Herpes simplex virus encephalitis in pregnancy Olivier Dupuis, MD, Francois Audibert, MD, Herve´ Fernandez, MD, and Rene´ Frydman, MD Background: Although polymerase chain reaction (PCR) can detect herpes simplex virus (HSV) in the cerebrospinal fluid (CSF), HSV encephalitis remains a significant cause of neurologic impairment in pregnant women. Assessment of fetal contamination also remains a problem. Cases: We report two cases in which HSV encephalitis initially was not suspected and led to significant maternal neurologic impairment. In both cases, HSV PCR of CSF confirmed the diagnosis. In one case, fetal serum HSV PCR excluded fetal contamination. Conclusion: As soon as encephalitis in pregnancy is suspected, a combination of acyclovir and penicillin is recommended because the potential benefits far outweigh the risks. Using the HSV PCR, HSV infection in the fetus can be diagnosed. (Obstet Gynecol 1999;94:810 –2. © 1999 by The American College of Obstetricians and Gynecologists.)
In 1966, Rawls1 reported the first case of herpes simplex virus (HSV) encephalitis in pregnancy. Twenty other cases were identified by a MEDLINE search of the English-language literature from 1966 through 1998 using the keywords herpes simplex virus, encephalitis, and pregnancy. Outlined in Table 1 are 13 cases1–11 in which diagnoses were made using positive brain biopsy, brain necropsy, or production of HSV antibody in cerebrospinal fluid (CSF). Eight other cases were published, but did not fulfill any of those criteria and were excluded. The present cases of HSV encephalitis in pregnancy are the first reported in which diagnoses were established by HSV polymerase chain reaction (PCR) of CSF and in which HSV PCR excluded fetal contamination. Cases Case 1 A previously healthy, 35-year-old gravida 3 para 2 at 27 weeks’ gestation was admitted after a generalized seizure. She had a 24-hour history of headache, fever, and photophobia. On admission, her blood pressure (BP) was 160/80 mmHg and her temperature was 38C. Neurologic examination was normal except for generalized hyperreflexia. Platelet count,
From the Department of Obstetrics and Gynecology, Paris XI University, Hoˆpital Antoine Becle`re, Clamart cedex, France.
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serum electrolytes, serum aspartate aminotransferase, and serum alanine aminotransferase were normal. White blood cell (WBC) count was 17,500 per mm3 and hemoglobin 11 g/dL. Cranial computed tomography (CT) was normal. At first eclampsia was suspected, but BP returned spontaneously to normal and urinalysis showed 310 mg/L of protein. A lumbar puncture found 156 white cells (74% lymphocytes) and no red cells. Cerebrospinal fluid protein was 0.35 g/L. Cerebrospinal fluid glucose was 0.33 mmol/dL (59.4 mg/dL). Blood glucose was 0.49 mmol/dL (88.2 mg/dL). The predominance of lymphocytes in her CSF and the prevalence of the disease in our country, led us to suspect listeria meningitis, and intravenous ampicillin was given. Despite antibiotics, her temperature reached 40C accompanied by stupor and confusion. An electroencephalogram found an abnormal signal in the left frontotemporal region. Three facts that led to diagnosis of HSV encephalitis were that the CSF contained mainly lymphocytes, the antibiotic treatment was ineffective, and the electroencephalogram showed an abnormal signal in the frontotemporal region. Acyclovir was then given. HSV PCR was requested on the initial CSF sample. Forty-eight hours after admission, diagnosis was confirmed by positive HSV PCR of CSF. Restriction enzyme analysis of the PCR product yielded a pattern specific to HSV type 1. At the same time, serum interferon-␣ was 4 IU/mL (normal under 2 IU/mL) and CSF interferon-␣ 150 IU/mL (normal under 2 IU/mL). The serum to CSF ratio for HSV immunoglobulin (Ig)G was 577 (normal range over 100). Viral cultures of CSF were sterile. On day 3, a cerebral magnetic resonance imaging (MRI) showed an increased signal in the left temporal region. Within 72 hours of admission, the woman was comatose, and after 2 days she had right-side paraplegia and a central facial palsy. She was intubated and ventilated. On day 17, she was extubated. Her mental and physical status gradually improved, with clearing of her motor deficit over the next 6 days. On day 23, she was able to walk. During the course of the disease, fetal monitoring was normal. To assess the risk of fetal contamination, amniocentesis and fetal cord blood sampling were done, and HSV DNA and HSV culture were negative from both samples. No HSV IgM was detected in the fetal blood. A fetal cerebral MRI was normal. Except for a seizure recurrence at 39 weeks’ gestation, which was managed successfully with phenobarbital, the remainder of her pregnancy was normal. She delivered at term a 3320 g female with Apgar scores of 9 and 10 at 1 and 5 minutes, respectively. No HSV IgM was detected in the newborn, and she is now a healthy 13-month-old child. One year later, the mother still showed severe anterograde memory loss without motor deficit. Case 2 A 31-year-old gravida 2 para 1 at 35 weeks’ gestation was admitted to a local hospital for severe headache, nausea, vomiting, and photophobia. On admission, temperature was 38.5C, BP was normal, and proteinuria was absent. Uric acid, platelet count, and liver enzymes were normal. White blood cell count was 10,300 per mm3. A clinical diagnosis of menin-
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Table 1. Herpes Simplex Virus Encephalitis in Pregnancy Age (y)
Gestational age at diagnosis (wk)
Rawls et al1 (1966) Anderson and Nicholls2 (1972) Jewett3 (1975) Roman-Campos et al4 (1979) Roman-Campos et al4 (1979) Roman-Campos et al4 (1979) Berger et al5 (1986)
30 Near term
Brain necropsy Brain biopsy
Bacterial infection Herpes encephalitis
Brain necropsy Brain necropsy
Herpes encephalitis Eclampsia
Greffe et al6 (1986) Hankey et al7 (1987)
Besser et al8 (1989)
Frieden et al9 (1990)
Anteby et al10 (1992)
Present study Present study
Antibody to HSV in the CSF Brain biopsy Antibody to HSV in the CSF Antibody to HSV in the CSF Antibody to HSV in the CSF Antibody to HSV in the CSF Antibody to HSV in the CSF HSV PCR of CSF HSV PCR of CSF
Psychiatric syndrome Herpes encephalitis
Author (year of publication)
Herpes encephalitis Bacterial infection Bacterial infection Herpes encephalitis Herpes encephalitis Herpes encephalitis Eclampsia Bacterial encephalitis
NA ⫽ not available; PCR ⫽ polymerase chain reaction; HSV ⫽ herpes simplex virus; CSF ⫽ cerebrospinal fluid. * Secondary to complications of prematurity.
gitis was made and, because the patient was pregnant, listeriosis was suspected and intravenous ampicillin was given. Despite treatment, she developed confusion, bizarre behavior, auditory hallucinations, and aphasia. On day 3, she was transferred to a teaching hospital where on admission, cerebral CT was normal, but MRI found an abnormal signal in the left temporal region. An electroencephalogram detected an epileptic foci in the same region. A lumbar puncture was done and CSF analysis showed 138 white cells (100% lymphocytes), 2 red cells, a normal serum to CSF glucose ratio and a protein content of 0.7 g/L. The serum to CSF ratio of HSV IgG was 28 (normal value over 100), therefore local HSV antibody production was suspected. No interferon synthesis was shown in the sera or the CSF. Four facts that led to diagnosis of HSV encephalitis were that the CSF contained mainly lymphocytes, antibiotic treatment was ineffective, and MRI as well as electroencephalogram showed abnormal temporal signal. Intravenous acyclovir was given, and 6 days later the diagnosis was confirmed by HSV PCR of CSF. Restriction enzyme analysis of the PCR product showed a pattern specific to HSV type 1. Viral cultures of CSF were sterile. She improved rapidly and delivered at term a healthy 2980 g male with Apgar scores of 9 and 10 at 1 and 5 minutes, respectively. The infant serum was negative for HSV IgM. Three months later, the mother exhibited moderate amnesia. Six months later, speech therapy was no longer necessary.
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Comment With 13 cases reported between 1966 and 1998, HSV encephalitis is rare during pregnancy. The occurrence of two cases in 16 months in the same hospital suggests that the true prevalence of the disease might be underestimated. Among 15 cases1–11 (Table 1), HSV encephalitis was misdiagnosed in eight,1,4,7,8 indicating the multifocal clinical appearance of the disease. Admission criteria were seizures, neurologic or psychiatric disorders (focal deficit, speech difficulty, hallucinations, confusion), or flu-like symptoms (fever, headache). Mucocutaneous herpetic lesions were rare (one case6), with no history of herpetic lesions. Biologic and radiologic findings were also not specific. Normal biologic (CSF analysis) and radiologic (cerebral CT, MRI) data do not exclude the diagnosis.10 Before the introduction of acyclovir, HSV encephalitis was frequently fatal. Recent reports indicate that good outcomes depend on an early acyclovir treatment.12 Even so, after 1984, only two of seven clinical teams treated suspected encephalitis with a combination of penicillin and acyclovir.6,9 Since 1984, the manufacturer maintains a prospective registry of
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exposure to acyclovir in pregnancy.13 To date, it includes 1115 pregnancies, and birth defects have not increased compared with the general population. In 1998, CDC guidelines14 stated “In the presence of lifethreatening maternal HSV infections, acyclovir administration is indicated.” As soon as encephalitis is suspected, an immediate regimen of acyclovir and penicillin should be given.6,9 Within 1 day, HSV PCR of CSF will allow a rapid, highly reliable diagnoses and typing of HSV encephalitis in 92% of cases.15,16 When done during acyclovir therapy, HSV PCR will remain positive.15 In Case 1, we sampled fetal cord blood to assess fetal contamination. That procedure deserves further discussion. Although rare, fetal contamination by maternal viremia has been described.5,17 In Case 1, the parents were aware of the risk of fetal contamination and the small but significant risk related to cord blood sampling. Nevertheless they requested a prenatal diagnosis. Had the fetus been infected, intravenous acyclovir would have been given to allow prolongation of pregnancy with decreased risk of fetal damage. Acyclovir crosses the placenta, is present in fetal blood, is excreted by fetal kidney and concentrated in the amniotic fluid;18 therefore, intrauterine therapy might be efficient. If severe fetal defects were detected by ultrasound or MRI, pregnancy termination would have been discussed (as authorized by French laws).
References 1. Rawls WE, Dyck PJ, Klass DW, Greer HD, Herrmann EC. Encephalitis associated with herpes simplex virus. Ann Intern Med 1966;64:104 –15. 2. Anderson JM, Nicholls MWN. Herpes encephalitis in pregnancy. BMJ 1972;1:632. 3. Jewett JF, Committee on Maternal Welfare. Herpes simplex encephalitis. N Engl J Med 1975;292:531. 4. Roman-Campos G, Navarro de Roman LI, Toro G, Vergara I. Herpes encephalitis in pregnancy. Am J Obstet Gynecol 1979;135: 158 –9. 5. Berger SA, Weinberg M, Treves T, Sorkin P, Geller E, Yedwab G, et al. Herpes encephalitis during pregnancy: Failure of acyclovir and adenine arabinoside to prevent neonatal herpes. Isr J Med Sci 1986;22:41– 4. 6. Greffe BS, Dooley SL, Deddish RB, Krasny HC. Transplacental passage of acyclovir. J Pediatr 1986;108:1020 –1. 7. Hankey GJ, Bucens MR, Chambers JS. Herpes simplex encephalitis in third trimester of pregnancy: Successful outcome for mother and child. Neurology 1987;37:1534 –7.
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8. Besser R, Vogt T, Thomke F. Successful treatment of HSV encephalitis during pregnancy. Neurology 1989;39:748. 9. Frieden FJ, Ordorica SA, Goodgold AL, Hoskins IA, Silverman F, Young BK. Successful pregnancy with isolated herpes simplex virus encephalitis: Case report and review of the literature. Obstet Gynecol 1990;75:511–3. 10. Anteby E, Reches A, Lavy Y, Yagel S. Fetal serology in maternal HSV encephalitis. Prenat Diagn 1992;12:855– 6. 11. Yaqub BA. Herpes simplex encephalitis in a pregnant woman: Successful outcome for the mother and her baby. Annals of Saudi Medicine 1994;14:149 –51. 12. Whitley RJ, Alford CA, Hirsch MS, Schooley RT, Luby JP, Aoki FY, et al. Vidarabine versus acyclovir therapy in herpes simplex encephalitis. N Engl J Med 1986;314:144 –9. 13. Andrews EB, Yankaskas BC, Cordero JF, Schoeffler K, Hampp S. Acyclovir in pregnancy registry: Six years’ experience. The Acyclovir in Pregnancy Registry Advisory Committee. Obstet Gynecol 1992;79:7–13. 14. Centers for Disease Control and Prevention. 1998 guidelines for treatment of sexually transmitted diseases. MMWR 1998;47(RR-1): 1–118. 15. Guffond T, Dewilde A, Lobert PE, Caparros-Lefebvre D, Hober D, Wattre P. Significance and clinical relevance of the detection of herpes simplex virus DNA by the polymerase chain reaction in cerebrospinal fluid from patients with presumed encephalitis. Clin Infect Dis 1994;18:744 –9. 16. Lakeman FD, Whitley RJ. Diagnosis of herpes simplex encephalitis: Application of polymerase chain reaction to cerebrospinal fluid from brain-biopsied patients and correlation with disease. National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group. J Infect Dis 1995;171:857– 63. 17. Sarkell B, Blaylock WK, Vernon H. Congenital neonatal herpes simplex virus infection. J Am Acad Dermatol 1992;27:817–21. 18. Frenkel LM, Brown ZA, Bryson YJ, Corey L, Unadkat JD, Hensleigh PA, et al. Pharmacokinetics of acyclovir in the term human pregnancy and neonate. Am J Obstet Gynecol 1991;164:569 –76.
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Olivier Dupuis, MD Service de Gynecologie Obstetrique CHU Bichat 46, rue Henri-Huchard Paris 75018 France E-mail: [email protected]
Received November 20, 1998. Received in revised form January 20, 1999. Accepted February 18, 1999. Copyright © 1999 by The American College of Obstetricians and Gynecologists. Published by Elsevier Science Inc.
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