Table Info

Table 1.

CNS and immune system manifestations in CZS

Study	Demographics	Findings
Salmeron et al. 2022 [6] Cross-sectional case-control study	• 22 CZS cases diagnosed at birth in Brazil (n = 22); negative for Zika virus in the blood • 20 healthy controls • Age range 9 months to 5.4 years; average age 35.8 months ± 19.2 months • Females (n = 21), males (n = 21)	• Microcephaly in CZS cases (n = 22) • Morphological alterations in lymphoid organs: (1) Thymus ultrasound: 100% increased longitudinal measure, increased vertical measure as compared to age groups-specific reference values (81%, n = 17), fibrosis (n = 1) (2) Spleen ultrasound: increased volume as compared to reference values for 9–48 months age group (52%, n = 11), altered echotexture (n = 1), cyst (n = 1) (3) Lymph nodes ultrasound: increased maximum diameter (81%, n = 17) • Leukocytes (WBC): increased count (46%, n = 6) • Eosinophils: increased count (62%, n = 8) • Lymphocytes: increased count (23%, n = 3), increased atypical morphology (P < 0.005), decreased normal morphology (P < 0.005) • Segmented neutrophils: increased count (15%, n = 2), increased number hypersegmented (P < 0.0001), increase hypersegmentation + cytoplasmic vacuolation (P = 0.019), decreased normal morphology (P < 0.0001) • Monocytes: increased count (23%, n = 3) • Cytokines: increased IFN-γ (P = 0.017), IL-2 (P = 0.017), IL-4 (P = 0.018), IL-5 (P = 0.022) • Reduced cellular immune memory: tuberculin skin test nonreactive (57%, n = 4), weakly reactive (43%, n = 3) in Bacillus Calmette-Guérin (BCG) vaccinated
Rua et al. 2022 [7] Prospective cohort study	• Cohort of 38 children • Median age 4.3 months; examined at 4, 8, 12, 18, and 24 months of age • Females (n = 11), males (n = 27)	• Microcephaly (79%, n = 30) • Cranial (magnetic resonance imaging) MRI scan: malformation of cortical development and brain parenchymal atrophy (82%), ventricle enlargement (76%), dysgenesis of corpus callosum (73%), subcortical calcifications (84%), T2-weighted fluid-attenuated inversion recovery (FLAIR): hyperintense periventricular signals suggestive of delayed myelination • Motor milestone not achieved (82%, n = 31) • Irritability 50% at 8 months, 27% at 24 months • Epilepsy (71%): spasms in the 1st year of life (52%), focal seizures in the 2nd year of life (50%) • Axial hypertonia 77% at 4 months, 50% at 24 months • Spastic tetraparesis (> 80%)
Nunes et al. 2021 [8] Cross-sectional case series study	• Cohort of 43 microcephalic children from Brazil • Age range 13 months to 42 months • Females (n = 19), males (n = 24)	• Proposed mild, moderate, and severe classification scheme for neuroimaging abnormalities • Documented multiple types of seizures by EEG ictal and interictal activity • Early seizures in younger than 6 months (42%) • Abnormal EEG total (72%), during sleep (63%) • Only 56% (n = 24) were able to register wakefulness and sleep • No awake recording (21%, n = 9) registered only sleep • No sleep recording (23%, n = 10) registered only wakefulness
Nascimento-Carvalho et al. 2021 [9] Cross-sectional case-control study	• 14 Zika virus-exposed neonates: 7 with microcephaly (50%) and 7 without microcephaly (50%) • 14 normal control neonates	• Perturbed inflammatory mediator profiles in CSF • Higher levels of IL-4 (P = 0.01) in cases with microcephaly (n = 7) as compared to normal controls • Lower levels of IL-1α (P = 0.004) in cases without microcephaly (n = 7) as compared to normal controls • Lower levels of IL-7 (P = 0.048), IP-10/CXCL10 (P = 0.03), and G-CSF (P = 0.047) in total Zika virus-exposed cases (n = 14) as compared to normal controls
Cavalcante et al. 2021 [10] Prospective cohort study	• Cohort of 110 CZS cases • Age up to 36 months • Females (n = 45), males (n = 65) • Compared CZS outcomes in cases born without microcephaly (n = 32) vs. cases with microcephaly identified at birth (n = 61)	• Only slight differences in manifestations and outcomes between CZS cases with and without microcephaly; postnatal-onset microcephaly (87.5%, n = 28; severe in 65.6%, n = 23) • Case fatality rate: 5.5% (n = 6), main cause was severe CZS congenital anomaly and pneumonia • Low birth weight (22%), preterm birth (13.3%) • Craniofacial disproportion (90.6%), frontotemporal retraction (71.7%), prominent occiput (55.7%), biparietal depression (46.2%) • Brain calcifications (93.5%), ventriculomegaly (88.8%, P = 0.002), reduced cerebral parenchyma (85.8%, P < 0.001), malformation of cortical development (78.3%, P = 0.047) • Spasticity (97%) • Epileptic seizures (90.7%) • Chorioretinal scar (22.5%) • Focal retinal pigmentary mottling (24.5%) • Excess nuchal skin (24.5%)
Štrafela et al. 2017 [11] Case report	• Stillborn 32-week gestation • Sex unknown	• Low brain weight (84 g) compared to age-matched control • Agyria and pachygyria in the cerebrum, cerebellum, brain stem • Microcalcifications in gray matter and cortical-white matter junction • Enlarged lateral ventricle in the parieto-occipital region • Large encephalomalacia cyst in the right occipital lobe • Scattered T lymphocytes throughout the brain
Driggers et al. 2016 [12] Case report	• Terminated 21-week gestation • Sex unknown	• Decrease in fetal head circumference from 47th percentile at 16 weeks to 24th percentile at 20 weeks • Presence of flavivirus in serum at 16 weeks • Abnormal intracranial anatomy at 19 weeks • Diffuse atrophy of cerebral mantle at 20 weeks • Low brain weight 30 g (reference weight, 49 g ± 15 g)
Mlakar et al. 2016 [13] Case report	• Stillborn 32-week gestation • Sex unknown	• Ultrasonography: intrauterine growth retardation, calcifications, microcephaly, ventriculomegaly, transcerebellar diameter below second percentile • 1,470 g bodyweight (5th percentile) • Almost complete agyria, open sylvian fissures, internal hydrocephalus of lateral ventricles • Activated microglial cells and some HLA-DR expressing macrophages throughout cerebral gray and white matter • Wallerian degenerations in brain stem and spinal cord • RT-PCR identified Zika virus in fetal brain sample
Cavalheiro et al. 2016 [14] Cross-sectional case series study	• 13 microcephalic newborns • Sex unknown	• Craniofacial disproportion (100%, n = 13) • Craniofacial hypoplasia of corpus callosum (100%, n = 13) • Craniofacial lissencephaly (100%, n = 13) • Craniofacial increased subarachnoid space (100%, n = 13) • Intracranial calcifications (100%, n = 13) • Ventriculomegaly (100%, n = 13) • Enlarged choroid plexus (61.5%, n = 8)
Sarno et al. 2016 [15] Case report	• Stillborn 32-week gestation • Female	• Zika RNA found in CNS tissues • Microcephaly, hydranencephaly, intracranial calcification, and posterior fossa with destruction of the cerebellar vermis at 26 weeks and 30 weeks gestation • Female fetus weighed around 930 g and had signs of microcephaly and arthrogryposis

Study

Demographics

Findings

Salmeron et al. 2022 [6]

Cross-sectional case-control study

• 22 CZS cases diagnosed at birth in Brazil (n = 22); negative for Zika virus in the blood

• 20 healthy controls

• Age range 9 months to 5.4 years; average age 35.8 months ± 19.2 months

• Females (n = 21), males (n = 21)

• Microcephaly in CZS cases (n = 22)

• Morphological alterations in lymphoid organs:

(1)
Thymus ultrasound: 100% increased longitudinal measure, increased vertical measure as compared to age groups-specific reference values (81%, n = 17), fibrosis (n = 1)
(2)
Spleen ultrasound: increased volume as compared to reference values for 9–48 months age group (52%, n = 11), altered echotexture (n = 1), cyst (n = 1)
(3)
Lymph nodes ultrasound: increased maximum diameter (81%, n = 17)

• Leukocytes (WBC): increased count (46%, n = 6)

• Eosinophils: increased count (62%, n = 8)

• Lymphocytes: increased count (23%, n = 3), increased atypical morphology (P < 0.005), decreased normal morphology (P < 0.005)

• Segmented neutrophils: increased count (15%, n = 2), increased number hypersegmented (P < 0.0001), increase hypersegmentation + cytoplasmic vacuolation (P = 0.019), decreased normal morphology (P < 0.0001)

• Monocytes: increased count (23%, n = 3)

• Cytokines: increased IFN-γ (P = 0.017), IL-2 (P = 0.017), IL-4 (P = 0.018), IL-5 (P = 0.022)

• Reduced cellular immune memory: tuberculin skin test nonreactive (57%, n = 4), weakly reactive (43%, n = 3) in Bacillus Calmette-Guérin (BCG) vaccinated

Rua et al. 2022 [7]

Prospective cohort study

• Cohort of 38 children

• Median age 4.3 months; examined at 4, 8, 12, 18, and 24 months of age

• Females (n = 11), males (n = 27)

• Microcephaly (79%, n = 30)

• Cranial (magnetic resonance imaging) MRI scan: malformation of cortical development and brain parenchymal atrophy (82%), ventricle enlargement (76%), dysgenesis of corpus callosum (73%), subcortical calcifications (84%), T2-weighted fluid-attenuated inversion recovery (FLAIR): hyperintense periventricular signals suggestive of delayed myelination

• Motor milestone not achieved (82%, n = 31)

• Irritability 50% at 8 months, 27% at 24 months

• Epilepsy (71%): spasms in the 1st year of life (52%), focal seizures in the 2nd year of life (50%)

• Axial hypertonia 77% at 4 months, 50% at 24 months

• Spastic tetraparesis (> 80%)

Nunes et al. 2021 [8]

Cross-sectional case series study

• Cohort of 43 microcephalic children from Brazil

• Age range 13 months to 42 months

• Females (n = 19), males (n = 24)

• Proposed mild, moderate, and severe classification scheme for neuroimaging abnormalities

• Documented multiple types of seizures by EEG ictal and interictal activity

• Early seizures in younger than 6 months (42%)

• Abnormal EEG total (72%), during sleep (63%)

• Only 56% (n = 24) were able to register wakefulness and sleep

• No awake recording (21%, n = 9) registered only sleep

• No sleep recording (23%, n = 10) registered only wakefulness

Nascimento-Carvalho et al. 2021 [9]

Cross-sectional case-control study

• 14 Zika virus-exposed neonates: 7 with microcephaly (50%) and 7 without microcephaly (50%)

• 14 normal control neonates

• Perturbed inflammatory mediator profiles in CSF

• Higher levels of IL-4 (P = 0.01) in cases with microcephaly (n = 7) as compared to normal controls

• Lower levels of IL-1α (P = 0.004) in cases without microcephaly (n = 7) as compared to normal controls

• Lower levels of IL-7 (P = 0.048), IP-10/CXCL10 (P = 0.03), and G-CSF (P = 0.047) in total Zika virus-exposed cases (n = 14) as compared to normal controls

Cavalcante et al. 2021 [10]

Prospective cohort study

• Cohort of 110 CZS cases

• Age up to 36 months

• Females (n = 45), males (n = 65)

• Compared CZS outcomes in cases born without microcephaly (n = 32) vs. cases with microcephaly identified at birth (n = 61)

• Only slight differences in manifestations and outcomes between CZS cases with and without microcephaly; postnatal-onset microcephaly (87.5%, n = 28; severe in 65.6%, n = 23)

• Case fatality rate: 5.5% (n = 6), main cause was severe CZS congenital anomaly and pneumonia

• Low birth weight (22%), preterm birth (13.3%)

• Craniofacial disproportion (90.6%), frontotemporal retraction (71.7%), prominent occiput (55.7%), biparietal depression (46.2%)

• Brain calcifications (93.5%), ventriculomegaly (88.8%, P = 0.002), reduced cerebral parenchyma (85.8%, P < 0.001), malformation of cortical development (78.3%, P = 0.047)

• Spasticity (97%)

• Epileptic seizures (90.7%)

• Chorioretinal scar (22.5%)

• Focal retinal pigmentary mottling (24.5%)

• Excess nuchal skin (24.5%)

Štrafela et al. 2017 [11]

Case report

• Stillborn 32-week gestation

• Sex unknown

• Low brain weight (84 g) compared to age-matched control

• Agyria and pachygyria in the cerebrum, cerebellum, brain stem

• Microcalcifications in gray matter and cortical-white matter junction

• Enlarged lateral ventricle in the parieto-occipital region

• Large encephalomalacia cyst in the right occipital lobe

• Scattered T lymphocytes throughout the brain

Driggers et al. 2016 [12]

Case report

• Terminated 21-week gestation

• Sex unknown

• Decrease in fetal head circumference from 47th percentile at 16 weeks to 24th percentile at 20 weeks

• Presence of flavivirus in serum at 16 weeks

• Abnormal intracranial anatomy at 19 weeks

• Diffuse atrophy of cerebral mantle at 20 weeks

• Low brain weight 30 g (reference weight, 49 g ± 15 g)

Mlakar et al. 2016 [13]

Case report

• Stillborn 32-week gestation

• Sex unknown

• Ultrasonography: intrauterine growth retardation, calcifications, microcephaly, ventriculomegaly, transcerebellar diameter below second percentile

• 1,470 g bodyweight (5th percentile)

• Almost complete agyria, open sylvian fissures, internal hydrocephalus of lateral ventricles

• Activated microglial cells and some HLA-DR expressing macrophages throughout cerebral gray and white matter

• Wallerian degenerations in brain stem and spinal cord

• RT-PCR identified Zika virus in fetal brain sample

Cavalheiro et al. 2016 [14]

Cross-sectional case series study

• 13 microcephalic newborns

• Sex unknown

• Craniofacial disproportion (100%, n = 13)

• Craniofacial hypoplasia of corpus callosum (100%, n = 13)

• Craniofacial lissencephaly (100%, n = 13)

• Craniofacial increased subarachnoid space (100%, n = 13)

• Intracranial calcifications (100%, n = 13)

• Ventriculomegaly (100%, n = 13)

• Enlarged choroid plexus (61.5%, n = 8)

Sarno et al. 2016 [15]

Case report

• Stillborn 32-week gestation

• Female

• Zika RNA found in CNS tissues

• Microcephaly, hydranencephaly, intracranial calcification, and posterior fossa with destruction of the cerebellar vermis at 26 weeks and 30 weeks gestation

• Female fetus weighed around 930 g and had signs of microcephaly and arthrogryposis

HLA-DR: human leukocyte antigen-DR; RT-PCR: reverse-transcriptase-polymerase-chain-reaction

Declarations

Acknowledgments

We are grateful for the support of Dr. Branka Filipovic, head of research, at the Saint James School of Medicine, for her early input in designing this study. We thank Mr. Oscar Andrade, chief librarian, at the Saint James School of Medicine, as well as the Kean University Library Nancy Thompson Learning Commons for assistance with accessing the full-text, peer-reviewed articles that were needed to conduct this review.

Author contributions

Dhaara S and Dhairavi S: Conceptualization, Methodology, Investigation, Writing—original draft, Writing—review & editing. OM: Conceptualization, Methodology, Investigation, Writing—original draft. RZ: Conceptualization, Methodology, Investigation, Writing—review & editing.

Conflicts of interest

The authors declare that they have no conflicts of interest.

Ethical approval

Not applicable.

Consent to participate

Not applicable.

Consent to publication

Not applicable.

Availability of data and materials

The data and materials obtained for this systematic review were obtained online using search engines and the research databases mentioned in the methodology. The articles referenced in this paper can be accessed freely by searching for them on PubMed, PMC, Ovid, Cochrane, or Google Scholar.

Funding

This research was supported by Kean University Office of Research and Sponsored Programs (ORSP). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Copyright

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