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A case of congenital herpes simplex virus infection diagnosed at 8 months of age
Brain & Development 42 (2020) 369–372 www.elsevier.com/locate/braindev
Case Report
A case of congenital herpes simplex virus infection diagnosed at 8 months of age Shiho Yamamoto a, Tsunehisa Nagamori b,⇑, Shigetsuna Komatsu c, Masaru Shirai a, Tatsuo Suzutani d, Junichi Oki a a Department of Pediatrics, Asahikawa Kosei Hospital, Japan Department of Pediatrics, Asahikawa Medical University, Japan c Department of Dermatology, Asahikawa Kosei Hospital, Japan d Department of Microbiology, Fukushima Medical University School of Medicine, Japan b
Received 7 August 2019; received in revised form 8 January 2020; accepted 10 January 2020
Abstract We present the case of an 8-month-old boy with the repeated recurrence of vesicles from the time of birth and who subsequently manifested psychomotor developmental delay. We retrospectively diagnosed the patient with congenital herpes simplex virus (HSV) infection. Computed tomography showed multiple calcifications in the periventricular white matter and thalami. The bilateral deep white matter showed an abnormally high signal intensity on T2-weighted magnetic resonance imaging. The patient required consecutive, suppressive therapy with valacyclovir to prevent the repeated recurrence of vesicles. This case presented a milder phenotype of congenital HSV infection in comparison to previous reports, and highlights the importance of the careful examination for this disease when neonates present with skin lesions. Ó 2020 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.
Keywords: Congenital herpes simplex virus infection; Intrauterine infection; Neonate; Skin lesion; Repetitive vesicles; Magnetic resonance image; White matter lesion; Suppressive therapy
1. Introduction Herpes simplex virus (HSV) is one of the important pathogens passed on through maternal-fetal transmission. It is reported that the adjusted number of cases of neonatal HSV infection caused by transvaginal infection in Japan is 2.6 per 100,000 live births [1], which is less than that in the US (4.5 per 10,000 live births) [2]. Congenital HSV infection is rare, with congenital HSV infection by intrauterine infection accounting for <5% ⇑ Corresponding author at: Department of Pediatrics, Asahikawa
Medical University, 2-1-1-1 Midorigaoka-Higashi, Asahikawa 0788510, Japan. E-mail address: [email protected] (T. Nagamori).
of cases of HSV infection in the perinatal period [3]. The prognosis for congenital HSV infection is very poor due to fetal demise and severe neurodevelopmental delays. However, there remain few reported cases of congenital HSV infection. We herein present a rare case of congenital HSV-2 infection that manifested as recurrent vesicles from the time of birth and subsequent psychomotor developmental delay. The diagnosis was made retrospectively at 8 months of age by the examination of frozen-stored umbilical cord blood. 2. Case report A male Japanese baby was born to a 21-year-old woman (gravida 1, para 1) by vaginal delivery at
https://doi.org/10.1016/j.braindev.2020.01.003 0387-7604/Ó 2020 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.
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S. Yamamoto et al. / Brain & Development 42 (2020) 369–372
37 weeks of gestation. The mother had no history of sexually transmitted infections nor any clinical signs of genital HSV infection before or during pregnancy. In addition, the pregnancy was without complications, such as premature rupture of the membrane. The infant’s body weight at birth was 2,342 g ( 1.49 standard deviations [SD] for gestational age), and the head circumference was 31.0 cm ( 1.35 SD). The Apgar scores at 1 and 5 min were 8 and 9, respectively. He did not show any systemic symptoms, and his muscle tonus and primitive reflexes were normal throughout the neonatal period. However, he had some papules and crusts on the left sole and chest at the time of birth. The papules changed into vesicles after a few days. New vesicles also appeared on his fingers, and crusts were found on his right auricle, fingers and left heel on day 12 (Fig. 1A–C). Eventually, the vesicles crusted and then epithelialized. Thereafter, isolated vesicles appeared intermittently on his fingers, heels, femurs, auricula, and scrotum and healed spontaneously (Fig. 1D and E). The vesicles did not disseminate. No bacteria were detected on Gram-stained smears or bacterial cultures from the vesicles. A skin biopsy only demonstrated dyskeratosis and pustules with an accumulation of neutrophils and debris, and did not result in a specific diagnosis. The patient developed pyelonephritis at 5 months
of age and acute otitis media at 8 months, but each condition followed a normal clinical course. However, a delay in his motor development gradually became apparent, with a lack of head control at 5 months of age, and he underwent a neurological workup at 8 months of age as he had still not acquired head control, and spasticity of the extremities was noted. Further, it was noticed that the vesicles had continued to recur at intervals of no more than 3 weeks. Brain computed tomography showed multiple calcifications in the periventricular white matter and thalami (Fig. 2, upper row). T2-weighted magnetic resonance imaging (MRI) showed diffuse areas of high signal intensity in the bilateral deep white matter (Fig. 2, lower row). The patient’s automated auditory brainstem response (AABR) was normal. As the brain imaging findings suggested a congenital infection, such as TORCH syndrome, serological examinations were performed. An analysis of the frozen-stored serum of umbilical cord blood revealed an HSV IgM value of 2.9 (enzyme immunoassay [EIA], cut-off value <0.8 index value), and an IgG value of 62.0 (EIA, cut-off value <2.0 EIA value). In addition, in a serum sample obtained at 8 months of age showed HSV IgM and IgG values of 0.34 and 67.2, respectively. Cytomegalovirus (CMV) IgM values were 0.02 in the cord blood
Fig. 1. Vesicles with crusts on fingers (A) and crusts on the left heel (B) and right auricle (C) at 12 days of age. The lesions on the fingers and the left heel epithelialized and healed at 26 days of age (D and E). At 9 months of age, a sample of the vesicular fluid from his finger (arrow) was taken for shell vial culture (F).
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Fig. 2. Brain images of the patient with congenital HSV infection at 8 months of age. Upper row: Computed tomography shows multiple calcifications in the periventricular white matter and thalami (arrows). Lower row: Magnetic resonance imaging shows areas of high signal intensity in the bilateral deep white matter on T2-weighted images (arrowheads).
and 0.34 at 8 months of age (EIA, cut-off value <0.8 index value). In addition, HSV-2 antigen was detected in fluid from a vesicle on his finger through shell vial culture (Fig. 1F). Based on these results, the patient was diagnosed with congenital HSV infection. An ophthalmologic examination did not reveal chorioretinitis or microphthalmia. Although he was treated with the oral administration of valacyclovir (25 mg/kg three times a day), the vesicles repeatedly recurred after the termination of treatment. Thus, the continuous administration of half-dose valacyclovir (37.5 mg/kg once a day) was required as suppressive therapy. After the initiation of the suppressive therapy, the recurrence of the vesicles was suppressed. At 1 year and 10 months of age, the delay in the patient’s psychomotor development was apparent, and he was unable to sit or use words in a meaningful manner; however, his spastic tetraplegia was mild, and he achieved purposeful movements, especially with the upper extremities, such as grabbing nearby things. Prophylactic oral valacyclovir is still required, with the vesicles reappearing after discontinuation of the drug and disappearing on its resumption.
3. Discussion The diagnosis of congenital HSV infection is difficult as such a diagnosis is made on the basis of the isolation of HSV or the detection of HSV-DNA through nucleic acid amplification from samples taken in the early postpartum period. Without clinical samples taken soon after birth, it is impossible to distinguish congenital HSV infection from intrapartum or postpartum infection in neonates. The average incubation period of HSV infection is 2–20 days, and neonatal HSV infection manifests 3 days after infection [4]. Thus, for the diagnosis of congenital infection, clinical samples must be taken within 2 days of birth. This point hampered our diagnosis, as we evaluated HSV-IgM, that is less reliable than HSV DNA PCR, and only luckily found a positive response in an umbilical cord blood sample. In addition, congenital CMV infection, a much more common cause of intrauterine infection, could not be conclusively excluded, as it is well known that umbilical cord blood CMV-IgM is negative in about a half of cases of congenital CMV infection [5]. However, the diagnosis of congenital HSV infection still seemed plausible, as he also
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had repetitive skin symptoms from the perinatal period, and HSV-2 antigen was directly detected from the vesicular contents. A suspicion of HSV infection might be possible from clinical manifestations, including skin lesions at birth, chorioretinitis, microcephaly, hydranencephaly, and microphthalmia [3]. The characteristic skin lesions of congenital HSV infection include vesicles, pustules, erythema, bullae, hypopigmentation, polycyclic patches, and erosions [6]. These findings may be seen with other benign or self-limited diseases, including bullous impetigo, erythema toxic neonatorum, and transient neonatal pustular melanosis. It was reported that the skin lesions associated with congenital HSV infection are widespread and more severe in comparison to those of other causes [7,8]. In our case, the diagnosis of congenital HSV infection was made after the recognition of motor developmental delay and recurring skin lesions. However, importantly, the clinical severity of the symptoms, including neurological symptoms and skin findings at birth, were milder than those of previously reported cases of congenital HSV infection. The present findings suggest that congenital HSV infection may induce a wider spectrum of disorders than is generally acknowledged. Thus, it is important to suspect congenital HSV infection when skin lesions are observed at birth, even when the lesions are mild, and it is important to store clinical samples immediately after birth for the subsequent diagnosis of congenital HSV infection. The morphological changes in the brain of patients with congenital HSV infection are mainly structural abnormalities, including microcephaly, hydranencephaly, intracranial calcifications, hydrocephalus, and porencephalic cysts [3]. There are few reports of the MRI findings of congenital HSV infection, with the reported MRI findings showing structural abnormalities [9,10]. However, the MRI findings in this case were cerebral diffuse deep white matter lesions rather than structural abnormalities. To the best of our knowledge, this is the first reported case of a patient with congenital HSV infection who showed cerebral diffuse deep white matter lesions without structural abnormalities. This suggests that some patients with congenital HSV infection show milder MRI findings than those of previously reported cases. There is no established treatment for congenital HSV infection. Patients with a diagnosis of congenital HSV infection in the prenatal or early neonatal period are empirically treated with high-dose intravenous acyclovir, which is a treatment regimen for neonatal HSV infection [7,8]. In our patient, as the diagnosis was made at 8 months of age, treatment was initiated with oral
valacyclovir, which was continued as a suppressive therapy based on the treatment for recurrent genital HSV infection. The suppressive therapy successfully prevented the recurrence of vesicles. Kimberlin et al. reported that suppressive therapy improves neurological outcomes in patients with neonatal HSV infection involving the central nervous system [11]. Although the effectiveness of suppressive therapy for congenital HSV infection remains unclear, further studies to examine the effects on congenital HSV infection are warranted.
Acknowledgement We are deeply grateful for the help and support of the late Dr. Hiroshi Sakata for his expert advice on infectious diseases. The authors declare no competing interests. References [1] Torii Y, Kimura H, Ito Y, Hayakawa M, Tanaka T, Tajiri H, et al. Clinicoepidemiologic status of mother-to-child infections: a nationwide survey in Japan. Pediatr Infect Dis J 2013;32:699–701. [2] Mahant S, Hall M, Schondelmeyer AC, Berry JG, Kimberlin DW, Shah SS, Pediatric Research in Inpatient Settings N, the Collaborative Antiviral Study G. Neonatal herpes simplex virus infection among Medicaid-enrolled children: 2009–2015. Pediatrics 2019;143:1–7. [3] Hutto C, Arvin A, Jacobs R, Steele R, Stagno S, Lyrene R, et al. Intrauterine herpes simplex virus infections. J Pediatr 1987;110:97–101. [4] Kobty M. Herpes simplex virus: beyond the basics. Neonatal Netw 2015;34:279–83. [5] Koyano S, Inoue N, Oka A, Moriuchi H, Asano K, Ito Y, et al. Screening for congenital cytomegalovirus infection using newborn urine samples collected on filter paper: feasibility and outcomes from a multicentre study. BMJ Open 2011;1 e000118. [6] Baldwin S, Whitley RJ. Intrauterine herpes simplex virus infection. Teratology 1989;39:1–10. [7] Demeulemeester V, Voeten M, Jacquemyn Y, Mahieu L. A rare infectious cause of severe neonatal skin lesions. BMJ Case Rep 2015, 2015. [8] Drumm CM, Caufield MC, DeKlotz CM, Pasieka HB, Abubakar KM. Intrauterine herpes simplex virus infection presenting as a zosteriform eruption in a newborn. AJP Rep 2018;8:e33–6. [9] Duin LK, Willekes C, Baldewijns MM, Robben SG, Offermans J, Vles J. Major brain lesions by intrauterine herpes simplex virus infection: MRI contribution. Prenat Diagn 2007;27:81–4. [10] Neuberger I, Garcia J, Meyers ML, Feygin T, Bulas DI, Mirsky DM. Imaging of congenital central nervous system infections. Pediatr Radiol 2018;48:513–23. [11] Kimberlin DW, Whitley RJ, Wan W, Powell DA, Storch G, Ahmed A, et al. Oral acyclovir suppression and neurodevelopment after neonatal herpes. N Engl J Med 2011;365: 1284–92.
Case Report
A case of congenital herpes simplex virus infection diagnosed at 8 months of age Shiho Yamamoto a, Tsunehisa Nagamori b,⇑, Shigetsuna Komatsu c, Masaru Shirai a, Tatsuo Suzutani d, Junichi Oki a a Department of Pediatrics, Asahikawa Kosei Hospital, Japan Department of Pediatrics, Asahikawa Medical University, Japan c Department of Dermatology, Asahikawa Kosei Hospital, Japan d Department of Microbiology, Fukushima Medical University School of Medicine, Japan b
Received 7 August 2019; received in revised form 8 January 2020; accepted 10 January 2020
Abstract We present the case of an 8-month-old boy with the repeated recurrence of vesicles from the time of birth and who subsequently manifested psychomotor developmental delay. We retrospectively diagnosed the patient with congenital herpes simplex virus (HSV) infection. Computed tomography showed multiple calcifications in the periventricular white matter and thalami. The bilateral deep white matter showed an abnormally high signal intensity on T2-weighted magnetic resonance imaging. The patient required consecutive, suppressive therapy with valacyclovir to prevent the repeated recurrence of vesicles. This case presented a milder phenotype of congenital HSV infection in comparison to previous reports, and highlights the importance of the careful examination for this disease when neonates present with skin lesions. Ó 2020 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.
Keywords: Congenital herpes simplex virus infection; Intrauterine infection; Neonate; Skin lesion; Repetitive vesicles; Magnetic resonance image; White matter lesion; Suppressive therapy
1. Introduction Herpes simplex virus (HSV) is one of the important pathogens passed on through maternal-fetal transmission. It is reported that the adjusted number of cases of neonatal HSV infection caused by transvaginal infection in Japan is 2.6 per 100,000 live births [1], which is less than that in the US (4.5 per 10,000 live births) [2]. Congenital HSV infection is rare, with congenital HSV infection by intrauterine infection accounting for <5% ⇑ Corresponding author at: Department of Pediatrics, Asahikawa
Medical University, 2-1-1-1 Midorigaoka-Higashi, Asahikawa 0788510, Japan. E-mail address: [email protected] (T. Nagamori).
of cases of HSV infection in the perinatal period [3]. The prognosis for congenital HSV infection is very poor due to fetal demise and severe neurodevelopmental delays. However, there remain few reported cases of congenital HSV infection. We herein present a rare case of congenital HSV-2 infection that manifested as recurrent vesicles from the time of birth and subsequent psychomotor developmental delay. The diagnosis was made retrospectively at 8 months of age by the examination of frozen-stored umbilical cord blood. 2. Case report A male Japanese baby was born to a 21-year-old woman (gravida 1, para 1) by vaginal delivery at
https://doi.org/10.1016/j.braindev.2020.01.003 0387-7604/Ó 2020 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.
370
S. Yamamoto et al. / Brain & Development 42 (2020) 369–372
37 weeks of gestation. The mother had no history of sexually transmitted infections nor any clinical signs of genital HSV infection before or during pregnancy. In addition, the pregnancy was without complications, such as premature rupture of the membrane. The infant’s body weight at birth was 2,342 g ( 1.49 standard deviations [SD] for gestational age), and the head circumference was 31.0 cm ( 1.35 SD). The Apgar scores at 1 and 5 min were 8 and 9, respectively. He did not show any systemic symptoms, and his muscle tonus and primitive reflexes were normal throughout the neonatal period. However, he had some papules and crusts on the left sole and chest at the time of birth. The papules changed into vesicles after a few days. New vesicles also appeared on his fingers, and crusts were found on his right auricle, fingers and left heel on day 12 (Fig. 1A–C). Eventually, the vesicles crusted and then epithelialized. Thereafter, isolated vesicles appeared intermittently on his fingers, heels, femurs, auricula, and scrotum and healed spontaneously (Fig. 1D and E). The vesicles did not disseminate. No bacteria were detected on Gram-stained smears or bacterial cultures from the vesicles. A skin biopsy only demonstrated dyskeratosis and pustules with an accumulation of neutrophils and debris, and did not result in a specific diagnosis. The patient developed pyelonephritis at 5 months
of age and acute otitis media at 8 months, but each condition followed a normal clinical course. However, a delay in his motor development gradually became apparent, with a lack of head control at 5 months of age, and he underwent a neurological workup at 8 months of age as he had still not acquired head control, and spasticity of the extremities was noted. Further, it was noticed that the vesicles had continued to recur at intervals of no more than 3 weeks. Brain computed tomography showed multiple calcifications in the periventricular white matter and thalami (Fig. 2, upper row). T2-weighted magnetic resonance imaging (MRI) showed diffuse areas of high signal intensity in the bilateral deep white matter (Fig. 2, lower row). The patient’s automated auditory brainstem response (AABR) was normal. As the brain imaging findings suggested a congenital infection, such as TORCH syndrome, serological examinations were performed. An analysis of the frozen-stored serum of umbilical cord blood revealed an HSV IgM value of 2.9 (enzyme immunoassay [EIA], cut-off value <0.8 index value), and an IgG value of 62.0 (EIA, cut-off value <2.0 EIA value). In addition, in a serum sample obtained at 8 months of age showed HSV IgM and IgG values of 0.34 and 67.2, respectively. Cytomegalovirus (CMV) IgM values were 0.02 in the cord blood
Fig. 1. Vesicles with crusts on fingers (A) and crusts on the left heel (B) and right auricle (C) at 12 days of age. The lesions on the fingers and the left heel epithelialized and healed at 26 days of age (D and E). At 9 months of age, a sample of the vesicular fluid from his finger (arrow) was taken for shell vial culture (F).
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Fig. 2. Brain images of the patient with congenital HSV infection at 8 months of age. Upper row: Computed tomography shows multiple calcifications in the periventricular white matter and thalami (arrows). Lower row: Magnetic resonance imaging shows areas of high signal intensity in the bilateral deep white matter on T2-weighted images (arrowheads).
and 0.34 at 8 months of age (EIA, cut-off value <0.8 index value). In addition, HSV-2 antigen was detected in fluid from a vesicle on his finger through shell vial culture (Fig. 1F). Based on these results, the patient was diagnosed with congenital HSV infection. An ophthalmologic examination did not reveal chorioretinitis or microphthalmia. Although he was treated with the oral administration of valacyclovir (25 mg/kg three times a day), the vesicles repeatedly recurred after the termination of treatment. Thus, the continuous administration of half-dose valacyclovir (37.5 mg/kg once a day) was required as suppressive therapy. After the initiation of the suppressive therapy, the recurrence of the vesicles was suppressed. At 1 year and 10 months of age, the delay in the patient’s psychomotor development was apparent, and he was unable to sit or use words in a meaningful manner; however, his spastic tetraplegia was mild, and he achieved purposeful movements, especially with the upper extremities, such as grabbing nearby things. Prophylactic oral valacyclovir is still required, with the vesicles reappearing after discontinuation of the drug and disappearing on its resumption.
3. Discussion The diagnosis of congenital HSV infection is difficult as such a diagnosis is made on the basis of the isolation of HSV or the detection of HSV-DNA through nucleic acid amplification from samples taken in the early postpartum period. Without clinical samples taken soon after birth, it is impossible to distinguish congenital HSV infection from intrapartum or postpartum infection in neonates. The average incubation period of HSV infection is 2–20 days, and neonatal HSV infection manifests 3 days after infection [4]. Thus, for the diagnosis of congenital infection, clinical samples must be taken within 2 days of birth. This point hampered our diagnosis, as we evaluated HSV-IgM, that is less reliable than HSV DNA PCR, and only luckily found a positive response in an umbilical cord blood sample. In addition, congenital CMV infection, a much more common cause of intrauterine infection, could not be conclusively excluded, as it is well known that umbilical cord blood CMV-IgM is negative in about a half of cases of congenital CMV infection [5]. However, the diagnosis of congenital HSV infection still seemed plausible, as he also
372
S. Yamamoto et al. / Brain & Development 42 (2020) 369–372
had repetitive skin symptoms from the perinatal period, and HSV-2 antigen was directly detected from the vesicular contents. A suspicion of HSV infection might be possible from clinical manifestations, including skin lesions at birth, chorioretinitis, microcephaly, hydranencephaly, and microphthalmia [3]. The characteristic skin lesions of congenital HSV infection include vesicles, pustules, erythema, bullae, hypopigmentation, polycyclic patches, and erosions [6]. These findings may be seen with other benign or self-limited diseases, including bullous impetigo, erythema toxic neonatorum, and transient neonatal pustular melanosis. It was reported that the skin lesions associated with congenital HSV infection are widespread and more severe in comparison to those of other causes [7,8]. In our case, the diagnosis of congenital HSV infection was made after the recognition of motor developmental delay and recurring skin lesions. However, importantly, the clinical severity of the symptoms, including neurological symptoms and skin findings at birth, were milder than those of previously reported cases of congenital HSV infection. The present findings suggest that congenital HSV infection may induce a wider spectrum of disorders than is generally acknowledged. Thus, it is important to suspect congenital HSV infection when skin lesions are observed at birth, even when the lesions are mild, and it is important to store clinical samples immediately after birth for the subsequent diagnosis of congenital HSV infection. The morphological changes in the brain of patients with congenital HSV infection are mainly structural abnormalities, including microcephaly, hydranencephaly, intracranial calcifications, hydrocephalus, and porencephalic cysts [3]. There are few reports of the MRI findings of congenital HSV infection, with the reported MRI findings showing structural abnormalities [9,10]. However, the MRI findings in this case were cerebral diffuse deep white matter lesions rather than structural abnormalities. To the best of our knowledge, this is the first reported case of a patient with congenital HSV infection who showed cerebral diffuse deep white matter lesions without structural abnormalities. This suggests that some patients with congenital HSV infection show milder MRI findings than those of previously reported cases. There is no established treatment for congenital HSV infection. Patients with a diagnosis of congenital HSV infection in the prenatal or early neonatal period are empirically treated with high-dose intravenous acyclovir, which is a treatment regimen for neonatal HSV infection [7,8]. In our patient, as the diagnosis was made at 8 months of age, treatment was initiated with oral
valacyclovir, which was continued as a suppressive therapy based on the treatment for recurrent genital HSV infection. The suppressive therapy successfully prevented the recurrence of vesicles. Kimberlin et al. reported that suppressive therapy improves neurological outcomes in patients with neonatal HSV infection involving the central nervous system [11]. Although the effectiveness of suppressive therapy for congenital HSV infection remains unclear, further studies to examine the effects on congenital HSV infection are warranted.
Acknowledgement We are deeply grateful for the help and support of the late Dr. Hiroshi Sakata for his expert advice on infectious diseases. The authors declare no competing interests. References [1] Torii Y, Kimura H, Ito Y, Hayakawa M, Tanaka T, Tajiri H, et al. Clinicoepidemiologic status of mother-to-child infections: a nationwide survey in Japan. Pediatr Infect Dis J 2013;32:699–701. [2] Mahant S, Hall M, Schondelmeyer AC, Berry JG, Kimberlin DW, Shah SS, Pediatric Research in Inpatient Settings N, the Collaborative Antiviral Study G. Neonatal herpes simplex virus infection among Medicaid-enrolled children: 2009–2015. Pediatrics 2019;143:1–7. [3] Hutto C, Arvin A, Jacobs R, Steele R, Stagno S, Lyrene R, et al. Intrauterine herpes simplex virus infections. J Pediatr 1987;110:97–101. [4] Kobty M. Herpes simplex virus: beyond the basics. Neonatal Netw 2015;34:279–83. [5] Koyano S, Inoue N, Oka A, Moriuchi H, Asano K, Ito Y, et al. Screening for congenital cytomegalovirus infection using newborn urine samples collected on filter paper: feasibility and outcomes from a multicentre study. BMJ Open 2011;1 e000118. [6] Baldwin S, Whitley RJ. Intrauterine herpes simplex virus infection. Teratology 1989;39:1–10. [7] Demeulemeester V, Voeten M, Jacquemyn Y, Mahieu L. A rare infectious cause of severe neonatal skin lesions. BMJ Case Rep 2015, 2015. [8] Drumm CM, Caufield MC, DeKlotz CM, Pasieka HB, Abubakar KM. Intrauterine herpes simplex virus infection presenting as a zosteriform eruption in a newborn. AJP Rep 2018;8:e33–6. [9] Duin LK, Willekes C, Baldewijns MM, Robben SG, Offermans J, Vles J. Major brain lesions by intrauterine herpes simplex virus infection: MRI contribution. Prenat Diagn 2007;27:81–4. [10] Neuberger I, Garcia J, Meyers ML, Feygin T, Bulas DI, Mirsky DM. Imaging of congenital central nervous system infections. Pediatr Radiol 2018;48:513–23. [11] Kimberlin DW, Whitley RJ, Wan W, Powell DA, Storch G, Ahmed A, et al. Oral acyclovir suppression and neurodevelopment after neonatal herpes. N Engl J Med 2011;365: 1284–92.