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Persistence of Herpes Simplex Virus DNA in Cerebrospinal Fluid

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Persistence of Herpes Simplex Virus DNA in Cerebrospinal Fluid Journal of Perinatology (2009) 29, 290–296 r 2009 Nature Publishing Group All rights reserved. 0743-8346/09 $32 www.nature.com/jp ORIGINAL ARTICLE Persistence of herpes simplex virus DNA in cerebrospinal fluid of neonates with herpes simplex virus encephalitis A Mej´ıas1, R Bustos2, MI Ardura1, C Ram´ırez1 and PJ Sa´nchez1 1Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX, USA and 2Department of Pediatrics, University of Concepcio´n, Chile outcome in the majority of survivors.4 Traditional risk factors that Objective: The significance of detecting herpes simplex virus (HSV) DNA contribute to increased morbidity in these infants include the in the cerebrospinal fluid (CSF) of infants with HSV encephalitis after presence of seizures, duration of illness (less than 2 or greater À1 À1 receipt of prolonged therapy with high-dose (60 mg kg day ) acyclovir than 8 days) before the initiation of therapy and infection with is unknown. We report the clinical and laboratory characteristics, HSV-II virus.5,6 neuroimaging studies and outcomes of four neonates with HSV encephalitis Polymerase chain reaction (PCR) for HSV DNA performed on who had persistence of CSF HSV DNA, by polymerase chain reaction (PCR) cerebrospinal fluid (CSF) is the best available method for diagnosis after 15 to 21 days of high-dose acyclovir therapy. of HSV CNS infection.7,8 The occurrence of a positive CSF HSV Study Design: Retrospective chart review. DNA PCR after receipt of prolonged therapy with high-dose (60 mg kgÀ1 per day) acyclovir has not been reported in detail and Results: All four infants had abnormal neuroimaging studies and its significance remains unknown. For this reason, we describe four subsequently experienced severe developmental delay or death. neonates with HSV encephalitis, three of whom were born in Texas Conclusion: A persistently positive CSF HSV PCR in neonates may be and one in Chile, who had persistence of CSF HSV DNA by PCR another risk factor for worse neurodevelopmental outcome. Prospective after 14 to 21 days of high-dose acyclovir therapy. This report also studies are needed to document how often HSV DNA persists in CSF, describes the adverse outcomes that these infants experienced, and elucidate whether it represents an initially high CSF viral load, ongoing it highlights the need for prospective studies to document how often viral replication or viral resistance, and determine its possible association HSV DNA persists in CSF of infected infants and understand its with neurodevelopmental impairment. prognostic significance. Journal of Perinatology (2009) 29, 290–296; doi:10.1038/jp.2008.235; published online 5 February 2009 Patients Keywords: HSV; PCR; encephalitis; acyclovir; neonate Case 1 A 2860-gram female infant was delivered vaginally at 36 weeks of gestation to a 29-year-old gravida4, para3003 Caucasian woman. Prenatal serologic tests revealed an absence of antibodies to the Introduction human immunodeficiency virus, a nonreactive rapid plasma B Neonatal herpes simplex virus (HSV) infection occurs in 1in reagin test, negative hepatitis B surface antigen and a negative 1250 to 20 000 neonates per year in the United States1,2 with 3 screening culture for group B streptococcus. There was no history approximately 30% having encephalitis. Although acyclovir of genital HSV infection. Rupture of fetal membranes occurred therapy has reduced significantly the mortality in infants with 24 h before delivery, and a scalp electrode was used for fetal heart herpes encephalitis, central nervous system (CNS) infection with rate monitoring. HSV continues to be associated with abnormal neurodevelopmental The infant was well until 15 days of age when she developed Correspondence: Dr Asuncio´n Mejı´as, Department of Pediatrics, Division of Pediatric focal seizures. She was hospitalized at 18 days of age at Children’s Infectious Diseases, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Medical Center Dallas (TX, USA) for persistent seizures and apneic Dallas, TX 75390-9063, USA. episodes. The infant was afebrile and physical examination was E-mail: [email protected] significant for a small vesicle on the left inguinal area and This work was presented in part at the Pediatric Academic Societies Meeting, Toronto, hypertonicity. There was no hepatosplenomegaly or petechiae, and Canada from May 5 to 7, 2007. Received 14 July 2008; revised 8 December 2008; accepted 12 December 2008; published online liver function tests, bilirubin concentration and complete blood 5 February 2009 cell count were normal (Table 1). HSV-2 DNA PCR (Children’s CSF HSV persistence in neonatal encephalitis A Mejı´as et al 291 Table 1 . Clinical and laboratory characteristics of four neonates who had encephalitis due to herpes simplex virus (HSV), and the cerebrospinal fluid HSV polymerase chain reaction was persistently positive Case 1 Case 2 Case 3 Case 4 Classification of HSV disease CNS CNS CNS CNS HSV type HSV-2 ND HSV-2 HSV-2 Age at onset of illness 15 days 28 days 2 hours 23 days Liver dysfunction No No No No Thrombocytopenia No No No No Seizures Yes Yes Yes Yes Duration of illness before initiation of acyclovir therapy (days) 3 10 <1 5 Age at onset of HD acyclovir 22 daysa 38 days 18 hours 28 days Hospital day of initiation of HD acyclovir 4 1 1 4 Duration of HD acyclovir therapy (days) 28 30 28 48 Neutropenia on acyclovir therapy No No No No Abbreviations: CNS, central nervous system; HD, high dose; ND, not done. aInfant received acyclovir at 40 mg kgÀ1 per day for 4 days before high-dose acyclovir was started at 22 days of age. Table 2 Day of high-dose (60 mg kgÀ1 per day) acyclovir therapy and results of cerebrospinal fluid (CSF) studies in the four neonates with herpes simplex virus (HSV) encephalitis Case 1 Case 2 Case 3 Case 4 Day of high-dose acyclovir treatment 1a 18b 28b 1a 20 1a 515261a 21 38 CSF HSV polymerase chain reaction + + À ++NS+ +À ++À Cerebrospinal fluid indices White blood cells per mm3 Total ( Â 106 per mm3) 83 88 38 38 200 82 53 32 26 140 38 44 Neutrophils (%) 8 1 0 3 2 76 4 6 6 56 20 ND Lymphoctyes (%) 28 91 80 80 98 10 62 67 79 44 80 ND Monocytes (%) 64 7 20 17 0 14 27 9 24 0 0 ND Red blood cells per mm3 267 703 25 51 10 600 <1 10 690 4 640 6 500 2 5 2 Protein (mg per 100 ml) 235 613 220 194 628 113 NS 480 217 45 33 231 Glucose (mg per 100 ml) 38 30 38 31 30 61 NS 32 43 42 34 68 Abbreviations: ND, not done; NS, not significant. aDay 1 reflects the results of the lumbar puncture before acyclovir therapy was initiated. bDays of high-dose acyclovir after infant had received 4 days of acyclovir at 40 mg kgÀ1 per day. Medical Center Dallas) performed on the initial CSF specimen was repeated 28 days after initiation of high-dose acyclovir. CSF and blood was positive (Table 2). HSV-2 PCR was negative, and high-dose acyclovir was discontinued Acyclovir was provided at a dose of 40 mg kgÀ1 per day at 54 days of age and after a total of 32 days. Acyclovir suppressive intravenously for 4 days and subsequently increased to 60 mg kgÀ1 therapy was not provided. per day. Viral cultures of the throat and vesicle did not yield HSV. The patient’s serum white blood cell count and creatinine Bacterial cultures of blood and CSF were sterile. concentration remained normal during acyclovir therapy. MRI of the Computed tomography (CT) and magnetic resonance imaging brain performed on day 22 of acyclovir (44 days of age) showed (MRI) of the brain at presentation showed extensive cytotoxic megacystic encephalomalacia with laminar necrosis, gliosis and edema involving both cerebral hemispheres. Electroencephalogram cortical atrophy with parieto-occipital subdural effusions (Figure 1a). performed on hospital admission showed extensive multifocal On follow-up at 5, 11, 16 and 24 months of age, she had severe sharp-wave activity with absence of normal background. developmental delay with hypertonicity and microcephaly. She has Ophthalmologic and hearing assessments were normal. not experienced any skin or CNS recurrences. At 40 days of age, after 18 days of high-dose acyclovir therapy, a second CSF examination revealed the persistence of HSV DNA by Case 2 PCR (Table 2). The infant was clinically stable without further A 2930-gram, 40-week female infant was delivered vaginally to a seizure activity. Acyclovir was continued and a lumbar puncture 23-year-old gravida4, para3003 African-American woman. There was Journal of Perinatology CSF HSV persistence in neonatal encephalitis A Mejı´as et al 292 Case 1 Case 2 Case 3 Case 4 Figure 1 Neuroimaging studies of the brain in four neonates diagnosed with herpes simplex virus encephalitis. (a and b) Magnetic resonance imaging (MRI) of the brain performed on week 3 (Case 1) and 1 (Case 2) of high-dose acyclovir, respectively, showed megacystic encephalomalacia with laminar necrosis and gliosis, and cortical atrophy with parieto-occipital subdural effusions. (c) MRI of the brain performed on day 5 of high-dose acyclovir showed diffuse supratentorial edema with large regions of restricted diffusion and a possible thrombus in the right transverse sinus. (d) Computed tomography of the brain performed without contrast on day 48 of high-dose acyclovir therapy showed severe bilateral encephalomalacia. no history of genital HSV infection but she was treated for and CSF, as well as viral cultures of throat, rectum and buffy coat gonococcal and chlamydial infections in the first trimester of were sterile. The infant received intravenous ampicillin, pregnancy. She lacked antibodies to human immunodeficiency cefotaxime, acyclovir (60 mg kgÀ1 per day) and oral nystatin.
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