The association between exposure to herpes simplex virus type 1 (HSV-1) and cognitive functioning in schizophrenia: A meta-analysis.

Cognitive deficits are characteristic of schizophrenia but their etiology is not understood. Previous studies show an association between viral exposures and cognitive impairment. This meta-analysis was undertaken to determine the relationship of herpes simplex virus type 1 (HSV-1) exposure and cognitive functioning in schizophrenia. A systematic search was performed for studies comparing the cognitive functioning of HSV-1 seropositive vs. seronegative persons with schizophrenia. The primary outcome was the standardized mean difference (SMD) in composite cognitive score using Hedges' g. Secondary outcomes were SMDs in 9cognitive domains. Study heterogeneity was estimated using the I2 index and formal tests of heterogeneity using Cochran's Q. In a sample of 3516 individuals from 9 studies the SMD was negative for the composite score and all 9 domains indicating a significant deficit for seropositive individuals in 8 domains. The SMDs ranged from -0.11 (Working Memory) to -0.36 (Visual Spatial). Cochran's Q test indicated heterogeneity for one domain. The I2 index of heterogeneity was in the low -moderate range for all but one domain. Exposure to HSV-1 is associated with decreased cognitive functioning in schizophrenia. An increased understanding of HSV-1 exposure might lead to improved methods for the prevention and treatment of cognitive deficits in schizophrenia.

Herpes Simplex Virus Type 1 infection is associated with suicidal behavior and first registered psychiatric diagnosis in a healthy population.

Increasing evidence shows that latent infections and inflammation is associated with cognitive and behavioral changes in humans. This case-control study investigates the association between Herpes Simplex Virus Type 1 (HSV-1) infection and C-reactive Protein (CRP) levels, and psychiatric disorders and suicidal behavior. Public health register data from 81,912 participants in the Danish Blood Donor Study, were reviewed to identify individuals registered with an ICD-10 code of any psychiatric diagnosis, or who had attempted or committed suicide. We found 1,504 psychiatric cases and 353 suicidal cases; for all cases, controls were frequency-matched by age and sex, resulting in 5,336 participants. Plasma samples were analyzed for IgG-class antibodies against HSV-1 and CRP. HSV-1 infection was associated with suicidal behavior (odds-ratio, 1.40; 95% confidence interval [CI] 1.11-1.77). Accounting for temporality, HSV-1 infection was associated with having first psychiatric disorder after the date of blood collection (incidence rate ration, 1.44; 95% CI, 1.05-1.95). No association between CRP and psychiatric disorders or suicidal behavior was found. The finding that HSV-1 was associated with suicidal behavior and first psychiatric disorder indicates that infection may play a role in the etiology and pathogenesis of suicidal behavior and development of psychiatric disorders.

Behavioral, Psychological, Gender, and Health Service Correlates to Herpes Simplex Virus Type 2 Infection among Young Adult Mexican-American Women Living in a Disadvantaged Community.

Herpes simplex virus type 2 (HSV-2) is among the most prevalent sexually transmitted infections in the United States. Despite this, there has been limited research on the correlates to HSV-2 among disadvantaged and marginalized women, particularly among Latinas. Data for the present analysis include 125 young adult Mexican-American women enrolled in a longitudinal study in a disadvantaged urban community in San Antonio, Texas. The current rate of tested HSV-2 infection is 56.8%. Our findings suggest strong comorbidity of genital herpes with injecting heroin use, Hepatitis C, sexual violence, incarceration, and mental illness. Contributing to this population's nexus of risk are the low rates of health service utilization among those infected with HSV-2. Integration between behavioral health and primary care, including access to preventative services, are essential for improving the health of Latinas living in disadvantaged neighborhoods.

The lack of association between herpes simplex virus 1 or Toxoplasma gondii infection and cognitive decline in the general population: An 11-year follow-up study.

BACKGROUND: Inflammation has been suggested to be one, possibly treatable, cause of cognitive decline and dementia. The purpose of the present article was to investigate whether the herpes simplex virus 1 (HSV-1) or Toxoplasma gondii (T. gondii) infections are related to cognitive decline or dementia. METHOD: The Health 2000 survey, conducted 2000-2001, is a population-representative sample of people over 30 years old that involved 7112 participants. The sample was followed up in the year 2011, in the Health 2011 study. At both time points, cognitive performance was assessed with two tests from the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) assessing verbal fluency and verbal learning. In addition, the abbreviated Mini-Mental State Examination was administered to people aged over 55. In addition, tests assessing reaction and movement time were performed at baseline. Dementia diagnoses from nationwide health care registers were followed up until the end of year 2013. The presence of HSV-1 and T. gondii immunoglobulin G (IgG) was determined by solid-phase immunoassay at baseline. RESULTS: HSV-1 or T. gondii seropositivity, or IgG antibody levels, were not associated with cognitive decline when investigated as infection × time interactions. In addition, the infections were not associated with the risk of dementia. CONCLUSIONS: In a large sample of participants that is representative of the whole country and with a long follow-up, the results suggest that latent HSV-1 or T. gondii infections are not related to either decline in cognitive performance or dementia risk.

Viral Hypothesis and Antiviral Treatment in Alzheimer's Disease.

PURPOSE OF REVIEW: Viruses, particularly herpes simplex virus (HSV), may be a cause of Alzheimer's disease (AD). The evidence supporting the viral hypothesis suggests that antiviral treatment trials, which have not been conducted, are warranted. RECENT FINDINGS: HSV1 (oral herpes) and HSV2 (genital herpes) can trigger amyloid aggregation, and their DNA is common in amyloid plaques. HSV1 reactivation is associated with tau hyperphosphorylation and possibly tau propagation. Anti-HSV drugs reduce Aß and p-tau accumulation in infected mouse brains. Clinically, after the initial oral infection, herpes simplex virus-1 (HSV1) becomes latent in the trigeminal ganglion and recurrent reactivation may produce neuronal damage and AD pathology. Clinical studies show cognitive impairment in HSV seropositive patients, and antiviral drugs show strong efficacy against HSV. An antiviral treatment trial in AD is clearly warranted. A phase II treatment trial with valacyclovir, an anti-HSV drug, recently began with evaluation of clinical and biomarker outcomes.

Seropositivity of neurotropic infectious agents in first-episode schizophrenia patients and the relationship with positive and negative symptoms.

BACKGROUND: According to the neurodevelopmental model, schizophrenia is a disorder that occurs as a result of different etiologic factors during brain development, including viral infections. However, it is unclear whether these infections are related to the disease or whether they affect the symptom pattern. We investigated the presence of four herpes viruses (EBV, CMV, HSV-1 and HSV-2) in first-episode schizophrenia patients and compared seropositive with seronegative patients and healthy volunteers to reveal the etiological role of viral agents on schizophrenia symptoms. SUBJECTS AND METHODS: Ninety-two first-episode patients who met the DSM-IV diagnostic criteria for schizophreniform disorder were included the study, along with 88 healthy volunteers. The presence of the four herpes viruses was investigated with serological methods (ELISA) in both groups. Positive and negative symptoms were evaluated with Scale for the Assessment of Negative Symptoms (SANS) and the Scale for the Assessment of Positive Symptoms (SAPS). RESULTS: There was no difference between the patient and control groups in terms of seropositivity of the four viruses. We found that SANS scores of HSV-1 and CMV seropositive schizophrenia patients were significantly higher than the scores of patients with seronegative schizophrenia. No difference was found in SAPS scores. CONCLUSIONS: The results suggest a role of HSV and CMV infections in negative symptoms. This supports the hypothesis that viruses do not directly give rise to schizophrenia, but patients who were previously been infected with these viral agents may be prone to schizophrenia, and some of the symptom patterns may be related to different agents.

Psychological distress, emotional stability, and emotion regulation moderate dynamics of herpes simplex virus type 2 recurrence.

BACKGROUND: Herpes simplex virus type 2 (HSV-2) genital lesion recurrence is modulated by psychological factors, but no such link with viral shedding (and thus asymptomatic transmission) has been observed in humans. PURPOSE: The moderating effects of average psychological distress, emotional stability, and emotion regulation on HSV-2 recurrence were tested. METHODS: Nineteen HSV-2 seropositive women were followed over 22 weeks. Daily measures of HSV-2 recurrence and psychological distress were collected. HSV-2 lesions and viral shedding were modeled as linear oscillator systems, with psychological distress moderating the periodicity of each process. RESULTS: High levels of distress, more labile moods, and less ability to regulate emotional states were associated with fewer days elapsed between the onset of lesion episodes. Viral shedding showed the same pattern. CONCLUSIONS: Results are consistent with research indicating that psychological distress suppresses immune system functioning, and provide new evidence that genital HSV-2 viral shedding is related to, and regulated by, psychological distress.

Persistent viral pathogens and cognitive impairment across the life course in the third national health and nutrition examination survey.

BACKGROUND: Herpesviruses have been linked to cognitive impairment in older individuals but little is known about the association in the general US population. METHODS: We determined whether cytomegalovirus (CMV) and herpes simplex virus 1 (HSV-1) seropositivity were associated with cognitive impairment among children (aged 6-16 years) and adults aged 20-59 or ≥60 years, using data from the National Health and Nutrition Examination Survey (NHANES) III. Linear and logistic regression models were used to examine the associations between pathogen seropositivity and cognitive impairment. RESULTS: Among children, HSV-1 seropositivity was associated with lower reading and spatial reasoning test scores (ß, -0.69; 95% confidence interval [CI], -1.18 to -.21 and ß, -0.82; 95% CI, -1.29 to -.36, respectively). Among middle-aged adults, HSV-1 and CMV seropositivity were associated with impaired coding speed (odds ratio [OR], 1.54; 95% CI, 1.13-2.11, and OR, 1.41; 95% CI, 1.09-1.82, respectively). CMV seropositivity was also associated with impaired learning and recall (OR, 1.43; 95% CI, 1.14-1.80). Among older adults, HSV-1 seropositivity was associated with immediate memory impairment (OR, 3.26; 95% CI, 1.68-6.32). CONCLUSIONS: Future studies examining the biological pathways by which herpesviruses influence cognitive impairment across the life course are warranted.

Diagnostic classification, viral sexually transmitted infections and discourses of femininity: limits of normalisation to erase stigma.

Clinicians in the field of women's sexual health typically classify the two most common viral sexually transmitted infections (STIs), the human papilloma virus and the herpes simplex virus, as relatively innocuous infections. Teaching interventions include 'normalising' adult sexual activity and the epidemiological ordinariness of infection. Normalising is intended to disarm the potential stigma of the diagnosis. In this study, in-depth email interviews were conducted with 26 women with a viral STI diagnosis and 12 sexual health clinicians. Data were analysed thematically using a feminist, poststructuralist approach. Normalising is contextualised as an example of the workings of western philosophical thought whereby dualistic classifications privilege certain terms and subordinate other terms. In this instance, the relative medical normalcy of viral STIs is given primacy compared to the social abnormality experienced by women. Although these viral STIs infect women and men, this research concentrates on women's learning about viral STIs. For women, beliefs about femininity, sexuality, health, morality and responsibility influence effects of a viral STI diagnosis. These discourses are clinically significant because beliefs that specifically link to ideas about how to be a woman are overlooked when clinicians devise educational interventions.

Exposure to herpes simplex virus type 1 and cognitive impairments in individuals with schizophrenia.

Latent infection with neurotropic herpes viruses, such as herpes simplex virus, type 1 (HSV1), has been generally considered benign in most immunocompetent individuals except for rare cases of encephalitis. However, several recent studies have shown impaired cognitive functions among individuals with schizophrenia exposed to HSV1 compared with schizophrenia patients not exposed to HSV1. Such impairments are robust and are prominently observed in working memory, verbal memory, and executive functions. Brain regions that play a key role in the regulation of these domains have shown smaller volumes, along with correlation between these morphometric changes and cognitive impairments in schizophrenia. One study noted temporal decline in executive function and gray matter loss among HSV1-exposed first-episode antipsychotic-naïve schizophrenia patients. Furthermore, a proof-of-concept double-blind placebo-controlled trial indicated improvement in cognitive performance following supplemental anti-herpes-specific medication among HSV1 seropositive schizophrenia patients. Cross-sectional studies have also identified an association between HSV1 exposure and lesser degrees of cognitive impairment among healthy control individuals and patients with bipolar disorder. These studies fulfill several Bradford-Hill criteria, suggesting etiological links between HSV1 exposure and cognitive impairment. Exposure to other human herpes viruses such as cytomegalovirus and herpes simplex virus type 2 (HSV2) may also be associated with cognitive impairment, but the data are less consistent. These studies are reviewed critically and further lines of enquiry recommended. The results are important from a public health perspective, as HSV1 exposure is highly prevalent in many populations.

Aging-related neurostructural, neuropathological, and behavioral changes associated with herpes simplex virus type 1 brain infection in mice.

To date, the main advances in understanding Alzheimer's disease (AD) have revolved around the genetic variants associated with the familial form of the disease, yet the majority of cases are sporadic. The main risk factor for AD is aging, followed by production of the E4 isoform of apolipoprotein E (APOE). Female gender also increases the risk of developing AD. Herpes simplex virus type 1 (HSV-1) has been epidemiologically and experimentally associated with AD, although no studies on its effects over aging have been undertaken. To assess the potential aging-related consequences of HSV-1 brain infection, 2 month-old wild-type and apoE-deficient mice were infected with the virus, and over the next 16 months analyses made of cerebral viral load, neuropathological, morphological, and metabolic changes in the brain, and cognitive performance. Viral load in the central nervous system (CNS) increased with age. The viral load in the brains of aged apoE+/+ female mice was 43 times that seen in apoE-/- male mice. No MRI-detectable morphological differences nor any clear neuropathological differences were seen between 18 month-old infected and mock-infected mice, although differences were seen in younger animals. Neuroinfection was associated with memory deficit and a reduction in metabolic indicators of CNS health.

The association of depression, risky sexual behaviours and herpes simplex virus type 2 in adults in NHANES, 2005-2008.

OBJECTIVES: Depression has been linked to risky sexual behaviours in adolescents, but there is little research among adults. The goal of this analysis was to examine the associations between current depression and self-reported risky sexual behaviours in a nationally representative sample of US adults aged 20-59 years. The authors also examined the association between depression and infection with herpes simplex virus type 2 (HSV-2), a biological marker of risky sexual behaviours. METHODS: The authors used data from the 2005-2008 National Health and Nutrition Examination Surveys. Current depression was measured by the Patient Health Questionnaire-9. Antibodies to HSV-2 were tested using the enzymatic immunodot assay. The authors used logistic regression to examine the associations controlling for socio-demographic variables. RESULTS: Among 5273 adults aged 20-59 years, 7% had depression, 36% reported 10 or more lifetime sex partners, 15% had two or more past-year sex partners and 13% had first sex before 15 years of age. Persons with each of the risky sexual behaviours were more likely to have depression than those without. In stratified analyses, risky sexual behaviours were associated with depression in women but not in men. Among 3940 adults aged 20-49 years, 19% had HSV-2 infection. Persons with HSV-2 infection were more likely to have depression (OR 2.1, 95% CI 1.5 to 2.9). CONCLUSIONS: Risky sexual behaviour is related to current depression in adult women. Healthcare providers should be aware of this association and its potential implications in order to deliver better care for patients with depression or sexually transmitted infections.

Impaired functioning in euthymic patients with bipolar disorder--HSV-1 as a predictor.

There is a possible association between infectious agents and psychiatric disorders. Previous studies in the US provided evidence for cognitive impairment correlated with Herpes simplex virus type 1 (HSV-1) infection. For a replication study in Europe we chosed individuals diagnosed with bipolar disorder to analyse the correlation with HSV-1 infection. Antibody prevalence was analyzed by using solid phase immunoassay techniques. Cognitive functioning was tested with the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) Form A, the Trail Making Test A&B, and two subtests from the WAIS III: the Letter Number Sequencing Task and the subtest on information. History and psychopathology was assessed using structured interviews and validated rating scales (SCID, HRSD-21, YMRS, PANSS). Additionally, we investigated social functioning and quality of life using self-assessment-scales (SAS, LQLP). Prevalence rates of antibodies against diverse infectious agents did not differ significantly between patients and controls. We found a significant correlation between cognitive impairment in patients with bipolar disorder and the prevalence of antibodies directed against HSV-1. Cognitive functions were significantly impaired including language, attention, and immediate memory. The results of this study confirm previous findings suggesting that HSV-1 affects cognitive functions in patients with bipolar disorder. This may also result in more impaired functioning, less quality of life and difficulties in social adjustment.

Psychosocial impact of a positive HSV-2 diagnosis on adults with unrecognized HSV-2 infection.

OBJECTIVE: To evaluate the current research on the psychosocial impact of a positive herpes simplex virus type 2 (HSV-2) diagnosis on asymptomatic adults. DESIGN AND SAMPLE: A structured review of PubMed, CINAHL, and MEDLINE resulted in 8 articles published between 2000 and 2008. MEASURES: Articles were included if they investigated psychosocial reactions to HSV serological testing, including asymptomatic individuals, and used measurement instruments with adequate psychometric properties. RESULTS: The studies included participants of various backgrounds, including individuals with a new HSV-2 diagnosis concurrently receiving human immunodeficiency virus treatment, students within a university setting, and an HMO population. Current research indicates that a diagnosis of HSV-2 does not result in persistent psychosocial morbidity. However, studies that assessed for more nuanced reactions noted an impact on quality of life related to herpes. CONCLUSIONS: Further research is needed to confirm these findings among varied populations, to explore quality of life following HSV screening, and to identify the characteristics that may make particular individuals more susceptible to adverse psychological consequences.

HSV serologic testing for pregnant women: willingness to be tested and factors affecting testing.

OBJECTIVE: This prospective study was undertaken to evaluate pregnant women's willingness to undergo HSV type-specific serologic testing and factors affecting willingness in an obstetrics/gynecology ambulatory unit. METHODS: At prenatal Visit 1, pregnant women (n = 303) with no history of HSV-2 were tested for HSV-1/HSV-2 before and after they received counseling on genital and neonatal herpes. RESULTS: In both the Unwilling Subgroup and the group that changed from being willing to being unwilling, the most common reasons for choosing not to be tested were not being at risk for genital herpes, being tested is too personal, and concern about what will be done with the results. Of the 134 participants in the Willing/Tested Subgroup, 27 (20%) were HSV-2 seropositive and 81 (60%) were HSV-1 seropositive. Conclusions. These results support the feasibility of HSV serologic testing and counseling in pregnant women.