Systematic
Review
Virology
Kasmera 49(1):e49133255, Enero-Junio, 2020
P-ISSN 0075-5222 E-ISSN
2477-9628
https://doi.org/10.5281/zenodo.4682063
Microcephaly and ZIKA Virus: Certainty or Presumption?
Systematic Review
Microcefalia y Virus Zika: ¿Certeza o Presunción? Revisión Sistemática
Velásquez
Serra, Glenda Coromoto (Autora de correspondencia). https://orcid.org/0000-0003-0942-2309.
Universidad de Guayaquil. Facultad de Ciencias Médicas. Carrera de Medicina. Guayaquil-Guayas. Ecuador. Dirección
Postal: Ciudadela Universitaria
Salvador Allende, Av. Delta y Av. Kennedy, Guayaquil-Guayas. Ecuador. Teléfono: +593-983176173. Email: glenda.velasquezs@ug.edu.ec. : https://www.researchgate.net/profile/Glenda_Velasquez
García-Yuquilema, Camila Janina. https://orcid.org/0000-0002-9956-2219.
Universidad de Guayaquil. Facultad de Ciencias Médicas. Carrera de Medicina.
Grupo de Investigación de Enfermedades Tropicales Desatendidas del Ecuador.
Guayaquil-Guayas. Ecuador. E-mail: camila.garciay@ud.edu.ec
Galarza-Cedeño, Joselyn Meylin. https://orcid.org/0000-0001-9585-9608.
Universidad de Guayaquil. Facultad de Ciencias Médicas. Carrera de Medicina.
Grupo de Investigación de Enfermedades Tropicales Desatendidas del Ecuador.
Guayaquil-Guayas. Ecuador. E-mail: joselyn.galarzac@ug.edu.ec
Preciado-Cañas, Oscar Enrique. https://orcid.org/0000-0001-5308-2888.
Universidad de Guayaquil. Facultad de Ciencias Médicas. Carrera de Medicina.
Cátedra Internado Rotatorio. Guayaquil-Guayas. Ecuador. E-mail: p.racsol14@gmail.com
Abstract
The Zika virus has
been associated with microcephaly since 2015 with established links based on
the epidemic in Brazil, which affected several pregnant women. The purpose of
this research was to demonstrate the link between Zika virus and microcephaly,
through the analysis of the characteristics related to the virus, the theories
of how it enters the organism and the clinical manifestations, which lead to
neurological affectations. This is a descriptive, and transversal research. The
main sources of information come from studies in various medical journals,
which support the proposed ideas. Some proper virus characteristics were
described, as: neurotropism, the capacity to cross the placental barrier and
the ability to produce degeneration of the neuroprogenitor cells, which are complement to the above-mentioned
theories. Likewise, molecular alterations in the structure of the virus,
allowing the virus to interfere with the brain development of fetus in pregnant
women. The clinical manifestation that
produces Zika virus is called Severe Congenital Syndrome which includes
manifestations in the newborn, such as, morphology of the skull, brain
anomalies, congenital contractures and neurological sequelae. All the damage
shown have been identified, thanks to neurological examinations to newborn,
neuroimaging studies, neuropathology to the cranium and its tissue.
Keywords: stem cells, fetal growth retardation, mutation, zika
virus.
Resumen
El virus Zika se ha asociado con la microcefalia desde 2015 con vínculos
establecidos con la epidemia en Brasil, que afectó a varias mujeres
embarazadas. El objetivo de esta investigación fue demostrar el vínculo entre
el virus Zika y la microcefalia, a través del análisis de características
relacionadas con el virus, teorías de cómo ingresa al organismo y las
manifestaciones clínicas, que conducen a afecciones neurológicas. Esta es una
investigación descriptiva y transversal. Las principales fuentes de información
provienen de estudios en varias revistas médicas, que respaldan las ideas
propuestas. Se describieron algunas características propias del virus, como neurotropismo, la capacidad de cruzar la barrera
placentaria y producir degeneración de las células neuroprogenitoras,
un complemento de las teorías mencionadas anteriormente. Asimismo, las
alteraciones moleculares en la estructura del virus, lo que permite que el
virus interfiera con el desarrollo cerebral del feto en mujeres embarazadas. La
manifestación clínica que produce virus Zika se llama Síndrome congénito
severo, que incluye manifestaciones en el recién nacido, como morfología del
cráneo, anomalías cerebrales, contracturas congénitas y secuelas neurológicas.
Todos los daños mostrados han sido identificados, gracias a exámenes
neurológicos a recién nacidos, estudios de neuroimagen, neuropatología del
cráneo y su tejido.
Palabras claves: células madre, retardo del crecimiento
fetal, mutación, virus zika.
Received: 28/07/2020 | Accepted: 20/02/2021 | Published: 26/04/2021
How to Cite: Velásquez-Serra
GC, García-Yuquilema CJ, Galarza-Cedeño JM, Preciado-Cañas Oscar Enrique. Microcephaly and ZIKA Virus: Certainty
or Presumption? Systematic Review. Kasmera.
2021;49(1):e49133255. doi: 10.5281/zenodo.4682063
Introduction
Zika virus (ZIKV) is an arbovirus
transmitted by the Aedes aegypti mosquito bite. It was first isolated in
the forests of Zika (Uganda) from a Rhesus monkey (1). Then in 1968,
from humans in Nigeria, Uganda and Senegal (2).
In 2007, the first outbreak of
infection was documented in Micronesia (island of Yap), with 185 suspected
cases reported, of which 49 (26%) were confirmed as proven cases and 59 (32%)
as probable cases, and Aedes hensilii was
identified as the vector (3). The outbreak lasted 13 weeks. In
2013, another outbreak was recorded in French Polynesia, where approximately
10,000 cases were reported, 70 of them severe and associated with neurological
complications or autoimmune disease (4). In this
situation, the identified vectors were the mosquitoes Aedes aegypti and Aedes
polynesiensis (5). During the
outbreak of ZIKV disease in this region, it was reported an increase in cases
of Guillain Barré syndrome, a neurological paralysis that is linked to immune
disruption generated by viruses, vaccines and/or environmental toxins (6).
Later, in 2014, ZIKV arrives in
America to Easter Island, Chile, where a case was presented; this patient,
native of the place, had traveled to an art fair in Tahiti; upon his return, he
presented a feverish picture and the analysis sent to Santiago, Chile,
confirmed Zika's diagnosis (7).
Therefore, the Asian lineage of ZIKV
is the one that circulates in Brazil and then in the Americas, according to the
sequencing carried out by Pasteur Institute in Dakar (8). A hypothesis of how it was
probably entered due to the visit of several tourists, for the World Cup of
Football in 2014, contributing to the infection of ZIKV (9). In Brazil, the first 16 confirmed
cases were reported on May 15, 2015 (10). The
cases occurred in the states of Bahia and Rio Grande do Norte, as well as in
the northeast of the country, with eight cases reported accordingly. The alarm
was raised when in October 2015, pregnant women affected by this new condition
appeared in the country, presenting children with microcephaly and disability (11).
Other findings related to acute
infection include low back pain, epigastralgia,
anorexia, dry cough, paresthesias in extremities,
ascending muscle weakness, pelvic limb areflexia, orthostatic hypotension,
photophobia, hematospermia, dysuria, perineal pain,
prostatitis, hand and ankle edema and subcutaneous bleeding (12).
Up to January 29 2016, 25 countries and territories in the Americas had
reported local transmission of the virus (indigenous cases): Barbados, Bolivia,
Brazil, Colombia, Costa Rica, Curaçao, Dominican Republic, Ecuador, Guyana, El
Salvador, French Guyana, Guatemala, Guadeloupe, Haiti, Honduras, Martinique,
Mexico, Nicaragua, Panama, Paraguay, Puerto Rico, Saint Martin, Suriname,
Virgin Islands and Venezuela (4).
In Ecuador, during January 2016, the
first two laboratory-confirmed cases of ZIKV infection were reported. The
patients were Ecuadorians living in Quito, with a history of traveling to
Neiva, a city in Colombia, who presented exanthema, pruritus, fever, headache,
generalized joint pain and conjunctival hyperemia. A total of 965 cases of pregnant women with
ZIKV infection were reported for the three-year period 2016-2018. In 2016, 242
cases were reported, by 2017, 722 cases were reported and by 2018, a case in
pregnant women corresponding to epidemiological week (EW) 14. In relation to
gestational age, the following were reported: 136 cases corresponding to a
patient with gestational age less than 12 weeks, 420 cases with gestational age
greater than 21 weeks and 167 cases with gestational age higher than 28 weeks. Also,
by 2016, until EW 14 in 2018, 17 children with vertical transmission of Zika,
without congenital malformation, were registered. These children were the
product of positive women and suspected ZIKV infection, proceeding from the
provinces: Manabí, Guayas, El Oro and Santo Domingo de los Tsachilas
(13).
With regard to the notification of
Congenital Syndromes; 20 cases of microcephaly associated with ZIKV and 1 case
of congenital malformation without microcephaly have been reported; according
to the province of residence they are distributed as follows: 5 cases in Manabi, 2 in Los Rios, 8 in Guayas, 1 in Santo Domingo de
los Tsachilas, 2 in Pichincha, 1 in Sucumbios and 2 in El Oro. Also, five cases of inconclusive
congenital malformations have been identified, coming from Guayas, Esmeraldas
and Manabí. These newborns are in the process of being investigated. New cases
have not been reported until SE 14 in 2018 (13).
Regarding studies related to this
topic, Chavali et al. (14) state that
ZIKV captures a human protein called Musashi-1 (MSI1), for its own replication,
preventing the protein from working properly and altering the expression of
many genes involved in neuronal development. Additional findings mention that
all MSI1 proteins in the developing embryo are produced by the neural stem
cells that will eventually become the infant's brain, which may be the reason
for why these cells are so vulnerable. On the other hand, authors such as
Gascon-Jiménez et al. (15) confirm the existence of subjects
with a rare type of inherited microcephaly (primary recessive autocephaly)
unrelated to ZIKV infection.
In this sense, while the majority of
infections caused by this virus remain undetected and have only minor
consequences, effects on pregnant women and newborns are becoming a serious
global problem of concern for public health (16). This investigation arises from the
fact that ZIKV infection is directly related to an increase in abortions and
the possibility that children, born to mothers who have acquired the virus, may
present neurological anomalies, convulsive syndromes and mental retardation (17). Therefore,
postnatal surveillance or monitoring of children in women who have suffered
from ZIKV infection during pregnancy is necessary (18).
This review consists in establishing
the relationship between ZIKV and the presence of microcephaly coming from
pregnant women who acquired the virus, possible theories of how the virus
enters the fetus, as well as identifying the causes of microcephaly, structural
damage (histological and molecular) as well as recognizing the clinical
manifestations in the newborn affected by ZIKV.
Methods
The research methodology was
structured as follows:
Information sources
and database: this article is based on a direct review with access
to the following databases: Scielo (www.scielo.org), Pubmed (www.ncbi.nlm.nih.gob/pubmed), ScienceDirect (www.sciencedirect.com), Science (https://science.sciencemag.org), Neurology (www.neurologia.com), offered by the Google platform, using the following
descriptors: Zika virus, ZIKAV, microcephaly and pregnancy. Articles published
by the UN (http://apps.who.int) were also considered. In the search engine bar of each repository the
following search equations were used as filters for the derivation of articles:
"Zika and pregnancy", "Zika and microcephaly", "Zika
in pregnant women", "Zika and neurological effects", "Physiopathogy and Zika".
Eligibility criteria: articles published from 2015 to December 2019 were considered. Within
the inclusion criteria, the following were considered: a) articles from primary
sources published in indexed journals, with a review nature, original research
articles, comparative studies, evaluation studies and meta-analysis; b)
articles in English and Spanish: c) articles that addressed the relationship
between the presence of microcephaly in pregnant women with Zika and how the
virus is transferred to the neonate, d) articles that used methods and
technologies of a biochemical and molecular nature to detect the presence of
the virus in brain tissues. The following were excluded: a) guides, letters to
the editor, editorials, theses, dissertations, b) Bibliographic material only
available in physical form, and c) articles published before 2015.
Additional criteria: To collate the different articles, a critical reading of each abstract and a general evaluation of the full text were made, considering the most important elements such as the methodology used, results and conclusions (Figure 1). This bibliographic review did not evaluate the methodological quality of the studies, but rather to verify the theories that described the cause of microcephaly in the newborn, the structural data, both histological and molecular, and the clinical manifestations of the newborn affected by ZIKV.
Figure 1. Methodological sequence of the research. Source: Own elaboration.
Results
Relationship between ZIKV and Microcephaly
Microcephaly is considered a
structural defect in which the fetus or infant has a smaller head size than
expected when compared to others of similar gestational age and sex (19). It is determined
by the head circumference (HC) which is -2 SDE (standard deviations) below the
mean for age and sex (20). This abnormality can also occur
when a pregnant woman is exposed to radiation, tobacco, alcohol and certain
viruses (including cytomegalovirus and ZIKV) (21).
In this regard, two outbreaks
confirm the link between microcephaly and ZIKV infection. Those are: the first
outbreak, which occurred in French Polynesia in 2014, involving 17 cases of
newborns with microcephaly (22). In this
epidemic, pregnant women did not present symptoms of having ZIKV infection;
however, IgG antibodies against flavivirus (Dengue) were found, in serology,
which may have been asymptomatic mothers (23). In contrast,
in the second outbreak, which occurred in Brazil in October 2015, the presence
of antigens was confirmed in the chorionic villi of placentas in the first
trimester. Likewise, the tissues investigated were positive for ZIKV RNA by
RT-PCR (24). In addition, pregnant women
presented itching and arthralgia which are characteristic features of ZIKV
infection, during the first trimester (25). These events
caused the World Health Organization (WHO) to declare a state of alert and all
its 140 member countries to register any ZIKV cases and to pay due attention.
From that moment, studies linking ZIKV to microcephaly began (26). Another study
recorded the genomic sequence of the virus taken from fetal brain tissue in a
pregnant woman who showed ZIKV symptoms at the end of the first trimester of
pregnancy, which was the thirteenth week of gestation. This phylogenetic study
showed a high coincidence of 99.7% with the genome of the virus isolated from
French Polynesia in 2013 as well as from Brazil, in Sao Paulo, in 2015. Given
the outbreak originated in Brazil, this country has shown the highest
prevalence of microcephaly (27). Mutations in
three proteins were highlighted: NS1, responsible for immune system evasion;
NS4B, inhibition of the response of interferon type I and NS5, the masking of
viral RNA in the host (28). Especially, the NS5 protein
mutation which facilitated viral replication in human cells, and that same
mutation was found in different countries of America (29).
Theories
Three hypotheses are presented as to
how ZIKV might infect the fetus. The first hypothesis considers that it occurs
through receptor-mediated endocytosis, which can be DC-SIGN, TIM and TAM
proteins (AXL and Tyro3). Of which, it was proved that AXL and Tryro3 are the
ones that give the virus more accessibility to enter the cells and start the
replication process (30). The AXL receptor, which is
expressed by radial glial cells, astrocytes and microglia during the
development of the human cortex, is the main entry factor for ZIKV and once it
crosses the placental barrier, it becomes neurotrophic (31). The second hypothesis suggests
transport with maternal antibodies, which are transferred to the fetus (32). However, this
theory was discarded because it did not coincide with the most likely time in
which the infection occurs which is during the first or second trimester and
infecting the placenta directly (33). Finally, the
third hypothesis is due to the fact that ZIKV infection of the placenta can
lead to a generalized immune reaction and cause inflammatory cytokines to
activate microglia and these cause disruptions of neurogenesis. Also, reducing the neuronal development, predisposing
to the appearance of microcephaly (34). On the other
hand, studies mention that the placenta synthesizes and secretes molecules that
are essential for the development of the brain, ZIKV interrupts its secretion,
and is propitious to produce mutations among these, the genes of microcephaly,
overexpressing them (35).
Characteristics
ZIKV shows three important
characteristics, these are: it possesses a neurotropism (36), it infects
astrocytes and neural matrix cells; it crosses the placental barrier (37) and by
invading the hippocampus and meninges it causes degeneration of neuroprogenitor cells and immature cortical neurons (38).
The neurotropism that ZIKV has in order to attack the neural cells evidenced by being efficiently replicated in the brain tissue of an embryonated mouse, where using cellular markers, proved that the virus affects directly the progenitor cells and radial glial cells. Causing the deregulation of the processes of proliferation, differentiation and development of the organ (36). On this regard, the authors found high levels of viral particles in the ventricular and sub-ventricular areas, where gliaradial cells and new neurons reside. In addition, nests of infected radial glial cells were detected in the germinal zone, mainly affecting neuronal migration, and expanding the infection to their descendant cells, which are neurons and astrocytes (Figure 2) (39).
Figure 2. Main cells affected by the ZIKV and consequences.
Source: Own elaboration.
Another feature is that ZIKV crosses the placental barrier, and thereby
infecting the fetus, causing damage in the brain development (37). The detection
of ZIKV in the amniotic fluid of two pregnant women from Paraiba state in
Brazil, whose fetuses were positive for diagnosis with microcephaly, confirms
this characteristic (40). Also, researches on human
placental cells from in vitro infections shows that ZIKV replicates in
placental macrophages (Hofbauer cells), trophoblasts
and endothelial fetal cells that induce the expression of antiviral genes (41). Primary
trophoblasts (placental cells) produce a type III interferon (IFN) IFNλ1
that acts as an antiviral, protecting placental epithelial cells from ZIKV
infection (42). However, the person becomes more
susceptible during the first trimester because the trophoblasts are still
developing, opening the way for a greater probability of infection, as opposed
to later in the pregnancy when the protection offered by the interferon is
already in place (43). This being the case, the placenta
in an advanced stage of pregnancy can protect the fetus and block the transfer
of the virus and provide its own inflammatory response. Therefore, the periods of greatest risk for
the presence of microcephaly occur in the pre-conception period, the first
trimester during the period of proliferation, differentiation and migration of
neuroepithelial tissue (44).
As for
the last feature, ZIKV has been shown to induce apoptosis and autophagy in mice
neural tissue (38). On pathological examination of a
ZIKV-infected fetus in utero, diffuse astrogliosis and activation of the
microglia cells present was observed (45). Also, it
affects the genes that regulate cytokine production and the regulation of
apoptotic pathways, interestingly, the cells of the cranial neural crest, also
a degree of apoptosis after ZIKV infection, by releasing a cytokine in response
to viral infection; causing cell death and aberrant neurogenesis for the neural
progenitor cells (46). One of the affected pathways is
the PI3K-Akt-mTOR, by the cooperation of the viral proteins NS4A and NS4B, and
the inhibition of mTOR in neuronal development produces microcephaly, promotes
autophagy, in a way that causes synergism with the promotion of viral
replication (47).
Effects on the newborn
The ZIKV has the ability to cross
the placental barrier, which allows it to feed on amniotic fluid, the site that
contains the fetus during its development, resulting in damage in brain
formation (48).
In most cases of congenital ZIKV
infection these damages have been found as an additional finding and not
specifically as microcephaly. Ultrasound suggests that there is a relationship
between a recent pathology and ZIKV infection, differentiating it from other
congenital infections (49). This is a new and severe
congenital syndrome, which has been called Congenital Zika Syndrome (CZS),
characterized by neurological damage and massive reduction of intracranial
volume with ventriculomegaly (50).
The most common clinical
manifestations that have been identified in infants with CZS are: microcephaly,
decreased brain tissue, optical damage, pigment changes, limited joint
movement, central nervous system malformation and muscular hypertonicity (51). Children born
with CZS at approximately 2 years of age show evidence of developmental delay,
and as a result of the sequelae of the syndrome, constant and lifelong medical
attention is required (52). However, severe affectations only
appear in approximately 10% of infants with infected mothers (53).
Neonates suffering from CZS can then
be classified into structural and functional affectations. The structural ones
include cranial morphology, ocular anomalies, cerebral anomalies and congenital
contractures. The functional alterations are linked to neurological wear,
reduced intrauterine growth and a birth weight less than 2,500g (28).
Cranial morphology: for the babies diagnosed with microcephaly, the size
of the head correlates with the underlying brain size, i.e.
if microcephaly is present it is an indication that the brain has not developed
properly or that growth has stopped. Even so, these measurements do not consistently
predict long-term sequelae (27).
Severe microcephaly, when there are
three or more standard deviations below the mean, is manifested in congenital
ZIKV infection, to this is commonly added the superimposed cranial suture,
prominence of the occipital bone and furrows in the scalp due to excess skin (54). Also, extreme
cranial-facial asymmetry is often present, where the forehead is tilted as a
consequence of frontal lobe hypoplasia, characteristic of severe cases and may
even occur in babies without microcephaly (55).
Ophthalmic
abnormalities: an investigation in Colombia and
Venezuela found that CZS has a high incidence to cause severe optic nerve as
well as macular defects (88%) also a substantial rate of anterior segment
abnormalities (12%). Bilateral ocular involvement was universal in their study.
Therefore, they recommend that an ophthalmic examination be performed in all
patients with CZS (56).
The relationship between maternal
infection during the first pregnancy and microcephaly generates a high-risk
factor for the newborn to present ocular abnormalities. CZS differs from other
congenital infections in chorioretinal atrophy, which
is well defined and the macroscopic pigmentation, which generally affects the
macular region, is unique in ZIKV infection (57).
The most commonly reported eye
injuries include macular pigment spots and choriorethian
atrophy that tend to be located in the posterior pole of the eye, especially in
the macular area. Also, microphthalmia and coloboma, congenital cataracts, and
intraocular calcifications have been reported (58). Among other
findings that have been reported in infants with CSZ are optic nerve
involvement, including hypoplasia, optic nerve venting and atrophy, severe
optic disc hollowing, lens subluxation and bilateral iris coloboma. Although
the mothers of the infants maintained normal visual function during and after
pregnancy (59).
The pathogenesis of posterior eye
injuries is not known yet, however, it could be due to direct cell damage by
ZIKV or inflammatory sequelae. Active chorioretinitis is a possible precursor
to chorioretinal atrophy (60). Likewise,
blindness has been associated with expression of the Axl
protein receptor found in retinal stem cells (61).
Brain abnormalities: the macroscopic brain pathology caused in CZS has a
great similarity to the neuropathology related to congenital cytomegalovirus
(CMV) (62). Most evident difference is the
distribution of intracranial calcifications, mostly subcortical in the
grey-white junction in congenital ZIKV infection and periventricular in CMV (23).
Among the anomalies detected are the
presence of diffuse calcifications in the subcortical area which can cause cell
death, differentiating them from other congenital infections. Furthermore, there is an increase in
ventricular and extra axial fluid spaces; cortical thinning with abnormalities
in the convolutions; hypoplasia or absence of the corpus callosum; reduced
myelin; and hypoplasia of the cerebellum or cerebellar vermis (63). Also,
calcifications have been evidenced in the basal ganglia and in the brain stem (64).
Brain abnormalities can be detected
prenatally with ultrasound or MRI (65). It is more
complex in severe microcephaly because the anterior fontanel is tiny or closed,
making transfontanellar ultrasound difficult in the
newborn (66). In this respect, in an evaluation
of women infected with ZIKV, fetal ultrasound showed that 17% of the fetuses
had calcifications or other CNS anomalies (23). Subsequently,
a study in which one-month old Rhesus monkeys (in humans, equivalent to three
months of life) were infected with ZIVK showed that brain damage and behavioural alterations can be caused even when the
infection has occurred after birth (67).
Congenital
contractures: congenital contractures that have
been reported occurring in one or more joints (arthrogryposis) on infants with
CZS, are likely to develop in association with hypoplasia of the brainstem and
thinning of the entire spinal cord (68). Other factors
that also influence in the etiology of anthrogryposis
are uterine malformations, genetic disorders and maternal disorders (69). Depending on
the location of the contracture, whether it is lateral, in the upper or lower
limb, its clinical presentation changes and in terms of severity it usually
manifests itself with neurological deterioration (70).
Neurogenic factors affecting the
corticospinal tract, motor neurons or their interactions can cause fetal motor
abnormalities, leading to decreased fetal movement and contractures (71).
Motor impairments can also lead to
other serious consequences. In addition to causing a delay in motor
development, dyspraxia can also have implications for feeding (e.g. chewing and swallowing). Dysphagia has caused them to
fail to develop their motor functions and many others have needed feeding tubes
(72).
Neurological sequelae:
information about the long-term development of
children with CSZ is minimal. Most have had severe neurological sequelae and
cognitive disabilities that vary depending on severity, in addition the
complications associated with respiratory infections, dysphagia and reflux,
epilepsy and hydrocephalus that could be fatal (73).
Neurological examination of infected
newborns showed hypertonia and spasticity, irritability with excessive crying
and hypotonia in a few cases (74). According to
records, other severe neurological manifestations include tremors and postures
consistent with extrapyramidal dysfunction (75), encephalitis,
meningoencephalitis, cerebellitis, acute disseminated
encephalomyelitis, encephalopathies with epileptic seizures, inflammatory
myelopathy and alterations of the cranial nerves (76).
Most CZS babies are expected to
survive, even if they require ongoing medical care. Reports suggest that many
of the children with CZS on their first birthday had a functioning of a 2 to 3
months old level (77). Presenting functional disability
and some level of intellectual disability, most likely in the range of severe
to profound. Lack or abnormal neuronal development, cerebral palsy,
intellectual disability and epilepsy are strongly related to microcephaly (78).
As for language, the ability to
understand and produce it is consistent with the level of intellectual
disability. Comorbid hearing problems suggest difficulty in communication in
children with CZS (79). The production of speech is made
more difficult by motor and cognitive deficiencies. Some children with CZS can
understand verbal communication but not express themselves in words (80).
Infants with CZS are likely to have
long-term social, emotional, and behavioral challenges. Facial distortions,
severe hyperactivity and irritability, and an inability to calm down have been
reported in infants with CZS (81). Irritability
can be caused by pain, difficulties in regulating sensory input, abnormal sleep
patterns, frustrations with communication, and outpatient challenges during
their growth (82).
They have a higher risk to present
psychiatric disorders, although the severity of the intellectual disability is
likely to make it harder to diagnose. Since children with CZS have multiple
vulnerabilities, they may have limitations in their development of functional
skills. Basic activities of daily living will be compromised, so most children
with CZS will require lifelong care (83).
In addition, a clear connection has
been established between ZIKV infection and Guillain-Bar syndrome (GBS) which
is a rare disorder in which the body's immune system attacks the nerves [84].
This association was identified in French Polynesia and other regions that have
a high rate of ZIKV morbidity (84,85).
In regard of the immune system, the organism fights the peripheral
nervous system (PNS) after infection with ZIKV, causing an albuminocyte
dissociation in the cerebrospinal fluid and a demyelination and inflammation of
various nerve roots (86). The symptoms that it causes are
muscle weakness, numbness or pain in the fingers and toes, pain that spreads to
the arms, walking problems, irritability, breathing problems and facial
weakness. It may be a benign condition, but it can also cause death if the
paralysis of the chest muscles is not treated, also leading to breathing
problems (87).
Discussion
The epidemiological link between
Zika and microcephaly was first reported in Brazil in 2015 (88). Prior to
this, cases of microcephaly were reported in French Polynesia in 2013; however,
this was not significant because no concrete data was established to associate
the virus with microcephaly, but it was possible to prove perinatal
transmission of ZIKV. This data represents an important event, which will be
related to the outbreak in Brazil 2015, where several patients with ZIKV symptomatology
were investigated and it was concluded that this was the agent that originated
the outbreak, and that it corresponded to an expansion of the Asian lineage (88).
Between the causes of microcephaly,
three theories have been established about how the virus manages to infect the
fetus, the most widely accepted is the entry of the virus through receptors,
even coinciding with the study carried out (89) about the
dependence of the receptor AXL responsible for infecting the fetal endothelial
cells. This finding differentiates ZIKV from other flaviviruses such as Dengue
(DENV) or West Nile virus (WNV). As such, it could be noted that ZIKV uses the
AXL receptor as an entry cofactor into umbilical vein endothelial cells. The
importance of this receptor is referred to in the study (61) as the
possibility of blocking this receptor in a way of preventing viral replication,
even though this would have negative consequences. Despite that, another report
to develop antivirals that target the components needed by the virus to
replicate, proposing the inhibition of AXL, however these do not eliminate the
possibility of infection to glial cells (90).
One of the characteristics mentioned
previously, agrees with a study of a sample from fetal tissue post mortem (67) in which a
large amount of apoptosis was found affecting mainly the developing neurons
migrating to the neocortex. That was associated with an early mineralization of
them, however, the neurons differentiated in the germinal matrix, were not
affected. Other authors mention that it specifically targets the process of
neural cell formation, and that the already differentiated cells have their own
defense mechanism that prevents them from being infected by ZIKV (91). In general
terms, the authors conclude that when ZIKV affects pregnant women, after
crossing the placental barrier it is neurotrophic, affecting the neurons during
their development.
As far as clinical manifestations
are concerned, we agree that intrauterine ZIKV infection appears to be directly
related to the appearance of congenital anomalies mainly cerebral anomalies
causing birth defects including microcephaly, neural tube damage,
ophthalmological abnormalities and other central nervous system disorders (92).
Apparently the most common period of
infection is the late first trimester and early second trimester; however, it
suggests that brain damage and behavioral disturbances may occur even when the
infection has taken place after birth (93). On the
contrary, Martínes et al. (24) mentioned that
there is only evidence for the first trimester, based on studies of placentas
where viral antigens have been found in the chorionic villi.
Microcephaly is considered to be the
main alteration in cranial morphology caused by CZV. This variation seems to be
caused by modification of the neuronal cells. This statement coincides with the
suggestion that demyelination of the white substance, and cerebellar hypoplasia
in most infants, suggests that ZIKV is connected to the disruption of neural development
by affecting neural and glial proliferation, as well as their migration (36). However, it
differs from the studies carried out by Roberts and Frosh (94), who indicate
that there is destruction in the brain tissue such as calcifications, gliosis
and necrosis, suggesting a process of cellular destruction, demonstrated by the
continuous presence of the virus.
When it comes to brain
abnormalities, the diffuse calcifications in the subcortical area, which can
cause cell death, are different from other congenital infections. In this
regard, in a postmortem study of seven neonates with congenital ZIKV infection,
macroscopic and microscopic calcifications were found in three patterns:
individual neuronal mineralization, a fine granular pattern and coarse banded
calcification (95). However, the lymphocytic
choriomeningitis virus also shows a strong tropism towards the neuroblasts,
causing periventricular calcifications, cortical dysplasia and focal brain
destruction (96).
Unfortunately, the specific
mechanism that develops contractures with CZS is uncertain. Neurogenic factors affecting the
corticospinal tract, motor neurons or their interactions are considered likely to
cause motor abnormalities, causing fetal movements and contractures to be
reduced. Arthrogryposis was connected to ZIKV for the damage it causes to
central and peripheral motor neurons, but not to the abnormalities of the
joints themselves (68). However, other authors consider
that it may be due to a physical limitation of intrauterine movement, maternal
disorders and genetic alterations and therefore ZIKV should not be established
as the definitive cause (97).
Information about the long-term development of
children with CSZ is minimal. Most have had severe neurological sequelae and
cognitive disabilities (75). For Cao-Lormeau et al. (98) there is a
clear association between ZIKV infection in infants and Guillain-Barré
syndrome.
Conclusion
There is a direct relationship
between the appearance of microcephaly together with ZIKV. The studies carried
out on the two main outbreaks in French Polynesia and Brazil, show pieces of
evidence that, when gathered together, are sufficient support. Since alterations
in the newborn arise when ZIKV enters the placenta, through receptors including
AXL, and this manages to reach the fetus, with a greater predilection towards
the hippocampus and cerebral cortex, affecting the developing neurogerm cells, therefore, the consequences are more
drastic when the pregnant woman is infected during the first trimester of
pregnancy.
The virus, not only causes
microcephaly, but also other neurological anomalies. This is mainly caused by
the way it enters the fetus and attacks the cells, preventing their development
and differentiation, thereby affecting their functioning.
The authors declare that they do not present
conflicts of relationships and activities during the development of this
research.
The authors declare that they have
not received any funding for the conduct of this research.
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Author’s
contributions
VSGC: conceptualization,
data curation, investigation, methodology, writing–original draft, writing –
review & editing. GYCA and GCJM: data curation,
writing–review & editing. PCOE: conceptualization, data curation, writing–review & editing
©2021. Los Autores. Kasmera.
Publicación del Departamento de Enfermedades Infecciosas y Tropicales de la
Facultad de Medicina. Universidad del Zulia. Maracaibo-Venezuela. Este
es un artículo de acceso abierto distribuido bajo los términos de la licencia Creative Commons atribución no
comercial (https://creativecommons.org/licenses/by-nc-sa/4.0/) que permite el uso no comercial,
distribución y reproducción sin restricciones en cualquier medio, siempre y
cuando la obra original sea debidamente citada.