PEDIATRICS Vol. 115 No. 3 March 2005, pp. 795-797 (doi:10.1542/peds.2004-1941)
COMMENTARY |
Challenges in the Diagnosis and Management of Neonatal Herpes Simplex Virus Encephalitis
Departments of Pediatrics and Laboratory Medicine
University of Washington and Children’s Hospital
Seattle, WA 98109
Research during the past 30 years has transformed our approach to the diagnosis and management of neonatal herpes simplex virus (HSV) encephalitis.1 Nevertheless, early diagnosis of HSV encephalitis and its long-term management continue to challenge practitioners, primarily because of the paucity of clinical symptoms and laboratory abnormalities associated with early disease.1–5 Fonseca-Aten et al,6 in this issue of Pediatrics, report on an infant who developed symptomatic HSV encephalitis during administration of daily oral acyclovir (ACV) given to "suppress" HSV disease. Elements of this case spotlight issues peculiar to HSV that may assist pediatric practitioners in the timely diagnosis and effective management of neonatal HSV encephalitis.1,5,7–10
Neonatal HSV infections are often categorized into 1 of 3 syndromes: skin-eye-mouth, disseminated, and central nervous system (CNS). However, these disease patterns are not discreet, with encephalitis often due to the extension of skin-eye-mouth or disseminated disease. HSV encephalitis affects the brain cortex or, less commonly, the brainstem.1 HSV replication in the cortex of infants can be clinically unapparent,1–5 because cortical function is not required for most activities of infants. HSV CNS infection can be difficult to diagnose by examination of cerebral spinal fluid (CSF), because the meninges may not be significantly inflamed. This is particularly true in the early phases of the illness, during which treatment can have the most impact on reducing long-term neurologic morbidity.1,5,7 Also problematic is that reactivation of HSV in the CNS, which is lytic to the brain parenchyma, may be asymptomatic in infants, with neurologic impairment becoming apparent by 6 to 12 months of age.1,11
The infant reported by Fonseca-Aten et al6 was first diagnosed with encephalitis after seizures at 3 months of age. No studies have clearly defined the time frame during which skin-eye-mouth disease can spread to involve the brain; however, evidence suggests that infection of the brain is established during acute infection, before HSV-specific immune responses, with persistent replication or later reactivation in some infants.1,12 Whether the brain of the infant reported by Fonseca-Aten6 had HSV infection before 3 months of age is unknown, but it seems likely based on laboratory and radiographic findings.
The diagnosis of HSV encephalitis in neonates, as well as in children and adults, has been markedly facilitated by the availability of assays that amplify viral DNA to detectable levels by using polymerase chain reaction (PCR).8,13–15 Nevertheless, PCR cannot always diagnose HSV encephalitis in the first few days of illness, as indicated by negative results from CSF specimens from individuals previously or prospectively diagnosed with HSV CNS disease.8,14,15 PCR of infants’ CSF suggest a sensitivity of 
70% early in infection.8 Testing of additional CSF specimens collected shortly after the onset of symptoms indicates that HSV DNA can eventually be detected in nearly 100% of individuals with HSV encephalitis.13–15 False-negative HSV PCR tests early in the course of disease could be caused by insufficient release of HSV nucleic acid from the brain into the CSF or technical limitations of the assay. Based on these data, most experts recommend serial evaluations of infants’ CSF by PCR during the first week of illness when HSV encephalitis is a possibility.1,8,14,15
The infant reported by Fonseca-Aten6 et al was first diagnosed with HSV when 19 days old. She was well except for a vesicular lesion noted on the chest, which grew HSV type 2 in culture. A lumbar puncture (LP) when she was 19 days old was traumatic. However, 54% of the 31 white blood cells (WBCs) per µL in the CSF were classified as neutrophils, which was increased compared with the peripheral blood. PCR assays are not standardized, and it is important to note that variations in sample handling and laboratory methods can affect the sensitivity of the assay. Relevant to this case is that specimens containing hemolyzed red blood cells (RBCs) or other inhibitors of PCR may be falsely negative. The elevation of neutrophils in this infant’s CSF suggests inflammation and is suspicious for HSV infection, because even subtle changes in CSF values have been observed in infants with HSV CNS disease.1–3,10 Because of the inherent difficulties in interpreting traumatic LP, many experts recommend that they be repeated, in addition to serial LP, which should be performed to evaluate both infants1,10 and adults14,15 for HSV encephalitis.
Smoldering recurrences of HSV CNS disease occur in most infants after acute encephalitis and in 6% after acute HSV skin-eye-mouth disease.1–3,5 The poor neurologic outcome of these infants has led to recommendations that they undergo serial long-term evaluations from qualified specialists.1 Modeled on the study design of protocols conducted by the National Institute of Allergy and Infectious Diseases’ Collaborative Antiviral Study Group (CASG), serial LPs are done during ACV treatment of infants with encephalitis at our center to document effective control of HSV replication by diminution of CSF HSV DNA detected by PCR.16 In addition, just before completion of ACV therapy a LP is done to document the CSF parameters for comparison to those obtained as part of posttreatment monitoring.9 To evaluate infants for HSV CNS recurrences, most experts recommend assessing the CSF at the time of cutaneous HSV recurrences; frequent skin recurrences were associated with poor neurologic outcome in 29% of infants after HSV type 2 skin-eye-mouth disease,5 which suggests that frequent skin recurrences may be a marker for poor immunologic control of HSV replication. To detect subclinical recurrences of HSV encephalitis at our center, CSF parameters are also evaluated at 1 to 2 and 4 to 6 weeks after completion of intravenous ACV treatment as well as on cutaneous recurrences or symptoms suggestive of CNS disease through at least 6 months of age. If CSF parameters suggest increased inflammation compared with the end of treatment, a course of high-dose intravenous ACV is administered.
The infant reported by Fonseca-Aten et al6 had a skin recurrence of HSV at the site of the original lesion 5 days after completing the initial course of intravenous ACV, with no reported neurologic or constitutional symptoms. The CSF at this time had a mild pleocytosis and elevated protein (CSF: 15 WBCs per µL with 3% neutrophils, 71% lymphocytes, 26% monocytes, 2 RBCs per µL, protein level of 97 mg/dL, and glucose level of 40 mg/dL). Intravenous ACV was given again to the infant until the HSV DNA PCR test of the CSF was reported to be negative 4 days later. As mentioned above, mildly abnormal CSF values may be typical of smoldering HSV CNS disease.1–3 It is therefore possible that the PCR of this infant’s CSF may have been negative because of the relative insensitivity of the assay in mild disease.1,8,14,15
Oral ACV (300 mg/M2 per dose given 3 times a day) was then prescribed for the infant with the hope of suppressing HSV recurrences. However, at 3 months of age the infant had seizures with markedly abnormal CSF parameters (CSF: 1415 WBCs per µL with 46% neutrophils, 27% lymphocytes, 27% monocytes, 97 RBCs per µL, protein level of 131 mg/dL, and glucose level of 47 mg/dL) and HSV DNA detected. The abnormalities found on MRI and computed tomography of the head at this time suggested that disease had been ongoing for some time. Subsequently, the infant’s brain disease seemed to progress further; an MRI at 12 months of age revealed generalized cortical volume loss and macrocystic encephalomalacia of most of the left temporal and parietal lobes.
Although abundant data support ACV suppression of genital HSV disease,17 Fonseca-Aten et al6 and Gutierrez and Arvin10 caution that, as this case demonstrates, it is inappropriate to assume that oral ACV suppresses HSV CNS disease in infants. During the past couple of decades, perhaps extrapolated from the success of ACV and its prodrugs in the suppression of genital recurrences, some practitioners have used chronic oral ACV with the goal of suppressing CNS recurrences in infants. Studies evaluating the efficacy of chronic oral ACV to suppress CNS recurrences, however, have not been completed. Such studies are now ongoing under the purview of the CASG in infants after either skin-eye-mouth disease or encephalitis.
Assuming that the family of the patient described by Fonseca-Aten et al6 administered the oral ACV, this case demonstrates what many fear: that ACV concentrations in the brain from administration of oral suspension may be inadequate to suppress HSV encephalitis. Oral absorption of ACV is poor and variable, ranging from 10% to 20%,18 and only 50% of serum concentrations pass into the brain.18 The relatively high oral doses used in the CASG studies (300 mg/M2 given 2 or 3 times a day) seem safe, although neutropenia (temporary in 10 of 12 infants) occurred in 46%.8 The mean (±SD) peak plasma ACV concentration after 3-times-daily dosing was 1.95 ± 0.75 µg/mL, whereas the trough concentrations were 1.09 ± 0.63.8 HSV type 2, the most prevalent cause of neonatal disease, is 50% inhibited in culture (IC50) by a mean ACV concentration of 0.10 µg/mL.17 The predicted 5- to 10-fold-greater concentration of ACV in the brain compared with the IC50 of HSV type 2 suggests that oral ACV may be adequate to treat HSV. However, this logic seems questionable given that "high-dose" intravenous ACV (20 mg/kg per dose given intravenously every 8 hours) produced peak plasma concentrations 10- to 20-fold higher than oral ACV, and this dose was significantly more effective in treating neonatal HSV encephalitis compared with lower intravenous doses.19
Often, suppression of genital HSV has been achieved with ACV doses lower than those needed for effective treatment.17 These observations form part of the rationale for studies evaluating whether oral ACV can suppress CNS disease. Five anecdotal reports described the use of "suppressive" oral ACV, including 3 "failures"20 including the Fonseca-Aten et al case6 and "two successes."11 Thus, although controlled trials are underway by the CASG to evaluate whether oral ACV can suppress HSV replication in the CNS, experts at this time do not recommend chronic administration of oral ACV to potentially suppress CNS recurrences.1,10
Neonatal HSV, in addition to posing diagnostic and management difficulties to pediatric practitioners, is a disturbing disease to affected families. This stems from its being life-threatening or producing severe morbidity, which may be exacerbated by HSV recurrences, and from prevalent misconceptions about HSV infections (Table 1). An unfamiliarity with the data showing that genital HSV infections are prevalent,1 that most genital HSV infections are asymptomatic,1 that early neonatal HSV encephalitis has few if any symptoms,1–3,7 and that HSV DNA PCR is not highly sensitive in the diagnosis of early CNS disease8 seems to be at the root of the progressive delay9 in practitioners’ diagnosing neonatal HSV encephalitis.
|
In summary, this case highlights important information for the pediatric practitioner: that HSV PCR of CSF may be negative in early encephalitis and repeated LP is indicated to diagnose HSV encephalitis; that CSF may be normal or mildly abnormal in infants with HSV encephalitis; that there is insufficient evidence to evaluate whether oral ACV "suppresses" HSV recurrences in the CNS; and that most experts do not recommend such use of oral ACV except as part of a clinical trial. The report also makes the case for additional research to define a long-term management strategy for infants with neonatal HSV. Studies need to evaluate the utility and optimal frequency of serial LP and PCR of plasma for diagnosis, the sensitivity of CSF PCR versus cell and chemistry parameters in predicting neurologic outcome, and the efficacy of chronic ACV and its prodrugs (that achieve higher levels in brain) to suppress CNS disease.
 |
FOOTNOTES |
|---|
Accepted Sep 21, 2004.
Address correspondence to Lisa M. Frenkel, MD, Departments of Pediatrics and Laboratory Medicine, University of Washington and Children’s Hospital, 307 Westlake Ave N, Suite 300, Room 330, Seattle, WA 98109. E-mail: lfrenkel{at}u.washington.edu
No conflict of interest declared.
|
REFERENCES |
|---|
 TOP REFERENCES |
|---|
- Arvin AM, Whitley RJ. Herpes simples virus infections. In: Infectious Diseases of the Fetus and Newborn Infant. Remington JS, Klein JO, eds. 5th ed. Philadelphia, PA: Saunders; 2001:425–446
- Whitley RJ, Nahmias AJ, Visintine AM, Fleming CL, Alford CA. The natural history of herpes simplex virus infection of mother and newborn.
Pediatrics. 1980;66
:489
–494
[Abstract/Free Full Text] - Whitley RJ, Yeager A, Kartus P, et al. Neonatal herpes simplex virus infection: follow-up evaluation of vidarabine therapy.
Pediatrics. 1983;72
:778
–785
[Abstract/Free Full Text] - Corey L, Whitley RJ, Stone EF, Mohan K. Difference between herpes simplex virus type 1 and type 2 neonatal encephalitis in neurological outcome. Lancet. 1988;1(8575–6) :1 –4
- Whitley R, Arvin A, Prober C, et al. Predictors of morbidity and mortality in neonates with herpes simplex virus infections. The National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group. N Engl J Med. 1991;324 :450 –454[Abstract]
- Fonseca-Aten M, Messina AF, Jafri HS, Sánchez PJ. Herpes simplex virus encephalitis during suppressive therapy with acyclovir in a premature infant.
Pediatrics. 2005;115
:804
–809
[Abstract/Free Full Text] - Whitley RJ, Corey L, Arvin A, et al. Changing presentation of herpes simplex virus infection in neonates. J Infect Dis. 1988;158 :109 –116[Web of Science][Medline]
- Kimberlin DW, Lakeman FD, Arvin AM, et al. Application of the polymerase chain reaction to the diagnosis and management of neonatal herpes simplex virus disease. National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group. J Infect Dis. 1996;174 :1162 –1167[Web of Science][Medline]
- Kimberlin DW, Lin CY, Jacobs RF, et al. Natural history of neonatal herpes simplex virus infections in the acyclovir era.
Pediatrics. 2001;108
:223
–229
[Abstract/Free Full Text] - Gutierrez K, Arvin AM. Long term antiviral suppression after treatment for neonatal herpes infection. Pediatr Infect Dis J. 2003;22 :371 –372[CrossRef][Web of Science][Medline]
- Gutman LT, Wilfert CM, Eppes S. Herpes simplex virus encephalitis in children: analysis of cerebrospinal fluid and progressive neurodevelopmental deterioration. J Infect Dis. 1986;154 :415 –421[Web of Science][Medline]
- Kohl S. A hypothesis on the pathophysiology of neonatal herpes simplex virus encephalitis: clinical recurrence after asymptomatic primary infection. Pediatr Infect Dis J. 1990;9 :307 –308[Web of Science][Medline]
- Aurelius E, Johansson B, Skoldenberg B, Staland A, Forsgren M. Rapid diagnosis of herpes simplex encephalitis by nested polymerase chain reaction assay of cerebrospinal fluid. Lancet. 1991;337 :189 –192[CrossRef][Web of Science][Medline]
- Studahl M, Bergstrom T, Hagberg L. Acute viral encephalitis in adults—a prospective study. Scand J Infect Dis. 1998;30 :215 –220[CrossRef][Web of Science][Medline]
- Weil AA, Glaser CA, Amad Z, Forghani B. Patients with suspected herpes simplex encephalitis: rethinking an initial negative polymerase chain reaction result. Clin Infect Dis. 2002;34 :1154 –1157[CrossRef][Web of Science][Medline]
- Diamond C, Mohan K, Hobson A, Frenkel L, Corey L. Viremia in neonatal herpes simplex virus infections. Pediatr Infect Dis J. 1999;18 :487 –489[CrossRef][Web of Science][Medline]
- Whitley RJ, Gnann JW Jr. Acyclovir: a decade later. N Engl J Med. 1992;327 :782 –789[Web of Science][Medline]
- Physicians’ Desk Reference. Montvale, NJ: Thomson PDR; 2004:1683–1687
- Kimberlin DW, Lin CY, Jacobs RF, et al. Safety and efficacy of high-dose intravenous acyclovir in the management of neonatal herpes simplex virus infections.
Pediatrics. 2001;108
:230
–238
[Abstract/Free Full Text] - Mandyla H, Anagnostakis D, Koutsovitis P, Siahanidou T, Youroukos S. Late recurrence of herpes simplex virus meningoencephalitis in two infants. Eur J Pediatr. 2001;160 :732 –735[Web of Science][Medline]
PEDIATRICS (ISSN 1098-4275). ©2005 by the American Academy of Pediatrics
CiteULike 
Connotea 
Del.icio.us 
Digg 
Facebook 
Reddit 
Technorati 
Twitter What's this?
This article has been cited by other articles:
|
|
 |
|
  PEDIATRICS & ADOLESCENT MEDICINE Arch. Dis. Child., August 1, 2005; 90(8): 873 - 874. [Full Text] [PDF]
|
|
|
|
 |
|
 Neonatal Herpes Simplex Infection: A Sad Yet Instructive Case Journal Watch Pediatrics and Adolescent Medicine, April 25, 2005; 2005(425): 4 - 4. [Full Text]
|
|
|
|
 |
|
 Recurrence of Neonatal Herpes Simplex Journal Watch Infectious Diseases, March 28, 2005; 2005(328): 5 - 5. [Full Text]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
