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Purpose: Animal studies have linked gastric herpesvirus infections to symptoms associated with functional gastrointestinal disorders (FGIDs). Herpesviruses have also been hypothesized to contribute to fibromyalgia (FM), a chronic pain syndrome frequently comorbid with FGIDs. The purpose of this study was to compare the prevalence of gastric herpesvirus infection in patients with FGIDs, with and without comorbid FM, to that of controls., Methods: For this pilot case-control study, we enrolled 30 patients who met both the Rome IV diagnostic criteria for one or more FGIDs and the American College of Rheumatology 2010 criteria for FM, 15 patients with one or more FGIDs without comorbid FM, and 15 control patients. Following endoscopic examination, gastric biopsies were analyzed for herpesvirus DNA and protein, Helicobacter pylori infection, and histological evidence of gastritis. Importantly, the viral nonstructural protein ICP8 was used as a marker to differentiate cell-associated actively replicating virus from latent infection and/or free virus passing through the GI tract., Results: Gastric herpes simplex virus type 1 (HSV-1) infection, as indicated by ICP8 presence, was significantly associated with FGIDs in the presence (OR 70.00, 95% CI 7.42-660.50; P < .001) and absence (OR 38.50, 95% CI 3.75-395.40; P < .001) of comorbid FM. Neither histological gastritis nor H. pylori infection were found to be associated with FGIDs or FM., Conclusions: HSV-1 infection was identified in gastric mucosal biopsies from patients with diverse FGIDs, with and without comorbid FM. Larger, multi-center studies investigating the prevalence of this association are warranted., (© 2022. The Author(s).)

Congenital cytomegalovirus infections are among the most common of the newborn in the developed world. These infections are the most common cause of sensorineural hearing loss. Studies utilizing ganciclovir and valganciclovir demonstrate improved hearing and Bailey Developmental scores. Because of the ease of administration, valganciclovir is the recommended treatment of choice for 6 months. Therapy should be reserved for those babies with symptomatic disease; no data are available regarding the impact of treatment on those babies with asymptomatic disease.

More than 14,000 neonates are infected with herpes simplex virus (HSV) annually. Approximately half display manifestations limited to the skin, eyes, or mouth (SEM disease). The rest develop invasive infections that spread to the central nervous system (CNS disease or encephalitis) or throughout the infected neonate (disseminated disease). Invasive HSV disease is associated with significant morbidity and mortality, but the viral and host factors that predispose neonates to these forms are unknown. To define viral diversity within the infected neonatal population, we evaluated 10 HSV-2 isolates from newborns with a range of clinical presentations. To assess viral fitness independently of host immune factors, we measured viral growth characteristics in cultured cells and found diverse in vitro phenotypes. Isolates from neonates with CNS disease were associated with larger plaque size and enhanced spread, with the isolates from cerebrospinal fluid (CSF) exhibiting the most robust growth. We sequenced complete viral genomes of all 10 neonatal viruses, providing new insights into HSV-2 genomic diversity in this clinical setting. We found extensive interhost and intrahost genomic diversity throughout the viral genome, including amino acid differences in more than 90% of the viral proteome. The genes encoding glycoprotein G (gG; US4), glycoprotein I (gI; US7), and glycoprotein K (gK; UL53) and viral proteins UL8, UL20, UL24, and US2 contained variants that were found in association with CNS isolates. Many of these viral proteins are known to contribute to cell spread and neurovirulence in mouse models of CNS disease. This report represents the first application of comparative pathogen genomics to neonatal HSV disease. IMPORTANCE Herpes simplex virus (HSV) causes invasive disease in half of infected neonates, resulting in significant mortality and permanent cognitive morbidity. The factors that contribute to invasive disease are not understood. This study revealed diversity among HSV isolates from infected neonates and detected the first associations between viral genetic variations and clinical disease manifestations. We found that viruses isolated from newborns with encephalitis showed enhanced spread in culture. These viruses contained protein-coding variations not found in viruses causing noninvasive disease. Many of these variations were found in proteins known to impact neurovirulence and viral spread between cells. This work advances our understanding of HSV diversity in the neonatal population and how it may impact disease outcome., (Copyright © 2019 Akhtar et al.)

Purpose of the Review: This article summarizes knowledge of herpes simplex virus (HSV) infections of the central nervous system (CNS). Disease pathogenesis, detection of DNA polymerase chain reaction (PCR) for diagnosis and prognosis, and approaches to therapy warrant consideration., Recent Findings: HSV infection of the CNS is one of few treatable viral diseases. Clinical trials indicate that outcome following neonatal herpes simplex virus type 2 (HSV-2) infections of the CNS is significantly improved when 6 months of suppressive oral acyclovir therapy follows IV antiviral therapy. In contrast, herpes simplex virus type 1 (HSV-1) infections of the brain do not benefit from extended oral antiviral therapy. This implies a difference in disease pathogenesis between HSV-2 and HSV-1 infections of the brain. PCR detection of viral DNA in the CSF is the gold standard for diagnosis. Use of PCR is now being adopted as a basis for determining the duration of therapy in the newborn., Summary: HSV infections are among the most common encountered by humans; seropositivity occurs in 50% to 90% of adult populations. Herpes simplex encephalitis, however, is an uncommon result of this infection. Since no new antiviral drugs have been introduced in nearly 3 decades, much effort has focused on learning how to better use acyclovir and how to use existing databases to establish earlier diagnosis.

Herpes simplex virus (HSV) evolved an elegant strategy that enables the virus to impact a large fraction of the human population. The virus replicates at the portal of entry (mouth, genitals) and concurrently it is transported retrograde to sensory neurons. In sensory neurons it establishes a silent (latent) infection. A variety of stimuli can reactivate the virus. The reactivated virus is transmitted anterograde to a site at the portal of entry for transmission by physical contact between infected and uninfected tissues to other individuals. The central issue is how a virus that vigorously replicates and successfully blocks the innate immune defenses of the host at the portal of entry into the body remains silent in sensory neurons. The presentation focuses on three key issues: (a) current assessment of the impact of HSV on human health, (b) the mechanisms by which the virus overcomes a key host defense mechanism at the portal of entry into the body and yet is silenced in latently infected neurons, and (c) the mechanisms by which the virus reactivates.

Parenteral therapy of viral infections of the newborn and infant began with vidarabine (adenine arabinoside) for the treatment of neonatal herpes simplex virus (HSV) infections in the early 1980s. Acyclovir has become the treatment of choice for neonatal HSV infections and a variety of other herpesvirus infections. Ganciclovir is beneficial for the treatment of congenital cytomegalovirus (CMV) infections involving the central nervous system (CNS). This article reviews the use of acyclovir and ganciclovir in the treatment of neonatal HSV and congenital CMV infections. A brief summary precedes a detailed discussion of available established and alternative therapeutics., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background: Poor neurodevelopmental outcomes and recurrences of cutaneous lesions remain unacceptably frequent among survivors of neonatal herpes simplex virus (HSV) disease., Methods: We enrolled neonates with HSV disease in two parallel, identical, double-blind, placebo-controlled studies. Neonates with central nervous system (CNS) involvement were enrolled in one study, and neonates with skin, eye, and mouth involvement only were enrolled in the other. After completing a regimen of 14 to 21 days of parenteral acyclovir, the infants were randomly assigned to immediate acyclovir suppression (300 mg per square meter of body-surface area per dose orally, three times daily for 6 months) or placebo. Cutaneous recurrences were treated with open-label episodic therapy., Results: A total of 74 neonates were enrolled--45 with CNS involvement and 29 with skin, eye, and mouth disease. The Mental Development Index of the Bayley Scales of Infant Development (in which scores range from 50 to 150, with a mean of 100 and with higher scores indicating better neurodevelopmental outcomes) was assessed in 28 of the 45 infants with CNS involvement (62%) at 12 months of age. After adjustment for covariates, infants with CNS involvement who had been randomly assigned to acyclovir suppression had significantly higher mean Bayley mental-development scores at 12 months than did infants randomly assigned to placebo (88.24 vs. 68.12, P=0.046). Overall, there was a trend toward more neutropenia in the acyclovir group than in the placebo group (P=0.09)., Conclusions: Infants surviving neonatal HSV disease with CNS involvement had improved neurodevelopmental outcomes when they received suppressive therapy with oral acyclovir for 6 months. (Funded by the National Institute of Allergy and Infectious Diseases; CASG 103 and CASG 104 ClinicalTrials.gov numbers, NCT00031460 and NCT00031447, respectively.).

Herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) are members of the Herpesviridae family and are characterized by their ability to establish latency after primary infection and subsequently reactivate. HSV infections in the neonatal and pediatric populations range from uncomplicated mucocutaneous diseases to severe, life-threatening infections involving the central nervous system (CNS). The antiviral agent acyclovir has significantly improved treatment outcomes of HSV infections, including the frequency of mucocutaneous recurrences and mortality associated with CNS and disseminated infections.

Herpesvirus infections of the central nervous system (CNS) are a significant cause of morbidity and mortality, including long-term neurologic sequelae. Among the family of herpesviruses, the most significant CNS infections are due to herpes simplex virus (HSV) and cytomegalovirus (CMV). The onset of HSV CNS infection can occur in neonates as well as older children and adults. CNS infection associated with CMV occurs predominantly in the perinatal period, but may also be seen rarely in children and adults, especially in immunocompromised individuals. Although advances in antiviral agents have led to improved outcomes, there is still a need for more effective treatments.

Disseminated herpes simplex virus (HSV) infection may lead to acute liver failure (ALF) and the need for emergency liver transplantation (LT). The primary aim of this study was to determine the utility of HSV serological testing and HSV DNA testing by polymerase chain reaction (PCR) in the diagnosis and management of indeterminate, pregnancy-related, and known HSV-related ALF. Stored sera obtained on study day 1 or 2 from patients enrolled in the United States ALF Study Group with indeterminate (n = 51), pregnancy-related (n = 12), and HSV-related (n = 4) ALF were screened for HSV DNA by PCR and serology. While 7 of the indeterminate and pregnant patients had positive anti-HSV immunoglobulin M, none had detectable HSV DNA. The 4 known HSV cases all had high-titer HSV DNA on presentation (range: 3.5 to 36 x 10(8) copies/mL). Two HSV patients underwent LT but developed posttransplant extrahepatic HSV infection despite suppression of HSV DNA with acyclovir treatment, and one of them eventually died. The 2 other fulminant HSV patients died within 48 hours of presentation. In conclusion, serum HSV DNA indicative of occult HSV infection was not detected in 51 indeterminate and 12 pregnancy-related ALF patients. The 4 patients with known HSV-related ALF all had high HSV DNA levels at presentation, and despite the rapid use of antiviral therapy and emergency LT, substantial morbidity and mortality were encountered, highlighting the poor prognosis with severe disseminated HSV infection., ((c) 2008 AASLD.)

Antiviral management options for recurrent herpes simplex virus (HSV) infection include daily suppressive and episodic therapy. New data on patient-initiated, short-course, high-dose antiviral therapy provide a new, more convenient option for patients who choose episodic therapy. A head-to-head comparison of suppressive valaciclovir versus famciclovir treatment indicates that both drugs have comparable clinical benefits, but that valaciclovir may have a greater impact on virological end-points. However, a more recent study shows that famciclovir effectively reduces the frequency of total and subclinical HSV shedding compared with placebo, as well as the percentage of days with genital lesions for subjects with or without a history of genital herpes. This article reports on presentations given at the IHMF Annual Meeting and International Congress of Antimicrobial Agents and Chemotherapy, both of which took place in late 2006.

Neonatal herpes is a devastating disease, the most serious complication of genital herpes, one of the most common serious congenital or perinatal infections, and the most frequent complication of sexually transmitted infections among children. Nevertheless, neonatal herpes is not reportable to health authorities in most states. The potential for prevention has been enhanced by recent diagnostic and therapeutic advances, and the disease meets widely accepted criteria for reporting, including incidence rates that exceed those of comparable conditions, epidemiologic instability, disease severity, direct and indirect socioeconomic costs, concern by persons at risk, the potential for prevention by public health interventions, and the prospect that the resulting data would influence public health policy. The absence of national surveillance contributes to beliefs by healthcare providers and the public health community that genital and neonatal herpes are uncommon conditions that affect small segments of society, beliefs that directly interfere with prevention. Neonatal herpes should be a reportable condition.

Neonatal herpes simplex virus (HSV) infection usually is acquired during the birth process, as the neonate comes in contact with the virus during passage through an infected birth canal. After an incubation period which can last as long as 2 to 4 weeks, neonatal HSV disease then manifests in 1 of 3 ways: (1) disseminated disease, with visceral organ involvement (including infection of the brain in two-thirds to three-quarters of patients); (2) central nervous system disease (with no other visceral organ involvement, but with skin lesions in two-thirds of patients); or (3) disease limited to the skin, eyes, and/or mouth (ie, SEM disease). Diagnostic advances in recent years have focused primarily on applying polymerase chain reaction technology to babies suspected of having neonatal HSV disease. Treatment of neonatal HSV disease with intravenous acyclovir has improved the likelihood of survival substantially, although neurologic morbidity remains a common sequelae, especially among survivors of central nervous system disease. Despite these advances, the duration of time from onset of symptoms and initiation of antiviral therapy has remained unchanged for the past 20 years. The surest way to improve outcomes rapidly at this point is to raise awareness of neonatal HSV disease, resulting in the establishment of earlier diagnoses and more rapid institution of antiviral therapy. In the longer term, development of a bedside nucleic acid detection kit for real-time detection of HSV DNA in the maternal genital tract at the time of delivery could identify which babies are at risk of developing neonatal HSV disease.

Viral shedding of HSV occurs frequently in infected individuals. HSV is shed asymptomatically from multiple anatomical sites and shedding, like exposure, is a significant risk for transmission. However, the relationship between shedding frequency, viral titer and transmission is unknown. HSV-2 shedding is affected by the site and time since acquisition of infection. The advent of sensitive PCR techniques has shown that the magnitude and frequency of viral shedding is higher than shown previously with viral culture techniques. It has also clearly demonstrated that suppressive (daily) antiviral therapy reduces clinical and subclinical reactivation rates, and has been successfully used in the prevention of recurrent oral and genital HSV infections. A recent study has demonstrated that daily antiviral therapy with valaciclovir can significantly reduce transmission of HSV-2 between discordant heterosexual couples in monogamous relationships.

Herpes simplex virus (HSV) infections are among the infections most frequently encountered by humans. Two types of HSV infections have been identified-HSV-1, which usually causes orolabial disease, and HSV-2, which is associated more frequently with genital and newborn infections. Usually, HSV causes mild and self-limited disease of the mouth and lips or at genital sites. However, on occasion, the disease can be life-threatening. Such is the case with neonatal HSV infection and HSV infections of the central nervous system. Furthermore, in the immunocompromised host, severe infection has been encountered and is a source of morbidity. Even in the immunocompetent host, frequent recurrences, particularly those of the genital tract, can be debilitating. Because HSV does cause genital ulcerative disease, it is associated with an increased risk of acquiring a human immunodeficiency virus infection. During the past 2 decades, selective and specific inhibitors of HSV replication have been developed. These agents, acyclovir, valaciclovir, and famciclovir, all accelerate the events of healing and decrease the probability of excreting the virus when they are taken in a suppressive fashion. The long-term safety of acyclovir has been unequivocally established. Its prodrug, valaciclovir, and the prodrug of penciclovir, famciclovir, have not been used in practice as long and, therefore, less is known about these agents; however, neither is available as a pediatric formulation.

Objective: During the 2 decades in which effective antiviral therapies have been available for neonatal herpes simplex virus (HSV) disease, changes have been documented not only in the outcomes of infected infants, but also in the natural history of the disease itself. Numerous studies previously have reported that early institution of antiviral therapy is beneficial to the outcome of the disease. The objective of this study was to provide an update of neonatal HSV disease to identify means by which future improvements in the management of HSV-infected neonates can be made., Design/methods: Neonates enrolled in 2 studies of parenteral acyclovir for the treatment of neonatal HSV disease provided the data source. The National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group conducted the studies between 1981 and 1997. A total of 186 patients are summarized, all of whom were treated with acyclovir. Demographic and clinical characteristics of these patients are reported., Results: Comparisons between patients treated in the periods between 1981-1988 and 1989-1997 according to extent of disease revealed that the mean time between the onset of disease symptoms and initiation of therapy has not changed significantly from the early 1980s to the late 1990s. Of all patients evaluated, 40% had fetal scalp monitors during the delivery process. A significant minority of patients did not have skin vesicles at the time of their presentation and did not develop them during the acute HSV disease (39% of patients with disseminated disease; 32% of patients with central nervous system [CNS] disease; and 17% of patients with skin, eye, and/or mouth disease). Among patients with CNS disease, mortality was associated with prematurity. Among patients with disseminated HSV disease treated with acyclovir at 30 mg/kg/d, mortality was associated with aspartate transaminase elevations of >/=10 times the upper limit of normal at the time of initiation of acyclovir therapy. Mortality was also associated with lethargy at initiation of antiviral therapy for patients with disseminated disease. Patients' morbidity status was associated with the extent of disease (skin, eye, and/or mouth disease vs CNS vs disseminated). For those patients with CNS disease, morbidity was also associated with seizures at initiation of antiviral therapy., Conclusion: Data presented in the current comparison of neonatal HSV disease over the 2 periods (1981-1988 vs 1989-1997) demonstrate that no progress has been made in decreasing the interval between onset of HSV symptoms and initiation of antiviral therapy. Additional strides in the improvement of disease outcome may occur only if the interval between onset of symptoms and initiation of therapy is shortened. The means by which this will be accomplished lie in increased consideration of neonatal HSV infections in acutely ill infants. Specific data and recommendations to facilitate this goal are contained within.

Objective: The objective of this investigation was to establish the safety of high-dose (HD) acyclovir for the treatment of neonatal herpes simplex virus (HSV) disease. In addition, an estimate of therapeutic efficacy was sought, both with respect to mortality and to morbidity. Virologic efficacy of HD acyclovir was also assessed., Participants: Infants who were

Herpes simplex virus (HSV) is a member of the herpesviridae family. Recognised since ancient Greek times, the virus frequently infects human beings, causing a range of diseases from mild uncomplicated mucocutaneous infection to those that are life threatening. In the past 50 years, substantial advances in our knowledge of the molecular biology of HSV have led to insights into disease pathogenesis and management. This review provides a contemporary interpretation of the biological properties, function, epidemiology, and treatment of HSV diseases.

The fundamental biological characteristic of herpes simplex virus (HSV) infection is its ability to establish latency and periodically reactivate, resulting in productive infectious virus. Recurrent HSV infections occur in spite of the presence of host immune responses to the virus. Because genital herpes is currently one of the three most prevalent sexually transmitted diseases worldwide, its potential public health impact has contributed to increased awareness in medical communities. The current state of knowledge on the immunological control of primary and recurrent HSV infections is reviewed, as well as the various immune-based therapeutic approaches to resultant disease. Finally, the potential benefit of immune response modifiers (IRMs), which have shown promise in early clinical studies, is discussed.

The purpose of the present study was to determine if the quantity of herpes simplex virus (HSV) DNA in the cerebrospinal fluid (CSF) of patients with herpes encephalitis would be useful in establishing the prognosis of the disease and to determine the effect of antiviral therapy on the clearance of viral DNA from the CSF. Quantitation of HSV DNA was done by constructing an internal standard (IS) from the glycoprotein B amplicon which had a 25-bp deletion between primer annealing sites. Each CSF specimen was coamplified with the IS and the ratio of the amount of HSV/amount of IS was compared to the ratios on a standard curve constructed with the same IS plus known amounts of HSV DNA. CSF specimens were available from 16 patients who were treated with intravenous acyclovir, and the amount of HSV DNA ranged from < 25 to 18,000 copies per microliter in CSF obtained before or within 4 days of the initiation of acyclovir therapy. Patients with > 100 copies of HSV DNA per microliter were older, were found by computed tomography to have lesions, and had poorer outcomes than patients with < 100 copies. Follow-up CSF specimens were available from seven patients. In six of these seven patients, the HSV DNA levels decreased during therapy. One patient had a twofold increase in HSV DNA levels after 1 week of therapy and died on day 8. The application of this assay may be helpful in establishing the prognosis and in the monitoring of patients with herpes simplex encephalitis.

Each year, about 1,600 infants in the United States are infected with neonatal herpes simplex virus. We conducted a cost-effectiveness analysis of antiviral drug therapy (acyclovir) for three forms of herpes simplex virus infection: skin, ear, and mouth (SEM), central nervous system (CNS), and disseminated multiorgan (DIS) disease. Five levels of patient outcomes were examined (normal, mild, moderate, severe, dead). We obtained information on disease occurrence and survival from clinical trials and historical reviews of untreated newborns. We considered approaches for treating all or any of the forms of the disease and compared them with no use of antiviral drugs. The main measure of effectiveness was lives saved, including those of descendants of survivors. Costs were measured from a societal perspective and included direct medical costs, institutional care, and special education. We used a discount rate of 3% and valued dollars at 1995 levels. We also considered the perspective of a managed care organization. From a societal viewpoint relative to no treatment, antiviral therapy for SEM resulted in a gain of 0.8 lives and a cost reduction of $78,601 per case. For the treatment of CNS and DIS disease, antiviral therapy saved more lives but at increased cost, with respective marginal costs per additional life saved of $75,125 and $46,619. From a managed care perspective, antiviral therapy is more cost-effective than from a societal viewpoint because costs of institutional care and special education are not the responsibility of managed care organizations. Development of at-home therapies will further improve the cost-effectiveness of antiviral therapy for neonatal herpes simplex virus infection.

Cerebrospinal fluid (CSF) specimens from 77 neonates with herpes simplex virus (HSV) disease were evaluated retrospectively by polymerase chain reaction (PCR). Samples were collected from 202 infants enrolled in a National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group trial that compared vidarabine with acyclovir for the treatment of neonatal HSV infection. HSV DNA was detected in the CSF of 26 (76%) of 34 infants with CNS disease, in 13 (93%) of 14 infants with disseminated infection, and in 7 (24%) of 29 with skin, eye, or mouth (SEM) involvement. One of the 7 PCR-positive SEM patients subsequently developed severe neurologic impairment. Eighteen (95%) of 19 infants with positive CSF PCR results after the completion of 10 days of antiviral therapy experienced significant morbidity or mortality. Application of PCR to neonatal HSV disease may provide additional information on which clinical decisions may be based, although its diagnostic utility outside the research setting is unproven.

Isolation of herpes simplex virus (HSV) from brain tissue after biopsy has been considered the reference standard for the diagnosis of herpes simplex encephalitis (HSE). During the evaluation of antiviral treatment of HSE, cerebrospinal fluid (CSF) was obtained from patients with clinical disease indicative of HSE who underwent diagnostic brain biopsy. HSV DNA was detected by polymerase chain reaction (PCR) in CSF of 53 (98%) of 54 patients with biopsy-proven HSE and was detected in all 18 CSF specimens obtained before brain biopsy from patients with proven HSE. Four of 19 CSF specimens were positive after 2 weeks of antiviral therapy. Positive results were found in 3 (6%) of 47 patients whose brain tissue was culture-negative. Detection of HSV DNA in the CSF correlated significantly with age and focal radiographic findings. Thus, PCR detection of HSV DNA should be the standard for diagnosis of HSE.

Herpes simplex virus infections of the central nervous system remain a significant cause of morbidity and mortality, in spite of safe and efficacious antiviral therapy. Advances in the treatment of neonatal herpes and herpes simplex encephalitis with acyclovir have improved outcome. The application of polymerase chain reaction has allowed for the prompt and specific diagnosis of herpes simplex virus infections of the brain. This review summarizes our current knowledge on the pathogenesis, diagnosis, and treatment of herpes simplex virus infections of the brain. Opportunities for the future will be defined.

Neonatal herpes simplex virus infections cause significant morbidity and mortality among infected babies, despite the availability of antiviral therapy. These infections manifest in one of three forms: skin, eye, and mouth involvement; encephalitis; or disseminated infection. The latter two forms of disease account for more than 50% of babies with neonatal herpes and are associated with mortality and severe morbidity rates that exceed 75% in infected children. Thus future therapeutic efforts must be directed toward improved disease outcome. One such effort is the evaluation of immunoglobulin products (humanized monoclonal antibodies, human monoclonal antibodies and hyperimmune globulin) as part of a concomitant therapeutic regimen for babies with encephalitis and disseminated infection. The logic for such an approach becomes especially apparent for babies with disseminated disease because little transplacental maternal antibody is received at the time of birth. Thus concomitant administration of antiviral therapy with antibody may improve disease outcome.

Herpes simplex virus infections of humans have been known since ancient times. Contemporary society has witnessed a series of devastating manifestations of herpes simplex virus infections--namely, genital herpes simplex virus infection and neonatal herpes simplex virus infection. With the evolution of society, particularly advances in birth control and increasing promiscuity, the seroprevalence of herpes simplex virus type 2 infections has increased worldwide, however, more so in developed societies. As a consequence, individuals of child-bearing age are at risk for either reactivation of herpes simplex virus at termination of gestation or acquisition of a new primary infection at that time. The consequences of vertical transmission of herpes simplex virus from mother to child, resulting in neonatal herpes simplex virus infection, can be devastating. Current efforts, which are directed toward the treatment of neonatal herpes, have established the value of drugs such as vidarabine and acyclovir. However, the real emphasis for future programs is the prevention of herpes simplex virus infections to avoid person-to-person transmission either horizontally or vertically. The development of vaccines directed against herpes simplex virus may be of value toward this end.

Neonatal herpes simplex virus infections are a common problem in the United States, occurring at an incidence of one in approximately 3,500 deliveries. In the absence of antiviral therapy significant morbidity and mortality is attendant with disease. Disease manifestations in the newborn include multiorgan involvement (disseminated disease), encephalitis, and/or infection limited to the skin, eye, or mouth. These three broad classifications provide distinctions in severity of disease for evaluation of outcome following antiviral therapy. The availability of antiviral therapy for life-threatening disease, particularly that which is disseminated or involves the brain, has been of particular benefit for children with neonatal herpes. Both acyclovir and vidarabine have proven effective in the management of neonatal herpes simplex virus infection. With current therapeutic modalities, mortality from disease localized to the skin, eye, and mouth is virtually non-existent, yet a few children (approximately 5%) are still at risk for a long-term neurologic sequelae. For babies with encephalitis, the mortality has been reduced to approximately 15% and nearly 50% of survivors develop normally 3 years after treatment. Outcome with disseminated infection is of less value as mortality remains high (50%), but the number of survivors who develop normally is approximately 85%. The introduction of new antivirals with enhanced lipophilicity and, potentially, greater activity in the central nervous system may further improve outcome from this devastating disease.

Neonatal herpes simplex virus (HSV) infections are of increasing incidence in North America, now occurring at a rate of approximately one in 3,500 to one in 5,000 deliveries per year. Disease manifests as one of three forms; namely, infection: localized to the skin, eye and mouth (SEM), encephalitis (CNS), or disseminated disease. With the advent of antiviral therapy, it has become possible to decrease mortality and improve morbidity for babies suffering from infection. Advances in antiviral therapy have allowed for prevention of disease progression beyond states of SEM involvement. Furthermore, life threatening infections of the CNS or of multiple organs, have mortality with either acyclovir or vidarabine therapy. Now approximately 15% (CNS) and 50% (disseminated disease) of babies die from neonatal HSV disease. The results of ongoing studies in the United States will summarize the pathogenesis and treatment of neonatal HSV infection.

Herpes simplex virus (HSV) infections are among the most commonly encountered in humans. Fortunately, the resulting diseases are more usually nuisances, such as recurrent fever blisters, rather than life threatening or morbidity inducing. Nevertheless, HSV can result in disease of the central nervous system (CNS) with attendant neurological complications. Examples of the latter include herpes simplex encephalitis (HSE) or neonatal HSV infection. The past decade has witnessed significant advances in our understanding of the pathogenesis of these 2 forms of disease and, even more importantly, their amenability to treatment. This review summarises our current understanding of the natural history, pathogenesis, presentation, and treatment of HSV infections of the CNS. Because of the life-threatening nature of herpes simplex infections of the CNS, particular attention is paid to clinical presentation and differential diagnosis of confounding entities which mimic herpes simplex encephalitis. The controversy of brain biopsy versus alternative noninvasive diagnostic procedures is discussed. Clinical presentation and, importantly, the lack of uniform clinical presentation, as well as the value of intervention with appropriate antiviral drugs such as aciclovir and vidarabine (adenine arabinoside, ara-A), are stressed. The clinical outcome of herpes simplex virus infections of the CNS with therapy is particularly relevant. In spite of early intervention with selective and specific inhibitors of viral replication, return to normal function is not always achieved. At the conclusion of this review, the reader should be aware of the potential value of therapy as well as the problems encountered with diagnosis and management of patients with herpes simplex virus infections of the CNS.

Using the decision analysis technique and multivariate regression methods, a statistical model was established to define the utility of brain biopsy for diagnostic evaluation of patients with suspected herpes simplex encephalitis (HSE). Two strategies were compared: strategy I, brain biopsy with acyclovir (ACV) treatment for 10 days in biopsy-positive patients, and strategy II, ACV therapy without brain biopsy. Strategy I resulted in a greater 6-month survival rate when the likelihood of patients having HSE was less than 70%. Based on the current estimated prevalence of HSE (for patients with suspected HSE) of 35%, strategy I showed a slight advantage of a 3.2% increase in 6-month survival rate. An individual patient's chance of a positive brain biopsy can be predicted using a mathematical equation based on several important clinical assessments. This equation in conjunction with the decision analysis is a useful guide for the clinical management of patients with regard to brain biopsy.

The gene designated gamma 134.5 maps in the inverted repeats flanking the long unique sequence of herpes simplex virus-1 (HSV-1) DNA, and therefore it is present in two copies per genome. This gene is not essential for viral growth in cell culture. Four recombinant viruses were genetically engineered to test the function of this gene. These were (i) a virus from which both copies of the gene were deleted, (ii) a virus containing a stop codon in both copies of the gene, (iii) a virus containing after the first codon an insert encoding a 16-amino acid epitope known to react with a specific monoclonal antibody, and (iv) a virus in which the deleted sequences were restored. The viruses from which the gene was deleted or which carried stop codons were avirulent on intracerebral inoculation of mice. The virus with the gene tagged by the sequence encoding the epitope was moderately virulent, whereas the restored virus reacquired the phenotype of the parent virus. Significant amounts of virus were recovered only from brains of animals inoculated with virulent viruses. Inasmuch as the product of the gamma 134.5 gene extended the host range of the virus by enabling it to replicate and destroy brain cells, it is a viral neurovirulence factor.

The genetically engineered herpes simplex virus strains R7017 and R7020 were tested in owl monkeys (Aotus trivirgatus) previously shown to model herpetic diseases of immunocompromised patients and neonates. In contrast to the lethal disease seen in monkeys receiving 100-1,000 plaque-forming units (pfu) of wild-type virus, inoculation of greater than or equal to 10(6) pfu of recombinant viruses produced local lesions and viral shedding but not disseminated disease. Latent recombinant viruses were recovered from some ganglia innervating the sites of inoculation. Monkeys protected from lethal infection with wild-type virus exhibit recurrent lesions that increase in frequency and severity after total lymphoid gamma irradiation (TLI). In contrast, monkeys immunosuppressed by TLI and inoculated with R7020 could not be differentiated from irradiated controls with respect to morbidity or mortality. Moreover, the virus was not transmitted from immunosuppressed infected females to normal male cage mates.

Survival from untreated herpes simplex type 1 encephalitis is well known to be accompanied by severe cognitive impairments. Recently, acyclovir has been proven to be the most effective available treatment for this disease, with the expectation that it would appreciably reduce morbidity. We performed detailed assessments of four consecutive patients who received acyclovir in the early stages of biopsy-proven herpes encephalitis and who now have been followed up for 1.5 to 4 years. All four patients showed definite residual on either clinical or formal neuropsychological testing, most commonly dysnomia and impaired new learning for both verbal and visual material, even though three had normal performance on a standard clinical mental status test. All four patients were unable to function at their prior level of achievement. Therefore, despite early administration of acyclovir in herpes encephalitis, long-lasting neuropsychological residua are likely. Furthermore, cognitive deficits of prognostic importance may not be detected by clinical screening.

Herpes-simplex-virus (HSV) DNA in cerebrospinal fluid was amplified by use of the polymerase chain reaction and identified by hybridisation to a specific oligonucleotide probe. Specimens of cerebrospinal fluid (CSF) from 4 of 4 patients with herpes simplex encephalitis were positive for HSV DNA, whereas CSF specimens from 6 patients with other central-nervous-system infections were negative. This technique may expedite diagnosis of herpes simplex encephalitis.

An open study of vidarabine (adenine arabinoside) therapy was performed to verify the mortality from neonatal herpes simplex virus infection and to define further long-term morbidity. A total of 39 babies not previously reported were treated with either 15 mg/kg/d (16 newborns) or 30 mg/kg/d (23 newborns) of vidarabine administered intravenously for ten to 14 days. Outcome was compared with that from 56 newborns evaluated in a prior trial. Irrespective of the dose of medication, therapy decreased the mortality in babies with disseminated and CNS disease to 40%. The extent of organ involvement and, in particular, pulmonary herpes simplex infection were predictive of mortality (P = .001, for both). For these babies, 32% achieved normal developmental milestones 2 years after therapy. Disease localized to the skin, eye, and/or mouth was not associated with death. However, neurologic impairment occurred in 12% of this treated group of newborns. These findings underscore the value of vidarabine therapy of neonatal herpes simplex virus infection. However, an increase in dosage did not appear to result in significant improvement in either mortality or morbidity. Further improvement in the mode of therapy and the utilization of more potent antiviral drugs are currently being tested.

From January 1973 through July 1981, 40 patients underwent brain biopsy for suspected herpes simplex encephalitis at the University of Alabama Medical Center. Biopsy was performed as a component of experimental antiviral studies to ensure correct diagnosis. A tentative diagnosis was made on clinical grounds, and the site of biopsy was chosen on the basis of localizing neurological signs, the electroencephalogram, and/or computed tomographic (CT) scan abnormalities. Patients ranged in age from 15 months to 73 years, with a median age of 19 years. Thirty patients were male, and 10 were female. Brain tissue from 17 of the 40 patients grew herpes simplex virus in tissue culture. There was one biopsy-related complication, a wound dehiscence requiring secondary closure. In no case was death attributable to the brain biopsy procedure. The outlook in patients with proven herpes encephalitis worsened directly with both an increasing interval between the onset of symptoms and the initiation of antiviral therapy and the age of the patient. The presence of a CT scan abnormality before the initiation of therapy was associated with a very poor prognosis. Three patients not included in this series were referred for brain biopsy to rule out herpes simplex encephalitis, but were found to have bacterial infections. Two had subdural empyemas and the third had a brain abscess with overlying subdural empyema. Current technique calls for biopsy of the anterior portion of the inferior temporal gyrus on the affected side.

We have reported an unusual presentation of herpes simplex encephalitis in a patient with a 3 1/2-year history of a schizo-affective disorder. In the month immediately before diagnosis, the patient lost contact with reality and became violent. After successful treatment with antipsychotic medication, he had agitation and disorientation, as well as fever and cerebrospinal fluid pleocytosis. There were no focal neurologic findings. When a low-density lesion in the right temporal lobe was defined by computerized axial tomography, brain biopsy and culture isolated herpes simplex virus type 1. After therapy with vidarabine, the patient regained independence in simple daily activities. This case stresses the possibility of herpes simplex encephalitis in patients with an acute mental change.

We compared the clinical presentation of 95 newborns with herpes simplex virus (HSV) infection from 1973 through 1981 (first period) with data from 196 newborns evaluated from 1982 through 1987 (second period). There was a significant change in the presentation of infection in these infants. From the first to the second period, the frequency of disseminated disease decreased from 50.5% to 22.9%, whereas the frequency of skin, eye, and mouth (SEM) diseases increased from 17.9% to 43.4% (P less than .001). The frequency of infants with central nervous system (CNS) disease remained relatively unchanged--31.6% versus 33.7%. We also compared the demographic and clinical characteristics of the infants and their mothers. For neonates with CNS or disseminated infection, disease duration and frequency of prematurity were significantly decreased in the second period, as was the frequency of skin vesicles for newborns with SEM or disseminated infection. These changes are most likely the consequence of recognizing and treating SEM infection before its progression to more-severe disease.