Review Article | Open Access
Shahid K. Sukhbir, "Neonatal Herpes Simplex Infection", International Scholarly Research Notices, vol. 2013, Article ID 473053, 7 pages, 2013. https://doi.org/10.5402/2013/473053
Neonatal Herpes Simplex Infection
Maternal genital herpes is a sexually transmitted infection; asymptomatic in 70% of cases. Newborn babies usually catch the infection from maternal birth tract during delivery. Neonatal herpes simplex infection is a highly morbid and fatal dreadful infection. Though there have been great advances in diagnosis and management of this neonatal infection in last 3 decades, its morbidity continues to be high due to greater lag-time between symptoms and diagnosis. This delay is due to its non-specific presentation and lack of adequate awareness about the disease amongst the practising physicians. A high level of clinical suspicion is vital for early treatment initiation and better outcomes. Maternal education on safe sex practices, selective and elective caesarean surgery and prophylactic acyclovir for recurrent maternal herpes would diminish transmission and disease in newborn.
Herpes (Greek for “creeping”) is viral infection caused by herpes simplex virus type 1 or type 2 (HSV-1 or 2). Batignani first described herpetic infection in an infant with isolated ker ato-conjunctivitis . Herpes can affect a newborn either through vertical transmission before or during labour, or due to direct contact with infected secretions from a patient in immediate postnatal period [2–4]. Its incidence varies widely worldwide from as low as 1 : 3200 births in USA to 1 : 60000 births in UK [4, 5]. The incidence has risen progressively in the past four decades . Risk factors for neonatal herpes infection include prematurity, instrumentation (e.g., scalp electrodes), and presence of maternal primary genital herpes of cervix during delivery [7, 8]. If left untreated, it has a fatality rate of around 60% with poor neurologic outcomes in three-quarters of survivors [2, 5, 7, 9, 10]. Prompt antiviral therapy can avert a number of these deaths and minimise CNS damage . But nonspecific presentation of this infection usually delays diagnosis . An enhanced awareness amongst treating physicians about this serious neonatal illness could aid early pickup and treatment with improved outcomes.
Genital herpes is a viral sexually transmitted infection caused by HSV-2 virus and rarely by HSV-1 virus . 45 million people above 12 years in USA are infected with genital herpes, with 1.5 million new cases being diagnosed each year . 5% of women in reproductive age give history of genital herpes. 2% of women acquire first infection during pregnancy. In majority, infection is asymptomatic and subclinical . Less than 30% of them have circulating antibodies to HSV-2 virus. Less than 1/4th with positive serology are symptomatic . Neonatal transmission rate is more than 40% with primary genital herpes infection in mother. In mothers with recurrent herpes and positive serology for HSV-2 virus, the transmission risk drops to 3%. Children born to mothers with first nonprimary infection have an intermediate risk [16–18]. Presence of specific HSV-1 antibodies does not protect against neonatal transmission . Around 1500–2000 cases of neonatal herpes are diagnosed each year. Regional differences are noticed in prevalence of newborns with HSV-1 or HSV-2 types of infection [2, 6, 20].
Herpes simplex virus is a neurotropic double-stranded DNA virus which belongs to Alphaherpesvirinae, a subfamily of Herpesviridae family . It was taxonomized as herpes hominis virus in 1953 but somehow this name has not gained much general acceptance in the literature or practice . The herpes simplex virus is of 2 types; HSV-1 and HSV-2. HSV-1 is responsible for most of orofacial lesions but it could also rarely cause genital disease. HSV-2 causes genital herpes infection. Both types have a roughly spherical central “core” of 750 Å diameter containing linear double-stranded DNA. Surrounding this core is the stable icosahedral capsid comprising of 162 capsomeres. Envelopes derived from host membrane encompass the capsid bringing the particle size to 1450–2000 Å. Some particles are “full” and complete; others are “empty” (without the core) while some are “naked” (with no envelope) . The virus is neurovirulent. It propagates in neural tissue and has tendency towards latency. With physical and emotional stress, these dormant virions can get activated and cause disease .
Neonatal herpes is devastating to an infant. Most infection is acquired during intrapartum period. Some are caught in utero (congenital HSV) or postnatally through contact with oral or skin lesions. The latter may be from mother, adults including nursery personnel, or other babies . Congenital HSV comprises 4% of neonatal herpes cases and is characterized by microcephaly, hydrocephalus, chorioretinitis, skin lesions, and visceral involvement . Transplacental transmission or ascending infection from vagina or cervix either through intact amniotic membrane or due to leaks and reseals causes the infection. Histopathological examination of placenta can differentiate between these two modes of transmission . Isolated cases have been reported in literature where herpes infection had spread from an infected breast lesion, HSV-1 infected breast milk and after traditional Jewish ritual of circumcision from the mouth sores of the infected mohel [23–26].
Skin and mucosal vesicular lesions are seen with neonatal herpes infection. There is viremia and since the virus has an affinity for the neural tissue, CNS involvement is an important component of the infection. Eye, liver, lungs, kidneys, adrenal glands, and so forth may be involved with formation of multinucleated giant cells or intranuclear inclusions in affected tissues.
5. Clinical Features
Early maternal genital infection leads to foetal wastage. Intrauterine growth retardation or prematurity often accompany maternal infection in late pregnancy. Newborns with congenital HSV infection have microcephaly, hydrocephalus, microphthalmia, chorioretinitis, intracranial calcifications, and vesicular mucocutaneous lesions. Infections acquired in antenatal or postnatal period may simulate neonatal sepsis. 33% of them present within 24 hours of birth and 61% in first week of life . Depending on extent of infection, neonatal herpes can be categorised into three types: (1) skin, eye, and mouth (SEM) infections, (2) central nervous system involvement (encephalitis) which can include SEM, and (3) disseminated infection involving multiple organs such as liver, lungs, adrenals, brain, eye, kidneys, and fskin . Nonspecific symptoms such as fever or hypothermia, lethargy, poor feeding, and irritability may be seen with or without mucocutaneous lesions [2, 27, 28]. By the time diagnosis is made, many infants have progressed to severe disease and have developed complications. Focal or generalized seizures, hepatitis, pneumonitis, eye inflammations, gastrointestinal, and adrenal involvement may be seen. Dendritic eye ulcers, chorioretinitis, or acute necrotizing retinitis may be seen [27, 29]. Herpes-virus-induced dense congenital cataract of right eye in an 18-month-old infant has been reported in literature . Bleeding diathesis, liver failure, coma, respiratory distress, and shock are usually seen in end-stage severe infections. Localised infections are more likely to be HSV-1 and central or disseminated infections due to HSV-2 virus . Long-term complications such as sfeizures, psychomotor retardation, spasticity, blindness, and learning disabilities are often seen in survivors [2, 27].
Neonatal herpes has a variable presentation and it may simulate other neonatal infective conditions. The treating paediatrician should always consider neonatal herpes in the differential diagnosis in a newborn that is brought with history of lethargy, irritability, fever or hypothermia, and skin vesicles with or without neurologic symptoms. Diagnosis requires a high degree of clinical suspicion especially because maternal history of genital herpes is usually not forthcoming. This should be especially considered when bacterial cultures at 48 hours are negative. Early initiation of specific therapy averts death and minimises neurologic damage .
Tzanck smear made from scrapings from skin or mucosal vesicles is a quick office test for confirmation of diagnosis of herpes infection. Wright, Giemsa, or Papanicolaou stained smears show characteristic multinucleated giant cells or intranuclear inclusion bodies. This test is only 60% as sensitive as viral culture, and it also cannot differentiate between herpes simplex virus and varicella-zoster infection . Direct fluorescent-antibody (DFA) technique using mouse monoclonal antibody to detect HSV antigen scores better and has a sensitivity and specificity of 74 and 85%, respectively, when compared with viral culture test . Isolation of virus in tissue culture is current “gold standard” confirmatory test for herpes infection. Blood, cerebrospinal fluid, urine, nasopharynx, eye secretions, and vesicular fluid can be cultured. HSV causes discernible typical cytopathic changes in a variety of cell culture lines and most specimens can be identified within 48–96 hours. The sensitivity of this test is higher in early vesicular stage as compared to ulcerative stage. It is also more sensitive for primary maternal lesions and in immunocompromised patients [33–35]. A negative test means that the virus was not isolated, but it does not rule out presence of the virus. It may be falsely negative when actively replicating virus is less in sample, or when sample transport has been under suboptimum conditions . HSV DNA analysis by polymerase chain reaction (PCR) is useful in such conditions. It also gives accurate results when sample is taken from an old lesion and from an asymptomatic patient. It is 25% more sensitive than viral isolation by culture. Refrigeration is not required for transport of sample for HSV PCR [37–39]. It has higher yield in herpes encephalitis [40, 41], and can also quantify viral load . Restriction endonuclease analysis of viral DNA allows subtyping of infection into HSV type 1 or HSV type 2 and differentiation of various strains of the subtypes. This is useful for epidemiologic purposes, for prediction of recurrence of the infection, and for identification common source outbreaks of HSV [43, 44]. Detection of antibodies against HSV-1 or HSV-2 in serum has limited usefulness in neonatal herpes. HSV IgM is seen in acute stage. HSV IgG comes up later but its determination may be unable to differentiate maternal transfer of antibody from that produced by newborn due to infection in self. A fourfold rise in HSV IgG titre in acute and convalescent sera proves current infection in baby. Recurrent infection in mother, however, may not show this fourfold rise [43, 45, 46]. Cerebrospinal fluid examination in neonatal herpes with neurologic signs reveals lymphocytic pleocytosis with increased proteins with or without decreased glucose. Viral cultures and PCR for HSV DNA of CSF are usually positive. Infants with SEM have only 24% chance to have positive HSV DNA in their CSF . Persistence of HSV DNA at the end of antiviral treatment is associated with poor prognosis . Computed tomography of brain is found to be abnormal in 67% of infected babies. The abnormalities include parenchymal attenuation abnormalities, parenchymal atrophy, parenchymal contrast enhancement, leptomeningeal contrast enhancement, extra-axial fluid collection, and parenchymal calcifications . MRI brain is quite often abnormal in neonatal herpes. Areas of hyperdensity and hemorrhage characterise CNS herpes. EEG abnormalities are detected in 100% of neonatal HSV encephalitis. These include focal epileptiform discharges, burst suppression, focal electrographic seizures, focal suppression, and diffuse slowing . The unique multifocal or quasiperiodic pattern of HSV encephalitis decreases with early appropriate treatment [49, 50]. Additional tests that may be needed when baby is sick include arterial blood gas analysis, complete blood count, coagulation studies, electrolyte estimation, liver function tests, and kidney function tests .
All newborns suspected to have or diagnosed with neonatal herpes should be started immediately on an effective and safe antiviral drug. 5-iodo-2-deoxyuridine (idoxuridine, IDU), cytosine arabinoside, adenine arabinoside, and acyclovir have been studied for their role and safety in neonatal herpes. These antiviral drugs inhibit DNA synthesis and hence virion replication. The effect is more marked with early treatment . Herrman found inhibition of herpes simplex virus plaques in cell cultures with IDU . Use of IDU ameliorates herpes symptoms [53–55]. 1-β-D-arabino-furanosyl-cytosinehydrochloride (cytosine arabinoside or CA or ara-C) was studied later and found to aid early recovery in herpes keratitis [56, 57]. In neonatal herpes, cytosine arabinoside is used in dose of 40–160 mg/m2/day as continuous intravenous infusion for 4–6 days. It can also be used intrathecally in herpes encephalitis . Vidarabine (adenine arabinoside or ara-A) in dosage of 10–20 mg/kg/day as a 12 hour continuous infusion for 10–14 days helped to decrease mortality in CNS and disseminated herpes from 74% to 38%. 50% of infants on vidarabine were normal at 1 year of age compared to 17% in control group [59–61]. Stepping up dosage to 30 mg/kg, however, did not improve survival or decrease morbidity . Acyclovir is current antiviral recommended for neonatal herpes infection. It is more effective, safer, and easier to administer than vidarabine [10, 63]. Suggested dose is 60 mg/kg/day in three divided doses intravenously as 1-hour infusion for 14 days for SEM disease and 21 days for central nervous system or disseminated disease . This high dose significantly improves survival. Also patients on high-dose acyclovir are 6.6 times more likely to be normal at 12 months of age when compared with those on standard dose of 30 mg/kg/day. There may be some transient neutropenia with this high dose but no serious adverse sequelae have been reported [64, 65]. Twice weekly serial absolute neutrophil count (ANC) estimation throughout this high-dose acyclovir course is advised. Decreasing acyclovir dosage or administration of granulocyte colony stimulating factor should be considered if low ANC count is prolonged. Transient renal insufficiency is likely due to crystallisation of acyclovir in renal parenchyma. This can be averted by proper hydration and acyclovir administration slowly over 1 hour . All patients with CNS HSV involvement require repeat lumbar puncture at end of acyclovir therapy to document PCR negativity and end-of-therapy CSF indices. Acyclovir should only be ceased once PCR is negative [43, 66]. HSV elimination from CNS is better with continuous intravenous infusion of acyclovir in neonatal encephalitis . A recent study has also revealed that after the 14/21 parenteral acyclovir therapy, acyclovir suppression at 300 mg/square meter per dose orally three times a day for 6 months causes significant improvement in the neurological outcome in children with CNS disease . Famciclovir and valacyclovir are two newly marketed antiviral drugs. They have better absorption and need less frequent dosing. Though pharmacokinetically superior to acyclovir, they offer no clinical advantage over acyclovir. Controlled studies in children are lacking and hence they are at present not recommended for neonatal HSV infection . Viral resistance to nucleoside analogues have been reported. The duration of disease before antiviral is initiated is significantly correlated with morbidity and mortality [2, 69]. A sick infant may need additional vigorous supportive care in form of intravenous fluids, alimentation, seizure control, coma care, respiratory support, blood transfusions, clotting abnormalities correction, and so forth . Careful hydration and renal function monitoring is vital. Topical antiviral drug with systemic acyclovir is used for herpetic keratitis. IDU was found to be effective in 80–90% of cases [53, 70, 71]. However, deep-rooted, chronic or resistant infections respond better to topical ara-C, trifluorothymidine, vidarabine, or steroids with IDU [56, 72–76]. Debridement with or without interferon therapy may be needed to hasten healing. Newer antiviral eye drops and ointments for herpes include acyclovir and ganciclovir. Acyclovir cream for skin vesicles is also available. Monthly immunoglobulin therapy decreased recurrence, severity, and duration of lesions in genital herpes [77, 78]. Though not recommended as standard treatment, Whitley extrapolated these findings and proposed HSV human monoclonal antibody or hyperimmune immunoglobulin as concomitant therapy for neonatal-disseminated HSV infection . Production of monoclonal antibodies targeted against glycoprotein B or D of HSV virus is still in experimental stage. When successful, these could be used as adjuvant therapy in neonatal herpes infection .
Untreated neonatal herpes is associated with high mortality and morbidity. Fatality is high in disseminated and CNS herpes. With treatment, overall mortality has come down drastically and also the number of normal survivors has increased from 30 to 85%. Prognosis depends on disease extent and treatment efficacy. Early diagnosis and initiation of specific therapy improves outcome.
Efforts directed towards prevention of neonatal herpes are minimally beneficial. Universal screening of mothers during pregnancy with serial viral cultures or type-specific serology has not been shown to be cost-effective. Most mothers with great risk of vertical transmission are in fact asymptomatic. Also, viral shedding is intermittent and weekly cultures may miss significant numbers of viral-shedding mothers. Herpes serology may diagnose mothers with past infection but the transmission rates in them are lower. It is therefore best practice to question mothers during prenatal visits about history of genital herpes in self or their sexual partner. Examine for signs of genital herpes. Educate mothers with recurrent genital herpes on safe sex practices. Risk of neonatal infection from mothers with primary or active genital herpes near term can be minimised with caesarean section. This is useful for up to 4–6 hours after amniotic membrane rupture. Scalp electrodes which increase neonatal transmission risk should be avoided in high-risk cases. Suppressive acyclovir can be tried but decrease in transmission rate is modest [81, 82]. Patients with active HSV mouth or skin ulcers should avoid contact with newborn babies. HSV vaccination trials are ongoing. HSV-2 gD subunit vaccine adjuvanted with alum combined with 3-deacylated monophosphoryl lipid A has demonstrated promising results . A high degree of suspicion of herpes simplex infection in a sick newborn must be maintained. Empiric initiation of antiviral therapy should be considered in suspected cases.
To summarise, neonatal herpes simplex infection is a highly morbid and mortal condition. Though survival has improved, neurological disabilities due to it are still high. In spite of many advances at the diagnostic and therapeutic front, this disease continues to scourge newborns due to low index of suspicion and longer diagnostic and treatment lag-time. Hence, what is more vital is to detect and treat the illness early. This can be achieved through enhancing awareness amongst the physicians about the early symptoms and signs of the disease. Also attempts to diminish transmission from mother to child would be highly beneficial.
- J. B. Hanshaw, “Herpesvirus hominis infections in the fetus and the newborn,” American Journal of Diseases of Children, vol. 126, no. 4, pp. 546–555, 1973.
- C. M. Rudnick, “Neonatal herpes simplex virus infections,” American Family Physician, vol. 65, no. 6, pp. 1138–1143, 2002.
- K. M. Stone, C. A. Brooks, M. E. Guinan, and E. R. Alexander, “National surveillance for neonatal herpes simplex virus infections,” Sexually Transmitted Diseases, vol. 16, no. 3, pp. 152–156, 1989.
- M. W. Adler, “ABC of sexually transmitted diseases. Pregnancy and the neonate,” BMJ, vol. 288, no. 6417, pp. 624–627, 1984.
- A. M. Kesson, “Management of neonatal herpes simplex virus infection,” Paediatric Drugs, vol. 3, no. 2, pp. 81–90, 2001.
- J. Sullivan Bolyai, H. F. Hull, C. Wilson, and L. Corey, “Neonatal herpes simplex virus infection in King County, Washington. Increasing incidence and epidemiologic correlates,” JAMA, vol. 250, no. 22, pp. 3059–3062, 1983.
- J. C. Overall, “Herpes simplex virus infection of the fetus and newborn,” Pediatric Annals, vol. 23, no. 3, pp. 131–136, 1994.
- L. S. Parvey and L. T. Chien, “Neonatal herpes simplex virus infection introduced by fetal-monitor scalp electrodes,” Pediatrics, vol. 65, no. 6, pp. 1150–1153, 1980.
- M. Koskiniemi, J. M. Happonen, A. L. Jarvenpaa, O. Pettay, and A. Vaheri, “Neonatal herpes simplex virus infection: a report of 43 patients,” Pediatric Infectious Disease Journal, vol. 8, no. 1, pp. 30–35, 1989.
- D. W. Kimberlin, “Neonatal herpes simplex infection,” Clinical Microbiology Reviews, vol. 17, no. 1, pp. 1–13, 2004.
- P. Tookey and C. S. Peckham, “Neonatal herpes simplex virus infection in the British Isles,” Paediatric and Perinatal Epidemiology, vol. 10, no. 4, pp. 432–442, 1996.
- K. Todar, Herpes and related viruses. In The Microbial Wrold, 2012, http://textbookofbacteriology.net/themicrobialworld/Herpes.html.
- L. Corey and A. Wald, “Maternal and neonatal herpes simplex virus infections,” The New England Journal of Medicine, vol. 361, no. 14, pp. 1328–1385, 2009.
- A. Nasoodi, S. Quah, and W. W. Dinsmore, “Neonatal herpes in herpes simplex virus type 2 and HIV-seropositive pregnant patients; the role of preventive measures in the absence of clinical disease of herpes,” International Journal of STD and AIDS, vol. 18, no. 12, pp. 863–866, 2007.
- R. L. Tideman, J. Taylor, C. Marks et al., “Sexual and demographic risk factors for herpes simplex type 1 and 2 in women attending an antenatal clinic,” Sexually Transmitted Infections, vol. 77, no. 6, pp. 413–415, 2001.
- Z. A. Brown, L. A. Vontver, and J. Benedetti, “Effects on infants of a first episode of genital herpes during pregnancy,” The New England Journal of Medicine, vol. 317, no. 20, pp. 1246–1251, 1987.
- Z. A. Brown, A. Wald, R. A. Morrow, S. Selke, J. Zeh, and L. Corey, “Effect of serologic status and cesarean delivery on transmission rates of herpes simplex virus from mother to infant,” JAMA, vol. 289, no. 2, pp. 203–209, 2003.
- A. Nahmias, W. E. Josey, Z. M. Naib, M. G. Freeman, R. J. Fernandez, and J. H. Wheeler, “Perinatal risk associated with maternal genital herpes simplex virus infection,” American Journal of Obstetrics and Gynecology, vol. 110, no. 6, pp. 825–837, 1971.
- Z. A. Brown, J. Benedetti, R. Ashley et al., “Neonatal herpes simplex virus infection in relation to asymptomatic maternal infection at the time of labor,” The New England Journal of Medicine, vol. 324, no. 18, pp. 1247–1252, 1991.
- R. Y. Kropp, T. Wong, L. Cormier et al., “Neonatal herpes simplex virus infections in Canada: results of a 3-year national prospective study,” Pediatrics, vol. 117, no. 6, pp. 1955–1962, 2006.
- T. Tokumaru and T. F. McNair Scott, “Herpes virus hominis (virus of herpes simplex),” Bacteriological Reviews, vol. 28, pp. 458–471, 1964.
- I. J. Light, “Postnatal acquisition of herpes simplex virus by the newborn infant: a review of the literature,” Pediatrics, vol. 63, no. 3, pp. 480–482, 1979.
- J. Z. Sullivan Bolyai, K. H. Fife, and R. F. Jacobs, “Disseminated neonatal herpes simplex virus type 1 from a maternal breast lesion,” Pediatrics, vol. 71, no. 3, pp. 455–457, 1983.
- L. M. Dunkle, R. R. Schmidt, and D. M. O'Connor, “Neonatal herpes simplex infection possibly acquired via maternal breast milk,” Pediatrics, vol. 63, no. 2, pp. 250–251, 1979.
- B. Gesundheit, G. Grisaru-Soen, D. Greenberg et al., “Neonatal genital herpes simplex virus type 1 infection after Jewish ritual circumcision: modern medicine and religious tradition,” Pediatrics, vol. 114, no. 2, pp. e259–e263, 2004.
- J. A. Schillinger, S. Blank, J. E. Myers et al., “Neonatal herpes simplex virus infection following Jewish ritual circumcisions that included direct orogenital suction—New York City, 2000–2011,” MMWR, vol. 61, no. 22, pp. 405–409.
- R. F. Jacobs, “Neonatal herpes simplex virus infections,” Seminars in Perinatology, vol. 22, no. 1, pp. 64–71, 1998.
- A. M. Arvin, A. S. Yeager, and F. W. Bruhn, “Neonatal herpes simplex infection in the absence of mucocutaneous lesions,” Journal of Pediatrics, vol. 100, no. 5, pp. 715–721, 1982.
- W. S. Hagler, P. V. Walters, and A. J. Nahmias, “Ocular involvement in neonatal herpes simplex virus infection,” Archives of Ophthalmology, vol. 82, no. 2, pp. 169–176, 1969.
- A. Cibis and R. M. Burde, “Herpes simplex virus-induced congenital cataracts,” Archives of Ophthalmology, vol. 85, no. 2, pp. 220–223, 1971.
- E. Folkers, A. P. Oranje, J. N. Duivenvoorden, J. P. W. Van Der Veen, J. U. Rijlaarsdam, and J. A. Emsbroek, “Tzanck smear in diagnosing genital herpes,” Genitourinary Medicine, vol. 64, no. 4, pp. 249–254, 1988.
- W. E. Lafferty, S. Krofft, and M. Remington, “Diagnosis of herpes simplex virus by direct immunofluorescence and viral isolation from samples of external genital lesions in a high-prevalence population,” Journal of Clinical Microbiology, vol. 25, no. 2, pp. 323–326, 1987.
- M. Motamedifar and A. Noorafshan, “Cytopathic effect of the herpes simplex virus type 1 appears stereologically as early as 4 h after infection of Vero cells,” Micron, vol. 39, no. 8, pp. 1331–1334, 2008.
- M. L. Landry, T. A. Zibello, and G. D. Hsiung, “Comparison of in situ hybridization and immunologic staining with cytopathology for detection and identification of herpes simplex virus infection in cultured cells,” Journal of Clinical Microbiology, vol. 24, no. 6, pp. 968–971, 1986.
- S. NII and J. KAMAHORA, “Cytopathic changes induced by herpes simplex virus,” Biken Journal, vol. 4, pp. 255–270, 1961.
- L. A. Koutsky, C. E. Stevens, K. K. Holmes et al., “Underdiagnosis of genital herpes by current clinical and viral-isolation procedures,” The New England Journal of Medicine, vol. 326, no. 23, pp. 1533–1539, 1992.
- H. Kimura, M. Futamura, H. Kito et al., “Detection of viral DNA in neonatal herpes simplex virus infections: frequent and prolonged presence in serum and cerebrospinal fluid,” Journal of Infectious Diseases, vol. 164, no. 2, pp. 289–293, 1991.
- H. H. Kessler, G. Mühlbauer, B. Rinner et al., “Detection of herpes simplex virus DNA by real-time PCR,” Journal of Clinical Microbiology, vol. 38, no. 7, pp. 2638–2642, 2000.
- M. J. Espy, J. R. Uhl, P. S. Mitchell et al., “Diagnosis of herpes simplex virus infections in the clinical laboratory by LightCycler PCR,” Journal of Clinical Microbiology, vol. 38, no. 2, pp. 795–799, 2000.
- G. Mertens, M. Ieven, D. Ursi, S. R. Pattyn, J. J. Martin, and P. M. Parizel, “Detection of herpes simplex virus in the cerebrospinal fluid of patients with encephalitis using the polymerase chain reaction,” Journal of the Neurological Sciences, vol. 118, no. 2, pp. 213–216, 1993.
- E. Puchhammer-Stockl, T. Popow-Kraupp, F. X. Heinz, C. W. Mandl, and C. Kunz, “Establishment of PCR for the early diagnosis of herpes simplex encephalitis,” Journal of Medical Virology, vol. 32, no. 2, pp. 77–82, 1990.
- Y. Ando, H. Kimura, H. Miwata, T. Kudo, M. Shibata, and T. Morishima, “Quantitative analysis of herpes simplex virus DNA in cerebrospinal fluid of children with herpes simplex encephalitis,” Journal of Medical Virology, vol. 41, no. 2, pp. 170–173, 1993.
- D. W. Kimberlin, F. D. Lakeman, A. M. Arvin et al., “Application of the polymerase chain reaction to the diagnosis and management of neonatal herpes simplex virus disease,” Journal of Infectious Diseases, vol. 174, no. 6, pp. 1162–1167, 1996.
- H. Sakaoka, T. Aomori, and I. Ozaki, “Restriction endonuclease cleavage analysis of herpes simplex virus isolates obtained from three pairs of siblings,” Infection and Immunity, vol. 43, no. 2, pp. 771–774, 1984.
- W. M. Sullender, L. L. Yasukawa, M. Schwartz et al., “Type-specific antibodies to herpes simplex virus type 2 (HSV-2) glycoprotein G in pregnant women, infants exposed to maternal HSV-2 infection at delivery, and infants with neonatal herpes,” Journal of Infectious Diseases, vol. 157, no. 1, pp. 164–171, 1988.
- P. Juto and B. Settergren, “Specific serum IgA, IgG and IgM antibody determination by a modified indirect ELISA-technique in primary and recurrent herpes simplex virus infection,” Journal of Virological Methods, vol. 20, no. 1, pp. 45–56, 1988.
- G. Malm and M. Forsgren, “Neonatal herpes simplex virus infections: HSV DNA in cerebrospinal fluid and serum,” Archives of Disease in Childhood, vol. 81, no. 1, pp. F24–F29, 1999.
- C. Toth, S. Harder, and J. Yager, “Neonatal herpes encephalitis: a case series and review of clinical presentation,” Canadian Journal of Neurological Sciences, vol. 30, no. 1, pp. 36–40, 2003.
- E. M. Mizrahi and B. R. Tharp, “A characteristic EEG pattern in neonatal herpes simplex encephalitis,” Neurology, vol. 32, no. 11, pp. 1215–1220, 1982.
- K. Sainio, M. L. Granstrom, O. Pettay, and M. Donner, “EEG in neonatal herpes simplex encephalitis,” Electroencephalography and Clinical Neurophysiology, vol. 56, no. 6, pp. 556–561, 1983.
- J. Levitt and Y. Becker, “The effect of cytosine arabinoside on the replication of herpes simplex virus,” Virology, vol. 31, no. 1, pp. 129–134, 1967.
- E. C. Herrman, “Plaque inhibition test for detection of specific inhibitors of DNA containing viruses,” Proceedings of the Society for Experimental Biology and Medicine, vol. 107, pp. 142–145, 1961.
- H. KAUFMAN, E. L. MARTOLA, and C. DOHLMAN, “Use of 5-iodo-2'-deoxyuridine (IDU) in treatment of herpes simplex keratitis,” Archives of Ophthalmology, vol. 68, pp. 235–239, 1962.
- H. E. KAUFMAN, “Clinical cure of herpes simplex keratitis by 5-iodo-2-deoxyuridine,” Proceedings of the Society for Experimental Biology and Medicine, vol. 109, pp. 251–252, 1962.
- H. E. Kaufman, “Chemotherapy of herpes keratitis,” Investigative Ophthalmology, vol. 2, pp. 504–518, 1963.
- H. E. KAUFMAN and E. D. MALONEY, “IDU and cytosine arabinoside in experimental herpetic keratitis,” Archives of Ophthalmology, vol. 69, pp. 626–629, 1963.
- G. E. Underwood, C. A. Wisner, and S. D. Weed, “Cytosine arabinoside (CA) and other nucleosides in herpes virus infections,” Archives of Ophthalmology, vol. 72, pp. 505–512, 1964.
- A. W. Chow, A. Roland, M. Fiala et al., “Cytosine arabinoside therapy for herpes simplex encephalitis—clinical experience with six patients,” Antimicrobial Agents and Chemotherapy, vol. 3, no. 3, pp. 412–417, 1973.
- L. T. Ch'ien, R. J. Whitley, and A. J. Nahmias, “Antiviral chemotherapy and neonatal herpes simplex virus infection: a pilot study. Experience with adenine arabinoside (ARA-A),” Pediatrics, vol. 55, no. 5, pp. 678–685, 1975.
- R. J. Whitley, A. J. Nahmias, and S. J. Soong, “Vidarabine therapy of neonatal herpes simplex virus infection,” Pediatrics, vol. 66, no. 4, pp. 495–501, 1980.
- R. J. Whitley, S. J. Soong, and P. R. Dolin, “Adenine arabinoside therapy of biopsy proved herpes simplex encephalitis. National institute of allergy and infectious diseases collaborative antiviral study,” The New England Journal of Medicine, vol. 297, no. 6, pp. 289–294, 1977.
- R. J. Whitley, A. Yeager, and P. Kartus, “Neonatal herpes simplex virus infection: follow-up evaluation of vidarabine therapy,” Pediatrics, vol. 72, no. 6, pp. 778–785, 1983.
- C. Thompson and R. Whitley, “Neonatal herpes simplex virus infections: where are we now?” Advances in Experimental Medicine and Biology, vol. 697, pp. 221–230, 2011.
- D. W. Kimberlin, C. Y. Lin, R. F. Jacobs et al., “Safety and efficacy of high-dose intravenous acyclovir in the management of neonatal herpes simplex virus infections,” Pediatrics, vol. 108, no. 2, pp. 230–238, 2001.
- “American academy of pediatrics committee on infectious diseases,” in Red Book: Report of the Committee on Infectious Diseases, L. K. Pickering, Ed., pp. 309–318, American Academy of Pediatrics, Elk Grove Village, Ill, USA, 25th edition, 2000.
- D. W. Kimberlin, C. Y. Lin, R. F. Jacobs et al., “Natural history of neonatal herpes simplex virus infections in the acyclovir era,” Pediatrics, vol. 108, no. 2, pp. 223–229, 2001.
- Y. Kakisaka, M. Ishitobi, K. Wakusawa et al., “Efficacy of continuous acyclovir infusion in neonatal herpes virus encephalitis,” Neuropediatrics, vol. 40, no. 4, pp. 199–200, 2009.
- D. W. Kimberlin, R. J. Whitley, W. Wan et al., “Oral acyclovir suppression and neurodevelopment after neonatal herpes,” The New England Journal of Medicine, vol. 365, no. 14, pp. 1284–1292, 2011.
- J. Z. Sullivan-Bolyai, H. F. Hull, and C. Wilson, “Presentation of neonatal herpes simplex virus infections: implications for a change in therapeutic strategy,” Pediatric Infectious Disease, vol. 5, no. 3, pp. 309–314, 1986.
- R. P. Burns, “A double-blind study of IDU in human herpes simplex keratitis,” Archives of Ophthalmology, vol. 70, pp. 381–384, 1963.
- D. R. Hart, V. J. Brightman, G. G. Readshaw, G. T. Porter, and M. J. Tully, “Treatment of human herpes simplex keratitis with IDU, a sequential double-blind controlled study,” Archives of Ophthalmology, vol. 73, pp. 623–634, 1965.
- C. N. Jepson, “Treatment of herpes simplex of the cornea with IDU. A double-blind study,” American Journal of Ophthalmology, vol. 57, no. 2, pp. 213–217, 1964.
- M. H. Luntz and F. O. Maccallum, “Treatment of herpes simplex keratitis with 5-iodo-2′-deoxyuridine,” British Journal of Ophthalmology, vol. 47, pp. 449–456, 1963.
- P. R. Laibson and T. W. Sery, “Leopold IH.The treatment of herpetic keratitis with 5-iodo-2′-deoxyuridine (IDU),” Archives of Ophthalmology, vol. 70, pp. 52–58, 1963.
- G. E. Underwood, “Activity of 1-fl-darabinofuranosyl cytosine hydrochloride against herpes simplex keratitis,” Proceedings of the Society for Experimental Biology and Medicine, vol. 111, pp. 660–664, 1962.
- H. E. KAUFMAN, E. L. MARTOLA, and C. H. DOHLMAN, “Herpes simplex treatment with IDU and corticosteroids,” Archives of Ophthalmology, vol. 69, pp. 468–472, 1963.
- M. A. Keller and E. R. Stiehm, “Passive immunity in prevention and treatment of infectious diseases,” Clinical Microbiology Reviews, vol. 13, no. 4, pp. 602–614, 2000.
- S. Masci, C. De Simone, G. Famularo et al., “Intravenous immunoglobulins suppress the recurrences of genital herpes simplex virus: a clinical and immunological study,” Immunopharmacology and Immunotoxicology, vol. 17, no. 1, pp. 33–47, 1995.
- R. J. Whitley and Balfour, “Neonatal herpes simplex virus infections: is there a role for immunoglobulin in disease prevention and therapy ?” Pediatric Infectious Disease Journal, vol. 13, no. 5, pp. 432–439, 1994.
- S. Fujinaga, T. Sugano, and Y. Matsumoto, “Antiviral activities of human monoclonal antibodies to herpes simplex virus,” Journal of Infectious Diseases, vol. 155, no. 1, pp. 45–53, 1987.
- W. I. van der Meijden, “Strategies for the prevention of neonatal herpes: just a matter of opinion?” International Congress Series, vol. 1279, pp. 109–114, 2005.
- A. G. Randolph, R. M. Hartshorn, and A. E. Washington, “Acyclovir prophylaxis in late pregnancy to prevent neonatal herpes: a cost-effectiveness analysis,” Obstetrics and Gynecology, vol. 88, no. 4, pp. 603–610, 1996.
- L. R. Stanberry, S. L. Spruance, A. L. Cunningham et al., “Glycoprotein-D-adjuvant vaccine to prevent genital herpes,” The New England Journal of Medicine, vol. 347, no. 21, pp. 1652–1661, 2002.
Copyright © 2013 Shahid K. Sukhbir. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.