computational Biology, McKusick-Nathans Institute of Genetic Medicine (S.L.S., F.P.B.), Department of Neurology (A.K., C.A.P.), Deep Sequencing and Microarray Core (H.H.), and Departments of Pathology (P.B., F.J.R., C.A.P.), Neurosurgery (M.L., A.Q.-H., G.L.G.), and Medicine (J.A.T., M.T.M., C.L.S.), School of Medicine, and Departments of Biomedical Engineering, Computer Science, and Biostatistics (S.L.S.), Johns Hopkins University, Baltimore, MD
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