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Herpes simplex encephalitis is a life-threatening disease of the central nervous system caused by herpes simplex viruses (HSVs). Following standard of care with antiviral acyclovir treatment, most patients still experience various neurological sequelae. Here we characterize HSV-1 infection of human brain organoids by combining single-cell RNA sequencing, electrophysiology and immunostaining. We observed strong perturbations of tissue integrity, neuronal function and cellular transcriptomes. Under acyclovir treatment viral replication was stopped, but did not prevent HSV-1-driven defects such as damage of neuronal processes and neuroepithelium. Unbiased analysis of pathways deregulated upon infection revealed tumour necrosis factor activation as a potential causal factor. Combination of anti-inflammatory drugs such as necrostatin-1 or bardoxolone methyl with antiviral treatment prevented the damages caused by infection, indicating that tuning the inflammatory response in acute infection may improve current therapeutic strategies., (© 2023. The Author(s).)

Although acute encephalopathy is quite commonly seen in patients of SARS-CoV-2 infection, encephalitis characterised by brain inflammation is relatively rare. Encephalitis caused by Herpes simplex type 1 is the most common cause of identified sporadic encephalitis, and early diagnosis and prompt treatment can prevent the devastating outcome. In this brief communication, we report a case of SARS-CoV-2 associated haemorrhagic encephalitis mimicking herpes encephalitis. In today's pandemic era, it is especially important to distinguish herpes encephalitis from SARS-CoV-2-associated encephalitis as treatment and prognosis of both the conditions differ greatly. This case highlights the importance of suspecting SARS-CoV-2 infection in a patient presenting with clinical symptoms and brain imaging suggestive of Herpes encephalitis., (© 2022. Crown.)

Newborns are particularly susceptible to severe forms of herpes simplex virus 1 (HSV-1) infection, including encephalitis and multisystemic disseminated disease. The underlying age-dependent differences in the immune response that explain this increased susceptibility relative to the adult population remain largely understudied. Using a murine model of HSV-1 infection, we found that newborn mice are largely susceptible to intracranial and intraperitoneal challenge while adult mice are highly resistant. This age-dependent difference correlated with differential basal-level expression of components of innate immune signaling pathways, which resulted in dampened interferon (IFN) signaling in the newborn brain. To explore the possibility of modulating the IFN response in the newborn brain to recapitulate the adult phenotype, we administered exogenous IFN-β in the context of disseminated HSV-1 infection. IFN-β treatment resulted in significantly increased survival and delayed viral neuroinvasion in the newborn. These effects were associated with changes in the type I IFN response in the brain, reduced viral replication in the periphery, and the stabilization of the blood-brain barrier (BBB). Our study reveals important age-dependent differences in the innate immune response to HSV-1 infection and suggests a contribution of the BBB and the brain parenchyma in mediating the increased susceptibility to HSV-1 infection observed in the newborn. These results could provide the basis for potential new therapeutic strategies for life-threatening HSV-1 infection in newborns. IMPORTANCE Herpes simplex virus (HSV) is a ubiquitous human pathogen affecting 50 to 80% of the population in North America and Europe. HSV infection is commonly asymptomatic in the adult population but can result in fatal encephalitis in the newborn. Current treatment with acyclovir has improved mortality in the newborn; however, severe neurologic sequelae are still a major concern following HSV encephalitis. For this reason, there is a critical need to better understand the underlying differences in the immune response between the two age groups that could be used to develop more effective treatments. In this study, we investigated differences in the innate immune response to viral infection in the brains of newborn and adult mice. We found that, similar to humans, newborn mice are more susceptible to HSV infection than the adult. Increased susceptibility was associated with dampened innate immune responses in the newborn brain that could be rescued by administering interferon beta., (Copyright © 2020 Giraldo et al.)

Background: Intravenous acyclovir is the treatment of choice for herpes simplex virus encephalitis. In 2006, the American Academy of Pediatrics updated its dosing recommendations for children aged 3 months to 12 years to receive high-dose acyclovir (60 mg/kg/day). The association between acyclovir dose and toxicity is unclear., Objective: The purpose of our study was to review our institution's experience with standard- and high-dose acyclovir for the empiric treatment of encephalitis., Study Design, Setting and Patients: This retrospective cohort study included patients aged 1 month to 18 years who received acyclovir as empiric treatment for encephalitis between 2005 and 2009 at a tertiary care children's hospital. We excluded patients with baseline renal impairment and those without serum creatinine measurements prior to and during treatment., Main Outcome Measure: The main outcome measure of this study was to compare the occurrence of renal injury or failure between children who received the standard- versus high-dose regimen., Results: Sixty-one patients were included (n = 32 standard-dose; n = 29 high-dose). There was no statistical difference in change in serum creatinine from baseline between children who received standard- versus high-dose acyclovir (0 vs. 5.1 %; p = 0.79). One child in the standard-dose group and three children in the high-dose group developed renal injury or failure during treatment (3.1 vs. 10.3 %; p = 0.34). Children with renal injury or failure were older, had a longer length of stay, and longer duration of therapy than children without., Conclusions: The incidence of renal injury or failure was similar between children who received standard-dose and high-dose acyclovir.

Knowledge on pediatric herpes simplex virus encephalitis is limited. Here we summarize 6 neonates and 32 children diagnosed by polymerase chain reaction (n = 37) or serological studies (n = 1), respectively. Diagnosis was difficult, as only 15 patients presented neurologic symptoms. Moreover, cerebrospinal fluid glucose, protein, and leukocytes were normal in 6 patients. Subsequently, all but 2 showed neurologic symptoms. Diffusion-weighted neuroimaging was the most sensitive early imaging method. Despite acyclovir treatment, 8 patients experienced early relapses, showing movement abnormalities, impaired vigilance, and seizures. Diffuse white matter changes, found in 3 of 5 relapse patients on neuroimaging, and a negative cerebrospinal fluid herpes simplex virus polymerase chain reaction suggested inflammatory processes. All relapse patients were again treated with acyclovir, and 3 responded to additional corticosteroid treatment. Whereas outcome after relapses was poor, overall outcome was good. No child died; 14 were asymptomatic at discharge, and neuroimaging remained normal in 7 of 30 patients studied.

Herpes simplex virus (HSV) infection in the neonate is a rare event with severe consequences for the child even if adequately treated with antiviral drugs. Mothers with primary genital herpes infections late in pregnancy or at delivery have a high risk of transferring the infection to the child, while the risk of transfer in mothers with recurrent genital infections is only a few percent. Neonatal herpes localized in skin-eye-mouth has no mortality and morbidity after antiviral treatment. In neonatal disseminated and central nervous system disease, early treatment is a predictor for better outcome. The morbidity in survivors is high; after herpes encephalitis, only one-third of children have normal development. While awaiting vaccines or reliable predictors for prevention of neonatal herpes, clinical awareness of primary maternal herpes during pregnancy and recommendations for prophylactic treatment are important tools. For pediatricians the differential diagnosis of a child aged two to four weeks with seizures, neonatal herpes encephalitis must be considered and either excluded or treated. Neurological follow-up and training programs to minimize the consequences of a disability are important clinical aspects.

The main predictor of outcomes in herpes simplex virus (HSV) encephalitis (HSE) is the delay between hospital admission and initiation of acyclovir. In this study, factors associated with late initiation of acyclovir were identified. The study included adults from northern France whose cerebrospinal fluid (CSF) was positive for HSV by PCR. Late initiation of acyclovir was defined as a delay of >1 day from hospital admission. In total, 184 patients were retrospectively enrolled from January 1991 to December 2002. The median age was 60 years (range: 17-91), and 102 (55.4%) were male. Acyclovir was initiated >1 day after hospital admission in 68 patients (37.0%). According to multivariate analysis, independent risk factors for late initiation of acyclovir were severe underlying disease (Knaus score >or=C) (OR 4.1; 95% CI 1.5-11.7); alcohol abuse (OR 3.4; 95% CI 1.3-8.9); and a delay of >1 day from admission to first brain imaging (OR 8.4; 95% CI 3.9-18.0). In addition, univariate analysis suggested an association between a finding of <10 leukocytes/mm(3) in CSF at admission (OR 2.5; 95% CI 0.7-5.8). These characteristics were found in 26 (14.1%), 23 (12.5%), 66 (35.9%) and 27 (14.7%) patients, respectively. One risk factor was identified in 109 (59.2%) patients, two in 29 (15.8%), and three in six (3.3%). Patients with HSE often present with severe underlying disease, chronic alcohol abuse, or atypical CSF findings, and such factors should not be allowed to delay diagnosis and administration of acyclovir.

Objective: Trichosanthin (TCS), a ribosome-inactivating protein extracted from the root tuber of Chinese medicinal herb Trichosanthes kirilowii maximowicz, has various pharmacological properties including abortifacient, anti-tumor and anti-virus. This study aimed to evaluate the effects of TCS on infectious brain injury induced by Herpes simplex virus-1 (HSV-1) in mice., Methods: Ninety mice were randomly assigned into three groups: Normal control group (n=30), Model group (n=30) and TCS-treated group (n=30). Viral encephalitis was induced by intracranial inoculation of HSV-1 in the latter two groups. The TCS-treated group was injected with TCS 30 minutes before HSV-1 inoculation. The water content of brain tissue was measured at 1, 12, 24 and 48 hrs, and at 4 and 7 days after HSV-1 inoculation. The viral titer of brain tissue and brain histopathological changes were detected at 7 days after HSV-1 inoculation. The neurological deficient scores were determined daily., Results: The water content of brain tissue in the TCS-treated group between 48 hrs and 7 days after HSV-1 inoculation was significantly lower than that in the Model group (P < 0.05), although it was significantly higher than that in the Normal control group (P < 0.05). The viral titer of brain tissue in the TCS-treated group was markedly lower than that in the Model group (1.16 +/- 0.45 vs 2.89 +/- 0.44; P < 0.05) 7 days after HSV-1 inoculation. The neurological deficient scores of the TCS-treated group after 24 hrs of HSV-1 inoculation were significantly lower than that in the Model group but were higher than those of the Normal control group. TCS treatment resulted in alleviated pathological changes of brain tissue compared with the Model group 7 days after HSV-1 inoculation., Conclusions: TCS has protective effects against infectious brain injury induced by HSV-1 in mice.

Focal viral encephalitis in childhood is a rare but life-threatening disease. Animal experiments and case reports suggest a positive effect of an additional therapy with interferon-beta on the course of the disease. Therefore, we initiated a prospective, double-blind placebo-controlled study to investigate the benefit of a combination therapy of Aciclovir (ACV) and recombinant interferon-beta (rIFN-beta) in juvenile focal viral encephalitis. - Initial inclusion criterium was suspicion of focal viral encephalitis. Diagnosis was proven by demonstration of characteristic focal lesions in cerebral imaging or virological evidence of HSV in cerebrospinal fluid. Patients were treated with ACV plus rIFN-beta or ACV plus placebo. Neurological outcome was determined 21 days and 3 months after onset of the disease. - Initially 59 patients were enrolled in the study. Encephalitis was proven in 14 patients (7 ACV + rIFN-beta, 7 ACV + placebo). The study groups were balanced in terms of important prognostic criteria. 10 patients (5 ACV + rIFN-beta, 5 ACV + placebo) were cured or had slight defects, 4 patients (2 ACV + rIFN-beta, 2 ACV + placebo) showed moderate to severe defects. There was no significant difference in favour of the additive therapy with rIFN-beta.

The authors present a case of a preterm newborn with congenital infection of herpes simplex virus type 2. The patient was treated with newly recommended high intravenous doses of acyclovir. It can be supposed that it reduces mortality, but the high morbidity continues to be a problem.

Herpes simplex virus (HSV) infections of the central nervous system (CNS) can occur within weeks after birth (neonatal HSV disease) or in childhood or adulthood [herpes simplex encephalitis (HSE)]. Most cases of neonatal HSV disease are caused by HSV type 2, whereas virtually all cases of HSE are caused by HSV type 1. Diagnostic advances made during the past decade include the application of polymerase chain reaction (PCR) technology to cerebrospinal fluid from patients with suspected HSV CNS disease to evaluate for the presence of HSV DNA. Although not foolproof, PCR is a powerful diagnostic tool that has supplanted brain biopsy as the modality of choice for diagnosing HSV CNS disease, in no small part because of the invasiveness of brain biopsy. PCR also can provide information regarding the therapeutic response to antiviral therapy. Efforts made during the past decade to improve the outcome of HSV CNS disease have focused on increased doses of intravenous acyclovir administered for longer durations of time. Although advances have been achieved, morbidity and mortality rates from neonatal HSV disease and HSE remain unacceptably high., (Copyright 2003 Elsevier Inc. All rights reserved.)

Despite early antiviral treatment, herpes simples virus encephalitis (HSVE) still remains a life-threatening sporadic disease with high mortality and morbidity. In patients and in experimental disease, chronic progressive magnetic resonance imaging (MRI) abnormalities have been found even after antiviral therapy. Secondary autoimmune-mediated and not directly virus-mediated mechanisms might play a key role for the outcome of disease. This study aimed to evaluate a possible beneficial effect of a therapy of acyclovir and corticosteroids versus acyclovir only. In a mouse model of HSVE (intranasal inoculation with 10(5) pfu [plaque-forming units] of HSV-1 strain F), a long-term MRI study was realized. Cranial MRI was performed serially at days 2, 7, 14, 21, 60, and 180 in different therapy groups: 1, saline; 2, acyclovir; 3, acyclovir, subsequently methylprednisolone; 4, sham-infected with saline. Brain viral load peaked at day 7 to decline thereafter to a low baseline value. Viral load in group 1 was significantly higher than in animals with antiviral therapy. In group 4, no viral DNA was detectable. Viral load did not differ significantly between acyclovir and acyclovir/corticosteroid-treated groups, suggesting that the use of corticosteroids in addition to acyclovir does not increase viral burden. MRI findings in untreated and acyclovir-treated animals revealed chronic progressive changes. In contrast, there was a significant reduction of the severity of long-term MRI abnormalities in acyclovir/corticosteroid-treated animals. With respect to abnormal MRI findings, this study demonstrates a clear beneficial effect of an acyclovir and corticosteroid therapy without influencing brain viral load.

Herpes simplex virus is the most common cause of acute viral encephalitis in children. Due to the variety of possible clinical manifestations the diagnosis is often overlooked in the early stages of the disease. Anti-viral therapy with acyclovir should be started whenever HSE is suspected. When there is further deterioration under virostatic therapy, a brain biopsy should be performed to verify the diagnosis. But even when the adequate medical therapy is established, massive brain edema and brain shift resulting in tentorial herniation can develop. Up to now the reported mortality of these patients is still around 30%. Here we report on a child with severe necrotizing herpes simplex encephalitis who developed severe tentorial herniation due to a right-sided mass lesion. The patient's status markedly improved after decompressive anterior temporal lobe resection. To our knowledge a similar case has not yet been reported in the literature. We suggest that anterior temporal lobe resection and decompressive craniotomy is of benefit in selected cases with tentorial herniation because both decompression and reduction of infectious material can be achieved.

This case report demonstrates the course of herpes simplex virus cerebritis in a patient aged 7 years 2 months who presented with non-specific symptoms followed by an epileptic attack. Subcortical, bilateral opercular and bilateral thalamic lesions were detected, but the temporal and inferior frontal lobes were spared. The patient developed anarthria, impairment of mastication and swallowing consistent with operculum syndrome. Diagnosis was made by magnetic resonance imaging and elevation of oligoclonal antibodies specific to herpes simplex virus in cerebrospinal fluid after an unexpectedly negative polymerase chain reaction test.

Twenty eight children with herpes simplex encephalitis were followed up for a mean of 5.5 years. Two children died and 26 survived, of whom 16 were left with no neurological sequelae and 10 had persistent neurological sequelae. Mean (SD) Glasgow coma score was significantly lower in the patients with neurological sequelae (7.7 (1.5)) and the patients who died (4.5 (0.7)), compared with the patients without neurological sequelae (11 (1.7)).

Purpose: To evaluate the utility of an assay based on a polymerase chain reaction (PCR) of cerebrospinal fluid in the management of patients with suspected herpes simplex encephalitis., Methods: A decision model was constructed and used to compare a PCR-based approach with empiric therapy. Inputs required by the model included the sensitivity (96%) and specificity (99%) of PCR (derived from review of the literature), the prevalence of herpes simplex encephalitis (5%, based on the actual prevalence at Barnes Hospital among patients treated empirically with acyclovir), the outcomes for patients with and without herpes simplex encephalitis (derived from clinical studies of the Collaborative Antiviral Study Group and the actual experience at Barnes Hospital), and the average duration of empiric acyclovir therapy for patients with possible herpes simplex encephalitis (5.3 days based on actual experience at Barnes Hospital)., Results: Using these input values, the decision model predicted better outcomes with empiric therapy. However, low rates of inappropriate discontinuation of empiric therapy in patients with herpes simplex encephalitis or improved diagnosis and outcome resulting from a negative PCR assay result in patients without herpes simplex encephalitis led to better outcomes with the PCR-based approach. The PCR-based approach was associated with 9.2 fewer doses of acyclovir per patient., Conclusion: Based on the decision model using conservative assumptions, a PCR-based approach can yield better outcomes and reduced acyclovir use compared with empiric therapy.

Purpose: Acute retinal necrosis (ARN) syndrome is associated with members of the herpes virus family, but the mechanisms of infection remain unclear. The purpose of this study is to report a unique case of acute retinal necrosis syndrome associated with herpetic encephalitis in order to elucidate possible factors involved in herpetic central nervous system disease., Method: Case report., Results: A 64-year-old woman who developed acute herpes simplex virus encephalitis associated with bilateral acute retinal necrosis syndrome after craniotomy for resection of a suprasellar craniopharyngioma is presented. The results of lumbar puncture, magnetic resonance imaging, and ophthalmologic examination are consistent with herpetic infection. The origin of acute retinal necrosis syndrome and the association of acute retinal necrosis syndrome with encephalitis are reviewed., Conclusions: After craniotomy, we hypothesize reactivation of previously latent herpes simplex virus in the area of the inferior frontal lobe and optic chiasm. Reactivated virus may have migrated to the retina by axonal transport, through the optic nerves, to produce the acute retinal necrosis syndrome.

Androstenediol (AED) is a metabolic product of dehydroepiandrosterone (DHEA), an adrenal steroid known to possess immunomodulatory characteristics. The present study was undertaken to assess the efficacy of AED treatment in mice ocularly infected with herpes simplex virus type 1 (HSV-1). The subcutaneous administration of 320 mg/kg AED 4 h prior to viral inoculation was found to enhance the survival of HSV-1-infected mice while lower doses (32.0-100.0 mg/kg) were without effect. However, there were no apparent differences in the viral load in the eye or trigeminal ganglion (TG) 3 or 6 days post infection (p.i.) in vehicle- or AED (320 mg/kg)-treated mice. Likewise, there were no differences in the expression of cytokine or chemokine mRNAs in the eyes or TG early (i.e., 3 days p.i.) following infection. However, by 6 days p.i., there was a significant increase in the expression of the chemokines IP-10, MCP-1, and RANTES and the cytokines interleukin-6 (IL-6) and interferon-gamma (IFN-gamma) in the AED (320 mg/kg)-treated mice compared to vehicle-treated controls as determined by reverse transcription (RT)-polymerase chain reaction (PCR) and quantitative PCR (for IFN-gamma). Likewise, there was a corresponding increase in IFN-gamma and IL-2 but not IL-12 protein in the TG of AED-treated mice 6 days p.i. AED-treatment also induced a rise in splenic natural killer activity in a dose- and time-dependent fashion. Collectively, these results suggest that the protective effect following subcutaneous administration of AED is associated in a rise in selective type 1 cytokines (IL-2 and IFN-gamma) as well as natural killer activity.

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.

We reported a 5-year-old boy with acute encephalitis due to suspected herpes simplex infection, who developed confusion, agitation and insomnia during intravenous administration of acyclovir. He recovered from these neuro-psychiatric symptoms two days after the cessation of acyclovir. The same symptoms recurred two days after its re-administration and resolved on the next day of the second cessation of the drug. Electroencephalogram (EEG) showed periodic lateralized epileptiform discharges (PLEDs) on hospital day 16, which disappeared on hospital day 27, suggesting that neurotoxicity of acyclovir may induce PLEDs. Although acyclovir is useful for the treatment of herpes simplex and varicella-zoster virus infections, we have to pay attention to its neurotoxicity.

Patients with herpes simplex encephalitis generally have altered mental function and are rarely able to provide a good medical history. Failure to diagnose this serious disease may result in permanent neurologic damage or death of the patient. Rapid institution of newer diagnostic tests such as polymerase chain reaction for herpes simplex virus is essential for proper diagnosis. Parenteral acyclovir therapy is efficacious but, clearly, improvements in prevention and therapy are still important research goals. This review is meant to inform physicians and nurses concerning the current diagnosis and management of this treatable but potentially fatal illness.

Background: The development of antiviral therapy increases the need for rapid, sensitive and reliable methods or combination of methods for diagnosis and monitoring herpes simplex encephalitis, HSE., Objectives: Evaluation of diagnostic performance of three successively developed HSV PCR assays when combined with a new capture ELISA for HSV intrathecal antibody production (ITT)., Study Design: During a 3.6 year period a total of 4.206 CSF and serum samples from about 4.140 hospitalized patients with a tentative diagnosis of HSE were analyzed by a new ELISA for ITT. 1.962 CSF samples were examined also by PCR. Clinical signs and symptoms and additional tests were obtained on all ITT and/or PCR positive patients. In 1993 the PCR was a double PCR. In 1994 the PCR was a single PCR with internal inhibition control. Positive samples were confirmed by a different confirmative PCR to increase the specificity. From 1995 the PCR was as in 1994 but samples were no longer divided in the serology routine laboratory., Results: A total of 33 HSE cases was found (incidence 1.8 HSE per million people). All patients were treated with aciclovir. Three patients died, 9 patients had primary infection, 2 patients had HSE previously, and 2 patients relapsed. Only 11 patients recovered satisfactory. Of all 37 positive ITT 7 were unlikely positive. False positive PCR was seen in 1993 and 1994, due to sample-to-sample contamination during division of samples, but was not seen since 1995 when this procedure was changed. The test results depended on the state of the disease. Thus, the sensitivity, specificity, PPV and NPV for ITT were highest when performed more than 1 week after debut of symptoms whereas these values were highest using PCR within the first week., Conclusion: Routine PCR diagnosis of HSE type 1 and 2 is a highly sensitive and specific method that should be performed together with serological ITT to cover the whole time span from debut of symptoms to several weeks after hospitalization.

We present a case of subacute focal encephalitis in a 62-year-old man whose clinical manifestations, neuroradiological findings and histopathological features mimicked those of a patient with malignant lymphoma of the central nervous system (CNS). In addition to routine histopathological examination, extensive studies including serological examination for encephalitic viruses, immunohistochemistry and DNA analysis were required to distinguish focal encephalitis from lymphoma of the CNS, clinical entities which differ in treatment.

Objectives: The frequency and characteristics of the long term sequelae of herpes simplex encephalitis were assessed after treatment with acyclovir., Methods: Patients were included if they were treated with acyclovir and the diagnosis of herpes simplex encephalitis was confirmed by culture of herpes simplex virus (HSV) from the brain, an increase in the CSF HSV antibody titre, or detection of HSV deoxyribonucleic acid in the CSF. Each patient's medical records were reviewed and surviving patients were interviewed and examined., Results: A diagnosis of herpes simplex encephalitis was confirmed in 42 patients. Five patients (12%) died in the first month. Three patients (7%) had severe neurological sequelae and died after a longer interval. All but one of the 34 surviving patients had neurological symptoms, an abnormal neurological examination, or both. Twenty patients (48%) performed everyday activities as well as before herpes simplex encephalitis; nine patients (21%) were living independently, but were functioning at a lower level than before the illness; and five patients (12%) had a severe neurological deficit. Twenty nine of the 34 survivors were assessed six months to 11 years after herpes simplex encephalitis. The most common long term symptoms were memory impairment (69%), personality and behavioural abnormalities (45%), and epilepsy (24%). Short term memory impairment (70%), anosmia (65%), and dysphasia (41%) were the most common signs., Conclusions: Although acyclovir has reduced the mortality of herpes simplex encephalitis, 30% of this group of patients either died or had a severe neurological deficit. The other 70% of the patients regained independence in activities of daily living, but most of these people had persistent neurological symptoms, signs, or both.

This study sought to produce a cognitive profile of herpes simplex encephalitis (HSE) survivors from a large group of definitively diagnosed, acyclovir-treated participants. Results from 22 adults who underwent a battery of neuropsychological tests indicated anterograde memory dysfunction to be the most severe and common deficit (although the variation was great), with less severe and less frequent impairments in the areas of retrograde memory, executive functions, and language functioning. Overall, neuropsychological outcome was unimpaired in six participants, mildly impaired in thirteen, moderately impaired in one, severely impaired in two. Older participants and those with a lower level of consciousness before the start of treatment produced poorer scores on certain aspects of cognitive outcome (p < 0.05). A significantly better cognitive outcome was found in participants for whom there was a short delay (fewer than 5 days) between symptom onset and acyclovir treatment compared with those participants for whom there was a longer delay. The two children in the study had disparate results on most tests, the exception being those assessing memory functioning on which both children had scores at population norms. On a naming task designed to explore category-specific knowledge deficits, the adults as a group made more errors on pictures of living things than nonliving things (matched pair-wise for word frequency and visual familiarity), although this difference disappeared on a smaller subset of pictures also matched for visual complexity.

We used a nested polymerase chain reaction assay to quantitate the number of viral copies in cells of CSF of eight patients with herpes simplex virus encephalitis (HSVE). The viral load was monitored in serial CSF samples during the course of disease and correlated to clinical symptoms, radiologic manifestations, efficacy of acyclovir treatment, and overall clinical outcome. Before treatment, HSV type 1 (HSV-1) copies were detected at a mean value of 1,786/10(5) (range, 5 to 8,333/10(5) cells; median, 81/10(5) cells). During therapy, HSV-1 DNA decreased gradually to a mean value of 6 copies/10(5) cells (range, 0 to 33 copies/10(5) cells; median, 0 copies/10(5) cells) within 6 to 21 days and disappeared or was barely detectable before treatment completion in most cases. The HSV-1 burden in the CSF did not clearly correlate with the severity of clinical signs or the degree of cranial imaging findings and overall outcome. Quantitation of HSV-1 copies allows rapid and reliable monitoring of antiviral therapy. The absence of a clear correlation between viral load in the CSF and morbidity may suggest a role for indirect mechanisms of brain injury in HSVE.

Protection and therapy of NMRI mice with experimental herpes virus (HSV-1) encephalitis were investigated using heat-killed, lyophilized Propionibacterium avidum KP-40 (PA) and/or the herpes-specific antiviral substance acyclovir (ACL) as immunomodifier. Poly I:C as a potent macrophage activator was used as a reference compound for PA. Survival of experimental HSV-1 infections during 18 days following the inoculation of viruses was used for the evaluation of the effects of immunotherapy. The applied model of HSV-1 infection resulted in a mortality of about 87% of NMRI mice at 7-16 days following the inoculation of the virus. Treatment with ACL or Poly I:C at the day of HSV-1 infection resulted in a lowering of the mortality rate to about 40% (p < 0.05). PA applied 4 days before HSV-1 infection lowered the mortality rate to 27%, while treatment 2 days after infection was less effective and the mortality rate reached 44%, although still being significantly lower (p < 0.01) than in untreated controls. A combined treatment with ACL and PA on the day of HSV-1 infection protected 93% of animals against the development of clinically detectable herpesvirus encephalitis.

A case of acute encephalopathy with selective bilateral symmetrical striatal lesions is reported. The patient was a previously healthy 4-year-old boy who became obtunded after a febrile illness and fell into a state of delirium with severe pain in the feet. He showed abnormal postures: hyperextension of the neck and upper limbs and extreme flexion of both lower limbs, and abnormal involuntary movements of the limbs: tremor, athetotic movement and right hemiballismus. Analysis of serum antibody titres suggested recent primary infection of herpes simplex type 1 (HSV-1). Cranial T2-weighted magnetic resonance imaging (MRI) demonstrated areas of high-signal intensity involving the whole basal ganglia bilaterally. He showed rapid clinical improvement after the initiation of corticosteroid therapy; complete clinical recovery was noted 3 months after the onset. Serial MRI studies demonstrated a rapid reduction of the lesions, resulting in only slight T2-hyperintense areas in both caudate nuclei. The pathogenesis of the disorder remains unknown, though an autoimmune mechanism has been speculated. The clinical and laboratory findings in this case suggested a possible role of HSV-1 in the pathomechanism of the disorder and a beneficial effect of early corticosteroid therapy.

We describe a preterm neonate delivered by cesarean section with intact membranes who had herpes simplex virus (HSV) encephalitis at 9 days of age and whose twin with a separate amniotic membrane that was pierced for insertion of a fetal scalp electrode simultaneously had HSV infection of the scalp. That no histologic evidence of HSV infection was seen in either placenta suggests the potential for HSV penetration of intact amniotic membranes as a mode of transmission of HSV to the neonate. Although the extent of risk of HSV infection in a second twin remains unclear, we believe that when infection is suspected in one of a set of twins, appropriate cultures should be obtained from both infants, and acyclovir therapy should be considered for both.

Herpes simplex encephalitis is an important disease characterized by focal haemorrhagic necrosis of the temporal and frontal lobes of the brain. The mortality rate may be as high as 70% of untreated cases. Isolation of the virus from brain tissue is the most reliable means of diagnosis. Although some non-invasive diagnostic modalities have been investigated, none is as reliable as brain tissue sampling. Despite acceptance that acyclovir sodium is the most effective drug for treatment, there is not a consensus on the dosage and duration of the antiviral therapy because some patients fail to respond and sometimes there is recurrence following therapy. We report a case of encephalitis in a previously normal host who died after a 13-day course of acyclovir therapy with isolation of HSV-type 1 from the brain post mortem.

Acute herpes simplex encephalitis (HSE) has a grave outcome, and detection of prognostic features is of clinical importance. Thirty patients with HSE were assessed in a retrospective study. Diagnosis was confirmed by serological methods using the indirect immunofluorescence technique (IFT). Antiviral treatment was given to 23 of the patients. Focal convulsions were more frequent in patients below 18 years of age, while confusion and memory disturbances were prevalent among patients above 18. The final outcome was influenced by the degree of severity of the disease at the peak and the state of consciousness and duration of disease prior to the initiation of anti-viral treatment. No correlation was found between antibody levels in serum or in CSF and the outcome. We conclude that the clinical degree of severity the duration of illness prior to treatment and state of consciousness at the initiation of anti-viral treatment are of prognostic importance.

We describe a newborn patient with herpes simplex infection localized to the central nervous system. The diagnosis was suspected on clinical grounds and it was corroborated by tissue culture isolation of the virus and by herpes simplex glycoprotein B DNA detection by PCR in cerebrospinal fluid. We describe the clinical manifestations of this patient and we present some considerations regarding pathogenesis, diagnosis, prognosis and treatment of this viral infection in the newborn period.

Herpes simplex encephalitis (HSE) is a life-threatening condition with high mortality as well as significant morbidity in survivors. In most cases herpes simplex virus type 1 (HSV-1) is responsible for the diseases, however, the type 2 virus (HSV-2) is involved in 4-6% of cases. Primary HSV infection is identified in only one-third of patients with HSE. The majority of cases are recorded in adults with recurrent HSV infection who are already seropositive for HSV at the onset of symptoms, but only 6-10% of these patients have a history of labial herpes. Acute focal, necrotizing encephalitis with inflammation and swelling of the brain tissue are consistent features of the pathology of HSE. HSV-induced cytolysis certainly damages neurones, oligodendrocytes and astrocytes, but the role of cellular and humoral immunopathology is important. A complex network of cytokines seems to be active in regulating the local immune response and inflammation during and after HSE. Brain biopsy, serological analysis of intrathecal HSV antibodies and detection of HSV-DNA in the cerebrospinal fluid (CSF) are all useful techniques to confirm the aetiology of HSE. Neurodiagnostic tests which support a presumptive diagnosis of HSE include: CSF analysis, electroencephalography, computer-assisted tomography and magnetic resonance imaging. Although aciclovir is the treatment of choice in HSE, mortality and morbidity still remain problematic. Long-term follow-up indicates that intrathecal cellular and humoral activation persist in HSE.

The effect of para-amino benzoic acid (PABA) on the virus of Herpes simplex (VHS-1, strain L2) was studied and it was shown to be active in vitro and in vivo. The action of PABA was virucidal in the culture of the cell-free virus-containing material. It lowered the death rate of the laboratory mice with experimental herpetic encephalitis (intraperitoneal contamination) at the average by 40 per cent and increased the mean life-span of the animals significantly decreasing the virus titre in the mouse brain. PABA was not toxic with respect to the Vero cells thus not preventing the virus-induced cytopathic effect in the cultures. However, PABA showed high ability to potentiate the antiherpetic action of acyclovir (Zovirax, acycloguanosine) in the infected cultures when acyclovir was used in inactive concentrations.

We report five children who had recurrent central nervous system signs after conventional acyclovir therapy for herpes simplex encephalitis. Secondary exacerbation was characterized clinically by severe ballismic movement disorder in all five children, associated with fever, impairment of consciousness, and seizures. Biologic analysis in all children and magnetic resonance imaging and neuropathology studies of the brain in three cases were compatible with inflammatory reaction. In contrast, all viral cultures remained negative, herpes simplex virus antigen in one child and DNA tested by polymerase chain reaction in four children were undetectable in the first samples of cerebrospinal fluid during the relapse, suggesting a postinfectious, immune-mediated mechanism of relapse in these patients.

We report a case of alexia without either agraphia or hemianopia following herpes simplex encephalitis. The patient had a temporal lobe lesion with involvement of the occipitotemporal gyrus. This is an unusual cause of alexia without agraphia. The location of the lesion supports the view that transcallosal fibers from the right hemisphere to the left angular gyrus course inferior to the posterior horn of the left lateral ventricle and pass close to the left occipitotemporal gyrus.

Herpes simplex encephalitis in adults and young patients carries a high mortality and morbidity. Its presentation may be nonspecific, sometimes hampering early diagnosis. Two young children are reported with herpes simplex encephalitis in whom the operculum syndrome was an outstanding feature. This syndrome is caused by focal, bilateral cortical damage to the anterior opercular regions resulting in anarthria and impairment of mastication and swallowing. After initiation of treatment with acyclovir in the early stage of the disease, the outcomes in both patients were characterized by good general recovery with persistence of deficits of speech, mastication, and swallowing, more pronounced in the patient who was comatose during the illness. Early recognition of the operculum syndrome as a presenting feature of herpes simplex encephalitis may expedite the diagnosis and thereby improve the prognosis.