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Liu YC, Hsiao SH, Chen PR. Herpes simplex virus 2-induced aseptic meningitis presenting with sudden deafness: A case report. World J Clin Cases 2025; 13:98320. [PMID: 40094113 PMCID: PMC11670016 DOI: 10.12998/wjcc.v13.i8.98320] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2024] [Revised: 11/03/2024] [Accepted: 11/22/2024] [Indexed: 12/04/2024] Open
Abstract
BACKGROUND Aseptic meningitis is defined as meningeal inflammation caused by various etiologies with negative cerebrospinal fluid (CSF) bacterial culture. The most common etiologies are viruses [enteroviruses, arboviruses, and herpes simplex virus type 2 (HSV-2)]. Aseptic meningitis can have various presentations, including sensorineural deafness. While sensorineural deafness from mumps meningoencephalitis has been reported, cases of HSV-2-induced hearing loss are rare. Herein, we report a case of HSV-2-induced meningitis that presented with sudden deafness. CASE SUMMARY A 68-year-old man experienced a profound sudden onset of left-sided hearing loss for one day. Pure-tone audiograms demonstrated sudden left-sided sensorineural hearing loss (thresholds 80-90 dB). After treatment with high-dose steroids for 1 week, he experienced an acute consciousness change with left hemiparesis. The laboratory data showed no significant abnormalities. Brain computed tomography without contrast and magnetic resonance imaging revealed no intracranial hemorrhage or obvious brain lesion. The CSF analysis and the Multiplex PCR panels showed HSV-2 positivity. Hence, under the diagnosis of herpes meningoencephalitis, acyclovir was prescribed and his symptoms gradually resolved. CONCLUSION This case report further demonstrates that a viral infection could be a cause of sudden sensorineural hearing loss.
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Affiliation(s)
- Yuan-Cheng Liu
- Department of Otolaryngology, Hualien Tzu Chi Hospital, Hualien 970, Taiwan
| | - Shih-Hsuan Hsiao
- Department of Otolaryngology, Hualien Tzu Chi Hospital, and Department of Otolaryngology, Head and Neck Surgery, School of Medicine, Tzu Chi University, Hualien 970, Taiwan
| | - Peir-Rong Chen
- Department of Otolaryngology, Hualien Tzu Chi Hospital, Hualien 970, Taiwan
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Barmak F, Issa J, Bajwa D, Inam SHA, Adams J, Nolte J, Ferguson P. Mollaret's Meningitis: A Case Report of Recurrent Aseptic Meningitis. Cureus 2025; 17:e81065. [PMID: 40271303 PMCID: PMC12015995 DOI: 10.7759/cureus.81065] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/23/2025] [Indexed: 04/25/2025] Open
Abstract
Benign recurrent meningitis, also known as Mollaret's meningitis, a rare form of recurrent aseptic meningitis, is often associated with herpes simplex virus type 2 (HSV-2) infection, which is characterized by fever, headache, meningeal irritation, and sterility of the cerebrospinal fluid (CSF) on examination. Although with clear diagnostic criteria, there are still many equivocal aspects of its pathogenesis and treatment. This paper presents a case report of a 40-year-old woman who experienced multiple episodes of this syndromic condition, highlighting its diagnostic challenges, clinical features, and treatment outcomes. The case reflects the importance of timely diagnosis and intervention in managing Mollaret's meningitis effectively. Furthermore, it sheds light on the complexities of its etiology and potential predisposing factors and the need for further research to better understand this condition.
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Affiliation(s)
- Fahim Barmak
- Neurology, Marshall University Joan C. Edwards School of Medicine, Huntington, USA
| | - James Issa
- Neurology, Marshall University Joan C. Edwards School of Medicine, Huntington, USA
| | - Danial Bajwa
- Internal Medicine, Armed Forces Institute of Cardiology, Rawalpindi, PAK
| | - Syed Hashim Ali Inam
- Internal Medicine, Army Medical College, Rawalpindi, PAK
- Neurology, Marshall University Joan C. Edwards School of Medicine, Huntington, USA
| | - Jason Adams
- Neurology, Marshall University Joan C. Edwards School of Medicine, Huntington, USA
| | - Justin Nolte
- Neurology, Marshall University Joan C. Edwards School of Medicine, Huntington, USA
| | - Paul Ferguson
- Neurology, Marshall University Joan C. Edwards School of Medicine, Huntington, USA
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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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Petersen PT, Bodilsen J, Jepsen MPG, Hansen BR, Storgaard M, Larsen L, Helweg‐Larsen J, Wiese L, Lüttichau HR, Andersen CØ, Mogensen TH, Nielsen H, Brandt CT, for the Danish Study Group of Infections of the Brain (DASGIB). Benign recurrent lymphocytic meningitis (Mollaret's meningitis) in Denmark: a nationwide cohort study. Eur J Neurol 2024; 31:e16081. [PMID: 37797296 PMCID: PMC11235955 DOI: 10.1111/ene.16081] [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: 08/08/2023] [Revised: 09/15/2023] [Accepted: 09/18/2023] [Indexed: 10/07/2023]
Abstract
BACKGROUND AND PURPOSE Data on clinical features and outcomes of benign recurrent lymphocytic meningitis (BRLM) are limited. METHODS This was a nationwide population-based cohort study of all adults hospitalized for BRLM associated with herpes simplex virus type 2 (HSV-2) at the departments of infectious diseases in Denmark from 2015 to 2020. Patients with single-episode HSV-2 meningitis were included for comparison. RESULTS Forty-seven patients with BRLM (mean annual incidence 1.2/1,000,000 adults) and 118 with single-episode HSV-2 meningitis were included. The progression risk from HSV-2 meningitis to BRLM was 22% (95% confidence interval [CI] 15%-30%). The proportion of patients with the triad of headache, neck stiffness and photophobia/hyperacusis was similar between BRLM and single-episode HSV-2 meningitis (16/43 [37%] vs. 46/103 [45%]; p = 0.41), whilst the median cerebrospinal fluid leukocyte count was lower in BRLM (221 cells vs. 398 cells; p = 0.02). Unfavourable functional outcomes (Glasgow Outcome Scale score of 1-4) were less frequent in BRLM at all post-discharge follow-up visits. During the study period, 10 (21%) patients with BRLM were hospitalized for an additional recurrence (annual rate 6%, 95% CI 3%-12%). The hazard ratio for an additional recurrence was 3.93 (95% CI 1.02-15.3) for patients with three or more previous episodes of meningitis. CONCLUSIONS Clinical features of BRLM were similar to those of single-episode HSV-2 meningitis, whilst post-discharge outcomes were more favourable. Patients with three or more previous episodes of meningitis had higher risk of an additional recurrence.
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Affiliation(s)
- Pelle Trier Petersen
- Department of Pulmonary and Infectious DiseasesNordsjællands HospitalHillerødDenmark
- Faculty of Health and Medical SciencesUniversity of CopenhagenCopenhagenDenmark
| | - Jacob Bodilsen
- Department of Infectious DiseasesAalborg University HospitalAalborgDenmark
- Department of Clinical MedicineAalborg UniversityAalborgDenmark
| | | | | | - Merete Storgaard
- Department of Infectious DiseasesAarhus University HospitalAarhusDenmark
| | - Lykke Larsen
- Department of Infectious DiseasesOdense University HospitalOdenseDenmark
| | | | - Lothar Wiese
- Department of MedicineZealand University HospitalRoskildeDenmark
| | | | | | - Trine Hyrup Mogensen
- Department of Infectious DiseasesAarhus University HospitalAarhusDenmark
- Department of BiomedicineAarhus University HospitalAarhusDenmark
| | - Henrik Nielsen
- Department of Infectious DiseasesAalborg University HospitalAalborgDenmark
- Department of Clinical MedicineAalborg UniversityAalborgDenmark
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Reyahi A, Studahl M, Skouboe MK, Fruhwürth S, Narita R, Ren F, Bjerhem Viklund M, Iversen MB, Christiansen M, Svensson A, Mogensen TH, Eriksson K, Paludan SR. An IKBKE variant conferring functional cGAS/STING pathway deficiency and susceptibility to recurrent HSV-2 meningitis. JCI Insight 2023; 8:e173066. [PMID: 37937644 PMCID: PMC10721272 DOI: 10.1172/jci.insight.173066] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2023] [Accepted: 09/20/2023] [Indexed: 11/09/2023] Open
Abstract
The mechanisms underlying susceptibility to recurrent herpes simplex virus type 2 (HSV-2) meningitis remain incompletely understood. In a patient experiencing multiple episodes of HSV-2 meningitis, we identified a monoallelic variant in the IKBKE gene, which encodes the IKKε kinase involved in induction of antiviral IFN genes. Patient cells displayed impaired induction of IFN-β1 (IFNB1) expression upon infection with HSV-2 or stimulation with double-stranded DNA (dsDNA) and failed to induce phosphorylation of STING, an activation marker of the DNA-sensing cyclic GMP-AMP synthase/stimulator of IFN genes (cGAS/STING) pathway. The patient allele encoded a truncated IKKε protein with loss of kinase activity and also capable of exerting dominant-negative activity. In stem cell-derived microglia, HSV-2-induced expression of IFNB1 was dependent on cGAS, TANK binding kinase 1 (TBK1), and IKBKE, but not TLR3, and supernatants from HSV-2-treated microglia exerted IKBKE-dependent type I IFN-mediated antiviral activity upon neurons. Reintroducing wild-type IKBKE into patient cells rescued IFNB1 induction following treatment with HSV-2 or dsDNA and restored antiviral activity. Collectively, we identify IKKε to be important for protection against HSV-2 meningitis and suggest a nonredundant role for the cGAS/STING pathway in human antiviral immunity.
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Affiliation(s)
- Azadeh Reyahi
- Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Department of Biomedicine, Aarhus University, Aarhus, Denmark
| | - Marie Studahl
- Department of Infectious Diseases, Region Västra Götaland, Sahlgrenska University Hospital, Gothenburg, Sweden
- Department of Infectious Diseases, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | | | - Stefanie Fruhwürth
- Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Ryo Narita
- Department of Biomedicine, Aarhus University, Aarhus, Denmark
| | - Fanghui Ren
- Department of Biomedicine, Aarhus University, Aarhus, Denmark
| | - Moa Bjerhem Viklund
- Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | | | | | - Alexandra Svensson
- Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Trine H. Mogensen
- Department of Biomedicine, Aarhus University, Aarhus, Denmark
- Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark
| | - Kristina Eriksson
- Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Søren R. Paludan
- Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Department of Biomedicine, Aarhus University, Aarhus, Denmark
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Abdelrahim NA, Mohammed N, Evander M, Ahlm C, Fadl-Elmula IM. Viral meningitis in Sudanese children: Differentiation, etiology and review of literature. Medicine (Baltimore) 2022; 101:e31588. [PMID: 36401437 PMCID: PMC9678499 DOI: 10.1097/md.0000000000031588] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/03/2022] Open
Abstract
Diagnosis of viral meningitis (VM) is uncommon practice in Sudan and there is no local viral etiological map. We therefore intended to differentiate VM using standardized clinical codes and determine the involvement of herpes simplex virus types-1 and 2 (HSV-1/2), varicella zoster virus, non-polio human enteroviruses (HEVs), and human parechoviruses in meningeal infections in children in Sudan. This is a cross-sectional hospital-based study. Viral meningitis was differentiated in 503 suspected febrile attendee of Omdurman Hospital for Children following the criteria listed in the Clinical Case Definition for Aseptic/Viral Meningitis. Patients were children age 0 to 15 years. Viral nucleic acids (DNA/RNA) were extracted from cerebrospinal fluid (CSF) specimens using QIAamp® UltraSens Virus Technology. Complementary DNA was prepared from viral RNA using GoScriptTM Reverse Transcription System. Viral nucleic acids were amplified and detected using quantitative TaqMan® Real-Time and conventional polymerase chain reactions (PCRs). Hospital diagnosis of VM was assigned to 0%, when clinical codes were applied; we considered 3.2% as having VM among the total study population and as 40% among those with proven infectious meningitis. Two (0.4%) out of total 503 CSF specimens were positive for HSV-1; Ct values were 37.05 and 39.10 and virus copies were 652/PCR run (261 × 103/mL CSF) and 123/PCR run (49.3 × 103/mL CSF), respectively. Other 2 (0.4%) CSF specimens were positive for non-polio HEVs; Ct values were 37.70 and 38.30, and the approximate virus copies were 5E2/PCR run (~2E5/mL CSF) and 2E2/PCR run (~8E4/mL CSF), respectively. No genetic materials were detected for HSV-2, varicella zoster virus, and human parechoviruses. The diagnosis of VM was never assigned by the hospital despite fulfilling the clinical case definition. Virus detection rate was 10% among cases with proven infectious meningitis. Detected viruses were HSV-1 and non-polio HEVs. Positive virus PCRs in CSFs with normal cellular counts were seen.
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Affiliation(s)
- Nada Abdelghani Abdelrahim
- Department of Pathology-Medical Microbiology, Faculty of Medicine, University of Medical Sciences and Technology, Khartoum, Sudan
- * Correspondence: Nada Abdelghani Abdelrahim, Department of Pathology-Medical Microbiology, Faculty of Medicine, University of Medical Sciences and Technology (UMST), P.O. Box 12810, Khartoum, Sudan (e-mail: )
| | - Nahla Mohammed
- Department of Clinical Microbiology, Umeå University, Umeå, Sweden
| | - Magnus Evander
- Department of Clinical Microbiology, Umeå University, Umeå, Sweden
| | - Clas Ahlm
- Department of Clinical Microbiology, Umeå University, Umeå, Sweden
| | - Imad Mohammed Fadl-Elmula
- Department of Pathology & Clinical Genetics, Al-Neelain University & Assafa Academy, Khartoum, Sudan
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7
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Primary HSV-2 Infection Complicated by Radiculomyelitis in a Young Immunocompetent Female Patient with Inherited Chromosomally Integrated HHV-6: A Case Report. Viruses 2022; 14:v14091979. [PMID: 36146785 PMCID: PMC9500849 DOI: 10.3390/v14091979] [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] [Received: 08/26/2022] [Revised: 09/02/2022] [Accepted: 09/03/2022] [Indexed: 11/17/2022] Open
Abstract
Background: HSV-1, HSV-2 and VZV are alpha Herpesviruses, neurotropic viruses that are associated with various neurologic complications upon primary infection or reactivation. Cases of myelitis and radiculomyelitis are rare and appropriate etiologic diagnoses can be tricky. Case presentation: Here we describe the case of a young immunocompetent woman who developed painful and extended vesicular genital lesions, with subsequent radiculomyelitis. HSV-1/-2 PCRs in the cerebrospinal fluid were misleadingly negative, whereas HHV-6 PCR was positive. Positive anti-HSV-2 IgM and IgG in serum was consistent with HSV-2 primary infection. On the other hand, the detection of HHV-6 DNA was explained by inherited chromosomally integrated HHV-6. The clinical course was favorable with high-dose IV acyclovir and corticosteroids. Conclusion: HSV-2-related radiculomyelitis is a rare clinical entity, which can be difficult to diagnose. In this case report, the causative virus was not detected in the patient’s CSF, whereas HHV-6 DNA, non-pathogenic in this situation, was paradoxically positive. The diagnosis was based on the clinical features typical for HSV-2 primary infection, confirmed by the serology results. The delay between the genital lesions and the appearance of the radiculomyelitis, along with the absence of HSV-2 detection in the CSF, suggests a possible immuno-mediated physiopathological process. As for the HHV-6 DNA detection in the patient’s CSF, it was explained by inherited chromosomally integrated HHV-6. This case illustrates how both negative and positive clinical virology results need careful interpretation according to the clinical findings.
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8
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Grinney M, Mohseni MM. Recurrent benign lymphocytic (Mollaret’s) meningitis due to herpes simplex virus type 2. Proc AMIA Symp 2022; 35:820-821. [DOI: 10.1080/08998280.2022.2108991] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/15/2022] Open
Affiliation(s)
- Michael Grinney
- Department of Emergency Medicine, Mayo Clinic, Jacksonville, Florida
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9
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Krett JD, Beckham JD, Tyler KL, Piquet AL, Chauhan L, Wallace CJ, Pastula DM, Kapadia RK. Neurology of Acute Viral Infections. Neurohospitalist 2022; 12:632-646. [PMID: 36147750 PMCID: PMC9485684 DOI: 10.1177/19418744221104778] [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] [Indexed: 11/16/2022] Open
Abstract
As specialists in acute neurology, neurohospitalists are often called upon to diagnose and manage acute viral infections affecting the nervous system. In this broad review covering the neurology of several acute viral infections, our aim is to provide key diagnostic and therapeutic pearls of practical use to the busy neurohospitalist. We will review acute presentations, diagnosis, and treatment of human herpesviruses, arboviruses, enteroviruses, and some vaccine-preventable viruses. The neurological effects of coronaviruses, including COVID-19, are not covered in this review.
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Affiliation(s)
- Jonathan D Krett
- Department of Clinical Neurosciences, University of Calgary, Calgary, AB, Canada
| | - J David Beckham
- Department of Neurology and Division of Infectious Diseases, Anschutz Medical Campus, University of Colorado Neurosciences Center, Aurora, CO, USA
- Departments of Immunology & Microbiology, Anschutz Medical Campus, University of Colorado, Aurora, CO, USA
| | - Kenneth L Tyler
- Department of Neurology and Division of Infectious Diseases, Anschutz Medical Campus, University of Colorado Neurosciences Center, Aurora, CO, USA
- Departments of Immunology & Microbiology, Anschutz Medical Campus, University of Colorado, Aurora, CO, USA
| | - Amanda L Piquet
- Department of Neurology and Division of Infectious Diseases, Anschutz Medical Campus, University of Colorado Neurosciences Center, Aurora, CO, USA
| | - Lakshmi Chauhan
- Department of Neurology and Division of Infectious Diseases, Anschutz Medical Campus, University of Colorado Neurosciences Center, Aurora, CO, USA
| | - Carla J Wallace
- Department of Radiology, University of Calgary, Calgary, AB, Canada
| | - Daniel M Pastula
- Department of Neurology and Division of Infectious Diseases, Anschutz Medical Campus, University of Colorado Neurosciences Center, Aurora, CO, USA
- Department of Epidemiology, Colorado School of Public Health, Aurora, CO, USA
| | - Ronak K Kapadia
- Department of Clinical Neurosciences, University of Calgary, Calgary, AB, Canada
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10
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Jakobsen A, Skov MT, Larsen L, Petersen PT, Brandt C, Wiese L, Hansen BR, Lüttichau HR, Tetens MM, Helweg-Larsen J, Storgaard M, Nielsen H, Bodilsen J. Herpes simplex virus 2 meningitis in adults: A prospective, nationwide, population-based cohort study. Clin Infect Dis 2022; 75:753-760. [PMID: 34979025 DOI: 10.1093/cid/ciab1071] [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: 10/28/2021] [Indexed: 11/13/2022] Open
Abstract
BACKGROUND Data on the clinical presentation are scarce and prognostic factors of Herpes simplex virus type 2 (HSV-2) meningitis remain unknown. METHODS Prospective, nationwide, population-based database identifying all adults treated for HSV-2 meningitis at departments of infectious diseases in Denmark from 2015-2020. Unfavorable outcome was defined as Glasgow Outcome Scale (GOS) score of 1-4 and extended GOS score of 1-6. Modified Poisson regression was used to compute relative risks with 95% confidence intervals (RR, 95% CI) for unfavorable outcome. RESULTS HSV-2 meningitis was diagnosed in 205 cases (76% female, median age 35 [IQR 27-49]) yielding an incidence of 0.7/100,000/year. Common symptoms were headache 195/204 (95%), photo/phonophobia 143/188 (76%), and neck stiffness 106/196 (54%). Median time to lumbar puncture was 2.0 hours (IQR 1-4.8) and cerebrospinal fluid (CSF) leukocyte count was 360x10 6/L (IQR 166-670) with a mononuclear predominance of 97% (IQR 91-99). Lumbar puncture was preceded by brain imaging in 61/205 (30%). Acyclovir/valaciclovir was administered in 197/205 (96%) cases for a median of 10 days (IQR 7-14).Unfavorable outcome was observed in 64/205 (31%) at discharge and 19/181 (11%) after six months and was not associated with female sex (RR 1.08, 95% CI 0.65-1.79), age ≥35 years (1.28, 0.83-1.97), immuno-compromise (1.07, 0.57-2.03), or CSF leukocyte count >1,000x10 6/L (0.78, 0.33-1.84). CONCLUSIONS HSV-2 meningitis often presented as meningeal symptoms in younger females. Unfavorable outcome at discharge was common and was not associated with sex, age, immune-compromise, or CSF leukocyte count. Sequelae persisted beyond six months in one tenth of patients.
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Affiliation(s)
- Anna Jakobsen
- Department of Infectious Diseases, Aalborg University Hospital, Aalborg, Denmark
| | - Marie Thaarup Skov
- Department of Infectious Diseases, Aalborg University Hospital, Aalborg, Denmark
| | - Lykke Larsen
- Research Unit for Infectious Diseases, Odense University Hospital, Odense, Denmark; University of Southern Denmark, Odense, Denmark
| | - Pelle Trier Petersen
- Department of Pulmonary and Infectious Diseases, Nordsjællands Hospital, Hillerød, Denmark
| | - Christian Brandt
- Department of Pulmonary and Infectious Diseases, Nordsjællands Hospital, Hillerød, Denmark.,Department of Infectious Diseases, Sjælland University Hospital, Roskilde, Denmark
| | - Lothar Wiese
- Department of Infectious Diseases, Sjælland University Hospital, Roskilde, Denmark
| | | | - Hans Rudolf Lüttichau
- Department of Medicine and Infectious Diseases, Herlev Gentofte Hospital, Herlev Copenhagen, Denmark
| | - Malte Mose Tetens
- Department of Infectious Diseases, Rigshospitalet, Copenhagen, Denmark
| | | | - Merete Storgaard
- Department of Infectious Diseases, Aarhus University Hospital, Skejby, Aarhus N, Denmark
| | - Henrik Nielsen
- Department of Infectious Diseases, Aalborg University Hospital, Aalborg, Denmark.,Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
| | - Jacob Bodilsen
- Department of Infectious Diseases, Aalborg University Hospital, Aalborg, Denmark
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Abstract
Infectious meningitis and encephalitis are associated with significant morbidity and mortality worldwide. Acute bacterial meningitis is rapidly fatal and early recognition and institution of therapy are imperative. Viral meningitis is typically a benign self-limited illness. Chronic meningitis (defined as presenting with >4 weeks of symptoms) is most often caused by tuberculosis and fungal infection. Because the diagnostic testing for tuberculous meningitis is insensitive and cultures often take weeks to grow, therapy is often initiated empirically when the diagnosis is suspected. Human simplex virus encephalitis is the most common cause of encephalitis and requires prompt treatment with intravenous acyclovir.
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Affiliation(s)
- Rachel J Bystritsky
- Department of Medicine, University of California San Francisco, 513 Parnassus Avenue, Room S-280, San Francisco, CA 94143, USA.
| | - Felicia C Chow
- Department of Neurology, University of California, San Francisco, 1001 Potrero Avenue, Building 1, Room 101, San Francisco, CA 94110, USA; Department of Medicine, University of California, San Francisco, 1001 Potrero Avenue, Building 1, Room 101, San Francisco, CA 94110, USA
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12
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Kennedy PGE, Mogensen TH, Cohrs RJ. Recent Issues in Varicella-Zoster Virus Latency. Viruses 2021; 13:v13102018. [PMID: 34696448 PMCID: PMC8540691 DOI: 10.3390/v13102018] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2021] [Revised: 09/30/2021] [Accepted: 10/02/2021] [Indexed: 12/16/2022] Open
Abstract
Varicella-zoster virus (VZV) is a human herpes virus which causes varicella (chicken pox) as a primary infection, and, following a variable period of latency in neurons in the peripheral ganglia, may reactivate to cause herpes zoster (shingles) as well as a variety of neurological syndromes. In this overview we consider some recent issues in alphaherpesvirus latency with special focus on VZV ganglionic latency. A key question is the nature and extent of viral gene transcription during viral latency. While it is known that this is highly restricted, it is only recently that the very high degree of that restriction has been clarified, with both VZV gene 63-encoded transcripts and discovery of a novel VZV transcript (VLT) that maps antisense to the viral transactivator gene 61. It has also emerged in recent years that there is significant epigenetic regulation of VZV gene transcription, and the mechanisms underlying this are complex and being unraveled. The last few years has also seen an increased interest in the immunological aspects of VZV latency and reactivation, in particular from the perspective of inborn errors of host immunity that predispose to different VZV reactivation syndromes.
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Affiliation(s)
- Peter G. E. Kennedy
- Institute of Neuroscience and Psychology, University of Glasgow, Glasgow G61 1QH, UK
- Correspondence:
| | - Trine H. Mogensen
- Department of Infectious Diseases, Aarhus University Hospital, 8000 Aarhus, Denmark;
- Department of Biomedicine, Aarhus University, 8000 Aarhus, Denmark
| | - Randall J. Cohrs
- Department of Neurology, University of Colorado School of Medicine, 80045 Aurora, CO, USA
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13
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Neuro-Ophthalmic Manifestations of Mollaret Meningitis. J Neuroophthalmol 2021; 41:e407-e409. [PMID: 33417418 DOI: 10.1097/wno.0000000000001152] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
ABSTRACT Mollaret meningitis (MM) refers to benign recurrent aseptic meningitis usually following herpes simplex virus 2 (HSV-2) infection. Neuro-ophthalmic manifestations associated with MM are rarely reported. We present a case of recurrent HSV-2 meningitis with the neuro-ophthalmic presentation of papilledema and sixth nerve palsy. To our knowledge, this is the first such description in the English language ophthalmic literature.
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Constitutive and latent immune mechanisms exert 'silent' control of virus infections in the central nervous system. Curr Opin Immunol 2021; 72:158-166. [PMID: 34062364 DOI: 10.1016/j.coi.2021.05.004] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2021] [Revised: 05/04/2021] [Accepted: 05/06/2021] [Indexed: 12/14/2022]
Abstract
Viral infections in the central nervous system (CNS) can lead to severe disease manifestations often mediated by a combination of viral cytopathic effects and immunopathology. Moreover, neuronal tissue and brain activities are highly sensitive to excessive inflammation that disturb homeostasis. Immune responses to virus infections in the CNS should therefore be tightly balanced and limited in magnitude and duration to avoid immunopathology and tissue damage. Recent data from genetic studies of patients with viral infections in the CNS as well as experimental cell and animal models have provided evidence of non-redundant roles for constitutive and latent immune mechanisms, which mediate a first line of antiviral control without significantly triggering inflammatory activities. Collectively, accumulating data suggest the existence of a layer of immune mechanisms in the CNS exerting immediate control of infection, hence buffering the need for activation of more potent immune reactions with inherent potential to induce immunopathology and disease.
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Assessment of Two Novel Live-Attenuated Vaccine Candidates for Herpes Simplex Virus 2 (HSV-2) in Guinea Pigs. Vaccines (Basel) 2021; 9:vaccines9030258. [PMID: 33805768 PMCID: PMC7999511 DOI: 10.3390/vaccines9030258] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2021] [Revised: 03/09/2021] [Accepted: 03/10/2021] [Indexed: 12/22/2022] Open
Abstract
Treatment to ameliorate the symptoms of infection with herpes simplex virus 2 (HSV-2) and to suppress reactivation has been available for decades. However, a safe and effective preventative or therapeutic vaccine has eluded development. Two novel live-attenuated HSV-2 vaccine candidates (RVx201 and RVx202) have been tested preclinically for safety. Hartley guinea pigs were inoculated vaginally (n = 3) or intradermally (n = 16) with either vaccine candidate (2 × 107 PFU) and observed for disease for 28 days. All animals survived to study end without developing HSV-2-associated disease. Neither vaccine candidate established latency in dorsal root or sacral sympathetic ganglia, as determined by viral DNA quantification, LAT expression, or explant reactivation. Infectious virus was shed in vaginal secretions for three days following vaginal inoculation with RVx202, but not RVx201, although active or latent HSV-2 was not detected at study end. In contrast, guinea pigs inoculated with wild-type HSV-2 MS (2 × 105 PFU) vaginally (n = 5) or intradermally (n = 16) developed acute disease, neurological signs, shed virus in vaginal secretions, experienced periodic recurrences throughout the study period, and had latent HSV-2 in their dorsal root and sacral sympathetic ganglia at study end. Both vaccine candidates generated neutralizing antibody. Taken together, these findings suggest that these novel vaccine candidates are safe in guinea pigs and should be tested for efficacy as preventative and/or therapeutic anti-HSV-2 vaccines.
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Hait AS, Olagnier D, Sancho-Shimizu V, Skipper KA, Helleberg M, Larsen SM, Bodda C, Moldovan LI, Ren F, Brinck Andersen NS, Thomsen MM, Freytag MR, Darmalinggam S, Parkes I, Kadekar DD, Rahbek SH, van der Horst D, Kristensen LS, Eriksson K, Kjems J, Mostowy S, Christiansen M, Mikkelsen JG, Brandt CT, Paludan SR, Mogensen TH. Defects in LC3B2 and ATG4A underlie HSV2 meningitis and reveal a critical role for autophagy in antiviral defense in humans. Sci Immunol 2020; 5:eabc2691. [PMID: 33310865 PMCID: PMC7611067 DOI: 10.1126/sciimmunol.abc2691] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2020] [Revised: 09/26/2020] [Accepted: 11/16/2020] [Indexed: 12/22/2022]
Abstract
Recurrent herpesvirus infections can manifest in different forms of disease, including cold sores, genital herpes, and encephalitis. There is an incomplete understanding of the genetic and immunological factors conferring susceptibility to recurrent herpes simplex virus 2 (HSV2) infection in the central nervous system (CNS). Here, we describe two adult patients with recurrent HSV2 lymphocytic Mollaret's meningitis that each carry a rare monoallelic variant in the autophagy proteins ATG4A or LC3B2. HSV2-activated autophagy was abrogated in patient primary fibroblasts, which also exhibited significantly increased viral replication and enhanced cell death. HSV2 antigen was captured in autophagosomes of infected cells, and genetic inhibition of autophagy by disruption of autophagy genes, including ATG4A and LC3B2, led to enhanced viral replication and cell death in primary fibroblasts and a neuroblastoma cell line. Activation of autophagy by HSV2 was sensitive to ultraviolet (UV) irradiation of the virus and inhibited in the presence of acyclovir, but HSV2-induced autophagy was independent of the DNA-activated STING pathway. Reconstitution of wild-type ATG4A and LC3B2 expression using lentiviral gene delivery or electroporation of in vitro transcribed mRNA into patient cells restored virus-induced autophagy and the ability to control HSV2 replication. This study describes a previously unknown link between defective autophagy and an inborn error of immunity that can lead to increased susceptibility to HSV2 infection, suggesting an important role for autophagy in antiviral immunity in the CNS.
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Affiliation(s)
- Alon Schneider Hait
- Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark
- Department of Biomedicine, Faculty of Health, Aarhus University, Aarhus, Denmark
| | - David Olagnier
- Department of Biomedicine, Faculty of Health, Aarhus University, Aarhus, Denmark
| | - Vanessa Sancho-Shimizu
- Faculty of Medicine, Department of Infectious Disease, Section of Pediatric Infectious Disease, Imperial Collage London, London, UK
| | | | - Marie Helleberg
- Department of Infectious Diseases, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Simon Muller Larsen
- Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark
| | - Chiranjeevi Bodda
- Department of Biomedicine, Faculty of Health, Aarhus University, Aarhus, Denmark
| | - Liviu Ionut Moldovan
- iNano, Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark
| | - Fanghui Ren
- Department of Biomedicine, Faculty of Health, Aarhus University, Aarhus, Denmark
| | - Nanna-Sophie Brinck Andersen
- Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark
- Department of Biomedicine, Faculty of Health, Aarhus University, Aarhus, Denmark
| | - Michelle M Thomsen
- Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark
- Department of Biomedicine, Faculty of Health, Aarhus University, Aarhus, Denmark
| | - Mette Ratzer Freytag
- Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark
- Department of Biomedicine, Faculty of Health, Aarhus University, Aarhus, Denmark
| | - Sathya Darmalinggam
- Faculty of Medicine, Department of Infectious Disease, Section of Pediatric Infectious Disease, Imperial Collage London, London, UK
| | - Isobel Parkes
- Faculty of Medicine, Department of Infectious Disease, Section of Pediatric Infectious Disease, Imperial Collage London, London, UK
| | - Darshana D Kadekar
- Department of Biomedicine, Faculty of Health, Aarhus University, Aarhus, Denmark
| | - Stine Hess Rahbek
- Department of Biomedicine, Faculty of Health, Aarhus University, Aarhus, Denmark
| | - Demi van der Horst
- Department of Biomedicine, Faculty of Health, Aarhus University, Aarhus, Denmark
| | - Lasse Sommer Kristensen
- Department of Biomedicine, Faculty of Health, Aarhus University, Aarhus, Denmark
- iNano, Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark
| | - Kristina Eriksson
- Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Jørgen Kjems
- iNano, Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark
| | - Serge Mostowy
- Department of Infection Biology, Faculty of Infectious and Tropical Diseases, London School of Hygiene & Tropical Medicine, London, UK
| | - Mette Christiansen
- Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark
| | | | - Christian Thomas Brandt
- Department of Infectious Diseases, Institute of Clinical Medicine, North Zealands Hospital, Hillerød, Denmark
| | - Søren R Paludan
- Department of Biomedicine, Faculty of Health, Aarhus University, Aarhus, Denmark
- Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Trine H Mogensen
- Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark.
- Department of Biomedicine, Faculty of Health, Aarhus University, Aarhus, Denmark
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
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Kirkland Z, Jeffery RE, Conte J, George J, Mercado R. Recurrent Aseptic Meningitis From Herpes Simplex Virus-2: Mollaret's Meningitis in a 30-Year-Old Female. Cureus 2020; 12:e11623. [PMID: 33376637 PMCID: PMC7755614 DOI: 10.7759/cureus.11623] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
Abstract
Aseptic meningitis is most commonly caused by herpes simplex virus (HSV), most often viral subtype 2. While typical meningeal symptoms include headache, photophobia/phonophobia, and nuchal rigidity, these are often much less severe than in bacterial meningitis. Rarely, patients may develop recurrent episodes of aseptic meningitis, sometimes with years between each presentation. A minimum of three episodes with at least one documented viral identification is classified as Mollaret meningitis. First described by Mollaret in 1945, the condition is self-limiting and often requires no intervention or suppressive antivirals. In fact, antiviral therapy may increase frequency of presentation. Our patient presented for her third bout of meningitis, with viral polymerase chain reaction positive for HSV-2 on lumbar puncture. The patient was successfully managed with supportive care without further suppressive antiviral therapy. As the disease is self-limiting, clinician education can mediate patient expectations, reduce unnecessary antiviral usage, and decrease superfluous healthcare resource utilization.
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Affiliation(s)
- Zachary Kirkland
- Internal Medicine, Florida State University College of Medicine Internal Medicine Residency Program, Sarasota Memorial Hospital, Sarasota, USA
| | - Ranese E Jeffery
- Internal Medicine, Florida State University College of Medicine Internal Medicine Residency Program, Sarasota, USA
| | - Jorge Conte
- Internal Medicine, Florida State University College of Medicine Internal Medicine Residency Program, Sarasota, USA
| | - Justin George
- Internal Medicine, Florida State University College of Medicine Internal Medicine Residency Program, Sarasota Memorial Hospital, Sarasota, USA
| | - Roberto Mercado
- Internal Medicine-Infectious Disease, Sarasota Memorial Healthcare System, Sarasota, USA
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18
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Hait AS, Thomsen MM, Larsen SM, Helleberg M, Mardahl M, Barfod TS, Christiansen M, Brandt C, Mogensen TH. Whole-Exome Sequencing of Patients With Recurrent HSV-2 Lymphocytic Mollaret Meningitis. J Infect Dis 2020; 223:1776-1786. [PMID: 32946550 DOI: 10.1093/infdis/jiaa589] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2020] [Accepted: 09/17/2020] [Indexed: 12/19/2022] Open
Abstract
Recurrent lymphocytic meningitis, also referred to as Mollaret meningitis, is a rare neurological disease characterized mainly by reactivation of herpes simplex virus 2 (HSV-2) from sensory ganglia. However, the underlying host immune determinants and viral factors rendering some individuals unable to maintain HSV-2 latency are largely unknown. We collected a cohort of 15 patients diagnosed with Mollaret meningitis. By whole-exome sequencing we identified rare host genetic variants predicted to be deleterious in molecules involved in (1) ubiquitin-proteasome pathways, (2) the autophagy machinery, and (3) cell proliferation/apoptosis. Moreover, infection of patient cells with HSV-2 or stimulation by virus-derived double-stranded DNA ligands revealed reduced antiviral interferon responses in most patients. These findings may contribute to a better understanding of disease pathogenesis and protective immunity to HSV in the central nervous system, and may ultimately be of importance for identification of targets for development of improved prophylaxis and treatment of this disease.
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Affiliation(s)
- Alon Schneider Hait
- Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark.,Department of Biomedicine, Aarhus University, Aarhus, Denmark
| | - Michelle M Thomsen
- Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark.,Department of Biomedicine, Aarhus University, Aarhus, Denmark
| | - Simon M Larsen
- Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark
| | - Marie Helleberg
- Department of Infectious Diseases, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
| | - Maibritt Mardahl
- Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark
| | - Toke S Barfod
- Department of Internal medicine, Section for Infectious Diseases, Zealand University Hospital, Roskilde, Denmark
| | - Mette Christiansen
- Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark
| | - Christian Brandt
- Department of Internal medicine, Section for Infectious Diseases, Zealand University Hospital, Roskilde, Denmark.,Department of Pulmonology and Infectious Diseases, Nordsjællands Hospital, Hillerød, Denmark
| | - Trine H Mogensen
- Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark.,Department of Biomedicine, Aarhus University, Aarhus, Denmark.,Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
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Abstract
PURPOSE OF REVIEW This article describes the clinical presentation, diagnostic approach (including the use of novel diagnostic platforms), and treatment of select infectious and noninfectious etiologies of chronic meningitis. RECENT FINDINGS Identification of the etiology of chronic meningitis remains challenging, with no cause identified in at least one-third of cases. Often, several serologic, CSF, and neuroimaging studies are indicated, although novel diagnostic platforms including metagenomic deep sequencing may hold promise for identifying organisms. Infectious etiologies are more common in those at risk for disseminated disease, specifically those who are immunocompromised because of human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS), transplantation, or immunosuppressant medications. An important step in identifying the etiology of chronic meningitis is assembling a multidisciplinary team of individuals, including those with specialized expertise in ophthalmology, dermatology, rheumatology, and infectious diseases, to provide guidance regarding diagnostic procedures. SUMMARY Chronic meningitis is defined as inflammation involving the meninges that lasts at least 4 weeks and is associated with a CSF pleocytosis. Chronic meningitis has numerous possible infectious and noninfectious etiologies, making it challenging to definitively diagnose patients. Therefore, a multifaceted approach that combines history, physical examination, neuroimaging, and laboratory analysis, including novel diagnostic platforms, is needed. This article focuses on key aspects of the evaluation of and approach to patients with chronic meningitis. Specific infectious etiologies and differential diagnoses of subacute and chronic meningitis, including noninfectious etiologies, are addressed.
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21
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A proposal for distinguishing between bacterial and viral meningitis using genetic programming and decision trees. Soft comput 2019. [DOI: 10.1007/s00500-018-03729-y] [Citation(s) in RCA: 41] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
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Abstract
PURPOSE OF REVIEW The purpose of this review is to give an overview of viral meningitis and then focus in on some of the areas of uncertainty in diagnostics, treatment and outcome. RECENT FINDINGS Bacterial meningitis has been declining in incidence over recent years. Over a similar time period molecular diagnostics have increasingly been used. Because of both of these developments viral meningitis is becoming relatively more important. However, there are still many unanswered questions. Despite improvements in diagnostics many laboratories do not use molecular methods and even when they are used many cases still remain without a proven viral aetiology identified. There are also no established treatments for viral meningitis and the one potential treatment, aciclovir, which is effective in vitro for herpes simplex virus, has never been subjected to a clinical trial. SUMMARY Viruses are in increasingly important cause of meningitis in the era of declining bacterial disease. The exact viral aetiology varies according to age and country. Molecular diagnostics can not only improve the rate of pathogen detection but also reduce unnecessary antibiotics use and length of hospitalization. Further research is required into treatments for viral meningitis and the impact in terms of longer term sequelae.
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Nolte FS. Molecular Microbiology. PRINCIPLES AND APPLICATIONS OF MOLECULAR DIAGNOSTICS 2018. [PMCID: PMC7150357 DOI: 10.1016/b978-0-12-816061-9.00005-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
Background Nucleic acid (NA) amplification techniques are now commonly used to diagnose and manage patients with infectious diseases. The growth in the number of Food and Drug Administration–approved test kits and analyte-specific reagents has facilitated the use of this technology in clinical laboratories. Technological advances in NA amplification techniques, automation, NA sequencing, and multiplex analysis have reinvigorated the field and created new opportunities for growth. Simple, sample-in, answer-out molecular test systems are now widely available that can be deployed in a variety of laboratory and clinical settings. Molecular microbiology remains the leading area in molecular pathology in terms of both the numbers of tests performed and clinical relevance. NA-based tests have reduced the dependency of the clinical microbiology laboratory on more traditional antigen detection and culture methods and created new opportunities for the laboratory to impact patient care. Content This chapter reviews NA testing as it applies to specific pathogens or infectious disease syndromes, with a focus on those diseases for which NA testing is now considered the standard of care and highlights the unique challenges and opportunities that these tests present for clinical laboratories.
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Koeller KK, Shih RY. Viral and Prion Infections of the Central Nervous System: Radiologic-Pathologic Correlation: From the Radiologic Pathology Archives. Radiographics 2017; 37:199-233. [PMID: 28076019 DOI: 10.1148/rg.2017160149] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
Viral infections of the central nervous system (CNS) range in clinical severity, with the most severe proving fatal within a matter of days. Some of the more than 100 different viruses known to affect the brain and spinal cord are neurotropic with a predilection for producing CNS infection. The host response to viral infection of the CNS is responsible for the pathophysiology and imaging findings seen in affected patients. Viral CNS infections can take the form of meningitis, encephalitis, encephalomyelitis, or, when involving the spinal cord and nerve roots, encephalomyeloradiculitis. In 1982, an infectious particle termed a prion that lacked nucleic acid and therefore was not a virus was reported to produce the fatal neurodegenerative disease Creutzfeldt-Jakob disease and related disorders. These prion diseases produce characteristic neuroimaging findings that are distinct from those seen in most viral infections. The clinical and imaging findings associated with viral CNS infection are often nonspecific, with microbiologic analysis of cerebrospinal fluid the most useful single test allowing for diagnosis of a specific viral infection. This review details the spectrum of viral CNS infections and uses case material from the archives of the American Institute for Radiologic Pathology, with a focus on the specific clinical characteristics and magnetic resonance imaging features seen in these infections. Where possible, the imaging features that allow distinction of these infections from other CNS inflammatory conditions are highlighted.
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Affiliation(s)
- Kelly K Koeller
- From the Department of Neuroradiology, American Institute for Radiologic Pathology, Silver Spring, Md (K.K.K., R.Y.S.); Department of Radiology, Mayo Clinic, 200 First St SW, Rochester, MN 55905 (K.K.K.); Uniformed Services University of the Health Sciences, Bethesda, Md (R.Y.S.); and Department of Radiology, Walter Reed National Military Medical Center, Bethesda, Md (R.Y.S.)
| | - Robert Y Shih
- From the Department of Neuroradiology, American Institute for Radiologic Pathology, Silver Spring, Md (K.K.K., R.Y.S.); Department of Radiology, Mayo Clinic, 200 First St SW, Rochester, MN 55905 (K.K.K.); Uniformed Services University of the Health Sciences, Bethesda, Md (R.Y.S.); and Department of Radiology, Walter Reed National Military Medical Center, Bethesda, Md (R.Y.S.)
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26
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Awasthi S, Hook LM, Shaw CE, Friedman HM. A trivalent subunit antigen glycoprotein vaccine as immunotherapy for genital herpes in the guinea pig genital infection model. Hum Vaccin Immunother 2017; 13:2785-2793. [PMID: 28481687 PMCID: PMC5718817 DOI: 10.1080/21645515.2017.1323604] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
An estimated 417 million people worldwide ages 15 to 49 are infected with herpes simplex virus type 2 (HSV-2), the most common cause of genital ulcer disease. Some individuals experience frequent recurrences of genital lesions, while others only have subclinical infection, yet all risk transmitting infection to their intimate partners. A vaccine was developed that prevents shingles, which is a recurrent infection caused by varicella-zoster virus (VZV), a closely related member of the Herpesviridae family. The success of the VZV vaccine has stimulated renewed interest in a therapeutic vaccine for genital herpes. We have been evaluating a trivalent subunit antigen vaccine for prevention of genital herpes. Here, we assess the trivalent vaccine as immunotherapy in guinea pigs that were previously infected intravaginally with HSV-2. The trivalent vaccine contains HSV-2 glycoproteins C, D, and E (gC2, gD2, gE2) subunit antigens administered with CpG and alum as adjuvants. We previously demonstrated that antibodies to gD2 neutralize the virus while antibodies to gC2 and gE2 block their immune evasion activities, including evading complement attack and inhibiting activities mediated by the IgG Fc domain, respectively. Here, we demonstrate that the trivalent vaccine significantly boosts ELISA titers and neutralizing antibody titers. The trivalent vaccine reduces the frequency of recurrent genital lesions and vaginal shedding of HSV-2 DNA by approximately 50% and almost totally eliminates vaginal shedding of replication-competent virus, suggesting that the trivalent vaccine is a worthy candidate for immunotherapy of genital herpes.
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Affiliation(s)
- Sita Awasthi
- a Infectious Disease Division, Department of Medicine , Perelman School of Medicine, University of Pennsylvania , Philadelphia , PA , USA
| | - Lauren M Hook
- a Infectious Disease Division, Department of Medicine , Perelman School of Medicine, University of Pennsylvania , Philadelphia , PA , USA
| | - Carolyn E Shaw
- a Infectious Disease Division, Department of Medicine , Perelman School of Medicine, University of Pennsylvania , Philadelphia , PA , USA
| | - Harvey M Friedman
- a Infectious Disease Division, Department of Medicine , Perelman School of Medicine, University of Pennsylvania , Philadelphia , PA , USA
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Chang GY. HIV-Associated CNS Vasculopathy in the Modern Era. J Clin Neurol 2017; 13:103-104. [PMID: 27730771 PMCID: PMC5242146 DOI: 10.3988/jcn.2017.13.1.103] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2016] [Revised: 06/06/2016] [Accepted: 06/09/2016] [Indexed: 11/17/2022] Open
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Abstract
Infections of the nervous system are an important and challenging aspect of clinical neurology. Immediate correct diagnosis enables to introduce effective therapy, in conditions that without diagnosis may leave the patient with severe neurological incapacitation and sometimes even death. The cerebrospinal fluid (CSF) is a mirror that reflects nervous system pathology and can promote early diagnosis and therapy. The present chapter focuses on the CSF findings in neuro-infections, mainly viral and bacterial. Opening pressure, protein and glucose levels, presence of cells and type of the cellular reaction should be monitored. Other tests can also shed light on the causative agent: serology, culture, staining, molecular techniques such as polymerase chain reaction. Specific examination such as panbacterial and panfungal examinations should be examined when relevant. Our chapter is a guide-text that combines clinical presentation and course with CSF findings as a usuaful tool in diagnosis of neuroinfections.
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Affiliation(s)
- Felix Benninger
- Department of Neurology, Rabin Medical Center, Petach Tikva, Israel
| | - Israel Steiner
- Department of Neurology, Rabin Medical Center, Petach Tikva, Israel
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The UK joint specialist societies guideline on the diagnosis and management of acute meningitis and meningococcal sepsis in immunocompetent adults. J Infect 2016; 72:405-38. [PMID: 26845731 DOI: 10.1016/j.jinf.2016.01.007] [Citation(s) in RCA: 109] [Impact Index Per Article: 12.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2015] [Revised: 01/14/2016] [Accepted: 01/23/2016] [Indexed: 02/06/2023]
Abstract
Bacterial meningitis and meningococcal sepsis are rare conditions with high case fatality rates. Early recognition and prompt treatment saves lives. In 1999 the British Infection Society produced a consensus statement for the management of immunocompetent adults with meningitis and meningococcal sepsis. Since 1999 there have been many changes. We therefore set out to produce revised guidelines which provide a standardised evidence-based approach to the management of acute community acquired meningitis and meningococcal sepsis in adults. A working party consisting of infectious diseases physicians, neurologists, acute physicians, intensivists, microbiologists, public health experts and patient group representatives was formed. Key questions were identified and the literature reviewed. All recommendations were graded and agreed upon by the working party. The guidelines, which for the first time include viral meningitis, are written in accordance with the AGREE 2 tool and recommendations graded according to the GRADE system. Main changes from the original statement include the indications for pre-hospital antibiotics, timing of the lumbar puncture and the indications for neuroimaging. The list of investigations has been updated and more emphasis is placed on molecular diagnosis. Approaches to both antibiotic and steroid therapy have been revised. Several recommendations have been given regarding the follow-up of patients.
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Kruis T, Kredel L, Nassir M, Godbersen M, Schneider T. Benigne rekurrierende aseptische Meningitis. Internist (Berl) 2016; 57:188-93. [DOI: 10.1007/s00108-015-0003-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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Ballaekere JS, Chebbi PP, Sundarmurthy H, Parameshwarappa A. Weber syndrome: herpes simplex virus brainstem encephalitis as an etiology. Am J Med 2014; 127:e5-6. [PMID: 25149428 DOI: 10.1016/j.amjmed.2014.08.005] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2014] [Revised: 07/17/2014] [Accepted: 08/08/2014] [Indexed: 11/16/2022]
Affiliation(s)
| | - Pramod Prahlad Chebbi
- Department of General Medicine, JSS Medical College and Hospital, JSS University, Mysore, India.
| | - Harsha Sundarmurthy
- Department of Neurology, JSS Medical College and Hospital, JSS University, Mysore, India
| | - Ashok Parameshwarappa
- Department of General Medicine, JSS Medical College and Hospital, JSS University, Mysore, India
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Moon SM, Kim T, Lee EM, Kang JK, Lee SA, Choi SH. Comparison of clinical manifestations, outcomes and cerebrospinal fluid findings between herpes simplex type 1 and type 2 central nervous system infections in adults. J Med Virol 2014; 86:1766-71. [PMID: 25042344 DOI: 10.1002/jmv.23999] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/30/2014] [Indexed: 12/28/2022]
Abstract
In previous reports on the viral causes of central nervous system (CNS) infections, it has been generally recognized that HSV-1 is a major cause of encephalitis, while HSV-2 is the predominant cause of aseptic meningitis in adults. To examine this matter, the clinical characteristics in the two types of HSV CNS infections were investigated. In a retrospective cohort study which included all adult patients (≥16 years) between January 1999 and December 2013 in a 2,700-bed tertiary care hospital, all the patients in whom PCR of the CSF for HSV was positive were identified. Ninety-five patients with positive CSF PCR results for HSV were included, 21 with HSV-1 and 74 with HSV-2. Many patients with HSV-1 had encephalitis (13/21, 61.9%), whereas most patients with HSV-2 had meningitis (62/74, 83.8%). However, HSV-1 and HSV-2 accounted for similar proportion of patients with HSV encephalitis (13/25, 52.0% vs. 12/25, 48.0%). Neurological sequelae were more frequent among patients with HSV-1 (9/21, 42.9% vs. 6/74, 8.1%; P = 0.001). The present study suggests that HSV-2 is not only a major cause of aseptic meningitis, but also it may cause serious manifestation as HSV-1 encephalitis in adults.
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Affiliation(s)
- Song Mi Moon
- Department of Infectious Diseases, Gachon University Gil Hospital, Incheon, Republic of Korea
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Tyler KL, Johnson ECB, Cantu DS, Haller BL. A 20-year-old woman with headache and transient numbness. Neurohospitalist 2013; 3:101-10. [PMID: 23983894 DOI: 10.1177/1941874412473118] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Affiliation(s)
- Kenneth L Tyler
- Department of Neurology, University of Colorado-Denver, Denver, CO, USA
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Muñoz-Sanz A, Rodríguez-Vidigal FF, Nogales-Muñoz N, Vera-Tomé A. Herpes simplex type-2 recurrent meningitis: Mollaret or not Mollaret? Enferm Infecc Microbiol Clin 2013; 31:271-2. [DOI: 10.1016/j.eimc.2012.10.005] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2012] [Revised: 10/16/2012] [Accepted: 10/17/2012] [Indexed: 11/16/2022]
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Herpes simplex virus 2 meningitis: a retrospective cohort study. J Neurovirol 2013; 19:166-71. [PMID: 23494382 DOI: 10.1007/s13365-013-0158-x] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2012] [Revised: 02/12/2013] [Accepted: 02/25/2013] [Indexed: 10/27/2022]
Abstract
Herpes simplex virus 2 is a leading cause of viral meningitis and the most commonly recognized infectious cause of benign, recurrent meningitis. We report a retrospective, observational cohort study of patients with herpes simplex virus type 2 (HSV-2) meningitis, confirmed by polymerase chain reaction (PCR) in the cerebrospinal fluid (CSF). The terms "herpes simplex," "meningitis," or "encephalitis" were searched in the medical records system of the Mayo Clinic in Rochester, Minnesota (1995-2008). Patients were included if they had a clinical diagnosis of meningitis and HSV-2 detected by PCR in the CSF. There were 28 patients with 33 episodes identified (83 % female; mean age at presentation of meningitis 36 years, range 17-53; mean time to HSV2 detection from symptom onset 3 days, range 0-6; history of genital herpes 23 %). No patient took oral antiviral treatment at the time of presentation. Episodes were most likely to include headache (100 %), photophobia (47 %), self-reported fever (45 %), meningismus (44 %), and nausea and/or vomiting (29 %). CSF at the time of meningitis was notable for elevated protein (mean 156 g/dL, range 60-258) and white cell count (mean 504 cells/μL, range 86-1,860) with normal glucose (mean 54 mg/dL, range 32-80). Mollaret cells were never detected. Neuroimaging was most often normal (83 %) when performed, although some cases showed nonspecific (14 %) or meningeal changes (3 %). There was no consistent relationship to genital herpes. The duration of treatment with intravenous acyclovir ranged from 3 to 14 days for the first meningitic episode (daily dose range from 500 to 1,000 mg and total dose range from 500 mg q8h for 3 days to 800 mg q8h for 14 days). For subsequent episodes, the duration of treatment of intravenous acyclovir ranged from less than 1 to 14 days (total dose range from 1,390 mg for 1 day to 900 mg q8h for 10 days). The dose of valacyclovir ranged from 500 mg once daily to 500 mg four times daily. The median duration of valacyclovir treatment following the first episode was 10 days (range 3 to 14 days, n = 13). The median duration of valacyclovir treatment following a subsequent meningitic episode was 9 days (range 7 days to indefinite period, n = 9). No patient was reported to have seizures, neurological disability, or death in extended follow-up (mean follow-up 3.4 years). Recurrence of meningitic symptoms was not universal.
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Herpes simplex meningitis after removal of a vestibular schwannoma: case report and review of the literature. Otol Neurotol 2013; 33:1422-5. [PMID: 22975906 DOI: 10.1097/mao.0b013e3182693a03] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
OBJECTIVE We present a case of postoperative herpes simplex type 1 viral meningitis after retrosigmoid craniotomy and uncomplicated removal of a vestibular schwannoma. This is a very rare complication that can mimic aseptic meningitis and could lead to devastating consequences for the patient, if unrecognized. PATIENT A healthy 49-year-old woman underwent retrosigmoid craniotomy and resection of a 2.4-cm vestibular schwannoma. She developed worsening headache and low-grade fever on postoperative Day 10 and underwent lumbar puncture showing a lymphocyte predominant pleocytosis. Polymerase chain reaction was positive for herpes simplex type 1 virus; bacterial cultures were negative. The patient subsequently developed a pseudomeningocele and mild hydrocephalus. INTERVENTION The patient was readmitted to the hospital, started on corticosteroids, and a lumbar drain was placed. She completed a 14-day course of antiviral therapy (4 d intravenous as an inpatient and 10 d oral outpatient therapy). RESULTS At 1 month follow-up, she was completely asymptomatic, and her pseudomeningocele had resolved. CONCLUSION The diagnosis of herpes simplex viral meningitis should be suspected in clinical cases of postsurgical meningitis with a lymphocyte predominant pleocytosis and negative bacterial cultures. Antiviral therapy should be initiated immediately after confirmatory polymerase chain reaction testing to avoid potential long-term sequelae of a herpes simplex infection of the central nervous system.
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Studahl M, Lindquist L, Eriksson BM, Günther G, Bengner M, Franzen-Röhl E, Fohlman J, Bergström T, Aurelius E. Acute viral infections of the central nervous system in immunocompetent adults: diagnosis and management. Drugs 2013; 73:131-58. [PMID: 23377760 DOI: 10.1007/s40265-013-0007-5] [Citation(s) in RCA: 50] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Patients with viral infections of the central nervous system (CNS) may present with a variety of neurological symptoms, most commonly dominated by either encephalitis or meningitis. The aetiological panorama varies in different parts of the world as well as over time. Thus, virological first-line diagnostics must be adapted to the current epidemiological situation and to the individual patient history, including recent travels. This review focuses on the diagnostics and treatment of viral CNS infections in the immunocompetent host from a Northern European perspective. Effective vaccines are available for viruses such as poliovirus and tick-borne encephalitis virus (TBEV) and for the childhood diseases morbilli (measles), rubella (German measles), parotitis (mumps) and varicella (chickenpox). However, cases do appear due to suboptimal immunization rates. In viral CNS infections, epidemiological surveillance is essential for establishing preventive strategies and for detecting emerging viruses. Knowledge of the possibilities and limitations of diagnostic methods for specific viral CNS infections is vital. A positive cerebral spinal fluid (CSF) polymerase chain reaction (PCR) finding is usually reliable for aetiological diagnosis. The demonstration of intrathecal antibody synthesis is useful for confirming the aetiology in a later stage of disease, hitherto sufficiently evaluated in herpes simplex encephalitis (HSE) and tick-borne encephalitis (TBE). Despite improved virological and differential diagnostic methods, aetiology remains unknown in about half of the cases with suspected viral encephalitis. Antiviral treatment is available chiefly for infections caused by herpesviruses, and acyclovir (aciclovir) is the drug of choice for empirical therapy in suspected viral encephalitis. However, randomized, controlled antiviral trials have only been conducted for HSE, while such studies are lacking in other viral CNS infections. Viral cytolysis and immune-mediated mechanisms may contribute to varying extents to neurological damage. Although the brain damage is believed to depend, to a varying degree, on the intrathecal host immune response, the use of corticosteroids in viral CNS infections is scarcely studied, as is specific treatment for neuroinflammation. Improved antiviral and immunomodulating treatment is desirable. Since neurological sequelae are still abundant, follow-up after severe viral CNS disease must include a neuropsychological assessment and an individually adapted rehabilitation plan.
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Affiliation(s)
- Marie Studahl
- Department of Infectious Diseases, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
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Mollaret cells detected in a patient with varicella-zoster virus meningitis. Clin Neurol Neurosurg 2012; 114:1086-7. [DOI: 10.1016/j.clineuro.2012.02.015] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2011] [Revised: 01/19/2012] [Accepted: 02/09/2012] [Indexed: 11/17/2022]
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Feld O, Yahalom G, Livneh A. Neurologic and other systemic manifestations in FMF: Published and own experience. Best Pract Res Clin Rheumatol 2012; 26:119-33. [DOI: 10.1016/j.berh.2012.01.004] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2011] [Accepted: 01/04/2012] [Indexed: 12/15/2022]
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Farazmand P, Woolley PD, Kinghorn GR. Mollaret's meningitis and herpes simplex virus type 2 infections. Int J STD AIDS 2011; 22:306-7. [PMID: 21680663 DOI: 10.1258/ijsa.2010.010405] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
Benign recurrent aseptic meningitis is a rare disorder described by Mollaret in 1944. When initially described, this form of aseptic meningitis had no identifiable infecting agent. New sophisticated diagnostic tools have now identified herpes simplex type 2 virus as the most commonly isolated agent. Antiviral treatment has been used successfully for prophylaxis and treatment.
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Affiliation(s)
- P Farazmand
- Sexual Health Department, South Manchester University Hospitals, Manchester, UK.
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Increased cell-mediated immune responses in patients with recurrent herpes simplex virus type 2 meningitis. CLINICAL AND VACCINE IMMUNOLOGY : CVI 2011; 18:655-60. [PMID: 21325490 DOI: 10.1128/cvi.00333-10] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
The clinical picture of herpes simplex virus type 2 (HSV-2) infection includes genital blisters and less frequently meningitis, and some individuals suffer from recurrent episodes of these manifestations. We hypothesized that adaptive and/or innate immune functional deficiencies may be a major contributing factor in susceptibility to recurrent HSV-2 meningitis. Ten patients with recurrent HSV-2 meningitis were studied during clinical remission. For comparison, 10 patients with recurrent genital HSV infections as well as 21 HSV-seropositive and 19 HSV-seronegative healthy blood donors were included. HSV-specific T cell blasting and cytokine secretion were evaluated in whole blood cultures. HSV-2-induced NK cell gamma interferon production, dendritic cell Toll-like receptor (TLR) expression, and TLR agonist-induced alpha interferon secretion were analyzed. Patients with recurrent HSV-2 meningitis had elevated T cell blasting and Th1 and Th2 cytokine production in response to HSV antigens compared to those of patients with recurrent genital infections. A somewhat increased NK cell response, increased dendritic cell expression of TLR3 and -9, and increased TLR-induced alpha interferon responses were also noted. Contrary to our expectation, recurrent HSV-2 meningitis patients have increased HSV-specific adaptive and innate immune responses, raising the possibility of immune-mediated pathology in the development of recurrent HSV2 meningitis.
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Soares CN, Cabral-Castro MJ, Peralta JM, de Freitas MRG, Zalis M, Puccioni-Sohler M. Review of the etiologies of viral meningitis and encephalitis in a dengue endemic region. J Neurol Sci 2011; 303:75-9. [PMID: 21292281 DOI: 10.1016/j.jns.2011.01.012] [Citation(s) in RCA: 72] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2010] [Revised: 12/27/2010] [Accepted: 01/12/2011] [Indexed: 10/18/2022]
Abstract
OBJECTIVES To evaluate the etiology of viral meningitis and encephalitis in adults and adolescents living in areas affected by dengue. METHODS Over two years, adults and adolescents with diagnoses of viral encephalitis or meningitis were selected for study in Brazil. PCRs for dengue, enterovirus, HSV1 and 2 and cytomegalovirus were performed in CSF samples. Serum and CSF samples were tested for the presence of anti-dengue IgM antibodies. RESULTS The etiologies of encephalitis and meningitis were determined in 70% of cases (30/47). Dengue was the leading cause of encephalitis (47%) with normal CSF cellularity in 75% of these patients. HSV1 was found in 17.6% of the cases, two of which had mild encephalitis. Enterovirus was the most common cause of meningitis (50%), followed by HSV1 (15%), cytomegalovirus and dengue (10%, each). CONCLUSIONS We identified the viral agents causing encephalitis and meningitis in a higher proportion of cases than has been reported in other studies. Dengue was the most frequent cause of encephalitis, which surpassed HSV. In endemic areas, dengue should be investigated as an important cause of encephalitis. Normal CSF cellularity should not exclude dengue encephalitis. Enterovirus is known to be the leading cause of meningitis in children, but here we found it was also the main cause of the disease in adults. HSV1 should be investigated in patients with mild forms of encephalitis and meningitis.
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Affiliation(s)
- Cristiane N Soares
- Neurology Service, Antônio Pedro Hospital/Federal Fluminense University, Brazil.
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Mihály I, Kolozsi T, Liptai Z, Lukács A, Molnár P, Budai J, Prinz G, Abrahám A, Palánszky M, Dóczy J. [Experience with multiplex nested PCR and fluorescent antibody tests in the diagnosis of acute central nervous system infections with herpes simplex virus type 1 and 2]. Orv Hetil 2010; 151:1896-903. [PMID: 21044940 DOI: 10.1556/oh.2010.28921] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
UNLABELLED The specific diagnosis of herpes simplex virus type 1 and 2 infections has an extreme importance in acute infections of central nervous system due to both availability of specific antiviral therapy and the possible serious consequences of the disease. AIMS Evaluation of the relevance and interpretation of the results of PCR and the specific antibody testing. METHODS Home made multiplex nested herpes simplex virus PCR and immunofluorescent IgM, IgA, IgG antibody tests were carried out in a total of 474 cerebrospinal fluid and 555 serum samples of 396 patients with acute infection of the central nervous system between 1. January, 2003 and 31. December, 2009. RESULTS The herpes simplex virus etiology was verified in 21% of 396 patients (82 patients, mean 12 cases per year): 26 were diagnosed by both methods (32%), 41 by PCR only (50%), 15 by the detection of intrathecal antibody production only (18%) (p<0.0001). HSV type1 or 2 DNA remained detectable in 35% of the samples drawn after the 30th day of the disease. These patients were all younger than two years of age. CONCLUSIONS 1. PCR increased the ratio of verified herpes simplex virus etiology in acute central nervous infections. 2. Testing the specific antibody response cannot be ceased even in the availability of PCR. 3. Herpes simplex virus type 1 or 2 DNA might persist in central nervous system in spite of the specific antiviral therapy especially in the infants. 4. Herpes simplex virus PCR can be repeated if an early sample is negative or if it is suspected false positive. 5. There is a need for cooperation between clinicians and virologists in the appropriate interpretation of the results and in finding etiology.
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Affiliation(s)
- Ilona Mihály
- Fővárosi Önkormányzat Egyesített Szent István és Szent László Kórház-Rendelőintézet, Mikrobiológiai Osztály, Virológiai Laboratórium, Budapest.
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Moustaki M, Sharifi F, Stasinopoulou A, Fretzayas A, Karpathios T. Recurrent meningitis attributable to herpes simplex virus-2 in a child. Pediatr Neurol 2010; 42:372-4. [PMID: 20399396 DOI: 10.1016/j.pediatrneurol.2010.01.007] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2009] [Revised: 11/10/2009] [Accepted: 01/10/2010] [Indexed: 11/26/2022]
Abstract
A boy manifested episodes of recurrent meningitis that were attributed to herpes simplex virus-2 infection. He presented no concurrent or previous history of involvement of the genitourinary system. He exhibited headaches, dizziness, photophobia, loss of balance, and vomiting. He underwent three episodes of aseptic meningitis. The herpes simplex virus-2 etiology was confirmed by polymerase chain reaction of the cerebrospinal fluid in the last two episodes. After the third occurrence, he was treated with acyclovir. Five years have elapsed since then, without the recurrence of aseptic meningitis.
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Affiliation(s)
- Maria Moustaki
- 3(rd) Department of Pediatrics, Athens University School of Medicine, Attikon University Hospital, Athens, Greece
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Kallio-Laine K, Seppänen M, Aittoniemi J, Kautiainen H, Seppälä I, Valtonen V, Färkkilä M, Kalso E, Lokki ML. HLA-DRB1*01 allele and low plasma immunoglobulin G1 concentration may predispose to herpes-associated recurrent lymphocytic meningitis. Hum Immunol 2010; 71:179-81. [DOI: 10.1016/j.humimm.2009.10.014] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2009] [Revised: 10/04/2009] [Accepted: 10/22/2009] [Indexed: 11/29/2022]
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Abstract
While HSV-2 meningitis has been described in prepubertal children in the context of sexual abuse, to the best of our knowledge recurrent episodes have not been described in this population. We report a 9-y-old girl with recurrent HSV-2 meningitis presenting as aseptic meningitis without any evidence of genital herpes. A high index of suspicion for this condition would be needed to make a diagnosis in this age group, which in turn would guide further therapeutic decisions.
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Affiliation(s)
- Swati Kumar
- Department of Pediatrics, State University of New York (SUNY), Downstate Medical Center, Brooklyn, NY 11203-2098, USA.
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Franzen-Röhl E, Larsson K, Skoog E, Tiveljung-Lindell A, Grillner L, Aurelius E, Glimåker M. High diagnostic yield by CSF-PCR for entero- and herpes simplex viruses and TBEV serology in adults with acute aseptic meningitis in Stockholm. ACTA ACUST UNITED AC 2009; 40:914-21. [DOI: 10.1080/00365540802235741] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
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Landry ML, Greenwold J, Vikram HR. Herpes simplex type-2 meningitis: presentation and lack of standardized therapy. Am J Med 2009; 122:688-91. [PMID: 19559173 DOI: 10.1016/j.amjmed.2009.02.017] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2009] [Revised: 02/03/2009] [Accepted: 02/03/2009] [Indexed: 10/20/2022]
Abstract
BACKGROUND Herpes simplex type-2 (HSV-2) causes both primary and recurrent lymphocytic meningitis, but optimal patient management is not well defined. METHODS In this retrospective observational study, we reviewed the medical records of patients with HSV-2-positive cerebrospinal fluid samples in our laboratory between January 2001 and January 2005. RESULTS During the study period, 23 patients, aged 16 to 83 years, had HSV-2 detected in spinal fluid. Nineteen (83%) had meningitis and 4 (17%) had evidence of meningoencephalitis. Seventy-four percent were female. Two (8.7%) had a history of prior genital herpes, and one (4.3%) had genital lesions noted at the time of presentation. Genital examinations were performed at presentation in only 3 patients. Seven (30.4%) patients reported previous episodes of meningitis. Two celibate women developed HSV-2 meningitis or meningoencephalitis following lumbar steroid injection for spinal stenosis. One woman developed HSV-2 meningoencephalitis 3 days postpartum following cesarean section. Antiviral treatment for uncomplicated HSV-2 meningitis varied from none (4 patients) to 14-21 days of intravenous (IV) acyclovir therapy (4 patients). The 11 remaining patients with meningitis received 1-7 days of IV therapy, followed by 7-21 days of oral antiviral therapy. Three of 4 patients with meningoencephalitis received 21 days of IV acyclovir, and one received 3 days IV acyclovir followed by 14 days of oral therapy. CONCLUSIONS HSV-2 meningitis presents most often without a history of genital herpes, recurrent meningitis, or genital symptoms. Current management practices are highly variable and may lead to unnecessary hospitalization and prolonged intravenous therapy.
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Affiliation(s)
- Marie L Landry
- Department of Laboratory Medicine, Yale University School of Medicine, New Haven, CT 06520-8035, USA.
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Herpes simplex virus type 2 (Mollaret's) meningitis: a case report. Int J Infect Dis 2009; 13:e476-9. [PMID: 19329344 DOI: 10.1016/j.ijid.2009.01.003] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2008] [Revised: 12/17/2008] [Accepted: 01/03/2009] [Indexed: 11/21/2022] Open
Abstract
INTRODUCTION Mollaret's meningitis is an unusual and under-appreciated syndrome of benign, recurrent aseptic meningitis. The available literature indicates that the causative agent is herpes simplex virus type 2 (HSV-2) in the majority of cases and much less frequently herpes simplex virus type 1 (HSV-1). CASE REPORT We report the case of a 49-year-old Indian female who had four attacks of recurrent lymphocytic meningitis (Mollaret's meningitis) occurring over a 7-year period. The diagnosis of herpes simplex meningitis was made at the time of the fourth episode by a positive PCR for herpes simplex virus infection in the cerebrospinal fluid. During the first three episodes, the patient was treated with anti-tuberculous drugs and antibiotics for bacterial meningitis; however for the last episode, once the diagnosis of herpes simplex meningitis was confirmed, only symptomatic treatment was given. No long-term suppressive therapy was given and no recurrence has been experienced so far. CONCLUSIONS Mollaret's meningitis should be suspected in all cases of recurrent lymphocytic meningitis. Early diagnosis may prevent prolonged hospital admissions, unnecessary investigations, and exposure to unnecessary medications, with the associated considerable costs. Treatment with acyclovir may be beneficial in decreasing the severity and duration of attacks and in preventing further episodes. [Au?1].
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