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Neurotherapeutics : the Journal of the... Jul 2016Herpetic infections have plagued humanity for thousands of years, but only recently have advances in antiviral medications and supportive treatments equipped physicians... (Review)
Review
Herpetic infections have plagued humanity for thousands of years, but only recently have advances in antiviral medications and supportive treatments equipped physicians to combat the most severe manifestations of disease. Prompt recognition and treatment can be life-saving in the care of patients with herpes simplex-1 virus encephalitis, the most commonly identified cause of sporadic encephalitis worldwide. Clinicians should be able to recognize the clinical signs and symptoms of the infection and familiarize themselves with a rational diagnostic approach and therapeutic modalities, as early recognition and treatment are key to improving outcomes. Clinicians should also be vigilant for the development of acute complications, including cerebral edema and status epilepticus, as well as chronic complications, including the development of autoimmune encephalitis associated with antibodies to the N-methyl-D-aspartate receptor and other neuronal cell surface and synaptic epitopes. Herein, we review the pathophysiology, differential diagnosis, and clinical and radiological features of herpes simplex virus-1 encephalitis in adults, including a discussion of the most common complications and their treatment. While great progress has been made in the treatment of this life-threatening infection, a majority of patients will not return to their previous neurologic baseline, indicating the need for further research efforts aimed at improving the long-term sequelae.
Topics: Adrenal Cortex Hormones; Adult; Aged; Antiviral Agents; Brain; Edema; Encephalitis, Herpes Simplex; Female; Herpesvirus 1, Human; Humans; Seizures; Treatment Outcome
PubMed: 27106239
DOI: 10.1007/s13311-016-0433-7 -
The Lancet. Neurology Sep 2018Herpes simplex encephalitis can trigger autoimmune encephalitis that leads to neurological worsening. We aimed to assess the frequency, symptoms, risk factors, and... (Observational Study)
Observational Study
Frequency, symptoms, risk factors, and outcomes of autoimmune encephalitis after herpes simplex encephalitis: a prospective observational study and retrospective analysis.
BACKGROUND
Herpes simplex encephalitis can trigger autoimmune encephalitis that leads to neurological worsening. We aimed to assess the frequency, symptoms, risk factors, and outcomes of this complication.
METHODS
We did a prospective observational study and retrospective analysis. In the prospective observational part of this study, we included patients with herpes simplex encephalitis diagnosed by neurologists, paediatricians, or infectious disease specialists in 19 secondary and tertiary Spanish centres (Cohort A). Outpatient follow-up was at 2, 6, and 12 months from onset of herpes simplex encephalitis. We studied another group of patients retrospectively, when they developed autoimmune encephalitis after herpes simplex encephalitis (Cohort B). We compared demographics and clinical features of patients who developed autoimmune encephalitis with those who did not, and in patients who developed autoimmune encephalitis we compared these features by age group (patients ≤4 years compared with patients >4 years). We also used multivariable binary logistic regression models to assess risk factors for autoimmune encephalitis after herpes simplex encephalitis.
FINDINGS
Between Jan 1, 2014, and Oct 31, 2017, 54 patients with herpes simplex encephalitis were recruited to Cohort A, and 51 were included in the analysis (median age 50 years [IQR 5-68]). At onset of herpes simplex encephalitis, none of the 51 patients had antibodies to neuronal antigens; during follow-up, 14 (27%) patients developed autoimmune encephalitis and all 14 (100%) had neuronal antibodies (nine [64%] had NMDA receptor [NMDAR] antibodies and five [36%] had other antibodies) at or before onset of symptoms. The other 37 patients did not develop autoimmune encephalitis, although 11 (30%) developed antibodies (n=3 to NMDAR, n=8 to unknown antigens; p<0·001). Antibody detection within 3 weeks of herpes simplex encephalitis was a risk factor for autoimmune encephalitis (odds ratio [OR] 11·5, 95% CI 2·7-48·8; p<0·001). Between Oct 7, 2011, and Oct 31, 2017, there were 48 patients in Cohort B with new-onset or worsening neurological symptoms not caused by herpes simplex virus reactivation (median age 8·8 years [IQR 1·1-44·2]; n=27 male); 44 (92%) patients had antibody-confirmed autoimmune encephalitis (34 had NMDAR antibodies and ten had other antibodies). In both cohorts (n=58 patients with antibody-confirmed autoimmune encephalitis), patients older than 4 years frequently presented with psychosis (18 [58%] of 31; younger children not assessable). Compared with patients older than 4 years, patients aged 4 years or younger (n=27) were more likely to have shorter intervals between onset of herpes simplex encephalitis and onset of autoimmune encephalitis (median 26 days [IQR 24-32] vs 43 days [25-54]; p=0·0073), choreoathetosis (27 [100%] of 27 vs 0 of 31; p<0·001), decreased level of consciousness (26 [96%] of 27 vs seven [23%] of 31; p<0·001), NMDAR antibodies (24 [89%] of 27 vs 19 [61%] of 31; p=0·033), and worse outcome at 1 year (median modified Rankin Scale 4 [IQR 4-4] vs 2 [2-3]; p<0·0010; seizures 12 [63%] of 19 vs three [13%] of 23; p=0·001).
INTERPRETATION
The results of our prospective study show that autoimmune encephalitis occurred in 27% of patients with herpes simplex encephalitis. It was associated with development of neuronal antibodies and usually presented within 2 months after treatment of herpes simplex encephalitis; the symptoms were age-dependent, and the neurological outcome was worse in young children. Prompt diagnosis is important because patients, primarily those older than 4 years, can respond to immunotherapy.
FUNDING
Mutua Madrileña Foundation, Fondation de l'Université de Lausanne et Centre Hospitalier Universitaire Vaudois, Instituto Carlos III, CIBERER, National Institutes of Health, Generalitat de Catalunya, Fundació CELLEX.
Topics: Adolescent; Adult; Aged; Animals; Autoantibodies; Child; Child, Preschool; Cohort Studies; Encephalitis; Encephalitis, Herpes Simplex; Female; Glutamate Decarboxylase; Hashimoto Disease; Hippocampus; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Rats; Receptors, N-Methyl-D-Aspartate; Risk Factors; Statistics, Nonparametric; Young Adult
PubMed: 30049614
DOI: 10.1016/S1474-4422(18)30244-8 -
Clinical Microbiology Reviews Mar 2020Herpes simplex virus 1 (HSV-1) can be responsible for life-threatening HSV encephalitis (HSE). The mortality rate of patients with HSE who do not receive antiviral... (Review)
Review
Herpes simplex virus 1 (HSV-1) can be responsible for life-threatening HSV encephalitis (HSE). The mortality rate of patients with HSE who do not receive antiviral treatment is 70%, with most survivors suffering from permanent neurological sequelae. The use of intravenous acyclovir together with improved diagnostic technologies such as PCR and magnetic resonance imaging has resulted in a reduction in the mortality rate to close to 20%. However, 70% of surviving patients still do not recover complete neurological functions. Thus, there is an urgent need to develop more effective treatments for a better clinical outcome. It is well recognized that cerebral damage resulting from HSE is caused by viral replication together with an overzealous inflammatory response. Both of these processes constitute potential targets for the development of innovative therapies against HSE. In this review, we discuss recent progress in therapy that may be used to ameliorate the outcome of patients with HSE, with a particular emphasis on immunomodulatory agents. Ideally, the administration of adjunctive immunomodulatory drugs should be initiated during the rise of the inflammatory response, and its duration should be limited in time to reduce undesired effects. This critical time frame should be optimized by the identification of reliable biomarkers of inflammation.
Topics: Acyclovir; Adrenal Cortex Hormones; Animals; Antiviral Agents; Drug Therapy; Encephalitis, Herpes Simplex; Genetic Predisposition to Disease; Humans; Immunity; Immunomodulation; Risk Factors; Simplexvirus; Treatment Outcome
PubMed: 32051176
DOI: 10.1128/CMR.00105-19 -
Journal of Biomedical Science Jul 2022Infections by viruses including severe acute respiratory syndrome coronavirus 2 could cause organ inflammations such as myocarditis, pneumonia and encephalitis. Innate...
BACKGROUND
Infections by viruses including severe acute respiratory syndrome coronavirus 2 could cause organ inflammations such as myocarditis, pneumonia and encephalitis. Innate immunity to viral nucleic acids mediates antiviral immunity as well as inflammatory organ injury. However, the innate immune mechanisms that control viral induced organ inflammations are unclear.
METHODS
To understand the role of the E3 ligase TRIM18 in controlling viral myocarditis and organ inflammation, wild-type and Trim18 knockout mice were infected with coxsackievirus B3 for inducing viral myocarditis, influenza A virus PR8 strain and human adenovirus for inducing viral pneumonia, and herpes simplex virus type I for inducing herpes simplex encephalitis. Mice survivals were monitored, and heart, lung and brain were harvested for histology and immunohistochemistry analysis. Real-time PCR, co-immunoprecipitation, immunoblot, enzyme-linked immunosorbent assay, luciferase assay, flow cytometry, over-expression and knockdown techniques were used to understand the molecular mechanisms of TRIM18 in regulating type I interferon (IFN) production after virus infection in this study.
RESULTS
We find that knockdown or deletion of TRIM18 in human or mouse macrophages enhances production of type I IFN in response to double strand (ds) RNA and dsDNA or RNA and DNA virus infection. Importantly, deletion of TRIM18 protects mice from viral myocarditis, viral pneumonia, and herpes simplex encephalitis due to enhanced type I IFN production in vivo. Mechanistically, we show that TRIM18 recruits protein phosphatase 1A (PPM1A) to dephosphorylate TANK binding kinase 1 (TBK1), which inactivates TBK1 to block TBK1 from interacting with its upstream adaptors, mitochondrial antiviral signaling (MAVS) and stimulator of interferon genes (STING), thereby dampening antiviral signaling during viral infections. Moreover, TRIM18 stabilizes PPM1A by inducing K63-linked ubiquitination of PPM1A.
CONCLUSIONS
Our results indicate that TRIM18 serves as a negative regulator of viral myocarditis, lung inflammation and brain damage by downregulating innate immune activation induced by both RNA and DNA viruses. Our data reveal that TRIM18 is a critical regulator of innate immunity in viral induced diseases, thereby identifying a potential therapeutic target for treatment.
Topics: Animals; Antiviral Agents; Encephalitis, Herpes Simplex; Humans; Immunity, Innate; Inflammation; Mice; Myocarditis; Protein Phosphatase 2C; RNA; Ubiquitin-Protein Ligases; Virus Diseases
PubMed: 35909127
DOI: 10.1186/s12929-022-00840-z -
Autophagy Feb 2023Herpes simplex encephalitis (HSE), mainly caused by herpes simplex virus type 1 (HSV-1), is a severe central nervous system disease commonly followed by cognitive...
Herpes simplex encephalitis (HSE), mainly caused by herpes simplex virus type 1 (HSV-1), is a severe central nervous system disease commonly followed by cognitive impairment, behavioral changes, and focal neurological signs. Although increasing evidence implicates the central role of microglia in HSE progression, the intrinsic restrictors or the acquired environmental factors that balance the beneficial or detrimental immune responses in microglia remain unclear. In a recent study, we find that a gut microbial metabolite activates mitophagy to regulate microglia-mediated neuroinflammation and to mitigate HSE progression. HSV-1 neurotropic infection causes gut microbiota dysbiosis and microglial antiviral immune response, whereas depletion of gut microbiota by oral antibiotics treatment further results in hyperactivated microglia and exacerbated HSE pathology. Notably, exogenous administration of nicotinamide n-oxide (NAMO), an oxidative product of nicotinamide mainly produced by intestinal neomycin-sensitive bacteria, especially Lactobacillus gasseri and Lactobacillus reuteri, can significantly suppress HSE progression. Mechanistically, HSV-1 infection causes mitochondrial dysfunction and impairs mitophagy to activate microglia and promote proinflammatory cytokine production, whereas NAMO restores NAD+-dependent mitophagy to restrain microglial over-activation and to prevent HSV-1 early infection in neuronal cells. This work reveals a novel function of gut microbial metabolites as intrinsic regulators of microglia homeostasis and neuroinflammation via mitophagy. AD: Alzheimer disease; ABX: antibiotics; HSE: herpes simplex encephalitis; HSV-1: herpes simplex virus type 1; NAD: nicotinamide adenine dinucleotide; NAMO: nicotinamide n-oxide; SCFAs: short-chain fatty acids.
Topics: Humans; Encephalitis, Herpes Simplex; Microglia; Neuroinflammatory Diseases; Brain-Gut Axis; Mitophagy; Autophagy; Herpesvirus 1, Human
PubMed: 35849507
DOI: 10.1080/15548627.2022.2102309 -
Neuron Jul 2018Amyloid-β peptide (Aβ) fibrilization and deposition as β-amyloid are hallmarks of Alzheimer's disease (AD) pathology. We recently reported Aβ is an innate immune...
Amyloid-β peptide (Aβ) fibrilization and deposition as β-amyloid are hallmarks of Alzheimer's disease (AD) pathology. We recently reported Aβ is an innate immune protein that protects against fungal and bacterial infections. Fibrilization pathways mediate Aβ antimicrobial activities. Thus, infection can seed and dramatically accelerate β-amyloid deposition. Here, we show Aβ oligomers bind herpesvirus surface glycoproteins, accelerating β-amyloid deposition and leading to protective viral entrapment activity in 5XFAD mouse and 3D human neural cell culture infection models against neurotropic herpes simplex virus 1 (HSV1) and human herpesvirus 6A and B. Herpesviridae are linked to AD, but it has been unclear how viruses may induce β-amyloidosis in brain. These data support the notion that Aβ might play a protective role in CNS innate immunity, and suggest an AD etiological mechanism in which herpesviridae infection may directly promote Aβ amyloidosis.
Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloidosis; Animals; Brain; Cells, Cultured; Disease Models, Animal; Encephalitis, Herpes Simplex; Encephalitis, Viral; Herpesviridae; Herpesvirus 1, Human; Herpesvirus 6, Human; Humans; Mice; Mice, Transgenic; Neurofibrillary Tangles; Neurons; Plaque, Amyloid; Roseolovirus Infections
PubMed: 30001512
DOI: 10.1016/j.neuron.2018.06.030 -
Science Immunology Apr 2023Inborn errors of TLR3-dependent type I IFN immunity in cortical neurons underlie forebrain herpes simplex virus-1 (HSV-1) encephalitis (HSE) due to uncontrolled viral...
Inborn errors of TLR3-dependent type I IFN immunity in cortical neurons underlie forebrain herpes simplex virus-1 (HSV-1) encephalitis (HSE) due to uncontrolled viral growth and subsequent cell death. We report an otherwise healthy patient with HSE who was compound heterozygous for nonsense (R422*) and frameshift (P493fs9*) variants. Receptor-interacting protein kinase 3 (RIPK3) is a ubiquitous cytoplasmic kinase regulating cell death outcomes, including apoptosis and necroptosis. In vitro, the R422* and P493fs9* RIPK3 proteins impaired cellular apoptosis and necroptosis upon TLR3, TLR4, or TNFR1 stimulation and ZBP1/DAI-mediated necroptotic cell death after HSV-1 infection. The patient's fibroblasts displayed no detectable RIPK3 expression. After TNFR1 or TLR3 stimulation, the patient's cells did not undergo apoptosis or necroptosis. After HSV-1 infection, the cells supported excessive viral growth despite normal induction of antiviral IFN-β and IFN-stimulated genes (ISGs). This phenotype was, nevertheless, rescued by application of exogenous type I IFN. The patient's human pluripotent stem cell (hPSC)-derived cortical neurons displayed impaired cell death and enhanced viral growth after HSV-1 infection, as did isogenic RIPK3-knockout hPSC-derived cortical neurons. Inherited RIPK3 deficiency therefore confers a predisposition to HSE by impairing the cell death-dependent control of HSV-1 in cortical neurons but not their production of or response to type I IFNs.
Topics: Humans; Cell Death; Encephalitis, Herpes Simplex; Herpes Simplex; Herpesvirus 1, Human; Receptor-Interacting Protein Serine-Threonine Kinases; Receptors, Tumor Necrosis Factor, Type I; Toll-Like Receptor 3
PubMed: 37083451
DOI: 10.1126/sciimmunol.ade2860 -
Journal of Neurology, Neurosurgery, and... Sep 2002
Topics: Acyclovir; Adult; Antigens, Viral; Antiviral Agents; Biopsy; Cerebrospinal Fluid; Child; Drug Administration Schedule; Encephalitis, Herpes Simplex; Ganciclovir; Herpesvirus 1, Human; Humans; Magnetic Resonance Imaging; Olfactory Pathways; Polymerase Chain Reaction; Temporal Lobe; Trigeminal Ganglion
PubMed: 12185148
DOI: 10.1136/jnnp.73.3.237 -
Ugeskrift For Laeger Jan 2017Herpes simplex encephalitis (HSE) is a rare disease, although it is the most common form of sporadic encephalitis worldwide. Recently, studies have provided important... (Review)
Review
Herpes simplex encephalitis (HSE) is a rare disease, although it is the most common form of sporadic encephalitis worldwide. Recently, studies have provided important new insight into the genetic and immunological basis of HSE. However, even in the presence of antiviral treatment, mortality and morbidity remain relatively high. Therefore, precise and early diagnosis together with basic and clinical studies to gain better insight into the pathogenesis of HSE is a prerequisite for the development of improved prophylaxis and treatment of this severe disease.
Topics: Acyclovir; Antiviral Agents; Encephalitis, Herpes Simplex; Humans; Interferon-alpha; Interferon-beta; Simplexvirus; Toll-Like Receptor 3
PubMed: 28074766
DOI: No ID Found