Herpes Simplex Virus In Cerebrospinal Fluid Research Articles

Herpes Simplex Virus Encephalitis With Initial Negative Polymerase Chain Reaction in the Cerebrospinal Fluid: Prevalence, Associated Factors, and Clinical Impact.

To describe the prevalence, associated factors, and clinical impact of an initial negative herpes simplex virus (HSV) polymerase chain reaction (PCR) in critically ill patients with PCR-proven HSV encephalitis. Retrospective multicenter study from 2007 to 2017. Forty-seven French ICUs. Critically ill patients admitted to the ICU with possible/probable acute encephalitis and a positive cerebrospinal fluid (CSF) PCR for HSV. None. We included 273 patients with a median Glasgow Coma Scale score of 9 (6-12) at ICU admission. CSF HSV PCR was negative in 11 cases (4%), exclusively in lumbar punctures (LPs) performed less than 4 days after symptoms onset. Patients with an initial negative PCR presented with more frequent focal neurologic signs (4/11 [36.4%] vs 35/256 [13.7%]; p = 0.04) and lower CSF leukocytosis (4 cells/mm3 [3-25 cells/mm3] vs 52 cells/mm3 [12-160 cells/mm3]; p < 0.01). An initial negative PCR was associated with an increased delay between LP and acyclovir treatment (3 d [2-7 ] vs 0 d [0-0 d]; p < 0.01) and was independently associated with a poor neurologic outcome at hospital discharge (modified Rankin Scale score ≥ 4) (adjusted odds ratio, 9.89; 95% CI, 1.18-82.78). In severe herpes simplex encephalitis, initial negative CSF HSV PCR occurred in 4% of cases and was independently associated with worse neurologic outcome at hospital discharge. In these patients, a systematic multimodal diagnostic approach including early brain MRI and EEG will help clinicians avoid delayed acyclovir initiation or early inappropriate discontinuation.

Determining Normative Values for Cerebrospinal Fluid Profiles in Infants.

Previous studies of reference values for cerebrospinal fluid (CSF) profiles have been limited by small sample size and few exclusion criteria. To determine age-specific normative CSF white blood cell count (WBC), glucose, and protein values in infants ≤90 days old. Performed a retrospective cross-sectional study of infants ≤90 days old who had a diagnostic lumbar puncture between 2008 and 2016. Infants with bacterial meningitis, bacteremia, UTI, positive CSF herpes simplex virus polymerase chain reaction (PCR) result, traumatic lumbar puncture, ventriculoperitoneal shunt, prematurity, recent seizure, previous antibiotic use, and history of a complex chronic condition were excluded for calculations to determine normative values. Data on demographics and CSF values (WBC with differential, protein, glucose, enterovirus PCR) were collected. CSF values were compared by age and by enterovirus PCR results using Kruskal-Wallis and Wilcoxon rank tests. A total of 1029 out of 2000 patients were included and divided into 3 age groups: 0 to 28 days, 29 to 60 days, 61 to 90 days. CSF WBC values were significantly greater for 0- to 28-day old infants (median: 3, 95th percentile: 14) than for 29- to 60-day and 61- to 90-day old infants (median: 2 and 2; 95th percentile: 7 and 11, respectively) (P < .001). With each month of life, the median CSF protein significantly decreased and glucose significantly increased. In the CSF WBC differential, monocytes were found to be prevalent. We determined age-specific normative components for CSF profile values for infants 0 to 90 days.

Factors Associated With HSV PCR CSF Testing and Empiric Acyclovir Therapy in Young Febrile Infants.

Herpes simplex virus (HSV) infection in infants is a devastating disease with an often subtle presentation. We examined cerebrospinal fluid (CSF) HSV PCR (polymerase chain reaction) testing and empiric acyclovir therapy in young febrile infants. Chart review identified hospitalized infants aged ≤60 days with fever ≥38°C who had undergone lumbar puncture. Previously published criteria were used to define patients at high risk for HSV. Primary outcomes were CSF HSV PCR testing and empiric acyclovir therapy. Of 536 febrile infants, 23% had HSV testing; empiric acyclovir was started in 15%. HSV testing and therapy were associated with younger age, seizure, maternal vaginal lesions, postnatal HSV contact, vesicles, poor tone, CSF pleocytosis, and enteroviral testing. Sixty-two percent of high-risk infants did not undergo HSV testing, and 75% did not receive acyclovir. High-risk infants were untested and untreated at relatively high rates. Evidence-based criteria to guide HSV testing and treatment are needed.

Association of Herpes Simplex Virus Testing with Hospital Length of Stay for Infants ≤60 Days of Age Undergoing Evaluation for Meningitis.

Although neonatal herpes simplex virus (HSV) causes significant morbidity, utilization of the cerebrospinal fluid (CSF) HSV polymerase chain reaction (PCR) test remains variable. Our objective was to examine the association of CSF HSV PCR testing with length of stay (LOS) in a 20-center retrospective cohort of hospitalized infants aged ≤60 days undergoing evaluation for meningitis after adjustment for patient-level factors and clustering by center. Of 20,496 eligible infants, 7,399 (36.1%) had a CSF HSV PCR test performed, and 46 (0.6% of those tested) had a positive test. Infants who had a CSF HSV PCR test performed had a 23% longer hospital LOS (incident rate ratio 1.23; 95% CI: 1.14-1.33). Targeted CSF HSV PCR testing may mitigate the impact on LOS for low-risk infants.

HERPES SIMPLEX VIRUS ENCEPHALITIS IN AN 8 YEARS OLD WITH NORMAL CEREBROSPINAL FLUID AND NEGATIVE HERPES SIMPLEX VIRUS POLYMERASE CHAIN REACTION - A CLINICAL AND RADIOLOGICAL DIAGNOSIS

Herpes simplex encephalitis is known to cause significant morbidity and mortality both in children and adults. Polymerase chain reaction (PCR) for herpes simplex virus (HSV) in cerebrospinal fluid (CSF) is the diagnostic modality accepted worldwide. However, a negative CSF HSV PCR result should always be interpreted in the context of the timing of specimen collection and also considering the clinical picture. We report a case of HSV encephalitis in an 8-year-old male child whose initial CSF picture was normal and CSF for HSV PCR was also negative. However, the magnetic resonance imaging brain findings and clinical profile along with a marked response to acyclovir therapy started very early in the course of illness left little doubts about the diagnosis.

Comparing molecular quantification of herpes simplex virus (HSV) in cerebrospinal fluid (CSF) with quantitative structural and functional disease severity in patients with HSV encephalitis (HSVE): Implications for improved therapeutic approaches

BackgroundHerpes Simplex Virus encephalitis (HSVE) is a devastating disease of all ages. Rigorous studies correlating viral load with neuroradiological and clinical severity have not been performed, particularly in neonates. Understanding these relationships may improve therapies. ObjectivesTo correlate molecularly quantified HSV in cerebrospinal fluid (CSF) and disease severity. Study DesignHSV loads (VL) were evaluated by real-time PCR from the CSF of 33 patients (20 neonates, 5 children, 8 adults) with HSVE. We studied relationships between CSF VL and structural and volumetric brain abnormalities (MRI); hospital morbidity; and discharge and long-term (>3 month) clinical outcomes. ResultsInitial CSF VL did not differ in neonates vs non-neonates (median 4.6 vs 5.1 log10 copies/mL, p = 0.75). Initial CSF VL was higher in neonates with HSV-2 vs HSV-1 (median 4.8 vs 3.2 log10 copies/mL, respectively, p = 0.02). Persistently detectable DNA in CSF despite acyclovir trended towards higher odds of unfavorable outcome at discharge for neonates [0.87 (CI 0.75–1), p = 0.07]. Initial VL correlated with higher CSF protein concentrations for the cohort and for neonates (p = 0.03 and 0.01, respectively), but not with lesion volume or subarachnoid exposure of involved brain (p all >0.05), hospital morbidity (p all >0.05), nor with higher odds of unfavorable discharge or long-term outcomes for the cohort [OR = 0.9(CI 0.5–1.6), p = 0.72; OR = 1.0(CI 0.5–1.8), p = 0.9] or for neonates [OR = 1.3(CI 0.5–3.3), p = 0.57; OR = 2.3(CI 0.7–8), p = 0.2]. ConclusionsInitial HSV VL did not predict neuroradiological or clinical outcomes in patients with HSVE, suggesting host inflammatory factors contribute to disease in treated patients with good viral clearance.

The spectrum of aseptic central nervous system infections in southern Germany - demographic, clinical and laboratory findings.

Aseptic infections of the central nervous system (CNS) are frequently observed in Germany. However, no study has systematically addressed the spectrum of aseptic CNS infections in Germany. Data on 191 adult patients diagnosed from January 2007 to December 2014 with aseptic meningitis or encephalitis/meningoencephalitis at our hospital were collected by chart review and analyzed for demographic, clinical and laboratory findings. Patients were stratified according to the causative virus and findings were compared between groups. In our cohort, meningitis was caused in 36% by enterovirus (EV), 15% by herpes simplex virus (HSV), 12% by varicella zoster virus (VZV) and 5% by tick borne encephalitis (TBE). Encephalitis/meningoencephalitis was caused in 13% by HSV, 13% by VZV, and three out of 11 tested patients were positive for TBE. The highest incidence of EV infections was between 25 and 35 years and of HSV infections between 30 and 60 years. VZV infections had a bimodal distribution peaking below 30 and above 70 years. VZV and EV infections were more frequently observed during summer, whereas HSV infections showed no seasonal preference. Inflammatory changes in cerebrospinal fluid (CSF) were highest in HSV and lowest in EV infections. Polymerase chain reaction tests for HSV, VZV and EV in CSF and TBE serology determined the causative virus in over 60% of tested patients. The age of affected patients, seasonal distribution, disease course and inflammatory changes in CSF differ between groups of patients affected by the most common viral infections.

Criteria to Screen Molecular Tests for the Diagnosis of Herpes Simplex Virus in the Central Nervous System have no Propensity to Harm

Objectives: Investigators have ruled out herpes simplex virus (HSV) infection without the detection of herpes simplex deoxyribonucleic acid in cerebrospinal fluid (CSF) (i.e., HSV polymerase chain reaction [PCR]) by laboratory (normal CSF white blood cell count and protein) and clinical criteria (age ≥2 years, no history of human immunodeficiency virus or solid-organ transplant). Compared to HSV PCR of all samples, the algorithm saves money in test costs and may decrease exposure to acyclovir by illustrating the low probability that the patient has HSV. Concern exists that algorithm use may cause harm through alteration of empiric acyclovir treatment in patients with true HSV central nervous system infection. Methods: All Department of Veterans Affair's patients with a positive HSV PCR of the CSF between 2000 and 2013 were identified and their medical records reviewed to determine the extent and possible impact of omitted HSV PCR testing by the algorithm. Results: Of 6357 total results, 101 patients had a positive CSF HSV PCR in the study period. Among the positive CSF HSV PCR results, the algorithm excluded 7 (7%) from PCR testing. Record review indicated these seven patients not tested by the algorithm with a positive CSF HSV PCR were considered by their attending physician not to have active HSV. Conclusion: The algorithm to screen HSV tests had no propensity to harm.

Clinical and Laboratory Markers and Risk for Cerebrospinal Fluid Herpes Simplex Virus (HSV) Deoxyribonucleic Acid Persistence HSV in Neonatal Disseminated and Central Nervous System Infection

Clinical and Laboratory Markers and Risk for Cerebrospinal Fluid Herpes Simplex Virus (HSV) Deoxyribonucleic Acid Persistence HSV in Neonatal Disseminated and Central Nervous System Infection

Managing atypical and typical herpetic central nervous system infections: results of a multinational study

There have been many studies pertaining to the management of herpetic meningoencephalitis (HME), but the majority of them have focussed on virologically unconfirmed cases or included only small sample sizes. We have conducted a multicentre study aimed at providing management strategies for HME. Overall, 501 adult patients with PCR-proven HME were included retrospectively from 35 referral centres in 10 countries; 496 patients were found to be eligible for the analysis. Cerebrospinal fluid (CSF) analysis using a PCR assay yielded herpes simplex virus (HSV)-1 DNA in 351 patients (70.8%), HSV-2 DNA in 83 patients (16.7%) and undefined HSV DNA type in 62 patients (12.5%). A total of 379 patients (76.4%) had at least one of the specified characteristics of encephalitis, and we placed these patients into the encephalitis presentation group. The remaining 117 patients (23.6%) had none of these findings, and these patients were placed in the nonencephalitis presentation group. Abnormalities suggestive of encephalitis were detected in magnetic resonance imaging (MRI) in 83.9% of the patients and in electroencephalography (EEG) in 91.0% of patients in the encephalitis presentation group. In the nonencephalitis presentation group, MRI and EEG data were suggestive of encephalitis in 33.3 and 61.9% of patients, respectively. However, the concomitant use of MRI and EEG indicated encephalitis in 96.3 and 87.5% of the cases with and without encephalitic clinical presentation, respectively. Considering the subtle nature of HME, CSF HSV PCR, EEG and MRI data should be collected for all patients with a central nervous system infection.

Epidemiology and Outcome in Neonatal and Pediatric Herpes Simplex Encephalitis: A 13-Year Experience in a Singapore Tertiary Children's Hospital

Herpes simplex encephalitis (HSE) remains one of the most devastating infections of the central nervous system in children despite available antiviral therapy. Our aim was to determine the clinical epidemiology and long-term neuro-developmental outcome of neonates and children admitted to our hospital with proven HSE. Patients with HSE during November 1998 to December 2011 were identified from discharge and laboratory records and data collection was done by retrospective review of their case notes. HSE was proven by culture or polymerase chain reaction (PCR) or by a positive Herpes simplex virus (HSV)–specific intrathecal antibody. We identified 13 patients during the study period: nine neonates and four older children, all of whom were treated with intravenous acyclovir. In the neonatal cohort, three (33%) presented with seizures and only four (44%) had vesicles. The initial cerebrospinal fluid (CSF) HSV PCR was positive in seven (78%) and HSV type 2 was the most common. Repeat CSF study showed HSV positivity of 100%. Two (22%) neonates died and three (43%) had long-term neurodevelopmental sequelae. Developmental delay, focal neurological deficit, and cognitive deficit were among the most frequent neurological sequelae noted. In the pediatric cohort, three children (75%) had positive CSF HSV PCR and seizures. One (25%) died and two of the three survivors (67%) had neurodevelopmental sequelae. Early CSF studies may be negative in HSE, so a repeat CSF analysis should be considered, particularly in neonates. Early administration of acyclovir could prevent adverse outcomes in HSE.

A nine-week-old girl with fever and seizures.

CASE PRESENTATION A nine-week-old girl presented to the emergency department with a 12 h history of fever and a 1 min generalized tonic-clonic seizure. Review of systems was otherwise negative. Her two-year-old sister experienced a fever and oropharyngeal ulcers two weeks before. On physical examination, she was febrile to 39.2°C rectal, but with otherwise normal vital signs. She was well-appearing and her examination was normal, including the neurological examination. Blood, urine and cerebrospinal fluid (CSF) specimens were obtained, and intravenous ceftriaxone, vancomycin and acyclovir were started. Laboratory investigations showed a normal complete blood cell count and transaminase levels. CSF examination revealed 55 white blood cells/μL (51% monocytes, 37% lymphocytes, 12% neutrophils), 7 red blood cells/μL, normal protein (0.35 g/L) and normal glucose (2.9 mmol/L). An electroencephalogram revealed active epileptiform activity over the right centroparietal regions. She was admitted to the pediatric ward and underwent magnetic resonance imaging of her head, which revealed multifocal nonenhancing lesions in the subcortical white matter of the right precentral gyrus, right cingular gyrus, right corticospinal tract, as well as the right internal capsule and thalamus (Figure 1). Bacterial cultures were without growth and antibiotics were discontinued after 48 h. CSF herpes simplex virus (HSV) 1 and HSV 2 polymerase chain reaction (PCR) (LightCycler 2.0 HSV 1/2 qualitative kit [Roche Diagnostics, Canada]) and enterovirus PCR were also negative. Repeat lumbar puncture and blood testing were performed on hospital day 3. DIAGNOSIS Both the CSF and blood samples obtained on hospital day 3 returned positive results for HSV-1 using PCR, confirming a diagnosis of HSV encephalitis. Extracted DNA from the initial CSF was re-tested using a different laboratory-developed HSV 1 and HSV 2 quantitative realtime PCR assay at another reference laboratory. In retrospect, the initial CSF specimen was positive for HSV 1 (2,675 copies/mL) using this assay, as were the second CSF specimen (21,905 copies/mL) and the blood sample (12,089 copies/mL).

Plasma and Cerebrospinal Fluid Herpes Simplex Virus Levels at Diagnosis and Outcome of Neonatal Infection

To evaluate the utility of quantitative herpes simplex virus (HSV) polymerase chain reaction (PCR) levels for prognosis and management of neonatal HSV disease. Clinical and virologic data were abstracted by medical record review from neonatal HSV cases treated at Seattle Children's Hospital between 1993 and 2012. HSV PCR results from plasma (n = 47), cerebrospinal fluid (n = 56), or both (n = 40) at the time of diagnosis were available from 63 infants; 26 with skin-eye-mouth (SEM), 18 with central nervous system (CNS), and 19 with disseminated (DIS) disease. Plasma HSV PCR was positive in 78% of the infants with SEM, 64% with CNS and 100% with DIS disease. Mean plasma viral level was 2.8 log10 copies/mL in SEM, 2.2 log10 copies/mL in CNS, and 7.2 log10 copies/mL in DIS infants. The HSV levels were higher among infants who died compared with surviving infants, 8.1 log10 copies/mL (range 7.7-8.6) vs 3.8 log10 copies/mL (range 0.0-8.6), P = .001, however, level of HSV DNA in the cerebrospinal fluid or in plasma did not correlate with neurologic outcome. Dynamics of HSV clearance from plasma during high-dose acyclovir treatment showed single-phase exponential decay with a median viral half-life of 1.26 days (range: 0.8-1.51). Plasma HSV levels correlate with clinical presentation of neonatal HSV disease and mortality, but not neurologic outcome.

Herpes simplex and Ebstein Barr virus encephalitis complicated with Klüver-Bucy syndrome

Abstract A case of sixteen-year-old boy with initial herpes simplex virus (HSV) and Epstein-Barr virus (EBV) encephalitis is reported. Herpesviruses are often found in cerebrospinal fluid (CSF) along with EBV. After eradication of HSV in CSF in this case, a positive polymerase chain reaction (PCR) to EBV in CSF remained along with a severe clinical picture (segmental myoclonus and Klüver-Bucy syndrome) and worsening of brain magnetic resonance imaging (MRI) findings. Neurological and psychological improvement occurred after treatment with intravenous immunoglobulin.

Pediatric Herpes Simplex Virus Encephalitis

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 Testing in Neonates in the Emergency Department

To determine the prevalence of central nervous system (CNS) herpes simplex virus (HSV) infection in neonates evaluated in the emergency department and to identify factors associated with cerebrospinal fluid (CSF) HSV polymerase chain reaction (PCR) testing. An existing testing paradigm was then applied to determine its potential impact on testing frequency. This nested case-control study included infants aged 0 to 28 days who had lumbar puncture in the emergency department. Multivariate logistic regression was used to identify factors associated with CSF HSV PCR testing. The CSF HSV PCR testing was performed in 266 (47%) of 570 neonates. The prevalence of CNS HSV infection was 0.5% compared with 1.6% for bacterial meningitis. Performance of CSF HSV PCR testing was not associated with known HSV risk factors. Application of a known HSV testing paradigm would have reduced the proportion of infants tested by 21% without missing any of the cases of CNS HSV infection. The HSV testing remains common despite the low prevalence of HSV infection. The CSF HSV PCR testing is not well aligned with known risk factors. Future testing strategies should incorporate community HSV prevalence, known neonatal risk factors, and clinical judgment.

Sulphasalazine-induced aseptic meningitis with facial and nuchal edema in a patient with spondyloarthritis

Sulphasalazine-induced aseptic meningitis with facial and nuchal edema in a patient with spondyloarthritis

Negative association of Epstein-Barr virus or herpes simplex virus-1 with tumefactive central nervous system inflammatory demyelinating disease

Central nervous system (CNS) demyelination has been suggested to be associated with infections caused by the Epstein-Barr virus (EBV) or herpes simplex virus (HSV)-1. CNS inflammatory demyelinating disease (IDD) rarely presents as a large lesion. We evaluated samples of serum and cerebrospinal fluid (CSF) by enzyme-linked immunosorbent assay to detect recent infection with these viruses and analyzed CSF and brain specimens by polymerase chain reaction (PCR) or immunohistochemical studies for evidence of these viruses in three patients with biopsy-proven CNS IDD. The results of PCR tests for EBV and HSV in CSF or brain specimens were negative. Elevated anti-EBV or -HSV antibody levels were not found in serum or CSF in any patient. Immunohistochemical studies showed that IDD lesions were negative for latent membrane protein (LMP)-1, Epstein-Barr nuclear antigen (EBNA)-2, and EBNA noncoding RNA (EBER)-1. These results suggest a negative association between CNS IDD and EBV or HSV.

Herpes Simplex Virus Testing and Hospital Length of Stay in Neonates and Young Infants

To examine whether ordering testing of cerebrospinal fluid (CSF) for herpes simplex virus (HSV) by polymerase chain reaction (PCR) in neonates and young infants is associated with increased hospital length of stay (LOS) or increased hospital charges. This retrospective cohort study enrolled infants age <or=56 days who underwent lumbar puncture in the emergency department in 2005-2006. The primary "exposure" was CSF HSV PCR, and the primary outcomes were LOS and hospital charges. CSF HSV PCR was performed in 282 of 889 eligible infants (31.7%). The median test turnaround time was 22 hours. The median LOS was 2 days, and median hospital charge was $10 166. In multivariate analysis, CSF HSV PCR testing was associated with a LOS increase of 28% for infants age <or=28 days and 39% for infants age 29-56 days. LOS increased by 22% for every 12-hour increase in test turnaround time. CSF HSV PCR testing was associated with a 41% increase in hospital charges. In infants evaluated by lumbar puncture in the emergency department, CSF HSV PCR testing was associated with a significantly longer LOS and higher hospital charges.

HERPES SIMPLEX ENCEPHALITIS IN OLDER ADULTS

To the Editor: Herpes simplex encephalitis (HSE) is the most frequent cause of sporadic necrotizing encephalitis in adults.1,2 HSE has a bimodal distribution, with one-third of patients younger than 20 and half aged 50 and older.3,4 Nevertheless, few data have been reported about HSE in older adults.3,5 The aim of this study was to describe the characteristics of an elderly subgroup of a larger series of inpatient adults.6 Inpatients aged 65 and older with a consistent clinical profile and a positive polymerase chain reaction (PCR) for herpes simplex virus (HSV) in the cerebrospinal fluid (CSF) or compatible neuroimaging of the brain were included. A compatible clinical profile was established when patients showed symptoms or signs consistent with central nervous system dysfunction of acute or subacute onset and an altered level of consciousness or fever. Neuroimaging of the brain was considered positive in the presence of hypodense images on computed tomography (CT) or hyperintense lesions in the temporal lobes or the orbitobasal region of the frontal lobes (unilaterally or bilaterally) in T2 and fluid-attenuated inversion recovery sequences on magnetic resonance imaging (MRI). An electroencephalographic study (EEG) was defined as positive if it showed focal slow waves, spikes, or spike-waves. Functional status was measured using the Barthel Index for basic activities of daily living. Cognitive function was measured using the Pfeiffer questionnaire after 6 months of follow-up. The Charlson Index was used to measure overall comorbidity. Neurological sequelae were evaluated and measured using the modified Rankin scale (mRS) at discharge and after a follow-up period of 6 months. Patients were divided into two groups according to the mRS: good outcome (≤Grade 2) and poor outcome (≥Grade 3).7 Twelve patients were studied. Demographic and clinical characteristics, diagnostic tests, and clinical course of these patients are summarized in Table 1. No patients were at Stage 3 or higher on the Global Deterioration Scale (GDS), and no dementia had been diagnosed before admission. The temporal lobe was affected in all, and in two (16.6%) patients, the involvement was bilateral. All patients received acyclovir for a mean of 14 days (range 12–20 days), 11 (91.7%) also received antiepileptic drugs (in 7 patients as treatment and in 4 patients as prophylaxis), and five (41.7%) patients were treated with dexamethasone for intracranial hypertension. The mean duration between starting acyclovir and the first day of apyrexia was 11 days (range 3–21 days). Four patients (33.3%) required admission to the intensive care unit (ICU), all of them needing orotracheal intubation for mechanical ventilation. At discharge, nine (75%) patients were found to have poor outcome, with a hospital mortality of three (25%) patients. After 6 months, three (33.3%) patients continued to have poor outcome, without any new deaths, according to the mRS. This subgroup of elderly patients had characteristics similar to those found in other series, such as the predominance of temporal-frontal symptoms, disorientation, behavioral changes, and aphasia, reflecting the tropism for this anatomical level,2,8 but the mortality rate was higher than in the general population, in agreement with other studies that identified age as an independent prognostic factor.2–4,6 Main symptoms of neurological sequelae are neurological deficits such as aphasia, seizures, or other neuropsychological dysfunctions, especially memory disorders, which have been found to be common. Several studies have suggested that HSV-1 might be involved in the pathogenesis of Alzheimer's disease, being a susceptibility factor due to specific characteristics of the virus.9 Major symptoms observed in the current series, such as behavioral changes and disorientation, are common signs of many infectious diseases in older adults. Therefore, especially if not accompanied by seizures, many cases could be misdiagnosed as nonspecific infections, delaying the initiation of acyclovir. Because cranial CT in the emergency department has low sensitivity, if HSE is suspected, treatment with acyclovir should be started until PCR for HSV in CSF and MRI come back negative. In elderly patients with HSE, fever is usually present, and it may persist for some days, despite administration of acyclovir. HSE results in high morbidity and mortality, frequent ICU admission, and a long hospital stay. If HSE is suspected, treatment with acyclovir should not be delayed despite a normal CT. Because of the high prevalence of seizures, antiepileptic drugs, either for treatment or prophylaxis, should be used in these patients. Conflict of Interest: The editor in chief has reviewed the conflict of interest checklist provided by the authors and has determined that the authors have no financial or any other kind of personal conflicts with this paper. Author Contributions: Antoni Riera-Mestre, Ana Requena, and Sergio Martínez-Yélamos: letter design, data acquisition and interpretation, letter preparation. Carmen Cabellos: data interpretation, letter preparation. Pedro Fernández-Viladrich: critical revision of the letter. Sponsor's Role: None.