Author: Velásquez-Serra Glenda Coromoto, García-Yuquilema Camila Janina, Galarza-Cedeño Joselyn Meylin, Preciado-Cañas Oscar Enrique
Date: 2021-04-26T04:00:00+00:00
Keywords: Revisión Sistemática
Publisher: Departamento de Enfermedades Infecciosas y Tropicales de la Facultad de Medicina. Universidad del Zulia. Maracaibo-Venezuela. Serbiluz.

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.

Conflict of Relationships and Activities

The authors declare that they do not present conflicts of relationships and activities during the development of this research.

Funding

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.

Table of Contents

- Conflict of Relationships and Activities

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