EDITORIAL
Neurologic complications of rotavirus in neonates More common than we thought?
Linda S. de Vries, MD, PhD David Bearden, MD
Correspondence to Dr. de Vries: [email protected] Neurology® 2015;84:13–14
Rotavirus is the most common cause of gastroenteritis in children worldwide, with near universal exposure to rotavirus by age 5.1 Rotaviruses belong to the family Reoviridae and are nonenveloped double-stranded RNA viruses.2 Neurologic complications are not uncommon in older children, occurring in approximately 2%–3% of all children with rotavirus gastroenteritis, with the most common manifestations being febrile or afebrile seizures.3 Less commonly, rotavirus can cause an acute encephalopathy or frank encephalitis. The mechanism by which rotavirus causes neurologic complications is unknown, although various hypotheses include direct viral invasion causing neuronal injury, viral toxin production, and excitotoxicity.3 Until recently, the conventional wisdom has been that while rotavirus is relatively common in neonates, neurologic complications are rare in this population.4 In this issue of Neurology®, Yeom et al.5 show an association between rotavirus infections in neonates presenting with seizures during the first week of life and a distinctive pattern of symmetric white matter diffusion restriction on MRI. These MRI changes occurred even in the absence of gastroenteritis or other systemic symptoms. The patients were previously healthy full-term or near-term infants, only one had a fever, and all presented between days 4 and 7 of life. All but one infant in their series with this presentation (94.4%) had a rotavirus-positive stool sample. Of note, no rotavirus (or other viruses such as enterovirus or parechovirus) was detected in CSF or serum. The findings presented are fairly compelling, although the lack of systematic testing for other viruses is clearly a weakness of the study. However, it raises the following question: Given the number of infants affected in this single-center study within a relatively limited catchment area, why has this association not been described more commonly in other centers? With increased use of MRI including diffusionweighted imaging (DWI) in infants with neonatal seizures, white matter injury likely occurs in a variety of viral infections, and we are just starting to
understand how common this may be. White matter injury in infants with enterovirus or parechovirus meningoencephalitis, for example, is welldescribed.6,7 Verboon-Maciolek et al.8 first suggested the possible association of rotavirus infection and white matter injury, described in a small group of predominantly preterm infants. Five presented with gastrointestinal problems, but 3 had no diarrhea. Cystic evolution in the white matter occurred in 5 infants, being extensive in 3 preterm infants. A weakly positive rotavirus PCR in the CSF was present in only one infant. Similar clinical and MRI findings were recently reported by Lee et al.9 in 30 full-term infants who presented with neonatal seizures within the first month after birth. Twelve of the 13 (92.3%) infants with restricted diffusion on their MRI, performed within 3 days after the onset of seizures, tested positive for rotavirus in their stool sample, compared to 2/12 (16.7%; 5 not tested) in the comparison group, who presented with neonatal seizures but did not show these symmetrical restricted diffusion changes on MRI. The age at seizure onset was between days 4–6 in those who had a rotavirus infection, while in those without a rotavirus infection, the age range varied (day 1–27). It is of interest that the onset of seizures in both the current study as well as the Lee et al.2 study was between days 4–6 after birth, which correlates roughly with the amount of time that it takes rotavirus to become symptomatic. There is a previously demonstrated association between neonatal rotavirus infection and fifth-day fits.10 In that study, all but one of the infants with fifth-day fits (18/19; 95%) had rotavirus in their feces, compared to 12/30 (40%) healthy controls. However, the association between rotavirus and fifth-day fits has not subsequently been replicated. The studies discussed above suggest selective vulnerability of the white matter in the preterm as well as the full-term infant in diverse viral infections. The pattern of white matter pattern injury described in the current study is not unique to rotavirus, and in
See page 21 From the Department of Neonatology (L.S.d.V.), Wilhelmina Children’s Hospital, University Medical Center Utrecht, the Netherlands; and the Division of Neurology (D.B.), Children’s Hospital of Philadelphia, PA. Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the editorial. © 2014 American Academy of Neurology
13
fact looks strikingly similar to the pattern seen in neonatal enterovirus and parechovirus infections, with a predilection for the white matter in the frontal lobes. Even though rotavirus was not demonstrated in the CSF in this study, CSF testing was not ideal as it was performed later on banked frozen specimens; however, other studies that have looked systematically for rotavirus in fresh samples have also often failed to find evidence of virus in the CSF.8,9 Direct CNS infection by rotavirus is still the most plausible mechanism of injury given the similarity to other neonatal viral infections, but the role of toxin-mediated injury deserves further consideration. Rotavirus is relatively unique in that it contains a transmembrane glycoprotein, NSP4, which functions as a viral enterotoxin capable of inducing diarrhea through complex mechanisms, including interfering with local calcium homeostasis or with tight junctions in the intestine.3 Variability in NSP4 across rotavirus strains in different geographic locations may be a key determinant of pathogenicity.3 This could explain why most rotavirus infections are relatively benign in neonates, while there are occasional clusters of large numbers of infants with substantial neurologic complications. Yeom et al. are correct to conclude that rotavirus should be added to the list of viruses that can lead to white matter injury in the neonatal period. Because rotavirus can spread quickly in neonatal intensive care units, this article suggests that we should be looking for rotavirus in neonates with seizures and white matter injury on MRI so that appropriate infection control measures can be taken. Further studies are necessary to clarify the mechanism of rotavirus neurotoxicity and to establish how common CNS rotavirus is in neonates in other geographic locations.
14
Neurology 84
January 6, 2015
STUDY FUNDING No targeted funding reported.
DISCLOSURE The authors report no disclosures. Go to Neurology.org for full disclosures.
REFERENCES 1. Parashar UD, Hummelman EG, Bresee JS, et al. Global illness and deaths caused by rotavirus disease in children. Emerg Infect Dis 2003;9:565–572. 2. Kapikian AZ, Hoshino Y. Rotaviruses. In: Knipe DM, Howley PM, editors. Fields Virology. Philadelphia: Lippincott Williams & Wilkins; 2001. 3. Goldwater P, Rowland K, Power R, et al. Rotavirus encephalopathy: pathogenesis reviewed. J Paediatr Child Health 2001;37:206–209. 4. Haffejee IE. Neonatal rotavirus infections. Rev Infect Dis 1991;13:957–962. 5. Yeom JS, Kim YS, Seo JH, et al. Distinctive pattern of white matter injury in neonates with rotavirus infection. Neurology 2015;84:21–27. 6. Verboon-Maciolek MA, Groenendaal F, Cowan F, Govaert P, van Loon AM, de Vries LS. White matter damage in neonatal enterovirus meningoencephalitis. Neurology 2006;66:1267–1269. 7. Verboon-Maciolek MA, Groenendaal F, Hahn CD, et al. Human parechovirus causes encephalitis with white matter injury in neonates. Ann Neurol 2008;64:266–273. 8. Verboon-Maciolek MA, Truttmann AC, Groenendaal F, et al. Development of cystic periventricular leukomalacia in newborn infants after rotavirus infection. J Pediatr 2012;160:165–168. 9. Lee KY, Oh KW, Weon YC, Choi SH. Neonatal seizures accompanied by diffuse cerebral white matter lesions on diffusion-weighted imaging are associated with rotavirus infection. Eur J Paediatr Neurol 2014;18:624–631. 10. Herrmann B, Lawrenz-Wolf B, Seewald C, et al. 5th day convulsions of the newborn infant in rotavirus infections [in German]. Monatsschr Kinderheilkd 1993;141:120–123.
Neurologic complications of rotavirus in neonates: More common than we thought? Linda S. de Vries and David Bearden Neurology 2015;84;13-14 Published Online before print December 3, 2014 DOI 10.1212/WNL.0000000000001115 This information is current as of December 3, 2014 Updated Information & Services
including high resolution figures, can be found at: http://www.neurology.org/content/84/1/13.full.html
References
This article cites 9 articles, 2 of which you can access for free at: http://www.neurology.org/content/84/1/13.full.html##ref-list-1
Subspecialty Collections
This article, along with others on similar topics, appears in the following collection(s): Critical care http://www.neurology.org//cgi/collection/critical_care Encephalitis http://www.neurology.org//cgi/collection/encephalitis MRI http://www.neurology.org//cgi/collection/mri Neonatal seizures http://www.neurology.org//cgi/collection/neonatal_seizures Viral infections http://www.neurology.org//cgi/collection/viral_infections
Permissions & Licensing
Information about reproducing this article in parts (figures,tables) or in its entirety can be found online at: http://www.neurology.org/misc/about.xhtml#permissions
Reprints
Information about ordering reprints can be found online: http://www.neurology.org/misc/addir.xhtml#reprintsus
Neurology ® is the official journal of the American Academy of Neurology. Published continuously since 1951, it is now a weekly with 48 issues per year. Copyright © 2014 American Academy of Neurology. All rights reserved. Print ISSN: 0028-3878. Online ISSN: 1526-632X.
Neurologic complications of rotavirus in neonates More common than we thought?
Linda S. de Vries, MD, PhD David Bearden, MD
Correspondence to Dr. de Vries: [email protected] Neurology® 2015;84:13–14
Rotavirus is the most common cause of gastroenteritis in children worldwide, with near universal exposure to rotavirus by age 5.1 Rotaviruses belong to the family Reoviridae and are nonenveloped double-stranded RNA viruses.2 Neurologic complications are not uncommon in older children, occurring in approximately 2%–3% of all children with rotavirus gastroenteritis, with the most common manifestations being febrile or afebrile seizures.3 Less commonly, rotavirus can cause an acute encephalopathy or frank encephalitis. The mechanism by which rotavirus causes neurologic complications is unknown, although various hypotheses include direct viral invasion causing neuronal injury, viral toxin production, and excitotoxicity.3 Until recently, the conventional wisdom has been that while rotavirus is relatively common in neonates, neurologic complications are rare in this population.4 In this issue of Neurology®, Yeom et al.5 show an association between rotavirus infections in neonates presenting with seizures during the first week of life and a distinctive pattern of symmetric white matter diffusion restriction on MRI. These MRI changes occurred even in the absence of gastroenteritis or other systemic symptoms. The patients were previously healthy full-term or near-term infants, only one had a fever, and all presented between days 4 and 7 of life. All but one infant in their series with this presentation (94.4%) had a rotavirus-positive stool sample. Of note, no rotavirus (or other viruses such as enterovirus or parechovirus) was detected in CSF or serum. The findings presented are fairly compelling, although the lack of systematic testing for other viruses is clearly a weakness of the study. However, it raises the following question: Given the number of infants affected in this single-center study within a relatively limited catchment area, why has this association not been described more commonly in other centers? With increased use of MRI including diffusionweighted imaging (DWI) in infants with neonatal seizures, white matter injury likely occurs in a variety of viral infections, and we are just starting to
understand how common this may be. White matter injury in infants with enterovirus or parechovirus meningoencephalitis, for example, is welldescribed.6,7 Verboon-Maciolek et al.8 first suggested the possible association of rotavirus infection and white matter injury, described in a small group of predominantly preterm infants. Five presented with gastrointestinal problems, but 3 had no diarrhea. Cystic evolution in the white matter occurred in 5 infants, being extensive in 3 preterm infants. A weakly positive rotavirus PCR in the CSF was present in only one infant. Similar clinical and MRI findings were recently reported by Lee et al.9 in 30 full-term infants who presented with neonatal seizures within the first month after birth. Twelve of the 13 (92.3%) infants with restricted diffusion on their MRI, performed within 3 days after the onset of seizures, tested positive for rotavirus in their stool sample, compared to 2/12 (16.7%; 5 not tested) in the comparison group, who presented with neonatal seizures but did not show these symmetrical restricted diffusion changes on MRI. The age at seizure onset was between days 4–6 in those who had a rotavirus infection, while in those without a rotavirus infection, the age range varied (day 1–27). It is of interest that the onset of seizures in both the current study as well as the Lee et al.2 study was between days 4–6 after birth, which correlates roughly with the amount of time that it takes rotavirus to become symptomatic. There is a previously demonstrated association between neonatal rotavirus infection and fifth-day fits.10 In that study, all but one of the infants with fifth-day fits (18/19; 95%) had rotavirus in their feces, compared to 12/30 (40%) healthy controls. However, the association between rotavirus and fifth-day fits has not subsequently been replicated. The studies discussed above suggest selective vulnerability of the white matter in the preterm as well as the full-term infant in diverse viral infections. The pattern of white matter pattern injury described in the current study is not unique to rotavirus, and in
See page 21 From the Department of Neonatology (L.S.d.V.), Wilhelmina Children’s Hospital, University Medical Center Utrecht, the Netherlands; and the Division of Neurology (D.B.), Children’s Hospital of Philadelphia, PA. Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the editorial. © 2014 American Academy of Neurology
13
fact looks strikingly similar to the pattern seen in neonatal enterovirus and parechovirus infections, with a predilection for the white matter in the frontal lobes. Even though rotavirus was not demonstrated in the CSF in this study, CSF testing was not ideal as it was performed later on banked frozen specimens; however, other studies that have looked systematically for rotavirus in fresh samples have also often failed to find evidence of virus in the CSF.8,9 Direct CNS infection by rotavirus is still the most plausible mechanism of injury given the similarity to other neonatal viral infections, but the role of toxin-mediated injury deserves further consideration. Rotavirus is relatively unique in that it contains a transmembrane glycoprotein, NSP4, which functions as a viral enterotoxin capable of inducing diarrhea through complex mechanisms, including interfering with local calcium homeostasis or with tight junctions in the intestine.3 Variability in NSP4 across rotavirus strains in different geographic locations may be a key determinant of pathogenicity.3 This could explain why most rotavirus infections are relatively benign in neonates, while there are occasional clusters of large numbers of infants with substantial neurologic complications. Yeom et al. are correct to conclude that rotavirus should be added to the list of viruses that can lead to white matter injury in the neonatal period. Because rotavirus can spread quickly in neonatal intensive care units, this article suggests that we should be looking for rotavirus in neonates with seizures and white matter injury on MRI so that appropriate infection control measures can be taken. Further studies are necessary to clarify the mechanism of rotavirus neurotoxicity and to establish how common CNS rotavirus is in neonates in other geographic locations.
14
Neurology 84
January 6, 2015
STUDY FUNDING No targeted funding reported.
DISCLOSURE The authors report no disclosures. Go to Neurology.org for full disclosures.
REFERENCES 1. Parashar UD, Hummelman EG, Bresee JS, et al. Global illness and deaths caused by rotavirus disease in children. Emerg Infect Dis 2003;9:565–572. 2. Kapikian AZ, Hoshino Y. Rotaviruses. In: Knipe DM, Howley PM, editors. Fields Virology. Philadelphia: Lippincott Williams & Wilkins; 2001. 3. Goldwater P, Rowland K, Power R, et al. Rotavirus encephalopathy: pathogenesis reviewed. J Paediatr Child Health 2001;37:206–209. 4. Haffejee IE. Neonatal rotavirus infections. Rev Infect Dis 1991;13:957–962. 5. Yeom JS, Kim YS, Seo JH, et al. Distinctive pattern of white matter injury in neonates with rotavirus infection. Neurology 2015;84:21–27. 6. Verboon-Maciolek MA, Groenendaal F, Cowan F, Govaert P, van Loon AM, de Vries LS. White matter damage in neonatal enterovirus meningoencephalitis. Neurology 2006;66:1267–1269. 7. Verboon-Maciolek MA, Groenendaal F, Hahn CD, et al. Human parechovirus causes encephalitis with white matter injury in neonates. Ann Neurol 2008;64:266–273. 8. Verboon-Maciolek MA, Truttmann AC, Groenendaal F, et al. Development of cystic periventricular leukomalacia in newborn infants after rotavirus infection. J Pediatr 2012;160:165–168. 9. Lee KY, Oh KW, Weon YC, Choi SH. Neonatal seizures accompanied by diffuse cerebral white matter lesions on diffusion-weighted imaging are associated with rotavirus infection. Eur J Paediatr Neurol 2014;18:624–631. 10. Herrmann B, Lawrenz-Wolf B, Seewald C, et al. 5th day convulsions of the newborn infant in rotavirus infections [in German]. Monatsschr Kinderheilkd 1993;141:120–123.
Neurologic complications of rotavirus in neonates: More common than we thought? Linda S. de Vries and David Bearden Neurology 2015;84;13-14 Published Online before print December 3, 2014 DOI 10.1212/WNL.0000000000001115 This information is current as of December 3, 2014 Updated Information & Services
including high resolution figures, can be found at: http://www.neurology.org/content/84/1/13.full.html
References
This article cites 9 articles, 2 of which you can access for free at: http://www.neurology.org/content/84/1/13.full.html##ref-list-1
Subspecialty Collections
This article, along with others on similar topics, appears in the following collection(s): Critical care http://www.neurology.org//cgi/collection/critical_care Encephalitis http://www.neurology.org//cgi/collection/encephalitis MRI http://www.neurology.org//cgi/collection/mri Neonatal seizures http://www.neurology.org//cgi/collection/neonatal_seizures Viral infections http://www.neurology.org//cgi/collection/viral_infections
Permissions & Licensing
Information about reproducing this article in parts (figures,tables) or in its entirety can be found online at: http://www.neurology.org/misc/about.xhtml#permissions
Reprints
Information about ordering reprints can be found online: http://www.neurology.org/misc/addir.xhtml#reprintsus
Neurology ® is the official journal of the American Academy of Neurology. Published continuously since 1951, it is now a weekly with 48 issues per year. Copyright © 2014 American Academy of Neurology. All rights reserved. Print ISSN: 0028-3878. Online ISSN: 1526-632X.
