Keywords Zika virus - cerebral palsy - nervous system - malformations
Introduction
Until 2015, Zika virus (ZIKV) infection reports in humans were isolated and sporadic,
and ZIKV infection was mainly asymptomatic.[1 ] In 2015, after Zika epidemics occurred throughout the Americas, intrauterine ZIKV
infection was found to be a cause of microcephaly and serious brain anomalies.[2 ]
[3 ]
A distinct pattern of birth defects, called congenital Zika syndrome (CZS), was described.[4 ] CZS has been observed in approximately 10% of cases of ZIKV infection in pregnancy,
with presentation ranging from mild symptoms to microcephaly with multiple organ involvement;
its full spectrum is still unknown.[5 ]
Defining cases is challenging in ZIKV studies. Molecular tests used to detect viral
genomic material are the preferred method of diagnosis because they can provide confirmed
evidence of infection, according to the Centers for Disease Control and Prevention
(CDC), but due to the temporal nature of ZIKV RNA in serum and urine, these tests
often produce false-negative results.[6 ] ZIKV immunoglobulin (Ig) M antibody testing, followed by the plate reduction neutralization
test (PRNT) for ZIKV, expands the diagnostic window and is recommended by the CDC
in certain situations. However, it has recently been shown that negative PRNT results
do not exclude the diagnosis of CZS, since among mothers who were ZIKV-positive according
to qRT-PCR (real-time quantitative polymerase chain reaction), 51.5% had a negative
PRNT result.[7 ] Therefore, laboratory testing has been integrated with clinical knowledge of CZS
and presumed CZS is commonly diagnosed.[8 ]
[9 ]
[10 ]
[11 ]
The motor function of children with probable CZS and cerebral palsy (CP) can be very
compromised when compared with populations with typical development according to normative
tests.[12 ]
[13 ]
[14 ] CZS children often present with CP[15 ]
[16 ] that differs from other congenital infections because of the following features:
(1) severe microcephaly with partially collapsed skull; (2) thin cerebral cortices
with subcortical calcifications; (3) macular scarring and focal pigmentary retinal
mottling; (4) congenital contractures; and (5) marked early hypertonia and symptoms
of extrapyramidal involvement,[17 ]
Criteria-referenced tests specifically developed for CP, such as the Gross Motor Function
Measure (GMFM-88 and GMFM-66),[18 ] are highly appropriate to describe motor function and detect changes over time.
Recent studies on gross motor function in CZS children administered the GMFM-88 in
small samples and presented transversal data.[9 ]
[19 ]
[20 ] The associations of severe cortical malformation and small head circumference at
birth,[9 ]
[20 ] early maternal infection,[20 ] and epilepsy and dysphagia[19 ] with decreased motor function were described.
One longitudinal study revealed evidence of marginal improvement in motor function
in the first 2 years of life in children with probable CZS.[11 ] Additional studies with older children using appropriate instruments and larger
samples are required to better understand motor abilities, limitations, and factors
associated with a poor prognosis in CZS children.[9 ]
[11 ]
[19 ]
The objective of this study was to evaluate gross motor function and its associated
factors in a larger sample of children with CZS aged up to 3 years using the GMFM
and to determine changes in this domain with a minimum interval of 6 months.
Methods
A prospective cohort was conducted between September 2017 and February 2019 at the
Reference Center on Neurodevelopment, Assistance and Rehabilitation of Children—NINAR,
affiliated with the State Department of Health of the State of Maranhão.
The study was part of the project “Congenital Zika Syndrome, Seroprevalence, and Spatial
and Temporal Analysis of Zika and Chikungunya Virus in Maranhão,” approved by the
Research Ethics Committee of the University Hospital of the Federal University of
Maranhão (approval number 2.111.125).
Participants
The inclusion criteria consisted of children who attended follow-ups with the multidisciplinary
team at NINAR and who had received a diagnosis of CZS confirmed by a PRNT for ZIKV
with a cutoff value of 90% (PRNT90; 40 children) or a presumed diagnosis (70 children)
based on computed tomography (CT) findings, ZIKV IgM detection, and serology tests
for other congenital infections.
PRNT90 was conducted in the Laboratory of Vector-Borne Infectious Diseases (LEITV)—Gonçalo
Muniz Institute (IGM)/Oswaldo Cruz Foundation (FIOCRUZ)/Bahia. This test was performed
based on a previously reported protocol,[21 ] with minor modifications. PRNT90 was performed to determine the maximum serum dilution
(1:8 to 1:4096) needed to reduce ZIKV plaque formation by 90% in Vero cells. For this,
the ZIKV PE/243 virus strain that was isolated in Brazil was used. All sera were heat-inactivated
(56°C, 30 minutes) prior to neutralization testing. The serum samples were diluted
on a plate with modified Dulbecco Eagle medium containing 2% fetal calf serum and
1% of penicillin/streptomycin. Next, 250 µL of virus (100 ffu/µL) was added to each
well containing diluted serum (1:1). The serum and virus dilutions were then incubated
at 37°C for 60 minutes. A final volume of 200 µL of each serum and virus dilution
was transferred to a well containing Vero cells and then incubated at 37°C for 60 minutes.
Following incubation, 300 µL of 0.3% agarose solution was added and plates were reincubated
at 37°C for 5 days. Reactions were then revealed using a 2% naphthol blue-black solution.
Titers ≥10 were considered positive.
Brain CT scans were evaluated by two experienced radiologists to identify specific
features associated with CZS,[22 ]
[23 ] including brain parenchymal volume loss, calcifications in the gray–white matter
junction, ventricular enlargement, delayed cortical development, cerebellar and/or
brainstem malformations, and a hypoplastic or absent corpus callosum. Children with
radiological findings compatible with CZS in addition to positive IgM for ZIKV (three
children), negative serology (33 children) or inconclusive serology (34 children)
for other congenital infections (syphilis, toxoplasmosis, rubella, cytomegalovirus,
and herpes simplex virus) were presumed to have CZS. Children for whom neuroimaging
examinations showed no abnormalities or signs of other causes for CP, who had no neuroimaging
examination results available, or who had positive serological detection of other
congenital infections were not included.
Two children died before data collection, two were excluded from this study due to
concomitant diagnosis of conditions that interfere with motor performance (hydrocephalus
and Dandy–Walker syndrome), two were clinically ill, and four were unavailable to
complete the motor function assessment. Therefore, for the purposes of this study,
100 children with CZS and CP were evaluated, including 36 with confirmed and 64 with
presumed CZS.
The mothers or guardians of the children who met the inclusion criteria were invited
to participate in the study and were included after signing an informed consent form.
GMFCS, GMFM-88, and GMFM-66
The children's spontaneous movements were evaluated by three trained physical therapists
and an occupational therapist who applied the GMFCS[24 ] version validated in Portuguese[25 ] and the GMFM-66 and GMFM-88.[18 ] The evaluations were video-recorded and later scored by the same experienced physiotherapist
(E.H.M.T.) who was trained in GMFM-66 and GMFM-88 scoring. The GMFCS is a five-level
pattern-recognition system to describe and classify the severity of movement disabilities
in children with CP. Level I represents the best gross motor abilities (CP children
and youth who walk without limitations), and level V represents the poorest function
(children who require a wheelchair).[24 ] The GMFM-88 is an ordinal scale that consists of five dimensions: (A) lying and
rolling, (B) sitting, (C) crawling and kneeling, (D) standing, and (5) walking, running,
and jumping. All items were classified on a 4-point scale and the raw scores were
converted into percentages. The GMFM-88 provides a more detailed description of motor
function in young children or highly impaired children. The GMFM-66, on the other
hand, is an interval measurement tool developed using Rasch analysis of the GMFM-88,[26 ] thereby making comparisons of changes in subjects, as well as changes over time
in subjects, more reliable and accurate. The Gross Motor Ability Estimator (GMAE-2)
was used to calculate the GMFM-66 scores, which were also analyzed as percentiles
according to the child's GMFCS classification.[27 ] A convenience sample of 46 children repeated the GMFM-66 assessment after a minimum
interval of 6 months.
Clinical and Socioeconomic Characteristics
A standardized questionnaire was completed by mothers or guardians, providing socioeconomic
data (mother's education level and age at the beginning of gestation, place of family
residence at the time of pregnancy, monthly family income, and economic classification
according to the Criterion of Economic Classification Brasil (CCEB[28 ]); presence of symptoms compatible with ZIKV infection during the gestational period,
type of delivery, gestational age at birth (in weeks); and the child's head circumference,
length, and weight at birth (the first two in centimeters and the last in grams).
The CCEB is based on the accumulation of material goods and education level of the
household head and groups of people into classes (A, B, C, D, or E) according to the
scores obtained. Class “A” refers to the highest socioeconomic status and class “E”
refers to the lowest. The head circumference was classified in z-scores according
to the INTERGROWTH-21st tables[29 ] to determine the presence of macrocephaly (z-score > 2), normocephaly (2 ≤ z-score
≤ − 2), or microcephaly (z-score < − 2). The presence and degree of brain parenchymal
volume loss (mild to moderate or severe) were determined in head CT. All children
were diagnosed with CP and classified according to topography and the presence of
pyramidal (hypertonia, clonus, hyperreflexia, and increased archaic reflexes) or extrapyramidal
signs (tonus fluctuation and asymmetric dyskinesias in the extremities that were absent
during sleep)[30 ] by the chief child neurologist of NINAR.
Data on the presence of symptomatic epilepsy were collected from medical records.
Statistical Analysis
The distribution of categorical variables and the medians and interquartile ranges
(IQRs) of numerical variables were analyzed.
Chi-square tests and Wilcoxon tests were performed to compare children with confirmed
and presumed CZS diagnoses.
Wilcoxon tests were used to evaluate associations between GMFM-66 baseline scores
and the independent variables, which were transformed into dichotomous variables.
The GMFM-66 scores of children aged 24 months or older were analyzed as percentiles
using motor development curves as references.[27 ]
The Wilcoxon test for paired samples was used to compare repeat GMFM-66 scores with
baseline scores. Change scores by age and GMFCS levels were calculated.
For all tests, a 5% level of significance was adopted. The statistical analysis was
conducted in Stata, version 14.0 (Stata Corp., College Station, Texas, United States).
Results
Maternal age at the beginning of gestation was the only characteristic with significant
difference (p = 0.044) between confirmed (median maternal age of 21.5 years; IQR: 19–26.5) and
presumed CZS children (median: 26 years; IQR 20–31); the other clinical and demographic
characteristics were similar ([Supplementary Table S1 ], available online only).
Table 1
Comparison of Gross Motor Function Measure (GMFM) scores and Gross Motor Function
Classification System (GMFCS) frequencies between confirmed and presumed congenital
Zika syndrome (CZS) children (Sao Luis, Maranhao, 2017–2019)
Total (n = 100)
CZS confirmed by PRNT90 (n = 36)
Presumed CZS (n = 64)
p -Value
GMFM scores median (IQR)
GMFM-88
8.0 (5.4–10.8)
7.9 (5.8–9.9)
8.0 (4.9–11.9)
0.747
GMFM-66
20.5 (14.8–23.1)
19.3 (15.4–21.6)
20.5 (14.8–24.0)
0.635
GMFCS level
GMFCS level I
3 (3.0%)
1 (2.8%)
2 (3,1%)
0.309
GMFCS level II
–
–
–
GMFCS level III
2 (2.0%)
0
2 (3.1%)
GMFCS level IV
6 (6.0%)
1 (2.8%)
5 (7.8%)
GMFCS level V
89 (89.0%)
34 (94.4%)
55 (86.0%)
Abbreviations: CZS, congenital Zika syndrome; IQR, interquartile range; PRNT90, plaque
reduction neutralization test with cutoff value of 90% (PRNT90).
Most children were male (59.0%), were delivered by cesarean (52%) and were microcephalic
(56.0%), presented tetraparetic CP (88.0%), exhibited both pyramidal and extrapyramidal
signs (67.0%), had symptomatic epilepsy (89.0%), and showed brain parenchymal volume
loss (68.0%). Prematurity and low birth weight were not uncommon (13.0 and 22.0%,
respectively). At the time of pregnancy, 76.0% of the families were living in urban
areas. Sixty-three percent of mothers had completed high school or incomplete higher
education and 52.0% had experienced symptoms of viral infection mainly in their first
trimester of pregnancy (52.%). Low socioeconomic status (economic classes D–E) was
the most common status (46.0%) . Families of confirmed and presumed CZS children had
similar monthly income (median: US$250; IQR 200–500; median: US$300, IQR 232.50–500,
respectively; p = 0,739).
At the first gross motor function evaluation, the mean age was similar (p = 0.974) among confirmed CZS children (25.6 ± 5.1 months) and presumed CZS children
(25.5 ± 5.8 months). Most children were classified as GMFCS level V (89.0%; [Table 1 ]). The proportion of mild/moderate cases (GMFCS levels I–III) and severe cases (GMFCS
IV–V) were similar between confirmed and presumed CZS children (p = 0.444). The baseline GMFM-88 and GMFM-66 scores of confirmed (median GMFM-88 score:
7.9; median GMFM-66 score: 19.3) and presumed CZS children (median GMFM-88 score:
8.0; median GMFM-66 score: 20.5) showed no significant difference (p = 0.747 and p = 0.635 respectively; [Table 1 ] and [Fig. 1 ]).
Fig. 1 (A ) Gross Motor Function Measure-88 (GMFM-88) total scores of children with confirmed
congenital Zika syndrome (CZS); (B ) GMFM-88 total scores of children with presumed CZS; (C ) GMFM-66 scores of children with confirmed CZS; (D ) GMFM-66 score of children with presumed CZS. ◊ Gross Motor Classification System
(GMFCS) level I; ▴GMFCS level III; ▪ GMFCS level IV; • GMFCS level V. São Luis, Maranhão,
2017–2019.
Considering that nearly all the clinical and socioeconomic characteristics, GMFM scores,
and GMFCS classifications ([Table 2 ]) from confirmed and probable cases were similar, the groups were combined in one
group for subsequent analyses.
Table 2
Baseline Gross Motor Function Measurement (GMFM-88 and GMFM-66) total scores and scores
per GMFM-88 dimension in children with confirmed and presumed congenital Zika syndrome
(CZS) according to the classification level of the Gross Motor Function Classification
System (GMFCS)
GMFM assessment
Minimum; maximum
Median (IQR)
GMFM-88
Level I (n = 3)
43.8; 86.2
44.7 (43.8–86.2)
Level II (n = 0)
–
–
Level III (n = 2)
30.3; 41.5
35.9 (30.3–41.5)
Level IV (n = 6)
15.2; 28.0
18.6 (15.6–19.6)
Level V (n = 89)
0.4; 18.2
7.5 (5.2–9.5)
Dimensions
(A) Lying and rolling
2; 100.0
27.5 (19.6–37.3)
(B) Seating
0; 90.0
11.7 (6.7–16.7)
(C) Crawling and kneeling
0; 71.4
0 (0–0)
(D) Standing
0; 79.5
0 (0–0)
(E) Walking, running, and jumping
0; 90.3
0 (0–0)
GMFM-66
Level I (n = 3)
46.1; 67.7
48.1 (46.1–67.7)
Level II (n = 0)
–
–
Level III (n = 2)
41.4; 48.1
44.8 (41.4–48.1)
Level IV (n = 6)
21.2; 33.9
28.3 (26.0–31.8)
Level V (n = 89)
0; 32.8
18.9 (14.8–21.2)
Abbreviation: IQR, interquartile range.
Note: The mean age of the children was 25.6 months, ranging from 8 to 43 months (n = 100). São Luís, Maranhão, 2017–2019.
There were no differences in the GMFM-66 scores according to place of family residence
during pregnancy, presence of infectious disease symptoms during pregnancy, type of
delivery, gestational age, birth weight, and presence of pyramidal signs versus combined
pyramidal and extrapyramidal signs ([Supplementary Table S2 ], available online only).
Children born with microcephaly had significantly lower GMFM-66 scores (p = 0.014) than children born with normocephaly. Lower scores on the GMFM-66 were also
observed in children who belonged to lower economic classes (p = 0.007), who presented symptomatic epilepsy (p < 0.001), and who had brain parenchymal volume loss (p < 0.001) ([Supplementary Table S2 ], available online only).
All children with microcephaly at birth were classified as GMFCS level V. The other
features of poor prognosis associated with low GMFM-66 scores, including lower economic
class, symptomatic epilepsy, and brain parenchymal volume loss, were observed in children
classified as GMFCS levels I–V ([Fig. 2 ]).
Fig. 2 Gross Motor Function Classification System (GMFCS) levels according feature associated
with a poor prognosis. São Luís, Maranhão, 2017–2019. Economic classification according
to the Criterion of Economic Classification Brasil—the letter “A” refers to the highest
economic status and the letter “E” refers to the lowest.
All 46 reevaluated children received the same GMFCS rating at the second assessment.
The median interval between evaluations was 8 months (6–14 months). In the second
evaluation, the average age of children was 31.4 months of age (17–38 months). Most
children were between 25 and 48 months old and classified as GMFCS level V ([Table 2 ]).
Two (4.3%) children were classified as GMFCS level I and presented changes in GMFM-66
scores greater than the measurement error, with change scores of 9.8 and 11.5. Repeated
motor assessments for one (2.2%) GMFCS level III (change score of 0.4) child and one
(change score of −0.6) out of two GMFCS level IV children (4.3%) were similar (overlapping
95% confidence intervals [CIs]). The other child classified as GMFCS level IV had
a significant increase in the GMFM-66 score, with a change score of 4.5. In the group
of GMFCS level V children (89.2%), no significant differences were observed in the
GMFM-66 scores of children who were initially evaluated at less than 2 years old (41.3%;
median change score of 0.6; IQR: 0–2.5; p = 0.050) or between 2 and 4 years old (47.9%; median change score of 1.5; IQR: 0–2.2;
p = 0.060) ([Table 3 ]).
Table 3
Gross Motor Function Measure (GMFM-66) scores in children with two assessments, according
to the Gross Motor Function Classification System (GMFCS) classification and age category
in the first assessment (São Luís, Maranhão, 2017–2019)
GMFCS classification
1st assessment
2nd assessment
GMFCS level I (n = 2)
Child A (under 2 years old)[a ]
48.1 (45.9–50.3)
57.9[b ] (55.6–60.2)
Child B (2–4 years old)[a ]
46.1 (44.0–48.1)
57.6[b ] (55.3–59.9)
GMFCS level III (n = 1)
Child C (2–4 years old)[a ]
48.1 (45.9–50.3)
48.5 (46.3–50.7)
GMFCS level IV (n = 2)
Child D (under 2 years old)[a ]
26.0 (22.1–29.1)
30.5[b ] (26.7–34.3)
Child E (2–4 years old)[a ]
31.8 (28.1–35.5)
31.2 (27.5–34.9)
GMFCS level V (n = 41)
Under 2 years old (n = 19)[c ]
21.2 (18.0–23.4)
21.2 (20.5–24.0)
2–4 years old (n = 22)[c ]
19.7 (14.8–21.2)
20.5 (17.0–22.7)
a GMFM-66 score (95% confidence interval).
b Significant increase in the GMFM-66 score on the second assessment.
c Median GMFM-66 score (interquartile range).
The median GMFM-66 score percentile[27 ] was 40 (IQR: 20–55) among the 109 evaluations performed when children were 24 months
old or older. One GMFCS level I child scored in the 3rd and 20th percentiles, respectively;
one in the 35th and the last in the 85th percentile. One GMFCS level III child scored
in the 70th and 60th percentiles, respectively, and the other scored in 15th percentile.
Among five children with GMFCS level IV, scores ranged from the 3rd to 50th percentiles.
Among GMFCS level V children, 71.9% were at or below the 50th percentile.
Discussion
In the present study, motor function in children with CZS was described, including
classification of the severity of CP and factors associated with poor motor function
and gross motor trajectories until the third year of life. The most common phenotype
observed was severe tetraparetic CP, with 95% of children classified as GMFCS level
V or IV. The proportion of GMFCS level V children (89%) was higher than those reported
by Carvalho et al[8 ] (40.2%) and Frota et al[19 ] (71.7%), but similar to those in the study of Melo et al[9 ] (81%) and Ventura et al[11 ] (96.1%). The differences are possibly explained by distinct inclusion criteria and
smaller and younger average ages in previous studies. In the present sample, 67% of
children were more than 24 months old, when the GMFCS classification is more precise.[25 ] As expected, the majority of GMFCS level IV and V children could not assume crawling
or standing positions, with poor prognosis for walking.[24 ]
Nevertheless, three children presented mild symptoms of CP and were classified as
GMFCS level I; those children were able to walk.
The baseline GMFM-88 score was low (median of 8.0). However, Frota et al[19 ] and Melo et al[9 ] reported even lower GMFM-88 scores (median score of 4.9 in 46 24-month-old children
and 6.5 in 59 children with a maximum age of 13.2 months, respectively). GMFM-66 scores
were not calculated in those studies,
An analysis of percentiles of scores from the GMFM-66, which has not been applied
in previous studies,[10 ]
[15 ] showed that most CZS children presented poor gross motor function (median GMFM-66
percentile score of 40) when compared with the median performance of other CP children
with the same age and GMFCS classification.
In the reassessment of 46 of the 100 CZS children, limited gross motor gains at median
age of 31.4 months was observed when compared with CP children. Longitudinal data
on motor function of CZS are scarce; Ventura et al[11 ] described presumed CZS children up to 24 months old. GMFCS level I children showed
significant improvements in motor function, but their performance was no better than
that observed in the typical course of static encephalopathy. One child had a change
score (9.8) according to expected (11.6 ± 3.2)[27 ] at the age of 2 years and 3 months, but the GMFM-66 score was in the 35th . The
other child with GMFCS level I had a change score that exceeded the expected gains
(11.5; reference value: 4.5 ± 3.6).[27 ] Nonetheless, their GMFM-66 score at 3 years and 2 months old kept them in a low
percentile ranking: it changed from the 3rd to the 20th percentile.
The GMFM-66 score of the GMFCS level III child dropped from the 70th to near the 60th
percentile by the age of 2 years and 9 months, with no significant score change between
the two evaluations possibly indicating a deceleration in motor development not expected
at this age in children in this classification. GMFCS level III children are expected
to continue showing improvement in their gross motor function and reach 90% of their
potential until the age of 3.7 years.[31 ]
GMFCS level IV children showed substandard motor function when compared with CP curves.
One GMFCS level IV child had a change score of 4.5, but the GMFM-66 score was only
in the 30th percentile at 2 years and 3 months old. The other GMFCS level IV child
had a small decrease in their GMFM-66 score, in the 30th percentile by the age of
2 years and 8 months.
For CZS children classified as GMFCS level V, GMFM-66 scores were statistically similar
between the subsequent evaluations, with median GMFM-66 scores at the second assessment
of 21.3 for the younger and 19.8 for the older group. The younger group was initially
evaluated at a median age of 20 months and then at a median age of 30 months; the
older group underwent the first assessment at a median age of 26.5 months, and the
second assessment was performed at a median age of 33 months. CP children with the
same GMFCS classification present a GMFM-66 limit score of 22.3 (95% CI: 20.7–24.0)
and usually reach their GMFM-66 score limit at an older age (32.4 months; 95% CI:
24–44.4 months).[31 ] These findings suggest that CZS children classified as GMFCS level V tend to reach
their maximal gross motor function potential relatively early, by their second birthday,
and they tend to underperform when compared with CP children with the same GMFCS classification.
The present study makes important contributions to understanding factors affecting
motor function in CZS children, a field with incipient knowledge.[8 ]
[9 ] Epilepsy was associated with decreased motor function, probably reflecting greater
central nervous system involvement. Symptomatic epilepsy was present in the majority
of the sample; this result supports the previously described results in children with
probable CZS.[12 ]
[16 ]
Brain parenchymal volume loss was observed in 82.9% of those with available cerebral
CT results and was associated with low GMFM-66 scores. This radiological sign can
be identified early in prenatal ultrasound or postnatal exams[32 ] and can be another useful tool to help clinicians to identify poor motor prognosis.
Normal head circumference at birth did not exclude the presence of motor impairment,
but children with microcephaly had worse gross motor function than those born with
normocephaly, with a statistically significant difference in GMFM-66 scores. Similar
findings were reported by other authors.[8 ]
[9 ] Among children with a known head circumference at birth, 66.3% had microcephaly
at birth, a proportion within the range reported by previous studies (39.7–88.6%).[4 ]
[10 ]
[33 ]
An unprecedented association between lower economic level and severe motor function
was observed. Recent studies have shown that low yellow fever vaccination coverage[34 ] and previous infections by viruses or other etiologic agents,[35 ] factors to which lower socioeconomic classes are more exposed, can increase the
severity of neurological involvement in congenital ZIKV infection. Moreover, CZS results
in high-magnitude disabilities or difficulties in function and body structure, activity,
and participation in daily life activities,[36 ] creating several demands that are potentially difficult to meet in families with
low socioeconomic status. The Brazilian National Health System offers basic care and
specialized rehabilitation treatment[37 ]; however, this system needs to be continually improved to minimize the impact of
CZS on the health and quality of life of children and their families.
Using the PRNT90 test for ZIKV was a strength of the study; this test provides robust
evidence for ZIKV infection.[7 ] However, it has recently been shown that negative PRNT results do not exclude the
diagnosis of CZS.[7 ] Therefore, no known specific criteria are capable of identifying all cases of CZS;
a combination of clinical and risk assessments, clinical knowledge, and laboratory
testing to create hierarchical classes of evidence of ZIKV infection,[7 ] as adopted in this study, is necessary.[6 ] Almost all clinical and socioeconomic characteristics (except for maternal age at
the beginning of gestation), GMFM scores, and GMFCS classifications from confirmed
and presumed CZS were similar, suggesting that CZS manifests similarly in children
with different levels of ZIKV infection evidence, supporting the decision of combining
both groups for the analysis.
Another strength of the study is the fact that gross motor function was evaluated
with the gold standard tools for CP evaluation, the GMFM-88 and GMFM-66, which are
widely used in the literature due to their high validity, reliability, and sensitivity
to changes,[26 ] in a larger sample than those evaluated in previous studies.[9 ]
[11 ]
[19 ]
[20 ] The 88 version has additional items and allows separate evaluation of the different
dimensions, providing a detailed picture for younger and severely impaired children.[26 ] The GMFM-66, on the other hand, enables better comparison over time, among groups
and with published for normative of CP children.[27 ] The use of both the GMFM versions resulted in a broader and more reliable assessment
of children's motor function in CZS than using either version alone. Data on follow-up
on gross motor function in CZS children aged up to 3 years, as presented in this study,
are scarce; the few studies available are generally restricted to the second year
of life.[11 ]
[26 ] Children assessed in this study can be reevaluated in future studies, expanding
the knowledge about motor function in children with CZS.
There are some limitations to consider in this study. First, some factors that could
affect motor function, such as visual and auditory impairment, were not analyzed.
Second, families with highly impaired children are more likely to seek medical care
at the rehabilitation center than those with mildly impaired children; thus families
with children with mild presentations may be underrepresented in this study. Third,
the number of children classified as GMFCS I–III was not large enough to allow further
statistical analysis of the prognostic factors and gross motor function curve. Therefore,
the sample size of this study (100 children) and the recruitment from a single rehabilitation
center (convenience sample) preclude the generalization of the results, but in a scenario
of limited knowledge about motor function in CZS children, this study provides a robust
contribution to elucidating the impact of this congenital infection on the nervous
system of developing fetuses.
Conclusion
Almost all children with CZS had severe CP and were considered as having with GMFCS
level IV or V, with limited motor function. Gross motor function was poorer than the
median performance of other CP children with the same age and GMFCS classification.
A lower economic class, microcephaly at birth, symptomatic epilepsy, and brain parenchymal
volume loss were associated with decreased gross motor function. In the third year
of life, most children with severe CP presented no improvement in gross motor function
and were probably approaching their maximal gross motor function potential.
