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Parent-administered Neurodevelopmental Follow up in Children After Picornavirus CNS Infections

Stephens, Carol MRCPI, MRCPCh*; Reynolds, Clare MRCPI*; Cremin, Molly*; Barry, Rachel MB BCh, MAO, MRCPi; Morley, Ursula MSc; Gibson, Louise MRCPI*; De Gascun, Cillian F. MD, FRCPI, FRCPath; Felsenstein, Susana MSc, DTMH§

Author Information
The Pediatric Infectious Disease Journal: October 2021 - Volume 40 - Issue 10 - p 867-872
doi: 10.1097/INF.0000000000003192


The epidemiology of central nervous system (CNS) infections in children has changed dramatically over recent decades with viral etiologies now predominant over bacterial causes.1–3 Successful vaccination programs, improved molecular diagnostics, and the discovery of new viral pathogens are all likely to have contributed to these changes.

Viral meningoencephalitis in infancy carries a risk of neurodevelopmental sequelae that may not be fully evident when assessments are limited to short-term outcomes. Viral CNS infections in childhood may double the risk of schizoaffective disorders later on.4–6 While follow up after bacterial meningitis is well established,7,8 viral CNS infections, with the exception of Herpes simplex infections, are often assumed to be more benign.9 Neurodevelopmental follow up is more informal, and outcome data are comparatively scarce and controversial as a result.10

The exact incidence of enterovirus (EV) and human parechovirus (hPeV) CNS infections in young children is unknown, as molecular testing is not universal. The relevance of picornaviruses however is illustrated by data from NESS (National Enterovirus Surveillance System, United States): 44% of enteroviral illnesses between 1970 and 2005 occurred in infants younger than 1 year, and almost half of the submitted specimens were cerebrospinal fluid (CSF) samples.11 The annual incidence of picornaviral meningitis in UK infants younger than 90 days has been estimated at 0.79 for enterovirus (EV) and 0.04 for human parechovirus (hPeV) per 1000 live births.12

Although picornaviruses dominate as causative agents of infant meningitis,12–14 studies investigating medium- to long-term outcomes are surprisingly scarce.15–19 Limited data suggest that hPeV meningoencephalitis in particular carries an underrecognized neurodevelopmental burden (Table, Supplemental Digital Content 1,

The COVID-19 pandemic has challenged healthcare systems globally, including in Ireland.

To identify if picornavirus CNS infections in children are associated with neurodevelopmental delay after medium- to long-term follow up while avoiding hospital visits for research assessments, we implemented a parent-administered neurodevelopmental screening tool. This was offered it to all families whose children had presented to our institution with an EV or hPeV meningitis/encephalitis (ME) from 2014 to 2019.


All children who presented to Cork University Hospital, Cork, Ireland, between January 2014 and December 2019, and whose CSF tested positive by polymerase chain reaction for EV and hPeV were included.20,21 The National Virus Reference Laboratory (University College Dublin) provided typing of entero- and parechovirus RNA where available.

CSF white cell count (WCC) was considered normal if ≤5 WCC/mm3 in those older than 28 days and if below the 90th centile of age-adjusted value in neonates.22 Traumatic lumbar puncture was defined as RBC of ≥5/mm3 in CSF.

Patients were identified through review of laboratory records. Their parents of children who experienced CNS infections with picornaviruses between January 2014 and December 2019 were contacted by telephone over a 2-month period, from February to April 2020, and consented for participation in a parent-directed, developmental assessment of the child. At this time, all children contacted were up to 66 months of age and were within the age range the ASQ3 is validated for. Up to 3 attempts at contacting each family were made. The Ages and Stages Instrument (ASQ3)23,24 is a neurodevelopmental screening tool25 for children up to 66 months of age, validated for use by parents in the child’s home environment. It consists of 21 age-specific questionnaires with 30 questions26 offering 3 response options (“yes,” “sometimes,” “not yet”) in the categories communication, gross motor, fine motor, problem solving, and personal-social skills. The parents returned the completed assessment and their answers were graded by coinvestigators blinded to clinical information on the child. Scores ≥2 SD below the mean indicate a need for further assessment; scores at 1–2 SD below the mean prompted monitoring; and scores above the cutoff indicate normal development. Separate data collectors performed a retrospective chart review and collated information on clinical details during the infective episode.

Statistical analysis was performed using SPSS 22.0 (SPSS Inc., Chicago, IL). Quantitative variables were reported as absolute numbers, percentages, means, and standard deviations, and by median and interquartile range (IQR) as appropriate. Comparisons of continuous variables between groups to test for equality were performed using t test and paired t test if normally distributed, or Mann-Whitney and Kruskal-Wallis test where not. Tests of association between categorical variables were based on χ2 and Fisher exact tests. P values reported are 2-sided and considered statistically significant if less than 0.05. The study was approved by the Ethics Committee at Cork University Hospital. No funding was received.


Picornaviruses Identified in CSF of Children 2014–2019

Of 101 CSF samples, 23 were hPeV and 78 EV positive. Seasonality of hPeV serotype 3 was not seen (Fig. 1). In 2018, hPeV was noticeably more frequent accounting for 12/23 (52.2%) of hPeV cases overall. Typing was available for 10/23 (43.5%) hPeV cases and in 9/10 (90%), serotype 3 was identified. In 1 patient, an irritable neonate, serotype 5 was found. Enterovirus typing was available in 43/78 (55.1%) samples. Many different enteroviruses were encountered, including Coxsackieviruses A9 (1), A16 (1), B1 (5), B3 (2), B4 (3), B5 (4); Echoviruses 3 (1), 5 (2), 6 (1), 7 (1), 9 (5), 16 (1), 18 (1), 21 (2), 30 (8) and Enterovirus 71 (4), without distinguishable temporal distribution pattern.

Temporal distribution of frequency of enterovirus resp. human parechovirus positive cerebrospinal fluid samples during the study period.

Patients with hPeV positive CSF were significantly younger at the time of the infection (median 25 days; IQR, 17–35; versus 48 days; IQR, 24–94; P = 0.04). All were <90 days old apart from 1 patient with 112 days of age. Among EV positive cases, age ranged widely from 3 days to 10 years.

Characteristics of Cohort Recruited to Developmental Follow up

Forty-three (42.6%) of 101 families consented to participate and returned questionnaires. Three declined participation, 27 could not be reached, 24 consented but failed to return the questionnaire, and in 4 cases, contact details could not be retrieved. Of those included, 33 had been EV and 10 hPeV positive. Most had experienced meningoencephalitis (ME) at a young age (median, 40 days; IQR, 16–83), hPeV positive patients earlier (median 19 days; IQR, 8–37) than those with EV (median 48 days; IQR, 23–92; P = 0.02). All hPeV positive children were less than 3 months old; the majority (7/10, 70%) were neonates at the time of the infective event.

CSF and Blood Results at Time of CNS Infection

Traumatic taps occurred in 19/43 CSF samples; 2/19 were hPeV positive. Among the remaining 24, pleocytosis was found only in the EV group (EV: mean CSF WCC 22.2/mm3, SD 25.4; hPeV: mean 1.7/mm3, SD 1.8; P < 0.01). None of the 10 children with hPeV had CSF WCC of >5/mm3. This is particularly noteworthy as most were neonates in whom a higher CSF WCC would still have been considered normal (Table 1). Conversely, only 6/17 EV patients had normal CSF WCC. CSF protein and glucose values did not differ significantly between groups (protein: EV mean 469.2 mg/L, SD 196.2; hPeV mean 522 mg/L, SD 203; glucose: EV mean 3.1 mmol/L; SD 0.36; hPeV 3.0 mmol/L; SD 0.29).

TABLE 1. - Clinical Characteristics of Children With Human Parechovirus CNS Infection Included in the Developmental Follow-up Cohort at Presentation
ID Age at Diagnosis (d) Presenting Symptoms WBC(×109/L) N (×109/L) Ly (×109/L) CRP (mg/dL) WCC (CSF) (/mm3)* Protein (CSF) (mg/L)
1 5 Pyrexia, jaundice, lethargy 7.3 3.17 2.23 2.3 3 802
2 7 Pyrexia, uncomfortable 9 5.13 2.09 11.3 5 869
3 8 Pyrexia, irritability 6.6 4.79 1.27 16.6 2 640
4 16 Pyrexia 4.2 1.32 1.79 3.0 TT TT
5 17 Hypoglycemia 6.1 3.13 1.56 1.7 1 572
6 21 Pyrexia, irritability, seizure 6.7 2.55 1.94 1.1 0 389
7 25 Pyrexia, irritability 3.7 1.39 1.72 5.6 0 309
8 32 Pyrexia, reduced feeds, lethargy 4.6 2.94 0.92 12.6 1 647
9 49 Pyrexia 4.9 1.39 2.65 3.2 1 456
10 56 Pyrexia, irritable, high pitched cry 6.4 2.37 4.03 4.0 3 346
CRP indicates C-reactive protein; Ly, lymphocytes; N, neutrophils; TT- traumatic tap; WBC, white blood cell count; WCC, white cell count.

RBC contamination was minimal (<1000 RBCs/mm3) in all, but 1 CSF sample and correction of CSF WCC by subtracting 1 WCC per 500 RBCs,27,28 while recognizing the limitations of this practice, would not have changed the interpretation of CSF WCC. Analysis of RBC-corrected CSF samples in 42/43 samples showed a mean WCC of 210/mm3 in the EV (SD 530) and 1.78/mm3 in the hPeV group (SD 1.6; P < 0.05). All hPeV positive CSF samples (9/9) showed a CSF WCC of ≤5/mm3, but only in a fifth (6/33, 18.2%) of EV positive CSF samples, CSF WCC was within normal range.

Children in the EV group had, on average, higher peripheral white blood count and C-reactive protein (CRP). Only 7 children overall had a white blood count >15 × 109/L (EV: 12.2 [SD 5.6] × 109/L; hPeV: 7.6 [SD 4.3] × 109/L, P = 0.02), and none had a CRP ≥30 mg/dL (EV: 14.9 [SD 15.6] mg/dL, hPeV: 6.1 [SD 5.4] mg/dL; P = 0.09).

Neurodevelopmental Follow Up

Questionnaires were completed adequately. One question was left blank or unintelligible in 3/43 questionnaires. Median age at assessment was 38.9 months (IQR, 15.4–54.8). This differed between groups (EV: median 41 months, IQR, 18.7–56.1; PEV: median 15.2 months, IQR, 14.4–41.0; P = 0.03), as a result of hPeVME clustering in 2018. The ASQ3 assessment occurred a median of 3 years (37 months, IQR 13.9–53.1) after the infective event. Although not statistically significant, this interval was shorter in those with hPeVME (EV 39.1 months, IQR 14.6–53.7; PEVME 14.7months, IQR 13.5–40.2; P = 0.12). There was no correlation between ASQ3 performance and WCC in CSF or blood inflammatory markers at the time of infection.

The ASQ3 results are detailed in Figure 2. The vast majority of patients were reported to develop on schedule. In 23/43 (17 EV, 6 hPeV), no concerns were expressed at all. In 9 children, a score ≥2 SD below the mean in at least 1 assessment category indicated that further assessment was recommended (8/33 EV, 1/10 hPeV). Five of 9 children scored ≥2 SD below the mean in more than 1 category. In an additional 11 (EV 8/33, hPeV 3/10), monitoring was advised in 1 category.

ASQ3 data for all children (A), participants with a history of human parechovirus infection (B), participants with a history of enterovirus infection (C) of the central nervous system. ASQ3 indicates The Ages and Stages Instrument.

Two patients who had come to medical attention before the infective event were removed from analysis. The first child, born prematurely at 27 weeks’ gestation, was diagnosed with periventricular leukomalacia in the neonatal period and developed cerebral palsy. The second child was diagnosed with ventriculomegaly antenatally and went on to develop a squint as well as gross and fine motor delay.

When the 2 children with preexisting conditions were removed from analysis, 7/41 (17%) will require professional review, scoring ≥2 SD below the mean (EV n = 6/31 [19.4%], hPeV n = 1/10 [10%]). Three scored low in more than 1 area. In the normally distributed validation cohort, 2.2% are expected to fall ≥2 SD below the mean. Children requiring professional review are therefore relatively overrepresented, especially in the areas of fine motor and psychosocial skills and among EV positive patients (Fig. 2).

For any level of concern recorded (≥1 SD below the mean) in at least 1 category, which accounted for just under half of children, there was no significant difference between the 2 groups (EV 14/31, 45.2% hPeV 4/10, 40%; P = 0.71).

There was no statistical correlation between neurodevelopmental sequelae, as measured by the ASQ3, and raised CRP, peripheral WCC, CSF protein, or corrected CSF WCC at the time of CNS infection. This was true for both EV and hPeV infections as individual variables and when examined collectively (data not shown).

Six of 33 EVME patients underwent MRI imaging: 5 were reported as normal and 1 showed known, preexisting ventricular asymmetry. Four of 10 children with hPeVME underwent imaging. Three were normal, 1 showed frontoparietal white matter changes in the context of seizures observed during the infection at 3 weeks of age. Scheduled medical followed-up documented normal development at 2 years of age.

When integrating parental concerns documented in prose, some degree of concern and need for developmental observation was reported in 4/10 hPeV and 16/33 of EV positive children.


Here, we present a cross-sectional, medium to long-term parent-administered neurodevelopmental follow up in children who had experienced entero- and parechovirus CNS infections.

Given the difficulties in maintaining outpatient and research visits during the COVID-19 pandemic, the parents who took part welcomed the opportunity to contribute to research without having to attend the hospital. Response rate, especially considering the long time period covered, was comparable with that of similar studies.

Studies examining neurodevelopment after picornavirus CNS infections often do not address long-term outcomes.15,16 A metanalysis of neurodevelopmental outcome following hPeV meningitis29 defined follow up of more than 12 months after the infective episode as long term, but emphasized the need for ongoing assessment until school age to optimize detection of potential sequelae. It included 20 studies that followed n = 290 children up to 6 weeks, n = 247 for 6–12 months after hospital discharge and only n = 183 for more than 12 months.

This study offers a longer follow-up period of 3 years, facilitating detection of more subtle signs presenting later and only recruited children in whom polymerase chain reaction on CSF was positive to limit the cohort to those with proven CNS involvement.

In the study reported herein, assessment of patients with EV identified a need for monitoring, or professional assessment, significantly more frequently than in the hPeV group, in contrast to most other cohorts that have compared these 2 entities, although almost always over a shorter follow-up period (Table, Supplemental Digital Content 1, As highlighted by van Hinsbergh et al,29 this may be an effect of the shorter follow-up period itself, and the psychosocial concerns expressed by parents in the enterovirus group may be more evident in slightly older children.

Since its discovery, 19 human pathogenic serotypes of hPeV have been identified.30 Our study did not replicate the previously described alternate-year cycle,31,32 possibly due to the short observation period. Ongoing surveillance will clarify if the hPeV peak in 2018 was the result of changing laboratory practice or viral circulation pattern. The absence of hPeV in 2019 would support the latter, as do incidence surges reported elsewhere.33

Most children with hPeV infections suffer only mild respiratory or gastrointestinal illnesses.34 However, more serious manifestations, sepsis-like presentations,35 myocarditis,36 hemophagocytic lymphohistiocytosis,37,38 and meningoencephalitis do occur, particularly due to serotype 3.12,39,40 Neurologic or cardiovascular compromise requiring intensive care level support is not uncommon.16,41 The reason for the particular pathogenicity and neurotropism42 of serotype 3, representing 9/10 of the parechoviral CNS infections described here, is unknown.30 It affects mainly infants younger than 3 months.43,44 Low titers of maternal hPeV3 antibodies may play a role.45–49

Parechovirus meningoencephalitis is frequently described as associated with neurologic symptoms and radiologic gray and white matter changes. CSF pleocytosis is mostly negligible, as in our cohort (Table 1). Imaging and histopathologic findings have prompted the hypothesis that hPeV associated CNS pathology may represent a virally driven vasculitic process.50,51

Protein levels and cytology of CSF in hPeV positive patients were similar to that of uninfected CSF,52 and CSF cytokine profiles were dominated by Th2-skewed cytokines.53 By contrast, EV positive CSF contained Th1-cytokines including IL1β, IL6 and IL17.53 Higher WCC in CSF or raised inflammatory markers in blood were not associated with adverse developmental outcomes in the here presented cohort.

Enteroviruses target neuronal cells of the developing CNS.54,55 The concern that enteroviral meningoencephalitis in infancy may affect neurodevelopmental outcomes was suggested over 2 decades ago.56,57 A Taiwanese follow-up study of children who experienced a CNS infection at any age (mean 41 months) found that enteroviral CNS infections increased the risk for epilepsy (RR 2.75), attention deficit hyperkinetic disorder (RR 2.34), and autistic spectrum disorder (RR 1.37).58 Others have found no developmental impact.59,60 EV type may be an important factor, as well as the degree of cardiopulmonary impairment during the infective episode.61,62 Studies have not consistently documented these characteristics, and thus, the effect size of these parameters is unknown. Among the 43 patients included here, none required intensive care level support, such as inotropes or mechanical ventilation, and our study cohort may well represent a less severely affected group of children (Table 1).

If associated with radiologically and clinically proven encephalitis, outcomes of enteroviral infection are comparative to HSV encephalitis.1 In our study, neuroimaging was performed infrequently and so a radiologic determination of encephalitis could not be made. A hPeV positive child who seized and had deep white matter changes on MRI had a favorable developmental outcome. The use of MRI during the infectious episode as a means to direct neurodevelopmental follow up, or as a prognostic tool, is yet to be defined.

The ASQ323,24 has demonstrated its validity when compared with neurodevelopmental assessments of children with 1–66 months of age by healthcare professionals.63,64 While this agreement varied at different ages, sensitivity and specificity for detecting neurodevelopmental delay was >70% in a validation cohort of 15,138 children from the United States across all assessed areas.65 In another study, overall sensitivity was 86% and specificity 85% and negative predictive values high,66 with a nonconcerning score providing reassurance. In our cohort, further assessment among children with a history of enteroviral CNS infection was recommended among 12.9% and 16.1% in fine motor and psychomotor skills, respectively. Whether or not the better ASQ3 performance in children after hPeVME is a result of the younger assessment age, with longer follow up being necessary to identify changes in these areas reliably, will require larger studies powered to detect these differences.

A validation in Ireland has not been performed, but the ASQ3 has been administered to children across many countries, cultural and socioeconomic settings, with comparable diagnostic accuracy.67 In addition to the general pediatric population,68–70 it has been used in the assessment of premature children71 and Zika virus fetopathy72 but performs best as a screening tool in low-risk populations. In conditions as common as enterovirus and parechovirus CNS infection, a screening test that can be administered by parents could be a pragmatic and cost-effective tool that may improve neurodevelopmental follow up and earlier identification of those in need of support. A wider implementation of this approach may offer assessment with a validated tool comparing patients to a normative validation cohort. This minimizes impact on an already pressured healthcare system and offers an alternative strategy for neurodevelopmental screening to better understand if and to what extent viral CNS infections in infancy impact later neurodevelopment.


Picornavirus infections of the CNS were commonly identified in infants and young children who presented to our center. Neurodevelopmental outcome, as assessed through a screening tool administered by the parents, was favorable for the vast majority of children after a follow-up period of 2–3 years. However, among those with enterovirus infections, the proportion of children in whom further assessment will be required was higher than expected, particularly in comparison to those with a history of parechovirus infections. This supports the emerging opinion that follow up to at least school age will be required to identify more subtle effects of viral CNS infections in early childhood. Large numbers will be required to power such studies, especially given the multifaceted and complex nature of childhood development. This study illustrates that utilization of assessment tools such as the ASQ3 is feasible, mindful of the limitations of healthcare resources, and may offer a useful strategy for the detection of subtle neurodevelopmental sequelae of CNS infections early in life.


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central nervous system; parechovirus; enterovirus; neurodevelopment

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