Congenital Varicella-Zoster Virus Infection After Maternal Subclinical Infection: Clinical and Neuropathological Findings

Home , Hypertonia

Kirsi Mustonen, MD INTRODUCTION Pia Mustakangas, BA Maternal chickenpox and herpes zoster may cause classic congenital Leena Valanne, PhD, MD varicella-zoster virus (VZV) infection. Typical manifestations of the Matti Haltia Professor, MD child include cutaneous scars, as well as eye, limb, and brain Marjaleena Koskiniemi, PhD, MD abnormalities. Chromosomal aberration, abortion, and prematurity have also been described.5 VZV remains in sensory ganglia after primary infection and can reactivate later as herpes zoster, neurologic disease, or subclinically.6,11 Childhood herpes zoster may be the first OBJECTIVE: sign of an intrauterine infection, or the infection may remain It is known that varicella-zoster virus (VZV) can cause asymptomatic asymptomatic.5 Fetal affection after maternal asymptomatic VZV infections, but it has not been described that congenital infection can be infection has not been described. caused by maternal subclinical infection. The purpose of this study is to The purpose of this study is to evaluate the clinical picture of four evaluate clinical and neuropathologic findings of infants with neonatal neonates who had antibodies against VZV in the cerebrospinal fluid seizures and cerebrospinal fluid (CSF) VZV antibodies, but no maternal (CSF). Here we present the results of neuroimaging, EEG, and clinical VZV infection during the pregnancy. clinical examinations as well as findings of the follow-up of these STUDY DESIGN: infants. One child died and neuropathologic findings are reported. Screening of 201 neonates were studied for congenital viral infections, The significance of maternal subclinical VZV reactivation or chronic because of neurologic problems of unknown origin. Antibodies to 16 infection during pregnancy is discussed. different microbes were investigated from the CSF and the serum of the neonates, as well as fromthe first trimesterand postpartumserumof their mothers. Clinical symptoms and signs as well as neuropathology of those CASE 1 infants with antibodies to VZV in CSF were evaluated in this study. Clinical Findings This boy was the first child of his 31-year-old healthy mother. She RESULTS: had had chickenpox in childhood and one spontaneous early Four neonates with antibodies to VZV in CSF were identified and CSF abortion 8 years earlier. During the present pregnancy she had had a findings were reported earlier. Their mothers had laboratory evidence of common cold in the second trimester and mild edema during the infection, based on a significant rise in serumVZV antibody level during third, but otherwise the pregnancy had been uneventful. The child pregnancy in three mothers, and a constantly high antibody level to VZV in was born full termafter normaldelivery (Apgar scores 8/9). Birth one mother. All four children had seizures and abnormalities in muscular weight was 2920 g ( À1.5 SD), length 45 cm( À3 SD) and head tone during the neonatal period, but no typical manifestations of a circumference 33 cm ( À2 SD). The child showed irritability, congenital VZV infection. One child died at the age of 4 months. At autopsy, muscular hypertonia, rowing movements of the limbs and petechiae neuropathologic examination showed foci of astrocytic hyperplasia and on the face. He reacted faintly to loud noise, but had a clear blinking hypertrophy but no specific signs of viral infection. reflex to light. He had contractures of knees and abduction of the hip was restricted. The tendon reflexes were weak but symmetric. No CONCLUSION: Moro reflex nor grasping could be elicited. Ophthalmological Maternal subclinical VZV infection can cause congenital infection with examination of the retina was normal. The patient was fed by neurologic symptoms and signs in the child. nasogastric tube, and needed 40% to 60% oxygen during the first Journal of Perinatology 2001; 21:141±146. days. His breathing was irregular and he had a high-pitched cry. At the age of 5 days he was connected to a respirator for 9 days because Department of Neuropediatrics ( K.M. ) , North Karelia Central Hospital, Joensuu, Finland; of hypoventilation. Department of Virology( K.M., P.M., M.K. ) , Haartman Institute Universityof Helsinki, Abnormal movements decreased after phenobarbital treatment, Helsinki, Finland; Department of Radiology( L.V. ) , Hospital for Children and Adolescents, Helsinki UniversityCentral Hospital, Helsinki, Finland; Department of Pathology ( M.H. ) , but still appeared during stimulation. Intravenous ampicillin and Haartman Institute Universityof Helsinki, Helsinki, Finland; Department of Child Neurology netilmycin were given for 14 days and acyclovir 30 mg three times a ( M.K. ) , Hospital for Children and Adolescents, Helsinki UniversityCentral Hospital, Helsinki, Finland. day for 5 days. The child needed calciumsubstitution for 13 days because of hypocalcemia. Other metabolic examinations were Address correspondence and reprint requests to Kirsi Mustonen, MD, Department of Neuropediatrics, North Karelia Central Hospital, 80210 Joensuu, Finland. normal (blood glucose, ammonium, lactate, and pyruvate; serum

potassium, sodium, hepatic, and kidney function tests; plasma and Neuropathologic Findings urinary amino acids; and urinary organic acids). Serum C±reactive At autopsy, brain weight was 720 g, and there were no necrotic protein (CRP), total blood count, and coagulation studies were areas, hemorrhages, nor signs of herniation. There was no normal. significant inflammatory infiltration. Immunoperoxidase staining Blood, urine, and CSF bacterial cultures were negative as well as for glial fibrillary acidic protein (GFAP) showed scattered foci of routine CSF studies (glucose, protein, white and red blood cells). astrocytic hypertrophy and hyperplasia in the cerebral cortex, IgG VZV antibody level by using enzyme immuno assay test as cerebellum, and brain stem. Small calcifications were found in the described14 increased (the rise is considered diagnostic when it is area of the basal ganglia. In the cerebellumthere was slight loss >40 EIUs) in serumduring the first monthof his life (82±58± of Purkinje cells. No viral inclusion bodies were found. 102±111 EIU, normal range: <20 negative, >100 high). VZV- Immunoperoxidase staining for VZV was negative. The polymerase specific IgM was positive, and VZV-specific antibodies in the CSF chain reaction (PCR) assay for VZV in brain tissue9,19 gave indicated intrathecal antibody production (16±6 EIU, VZV IgG negative results. serum:CSF IgG ratio 3.6 to 18.5, normal >20). There were no other virus antibodies in CSF. The mother's VZV antibody level was high during the pregnancy and after the delivery (107±94±104 EIU). CASE 2 Virological examinations are reported in detail elsewhere.14 This boy was the first child of his 21-year-old healthy mother who Since the age of 16 days the patient was hypotonic and his had had chickenpox in her early years. In the second trimester of the spontaneous movements were few. At the age of 1 month he was able to pregnancy she had been in contact with children who had suck up to 80 ml milk, and his spontaneous movements improved, but chickenpox; otherwise the pregnancy was uneventful. The delivery were still uncoordinated and jerky. Occasionally he was able to look at was normal at term and the child got 9/9/9 Apgar scores. His birth an object. He had one tonic seizure for 2 hours at the age of 1 month, weight was 3280 g, length 50.5 cm, and head circumference 34 cm, and some minor seizures at the age of 2 months. During the follow-up all appropriate for gestation. At the fourth day he had recurrent the child's condition did not improve any further. At the age of 4 clonic movements in his left arm and right leg during sleep for months he had breathing difficulties in association with a respiratory periods of up to 10 minutes. Loading dose of 60 mg phenobarbital infection. He was treated with intravenous ceftriaxone, oral theophyllin and maintenance dose of 7 mg twice a day was given intravenously. and extra oxygen. His general condition deteriorated and he died 2 After that he had only a few clonic movements. Acyclovir 35 mg three weeks later. His body weight was 5700 g and the head circumference times a day was also given intravenously for 10 days. Slight muscular was 41.5 cm. The clinical data are summarized in Table 1. hypertonia was observed, but otherwise the neurologic examination gave normal results. Neuroimaging and EEG Findings EEG was normal and neuroimaging studies were not Computed tomography (CT) study showed supratentorial sulcal performed. Blood count, serum CRP, and metabolic tests (blood effacement and hypodensity of the basal ganglia, consistent with glucose and gas analysis; serum calcium, sodium, and edema at day 3. Magnetic resonance imaging (MRI) showed potassium) were normal. Bacterial cultures from blood and CSF hyperintensity of the lentiformand caudate nuclei bilaterally in T2- specimens were negative as well as other CSF studies (glucose, weighted images at day 4 (Figure 1). Ultrasound (US) of the brain protein, white and red cells). The only abnormal finding was was normal. Electroencephalography (EEG) showed periodic delta IgG antibodies to VZV in the CSF (10±8 EIU, VZV IgG waves in left temporal areas. HM-PAO single-photon emission serum:CSF EIU ratio 8.2±7.4). The mother had a rise in IgG tomography of the brain showed a slight asymmetry in the parietal antibodies to VZV (from69 to 102 EIU) during the pregnancy. area at the age of 15 days. VZV specific IgM was negative. The child had VZV-specific IgG

Table 1 Summary of Four Cases of Congenital VZV Infection Without Maternal Clinical Disease During Pregnancy

Age at onset of symptoms Duration of Patient (days) symptoms Main symptoms Outcome

1 0 4 mo Contractures and rowing movements Exitus at the age of 4 mo of lower limbs, irritability, clonic seizures, spasticity, dysphagia and hypoventilation 2 3 1 d Clonic seizures, slight muscular hypertonia Development normal at the age of 2.5 yr 3 2 3 d Jitteriness, slight muscular hypotonia, clonic seizures Development normal at the age of 18 mo 4 24 5 d Apneic spells, tonic and clonic seizures, muscular hypertonia Slight muscular hypertonia at the age of 6 mo

142 Journal of Perinatology 2001; 21:141 ± 146 Congenital Varicella-Zoster Virus Infection Mustonen et al.

Figure 1. A T2-weighted MR image through the basal ganglia region shows bilateral symmetric hyperintensities of the lentiform and caudate nuclei (arrows). The mild hyperintensity of the right frontal and left parieto-occipital regions is due to magnetic field in homogeneities and not true edema.

antibodies in serum(38 EIU) still at the age of 7 monthsbut was uneventful, and the delivery occurred at termwith some they disappeared fromthe CSF. fetal bradycardia at the end. The Apgar scores were 8/8/9. The The child got phenobarbital for 2 months. Development, growth umbilical arterial blood gas analysis showed acidosis (pH 7.015 and neurologic examination were normal at the age of 2.5 years. By and BE À13.6). The birth weight was 3265 g, length 51 cm that age he had had neither chickenpox nor herpes zoster. and head circumference 34 cm, all within normal limits. During the first days of his life the patient had jitteriness and at the age of 6 days clonic movements of his body and arms. CASE 3 The seizure lasted about 20 minutes but no medication was This boy was the first child of his 20-year-old healthy mother given. Muscles were slightly hypotonic, but he had no other who had had chickenpox at the age of 10 years. The pregnancy neurologic findings.

Journal of Perinatology 2001; 21:141 ± 146 143 Mustonen et al. Congenital Varicella-Zoster Virus Infection

Table 2 Neuropathologic and Virological Examinations of Brain in Infants With Congenital VZV Infection With Fatal Outcome

Authors Macroscopic Microscopic Virological Strabstein Fluid-filled cysts on Necrotizing encephalomyelitis Culture negative et al., 197418 cerebral hemispheres (cerebrum, thalamus, cerebellum) Spinal cord atrophy (anterior columns) No viral inclusions Bennet White dense areas 3 mm in Necrotizing encephalitis (thalamus) Culture negative et al., 19851 diameter in the thalamus Ventriculomegaly Ventriculitis Immunocytochemical stains negative Intrathecal VZV IgM and IgG antibodies Harding and Linear yellow scars over Necrotizing encephalitis Culture negative Baumer, 19888 surfaces of hemispheres (leptomeninges, cortex, No viral inclusions white matter, thalamus) Insular and parietal polymicrogyria, heterotopias in cerebellar cortex Da Silva Atrophy Destruction of white and gray matter ND et al., 19903 (frontal, parietal, occipital and temporal lobes, cerebellar cortex) Degeneration (brain stem, spinal cord) Magliocco Cystic encephalopathy Cystic necrosis of white and gray matter Culture negative et al., 199210 (frontal, parietal, occipital) (frontal, parietal, temporal No viral inclusions and occipital lobes) Hypoplasia of brain stem Extensive neuronal loss (spinal cord) Immunocytochemical stains negative Ventriculomegaly No viral inclusions Our case No changes Focal hypertrophy and hyperplasia Immunocytochemical stains of fibrillary astrocytes and PCR negative Slight Purkinje cell loss No viral inclusions Small calcified areas in the area Intrathecal VZV IgG antibodies of basal ganglia

ND=not done.

EEG and US of the brain were normal. Blood count, serum CRP, confirmed by culture and treated by antibiotics. Her previous children metabolic tests (blood glucose; serum sodium, potassium, and had been born at term, but this delivery occurred at the gestational bilirubin) as well as CSF routine examinations (protein, glucose, age of 33 weeks. The child's birthweight was 1994 g, length 44.5 cm, white and red cells) were normal. The only abnormal finding was and head circumference 30.9 cm, all appropriate for the gestational VZV-specific antibodies in the CSF at the age of nine days (11 EIU, weeks. Apgar scores were 9/8/9. During the first days she had VZV IgG serum:CSF EIU ratio 11), weakly positive VZV-specific IgM transient tachypnea and, at the age of 24 days, signs of respiratory in serumat the age of 5 months,and persistence of VZV-specific IgG infection. Apneic spells and tonic seizures appeared during the antibodies in serum at the age of 11 months (24 EIU). His mother infection. She was intubated and got respiratory support for seven had a rise in VZV antibodies during the pregnancy (from54 to 86 days. Phenobarbital was given at a loading dose of 50 mg and at a EIU). The child's neurologic examination, growth and development maintenance dose of 5 mg twice a day intravenously. Netilmycin, were normal at the age of 18 months. He had not had chickenpox or penicillin G, and acyclovir 45 mg three times a day were herpes zoster during the follow-up. administered for 3 days, and dexamethasone in decreasing doses for 10 days. The child got also inhaled cortisone and some doses of racemic epinephrine. She was hospitalised for 2 weeks. At neurologic CASE 4 examination slight muscular hypertonia was found. CT of the brain was normal. EEG showed slight depression of This girl was born as the third child of her 24-year-old healthy background activity at first but after 3 days it returned to normal. A mother. The mother was not aware whether she had had chickenpox, small ventricular defect of the heart was found by US. Following but she had antibodies to VZV in her first trimester serum. During the examinations were normal: blood count and glucose; serum CRP, pregnancy the mother had had two urinary tract infections, sodium, potassium, and calcium; CSF protein, glucose, white and red

144 Journal of Perinatology 2001; 21:141 ± 146 Congenital Varicella-Zoster Virus Infection Mustonen et al.

cells. Respiratory syncytial virus was found by antigen staining from cutaneous signs. Serological tests are useful if first trimester serum the nasopharyngeal secretion. IgG antibodies to VZV were found in samples are available as in our cases. Virus-specific IgM, the CSF (15±8 EIU, VZV IgG serum:CSF EIU ratio 4.3±8.3), and seroconversion or clear increase in specific antibodies is diagnostic. VZV-specific IgM in the serumat the age of 6 months.There were However, timing of studies is problematic. Screening tests during IgG antibodies to VZV in serumat the age of 2 months (66 EIU), but pregnancy are worth considering. not any more at the age of 6 months. Her mother had a diagnostic Cytomegalovirus (CMV) as well as VZV belong to the rise in IgG antibodies to VZV during the pregnancy (from74 to 141 herpesvirus family and can cause congenital infections. Congenital EIU) and VZV-specific IgM when the child was 2 months old. CMV infection may occur after primary or chronic maternal The child got phenobarbital for 2 months. At follow-up at the age infection, but in the latter case the congenital disease is milder.4 of 6 months she had slight muscle hypertonia of the lower limbs, but Also VZV can reactivate without clinical symptoms.6 VZV antibodies otherwise her neurologic examination was normal. She had had cross the placenta 2 and it is possible that in our cases antibodies neither chickenpox nor herpes zoster by that age. acquired from the mother modified the infection. The same with regard to perinatal varicella: if the mother has chickenpox from 4 days before to 2 days after delivery, the mortality rate is 30.5%, but DISCUSSION if she has the infection 5 days before the delivery, the mortality There are no previous reports on the neurologic manifestations of rate is zero.12 congenital VZV infection without maternal cutaneous manifesta- According to our findings, congenital VZV infection may occur tions during pregnancy. Asymptomatic varicella infections during and cause neurologic problems during the neonatal period even pregnancy have been diagnosed by specific IgM antibodies or by without maternal VZV eruption. In our series the mothers had diagnostic increase in IgG antibodies to VZV.7 Perinatal varicella at laboratory evidence of either reactivation or chronic VZV infection birth and on the ninth day of life have been reported in neonates during the pregnancy. Congenital VZV infection should be whose mothers have not had clinical infection.15,16 We identified suspected if a neonate has seizures without obvious causes, even if four neonates with apparent congenital VZV infection but with no the mother has had no rash during pregnancy. The diagnosis can maternal clinical disease during pregnancy. However, all mothers be made by studying specific antibodies in the CSF during the had had laboratory evidence of reactivated or chronic VZV neonatal period and supported by the presence of specific IgM or infection. persistence of specific antibodies in serumover the age of 6 All four infected neonates had neurologic symptoms. One months. Further studies are needed to evaluate the long-term child died at the age of 4 months. At neuropathologic effects on the developing central nervous system. examination, small foci of hypertrophic astrocytes were seen as an indication of past widespread but slight gray and white matter damage. The presence of small calcifications in the basal Acknowledgements ganglia and a slight loss of Purkinje cells are in accordance M. K. was a member of the European Union on Concerted Action on Viral Meningitis and Encephalitis during the study. with this interpretation. There were no active inflammatory lesions or specific findings. Both antigen detection and PCR for This study was supported by the Arvo and Lea Ylpp Foundation and the Helsinki VZV were negative frombrain tissue. Periodic delta waves in EEG University Central Hospital Research Funds. suggested to neuronal damage. Progressive neurologic deterioration in congenital VZV infection after maternal chickenpox has been reported before by several References authors1,3,8,10,18 (Table 2). Those infants survived 7 days to 6.5 months. 1. Bennet R, Forsgren M, Herin P. Herpes zoster in a 2-week-old premature Necrotizing encephalitis was present in all, but neither viral infant with possible congenital varicella encephalitis. Acta Paediatr Scand inclusions nor virus were found. Maternal infection had occurred 3.4 1985;74:979±81. to 10.4 months before the death of the child. VZV DNA has only been 2. Brunell PA. Placental transfer of varicella-zoster antibody. Pediatrics found frombrain tissue of two prematureneonates who died 6 and 1966;38:1034±8. 3. Da Silva O, Hammerberg O, Chance GW. Fetal varicella syndrome. Pediatr 10 weeks after maternal chickenpox, a few days after delivery.13,17 In our fatal case there was clinical and neuropathologic evidence of Infect Dis J 1990;9:854±55. 4. Fowler KB, Stagno S, Pass RF, Britt WJ, Boll TJ, Alford CA. The outcome of brain damage but viral DNA could not be demonstrated. In view of congenital cytomegalovirus infection in relation to maternal antibody status. the severity of the disease of the child at birth and intrauterine growth N Engl J Med 1992;326:663±7. retardation, the possible VZV infection had occurred several months 5. Gershon AA. Chickenpox, measles and mumps. In: Remington JS, Klein JO, before the delivery and the diagnosis was based on intrathecal editors. Infectious Diseases of the Fetus and Newborn Infant. 4th ed. antibody production against VZV. Philadelphia, PA: Saunders; 1995. p. 565±618. Maternal infection during pregnancy is difficult to identify if the 6. Gilden DH, Dueland AN, Devlin ME, MahalingamR. Varicella-zoster virus disease mimics a common cold or undefined illness without reactivation without rash. J Infect Dis 1992;166(Suppl 1):S30±4.

Journal of Perinatology 2001; 21:141 ± 146 145 Mustonen et al. Congenital Varicella-Zoster Virus Infection

7. Gruninger T, Dobec M, Keller A. Asymptomatic varicella infections in 13. Michie CA, Acolet D, Charlton R, et al. Varicella-zoster contracted in the pregnancy: detection and problems. Gynekol Geburtshilfliche Rundsch second trimester of pregnancy. Pediatr Infect Dis J 1992;11:1050±3. 1994;34:171±4. 14. Mustonen K, Mustakangas P, Smeds M, et al. Antibodies to varicella-zoster 8. Harding B, Baumer JA. Congenital varicella-zoster. A serologically proven virus in the cerebrospinal fluid of newborns with seizures. Arch Dis Child case with necrotizing encephalitis and malformation. Acta Neuropathol Fetal Neonat Ed 1998;78:F57±61. 1988;76:311±5. 15. Newman CGH. Perinatal varicella. Lancet 1965;2:1159±61. 9. Koskiniemi M, Mannonen L, Kallio A, Vaheri A. Luminometric microplate 16. PridhamFC. Chicken-pox during intrauterine life. BMJ 1913;1:1054. hybridization for detection of varicella-zoster virus PCR product from 17. Puchhammer-StoÈckl E, Kunz C, Wagner G, Enders G. Detection of varicella- cerebrospinal fluid. J Virol Methods 1997;12:71±9. zoster virus (VZV) DNA in fetal tissue by polymerase chain reaction. J 10. Magliocco AM, Demetrick DJ, Sarnat HB, Hwang WS. Varicella embryopathy. Perinat Med 1994;22:65±9. Arch Pathol Lab Med 1992;116:181±6. 18. Strabstein JC, Morris N, Larke RPB, deSa DJ, Castelino BB, SumE. Is there a 11. Mayo DR, Booss J. Varicella zoster associated neurologic disease without skin congenital varicella syndrome? J Pediatr 1974;84:239±43. lesions. Arch Neurol 1989;46:313±5. 19. Vesanen M, Piiparinen H, Kallio A, Vaheri A. Detection of herpes simplex DNA 12. Meyers JD. Congenital varicella in terminfants: risk reconsidered. J Infect Dis in cerebrospinal fluid samples using polymerase chain reaction and 1975;129:215±7. microplate hybridization. J Virol Methods 1996;59:1±11.

146 Journal of Perinatology 2001; 21:141 ± 146