Necrostatin-1s Suppresses RIPK1-driven Necroptosis and Inflammation in Periventricular Leukomalacia Neonatal Mice.

Periventricular leukomalacia (PVL), a predominant form of brain injury in preterm survivors, is characterized by hypomyelination and microgliosis and is also the major cause of long-term neurobehavioral abnormalities in premature infants. Receptor-interacting protein kinase 1 (RIPK1) plays a pivotal role in mediating cell death and inflammatory signaling cascade. However, very little is known about the potential effect of RIPK1 in PVL and the underlying mechanism. Herein, we found that the expression level of RIPK1 was drastically increased in the brain of PVL neonatal mice models, and treatment of PVL neonatal mice with Necrostatin-1s (Nec-1s), an inhibitor of RIPK1, greatly ameliorated cerebral ischemic injury, exhibiting an increase of body weights, reduction of cerebral infarct size, neuronal loss, and occurrence of necrosis-like cells, and significantly improved the long-term abnormal neurobehaviors of PVL. In addition, Nec-1s significantly suppressed hypomyelination and promoted the differentiation of oligodendrocyte precursor cells (OPCs), as demonstrated by the increased expression levels of MBP and Olig2, the decreased expression level of GPR17, a significant increase in the number of CC-1-positive cells, and suppression of myelin ultrastructure impairment. Moreover, the mechanism of neuroprotective effects of Nec-1s against PVL is closely associated with its suppression of the RIPK1-mediated necrosis signaling molecules, RIPK1, PIPK3, and MLKL. More importantly, inhibition of RIPK1 could reduce microglial inflammatory injury by triggering the M1 to M2 microglial phenotype, appreciably decreasing the levels of M1 marker CD86 and increasing the levels of M2 markers Arg1 or CD206 in PVL mice. Taken together, inhibition of RIPK1 markedly ameliorates the brain injury and long-term neurobehavioral abnormalities of PVL mice through the reduction of neural cell necroptosis and reversing neuroinflammation.

Impaired glymphatic system revealed by DTI-ALPS in cerebral palsy due to periventricular leukomalacia: relation with brain lesion burden and hand dysfunction.

PURPOSE: Preterm children with cerebral palsy (CP) often have varying hand dysfunction, while the specific brain injury with periventricular leukomalacia (PVL) cannot quite explain its mechanism. We aimed to investigate glymphatic activity using diffusion tensor image analysis along the perivascular space (DTI-ALPS) method and evaluate its association with brain lesion burden and hand dysfunction in children with CP secondary to PVL. METHODS: We retrospectively enrolled 18 children with bilateral spastic CP due to PVL and 29 age- and sex-matched typically developing controls. The Manual Ability Classification System (MACS) was used to assess severity of hand dysfunction in CP. A mediation model was performed to explore the relationship among the DTI-ALPS index, brain lesion burden, and the MACS level in children with CP. RESULTS: There were significant differences in the DTI-ALPS index between children with CP and their typically developing peers. The DTI-ALPS index of the children with CP was lower than that of the controls (1.448 vs. 1.625, P = 0.003). The mediation analysis showed that the DTI-ALPS index fully mediated the relationship between brain lesion burden and the MACS level (c' = 0.061, P = 0.665), explaining 80% of the effect. CONCLUSION: This study provides new insights into the neural basis of hand dysfunction in children with CP, demonstrating an important role of glymphatic impairment in such patients. These results suggest that PVL might affect hand function in children with CP by disrupting glymphatic drainage.

Clinical characteristics and long-term neurodevelopmental outcomes of leukomalacia in preterm infants and term infants: a cohort study.

BACKGROUND: Leukomalacia is a serious form of neonatal brain injury that often leads to neurodevelopmental impairment, and studies on neonatal leukomalacia and its long-term outcomes are lacking. The aim of this study was to analyze the clinical manifestations, imaging features, and long-term neurodevelopmental outcomes in preterm infants and term infants with leukomalacia. METHODS: Newborns diagnosed with leukomalacia by head magnetic resonance imaging (MRI) and who were admitted to intensive care units from January 2015 to June 2020 were enrolled. All infants were followed up to June 2022 (2-7 years old), and their neurodevelopmental outcomes were evaluated. The clinical data and long- term outcomes of preterm infants and term infants was analyzed by Chi-square tests. RESULTS: A total of 218 surviving infants with leukomalacia including 114 preterm infants and 104 term infants completed the follow-up. The major typesof leukomalacia on MRI were periventricular leukomalacia in the preterm group and subcortical cystic leukomalacia in the term group, respectively (χ2 = 55.166; p < 0.001). When followed up to 2-7 years old, the incidence of neurodevelopmental impairment in the preterm group and term group was not significantly different (χ2 = 0.917; p = 0.338). However, the incidence of cerebral palsy (CP) in the preterm group was significantly higher (χ2 = 4.896; p = 0.027), while the incidence of intellectual disability (ID) (χ2 = 9.445; p = 0.002), epilepsy (EP) (χ2 = 23.049; p < 0.001), and CP combined with ID andEP (χ2 = 4.122; p = 0.042) was significantly lower than that in the term group. CONCLUSIONS: Periventricular leukomalacia mainly occurred in preterm infants while subcortical cystic leukomalacia was commonly seen in term infants. Although the long-term neurodevelopmental outcomes of leukomalacia were both poor, preterm infants were more prone to CP, while term infants were more prone to ID, EP, and the combination of CP with ID and EP.

Acute Diffusion-Weighted Imaging Signaling Severe Periventricular Leukomalacia in Preterm Infants: Case Report and Review of Literature.

Introduction: Periventricular leukomalacia occurs in up to 25% of very preterm infants resulting in adverse neurodevelopmental outcomes. In its acute phase, periventricular leukomalacia is clinically silent. Although ultrasonography is widely available, its sensitivity in the early detection of periventricular leukomalacia is low. Case Report and Published Literature: We identified a preterm infant with early diffusion-weighted imaging changes that later evolved to periventricular leukomalacia. Thirty-two cases of abnormal diffusion-weighted imaging reliably heralding severe periventricular leukomalacia in the preterm infant have been published in the literature. Notable features include the following: (1) infants were more mature preterm infants (29-36 weeks' gestation); (2) findings were often serendipitous with benign clinical courses; (3) diffusion-weighted imaging changes only were evident in the first weeks of life with later evolution to more classical abnormalities on conventional magnetic resonance imaging (MRI) or ultrasonography. Conclusion: Diffusion-weighted imaging in the first week of life may be a reliable early marker of severe periventricular leukomalacia injury in more mature preterm infants.

A screening method for visual attention disabilities in cerebral palsy with periventricular leukomalacia.

PURPOSE: Patients with periventricular leukomalacia (PVL) have been reported to have a variety of complications; however, whether these involve impaired visual attention disabilities remains unclear. Therefore, this study aimed to investigate the presence or absence and degree of visual attention disabilities in patients with PVL and propose a screening test that would allow anyone to check for visual attention disabilities easily. METHODS: The study participants were 14 patients with PVL and seven controls with dyskinetic cerebral palsy. All participants performed three types of visual attention tasks: spatial attention tasks, feature-based attention tasks, and object-based attention tasks. The participants also performed counting tasks to determine how many squares of the same size and color could be counted (up to nine). Receiver operating characteristic analysis was used to calculate cutoff values, with disability as the objective variable and the value of the counting task as the explanatory variable. RESULTS: The results revealed that patients with PVL often had visual attention disabilities, as indicated by a significant reduction in tasks requiring divided attention. Visual attention disabilities could be detected by a score of ≤8 in the square counting task. CONCLUSIONS: These findings suggest that family members and teachers of patients with PVL can easily screen for visual attention disabilities at home and school to improve mobility precautions in patients with this disability.

The Impact of Intraventricular Hemorrhage and Periventricular Leukomalacia on Mortality and Neurodevelopmental Outcome in Very Preterm and Very Low Birthweight Infants: A Prospective Population-based Cohort Study.

OBJECTIVE: To survey the incidence of intraventricular hemorrhage (IVH) and periventricular leukomalacia (PVL) by gestational age and to report the impact on mortality and neurodevelopmental outcome in very preterm/very low birthweight infants. STUDY DESIGN: This was a population-based cohort study of 1927 very preterm/very low birthweight infants born in 2014-2016 and admitted to Flemish neonatal intensive care units. Infants underwent standard follow-up assessment until 2 years corrected age with the Bayley Scales of Infant and Toddler Development and neurological assessments. RESULTS: No brain lesion was present in 31% of infants born at <26 weeks of gestation and 75.8% in infants born at 29-32 weeks of gestation. The prevalence of low-grade IVH/PVL (grades I and II) was 16.8% and 12.7%, respectively. Low-grade IVH/PVL was not related significantly to an increased likelihood of mortality, motor delay, or cognitive delay, except for PVL grade II, which was associated with a 4-fold increase in developing cerebral palsy (OR, 4.1; 95% CI, 1.2-14.6). High-grade lesions (III-IV) were present in 22.0% of the infants born at <26 weeks of gestational and 3.1% at 29-32 weeks of gestation, and the odds of death were ≥14.0 (IVH: OR, 14.0; 95% CI, 9.0-21.9; PVL: OR, 14.1; 95% CI, 6.6-29.9). PVL grades III-IV showed an increased odds of 17.2 for motor delay and 12.3 for cerebral palsy, but were not found to be associated significantly with cognitive delay (OR, 2.9; 95% CI, 0.5-17.5; P = .24). CONCLUSIONS: Both the prevalence and severity of IVH/PVL decreased significantly with advancing gestational age. More than 75% of all infants with low grades of IVH/PVL showed normal motor and cognitive outcome at 2 years corrected age. High-grade PVL/IVH has become less common and is associated with adverse outcomes.

Placental fetal vascular malperfusion, neonatal neurologic morbidity, and infant neurodevelopmental outcomes: a systematic review and meta-analysis.

OBJECTIVE: This study aimed to evaluate the association of placental fetal vascular malperfusion lesions with neonatal brain injury and adverse infant neurodevelopmental outcomes. DATA SOURCES: PubMed and Medline, Scopus, and Cochrane databases were searched from inception to July 2022. STUDY ELIGIBILITY CRITERIA: We included cohort and case-control studies reporting the associations of fetal vascular malperfusion lesions with neonatal encephalopathy, perinatal stroke, intracranial hemorrhage, periventricular leukomalacia, and infant neurodevelopmental and cognitive outcomes. METHODS: Data were analyzed by including fetal vascular malperfusion lesions as an exposure variable and brain injuries or neurodevelopmental impairment as outcomes using random-effects models. The effect of moderators, such as gestational age or study type, was assessed by subgroup analysis. Study quality and risk of bias were assessed by applying the Observational Study Quality Evaluation method. RESULTS: Out of the 1115 identified articles, 26 were selected for quantitative analysis. The rates of neonatal central nervous system injury (neonatal encephalopathy or perinatal stroke) in term or near-term infants were more common among fetal vascular malperfusion cases (n=145) than among controls (n=1623) (odds ratio, 4.00; 95% confidence interval, 2.72-5.90). In premature deliveries, fetal vascular malperfusion lesions did not influence the risk of intracranial hemorrhage or periventricular leukomalacia (odds ratio, 1.40; 95% confidence interval, 0.90-2.18). Fetal vascular malperfusion-associated risk of abnormal infant neurodevelopmental outcome (314 fetal vascular malperfusion cases and 1329 controls) was modulated by gestational age being higher in term infants (odds ratio, 5.02; 95% confidence interval, 1.59-15.91) than in preterm infants (odds ratio, 1.70; 95% confidence interval, 1.13-2.56). Abnormal infant cognitive development and mental development were more common among fetal vascular malperfusion cases (n=241) than among controls (n=2477) (odds ratio, 2.14; 95% confidence interval, 1.40-3.27). The type of study (cohort vs case-control) did not influence the association between fetal vascular malperfusion and subsequent infant brain injury or abnormal neurodevelopmental outcome. CONCLUSION: The findings of cohort and case-control studies indicate a considerable association between fetal vascular malperfusion placental lesions and increased risk of brain injury in term neonates, and neurodevelopmental impairment in both term and preterm infants. A diagnosis of placental fetal vascular malperfusion should be taken into consideration by both pediatricians and neurologists during the follow-up of infants at risk of adverse neurodevelopmental outcomes.

Predictors of Risk for Cerebral Palsy: A Review.

PURPOSE: To identify the earliest predictors of risk for diagnosis of cerebral palsy (CP). METHODS: A comprehensive literature search was conducted using various databases. The publications were reviewed to identify risk factors for CP from conception to early infancy. Studies were critically appraised with Joanna Briggs Institute guidelines for quality appraisal and evaluated for risk of bias using the Agency for Health Care Research and Quality guidelines. RESULTS: The initial search yielded 129 studies and 20 studies were included. Forty-seven risk factors for CP were extracted of which several were duplicate terms. The significant risk factors found to be indicative of CP were low birth weight (<1500 g), birth at less than 28 weeks of gestational age, periventricular leukomalacia, grade 3 or 4 intraventricular hemorrhage, preeclampsia, prematurity, an Apgar score of less than 4 at the first minute, birth asphyxia, preterm premature rupture of membrane, and absent fidgety movements. CONCLUSION: Twenty-three factors were consistently reported as predictors of CP.

Use of Thalamus L-Sign to Differentiate Periventricular Leukomalacia From Neurometabolic Disorders.

PURPOSE: To assess the diagnostic value of the thalamus L-sign on magnetic resonance imaging (MRI) in distinguishing between periventricular leukomalacia and neurometabolic disorders in pediatric patients. METHODS: In this retrospective study, clinical and imaging information was collected from 50 children with periventricular leukomalacia and 52 children with neurometabolic disorders. MRI was used to evaluate the L-sign of the thalamus (ie, injury to the posterolateral thalamus) and the lobar distribution of signal intensity changes. Age, sex, gestational age, and level of Gross Motor Function Classification System (only for periventricular leukomalacia) constituted the clinical parameters. Statistical evaluation of group differences for imaging and clinical variables were conducted using univariable statistical methods. The intra- and inter-observer agreement was evaluated using Cohen's kappa. Univariable or multivariable logistic regression was employed for selection of variables, determining independent predictors, and modeling. RESULTS: The thalamus L-sign was observed in 70% (35/50) of patients in the periventricular leukomalacia group, but in none of the patients with neurometabolic disorder (P < .001). The gestational age between groups varied significantly (P < .001). Involvement of frontal, parietal, and occipital lobes differed significantly between groups (P < .001). In the logistic regression, the best model included negative thalamus L-sign and gestational age, yielding an area under the curve, accuracy, sensitivity, specificity, and precision values of 0.995, 96.1%, 96%, 96.2%, and 96%, respectively. Both the lack of thalamus L-sign and gestational age were independent predictors (P < .001). CONCLUSIONS: The thalamus L-sign and gestational age may be useful in distinguishing between periventricular leukomalacia and neurometabolic disorders.

Improved Myelination following Camp Leg Power, a Selective Motor Control Intervention for Children with Spastic Bilateral Cerebral Palsy: A Diffusion Tensor MRI Study.

BACKGROUND AND PURPOSE: Children with spastic cerebral palsy have motor deficits associated with periventricular leukomalacia indicating WM damage to the corticospinal tracts. We investigated whether practice of skilled lower extremity selective motor control movements would elicit neuroplasticity. MATERIALS AND METHODS: Twelve children with spastic bilateral cerebral palsy and periventricular leukomalacia born preterm (mean age, 11.5 years; age range, 7.3-16.6 years) participated in a lower extremity selective motor control intervention, Camp Leg Power. Activities promoted isolated joint movement including isokinetic knee exercises, ankle-controlled gaming, gait training, and sensorimotor activities (3 hours/day, 15 sessions, 1 month). DWI scans were collected pre- and postintervention. Tract-Based Spatial Statistics was used to analyze changes in fractional anisotropy, radial diffusivity, axial diffusivity, and mean diffusivity. RESULTS: Significantly reduced radial diffusivity (P < . 05) was found within corticospinal tract ROIs, including 28.4% of the left and 3.6% of the right posterior limb of the internal capsule and 14.1% of the left superior corona radiata. Reduced mean diffusivity was found within the same ROIs (13.3%, 11.6%, and 6.6%, respectively). Additionally, decreased radial diffusivity was observed in the left primary motor cortex. Additional WM tracts had decreased radial diffusivity and mean diffusivity, including the anterior limb of the internal capsule, external capsule, anterior corona radiata, and corpus callosum body and genu. CONCLUSIONS: Myelination of the corticospinal tracts improved following Camp Leg Power. Neighboring WM changes suggest recruitment of additional tracts involved in regulating neuroplasticity of the motor regions. Intensive practice of skilled lower extremity selective motor control movements promotes neuroplasticity in children with spastic bilateral cerebral palsy.

The validity of hospital diagnostic and procedure codes reflecting morbidity in preterm neonates born <32 weeks gestation.

OBJECTIVE: To determine the validity of diagnostic hospital billing codes for complications of prematurity in neonates <32 weeks gestation. STUDY DESIGN: Retrospective cohort data from discharge summaries and clinical notes (n = 160) were reviewed by trained, blinded abstractors for the presence of intraventricular hemorrhage (IVH) grades 3 or 4, periventricular leukomalacia (PVL), necrotizing enterocolitis (NEC), stage 3 or higher, retinopathy of prematurity (ROP), and surgery for NEC or ROP. Data were compared to diagnostic billing codes from the neonatal electronic health record. RESULTS: IVH, PVL, ROP and ROP surgery had strong positive predictive values (PPV > 75%) and excellent negative predictive values (NPV > 95%). The PPVs for NEC (66.7%) and NEC surgery (37.1%) were low. CONCLUSION: Diagnostic hospital billing codes were observed to be a valid metric to evaluate preterm neonatal morbidities and surgeries except in the instance of more ambiguous diagnoses such as NEC and NEC surgery.

Long-term analysis of adrenocorticotropic hormone monotherapy for infantile epileptic spasms syndrome with periventricular leukomalacia.

PURPOSE: Infantile epileptic spasms syndrome (IESS) with periventricular leukomalacia (PVL) has a poor neurological prognosis. Adrenocorticotropic hormone (ACTH) and vigabatrin therapies are the recommended first-line treatments for IESS. However, ACTH monotherapy for IESS with PVL has not been studied in detail. We analysed long-term outcomes of ACTH monotherapy for IESS with PVL. METHODS: We retrospectively examined 12 patients with IESS and PVL at Saitama Children's Medical Center between January 1993 and September 2022. We evaluated seizure outcomes 3 months post-ACTH therapy and at the last visit. We also assessed electroencephalography findings and developmental outcomes. A positive response was defined as complete remission of epileptic spasms, no other seizure types, and hypsarrhythmia resolution post-ACTH therapy. RESULTS: The median onset age of epileptic spasms was 7 (range: 3-14) months. The median age at initiation of ACTH therapy was 9 (7-17) months. Seven of 12 patients (58.3%) showed a positive response. The median age at the last visit was 5 years and 6 months (1 year and 5 months-22 years and 2 months). At the last visit, only 2 of 7 initial responders remained seizure-free who demonstrated normal electroencephalography findings within 1-month post-ACTH therapy. Patients with epileptic discharge in the parieto-occipital region within 1-month post-ACTH therapy showed relapse of epileptic spasms or other seizure types. CONCLUSION: Patients having epileptic discharge in the parietal or occipital regions on electroencephalography within 1-month post-ACTH therapy may be at a high risk of epileptic spasm recurrence or other seizure types in the long term.

Factors associated with the development of epilepsy in very low birth weight infants.

BACKGROUND: The survival rate of very low birth weight (VLBW) infants has recently improved. However, the occurrence of and factors associated with epilepsy in VLBW infants remain unknown. This study aimed to clarify the incidence, characteristics, and factors associated with epilepsy development in VLBW infants. METHODS: All VLBW infants admitted to our hospital between 2012 and 2017 were included in this study. VLBW infants with a follow-up period of <1 year were excluded. Chromosomal abnormalities, brain anomalies, severe intraventricular hemorrhage (IVH), cystic periventricular leukomalacia (PVL), and hypoxic ischemic encephalopathy (HIE) were considered to be risk factors. RESULTS: Epilepsy occurred in 21/526 (4.0%) VLBW infants. Chromosomal abnormalities, brain anomalies, severe IVH, cystic PVL, HIE, neonatal seizures, advanced maternal age, maternal diabetes mellitus, no administration of antenatal corticosteroids, and low Apgar scores at 1 and 5 min were associated with a risk of epilepsy. The median time to epilepsy onset was 8 months (range: 0-59 months), and the onset occurred within 2 years in 15/21 patients (71.4%) and within 4 years in 18/21 patients (85.7%). VLBW infants with risk factors developed epilepsy earlier and at a significantly higher rate than those without risk factors. Among infants who had risk factors and who developed epilepsy, 86.7% did so within 2 years of age, compared to 33.3% of those who developed epilepsy but did not have risk factors. CONCLUSION: These findings regarding factors associated with a risk of development of epilepsy and temporal feature of epilepsy may contribute to the development of monitoring and treatment protocols for epilepsy in VLBW infants.

Association of Cystic Periventricular Leukomalacia and Postnatal Epilepsy in Very Preterm Infants.

INTRODUCTION: Cystic periventricular leukomalacia (PVL) is the most common white matter injury and a common cause of cerebral palsy in preterm infants. Postnatal epilepsy may occur after cystic PVL, but their causal relationship remains uncertain. Our aim was to validate the contribution of cystic PVL to postnatal epilepsy in very preterm infants and demonstrate their seizure characteristics. METHODS: This prospective cohort study enrolled 1,342 preterm infants (birth weight <1,500 g and gestational age <32 weeks) from 2003 to 2015. Cystic PVL was diagnosed by serial cerebral ultrasound, and other comorbidities were recorded during hospitalization. Neurological developments and consequences, including epilepsy, were serially accessed until the age of 5. RESULTS: A total of 976 preterm infants completed a 5-year neurological follow-up; 47 (4.8%) had cystic PVL. Preterm infants with cystic PVL were commonly associated with other comorbidities, including necrotizing enterocolitis stage III, neonatal seizures, and intraventricular hemorrhage during hospitalization. At age 5, 14 of the 47 (29.8%) preterm infants with cystic PVL had postnatal epilepsy. After adjusting for gender, gestational age, and three common comorbidities, cystic PVL was an independent risk factor for postnatal epilepsy (adjust OR: 16.2; 95% CI: 6.8-38.4; p < 0.001). Postnatal epilepsy after cystic PVL was commonly the generalized type (13 of 14, 92.9%), not intractable and most occurred after 1 year of age. DISCUSSION/CONCLUSION: Cystic PVL would independently lead to postnatal epilepsy. Preterm infants with cystic PVL are at risk of postnatal epilepsy after age 1 in addition to cerebral palsy.

Incidence of Cerebral Palsy, Risk Factors, and Neuroimaging in Northeast Mexico.

BACKGROUND: Cerebral palsy (CP) comprises a group of lifelong motor and postural development disorders that can cause static motor encephalopathy. The etiology of CP is attributed to nonprogressive lesions of the central nervous system during fetal or infant brain development. A diagnosis of CP is based on a combination of clinical and neurological signs, typically identified between 12 and 24 months. A medical history, several available standardized tools, including the Neoneuro assessment, and the Hammersmith infant neurological examination (HINE) can be used to predict risk. Magnetic resonance imaging (MRI) can contribute to the diagnosis of CP. The incidence of CP is 2 to 3 per 1000 live births, and in Western industrialized nations, it is 2.0-2.5 per 1000 live births; to our knowledge, no epidemiological studies have reported the incidence of CP in Mexico. AIM: To assess the incidence of CP in children aged up to 18 months in northeast Mexico and analyze the risk factors and neuroimaging findings. METHODS: This was a multicenter, randomized, prospective, cohort, analytical study of newborn children in three community hospitals and an early intervention and CP center in Nuevo Leon, Mexico, from 2017 to 2021. This study included 3861 newborns randomly selected from a population of 75,951 mothers in the immediate puerperium. According to the Neoneuro tool, high-risk children (n = 432) had abnormal neurological results at birth; they were followed and assessed with the Spanish version of the HINE test by a pediatric neurologist and underwent neuroimaging studies. Neonates with normal results were randomly selected to be in the low-risk group (n= 864). These neonates were followed and assessed with the HINE by a neonatologist. RESULTS: The incidence of CP was 4.4 of 1000 up to 18 months old, which was higher than that reported in developed countries. Perinatal risk factors were predominantly recognized in the etiology of CP, such as brain hemorrhage, and prematurity, in addition to congenital anomalies. The most frequent neuroimaging findings were ventricular dilation/cortical atrophy and intraventricular/subependymal hemorrhage and periventricular leukomalacia on MRI. CONCLUSIONS: This study is the first on the incidence/prevalence of CP in Mexico, and there are no formal studies in this field in other Latin American countries either. The incidence of CP in northeast Mexico is higher than that reported in developed countries. The follow-up of high-risk young children must be reinforced in the Mexican population, as children with disabilities have high and sequential health-care needs and may usually be lost to follow-up. Neuroimaging of PVL was the more frequent finding by MRI in this population.

Inhibition of Microglial Activation by Delayed Mild Hypothermia Reduced Preoligodendrocyte Injury in a Neonatal Rat Brain Slice Model.

Periventricular leukomalacia (PVL), characterized by distinctive form of white matter injury, often arises after neonatal cardiac surgery. Proven therapies for PVL are absent. In this study, we designed to quest therapeutic effects of delayed mild hypothermia on PVL and its mechanism in a neonatal rat brain slice model. With the increase of delayed mild hypothermia-treating time, the reduced expression of myelin basic protein and loss of preoligodendrocytes were significantly attenuated after oxygen-glucose deprivation. In addition, the proportion of ionized calcium binding adapter molecule 1 (Iba-1)-positive cells and the expression of Iba-1 were apparently reduced with the increased duration of mild hypothermia treatment. Furthermore, the levels of tumor necrosis factor alpha and interleukin-6 reduced after the mild hypothermia treatment relative to the control. Inhibition of microglial activation with prolonged mild hypothermia may be a potential strategy for white matter protection during cardiopulmonary bypass and hypothermic circulatory arrest.

Late-onset sepsis in very preterm infants in Norway in 2009-2018: a population-based study.

OBJECTIVE: To evaluate epidemiology and outcomes among very preterm infants (<32 weeks' gestation) with culture-positive and culture-negative late-onset sepsis (LOS). DESIGN: Cohort study using a nationwide, population-based registry. SETTING: 21 neonatal units in Norway. PARTICIPANTS: All very preterm infants born 1 January 2009-31 December 2018 and admitted to a neonatal unit. MAIN OUTCOME MEASURES: Incidences, pathogen distribution, LOS-attributable mortality and associated morbidity at discharge. RESULTS: Among 5296 very preterm infants, we identified 582 culture-positive LOS episodes in 493 infants (incidence 9.3%) and 282 culture-negative LOS episodes in 282 infants (incidence 5.3%). Extremely preterm infants (<28 weeks' gestation) had highest incidences of culture-positive (21.6%) and culture-negative (11.1%) LOS. The major causative pathogens were coagulase-negative staphylococci (49%), Staphylococcus aureus (15%), group B streptococci (10%) and Escherichia coli (8%). We observed increased odds of severe bronchopulmonary dysplasia (BPD) associated with both culture-positive (adjusted OR (aOR) 1.7; 95% CI 1.3 to 2.2) and culture-negative (aOR 1.6; 95% CI 1.3 to 2.6) LOS. Only culture-positive LOS was associated with increased odds of cystic periventricular leukomalacia (cPVL) (aOR 2.2; 95% CI 1.4 to 3.4) and severe retinopathy of prematurity (ROP) (aOR 1.8; 95% CI 1.2 to 2.8). Culture-positive LOS-attributable mortality was 6.3%, higher in Gram-negative (15.8%) compared with Gram-positive (4.1%) LOS, p=0.009. Among extremely preterm infants, survival rates increased from 75.2% in 2009-2013 to 81.0% in 2014-2018, p=0.005. In the same period culture-positive LOS rates increased from 17.1% to 25.6%, p<0.001. CONCLUSIONS: LOS contributes to a significant burden of disease in very preterm infants and is associated with increased odds of severe BPD, cPVL and severe ROP.

Visual impairment and periventricular leukomalacia in children: A systematic review.

BACKGROUND: Thanks to Magnetic Resonance Imaging (MRI) it is now possible to diagnose lesions of the central nervous system (CNS) such as periventricular leukomalacia (PVL) from the first days of life. However, there are still few studies aimed at describing the relationship between MRI and the outcome of visual function in patients with PVL. AIM: To systematically review and investigate the relationship between MRI neuroimaging and visual impairment arising from PVL. METHODS AND PROCEDURES: Three electronic databases (PubMed, SCOPUS, Web of Science) were consulted from 15 June 2021-30 September 2021. Of the 81 records identified, 10 were selected for the systematic review. The STROBE Checklist was used to assess the quality of the observational studies. OUTCOME AND RESULTS: PVL on MRI was found to have a strong association with visual impairment in the various aspects of visual function (visual acuity, ocular motility, visual field); in 60% of these articles, the selected subjects also reported damage to optical radiations. CONCLUSION AND IMPLICATIONS: there is a clear need for more extensive and detailed studies on the correlation between PVL and visual impairment, in order to set up a personalized early therapeutic-rehabilitation plan. WHAT THIS PAPER ADDS?: Over the past decades numerous studies have reported increasing evidence that one of the most frequent sequelae in subjects with PVL, in addition to motor impairment, is the impairment of visual function even if it is still not clear what different authors mean with the term visual impairment. This systematic review presents an overview of the relationship between structural correlates of MRI and visual impairment in children with periventricular leukomalacia. Interesting correlations emerge between MRI radiological finding and consequences on visual function especially between damage to the periventricular white matter and the impairment of various aspects of visual function and also between the impairment of optical radiation and visual acuity. Thanks to this literature revision, it is now clear that MRI plays an important role in the screening and diagnosis of significant intracranial brain changes in very young children in particular about the outcome of visual function. This is of great relevance since that visual function represents one of the main adaptive functions in the development of the child.

Intracranial ultrasound abnormalities and mortality in preterm infants with and without fetal growth restriction stratified by fetal Doppler study results.

OBJECTIVE: To evaluate whether fetal growth restriction (FGR) with or without abnormal Dopplers is associated with intracranial abnormalities and death in premature infants. STUDY DESIGN: Premature infants with and without FGR born between 2016 and 2019 were included. Primary outcome was death, severe intraventricular hemorrhage (IVH) or periventricular leukomalacia (PVL). Groups were compared using standard bivariate testing and multivariable regression. RESULTS: Among 168 FGR and 560 non-FGR infants, FGR infants with abnormal Dopplers had an increased incidence of death, severe IVH or PVL compared to non-FGR infants (13% (16/123) vs. 7% (41/560); p = 0.03) while FGR infants with normal Dopplers had a nonsignificant decrease. In a logistic regression model, FGR with abnormal Dopplers was associated with more than three times higher odds of death, severe IVH or PVL (OR 3.2, 95% CI 1.54,6.49; p < 0.001). CONCLUSIONS: Growth-restricted infants with abnormal Dopplers had an increased risk of death, intracranial abnormalities, and prematurity-related morbidities.

Dystonia in individuals with spastic cerebral palsy and isolated periventricular leukomalacia.

AIM: To determine the prevalence of dystonia in individuals with periventricular leukomalacia (PVL) and spastic cerebral palsy (CP), but without basal ganglia and thalamic injury (BGTI) on brain magnetic resonance imaging (MRI). METHOD: This was a retrospective study of individuals with spastic CP and PVL on MRI evaluated between 2005 and 2018 in a CP center. Individuals with non-PVL brain lesions on MRI, including BGTI, were excluded. Dystonia was assessed via blinded review of neurological exam videos by pediatric movement disorders specialists. RESULTS: Eighty-five participants (45 males, 40 females; mean age at videotaping 12 years [standard deviation 5 years 6 months], range 4-26 years) met inclusion and exclusion criteria. Of these participants, 50 (59%) displayed dystonia in their exam videos. The most common locations of dystonia were the fingers and hip adductors. The prevalence of dystonia was unaffected by the gestational age or severity of PVL, and was affected by Gross Motor Function Classification System level. INTERPRETATION: Dystonia is common in individuals with spastic CP and PVL, even without BGTI on MRI. Our findings suggest vigilance for dystonia in individuals with spastic CP should remain high, even without MRI evidence of BGTI. WHAT THIS PAPER ADDS: Individuals with spastic cerebral palsy and isolated periventricular leukomalacia on magnetic resonance imaging commonly display dystonia. Common sites of dystonia are in the fingers and hip adductors.