Pediatric Annals

Would Anyone Start Acyclovir?

Joseph E Sullivan, III, MD

Abstract

Would anyone start acyclovir? This infamous question has come up on numerous occasions in resident morning report, and there is almost never a general consensus as to what to do. It seems to depend on the answers to such pertinent questions as: How sick does the kid look?, What was the child's mental status?. If there was a seizure, was the seizure focal? In this brief article I discuss whether there are any clear clinical scenarios in which herpes simplex virus (HSV) should be suspected and how reliable specific information regarding mental status, focal seizures, polymerase chain reaction (PCR) results, and electroencephalogram (EEG) data are for diagnosing HSV encephalitis.

As Dr. Kohl mentions in his article (page 726), there has not been a significant decrease in the time between recognition of neonatal HSV disease and initiation of antiviral therapy. This is true despite the widely available HSV PCR (DNA amplification) technique, probably because if there is a low index of suspicion, cerebrospinal fluid (CSF) won't be obtained, or if it is obtained, it will not be sent for HSV PCR. What are residents working in the emergency department or on the floor to do?

In the presence of vesicles and a neonate who appears to be sick, evaluation and treatment for HSV is standard of care. However, fewer than two thirds of children with central nervous system (CNS) disease have vesicles at presentation, and only about half are lethargic or present with a seizure.1 Furthermore, while focal seizures are the classic presentation of HSV encephalitis in adults and children, this is not always the case in neonates. Finally, neonatal seizures are often subtle and can fool even the experienced observer, as has been corroborated even better with modern video EEG technology and experienced epileptologists reviewing the tapes. Therefore, the absence of seizures or seizure focality in a neonate is not reassurance that HSV need not be in the differential diagnosis.

We have had experience at Children's Memorial with a few infants who have presented with fever alone, received the usual rule out sepsis work-up, and who later became very ill and were ultimately diagnosed with disseminated HSV disease.2 Nevertheless, this experience should not cause clinicians to add acyclovir to their routine "rule out sepsis" antimicrobial coverage, nor should HSV PCR be ordered on every neonate with a fever. It does, however, suggest, as Dr. Kohl advises in his article, that in those neonates with fever who are in any way different from the usual fever in neonate patient, HSV should be a consideration. This is especially the case if there is CSF pleocytosis. Herpes simplex virus encephalitis is one of the few treatable forms of viral encephalitis, and the earlier therapy is instituted, the better the neurological outcome.3 With the widespread availability of HSV PCR and the improving turnaround time of this test, it seems fair to advocate for the evaluation of HSV in those children who appear sicker than expected, or who have evidence of CSF pleocytosis. It must be noted/ however, that during the neonatal period the sensitivity and specificity of HSV PCR in diagnosing CNS involvement are only 80% and 71% respectively, considerably lower than the sensitivity and specificity of the test for children older than 3 months.4 Given the inadequacy of this test to "catch" all infants, is there anything else that can be done?

Fortunately, in the near future we may be able to make use of the fact that neonatal seizures are often clinically inapparent. In children who have documented involvement of the CNS from HSV infection, 80% to 90% have an abnormal EEG…

Would anyone start acyclovir? This infamous question has come up on numerous occasions in resident morning report, and there is almost never a general consensus as to what to do. It seems to depend on the answers to such pertinent questions as: How sick does the kid look?, What was the child's mental status?. If there was a seizure, was the seizure focal? In this brief article I discuss whether there are any clear clinical scenarios in which herpes simplex virus (HSV) should be suspected and how reliable specific information regarding mental status, focal seizures, polymerase chain reaction (PCR) results, and electroencephalogram (EEG) data are for diagnosing HSV encephalitis.

As Dr. Kohl mentions in his article (page 726), there has not been a significant decrease in the time between recognition of neonatal HSV disease and initiation of antiviral therapy. This is true despite the widely available HSV PCR (DNA amplification) technique, probably because if there is a low index of suspicion, cerebrospinal fluid (CSF) won't be obtained, or if it is obtained, it will not be sent for HSV PCR. What are residents working in the emergency department or on the floor to do?

In the presence of vesicles and a neonate who appears to be sick, evaluation and treatment for HSV is standard of care. However, fewer than two thirds of children with central nervous system (CNS) disease have vesicles at presentation, and only about half are lethargic or present with a seizure.1 Furthermore, while focal seizures are the classic presentation of HSV encephalitis in adults and children, this is not always the case in neonates. Finally, neonatal seizures are often subtle and can fool even the experienced observer, as has been corroborated even better with modern video EEG technology and experienced epileptologists reviewing the tapes. Therefore, the absence of seizures or seizure focality in a neonate is not reassurance that HSV need not be in the differential diagnosis.

We have had experience at Children's Memorial with a few infants who have presented with fever alone, received the usual rule out sepsis work-up, and who later became very ill and were ultimately diagnosed with disseminated HSV disease.2 Nevertheless, this experience should not cause clinicians to add acyclovir to their routine "rule out sepsis" antimicrobial coverage, nor should HSV PCR be ordered on every neonate with a fever. It does, however, suggest, as Dr. Kohl advises in his article, that in those neonates with fever who are in any way different from the usual fever in neonate patient, HSV should be a consideration. This is especially the case if there is CSF pleocytosis. Herpes simplex virus encephalitis is one of the few treatable forms of viral encephalitis, and the earlier therapy is instituted, the better the neurological outcome.3 With the widespread availability of HSV PCR and the improving turnaround time of this test, it seems fair to advocate for the evaluation of HSV in those children who appear sicker than expected, or who have evidence of CSF pleocytosis. It must be noted/ however, that during the neonatal period the sensitivity and specificity of HSV PCR in diagnosing CNS involvement are only 80% and 71% respectively, considerably lower than the sensitivity and specificity of the test for children older than 3 months.4 Given the inadequacy of this test to "catch" all infants, is there anything else that can be done?

Fortunately, in the near future we may be able to make use of the fact that neonatal seizures are often clinically inapparent. In children who have documented involvement of the CNS from HSV infection, 80% to 90% have an abnormal EEG when read and interpreted by an experienced pediatric epileptologist familiar with agerelated changes in the neonatal EEG background, and there are a wide variety of abnormalities reported on the EEG in neonates who have HSV encephalitis. Although the classically described finding of a periodic EEG is not always seen, this appears to be a very specific finding for HSV infection, especially if the patient has CSF pleocytosis.5 The periodicity may be focal, in which case the findings are called periodic lateralizing epileptiform discharges (PLEDs), or it may be multi-focal, where each focus has its own repetition rate. Even in the study by Kimberlin et al. in which only 26 of 34 neonates with HSV involvement of the CNS had a positive CSFHSV PCR, 27 of 34 had EEG evidence of HSV disease, including six patients who were HSV PCRnegative. Thus, taken together, HSV PCR and EEG were able to identify 32 of 34 patients with CNS HSV disease in this series. The EEG has also been shown to be. more sensitive than computed tomographic (CT) scan or ultrasound, as some patients had normal head CTs and /or ultrasounds even though they had an abnormal EEG within the same 24-hour period. Magnetic resonance imaging is better at demonstrating cortical gray matter and temporal lobe abnormalities than CT; however, it is not known how specific these findings are for neonatal HSV encephalitis.

In summary, in the near future the combination of HSV PCR and a well-done neonatal EEG may be the best diagnostic methods to identify a neonate with HSV CNS involvement. By using these two diagnostic modalities together in the appropriate clinical setting, timely institution of appropriate antiviral therapy may be able to prevent a significant degree of morbidity and mortality from this not uncommon disease.

REFERENCES

1. 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.

2. Filippine M, Katz BZ. Neonatal herpes simplex virus infection presenting with fever alone. J Hum Virol. 2001;4:223-225.

3. 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;108:230-237.

4. Kimberlin DW, Lakeman FD, Arvin AM, et al. Application of polymerase chain reaction to the diagnosis and management of neonatal herpes virus disease. National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group. J Infect Dis. 1996;174:1162-1167.

5. Mikati M, Feraru E, Krishnamoorthy K, Lombroso CT. Neonatal herpes simplex meningoencephalitis: EEG investigations and clinical correlates. Neurology. 1990;40:1433-1437.

6. Mizrahi E, Tharp BR. A characteristic EEG pattern in neonatal herpes simplex encephalitis. Neurology. 1982;32:1215-1220.

10.3928/0090-4481-20021101-11

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