Neonatal Herpes Simplex Virus Encephalitis Research Articles

Herpes simplex virus infection induces necroptosis of neurons and astrocytes in human fetal organotypic brain slice cultures.

Herpes simplex virus (HSV) encephalitis (HSE) is a serious and potentially life-threatening disease, affecting both adults and newborns. Progress in understanding the virus and host factors involved in neonatal HSE has been hampered by the limitations of current brain models that do not fully recapitulate the tissue structure and cell composition of the developing human brain in health and disease. Here, we developed a human fetal organotypic brain slice culture (hfOBSC) model and determined its value in mimicking the HSE neuropathology in vitro. Cell viability and tissues integrity were determined by lactate dehydrogenase release in supernatant and immunohistological (IHC) analyses. Brain slices were infected with green fluorescent protein (GFP-) expressing HSV-1 and HSV-2. Virus replication and spread were determined by confocal microscopy, PCR and virus culture. Expression of pro-inflammatory cytokines and chemokines were detected by PCR. Cell tropism and HSV-induced neuropathology were determined by IHC analysis. Finally, the in situ data of HSV-infected hfOBSC were compared to the neuropathology detected in human HSE brain sections. Slicing and serum-free culture conditions were optimized to maintain the viability and tissue architecture of ex vivo human fetal brain slices for at least 14days at 37°C in a CO2 incubator. The hfOBSC supported productive HSV-1 and HSV-2 infection, involving predominantly infection of neurons and astrocytes, leading to expression of pro-inflammatory cytokines and chemokines. Both viruses induced programmed cell death-especially necroptosis-in infected brain slices at later time points after infection. The virus spread, cell tropism and role of programmed cell death in HSV-induced cell death resembled the neuropathology of HSE. We developed a novel human brain culture model in which the viability of the major brain-resident cells-including neurons, microglia, astrocytes and oligodendrocytes-and the tissue architecture is maintained for at least 2weeks in vitro under serum-free culture conditions. The close resemblance of cell tropism, spread and neurovirulence of HSV-1 and HSV-2 in the hfOBSC model with the neuropathological features of human HSE cases underscores its potential to detail the pathophysiology of other neurotropic viruses and as preclinical model to test novel therapeutic interventions.

IFIH1 deficiency causing neonatal herpes simplex virus encephalitis and recurrent retinitis

Homozygous loss-of-function variants in Interferon induced with helicase C domain 1 (IFIH1) leads to immunodeficiency with early onset recurrent and severe viral respiratory infections (Immunodeficiency 95; MIM 619773). Severe respiratory infections with RNA viruses such as rhinovirus and respiratory syncytial virus (RSV) are most characteristic of IFIH1 deficiency. IFIH1 encodes melanoma differentiation-associated protein 5 (MDA5), an intracellular sensor of mainly long double-stranded RNA (ds-RNA), a viral replication intermediate. When activated, MDA5 triggers antiviral pathways including increased transcription of Type 1-interferon. The antiviral role of MDA5 is best described for positive (+) RNA viruses such as Picornavirus family which produce long ds-RNA as a replication intermediate. We present a patient with neonatal herpes simplex virus (HSV) encephalitis and recurrent retinitis with homozygous variant of unknown significance (VUS) in IFIH1, c.2062A>G (p.Lys688Glu).Patient is a 10-year-old male, born of consanguineous parents from the United Arab Emirates. Past medical history is notable for neonatal HSV encephalitis, grade 3 intraventricular hemorrhage, cerebral palsy, epilepsy, optic atrophy and recurrent HSV retinitis. Patient has no additional history of severe or recurrent infections. No family history of recurrent or severe infections, malignancy, autoimmunity or autoinflammation.Immune evaluation demonstrated anemia with elevated mean corpuscular volume and mild elevation of platelets and monocytes. Patient had normal lymphocyte subsets, normal T and B cell subset distributions, protective vaccine titers and normal immunoglobins apart from mildly elevated immunoglobulin G. An Invitae primary immunodeficiency panel demonstrated homozygous VUS in IFIH1, c.2062A>G (p.Lys688Glu). This variant is not found in gnomAD or ClinVar and has a Combined Annotation Dependent Depletion score of 22.6. Functional testing demonstrated decreased interferon induction after stimulation with intracellular RNA, intracellular DNA and agonists of both Toll-like receptor 7 and 9. These findings are consistent with MDA5 deficiency given decreased interferon response with known MDA5 agonists.In summary, we describe a patient with recurrent and severe infections with a DNA virus and no known infections with respiratory RNA viruses. Both DNA and RNA viruses produce long ds-RNA as replication intermediates, an MDA5 agonist. This patient highlights the anti-viral role of MDA5 for both DNA and RNA viruses.

Acyclovir Sensitivity and Neurovirulence of Herpes Simplex Virus Type 1 with Amino Acid Substitutions in the Viral Thymidine Kinase Gene, Which Were Detected in the Patients with Intractable Herpes Simplex Encephalitis Previously Reported.

Several cases of herpes simplex encephalitis (HSE) caused by acyclovir (ACV)-resistant herpes simplex virus type 1 (HSV-1) have been reported. Amino acid substitutions of R41H, Q125H, and A156V in the viral thymidine kinase (vTK) gene have been reported to confer ACV resistance. Recombinant HSV-1 clones, containing each amino acid substitution in the vTK gene, were generated using the bacterial artificial chromosome system. A recombinant HSV-1 with the Q125H substitution showed ACV resistance while the R41H or A156V substitutions were ACV-sensitive. Furthermore, the Q125H recombinant HSV-1 was less virulent than the repaired virus, but it maintained neurovirulence in mice at relatively high levels. Substitution of Q125H, which was detected in the neonatal HSE patient, conferred ACV resistance, but the substitutions of R41H and A156V, which were detected in immunocompetent adult HSE patients, did not. This suggests that HSE caused by ACV-resistant HSV-1 might be a very rare event to occur during the course of ACV treatment in immunocompetent patients. Showing resistance to ACV treatment does not always indicate emergence of ACV-resistant HSV-1 in HSE patients.

Predominant area of brain lesions in neonates with herpes simplex encephalitis.

Nonspecific manifestations and a varied distribution of brain lesions can delay the diagnosis of herpes simplex encephalitis (HSE) in neonates. The aim of this study was to report predominant brain lesions in neonatal HSE, and then to investigate the association between pattern of predominant brain lesions, clinical variables and neurodevelopmental outcome. A multicenter retrospective study was performed in neonates diagnosed with HSE between 2009 and 2014. Magnetic resonance (MR) images, including diffusion-weighted images, were obtained in the acute and chronic phase. Three predominant areas of brain injury could be defined based on characteristic MRI findings in 10 of the 13 infants (77%). The inferior frontal/temporal pole area was involved in five (38%) patients. The watershed distribution was present in six (46%) patients. Four (31%) infants involved the corticospinal tract area. No significant association was found between any predominant distribution of brain lesion pattern and sex, country, viral type or viral load. However, the corticospinal tract involvement was significantly associated with motor impairment (P=0.045). Three predominant areas of brain lesion could be recognized in neonatal HSE. Recognition of those areas can improve prediction of neurodevelopmental outcome.

Treatment of perinatal viral infections to improve neurologic outcomes.

Viral infections in the fetus or newborn often involve the central nervous system (CNS) and can lead to significant morbidity and mortality. Substantial progress has been made in identifying interventions decreasing adverse neurodevelopmental outcomes in this population. This review highlights progress in treatment of important viruses affecting the CNS in these susceptible hosts, focusing on herpes simplex virus (HSV), cytomegalovirus (CMV), human immunodeficiency virus (HIV), and enteroviruses. The observation that high-dose acyclovir improves mortality in neonatal HSV disease culminated decades of antiviral research for this disease. More recently, prolonged oral acyclovir was found to improve neurologic morbidity after neonatal HSV encephalitis. Ganciclovir, and more recently its oral prodrug valganciclovir, is effective in improving hearing and neurodevelopment after congenital CMV infection. Increasing evidence suggests early control of perinatal HIV infection has implications for neurocognitive functioning into school age. Lastly, the antiviral pleconaril has been studied for nearly two decades for treating severe enteroviral infections, with newer data supporting a role for this drug in neonates. Identifying common mechanisms for pathogenesis of viral CNS disease during this critical period of brain development is an important research goal, highlighted by the recent emergence of Zika virus as a potential cause of fetal neurodevelopmental abnormalities.

Differential reliance on autophagy for protection from HSV encephalitis between newborns and adults.

Newborns are more susceptible to severe disease from infection than adults, with maturation of immune responses implicated as a major factor. The type I interferon response delays mortality and limits viral replication in adult mice in a model of herpes simplex virus (HSV) encephalitis. We found that intact type I interferon signaling did not control HSV disease in the neonatal brain. However, the multifunctional HSV protein γ34.5 involved in countering type I interferon responses was important for virulence in the brain in both age groups. To investigate this observation further, we studied a specific function of γ34.5 which contributes to HSV pathogenesis in the adult brain, inhibition of the cellular process of autophagy. Surprisingly, we found that the beclin binding domain of γ34.5 responsible for inhibiting autophagy was dispensable for HSV disease in the neonatal brain, as infection of newborns with the deletion mutant decreased time to mortality compared to the rescue virus. Additionally, a functional beclin binding domain in HSV γ34.5 did not effectively inhibit autophagy in the neonate, unlike in the adult. Type I IFN responses promote autophagy in adult, a finding we confirmed in the adult brain after HSV infection; however, in the newborn brain we observed that autophagy was activated through a type I IFN-independent mechanism. Furthermore, autophagy in the wild-type neonatal mouse was associated with increased apoptosis in infected regions of the brain. Observations in the mouse model were consistent with those in a human case of neonatal HSV encephalitis. Our findings reveal age-dependent differences in autophagy for protection from HSV encephalitis, indicating developmental differences in induction and regulation of this innate defense mechanism after HSV infection in the neonatal brain.

Diffusion-weighted MRI for early diagnosis of neonatal herpes simplex encephalitis.

To determine the early changes and evolutions of brain diffusion-weighted imaging (DWI), and analyze prognostic factors of the early changes among patients with neonatal herpes simplex encephalitis (NHSE). We selected patients who developed encephalitis by 28 d after birth; had herpes simplex infection; and who underwent magnetic resonance imaging, including DWI, ⩽7 d of symptom onset. Thirty-two DWI scans between 0 and 28 d after onset in 13 patients and the clinical data were recruited. The distribution, evolution of the lesions, and neurological outcome were analyzed. DWI frequently showed multiple cortical lesions in both hemispheres in the early period and both hemispheres on DWI (8/9 scans at ⩽48 h, 7/7 patients). As time from onset increased, the cortical lesions tended to coincide with subcortical white matter lesions beneath the initial cortical lesions (p<0.01). Lesions from the cortex extended to the subcortical white matter in 7 patients. Deep cerebral lesions, involving basal ganglia, internal capsules, thalamus, were also found in 9 patients ⩽7 d of onset. The distributions of deep cerebral lesions (none/unilateral/bilateral) ⩽7 d of onset showed significant correlations with neurological prognoses (gross motor functions: p<0.01; developmental or intellectual quotient scores: p<0.01). Cortical lesions were main findings of DWI in NHSE in the early period. Bilateral deep cerebral lesions ⩽7 d were highly indicative of poor motor and cognitive outcomes.

A case of neonatal herpes simplex virus encephalitis with characteristic MRI features in the early period

A case of neonatal herpes simplex virus encephalitis with characteristic MRI features in the early period

Efficacy of Continuous Acyclovir Infusion in Neonatal Herpes Virus Encephalitis

We have successfully eliminated herpes simplex virus-2 from the central nervous system in a case of neonatal herpes simplex virus encephalitis with a continuous acyclovir infusion. A male infant delivered from a healthy 22-year-old woman without genital or systemic herpes symptoms around delivery began to develop fever and intractable seizures. He was started on intermittent intravenous acyclovir (20 mg/kg every 8 h) based on the diagnosis of herpes encephalitis. The virus was not eliminated with intermittent acyclovir and vidarabine, while continuous acyclovir was ultimately effective in eliminating herpes simplex virus from his central nervous system. This report demonstrates the efficacy of continuous acyclovir infusion in neonatal herpes simplex virus encephalitis.

Serial diffusion-weighted imaging of neonatal herpes encephalitis: A case report

We reported a patient with neonatal herpes simplex encephalitis in whom diffusion-weighted imaging was performed repeatedly. Diffusion-weighted imaging at 20 h after the onset of seizures revealed scattered small spotty high intensity lesions in both hemispheres and a high intensity area in the left fronto-temporal lobe. There was no abnormal finding on conventional magnetic resonance imaging. Second diffusion-weighted imaging 72 h after the onset revealed expanded scattered high intensity lesions in the bilateral hemisphere, a high intensity area in the left fronto-temporal lobe, and a new high intensity area in the right temporal lobe. There was no report on neonatal herpes simplex encephalitis that showed scattered high intensities in diffusion-weighted imaging. Scattered small high intensities on diffusion-weighted imaging may suggest endothelial cell infection with swelling and small vessel necrosis. Early diffusion-weighted imaging will be valuable for early detection and diagnosis of neonatal herpes simplex encephalitis.

ERRATA

Errata| May 01 2005 ERRATA Pediatrics (2005) 115 (5): 1454. https://doi.org/10.1542/peds.2005-0684 Connected Content This is a correction to: Challenges in the Diagnosis and Management of Neonatal Herpes Simplex Virus Encephalitis Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Share Icon Share Facebook Twitter LinkedIn MailTo Tools Icon Tools Get Permissions Cite Icon Cite Search Site Citation ERRATA. Pediatrics May 2005; 115 (5): 1454. 10.1542/peds.2005-0684 Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search toolbar search search input Search input auto suggest filter your search All PublicationsAll JournalsPediatricsHospital PediatricsPediatrics In ReviewNeoReviewsAAP Grand RoundsAAP NewsAll AAP Sites Search Advanced Search Topics: cerebrospinal fluid, cerebrospinal fluid analysis, colony-stimulating factors, csf pleocytosis, dna, encephalitis, glucose, leukocyte count, lymphocytes, monocytes An error appeared in the commentary by Frenkel titled “Challenges in the Diagnosis and Management of Neonatal Herpes Simplex Virus Encephalitis” that was published in the March 2005 issue of Pediatrics (2005;115:795–797). On page 796, the second full paragraph, the author wrote: “However, at 3 months of age the infant had seizures with markedly abnormal CSF parameters (CSF: 1415 WBCs per μL with 46% neutrophils, 27% lymphocytes, 27% monocytes, 97 RBCs per μL, protein level of 131 mg/dL, and glucose level of 47 mg/dL) and HSV DNA detected.” This sentence should have read as follows: “However, at 3 months of age the infant had seizures with markedly abnormal CSF parameters (CSF: 97 WBCs per μL with 46% neutrophils, 27% lymphocytes, 27% monocytes, 1415 RBCs per μL, protein level of 131 mg/dL, and glucose level of 47 mg/dL) and HSV DNA detected.” While I regret this error, a CSF... View Original Article You do not currently have access to this content.

Herpes simplex virus infections of the newborn

Herpes simplex virus (HSV) infection in newborns is an important cause of death and permanent neurodevelopmental disability among young children. Neonatal HSV infections can be categorized as 1) mucocutaneous (skin-eyes-mouth), 2) disseminated, or 3) encephalitic. In addition, congenital HSV infection, a distinct clinical syndrome, accounts for approximately 5% of HSV infections identified in the neonatal period. Polymerase chain reaction greatly enhances the clinician's ability to diagnosis HSV infections, but as many as 25% of infants with neonatal HSV encephalitis have negative polymerase chain reaction studies of cerebrospinal fluid. Infants with proven or suspected HSV infections should receive acyclovir 60 mg/kg/day divided every 8 hours for 14 days if disease is restricted to the skin, eyes, or mucous membranes and for 21 days if the infant has disseminated infection or encephalitis. The benefit of long-term suppression therapy after completion of the initial treatment regimen has not been established definitively. Despite therapy with acyclovir, the best available anti-HSV drug, a substantial number of HSV-infected infants with disseminated infections or encephalitis die or have long-term neurodevelopmental sequelae.

Challenges in the Diagnosis and Management of Neonatal Herpes Simplex Virus Encephalitis

Research during the past 30 years has transformed our approach to the diagnosis and management of neonatal herpes simplex virus (HSV) encephalitis.1 Nevertheless, early diagnosis of HSV encephalitis and its long-term management continue to challenge practitioners, primarily because of the paucity of clinical symptoms and laboratory abnormalities associated with early disease.1–5 Fonseca-Aten et al,6 in this issue of Pediatrics , report on an infant who developed symptomatic HSV encephalitis during administration of daily oral acyclovir (ACV) given to “suppress” HSV disease. Elements of this case spotlight issues peculiar to HSV that may assist pediatric practitioners in the timely diagnosis and effective management of neonatal HSV encephalitis.1,5,7–10 Neonatal HSV infections are often categorized into 1 of 3 syndromes: skin-eye-mouth, disseminated, and central nervous system (CNS). However, these disease patterns are not discreet, with encephalitis often due to the extension of skin-eye-mouth or disseminated disease. HSV encephalitis affects the brain cortex or, less commonly, the brainstem.1 HSV replication in the cortex of infants can be clinically unapparent,1–5 because cortical function is not required for most activities of infants. HSV CNS infection can be difficult to diagnose by examination of cerebral spinal fluid (CSF), because the meninges may not be significantly inflamed. This is particularly true in the early phases of the illness, during which treatment can have the most impact on reducing long-term neurologic morbidity.1,5,7 Also problematic is that reactivation of HSV in the CNS, which is lytic to the brain parenchyma, may be asymptomatic in infants, with neurologic impairment becoming apparent by 6 to 12 months of age.1,11 The infant reported by Fonseca-Aten et al6 was first diagnosed with encephalitis after seizures at 3 months of … Address correspondence to Lisa M. Frenkel, MD, Departments of Pediatrics and Laboratory Medicine, University of Washington and Children’s Hospital, 307 Westlake Ave N, Suite 300, Room 330, Seattle, WA 98109. E-mail: lfrenkel{at}u.washington.edu

Case report: The sonographic appearances of neonatal herpes simplex encephalitis

This case report describes the sonographic appearances in a proven case of neonatal Herpes Simplex encephalitis. Both early and late phase appearances are discussed, and are compared with other reports of imaging in similar disease processes. A role for sonography in the management of neonatal Herpes Simplex encephalitis is suggested.

A hypothesis on the pathophysiology of neonatal herpes simplex virus encephalitis

A hypothesis on the pathophysiology of neonatal herpes simplex virus encephalitis

MR Findings in Neonatal Herpes Simplex Encephalitis Type II

The CT findings in neonatal herpes simplex encephalitis (HSE) type II have been previously described, whereas magnetic resonance (MR) findings as yet have not. Early CT findings can be subtle and difficult to detect. However, as the abnormalities evolve, most notably the strikingly increased density of cortical gray matter, they appear highly characteristic of neonatal HSE type II. This case report with neuropathologic verification describes serial MR and CT findings in HSE type II that suggest an etiology of the increased density characteristically seen on CT scans; it does not appear to be hemorrhage or calcification.

Periodic lateralized epileptiform discharges in asphyxiated neonates

Electrographic seizures (EGS) were detected in 13 of 16 asphyxiated neonates who were undergoing continuous electroencephalographic monitoring for detection of evidence of central nervous system injury. five of the 13 neonates with EGS also had periodic lateralized epileptiform discharges (PLEDs). The electrographic characteristics of PLEDs in these infants were similar to those reported in neonatal herpes simplex encephalitis and in older children and adults. Of the 5 neonates with PLEDs, 2 died, 2 are developmentally delayed and only 1 is normal at 12 months. This is in contrast to the normal outcome for 8 of the 11 infants who did not have PLEDs. One other was neurologically normal but died of pulmonary disease at 3 months and the other two were developmentally delayed. PLEDs in neonates, as in other age groups, lack diagnostic specificity, but when associated with neonatal asphyxia, may indicate a poor prognosis. Continuous EEG monitoring is helpful in identifying PLEDs in these cases.

Neonatal Type 2 Herpes simplex Encephalitis in an Identical Twin

A case of type 2 neonatal herpes simplex encephalitis is presented. The mechanism of infection is discussed in view of the fact that the firstborn identical twin was unaffected. Longer exposure to the virus during delivery is proposed as an explanation for the involvement of only the secondborn twin.