Original Studies
Neurologic Complications of Rotavirus Infections in Children
David E. F. Slotboom, MD,* Daphne Peeters, MD,* Stefan Groeneweg, MD, PhD,*
Anneloes van Rijn-Klink, MD, PhD,† Elke Jacobs, MD,‡ Michiel H. D. Schoenaker, MD, PhD,* and
Mirjam van Veen , MD, PhD*
Background: Rotavirus is the leading cause of complicated gastroenteritis The pathogenic mechanism by which rotavirus causes neu-
in children younger than 5 years in countries where rotavirus vaccination rologic symptoms has not been fully elucidated and may well be
is not implemented as a routine vaccination. Besides the intestinal symp- multifactorial. Some studies showed the presence of rotavirus anti-
toms that are associated with ordinary gastroenteritis, rotavirus can cause gens in the cerebral spinal fluid (CSF), whereas viral antigens were
neurological complications. The aim of this study is to describe the clinical absent in others.9,10 This may suggest that beside the direct invasion
characteristics of complicated rotavirus infections. of viral particles into the brain across the blood-brain barriers, indi-
Methods: From January 1, 2016 to January 31, 2022, all children (below rect mechanisms such as the entry of brain-damaging mediators
the age of 18 years) with a positive rotavirus test in feces that were either and activated immune cells into the brain over breached blood ves-
hospitalized or presented at the outpatient clinic or emergency department sels may also contribute.8
of a large pediatric hospital in the Netherlands were included. Rotavirus was Vaccination against rotavirus may prevent neurologic mani-
only tested in case of a severe or abnormal disease course. We described the festations.11 Since 2006, rotavirus vaccinations for children have
clinical characteristics and outcomes with a particular focus on neurological been implemented in over 100 countries worldwide, this resulted
manifestations. in a significant reduction in the hospital admission rate.12 Further-
Results: In total, 59 patients with rotavirus were included of whom 50 more, upon the introduction of rotavirus vaccination the hospital
(84.7%) were hospitalized and 18 (30.5%) needed intravenous rehydration. admissions of children younger than 5 years with acute gastroen-
Ten patients (16.9%) had neurologic complications, of whom 6 patients teritis–associated seizures declined.13,14
(60.0%) presented encephalopathy. Two patients (20.0%) with neurological The clinical course of neurologic complicated rotavirus
symptoms showed abnormalities on diagnostic imaging. infections is relatively unknown. Data on the incidence of neuro-
Conclusions: Rotavirus can cause gastroenteritis with severe, but appar- logic complications of rotavirus infection are currently lacking and
ently self-limiting, neurological manifestations. Considering rotavirus in (long-term) outcomes of such sequelae have not been documented.15
pediatric patients with neurological symptoms such as encephalopathy Moreover, it is unclear which patients are at risk to develop neuro-
and encephalitis is therefore important. Early detection of rotavirus infec- logic complications, and if these should be treated. To fill this gap,
tion may predict a favorable course of the disease and may thereby prevent we performed a retrospective case-file study in which we reviewed
unnecessary treatment and should be further investigated. the clinical characteristics and outcome of children with a con-
firmed rotavirus infection visiting the emergency department of or
Key Words: rotavirus, complications, neurologic, encephalopathy
being admitted to a large pediatric hospital in the Netherlands.
(Pediatr Infect Dis J 2023;42:533–536) The aim of this study is to describe the clinical character-
istics of complicated rotavirus infection, in particular the clinical
course of children with involvement of the central nervous system
(CNS).
R otavirus is the leading cause of complicated gastroenteritis in
children younger than 5 years in countries where rotavirus vac-
cination is not implemented as a routine vaccination.1 In the Neth- METHODS
erlands, about 1900–3400 children are hospitalized every year due Study Design and Patient Selection
to rotavirus infection.2 Besides the intestinal symptoms that are All pediatric patients (0–18 years old) with a positive test
associated with ordinary gastroenteritis, several studies, based on on rotavirus in feces that were either hospitalized or presented
individual cases or small case series, also described the occurrence at the outpatient clinic or emergency department were included.
of neurologic manifestations such as encephalitis, encephalopa- Viral testing was performed in case of a prolonged admission dura-
thy, cerebellitis, meningitis, status epilepticus and afebrile convul- tion for more than 48 hours, intravenous rehydration, neurologic
sions.3–7 In some of these cases, the clinical manifestations were symptoms or a deviated disease course as decided by the treating
accompanied by abnormalities in brain magnetic resonance imag- physician. Patients were excluded when the test was ordered via
ing (MRI), which were usually reversible.6,8,9 their general practitioner. A laboratory database (GLIMS, MIPS,
Belgium) was searched for positive rotavirus tests in feces between
January 1, 2016 and January 31, 2022 in a large general pediatric
hospital in the Netherlands. Rotavirus testing consisted of anti-
Accepted for publication February 15, 2023
From the *Department of Pediatrics, Juliana Kinderziekenhuis, CH Den Haag, gen testing (LIAISON rotavirus, DiaSorin S.p.A. - Saluggia) until
Zuid-Holland, The Netherlands; †Department of Medical Microbiology, November 2021 and positive polymerase chain reaction (PCR)
Haga Ziekenhuis, CH Den Haag, Zuid-Holland, The Netherlands; and (viral gastro-enteritis Fast Track Diagnostics, Luxembourg) from
‡Department of Pediatric Neurology, Juliana Kinderziekenhuis, CH Den November 2021.
Haag, Zuid-Holland, The Netherlands
The authors have no funding or conflicts of interest to disclose.
Address for correspondence: M. van Veen, Department of Pediatrics, Juliana Data Collection and Study Outcomes
Children’s Hospital, Els Borst-Eilersplein 275, 2545 CH The Hague, the Anonymized data were retrieved from electronic medical
Netherlands. E-mail:
[email protected]. records. Variables that were collected include general patient charac-
Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.
ISSN: 0891-3668/23/427-533536 teristics such as age, gender, height, weight, vaccination status, prior
DOI: 10.1097/INF.0000000000003921 medical history, medication and the course of illness. Variables that
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Slotboom et al The Pediatric Infectious Disease Journal • Volume 42, Number 7, July 2023
describe the course of illness are clinical symptoms, dehydration, Statistical Analysis
type of rehydration [oral, via nasogastric tube or intravenously (iv)], Categorical variables were summarized in terms of fre-
length of stay, admission to pediatric intensive care unit (PICU), quency and percentage. Every continuous variable was, depending
complications, discharge destination and co-infection. Additional on their distribution, presented either as mean ± standard deviation
variables that were collected for patients with involvement of the (SD) or median ± interquartile range (IQR). Statistical analysis was
CNS were neurologic symptoms and diagnosis, results of MRI, com- performed using IBM SPSS Statistics for Mac, version 27.
puterized tomography (CT), electroencephalogram (EEG), cerebro-
spinal fluid culture and viral PCR, screening of urine and/or plasma
for metabolic disorders, the use and type of medication, follow-up of RESULTS
neurologic symptoms, length of follow-up and readmission. Description of a Case
A 2-year-old previously healthy girl was admitted at a
Ethics Approval and Consent to Participate regional servicing hospital with symptoms of fever and vomiting. At
Ethical approval for this retrospective study was obtained presentation, she was hypotonic, had an altered mental status and
from the Medical Ethics Committee of Leiden-Den Haag-Delft was unable to speak. EEG and CT-scan were performed and showed
and the requirement for written informed consent was waived. This no abnormalities. Abdominal ultrasound and MRI were indicative
study was not subjected to the Medical Research Involving Human for an intussusception. For that reason, she was transferred to our
Subjects Act (WMO) as participants were not imposed to proce- hospital. On arrival, she had a lowered consciousness alternated with
dures nor required to follow rules of behavior. crying, hypotonia of trunk and arms, shocking and stiffening move-
ments of the arms and anisocoria. Acute disseminated encephalo-
Definitions myelitis (ADEM), encephalitis, metabolic disorder, intoxication and
Gastroenteritis was defined as an increased frequency of N-methyl-D-aspartate-encephalitis were considered as diagnosis.
watery stools and vomiting. The lumbar puncture showed a pleocytosis and PCR in the feces was
Patients with gastroenteritis that needed intravenous rehy- positive for rotavirus. An MRI scan showed restricted diffusion in the
dration were identified as cases of severe gastroenteritis. dentate nucleus on both sides and signs of cerebellitis, this supported
Rotavirus infection was established when rotavirus was the diagnosis of ADEM in this case triggered by rotavirus infection.
detected in the feces. She was treated with ceftriaxone that was stopped after a
Reporting of dehydration was based on documentation from negative blood culture. Furthermore, she received analgesic medica-
the attending clinician in the electronic medical records and based tion and Gabapentin for a short period of time because of agitation.
on clinical symptoms according to Dutch national guidelines.16 She gradually improved without further medical treatment and was
Patients that were rehydrated both intravenously as well as discharged after 16 days without persisting neurologic symptoms.
via nasogastric tube were classified as “intravenous rehydration.”
Encephalopathy was defined as a syndrome characterized by Baseline Characteristics and Clinical Presentation
an acute onset of long-lasting and severe disturbance of conscious- In total, 59 patients with rotavirus infection were included
ness. The diagnosis was made by the pediatrician and confirmed by of which 10 (16.9%) had neurologic complications (Fig. 1). No
a pediatric neurologist.17 patients had a history of an underlying neurologic condition. Base-
Cerebellitis, meningitis and encephalitis were diagnoses line characteristics and clinical presentation from all patients are
based on clinical presentation and additional investigations such as shown in Table 1. Almost all patients had symptoms of gastroen-
MRI and lumbar puncture. teritis (93%). Other clinical presentations were chronic diarrhea,
FIGURE 1. Number of admissions per year.
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The Pediatric Infectious Disease Journal • Volume 42, Number 7, July 2023 Neurologic Complications of Rotavirus
TABLE 1. Baseline Characteristics and Clinical Pres- TABLE 2. Features of Patients with Neurologic Com-
entation plications
Sex, n (%) Neurologic diagnosis, n (%)
Female 30 (50.8) Cerebellitis and ADEM 1 (10.0)
Age (years), median (IQR) 1.17 (0.55–2.49) Meningoencephalitis 1 (10.0)
Underlying neurologic condition, n (%) 0 Encephalopathy 6 (60.0)
Medical diagnosis, n (%) Seizures 2 (20.0)
Gastroenteritis 55 (93.2) Length of neurologic symptoms (days), median (IQR) 3 (1.00–5.00)
Other 4 (6.8) Unknown, n (%) 2 (20.0)
Dehydration, n (%) 26 (44.1) Timing of the onset of neurologic symptoms, n (%)
Metabolic acidosis*, n (%) 6 (10.2) Before developing symptoms of gastroenteritis 2 (20.0)
Hospitalized, n (%) 50 (84.7) During developing symptoms of gastroenteritis 2 (20.0)
Due to rotavirus infection, n (%) 39 (78.0) After developing symptoms of gastroenteritis 6 (60.0)
Length of stay (days), median (IQR) 4 (2-6) Medication, n (%)
Admission to PICU** due to rotavirus infection, n (%) 1 (1.7) Dexamethasone 1 (10.0)
Type of rehydration, n (%) Methylprednisolone 1 (10.0)
Oral 23 (39.0) Ceftriaxone 5 (50.0)
Nasogastric tube 18 (30.5) Acyclovir 3 (30.0)
Intravenous*** 18 (30.5) Levetiracetam 2 (20.0)
Neurologic complications, n (%) 10 (16.9) Length of follow-up (days), median (IQR) 60 (45–99)
Enduring symptoms during follow-up, n (%) 1 (10.0)
*pH below 7.35.
Additional investigations, n (%)
**Pediatric Intensive Care Unit.
***Some patients only received one bolus of fluid intravenously.
Abnormal MRI 2/6 (33.3)
Abnormal CT-can 0/2 (0.0)
Abnormal EEG 2/5 (40.0)
oxygen desaturation and hypercapnia in a neonate, intussuscep- High cell count in lumbar puncture 1/5 (10.0)
tion and pyelonephritis. Two patients were admitted to the PICU Abnormal metabolic screening 0/3 (0.0)
of which 1 was admitted because of a neurologically complicated ADEM, Acute disseminated encephalomyelitis; CT, computerized tomography;
infection with rotavirus. The other patient was admitted for respira- EEG, electroencephalogram; MRI, magnetic resonance imaging.
tory failure caused by laryngeal obstruction. Fifty (84.7%) of the
patients were hospitalized and 18 (30.5%) of them were severely Number of Admissions Per Year
dehydrated and needed intravenous rehydration.
Figure 1 shows an overview of the number of admissions per
Features of Patients with Neurologic year in the Juliana Children’s Hospital.
Complications
Ten of 59 patients exhibited neurologic features. Their median DISCUSSION
age was 2.4 years, and none of them had a previous history of neu- This retrospective study demonstrates that a considerable
rologic disease. Four patients (40.0%) were dehydrated. Data about part (10.0%) of the patients with rotavirus infections requiring
the diagnosis, length of symptoms, timing of onset, management presentation at the emergency department of general (pediatric)
and additional investigation of 10 patients with neurologic compli- hospitals may exhibit neurologic complications such as encepha-
cations are shown in Table 2. Encephalopathy was the most common lopathy and seizures. Importantly, neurologic manifestations spon-
neurologic manifestation (6/10, 60.0%). Two (20.0%) patients with taneously subside without obvious persisting symptoms.
encephalopathy developed a status epilepticus and were treated with The patients with CNS complications were previously healthy,
anticonvulsants. The median length of neurologic symptoms was 3 normally developed children that had no history of underlying neu-
days. The timing of the onset of neurologic complications differed, rologic conditions. This suggests that medical history plays a limited
most patients (6/10, 60.0%) developed neurologic symptoms after role in the development of neurologic symptoms and complicates the
the onset of gastroenteritis. Five (50.0%) patients with neurologic identification of patients at risk to develop neurologic manifestations.
complications were treated with ceftriaxone because bacterial men- As shown by this study, infection with rotavirus can induce a wide
ingitis was suspected. Three of these patients were treated with both variety of CNS complications. It is therefore unlikely that treatment
ceftriaxone and acyclovir when a viral meningitis could not be ruled for these patients can be standardized. Our study population received
out. For all 3 patients, treatment with ceftriaxone and acyclovir was symptomatic treatment and supportive care. In contrast to the cur-
discontinued after CSF culture revealed no bacterial growth and rent literature, most of our patients (8/10, 80.0%) did not receive
PCR was negative for herpes simplex virus, enterovirus and adeno- dexamethasone or methylprednisolone.7,18 Despite the retrospective
virus. One patient that was diagnosed with ADEM had enduring design of our study and thus lack of standardized follow-up, these
neurologic symptoms during follow-up. observations suggest that no specific intervention other than support-
ive care is needed to treat neurologic complications of rotaviral infec-
Results of Additional Investigation tions. Future prospective (intervention) studies are required to further
Six patients underwent an MRI scan and 2 (33.3%) of those address this issue.
patients had an aberrant scan. Abnormalities that were seen on the Importantly, 9 of 10 (90.0%) patients with neurologic manifes-
MRI were cytotoxic lesions in the splenium of the corpus callosum tations had no enduring symptoms at follow-up. The only patient with
and symmetric diffusion restrictions in the dentate nucleus indica- enduring CNS symptoms was diagnosed with ADEM. Therefore, the
tive of cerebellitis. All CT scans were normal. Two patients had prognosis in most rotavirus infections with neurologic manifestations
abnormalities on their EEG suggestive for encephalopathy. One seems favorable. Furthermore, the duration of the neurologic symp-
patient had a lumbar puncture with an elevated white blood cell toms seems to be relatively short with a median length of 3 days.
count of 28 × 109 per microliter. All screening for metabolic disor- This case series presents 1 of the largest cohorts of children
ders was normal. with neurologic complications due to rotavirus infections, however,
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Slotboom et al The Pediatric Infectious Disease Journal • Volume 42, Number 7, July 2023
definitive conclusions about the clinical course and supporting treat- REFERENCES
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