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Premature Termination of Treatment in Neonatal Herpes Simplex Virus Encephalitis
Accepted Manuscript Title: Premature Termination of Treatment in Neonatal Herpes Simplex Virus Encephalitis-a Case of False Negative Initial HSV PCR and Corpus Callosum Diffusion Restriction Author: Kabelo Thusang, Kallol K. Set, Huiyuan Jiang PII: DOI: Reference:
S0887-8994(17)30790-7 http://dx.doi.org/doi: 10.1016/j.pediatrneurol.2017.09.005 PNU 9225
To appear in:
Pediatric Neurology
Received date: Revised date: Accepted date:
25-7-2017 23-8-2017 7-9-2017
Please cite this article as: Kabelo Thusang, Kallol K. Set, Huiyuan Jiang, Premature Termination of Treatment in Neonatal Herpes Simplex Virus Encephalitis-a Case of False Negative Initial HSV PCR and Corpus Callosum Diffusion Restriction, Pediatric Neurology (2017), http://dx.doi.org/doi: 10.1016/j.pediatrneurol.2017.09.005. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
1 Premature termination of treatment in neonatal herpes simplex virus encephalitis-a case of false negative initial HSV PCR and corpus callosum diffusion restriction Kabelo Thusang a Kallol K Set a Huiyuan Jiang a a
Division of Neurology, Carman and Ann Adams Department of Pediatrics, Children's Hospital
of Michigan, Wayne State University School of Medicine Detroit, MI
Corresponding author: Kabelo Thusang, M.D. Children’s Hospital of Michigan 3950 Beaubien street Detroit, MI 48201 USA Phone: 313-832-9612; Fax: 313-745-0955 Email: [email protected]
Other authors: Kallol Kumar Set, M.D. Children’s Hospital of Michigan 3950 Beaubien street Detroit, MI 48201 USA Phone: 313-832-9612; Fax: 313-745-0955 Email: [email protected] Huiyuan Jiang, M.D. Children’s Hospital of Michigan 3950 Beaubien Street Detroit, MI 48201 USA Phone: 313-832-9612; Fax: 313-745-0955 Email: Huiyuan Jiang: [email protected]
Search terms: pediatric, MRI, neonatal HSV encephalitis
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A 6 day old female infant born through uncomplicated delivery at 36 weeks gestational age presented to the emergency room with apnea, weak suck and decreased feeding. Her neurological examination was significant for decreased motor activity, level of consciousness, hypotonia and absence of neonatal reflexes. Magnetic resonance imaging (MRI) of the brain revealed extensive diffusion restriction involving bilateral thalami, corpus callosum and frontal subcortical white matter (fig 1A and 1B). There was also diffusion restriction of frontal cortex and bilateral cortical spinal tracts. Findings were thought to be suggestive of hypoxic ischemic injury or inborn error of metabolism. Initial laboratory evaluation revealed cerebrospinal fluid 12/mm3 nucleated cells, 6/mm3 red blood cells, glucose 33mg/dL, protein 113 mg/dL and negative herpes simplex virus (HSV) polymerase chain reaction (PCR). Preliminary evaluation for inborn errors of metabolism and newborn screening were normal. Electroencephalography showed frequent independent left and right hemispheric electrographic seizures. Because of refractory subclinical seizures a repeat cerebrospinal fluid analysis was performed which was positive for HSV2 PCR, had 59/mm3 nucleated cells, 84% lymphocytes, 100/ mm3 red blood cells, glucose 56 mg/dL and protein 204 mg/dL
DISCUSSION Host response of the newborn to HSV differs from that of older individuals. Infected newborns produce IgM antibodies specific for HSV within the first 3 weeks of infection peaking at 3 months1. Most infants have no detectable T-lymphocyte responses to HSV 2–4 weeks after the onset of clinical symptoms1. HSV2 cerebrospinal fluid PCR may be negative within 72 hours of onset of the disease2. Possible explanations for negative initial PCR results include: low lytic replication (within days 1-4 of neurological symptoms), low viral load for detection and a small volume of cerebrospinal fluid3. On imaging, involvement of corpus callosum has not been reported in neonatal HSV encephalitis. Our patient’s false negative initial HSV PCR and corpus callosal diffusion restriction led to premature termination of treatment.
Author disclosure: The authors report no financial disclosure and conflict of interest to disclose
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3 No funding or sponsorship was obtained for producing this manuscript.
REFERENCES 1. Sullender W. M., Miller J. L., Yasukawa L. L., et al. Humoral and cell-mediated immunity in neonates with herpes simplex virus infection. J. Infect. Dis. 1987;155:28–37. [PubMed] 2. 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 [ 3. Adler AC, Kadimi S, Apaloo C, Marcu C. Herpes Simplex Encephalitis with Two False-Negative Cerebrospinal Fluid PCR Tests and Review of Negative PCR Results in the Clinical Setting. Case Reports in Neurology. 2011; 3(2):172-178. Doi: 10.1159/000330298.
Figure 1: MRI of the brain, axial images A(diffusion weighted image ) & B( aparent diffusion coefficient) showing diffusion restriction involving bilateral thalami ( green arrows), corpus callosum ( yellow arrows), and frontal subcortical white matter ( red arrows).
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S0887-8994(17)30790-7 http://dx.doi.org/doi: 10.1016/j.pediatrneurol.2017.09.005 PNU 9225
To appear in:
Pediatric Neurology
Received date: Revised date: Accepted date:
25-7-2017 23-8-2017 7-9-2017
Please cite this article as: Kabelo Thusang, Kallol K. Set, Huiyuan Jiang, Premature Termination of Treatment in Neonatal Herpes Simplex Virus Encephalitis-a Case of False Negative Initial HSV PCR and Corpus Callosum Diffusion Restriction, Pediatric Neurology (2017), http://dx.doi.org/doi: 10.1016/j.pediatrneurol.2017.09.005. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
1 Premature termination of treatment in neonatal herpes simplex virus encephalitis-a case of false negative initial HSV PCR and corpus callosum diffusion restriction Kabelo Thusang a Kallol K Set a Huiyuan Jiang a a
Division of Neurology, Carman and Ann Adams Department of Pediatrics, Children's Hospital
of Michigan, Wayne State University School of Medicine Detroit, MI
Corresponding author: Kabelo Thusang, M.D. Children’s Hospital of Michigan 3950 Beaubien street Detroit, MI 48201 USA Phone: 313-832-9612; Fax: 313-745-0955 Email: [email protected]
Other authors: Kallol Kumar Set, M.D. Children’s Hospital of Michigan 3950 Beaubien street Detroit, MI 48201 USA Phone: 313-832-9612; Fax: 313-745-0955 Email: [email protected] Huiyuan Jiang, M.D. Children’s Hospital of Michigan 3950 Beaubien Street Detroit, MI 48201 USA Phone: 313-832-9612; Fax: 313-745-0955 Email: Huiyuan Jiang: [email protected]
Search terms: pediatric, MRI, neonatal HSV encephalitis
Page 1 of 5
2
A 6 day old female infant born through uncomplicated delivery at 36 weeks gestational age presented to the emergency room with apnea, weak suck and decreased feeding. Her neurological examination was significant for decreased motor activity, level of consciousness, hypotonia and absence of neonatal reflexes. Magnetic resonance imaging (MRI) of the brain revealed extensive diffusion restriction involving bilateral thalami, corpus callosum and frontal subcortical white matter (fig 1A and 1B). There was also diffusion restriction of frontal cortex and bilateral cortical spinal tracts. Findings were thought to be suggestive of hypoxic ischemic injury or inborn error of metabolism. Initial laboratory evaluation revealed cerebrospinal fluid 12/mm3 nucleated cells, 6/mm3 red blood cells, glucose 33mg/dL, protein 113 mg/dL and negative herpes simplex virus (HSV) polymerase chain reaction (PCR). Preliminary evaluation for inborn errors of metabolism and newborn screening were normal. Electroencephalography showed frequent independent left and right hemispheric electrographic seizures. Because of refractory subclinical seizures a repeat cerebrospinal fluid analysis was performed which was positive for HSV2 PCR, had 59/mm3 nucleated cells, 84% lymphocytes, 100/ mm3 red blood cells, glucose 56 mg/dL and protein 204 mg/dL
DISCUSSION Host response of the newborn to HSV differs from that of older individuals. Infected newborns produce IgM antibodies specific for HSV within the first 3 weeks of infection peaking at 3 months1. Most infants have no detectable T-lymphocyte responses to HSV 2–4 weeks after the onset of clinical symptoms1. HSV2 cerebrospinal fluid PCR may be negative within 72 hours of onset of the disease2. Possible explanations for negative initial PCR results include: low lytic replication (within days 1-4 of neurological symptoms), low viral load for detection and a small volume of cerebrospinal fluid3. On imaging, involvement of corpus callosum has not been reported in neonatal HSV encephalitis. Our patient’s false negative initial HSV PCR and corpus callosal diffusion restriction led to premature termination of treatment.
Author disclosure: The authors report no financial disclosure and conflict of interest to disclose
Page 2 of 5
3 No funding or sponsorship was obtained for producing this manuscript.
REFERENCES 1. Sullender W. M., Miller J. L., Yasukawa L. L., et al. Humoral and cell-mediated immunity in neonates with herpes simplex virus infection. J. Infect. Dis. 1987;155:28–37. [PubMed] 2. 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 [ 3. Adler AC, Kadimi S, Apaloo C, Marcu C. Herpes Simplex Encephalitis with Two False-Negative Cerebrospinal Fluid PCR Tests and Review of Negative PCR Results in the Clinical Setting. Case Reports in Neurology. 2011; 3(2):172-178. Doi: 10.1159/000330298.
Figure 1: MRI of the brain, axial images A(diffusion weighted image ) & B( aparent diffusion coefficient) showing diffusion restriction involving bilateral thalami ( green arrows), corpus callosum ( yellow arrows), and frontal subcortical white matter ( red arrows).
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