Association between Sleep and Language Development in Children with Congenital Zika Syndrome.

AIM: Congenital Zika Virus Syndrome (CZS) presents notable hurdles to neurodevelopment, with language development emerging as a crucial aspect. This study investigates sleep patterns and language skills in children with CZS, aiming to explore the potential synchronization of sleep development with their neurodevelopment. METHOD: We studied cross-sectionally 135 children with CZS aged 0 to 48 months, investigating sleep using the BISQ Questionnaire. Language development was assessed using the Early Language Milestone Scale, while motor development and cognitive and social ability were assessed using the Bayley Scales of Infant and Young Child Development 3rd edition. We also studied longitudinally a cohort of 16 children (initially aged 0 to 12 months) whom we followed for four years, assessing at one-year intervals. RESULTS: Sleep disturbances and language deficits were highly frequent in this population. In the 0-12 months group, a late bedtime and frequent nighttime awakenings were associated with poorer auditory expressive skills. At 13-24 months, nighttime awakenings were associated with poorer auditory expressive skills, while among 25-36-month-olds decreased auditory receptive skills were associated with longer sleep onset latency and reduced nighttime sleep duration. CONCLUSION: The brain alterations caused by Zika virus infection affect both sleep disturbances and delays in language development. It is possible that sleep disturbance may be a mediating factor in the pathway between CZS and delayed language development, as the three analyzed language skills showed a correlation with sleep parameters.

Continuous epileptiform discharges are associated with worse neurodevelopmental findings in a congenital Zika syndrome prospective cohort.

PURPOSE: This study aimed to identify continuous epileptiform discharges (CEDs) on electroencephalograms (EEG) and to determine their clinical significance in children with congenital Zika syndrome (CZS). METHODS: This prospective cohort study included 75 children diagnosed with CZS born from March 2015 and followed up until September 2018 (age up to 36 months). EEG was performed to detect CEDs up to 24 months old. Data on obstetric, demographic, and clinical signs; cranial computed tomography (CT); ophthalmology examination; anti-seizure medication; growth; and motor development were collected. Fisher's exact test was used to verify the associations between categorical variables, and the T- test was used to compare the mean z-scores of anthropometric measurements between the groups with and without CED. RESULTS: CEDs were identified in 41 (54.67 %) children. The mean age of CEDs identification was 12.24 ± 6.86 months. Bilateral CEDs were shown in 62.89 % of EEGs. CEDs were associated with severe congenital microcephaly, defined by z-score >3 standard deviation of head circumference (HC) below the mean for sex and age (p = 0.025), and worse outcomes, including first seizure before 6 months (p = 0.004), drug-resistant epilepsy (p < 0.001), chorioretinal scarring or mottling (p = 0.002), and severe CT findings (p = 0.002). The CED group had lower mean z-scores of HC up to 24 months of age. CONCLUSION: This is the first description of the prevalence and significance of CEDs that also remains during wakefulness in patients with CZS. New investigations may suggest that it is more appropriate to classify the EEG not as a CED, but as a periodic pattern. Anyway, CEDs may be a marker of neurological severity in children with CSZ.

Auditory Neural Responses and Communicative Functioning in Children With Microcephaly Related to Congenital Zika Syndrome.

OBJECTIVES: Children with microcephaly exhibit neurodevelopmental delays and compromised communicative functioning, yielding challenges for clinical assessment and informed intervention. This study characterized auditory neural function and communication abilities in children with microcephaly due to congenital Zika syndrome (CZS). DESIGN: Click-evoked auditory brainstem responses (ABR) at fast and slow stimulation rates and natural speech-evoked cortical auditory evoked potentials (CAEP) were recorded in 25 Brazilian children with microcephaly related to CZS ( M age: 5.93 ± 0.62 years) and a comparison group of 25 healthy children ( M age: 5.59 ± 0.80 years) matched on age, sex, ethnicity, and socioeconomic status. Communication abilities in daily life were evaluated using caregiver reports on Vineland Adaptive Behavior Scales-3. RESULTS: Caregivers of children with microcephaly reported significantly lower than typical adaptive functioning in the communication and socialization domains. ABR wave I latency did not differ significantly between the groups, suggesting comparable peripheral auditory function. ABR wave V absolute latency and waves I-V interwave latency were significantly shorter in the microcephaly group for both ears and rates. CAEP analyses identified reduced N2 amplitudes in children with microcephaly as well as limited evidence of speech sound differentiation, evidenced mainly by the N2 response latency. Conversely, in the comparison group, speech sound differences were observed for both the P1 and N2 latencies. Exploratory analyses in the microcephaly group indicated that more adaptive communication was associated with greater speech sound differences in the P1 and N2 amplitudes. The trimester of virus exposure did not have an effect on the ABRs or CAEPs. CONCLUSIONS: Microcephaly related to CZS is associated with alterations in subcortical and cortical auditory neural function. Reduced ABR latencies differ from previous reports, possibly due to the older age of this cohort and careful assessment of peripheral auditory function. Cortical speech sound detection and differentiation are present but reduced in children with microcephaly. Associations between communication performance in daily life and CAEPs highlight the value of auditory evoked potentials in assessing clinical populations with significant neurodevelopmental disabilities.

Lipid droplets in Zika neuroinfection: Potential targets for intervention?

Lipid droplets (LD) are evolutionarily conserved lipid-enriched organelles with a diverse array of cell- and stimulus-regulated proteins. Accumulating evidence demonstrates that intracellular pathogens exploit LD as energy sources, replication sites, and part of the mechanisms of immune evasion. Nevertheless, LD can also favor the host as part of the immune and inflammatory response to pathogens. The functions of LD in the central nervous system have gained great interest due to their presence in various cell types in the brain and for their suggested involvement in neurodevelopment and neurodegenerative diseases. Only recently have the roles of LD in neuroinfections begun to be explored. Recent findings reveal that lipid remodelling and increased LD biogenesis play important roles for Zika virus (ZIKV) replication and pathogenesis in neural cells. Moreover, blocking LD formation by targeting DGAT-1 in vivo inhibited virus replication and inflammation in the brain. Therefore, targeting lipid metabolism and LD biogenesis may represent potential strategies for anti-ZIKV treatment development. Here, we review the progress in understanding LD functions in the central nervous system in the context of the host response to Zika infection.

Longitudinal evolution of electroencephalogram (EEG): Findings over five years of follow-up in children with Zika-related microcephaly from the Microcephaly Epidemic Research Group Pediatric Cohort (2015-2020).

OBJECTIVE: To assess the longitudinal evolution of EEG findings in children with Zika related-microcephaly (ZRM) and to evaluate the associations of these patterns with the children's clinical and neuroimaging characteristics. METHODS: As part of the follow-up of the Microcephaly Epidemic Research Group Pediatric Cohort (MERG-PC) in Recife, Brazil, we performed serial EEG recordings in a subgroup of children with ZRM to evaluate changes in background rhythms and epileptiform activity (EA). Latent class analysis was used to identify patterns in the evolution of EA over time; clinical and neuroimaging findings were compared across the identified groups. RESULTS: Out of the 72 children with ZRM who were evaluated during 190 EEGs/videoEEGs, all participants presented with abnormal background activity, 37.5% presented with an alpha-theta rhythmic activity, and 25% presented with sleep spindles, which were less commonly observed in children with epilepsy. EA changed over time in 79.2% of children, and three distinct trajectories were identified: (i) multifocal EA over time, (ii) no discharges/focal EA evolving to focal/multifocal EA, and (iii) focal/multifocal EA evolving to epileptic encephalopathy patterns (e.g., hypsarrhythmia or continuous EA in sleep). The multifocal EA over time trajectory was associated with periventricular and thalamus/basal ganglia calcifications, brainstem and corpus callosum atrophy and had less focal epilepsy, whereas the children in the trajectory which evolved to epileptic encephalopathy patterns had more frequently focal epilepsy. SIGNIFICANCE: These findings suggest that, in most children with ZRM, trajectories of changes in EA can be identified and associated with neuroimaging and clinical features.

Manifestaciones oftalmológicas del dengue, el zika y el chikungunya / Ophthalmic manifestations of dengue, zika and chikungunya

Las infecciones por arbovirus constituyen un reto significativo para los sistemas de salud. Cada vez se incrementa el reconocimiento de complicaciones del sistema nervioso central secundarias a ellas, lo que puede ser un dilema para su diagnóstico y tratamiento. Los arbovirus pueden alterar los mecanismos de inmunidad innatos del ojo al dañar las barreras óculo-hemáticas. En esta revisión nos propusimos caracterizar los principales hallazgos oftalmológicos de las enfermedades transmitidas por mosquito, como el dengue, el zika y el chikungunya, y su posible fisiopatología. Se realizó una búsqueda de la literatura sobre el tema en la base de datos de PubMED. En los pacientes con zika y chikungunya se reconocieron frecuentemente la conjuntivitis no purulenta y la queratitis. En los casos de dengue el edema macular y las hemorragias retinianas maculares fueron frecuentes; causaron disminución de la visión y defectos campimétricos; la vasculitis y coriorretinitis periférica podía ser asintomática si la mácula no estaba comprometida. Estuvieron implicados la trombocitopenia y otros procesos fisiopatológicos. En las enfermedades estudiadas se reportaron casos raros con parálisis de nervios oculomotores o neuritis óptica como respuesta autoinmune tardía. Recientemente se reportó el síndrome de zika congénito que incluyó múltiples anomalías del desarrollo. En los neonatos afectados se describió la atrofia macular, así como la pigmentación macular bilateral, la hipoplasia del nervio óptico, la catarata, entre otros. Existen diversas lesiones oculares secundarias a infecciones por dengue, zika y chikungunya que merecen reconocimiento, pues deterioran la función visual temporal o permanentemente(AU)

Arbovirus infections pose a significant challenge to health systems. Awareness of the secondary central nervous system complications caused by these infections is on the increase, which may be a dilemma for their diagnosis and treatment. Arboviruses may alter the innate immunity mechanisms of the eye by damaging blood-retinal barriers. The objective of this review was to characterize the main ophthalmological findings of mosquito-borne diseases, such as dengue, zika and chikungunya, and their possible physiopathology. A bibliographic search about the topic was conducted in the database PubMed. Non-purulent conjunctivitis and keratitis were frequently found in zika and chikungunya patients. Dengue cases often presented macular edema and macular retinal hemorrhage, which caused vision reduction, as well as campimetric defects. Vasculitis and peripheral chorioretinitis could be asymptomatic if the macula was not involved. Thrombocytopenia and other physiopathological processes were also present. Oculomotor nerve palsy and optic neuritis as a late autoimmune response were rarely reported in the diseases studied. Recent reports refer to congenital zika syndrome, which causes multiple developmental abnormalities. Macular atrophy, bilateral macular pigmentation, optic nerve hypoplasia and cataract, among other disorders, were described in affected neonates. A variety of ocular lesions secondary to dengue, zika and chikungunya infection deserve recognition, for they damage visual function either temporarily or permanently(AU)

Reactive Oxygen Species (ROS) Are Not a Key Determinant for Zika Virus-Induced Apoptosis in SH-SY5Y Neuroblastoma Cells.

INTRODUCTION: ZIKV is a highly neurotropic virus that can cause the death of infected neuroprogenitor cells through mitochondrial damage and intrinsic apoptotic signaling. In this context, the role of reactive oxygen species (ROS) in neuronal cell death caused by ZIKV still remains elusive. OBJECTIVE: We aimed at evaluating the role of these cellular components in the death of human undifferentiated neuroblastoma cell line infected with ZIKV. RESULTS: ZIKV infection resulted in the extensive death of SH-SY5Y cells with the upregulation of several genes involved in survival and apoptotic responses as well as the colocalization of mitochondrial staining with ZIKV Envelope (E) protein. Notably, levels of intracellular reactive oxygen species (ROS) were not altered during ZIKV infection in undifferentiated SH-SY5Y cells, and consistent with these results, the treatment of infected cells with the widely studied ROS scavenger N-acetylcysteine (NAC) did not prevent cell death in these cells. CONCLUSION: Altogether, our results suggest that excessive ROS production is not the main trigger of SH-SY5Y cells death in ZIKV infection.

A Rat Model of Prenatal Zika Virus Infection and Associated Long-Term Outcomes.

Zika virus (ZIKV) is a mosquito-borne flavivirus that became widely recognized due to the epidemic in Brazil in 2015. Since then, there has been nearly a 20-fold increase in the incidence of microcephaly and birth defects seen among women giving birth in Brazil, leading the Centers for Disease Control and Prevention (CDC) to officially declare a causal link between prenatal ZIKV infection and the serious brain abnormalities seen in affected infants. Here, we used a unique rat model of prenatal ZIKV infection to study three possible long-term outcomes of congenital ZIKV infection: (1) behavior, (2) cell proliferation, survival, and differentiation in the brain, and (3) immune responses later in life. Adult offspring that were prenatally infected with ZIKV exhibited motor deficits in a sex-specific manner, and failed to mount a normal interferon response to a viral immune challenge later in life. Despite undetectable levels of ZIKV in the brain and serum in these offspring at P2, P24, or P60, these results suggest that prenatal exposure to ZIKV results in lasting consequences that could significantly impact the health of the offspring. To help individuals already exposed to ZIKV, as well as be prepared for future outbreaks, we need to understand the full spectrum of neurological and immunological consequences that could arise following prenatal ZIKV infection.

Neurological pathophysiology of SARS-CoV-2 and pandemic potential RNA viruses: a comparative analysis.

SARS-CoV-2 has infected hundreds of millions of people with over four million dead, resulting in one of the worst global pandemics in recent history. Neurological symptoms associated with COVID-19 include anosmia, ageusia, headaches, confusion, delirium, and strokes. These may manifest due to viral entry into the central nervous system (CNS) through the blood-brain barrier (BBB) by means of ill-defined mechanisms. Here, we summarize the abilities of SARS-CoV-2 and other neurotropic RNA viruses, including Zika virus and Nipah virus, to cross the BBB into the CNS, highlighting the role of magnetic resonance imaging (MRI) in assessing presence and severity of brain structural changes in COVID-19 patients. We present new insight into key mutations in SARS-CoV-2 variants B.1.1.7 (P681H) and B.1.617.2 (P681R), which may impact on neuropilin 1 (NRP1) binding and CNS invasion. We postulate that SARS-CoV-2 may infect both peripheral cells capable of crossing the BBB and brain endothelial cells to traverse the BBB and spread into the brain. COVID-19 patients can be followed up with MRI modalities to better understand the long-term effects of COVID-19 on the brain.

NS5-independent Ablation of STAT2 by Zika virus to antagonize interferon signalling.

Flavivirus genus includes numerous arthropod-borne human pathogens that are clinically important. Flaviviruses are notorious for their ability to antagonize host interferon (IFN) induced anti-viral signalling. It has been documented that NS5s of flaviviruses mediate proteasome degradation of STAT2 to evade IFN signalling. Deciphering the molecular mechanism of the IFN antagonism by the viruses and reversing this antagonism may dictate anti-viral responses and provide novel antiviral approaches. In this report, by using Zika virus (ZIKV) as a model, we first demonstrated that ZIKV antagonized interferon signalling in an infectious dose-dependent manner; in other words, the virus antagonized interferon signalling at a high multiple of infection (MOI) and was sensitive to interferon signalling at a low MOI. Mechanistically, we found that ZIKV infection triggered degradation of ubiquitinated STAT2 and host short-lived proteins while didn't affect the proteasome activity per se. ZIKV infection resulted in suppression of host de novo protein synthesis. Overexpression of NS5 alone only marginally reduced STAT2 and had no effect on the host de novo protein synthesis. Ectopically expressed murine STAT2 that was resistant to NS5- and ZIKV-induced ablation exaggerated the IFN-induced anti-viral signalling. These data favour a new model of the innate immune evasion of ZIKV in which the viral infection triggers suppression of host de novo protein synthesis to accelerate the degradation of short-lived, ubiquitinated STAT2. As flaviviruses share a very conserved replication strategy, the mechanisms of IFN antagonism elucidated here might also be employed by other flaviviruses.

Maternal Infection and Adverse Pregnancy Outcomes among Pregnant Travellers: Results of the International Zika Virus in Pregnancy Registry.

In this multicentre cohort study, we evaluated the risks of maternal ZIKV infections and adverse pregnancy outcomes among exposed travellers compared to women living in areas with ZIKV circulation (residents). The risk of maternal infection was lower among travellers compared to residents: 25.0% (n = 36/144) versus 42.9% (n = 309/721); aRR 0.6; 95% CI 0.5-0.8. Risk factors associated with maternal infection among travellers were travelling during the epidemic period (i.e., June 2015 to December 2016) (aOR 29.4; 95% CI 3.7-228.1), travelling to the Caribbean Islands (aOR 3.2; 95% CI 1.2-8.7) and stay duration >2 weeks (aOR 8.7; 95% CI 1.1-71.5). Adverse pregnancy outcomes were observed in 8.3% (n = 3/36) of infected travellers and 12.7% (n = 39/309) of infected residents. Overall, the risk of maternal infections is lower among travellers compared to residents and related to the presence of ongoing outbreaks and stay duration, with stays <2 weeks associated with minimal risk in the absence of ongoing outbreaks.

Congenital Zika syndrome: Growth, clinical, and motor development outcomes up to 36 months of age and differences according to microcephaly at birth.

BACKGROUND: Little is known regarding the developmental consequences of congenital Zika syndrome (CZS) without microcephaly at birth. Most previously published clinical series were descriptive and they had small sample sizes. STUDY DESIGN: We conducted a cohort study to compare the growth, clinical, and motor development outcomes for 110 children with CZS born with and without microcephaly up to their third birthday. Ninety-three had their head circumference (HC) at birth abstracted and they did not have hypertensive hydrocephalus at birth, where 61 were born with microcephaly and 32 without. RESULTS: The HC z-scores decreased steeply from birth to six months of age, i.e., from -3.77 to -6.39 among those with microcephaly at birth and from -1.03 to -3.84 among those without. Thus, at 6 months of age, the mean HC z-scores for children born without microcephaly were nearly the same as those for children born with microcephaly. Children born without microcephaly were less likely to have brain damage, ophthalmic abnormalities, and drug-resistant epilepsy, but the differences in many conditions were not statistically significant. CONCLUSIONS: Children born without microcephaly were only slightly less likely to present severe neurologic impairment and to develop postnatal-onset microcephaly, and some of the original differences between the groups tended to dissipate with age.

Classification of Congenital Zika Syndrome: Muscle Tone, Motor Type, Body Segments Affected, and Gross Motor Function.

Aim: To identify abnormalities in muscle tone and motor function associated with congenital Zika syndrome (CZS).Method: A cross-sectional observational study involving 96 children (55 males) with CZS at a mean (SD) age 35.2 ± 2.9 months. Children's muscle tone was investigated using the pull to sit, scarf sign, shoulder suspension and ventral suspension tests and the modified Ashworth scale (MAS). Motor impairment was determined using the Gross Motor Function Classification System (GMFCS) and body segments most affected with motor impairment.Results: 58 (60,5%) children tested positive for ≥1 maneuver used to evaluate muscle tone, while 38 (39.5%) tested negative in all the tests. MAS score was >0 for at least one of the appendicular muscles in 91 children (94.8%). In 88 children (91.7%), all four limbs were affected.Conclusion: Findings suggestive of axial hypotonia and appendicular hypertonia associated with severe motor impairment were prevalent in children with CZS.

Viral infections and implications for male reproductive health.

Viral infections have haunted humankind since times immemorial. Overpopulation, globalization, and extensive deforestation have created an ideal environment for a viral spread with unknown and multiple shedding routes. Many viruses can infect the male reproductive tract, with potential adverse consequences to male reproductive health, including infertility and cancer. Moreover, some genital tract viral infections can be sexually transmitted, potentially impacting the resulting offspring's health. We have summarized the evidence concerning the presence and adverse effects of the relevant viruses on the reproductive tract (mumps virus, human immunodeficiency virus, herpes virus, human papillomavirus, hepatitis B and C viruses, Ebola virus, Zika virus, influenza virus, and coronaviruses), their routes of infection, target organs and cells, prevalence and pattern of virus shedding in semen, as well as diagnosis/testing and treatment strategies. The pathophysiological understanding in the male genital tract is essential to assess its clinical impact on male reproductive health and guide future research.

Effect of Intensive Physiotherapy Training for Children With Congenital Zika Syndrome: A Retrospective Cohort Study.

OBJECTIVE: To investigate the effect of intensive physiotherapy training on the motor function of children with congenital Zika syndrome (CZS). DESIGN: A retrospective cohort study. SETTING: A support center for children with microcephaly. PARTICIPANTS: Children (N=7) aged 14 to 18 months old who were diagnosed with CZS and previously monitored more than 1 year. INTERVENTIONS: A 2-stage protocol repeated uninterruptedly for 1 year. In the first stage, the children were submitted to 1 hour of conventional physiotherapy and 1 hour of suit therapy 5 times a week for 4 weeks. The second stage consisted of 1 hour of suit therapy 3 times a week for 2 weeks. MAIN OUTCOME MEASURES: Gross motor function measure (GMFM) and body weight. RESULTS: Six evaluations were conducted approximately 3 months apart. An increase in the overall GMFM score was observed between the first and second (P=.046), first and third (P=.018), first and fourth (P=.018), first and fifth (P=.043), and first and sixth evaluations (P=.018). Differences in the scores of the individual GMFM dimensions were found only for dimension A (lying and rolling) between the first and fourth evaluations (P=.027) and for dimension B (sitting) between the first and third (P=.018), first and fourth (P=.046), and first and sixth evaluations (P=.027). No difference was found in body weight between the first and sixth evaluations (P=.009). During follow-up, only 1 child required hospitalization, and another had increased irritability. CONCLUSIONS: Children with CZS were able to perform 2 hours of motor physiotherapy daily with no serious complications, resulting in an increase or stabilization in GMFM scores.

The Zika virus: Lurking behind the COVID-19 pandemic?

WHAT IS KNOWN AND OBJECTIVE: The sudden and extensive outbreak of coronavirus (SARS-CoV-2) has overshadowed another developing viral threat: the Zika flavivirus. Of particular concern is that pregnant women can pass Zika virus to the foetus, and there is a strong implication of an association between Zika virus infection and foetal microcephaly. Currently, there is no vaccine, and there is no cure. METHODS: Published literature and Internet sources were searched for information related to Zika virus, its transmission, its clinical presentation and sequalae, prevention and implications (practice and regulatory) for healthcare providers. The identified English sources were reviewed, assessed and synthesized. Emphasis was placed on providing an overview of the problem, and identification of unmet needs and future directions. RESULTS AND DISCUSSION: Zika virus poses a major challenge for healthcare providers, particularly in areas unaccustomed to it, since it is transmitted to humans by the vector Aedes aegypti mosquito. The outbreak impacts every healthcare provider, because every provider is required to report cases of Zika infection to their state or local health agencies--whether the infection is confirmed or merely suspected. Since the virus has become a worldwide crisis, healthcare providers will need to work across national boundaries and medical disciplines in order to educate patients about Zika symptoms and the mosquito vector. Until further information is known, infected patients (male and female) are being advised to avoid conceiving a child. WHAT IS NEW AND CONCLUSION: Until a vaccine is developed or effective treatment for Zika virus is discovered, healthcare providers must be AVP (aware, vigilant and proactive) in order to lessen the spread and impact of the implicated devastating birth defects (microcephaly) and other neurological disorders (eg Guillain-Barré Syndrome) of this infection. Unfortunately, many knowledge gaps exist. There is an urgent need for a reliable, inexpensive diagnostic test, an effective treatment and an approved and readily available vaccine.

Gross Motor Function in Children with Congenital Zika Syndrome.

BACKGROUND: Little information on gross motor function of congenital Zika syndrome (CZS) children is available. OBJECTIVES: To evaluate gross motor function in CZS children aged up to 3 years, and its associated factors and changes in a minimum interval of 6 months. METHODS: One hundred children with CZS and cerebral palsy (36 with confirmed and 64 with presumed CZS) were evaluated with the Gross Motor Function Classification System (GMFCS) and Gross Motor Function Measure (GMFM-88/GMFM-66). Forty-six were reevaluated. Wilcoxon tests, Wilcoxon tests for paired samples, percentile scores, and score changes were performed. RESULTS: Clinical and socioeconomic characteristics (except maternal age), GMFM scores and GMFCS classification of confirmed and probable cases, which were analyzed together, were similar. The mean age was 25.6 months (±5.5); the median GMFM-88 score was 8.0 (5.4-10.8); and the median GMFM-66 score was 20.5 (14.8-23.1); 89% were classified as GMFCS level V. Low economic class, microcephaly at birth, epilepsy, and brain parenchymal volume loss were associated with low GMFM-66 scores. The median GMFM-66 percentile score was 40 (20-55). On the second assessment, the GMFM-66 scores in two GMFCS level I children and one GMFCS level IV child improved significantly. In one GMFCS level III child, one GMFCS level IV child, and the group of GMFCS level V children, no significant changes were observed. CONCLUSIONS: Almost all CZS children had severe cerebral palsy; in the third year of life, most presented no improvement in gross motor function and were likely approaching their maximal gross motor function potential.

Long-term persistence of infectious Zika virus: Inflammation and behavioral sequela in mice.

The neurodevelopmental defects associated with ZIKV infections early in pregnancy are well documented, however the potential defects and long-term consequences associated with milder infections in late pregnancy and perinatal period are less well understood. To model these, we challenged 1 day old (P1) immunocompetent C57BL/6 mice with ZIKV. The animals developed a transient neurological syndrome including unsteady gait, kinetic tremors, severe ataxia and seizures 10-15 days post-infection (dpi) but symptoms subsided after a week, and most animals survived. Despite apparent recovery, MRI of convalescent mice show reduced cerebellar volume that correlates with altered coordination and motor function as well as hyperactivity and impulsivity. Persistent mRNA levels of pro-inflammatory genes including Cd80, Il-1α, and Ifn-γ together with Cd3, Cd8 and perforin (PrfA), suggested persistence of low-grade inflammation. Surprisingly, the brain parenchyma of convalescent mice harbor multiple small discrete foci with viral antigen, active apoptotic processes in neurons, and cellular infiltrates, surrounded by activated astrocytes and microglia as late as 1-year post-infection. Detection of negative-sense strand viral RNA and isolation of infectious virus derived from these convalescent mice by blinded passage in Vero cells confirmed long-term persistence of replicating ZIKV in CNS of convalescent mice. Although the infection appears to persist in defined reservoirs within CNS, the resulting inflammation could increase the risk of neurodegenerative disorders. This raises concern regarding possible long-term effects in asymptomatic children exposed to the virus and suggests that long-term neurological and behavioral monitoring as well as anti-viral treatment to clear virus from the CNS may be useful in patients exposed to ZIKV at an early age.

Evolution of ocular defects in infant macaques following in utero Zika virus infection.

Congenital Zika syndrome (CZS) is associated with microcephaly and various neurological, musculoskeletal, and ocular abnormalities, but the long-term pathogenesis and postnatal progression of ocular defects in infants are not well characterized. Rhesus macaques are superior to rodents as models of CZS because they are natural hosts of the virus and share similar immune and ocular characteristics, including blood-retinal barrier characteristics and the unique presence of a macula. Using a previously described model of CZS, we infected pregnant rhesus macaques with Zika virus (ZIKV) during the late first trimester and characterized postnatal ocular development and evolution of ocular defects in 2 infant macaques over 2 years. We found that one of them exhibited colobomatous chorioretinal atrophic lesions with macular and vascular dragging as well as retinal thinning caused by loss of retinal ganglion neuron and photoreceptor layers. Despite these congenital ocular malformations, axial elongation and retinal development in these infants progressed at normal rates compared with healthy animals. The ZIKV-exposed infants displayed a rapid loss of ZIKV-specific antibodies, suggesting the absence of viral replication after birth, and did not show any behavioral or neurological defects postnatally. Our findings suggest that ZIKV infection during early pregnancy can impact fetal retinal development and cause congenital ocular anomalies but does not appear to affect postnatal ocular growth.

Recent Clinical and Preclinical Studies of Hydroxychloroquine on RNA Viruses and Chronic Diseases: A Systematic Review.

The rapid spread of the new Coronavirus Disease 2019 (COVID-19) has actually become the newest challenge for the healthcare system since, to date, there is not an effective treatment. Among all drugs tested, Hydroxychloroquine (HCQ) has attracted significant attention. This systematic review aims to analyze preclinical and clinical studies on HCQ potential use in viral infection and chronic diseases. A systematic search of Scopus and PubMed databases was performed to identify clinical and preclinical studies on this argument; 2463 papers were identified and 133 studies were included. Regarding HCQ activity against COVID-19, it was noticed that despite the first data were promising, the latest outcomes highlighted the ineffectiveness of HCQ in the treatment of viral infection. Several trials have seen that HCQ administration did not improve severe illness and did not prevent the infection outbreak after virus exposure. By contrast, HCQ arises as a first-line treatment in managing autoimmune diseases such as rheumatoid arthritis, lupus erythematosus, and Sjögren syndrome. It also improves glucose and lipid homeostasis and reveals significant antibacterial activity.