Herpes Simplex virus type 2 myeloradiculitis with a pure motor presentation in a liver transplant recipient.

In this case report, we describe the first PCR-confirmed case of HSV2 myeloradiculitis with a purely motor presentation, occurring in a 68-year-old liver transplant recipient. The patient reported ascending weakness with no sensory nor sphincteric symptoms, thereby resembling acute demyelinating inflammatory neuropathy, or Guillain-Barré syndrome. HSV2 was detected in cerebrospinal fluid by PCR, and the patient was successfully treated with intravenous Acyclovir.

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

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

Reaction of complement factors and proteasomes in experimental encephalitis.

Herpes simplex virus type 1 (HSV-1) encephalitis causes a deleterious inflammation and elevated intracranial pressure. As a step towards examining the origin of the inflammation, we here report the response of circulating proteasomes and complement factors in blood and cerebrospinal fluid (CSF) in rats infected with HSV-1. Infection was via the nasal route, with 1.1 × 104 plaque-forming units of HSV-1 strain 2762 given in one or both nostrils. A sandwich enzyme-linked immunosorbent assay was used to study the level of 26S proteasomes and their complex formation with complement factors 3 and 4. HSV-1 infection in the rat causes a complex formation between complement factors and proteasomes, which we designate compleasomes. In the first experiment, with HSV-1 given in both nostrils, compleasomes containing complement factors 3 and 4 increased significantly in both blood plasma and CSF. The concentration of proteasomes in plasma was similar in controls and infected rats (320 ± 163 vs. 333 ± 125 ng/ml). In the second experiment, with HSV-1 given in one nostril, CSF levels were 1 ± 1 ng/ml in controls and 56 ± 22 ng/ml in the HSV-1 group, whereas the total protein concentration in CSF remained the same in the two groups. The compleasome response was limited to CSF, with a highly significant difference between infected rats and controls (n = 11, p < 0.001). It was possible to mimic the reaction between proteasomes and complements 3 and 4 in vitro in the presence of ATP.

Interpretation of Cerebrospinal Fluid White Blood Cell Counts in Young Infants With a Traumatic Lumbar Puncture.

STUDY OBJECTIVE: We determine the optimal correction factor for cerebrospinal fluid WBC counts in infants with traumatic lumbar punctures. METHODS: We performed a secondary analysis of a retrospective cohort of infants aged 60 days or younger and with a traumatic lumbar puncture (cerebrospinal fluid RBC count ≥10,000 cells/mm3) at 20 participating centers. Cerebrospinal fluid pleocytosis was defined as a cerebrospinal fluid WBC count greater than or equal to 20 cells/mm3 for infants aged 28 days or younger and greater than or equal to 10 cells/mm3 for infants aged 29 to 60 days; bacterial meningitis was defined as growth of pathogenic bacteria from cerebrospinal fluid culture. Using linear regression, we derived a cerebrospinal fluid WBC correction factor and compared the uncorrected with the corrected cerebrospinal fluid WBC count for the detection of bacterial meningitis. RESULTS: Of the eligible 20,319 lumbar punctures, 2,880 (14%) were traumatic, and 33 of these patients (1.1%) had bacterial meningitis. The derived cerebrospinal fluid RBCs:WBCs ratio was 877:1 (95% confidence interval [CI] 805 to 961:1). Compared with the uncorrected cerebrospinal fluid WBC count, the corrected one had lower sensitivity for bacterial meningitis (88% uncorrected versus 67% corrected; difference 21%; 95% CI 10% to 37%) but resulted in fewer infants with cerebrospinal fluid pleocytosis (78% uncorrected versus 33% corrected; difference 45%; 95% CI 43% to 47%). Cerebrospinal fluid WBC count correction resulted in the misclassification of 7 additional infants with bacterial meningitis, who were misclassified as not having cerebrospinal fluid pleocytosis; only 1 of these infants was older than 28 days. CONCLUSION: Correction of the cerebrospinal fluid WBC count substantially reduced the number of infants with cerebrospinal fluid pleocytosis while misclassifying only 1 infant with bacterial meningitis of those aged 29 to 60 days.

Impact of an Institutional Guideline on the Care of Neonates at Risk for Herpes Simplex Virus in the Emergency Department.

BACKGROUND AND OBJECTIVES: Herpes simplex virus (HSV) is rare in neonates but carries significant morbidity and mortality in that group. Emergency department (ED) clinicians have little guidance to decide when to test for HSV and give acyclovir. We created an institutional guideline to provide guidance in patients younger than 6 weeks. Our objective was to evaluate whether guideline implementation affected the ED's decision to test for HSV, and ED use of HSV polymerase chain reactions (PCRs) and acyclovir. METHODS: We reviewed charts for patients 1 year before implementation and 1 year after implementation of our guideline. Inclusion criteria were younger than 60 days, admitted through the ED, symptom onset younger than 6 weeks, and any one of the following criteria: (1) ED blood culture obtained, (2) ED or inpatient HSV PCR obtained, and (3) ED or inpatient acyclovir treatment. Premature patients and transfer patients were excluded. We compared whether the decision to initiate HSV testing, ED use of HSV PCRs, serum alanine aminotransferase, and acyclovir use changed post-guideline implementation. RESULTS: We reviewed 173 charts pre-implementation and 129 post-implementation. We found a significant decrease in ED testing for HSV among patients who did not meet guideline criteria (P < 0.01). We saw an improvement in the use of alanine aminotransferase among patients who met criteria for testing (P = 0.02), but no change in the use of HSV PCRs or acyclovir use among tested patients. CONCLUSIONS: Guideline implementation reduced HSV evaluations in low-risk patients, but did not improve test utilization or acyclovir administration among those tested. Additional work is needed to improve guideline utilization.

Simultaneous detection of herpes simplex virus 1 and 2 in the cerebrospinal fluid of a patient with seizures and encephalitis.

We report a case of a 62-year-old female with seizures and encephalitis. Molecular testing of the patient's cerebrospinal fluid was positive for both herpes simplex virus 1 and 2 (HSV-1 and HSV-2). To our knowledge, this is the first report of simultaneous detection of HSV-1 and HSV-2 in cerebrospinal fluid.

Plasma and cerebrospinal fluid herpes simplex virus levels at diagnosis and outcome of neonatal infection.

OBJECTIVE: To evaluate the utility of quantitative herpes simplex virus (HSV) polymerase chain reaction (PCR) levels for prognosis and management of neonatal HSV disease. STUDY DESIGN: 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. RESULTS: 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). CONCLUSIONS: Plasma HSV levels correlate with clinical presentation of neonatal HSV disease and mortality, but not neurologic outcome.

Heat exposure and bicycling trigger recurrent aseptic meningitis: a case report.

BACKGROUND: Aseptic meningitis associated with herpes simplex virus type 2 often has a relapsing-remitting clinical phenotype. Factors that lead to disease activation and reactivation are currently incompletely understood. CASE PRESENTATION: We describe the case of a 49-year-old Caucasian man who developed recurrent episodes of herpes simplex virus type 2-associated aseptic meningitis in the setting of heat exposure and bicycling. This case is compelling in that substantial data were available to the examining physicians on the amount of physical exercise and heat exposure. Strenuous physical activities or heat exposure in isolation did not cause re-occurrence of clinical signs and symptoms. CONCLUSIONS: This case illustrates that the dual activation of mechanical and temperature receptors in dorsal root ganglia may lead to the recurrent reactivation and afferent dissemination of latent herpes simplex virus type 2 in some patients.

Systematic review on molecular detection of congenital and neonatal infections caused by TORCH and SARS-CoV-2 in newborns' cerebrospinal fluid.

OBJECTIVE: To verify the use and identify advantages of molecular methods for congenital infections diagnosis in cerebrospinal fluid of neonates. DATA SOURCE: The review was registered in the International Prospective Register of Systematic Reviews (PROSPERO), under CRD42021274210. The literature search was performed in databases: PubMed, Virtual Health Library/ Latin American and Caribbean Center on Health Sciences Information (VHL/BIREME), Scopus, Web of Science, Excerpta Medica database (EMBASE), Cochrane, ProQuest, and EBSCOhost. The search was carried out from August to October 2021 and updated in December 2022, respecting the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The selection sequence was: 1) Duplicate title removal; 2) Examination of titles and abstracts; 3) Full-text retrieval of potentially relevant reports; and 4) Evaluation of the full text according to eligibility criteria by two independent authors. Inclusion criteria considered randomized and non-randomized control trials, longitudinal, cross-sectional, and peer-reviewed studies in humans, published in English, Spanish, Italian, and Portuguese, with newborns up to 28 days old who had congenital neuroinfections by toxoplasmosis, rubella, cytomegalovirus, herpes simplex (TORCH), and others such as Treponema pallidum, Zika, parvovirus B-19, varicella zoster, Epstein-Barr, and SARS-CoV2, diagnosed by polymerase chain reaction (PCR). Two evaluators extracted the following information: author, year of publication, nationality, subjects, study type, methods, results, and conclusion. DATA SYNTHESIS: The most studied pathogen was herpes simplex. Several articles reported only nonspecific initial symptoms, motivating the collection of cerebrospinal fluid and performing PCR for etiological investigation. CONCLUSIONS: Molecular methods are effective to detect pathogen genomes in cerebrospinal fluid, which can impact clinical evolution and neurological prognosis.

Herpes simplex virus 2 meningitis: a retrospective cohort study.

Herpes simplex virus 2 is a leading cause of viral meningitis and the most commonly recognized infectious cause of benign, recurrent meningitis. We report a retrospective, observational cohort study of patients with herpes simplex virus type 2 (HSV-2) meningitis, confirmed by polymerase chain reaction (PCR) in the cerebrospinal fluid (CSF). The terms "herpes simplex," "meningitis," or "encephalitis" were searched in the medical records system of the Mayo Clinic in Rochester, Minnesota (1995-2008). Patients were included if they had a clinical diagnosis of meningitis and HSV-2 detected by PCR in the CSF. There were 28 patients with 33 episodes identified (83 % female; mean age at presentation of meningitis 36 years, range 17-53; mean time to HSV2 detection from symptom onset 3 days, range 0-6; history of genital herpes 23 %). No patient took oral antiviral treatment at the time of presentation. Episodes were most likely to include headache (100 %), photophobia (47 %), self-reported fever (45 %), meningismus (44 %), and nausea and/or vomiting (29 %). CSF at the time of meningitis was notable for elevated protein (mean 156 g/dL, range 60-258) and white cell count (mean 504 cells/µL, range 86-1,860) with normal glucose (mean 54 mg/dL, range 32-80). Mollaret cells were never detected. Neuroimaging was most often normal (83 %) when performed, although some cases showed nonspecific (14 %) or meningeal changes (3 %). There was no consistent relationship to genital herpes. The duration of treatment with intravenous acyclovir ranged from 3 to 14 days for the first meningitic episode (daily dose range from 500 to 1,000 mg and total dose range from 500 mg q8h for 3 days to 800 mg q8h for 14 days). For subsequent episodes, the duration of treatment of intravenous acyclovir ranged from less than 1 to 14 days (total dose range from 1,390 mg for 1 day to 900 mg q8h for 10 days). The dose of valacyclovir ranged from 500 mg once daily to 500 mg four times daily. The median duration of valacyclovir treatment following the first episode was 10 days (range 3 to 14 days, n = 13). The median duration of valacyclovir treatment following a subsequent meningitic episode was 9 days (range 7 days to indefinite period, n = 9). No patient was reported to have seizures, neurological disability, or death in extended follow-up (mean follow-up 3.4 years). Recurrence of meningitic symptoms was not universal.

Delays in initiation of acyclovir therapy in herpes simplex encephalitis.

BACKGROUND: Diagnosis of herpes simplex encephalitis (HSE) is based on clinical findings, MRI, and detection of herpes simplex virus (HSV) DNA in cerebrospinal fluid (CSF) using polymerase chain reaction amplification. Delays in starting treatment are associated with poorer clinical outcomes. We assessed the timing of initiation of acyclovir therapy in HSE. METHODS: Inpatient databases from seven hospitals in Winnipeg, Manitoba were used to identify individuals diagnosed with encephalitis and HSE from 2004 to 2009. The time taken to initiate therapy with acyclovir and the reasons for delays were determined. RESULTS: Seventy-seven patients were identified; 69 (90%) received acyclovir; in the others a non-HSV infection was strongly suspected. Thirteen patients were subsequently confirmed to have HSE. Acyclovir was initiated a median of 21 hours (3-407) after presentation in encephalitis cases, and a median of 11 hours (3-118) in HSE. The most common reason for delay was a failure to consider HSE in the differential diagnosis, despite suggestive clinical features. Where therapy was delayed in HSE patients, the decision to begin acyclovir was prompted by transfer of the patient to a different service (55%), recommendations by consultants (18%), imaging results (18%), and CSF pleocytosis (9%). CONCLUSIONS: Delays in initiating acyclovir for HSE are common, and are most often due to a failure to consider HSE in a timely fashion on presentation. In order to improve patient outcomes, physicians should be more vigilant for HSE, and begin acyclovir therapy expeditiously on the basis of clinical suspicion rather than waiting for confirmatory tests.

Herpes simplex testing in neonates in the emergency department.

OBJECTIVES: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Herpes simplex encephalitis following spinal ependymoma resection: case report and literature review.

Herpes simplex encephalitis (HSE) is a rare complication of neurosurgical procedures but must be considered in early deterioration of the postoperative patient. This is the first report of HSE following spinal cord tumor resection. A 65-year-old woman had C2-C5 laminectomy for subtotal resection of intramedullary ependymoma. Six days postoperatively she developed fever, vomiting and rapid decline in mental status. Brain MRI revealed enhancement of left insular cortex. Polymerase chain reaction on cerebrospinal fluid (CSF) identified herpes simplex virus type 1 (HSV-1) as the causal agent. Twenty-one days of acyclovir led to improvement. Three subsequent admissions to neurological intensive care unit were required for deterioration in mental status, including pneumonia, hydrocephalus and deep vein thromboses. Ventriculoperitoneal shunt (VPS), tracheotomy, percutaneous intravenous central catheter (PICC) line and percutaneous endoscopic gastrostomy (PEG) were placed. She was discharged to skilled nursing home care. Acyclovir is effective therapy against HSV, though outcomes may be poor even in optimally treated cases. Empiric treatment must be started even in the absence of serologic evidence of HSV infection if suspicion for HSE is high.

Herpes Simplex Virus-1 and -2 Rapid Detection in Whole Blood.

BACKGROUND: Disseminated herpes simplex virus (HSV) infection has high morbidity and mortality, particularly in neonates, and requires rapid diagnosis for proper treatment. Currently, there are no US FDA-approved assays available to perform HSV testing on blood. OBJECTIVES: Our goal was to evaluate the analytical sensitivity and clinical performance of an available sample-to-answer real-time polymerase chain reaction (PCR) platform used as a laboratory-developed test (LDT) for the detection of HSV-1 and -2 in whole blood (WB). METHODS: A clinical comparison study comparing a real-time PCR reference assay to a LDT based on the DiaSorin Simplexa Direct assay kit was performed. Analytical sensitivity studies comparing WB to the FDA-approved specimen type, cerebrospinal fluid (CSF), were also conducted with contrived quantified HSV-1 and -2 samples in WB and CSF matrix. RESULTS: In total, 102 samples were tested using the LDT and reference assay for the clinical correlation study, with 91 negative and 10 positive results for HSV-1 (n = 7) and HSV-2 (n = 3), exhibiting 100% concordance with comparator results. The overall limit of detection (LoD) for HSV-1 and HSV-2 in WB was comparable to that seen in CSF, with the calculated 95% LoD for blood being 1489 ± 16 copies/ml for HSV-1 and 1187 ± 18 copies/ml for HSV-2 and for CSF being 1168 ± 17 copies/ml for HSV-1 and 953 ± 21 copies/ml for HSV-2. CONCLUSIONS: The performance of the LDT for detection of HSV-1 and HSV-2 in WB specimens is adequate for clinical use. The LoD for HSV-1 and HSV-2 is comparable to that in CSF, the FDA-approved specimen type.

Herpes simplex virus testing and hospital length of stay in neonates and young infants.

OBJECTIVE: 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. STUDY DESIGN: This retrospective cohort study enrolled infants age

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.

Cerebrospinal fluid challenges for the diagnosis of herpes simplex infection in the central nervous system.

Herpes simplex virus (HSV) is a cause of a severe disease of the central nervous system (CNS) in humans. The demonstration of specific antibodies in the cerebrospinal fluid (CSF) may contribute to the retrospective neurological diagnosis. However, the commercial immunological tests for HSV infection are for use in serum samples. OBJECTIVE: The aim of the present study was to adapt a commercial kit anti-HSV IgG used for serum samples to be performed with a CSF sample. METHODS: Forty CSF specimens from 38 patients with suspected CNS HSV infection were serially diluted for detecting anti-HSV IgG by enzyme immunoassay (EIA). The same samples were also analyzed with the polymerase chain reaction (PCR). RESULTS: The sensitivity of EIA test for HSV was 5% (dilution 1:40) and 65% (dilution 1:2) in CSF, and HSV DNA PCR was 15%. The combined analysis of EIA (dilution 1:2) and PCR increased the sensitivity up to 72.5%. The inflammatory CSF was associated with positive HSV PCR. CONCLUSIONS: We demonstrated the importance to adapt serological anti-HSV IgG EIA test for CSF assays to increase the accuracy of the analysis, considering the low concentration of specific antibodies in CSF.

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.