Search Results (63)

Coccidioidal meningitis (CM) is a rare but life-threatening complication of disseminated coccidioidomycosis, occurring in ~16% of cases, particularly among children in endemic regions such as the southwestern US and northern Mexico. Without timely diagnosis and antifungal therapy, pediatric CM is almost universally fatal within the first year. Hydrocephalus develops in up to 50% of cases. In 2000, Galgiani et al. established fluconazole as first-line therapy for CM. Subsequent guidelines refined management but did not specifically address pediatric patients (>1 month–≤19 years). No studies in the fluconazole era have systematically evaluated risk factors for complications in this population. We therefore conducted a systematic review and proportional synthesis of pediatric CM cases, focusing on CNS complications and outcomes. PubMed/MEDLINE, Embase (Ovid), and Web of Science were systematically searched (2000–2025). PROSPERO registration ID (1130290). Inclusion criteria encompassed epidemiological studies, case series, and case reports that described at least one pediatric case of CM or CNS involvement, confirmed by diagnostic methods. Cases in adults, neonates (<1 month), congenital infections, teratogenicity studies, reviews, or incomplete reports were excluded. Only cases with complete individual data (n = 48) were included. Methodological rigor was ensured using JBI Critical Appraisal Tools. Of 1089 studies, 31 met the inclusion criteria, representing 3874 pediatric cases. CM/CNS involvement was confirmed in 165 cases (4.25%; 95% CI: 3.6–4.9%), with hydrocephalus in 62 (37.5%). Among 48 case reports with complete data, fluconazole was first-line therapy in 65%. Serum CF titers ≥ 1:16 were associated with hydrocephalus plus stroke (p = 0.027) and independently predicted adverse outcomes (relapse/death; OR = 4.5, p = 0.037), whereas lifelong azole therapy was associated with improved outcomes (overall survival mean, 82 vs. 32 months; p = 0.002). Pediatric CM remains highly lethal, with hydrocephalus a frequent and severe complication. High serum CF titers (≥1:16) predict poor outcomes, emphasizing the urgent need for standardized, pediatric-specific diagnosis and management guidelines. Full article

Within the first 28 days after birth, more than 1 in every 2500 newborns will suffer a stroke. The weekly-adjusted risk of stroke for a term-born infant is threefold higher than for a male smoker aged 50 to 59 years with hypertension and diabetes. Neonatal stroke has significant clinical and socio-economic consequences, leading to cerebral palsy, epilepsy, and a range of motor, sensory, and cognitive impairments. Currently, there is no treatment for the brain damage caused by neonatal stroke. In this review, we outline the differences in the complex interplay of inflammation, excitotoxicity, oxidative stress, and cell death after stroke between adults and neonates, which limits the direct transfer of knowledge between studies for understanding injury. We comprehensively document what is known about the pathophysiology of neonatal stroke and critically evaluate current therapeutic strategies, emphasising the urgent need for innovative treatments tailored to suit the neonatal brain. This analysis reveals that treatment with an injectable hydrogel scaffold, a three-dimensional, water-swollen polymer network, may be an innovative, viable approach to improve outcomes for infants suffering from the most severe forms of brain injury arising from neonatal stroke. Full article

The objective of this study was to determine the epidemiological, clinical, and laboratory characteristics of newborns with sepsis in northwestern Mexico, identify the microorganisms causing early- and late-onset sepsis, and assess antimicrobial resistance. Additionally, it sought to associate neonatal characteristics with antimicrobial resistance or mortality. A retrospective study was conducted from August 2021 to April 2023, during which 8382 neonatal clinical records were analyzed to collect epidemiological, clinical, and laboratory characteristics, as well as microorganisms isolated from neonates and their antimicrobial resistance profiles. Of these, 314 neonates with sepsis were included. The incidence of neonatal sepsis was 4% (314/8382), and the mortality was 12.7% (40/314); late-onset sepsis (65.3%) was more frequent than early-onset sepsis (34.7%). Staphylococcus epidermidis was the most frequently isolated bacterium in neonates with sepsis (both early- and late-onset). Gram-positive bacteria, such as Staphylococcus hominis and Enterococcus faecium, were associated with early-onset sepsis, whereas fungi, particularly Candida albicans, were associated with late-onset sepsis. Of the microorganisms, 52.6% were multidrug resistant (MDR), 10.8% were extensively drug resistant (XDR), and 5.5% were pan-drug resistant (PDR). Low birth weight, prematurity, cesarean section, mechanical ventilation, tachycardia, and low hemoglobin and platelet levels, among others, were associated with XDR or MDR microorganisms. In contrast, low birth weight, mechanical ventilation, stroke, unexpected delivery, respiratory distress, tachycardia, convulsive crisis, high procalcitonin, urea, and AST/TGO levels, among others, were associated with mortality. The incidence, types of sepsis, antimicrobial resistance, and associations identified in this study will aid in diagnosing neonatal sepsis earlier and may reduce mortality in our region. Full article

Background and purpose: Perforator stroke (PS) is a subtype of perinatal arterial ischemic stroke (PAIS), in which injuries occur in the territory of the perforator branches of the main cerebral arteries. This study aims to explore the incidence, timing, risk factors, and clinical presentation of PS in both preterm and full-term neonates. Material and methods: We retrospectively analyzed data about all the neonatal brain MRIs carried out in our hospital from March 2012 to March 2023. Criterium of inclusion was the radiologically confirmed diagnosis of perforator stroke involving one or more arterial districts. Results: A total of 1928 patients underwent brain MRIs during the period considered. PAIS was present in 50 patients, of which 19 had PS (38%). Among the patients with PS, nine were preterm babies (47%), and six suffered from perinatal asphyxia (31.5%). PS cUS diagnosis preceded MRI diagnosis in 88% of preterm babies. The mean age at cUS diagnosis was 20 ± 7 days. Preterm babies were often asymptomatic, whereas term babies showed neurological symptoms (mainly seizures). The outcome was favorable as long as PS was isolated. Conclusions: PS is surprisingly frequent among PAIS. It represents the most common form of PAIS in preterm babies and in babies suffering from birth asphyxia. Prenatal and perinatal factors suggesting a possible thromboembolic etiology leading to PAIS are rare in our population of preterm babies, in which the diagnosis was always preceded by negative cUS. These assumptions suggest a postnatal development of PS in premature babies more than a perinatal one. Full article

Background/Objectives: The Hammersmith Infant Neurological Examination (HINE) is a standardized neurologic exam for infants between 2 and 24 months. Scores can be compared to optimality cutoffs as one component to support an early diagnosis of cerebral palsy (CP). Some prognosis is also possible for infants diagnosed with CP. We aimed to understand the longitudinal trajectories of HINE scores in infants who were ultimately diagnosed with CP. Methods: Clinical records were reviewed for children who were diagnosed with CP in two high-risk infant follow-up clinics with HINE scores from at least two visits between the corrected ages of 3 months and 2 years. Trajectories were calculated individually and by group for infants in four categories—term neonatal hypoxic ischemic encephalopathy (HIE), term perinatal arterial ischemic stroke (PAIS), premature infants with brain injury, and “Other” (term infants with congenital malformations and/or congenital hydrocephalus). The changes in HINE scores between clinic visits were compared using linear mixed-effect models with a random intercept, pulling data by diagnostic group across visits and accounting for within-child correlations of scores over the follow-up time. Results: The changes in HINE scores for sixty children (twenty-five with prematurity, eighteen with HIE, seven with PAIS, and ten in the other category) were assessed. The linear mixed-effect models indicated that the infants with PAIS had an estimated 10.8-point increase in total HINE scores after 9 months of age compared to earlier assessments (95% CI [2.5, 19.2]. There was no statistically significant improvement in the scores among the infants in the other brain injury groups. The infants with PAIS had an estimated 2.9-point increase in HINE asymmetry scores after 9 months of age compared to prior visits (95% CI [0.7, 5.1]). None of the other diagnostic categories had statistically significant increases in asymmetry scores over time. Conclusions: The children with PAIS with resultant hemiplegia showed increasing HINE scores throughout the first two years of life. In contrast, the HINE scores remained stable for those children with term HIE, prematurity-associated brain injury, and congenital malformations and/or congenital hydrocephalus diagnosed with CP. Tracking individual changes (or stability) in HINE scores can aid diagnosis, inform prognosis, and guide the design of clinical trials targeting neurologic injury. Full article

Background/Objectives: Ischemic arterial stroke (AIS) is a cerebrovascular event that can occur acutely within the first hours or days of life, presenting as a neurological emergency. To date, clearly defined genetic risk factors for AIS have not been established, although certain genes involved in cerebrovascular regulation mechanisms are suspected to play a role. The Interferon Regulatory Factor 6 (IRF6) gene is a transcription factor involved in craniofacial and epidermal development. Recently, pathogenic variants of IRF6 have been implicated in the cytoprotective pathway of ischemic cerebrovascular disease. The aim of this manuscript is to further support the already-reported association between IRF6 and AIS. Materials and Methods: Genetic counseling and exome sequencing analysis were conducted for diagnostic purposes. Results: We report the case of a female newborn with palatoschisis, cleft palate, sensorineural deafness, facial dysmorphisms, and cutaneous defects who suffered an ischemic stroke in the territory of the left middle cerebral artery on day 1 of life. Family and pregnancy histories revealed no identifiable risk factors, and coagulation studies were normal. Exome sequencing identified a de novo c.1124T>C (p.Phe375Ser) variant in the IRF6 gene. The child developed right spastic hemiplegia and began motor rehabilitation therapy. Recently, a genome-wide association study (GWAS) using m6A-SNPs identified a statistical association between AIS and a single nucleotide polymorphism (SNP) that influences the expression of the IRF6 gene as an expression quantitative trait locus (eQTL). Conclusions: To our knowledge, this is the first report of neonatal ischemic stroke in a child carrying a de novo IRF6 pathogenic variant, further supporting its potential role as a genetic factor influencing cerebrovascular events. Further studies are needed to elucidate the precise relationship between IRF6 and AIS. Full article

Pediatric stroke, a significant cause of long-term neurological deficits in children, often arises from disruptions within neurovascular unit (NVU) components. The NVU, a dynamic ensemble of astrocytes, endothelial cells, pericytes, and microglia, is vital for maintaining cerebral homeostasis and regulating vascular brain development. Its structural integrity, particularly at the blood–brain barrier (BBB), depends on intercellular junctions and the basement membrane, which together restrict paracellular transport and shield the brain from systemic insults. Dysfunction in this intricate system is increasingly linked to pediatric stroke and related cerebrovascular conditions. Mutations disrupting endothelial cell adhesion or pericyte–endothelial interactions can compromise BBB stability, leading to pathological outcomes such as intraventricular hemorrhage in the germinal matrix, a hallmark of vascular brain immaturity. Additionally, inflammation, ferroptosis, necroptosis, and autophagy are key cellular processes influencing brain damage and repair. Excessive activation of these mechanisms can exacerbate NVU injury, whereas targeted therapeutic modulation offers potential pathways to mitigate damage and support recovery. This review explores the cellular and molecular mechanisms underlying NVU dysfunction, BBB disruption, and subsequent brain injury in pediatric stroke. Understanding the interplay between genetic mutations, environmental stressors, and NVU dynamics provides new insights into stroke pathogenesis. The susceptibility of the germinal matrix to vascular rupture further emphasizes the critical role of NVU integrity in early brain development. Targeting inflammatory pathways and cell death mechanisms presents promising strategies to preserve NVU function and improve outcomes for affected neonates. Full article

Background/Objectives: Examining hemodynamic changes during the early transition period aids in identifying variations in neonatal outcomes linked to ante- or intrapartum events. It facilitates the recognition of potential impacts stemming from common intrapartum management practices. The current literature provides scant insights into cardio-circulatory changes during the crucial first 10 min after birth. The application of Electrical Cardiometry (EC) emerges as a valuable noninvasive clinical tool for measuring neonatal hemodynamics. This prospective cohort study aimed to assess hemodynamic variables, including heart rate (HR), stroke volume index (SVI), index of contractility (ICON), and cardiac output index (COI) during the first hour of life in late preterm and full-term infants. Additionally, this study investigated the relationship between the mode of delivery and cardiovascular adaptation. Methods: Two hundred infants, encompassing both full-term and preterm, were enrolled, with categorization into four groups based on mode of delivery and gestational age. Hemodynamic variables were continuously evaluated using an EC device throughout the first hour of life. Findings: A significant decreasing trend was observed in HR, SVI, COI, and ICON over the first hour of life (p < 0.001). Infants delivered vaginally exhibited significantly higher HR, COI, SVI, and ICON compared to those born via Cesarean section (CS) (p = 0.006 and <0.001 and 0.035 and 0.001, respectively). Conclusions: This study highlights a consistent decreasing trend in HR, SVI, COI, and ICON over the first hour of life in both full-term and preterm infants. Notably, hemodynamic variables exhibited heightened levels in infants delivered vaginally compared to those born by CS. Full article

(1) Introduction. Eclampsia is a rare complication that can occur during pregnancy and has a significant impact on maternal and neonatal outcomes. The aim of this study was to investigate the risk factors associated with significant maternal morbidity after an eclamptic seizure. (2) Methods. An observational retrospective study was performed in three maternity hospitals in Romania between 2015 and 2023 and included pregnant patients diagnosed with eclampsia. Clinical and paraclinical data were investigated, and the impact of several risk factors was assessed using multiple logistic regression analysis. The results were reported as risk ratios (RRs) and 95% confidence intervals (Cis). (3) Results. A total of 104 patients with preeclampsia, of whom 23 experienced eclamptic seizures, were included in this study. A total of 82.6% of the patients diagnosed with eclampsia experienced a form of significant morbidity (stroke, PRES syndrome, or any organ failure/dysfunction). Our regression analysis revealed that advanced maternal age (RR: 12.24 95% CI: 4.29–36.61, p = 0.002), the presence of thrombotic disorders (RR: 9.17, 95% CI: 3.41–23.70, p = 0.03), obesity (RR: 4.89, 95% CI: 0.78–18.15, p = 0.036), and smoking status (RR: 2.18, 95% CI: 0.13- 6.51, p = 0.042) significantly increase the risk of maternal comorbidities. (4) Conclusions. Careful monitoring of pregnant patients, adequate weight control during pregnancy, and correct anticoagulation of individual patients could reduce the extent of postpartum comorbidities that can result from an eclamptic seizure. Full article

A 16-year-old patient, while an infant, incurred right-sided hemiparesis and had difficulty breast feeding. She was later diagnosed with a neonatal stroke and her genetic testing showed a missense mutation in her PROS1 (Protein S) gene. Both her grandfather and father, but not her mother, had hereditary Protein S (PS) deficiency. The patient was not prescribed any mediation due to her young age but was frequently checked by her physician. The patient’s plasma was first collected at the age of 13, and the isolated plasma from the patient and her father were analyzed by aPTT, thrombin generation, and enzyme-linked immunosorbent assays. These analyses showed low PS activity and clotting time associated with the missense mutation in the PROS1 gene. During the COVID-19 pandemic, the patient received her first Pfizer vaccination dose in 2021, followed by a booster dose in 2022. The plasma samples were collected 8 weeks post-immunization, after which her clotting parameters had improved for up to 6 months following vaccination. The patient’s plasma showed a significant reduction in thrombin generation and an improved aPTT clotting time. Mass spectrometry analysis revealed that her antithrombin-III level was significantly higher post-vaccination, and both thrombin and FXII levels were significantly lowered compared with her father. To our knowledge, this is the first report to document that COVID-19 vaccination can lower the risk of thrombosis in a patient with inherited thrombophilia. Although the effect was observed on a single mutation, it would be interesting to investigate the effect of COVID-19 vaccinations on other thrombophilia. Full article

Dextro-transposition of the great arteries (D-TGA) is a critical congenital heart defect that can impact neurodevelopment due to cerebral perfusion and oxygenation disorders followed by alterations in synaptogenesis, gyrification, sulcation, and the microstructure. Brain injuries can occur both pre-operatively and postoperatively, especially white matter injuries, neuronal loss, and stroke. Materials and Methods: In a retrospective study conducted at a tertiary center between 2016 and 2023, we investigated the early effects of Prostaglandin E1 (PGE1) administration and balloon atrial septostomy (BAS) on cerebral blood flow and oxygenation in inborn neonates with D-TGA. Cerebral Doppler Ultrasound in the anterior cerebral artery (ACA) was performed to assess the resistive index (RI), Peak Systolic Velocity (PSV), and End-Diastolic Velocity (EVD) before PGE1, before the BAS procedure, and 24 h after birth. Cerebral regional saturations of oxygen (crSO₂) and cerebral fractional tissue oxygen extraction (cFTOE) were evaluated. D-TGA patients were divided into the PGE1 group and the PGE1 + BAS group. Age-matched healthy controls were used for comparison. Results: All 83 D-TGA newborns received PGE1 within two hours after delivery, of whom 46 (55.42%) underwent BAS. In addition, 77 newborns composed the control group. PGE1 administration increased crSO₂ from 47% to 50% in the PGE1 group, but lower than in controls at 24 h of life, while cFTOE remained elevated. The RI increased 24 h after delivery (0.718 vs. 0.769; p = 0.000002) due to decreased EDV (10.71 vs. 8.74; p < 0.0001) following PGE1 treatment. The BAS procedure resulted in a significant increase in crSO₂ from 42% to 51% at 24 h of life in the PGE1 + BAS group. Doppler parameters exhibited a similar trend as observed in the PGE1 group. Conclusions: PGE1 treatment and BAS are lifesaving interventions that may improve cerebral perfusion and oxygenation in newborns with D-TGA during the transition period, as reflected by increasing SpO₂ and crSO₂. Full article

Cerebral palsy (CP) is a common neurodevelopmental disorder characterized by pronounced motor dysfunction and resulting in physical disability. Neural precursor cells (NPCs) have shown therapeutic promise in mouse models of hypoxic-ischemic (HI) perinatal brain injury, which mirror hemiplegic CP. Constraint-induced movement therapy (CIMT) enhances the functional use of the impaired limb and has emerged as a beneficial intervention for hemiplegic CP. However, the precise mechanisms and optimal application of CIMT remain poorly understood. The potential synergy between a regenerative approach using NPCs and a rehabilitation strategy using CIMT has not been explored. We employed the Rice–Vannucci HI model on C57Bl/6 mice at postnatal day (PND) 7, effectively replicating the clinical and neuroanatomical characteristics of hemiplegic CP. NPCs were transplanted in the corpus callosum (CC) at PND21, which is the age corresponding to a 2-year-old child from a developmental perspective and until which CP is often not formally diagnosed, followed or not by Botulinum toxin injections in the unaffected forelimb muscles at PND23, 26, 29 and 32 to apply CIMT. Both interventions led to enhanced CC myelination and significant functional recovery (as shown by rearing and gait analysis testing), through the recruitment of endogenous oligodendrocytes. The combinatorial treatment indicated a synergistic effect, as shown by newly recruited oligodendrocytes and functional recovery. This work demonstrates the mechanistic effects of CIMT and NPC transplantation and advocates for their combined therapeutic potential in addressing hemiplegic CP. Full article

Background: Alzheimer’s disease (AD) is a neurodegenerative disease characterized by beta-amyloid (Aβ) deposition and increased acetylcholinesterase (AchE) enzyme activities. Indole 3 carbinol (I3C) and diindolylmethane (DIM) are reported to have neuroprotective activities against various neurological diseases, including ischemic stroke, Parkinson’s disease, neonatal asphyxia, depression, stress, neuroinflammation, and excitotoxicity, except for AD. In the present study, we have investigated the anti-AD effects of I3C and DIM. Methods: Docking and molecular dynamic studies against AchE enzyme and network pharmacological studies were conducted for I3C and DIM. I3C and DIM’s neuroprotective effects against self and AchE-induced Aβ aggregation were investigated. The neuroprotective effects of I3C and DIM against Aβ-induced neurotoxicity were assessed in SH-S5Y5 cells by observing cell viability and ROS. Results: Docking studies against AchE enzyme with I3C and DIM show binding efficiency of −7.0 and −10.3, respectively, and molecular dynamics studies revealed a better interaction and stability between I3C and AchE and DIM and AchE. Network pharmacological studies indicated that I3C and DIM interacted with several proteins involved in the pathophysiology of AD. Further, I3C and DIM significantly inhibited the AchE (IC₅₀: I3C (18.98 µM) and DIM (11.84 µM)) and self-induced Aβ aggregation. Both compounds enhanced the viability of SH-S5Y5 cells that are exposed to Aβ and reduced ROS. Further, I3C and DIM show equipotential neuroprotection when compared to donepezil. Conclusions: Our findings indicate that both I3C and DIM show anti-AD effects by inhibiting the Aβ induced neurotoxicity and AchE activities. Full article

Background: Neonatal cerebral stroke includes a range of focal and multifocal ischemic and hemorrhagic brain lesions, occurring in about one of 3000 live births. More than 50% of children with neonatal stroke develop adverse outcomes, mainly unilateral cerebral palsy. Asymmetries in segmental movements at three months have been proven to be an early sign of CP in infants with unilateral brain damage. Recognition of additional early signs could enhance prognostic assessment and enable an early and targeted intervention. Aim: The aim of the study was to assess early signs of CP in infants with arterial cerebral stroke through the General Movements Assessment and the Motor Optimality Score—Revised (MOS-R). Method: Twenty-four infants born at term (12 females and 12 males) diagnosed with ACS, and 24 healthy infants (16 females and 8 males) were assessed. The GMs (fidgety movements) and MOS-R were assessed from videos recorded at 11–14 weeks of post-term age. Cognitive and motor outcomes were assessed at 24 months using the Griffiths III developmental quotient and Amiel-Tison neurological examination. The gross motor function classification system expanded and revised (GMFCS-E&R) was adopted to categorize CP. Results: Among infants with ACS, 21 (87.5%) developed unilateral CP. Most of them showed non-disabling CP (14 had GMFCS-E&R grade 1 [66.6%], 6 grade 2 [28.6%], and 1 grade 5 [4.8%]). Fidgety movements (FMs) were absent in 17 (70.8%), sporadic in 4 (16.7%) infants, and normal in 3 (12.5%). Segmental movement asymmetry was found in 22/24 (91.7%). According to the MOS-R, motor items (kicking, mouth movements), postural patterns (midline centered head, finger posture variability), and movement character (monotonous and stiff) were statistically different among infants with ACS and healthy infants. The MOS-R median global score was lower in the group with ACS compared to the control group (6 vs 26; p < 0.01). FMs, segmental movement asymmetry, and MOS-R global score were significantly correlated with abnormal outcome. MOS-R global scores less than or equal to 13 had 100% specificity and sensitivity in predicting GMFCS-E&R grade ≥ 2 CP in infants with ACS. Conclusions: The rate of CP was high among infants with ACS, but in most cases it showed low GMFCS-E&R grades. The study highlighted a significant correlation between MOS-R, together with absent FMs and unilateral CP in infants with ACS. Moreover, the MOS-R showed high sensitivity and specificity in the prediction of CP. Combined assessment of FMs and MOS-R could help to better identify infants at high risk of developing UCP in a population of infants with ACS. Early identification of precocious signs of unilateral CP is fundamental to providing an early individualized intervention. Full article

Chronic hypertension is a major risk factor for preeclampsia (PE), associated with significant maternal and neonatal morbidity. We previously demonstrated that pregnant stroke-prone spontaneously hypertensive rats (SHRSP) display a spontaneous PE-like phenotype with distinct placental, fetal, and maternal features. Here, we hypothesized that supplementation with alpha lipoic acid (ALA), a potent antioxidant, during early pregnancy could ameliorate the PE phenotype in this model. To test this hypothesis, timed pregnancies were established using 10 to 12-week-old SHRSP females (n = 19–16/group), which were assigned to two treatment groups: ALA (injected intraperitoneally with 25 mg/kg body weight ALA on gestation day (GD1, GD8, and GD12) or control, receiving saline following the same protocol. Our analysis of maternal signs showed that ALA prevented the pregnancy-dependent maternal blood pressure rise (GD14 blood pressure control 169.3 ± 19.4 mmHg vs. 146.1 ± 13.4 mmHg, p = 0.0001) and ameliorated renal function, as noted by the increased creatinine clearance and improved glomerular histology in treated dams. Treatment also improved the fetal growth restriction (FGR) phenotype, leading to increased fetal weights (ALA 2.19 ± 0.5 g vs. control 1.98 ± 0.3 g, p = 0.0074) and decreased cephalization indexes, indicating a more symmetric fetal growth pattern. This was associated with improved placental efficiency, decreased oxidative stress marker expression on GD14, and serum soluble fms-like tyrosine kinase 1 (sFlt1) levels on GD20. In conclusion, ALA supplementation mitigated maternal signs and improved placental function and fetal growth in SHRSP pregnancies, emerging as a promising therapy in pregnancies at high risk for PE. Full article