Human in vivo evidence of associations between herpes simplex virus and cerebral amyloid-beta load in normal aging.

BACKGROUND: Mounting data suggests that herpes simplex virus type 1 (HSV-1) is involved in the pathogenesis of AD, possibly instigating amyloid-beta (Aß) accumulation decades before the onset of clinical symptoms. However, human in vivo evidence linking HSV-1 infection to AD pathology is lacking in normal aging, which may contribute to the elucidation of the role of HSV-1 infection as a potential AD risk factor. METHODS: To shed light into this question, serum anti-HSV IgG levels were correlated with 18F-Florbetaben-PET binding to Aß deposits and blood markers of neurodegeneration (pTau181 and neurofilament light chain) in cognitively normal older adults. Additionally, we investigated whether associations between anti-HSV IgG and AD markers were more evident in APOE4 carriers. RESULTS: We showed that increased anti-HSV IgG levels are associated with higher Aß load in fronto-temporal regions of cognitively normal older adults. Remarkably, these cortical regions exhibited abnormal patterns of resting state-functional connectivity (rs-FC) only in those individuals showing the highest levels of anti-HSV IgG. We further found that positive relationships between anti-HSV IgG levels and Aß load, particularly in the anterior cingulate cortex, are moderated by the APOE4 genotype, the strongest genetic risk factor for AD. Importantly, anti-HSV IgG levels were unrelated to either subclinical cognitive deficits or to blood markers of neurodegeneration. CONCLUSIONS: All together, these results suggest that HSV infection is selectively related to cortical Aß deposition in normal aging, supporting the inclusion of cognitively normal older adults in prospective trials of antimicrobial therapy aimed at decreasing the AD risk in the aging population.

Herpes simplex virus 2 serology is associated with thinner whole-brain cortex in community-dwelling older adults.

Prior work in the Northern Manhattan Study (NOMAS) identified impaired cognition in cross-sectional analyses and more rapid memory decline in individuals with evidence of prior common infectious disease exposures. In this study, we sought to determine the cross-sectional relationship between prior exposure to cytomegalovirus, herpes simplex viruses 1 and 2, Chlamydia pneumoniae, and Helicobacter pylori and three magnetic resonance imaging (MRI) signatures (whole-brain cortical thickness, a previously validated AD signature, and hippocampal volume) in 455 NOMAS participants. We performed confounder-adjusted linear regression analyses between neuroimaging scores and both continuous serologies and categorical seropositivity of each pathogen, as well as a combined infectious burden index (IBI). We identified that increased serologic titers of herpes simplex virus 2 were associated with reduced whole-brain cortical thickness, and a combined score of HSV-2 and C. pneumoniae displayed an additive effect on reduced cortical thickness. Our findings suggest herpes simplex virus 2 seropositivity may contribute to accelerated brain aging, possibly resulting in an increased vulnerability to cognitive impairment and neurodegenerative disease in aging populations.

Near-native state imaging by cryo-soft-X-ray tomography reveals remodelling of multiple cellular organelles during HSV-1 infection.

Herpes simplex virus-1 (HSV-1) is a large, enveloped DNA virus and its assembly in the cell is a complex multi-step process during which viral particles interact with numerous cellular compartments such as the nucleus and organelles of the secretory pathway. Transmission electron microscopy and fluorescence microscopy are commonly used to study HSV-1 infection. However, 2D imaging limits our understanding of the 3D geometric changes to cellular compartments that accompany infection and sample processing can introduce morphological artefacts that complicate interpretation. In this study, we used soft X-ray tomography to observe differences in whole-cell architecture between HSV-1 infected and uninfected cells. To protect the near-native structure of cellular compartments we used a non-disruptive sample preparation technique involving rapid cryopreservation, and a fluorescent reporter virus was used to facilitate correlation of structural changes with the stage of infection in individual cells. We observed viral capsids and assembly intermediates interacting with nuclear and cytoplasmic membranes. Additionally, we observed differences in the morphology of specific organelles between uninfected and infected cells. The local concentration of cytoplasmic vesicles at the juxtanuclear compartment increased and their mean width decreased as infection proceeded, and lipid droplets transiently increased in size. Furthermore, mitochondria in infected cells were elongated and highly branched, suggesting that HSV-1 infection alters the dynamics of mitochondrial fission/fusion. Our results demonstrate that high-resolution 3D images of cellular compartments can be captured in a near-native state using soft X-ray tomography and have revealed that infection causes striking changes to the morphology of intracellular organelles.

Uncommon acute neuroimaging findings in severe neonatal herpes simplex virus 2 and consequences of delayed diagnosis.

Neonatal herpes simplex virus (HSV) infection of the central nervous system (CNS) is an emergency that can have devastating structural consequences and clinical outcomes. As it presents non-specifically in neonates, it is difficult to rapidly diagnose without neuroimaging. Although once thought to cause widespread parenchymal destruction, neonatal CNS HSV infection may present with more focal parenchymal injury on neuroimaging, not involving the medial temporal lobes as in adults. We report a case of a three-week-old girl with herpes simplex virus type 2 (HSV-2) encephalitis with exclusive bilateral corticospinal and frontal opercular involvement, which remained undiagnosed and untreated until three months of age. Neuroimaging upon presentation to the emergency room demonstrates a highly suggestive pattern of severe neonatal CNS HSV-2 infection which followed the natural history on subsequent imaging, highlighting the importance of emergency neuroimaging as well as having a high index of suspicion for making the diagnosis.

Opsoclonus-myoclonus syndrome associated with herpes simplex virus infection: a case report.

Purpose: Opsoclonus-myoclonus syndrome (OMS) is a rare neurological disease that can be associated with autoimmunity, paraneoplastic tumour, infection or unknown aetiology.Methods: We describe a 54-year-old woman who developed severe OMS, with the clinical onset occurring 2 months and 15 days after she experienced dizziness, vomiting and fever related to a herpes simplex virus infection. The patient was treated with hormones and clonazepam, and the symptoms of myoclonus and ataxia disappeared.Results: The patient was followed up for 1 year with no recurrence of symptoms.Conclusions: The case suggests that herpes simplex virus infection is a possible cause of OMS.

Herpes simplex virus type 2 myelitis mimicking ICU-acquired weakness as a complication of meningococcal meningitis: A case report.

Herpes simplex virus 2 (HSV-2) is a well-known cause of neurological complications. This case study describes the first reported case of reactivated HSV-2 myelitis, which was induced by immunosuppression due to sepsis. During the treatment of meningococcal meningitis, the patient developed quadriparesis and was later diagnosed as HSV-2 myelitis, mimicking ICU-acquired weakness. The case emphasizes the importance of excluding viral myelitis before making the diagnosis of ICU-acquired weakness.

Herpes simplex virus 2 vasculitis as cause of ischemic stroke in a young immunocompromised patient.

Herpes simplex virus 2 (HSV-2) is a very rare cause of central nervous system (CNS) infections. We report a case of a young woman with a left middle cerebral artery (MCA) ischemic stroke. The patient had history of HIV-1 infection, with periods of therapeutic non-compliance. Initial computed tomography (CT) imaging studies showed stenosis of the M1 segment of the left MCA, and magnetic resonance imaging (MRI) confirmed infarction of the MCA territory. Serial transcranial Doppler ultrasound revealed progressive occlusion of the MCA and stenosis of the left anterior cerebral artery. Systemic investigation for other causes of stroke was normal. Lumbar puncture revealed a mildly inflammatory cerebrospinal fluid, and HSV-2 DNA was identified by PCR, with a positive viral load in favor of active replication. No other viral or microbiological infections were identified. MRI angiography confirmed a vasculitic process involving the left carotid artery, and a HSV-2 vasculitis diagnosis was assumed. The patient started acyclovir with improvement of clinical features and imaging abnormalities. In the HIV-infected patient, stroke is a multifactorial common cause of morbidity. The physician should take into account a broad differential diagnosis including rare causes and atypical presentations of common etiologies, including HSV-1 and HSV-2 CNS infection.

Travel-associated neurological disease terminated in a postmortem diagnosed atypical HSV-1 encephalitis after high-dose steroid therapy - a case report.

BACKGROUND: Human encephalitis can originate from a variety of different aetiologies, of which infection is the most common one. The diagnostic work-up is specifically challenging in patients with travel history since a broader spectrum of unfamiliar additional infectious agents, e. g. tropical disease pathogens, needs to be considered. Here we present a case of encephalitis of unclear aetiology in a female traveller returning from Africa, who in addition developed an atypical herpes simplex virus (HSV) encephalitis in close temporal relation with high-dose steroid treatment. CASE PRESENTATION: A previously healthy 48-year-old female presented with confusion syndrome and impaired vigilance which had developed during a six-day trip to The Gambia. The condition rapidly worsened to a comatose state. Extensive search for infectious agents including a variety of tropical disease pathogens was unsuccessful. As encephalitic signs persisted despite of calculated antimicrobial and antiviral therapy, high-dose corticosteroids were applied intravenously based on the working diagnosis of an autoimmune encephalitis. The treatment did, however, not improve the patient's condition. Four days later, bihemispheric signal amplification in the insular and frontobasal cortex was observed on magnetic resonance imaging (MRI). The intracranial pressure rapidly increased and could not be controlled by conservative treatment. The patient died due to tonsillar herniation 21 days after onset of symptoms. Histological examination of postmortem brain tissue demonstrated a generalized lymphocytic meningoencephalitis. Immunohistochemical reactions against HSV-1/2 indicated an atypical manifestation of herpesviral encephalitis in brain tissue. Moreover, HSV-1 DNA was detected by a next-generation sequencing (NGS) metagenomics approach. Retrospective analysis of cerebrospinal fluid (CSF) and serum samples revealed HSV-1 DNA only in specimens one day ante mortem. CONCLUSIONS: This case shows that standard high-dose steroid therapy can contribute to or possibly even trigger fulminant cerebral HSV reactivation in a critically ill patient. Thus, even if extensive laboratory diagnostics including wide-ranging search for infectious pathogens has been performed before and remained without results, continuous re-evaluation of potential differential diagnoses especially regarding opportunistic infections or reactivation of latent infections is of utmost importance, particularly if new symptoms occur.

A Creeping Malaise Leading to Calamity: Herpes Esophagitis Perforation.

Herpes simplex virus is an uncommon cause of esophagitis and particularly so in immunocompetent individuals. Although the common presentation tends to be odynophagia and/or dysphagia, fever, and retrosternal chest pain, there are variations and rarely it can present more ominously as esophageal rupture. We report a rare case of esophageal perforation with penetration into the vertebral space secondary to chronic herpes simplex virus esophagitis in a 71-year-old immunocompetent woman. This is the second known such occurrence. The patient had a long stay in the hospital but recovered from the condition and was followed up for 1 year after initial presentation.

Fetal and neonatal abnormalities due to congenital herpes simplex virus infection: a literature review.

OBJECTIVE: Herpes simplex virus (HSV) infection during pregnancy can cause severe neonatal infections. It is also a rare cause of congenital infections. We aimed to describe fetal and neonatal abnormalities of congenital HSV infection in order to define the features that are accessible to prenatal diagnosis during ultrasound screening and/or during a work-up for congenital malformations. METHODS: We analysed all cases of congenital HSV infection (CHI) described before and/or after birth and identified in Pubed and classified the findings as accessible or not to prenatal diagnosis. RESULTS: Thirty-six cases of congenital herpes infection were reported, of which 15 were described prenatally and 21 postnatally. The most frequently reported malformations accessible to prenatal diagnosis were cerebral anomalies. The most common abnormalities described after birth were skin lesions and keratitis, which are not considered amenable to prenatal ultrasound detection. CHI can due to either HSV1 or HSV2 infection, whether primary or non-primary infection, with or without the presence of maternal symptoms. CONCLUSION: Prenatal ultrasound abnormalities due to CHI are rare, varied and non-specific. There is no clear role for fetal ultrasound in the routine management of women with primary or non-primary HSV infection in pregnancy. However, in fetuses with ultrasound abnormalities suggestive of congenital infection, HSV should still be considered as a differential diagnosis after the more common in utero infections, such as cytomegalovirus, are excluded.

Infectious causes and outcomes in patients presenting with cerebral spinal fluid pleocytosis.

To evaluate the infectious etiologies, clinical features, and outcomes of patients with CNS infections at a tertiary care center. Patients that present with a pleocytosis in the cerebral spinal fluid (CSF), defined as a CSF WBC count > 5 cells/mm3, from July 2015 to June 2016 at a tertiary care hospital were analyzed for this report. Data from patients with confirmed (n = 43) and presumed (n = 51) CNS infections were analyzed. CNS infection was the leading known cause of CSF pleocytosis (n = 43, 18% of all patients with a pleocytosis in the CSF), and HSV-2 was identified as the leading causative pathogen (n = 10) followed by varicella zoster virus (n = 5). Fifty-three percent of patients with a pleocytosis in the CSF did not receive a diagnosis. In the patients that did not receive a diagnosis, CNS infection was presumed to be the cause in 51 patients (21% of patients with CSF pleocytosis). The mean time to diagnosis for patients with confirmed CNS infection was 16 days, but time to diagnosis was highly variable depending on the causative pathogen. There was a significant overlap in CSF parameters and peripheral white blood cell counts in patients diagnosed with a viral, bacterial, or fungal infection. Neuroimaging changes were present in only 44% of CNS infections. The overall mortality was 7% for CNS infections, and 17% of patients with a CNS infection had a severe neurologic deficit at presentation while only 3% had a severe deficit at the last neurologic assessment. This study provides new insights into the infectious causes of disease in a cohort of patients with pleocytosis in the CSF. The study provides new insights into the time to diagnosis and outcomes in patients that present with pleocytosis in the CSF.

Human Herpesvirus Alpha Subfamily (Herpes Simplex and Varicella Zoster) Viral Pneumonias: CT Findings.

PURPOSE: The aim of this study was to evaluate CT features of pneumonias caused by the alpha Herpesviruses, herpes simplex virus (HSV), and varicella-zoster virus (VZV). MATERIALS AND METHODS: By searching the electronic medical record from 2005 to 2017, we identified 12 patients with HSV and 15 with VZV pneumonia. Four patients with coinfection were excluded from imaging analysis. Two radiologists reviewed computed tomography scans (CTs) for findings including ground glass and nodules. CTs were assigned to a predominant pattern of crazy paving, nodular, or other. RESULTS: The most common risk factor was hematologic malignancy, present in 58% of HSV and 47% of VZV patients. Crazy paving was seen in 50% of HSV and 31% of VZV cases; a nodular pattern was present in 20% of HSV and 69% of VZV patients (P=0.03). CONCLUSIONS: Most patients with alpha Herpesvirus pneumonias demonstrated either a crazy paving or nodular pattern on CT. The nodular pattern was significantly more common in VZV than in HSV. Radiologists should consider these rare infections when evaluating immunocompromised patients with these imaging patterns.

Imaging of congenital central nervous system infections.

Congenital central nervous system (CNS) infections are a cause of significant morbidity and mortality. The recent Zika virus outbreak raised awareness of congenital CNS infections. Imaging can be effective in diagnosing the presence and severity of infection. In this paper we review the clinical presentations and imaging characteristics of several common and less common congenital CNS infections.

Acyclovir resistance in herpes simplex virus type I encephalitis: a case report.

Acyclovir resistance is rarely seen in herpes simplex virus (HSV) type I encephalitis. Prevalence rates vary between 0.5 % in immunocompetent patients (Christophers et al. 1998; Fife et al. 1994) and 3.5-10 % in immunocompromised patients (Stranska et al. 2005). We report a 45-year-old, immunocompetent (negative HIV antigen/antibody testing), female patient, without previous illness who developed-after a febrile prodromal stage-aphasia and psychomotor slowing. Cerebral magnetic resonance imaging (cMRI) showed right temporal and insular T2-hyperintense lesions with spreading to the contralateral temporal lobe. Cerebrospinal fluid (CSF) analysis yielded lymphocytic pleocytosis and elevated protein level. Polymerase chain reaction testing for HSV type I showed a positive result in repeat lumbar puncture. HSV type I encephalitis was diagnosed and intravenous acyclovir treatment was initiated (750 mg t.i.d.). Acyclovir treatment was intensified to 1000 mg t.i.d., due to clinical deterioration, ongoing pleocytosis and progression on cMRI 5 days after initiation of antiviral therapy. In parallel, acyclovir resistance testing showed mutation of thymidine kinase gene at position A156V prompting foscarnet therapy (60 mg t.i.d.). Patient's condition improved dramatically over 2 weeks. Acyclovir resistance is rare but should be considered in case of clinical worsening of patient's condition. To our knowledge, this is the first report of acyclovir resistance in HSV type I encephalitis of an immunocompetent and previously healthy patient in Austria.