Perinatal Insults Research Articles

Spinal Anaesthesia for Lower Limb Orthopaedic Surgery in a Child with Spastic Cerebral Palsy

Cerebral palsy (CP) refers to a spectrum of nonprogressive neurological disorders with disturbances in posture and movement, resulting from perinatal intrauterine insult to developing infant brain. Many conditions associated with CP require surgery. Such cases pose important gastrointestinal, respiratory, and other perioperative considerations. Anaesthetic management in these cases is delicate. Intraoperative complications including hypovolemia, hypothermia, muscle spasms, seizures, and delayed recovery might complicate the anaesthetic management. A thorough preanesthetic evaluation allows for a better intra- and post-operative care. Perioperative analgesia is important, particularly in orthopaedic surgeries one for pain relief. Here, we have discussed the successful management of a case of spastic CP for orthopaedic lower limb surgery.

Pediatric pulmonary vascular disease associated with perinatal insults

Pediatric pulmonary vascular disease associated with perinatal insults

Precision medicine for developmental and epileptic encephalopathies in Africa—strategies for a resource-limited setting

PurposeSub-Saharan Africa bears the highest burden of epilepsy worldwide. A presumed proportion is genetic, but this etiology is buried under the burden of infections and perinatal insults in a setting of limited awareness and few options for testing. Children with developmental and epileptic encephalopathies (DEEs) are most severely affected by this diagnostic gap in Africa, because the rate of actionable findings is highest in DEE-associated genes. MethodsWe tested 234 genetically naive South African children diagnosed with/possible DEE using gene panels, exome sequencing, and chromosomal microarray. Statistical comparison of electroclinical features in children with and children without candidate variants was performed to identify characteristics most likely predictive of a positive genetic finding. ResultsOf the 41 (of 234) children with likely/pathogenic variants, 26 had variants supporting precision therapy. Multivariate regression modeling highlighted neonatal or infantile-onset seizures and movement abnormalities as predictive of a positive genetic finding. We used this, coupled with an emphasis on precision medicine outcomes, to propose the pragmatic “Think-Genetics” strategy for early recognition of a possible genetic etiology. ConclusionOur findings emphasize the importance of an early genetic diagnosis in DEE. We designed the Think-Genetics strategy for early recognition, appropriate interim management, and genetic testing for DEE in resource-constrained settings.

Cerebral palsy and related neuromotor disorders: Overview of genetic and genomic studies.

Cerebral palsy (CP) is a debilitating condition characterized by abnormal movement or posture, beginning early in development. Early family and twin studies and more recent genomic investigations clearly demonstrate that genetic factors of major effect contribute to the etiology of CP. Most copy number variants and small alterations of nucleotide sequence that cause CP arise as a result of de novo mutations, so studies that estimate heritability on basis of recurrence frequency within families substantially underestimate genetic contributions to the etiology. At least 4% of patients with typical CP have disease-causing CNVs, and at least 14% have disease-causing single nucleotide variants or indels. The rate of pathogenic genomic lesions is probably more than twice as high among patients who have atypical CP, i.e., neuromotor dysfunction with additional neurodevelopmental abnormalities or malformations, or with MRI findings and medical history that are not characteristic of a perinatal insult. Mutations of many different genetic loci can produce a CP-like phenotype. The importance of genetic variants of minor effect and of epigenetic modifications in producing a multifactorial predisposition to CP is less clear. Recognizing the specific cause of CP in an affected individual is essential to providing optimal clinical management. An etiological diagnosis provides families an "enhanced compass" that improves overall well-being, facilitates access to educational and social services, permits accurate genetic counseling, and, for a subset of patients such as those with underlying inherited metabolic disorders, may make precision therapy that targets the pathophysiology available. Trio exome sequencing with assessment of copy number or trio genome sequencing with bioinformatics analysis for single nucleotide variants, indels, and copy number variants is clinically indicated in the initial workup of CP patients, especially those with additional malformations or neurodevelopmental abnormalities.

Childhood movement disorders: Clinicoetiological pattern and long-term follow-up at tertiary care center from South India.

Movement disorders are common neurological problems. There is a considerable delay in the diagnosis of movement disorders which indirectly indicates their under-recognition. The studies regarding relative frequencies and their underlying etiology are limited. Describing and classifying them with a diagnosis helps in treating the condition. To study the clinical pattern of various movement disorders in children and to establish their etiology and outcome. This observational study was conducted in tertiary care hospital from January 2018 to June 2019. Children from 2 mo. to 18 years of age presenting with involuntary movements on the first Monday of every week were included in the study. History and clinical examination were carried out with a pre-designed proforma. A diagnostic workup was done, results were analyzed to find the common movement disorders and their etiology, and follow-up was analyzed for 3 years. A total of 100 cases out of 158 with known etiology were included in the study of which 52% were females and 48% were males. The mean age at presentation was 3.15 years. The various movement disorders are dystonia-39(39%), choreoathetosis-29(29%), tremors-22(22%), gratification reaction-7(7%), and shuddering attacks-4(4%). Ballismus and myoclonus were found in 3(3%) children each. Tics, stereotypes, and hypokinesia were found in 2(2%) children each. A total of 113 movement disorders were found in 100 children. Etiologically, perinatal insult was the most common cause 27(27%), followed by metabolic/genetic/hereditary causes 25(25%). Infantile tremor syndrome due to Vitamin B12 deficiency-16/22(73%), was a major contributor in children with tremors. Rheumatic chorea was less in our study 5(5%). Out of the 100 study subjects, 72 cases were followed up. Out of which 26 children have completely recovered. Based on the modified Rankins score(MRS), 7 children belong to category I, 2 children belong to category II, 1 child to category III, 6 children to category IV, and 14 children to category V of MRS. A total of 16 children have died (MRS VI). Perinatal insult and Infantile tremor syndrome are more important and preventable causes. Rheumatic chorea is found to be less common. A significant number of children had more than one type of movement disorder, which warrants the need to look for varied types of movement disorders in the same child. Long-term follow-up shows complete recovery in one-fourth of children and the remaining surviving with disability.

Epileptic spasms: A South African overview of aetiologies, interventions, and outcomes.

To better understand the aetiologies of epileptic spasms in infants, as well as the safety and efficacy of high dose corticosteroids in tuberculosis and human immunodeficiency virus (HIV) endemic resource-limited settings. This was a retrospective analysis of infants with epileptic spasms managed at the tertiary referral centres in the Western Cape, South Africa. Of 175 children with epileptic spasms, the median age at onset was 6 months (interquartile range 4-8 months). Structural aetiologies were most common (115 out of 175 [66%]), with two-thirds related to perinatal insults. A lead time to treatment (LTTT) of less than 1 month was more likely in the epileptic encephalopathy/developmental and epileptic encephalopathy (DEE) group: 58 out of 92 (63%), compared to 28 out of 76 (37%) of those with developmental encephalopathy (p=0.001). Failure to recognize preceding developmental delay was common. Ninety-nine children (57%) received first line hormonal therapy such as adrenocorticotropic hormone. A total of 111 out of 172 children (65%) from the developmental encephalopathy and epileptic encephalopathy/DEE groups had clinical and/or electroencephalogram resolution of spasms within 14 days. In our population, children in whom an aetiology could not be identified were statistically more likely to have moderate to profound developmental delay at 1 year of age: 33 out of 44 (p=0.001). Based on reported incidence of epileptic spasms, 23 to 58 cases per annum would be expected but a far smaller proportion presented to our centres. Whilst this is the largest cohort of infants with epileptic spasms from sub-Saharan Africa, the study size is less than expected; this may reflect misdiagnosis and failure of referral pathways. Despite a reported shorter LTTT, infants with DEE had worse developmental outcomes compared to international studies. Hormonal therapy was safe and effective in our setting, despite exposure to high levels of tuberculosis and HIV. The number of unreferred cases of epileptic spasms in South Africa remains high. Caregivers and health care workers in primary care facilities often fail to recognize developmental delay. The burden of disease from hypoxic-ischaemic encephalopathy remains high in our resource-limited setting. Hormonal treatment (e.g. adrenocorticotropic hormone) was safe and effective despite the high prevalence of human immunodeficiency virus and tuberculosis.

Early Plasma Magnesium in Near-Term and Term Infants with Neonatal Encephalopathy in the Context of Perinatal Asphyxia.

Magnesium ions are implicated in brain functioning. The disruption of brain metabolism subsequent to a perinatal hypoxic-ischaemic insult may be reflected by plasma magnesium. Infants at 36 weeks after birth or later with neonatal encephalopathy and who were admitted to our neonatal unit from 2011 to 2019 were retrospectively included. The kinetics of plasma magnesium were investigated for the first 72 h of life and correlated to the Barkovich MRI score. Among the 125 infants who met the inclusion criteria, 45 patients (36%) had moderate to severe brain lesions on neonatal MRI. Plasma magnesium values were not strongly associated with the severity of clinical encephalopathy, initial EEG background and brain lesions. Intriguingly, higher plasma magnesium values during the 0–6 h period were linked to the presence of brain injuries that predominated within the white matter (p < 0.001) and to the requirement of cardiac resuscitation in the delivery room (p = 0.001). The occurrence of seizures was associated with a lower mean magnesium value around the 24th hour of life (p = 0.005). This study supports that neonatal encephalopathy is a complex and multifactorial condition. Plasma magnesium could help to better identify the subtypes of neonatal encephalopathy. Further studies are needed to confirm these results in this prospect.

Sensorimotor development of male and female rats subjected to neonatal anoxia.

Neonatal hypoxic-ischemic encephalopathy (HIE) is one of the most important reasons for morbidity and mortality in term-born infants. HIE impacts early somatic, neurological, and motor development including social. To illustrate the damages in the sensorimotor system, an adapted and validated model of neonatal anoxia is used. This study evaluated the sex differences in Wistar rats, neurological reflex, and motor development at the suckling period. Short- and long-term impairments associated with sex differences were observed. In general, anoxic males were more affected in comparison to their control group and to anoxic females. Long-lasting effects of the injury in adolescent rats predominately affected males. Similar to previous studies, we also found a decrease in the number of the substantia nigra cells in both sexes, compared to their control. So far, the results indicate that HIE caused neurobehavioral alterations and asymmetrical motor behavior with brain damage, possibly related to cognitive impairments previously observed at adolescence. These alterations may represent a useful endpoint for studying the efficacy of potential strategies that may improve the developmental consequences of a perinatal asphyxia insult in humans.

The effect of sulforaphane on perinatal hypoxic-ischemic brain injury in rats.

Perinatal hypoxic-ischemic insult (HII) is one of the main devastating causes of morbidity and mortality in newborns. HII induces brain injury which evolves to neurological sequelae later in life. Hypothermia is the only therapeutic approach available capable of diminishing brain impairment after HII. Finding a novel therapeutic method to reduce the severity of brain injury and its consequences is critical in neonatology. The present paper aimed to evaluate the effect of sulforaphane (SFN) pre-treatment on glucose metabolism, neurodegeneration, and functional outcome at the acute, sub-acute, and sub-chronic time intervals in the experimental model of perinatal hypoxic-ischemic insult in rats. To estimate the effect of SFN on brain glucose uptake we have performed 18F-deoxyglucose (FDG) microCT/PET. The activity of FDG was determined in the hippocampus and sensorimotor cortex. Neurodegeneration was assessed by histological analysis of Nissl-stained brain sections. To investigate functional outcomes a battery of behavioral tests was employed. We have shown that although SFN possesses a protective effect on glucose uptake in the ischemic hippocampus 24 h and 1 week after HII, no effect has been observed in the motor cortex. We have further shown that the ischemic hippocampal formation tends to be thinner in HIE and SFN treatment tends to reverse this pattern. We have observed subtle chronic movement deficit after HII detected by ladder rung walking test with no protective effect of SFN. SFN should be thus considered as a potent neuroprotective drug with the capability to interfere with pathophysiological processes triggered by perinatal hypoxic-ischemic insult.

Perinatal hypoxia aggravates occlusive pulmonary vasculopathy in SU5416/hypoxia-treated rats later in life.

Pulmonary arterial hypertension (PAH) is a fatal disease, which is characterized by occlusive pulmonary vascular disease (PVD) in small pulmonary arteries. It remains unknown whether perinatal insults aggravate occlusive PVD later in life. We tested the hypothesis that perinatal hypoxia aggravates PVD and survival in rats. PVD was induced in rats with/without perinatal hypoxia (embryonic day 14 to postnatal day 3) by injecting SU5416 at 7 wk of age and subsequent exposure to hypoxia for 3 wk (SU5416/hypoxia). Hemodynamic and morphological analyses were performed in rats with/without perinatal hypoxia at 7 wk of age (baseline rats, n = 12) and at 15 wk of age in 4 groups of rats: SU5416/hypoxia or control rats with/without perinatal hypoxia (n = 40). Pulmonary artery smooth muscle cells (PASMCs) from the baseline rats with/without perinatal hypoxia were used to assess cell proliferation, inflammation, and genomic DNA methylation profile. Although perinatal hypoxia alone did not affect survival, physiological, or pathological parameters at baseline or at the end of the experimental period in controls, perinatal hypoxia decreased weight gain and survival rate and increased right ventricular systolic pressure, right ventricular hypertrophy, and indices of PVD in SU5416/hypoxia rats. Perinatal hypoxia alone accelerated the proliferation and inflammation of cultured PASMCs from baseline rats, which was associated with DNA methylation. In conclusion, we established the first fatal animal model of PAH with worsening hemodynamics and occlusive PVD elicited by perinatal hypoxia, which was associated with hyperproliferative, proinflammatory, and epigenetic changes in cultured PASMCs. These findings provide insights into the treatment and prevention of occlusive PVD.

Congenital muscle dystrophies: Role of singleton whole exome sequencing in countries with limited resources

AimIdentify the genetic determinants of congenital muscle dystrophy (CMD) in Jordanian children. MethodsThis prospective study included patients suspected to have CMD. Singleton whole-exome sequencing (WES) was performed as the first-tier diagnostic test. Results44 patients were included: 27 boys and 17 girls. Consanguinity was reported in 32/44 (72.7%) patients, and a positive family history in 16/44 (36.3%) patients.WES uncovered pathogenic/ likely pathogenic variants in 19/44 (43.1%) patients, variants of uncertain significance (VUS) and negative results were identified in 15/44 (34.0%) and 10/44 (22.7%) patients respectively.Variants related to CMD were identified in 23/44 (52.2%) patients; pathogenic /likely pathogenic variants were identified in 12/23 (52.1%) and VUS in 11/23 (47.8%). The most common genes were related to basal membrane/extracellular proteins followed by genes related to alpha‑dystroglycanopathies. We have identified a rare association of one family with one sibling affected by CMD and the other sibling with Duchenne muscle dystrophy. A history suggestive of perinatal insult was found in 6/23 (26.0%) patients necessitating a high index of suspicion as CMD may present as cerebral palsy mimickers.Several strong candidate VUSs were identified and need future second tier testing for confirmation.WES identified genes related to other neuromuscular and non neuromuscular disorders in 21/44 (47.7%) patients;7/21 were pathogenic/likely pathogenic and 14/21 (66.6%) were VUS. ConclusionsIn countries with limited resources singleton WES could be considered the first tier diagnostic test to limit costs.

Feasibility of Tailored Unilateral Disconnection vs Callosotomy for Refractory Epilepsy in Patients with Bilateral Parieto-Occipital Gliosis Following Perinatal Insult.

Patients with perinatal hypoxia (PH) and drug-refractory epilepsy (DRE) often have bilateral parieto-occipital gliosis. Surgical management of such patients is a dilemma. To identify preoperative determinants for unilateral disconnection vs callosotomy, and analyze the surgical outcome in such patients. This was a retrospective analysis of patients with DRE and history of PH, with MRI abnormalities restricted to bilateral posterior quadrants. Preoperative semiology, epilepsy duration and seizure frequency were recorded. Based on the concordance between the results of non-invasive tests, patients underwent either posterior quadrant disconnection (PQD) or corpus callosotomy (CC). Preoperative variables were analyzed and corelated to the postoperative seizure freedom. Fourteen patients were identified, 6 underwent PQD and 8 underwent CC. At follow up of 39.17 ± 23.75 months, 66.66% of patients (4/6) in the PQD subgroup had an ILAE Class I outcome. While none in the CC group attained seizure freedom, 87.5% (7/8) had more than 50% reduction in seizure frequency (follow up: 42 ± 27.31 months). Patients with a poor outcome had significantly greater seizure frequency (P = 0.05) and history of drop attacks (P = 0.04) in both the groups. Magnetoencephalography (MEG) accurately localized the epileptogenic zone in all of the patients with good outcome (P = 0.015). Concordance with single photon emission tomography (SPECT) was also a predictor of favorable outcome (P = 0.041). A history of drop attacks with high seizure frequency is associated with poor postoperative seizure outcome. Unilateral PQD is feasible and leads to superior seizure-free outcomes, even in cases with widespread and bilateral imaging and electrical abnormalities, provided the other preoperative investigations are concordant in localizing the epileptogenic zone.

Brain Magnetic Resonance Imaging-Based Evaluation of Pediatric Patients With Developmental Delay: A Cross-Sectional Study.

BackgroundDevelopmental delay refers to the insufficient acquisition of age-appropriate developmental milestones. According to World Health Organization, approximately 5% of all children under the age of 14 years display some developmental disability.Aim and objectiveOur objective was to investigate the prevalence of abnormal magnetic resonance imaging (MRI) brain findings in pediatric patients with non-syndromic developmental delay and to establish the utility of MRI for the same.Material and MethodThis cross-sectional study prospectively enrolled 60 pediatric patients (three months to 12 years) and data were analyzed using SPSS software.ResultAbnormalities on MRI were seen in 80% of cases, with findings indicating perinatal hypoxic insult (36.67%) being the most common, followed by structural abnormalities of the brain (20%). There was no significant difference in the prevalence of abnormal findings when classified by gender or age, or between global developmental delay (GDD) alone and GDD with epilepsy. However, perinatal hypoxic insult was significantly associated with GDD with epilepsy rather than GDD alone (p < 0.01).ConclusionIn this study, brain MRI provides a high yield of abnormal findings and helps calculate the relative prevalence of various common etiologies in non-syndromic developmental delay. This study supports several international guidelines that include MRI as the first-line investigation for non-syndromic developmental delay.

Etiological spectrum and predictors of intractability in early-onset epilepsy (3 months–2 years): A cross-sectional observational study

Abstract Introduction: Epilepsy is the most common childhood neurological illness, which occurs in four to six per 1000 children. The maximum incidence of epilepsy occurs in children less than 3 years of age. The main objective of our study was to describe the etiological spectrum, EEG, and neuroimaging abnormalities and predictors of intractability in epilepsy. Methodology: A cross-sectional observational study was conducted over a 2-year duration at Dr DY Patil Medical College, Pune, Maharashtra, India. Hundred eligible children with epilepsy aged 3months to 2 years were included in the study. Appropriate statistical test such as Chi-square test and P value has been applied. SPSS software version 23 was used in our study. Results: Out of 100 children, 45% were in the age group of 19–24 months with M:F = 1.1:1. The mean age of onset of seizure was 11.6 ± 3.3 months. The majority of children belonged to lower-middle-class families (56%). Developmental delay was seen in 50%, and 43% had refractory epilepsy. The most common seizure type was focal onset (47%), followed by generalized onset seizures (37%). EEG findings were abnormal in 66%, multifocal IEDs being the most common abnormality (54.55%). MRI brain was normal in 27 cases, and out of 73 abnormal MRIs, the most common pattern seen was changes of perinatal and postnatal insults (75.3%). There was a statistically significant correlation between the type of seizures and MRI pattern with abnormal EEG (P &lt;0.001). In 23% of children, no etiology was found, structural cause—62 (perinatal: 55; cortical malformation: 7), metabolic cause—nine, genetic etiology—six cases. The factors associated with refractory epilepsy in our cohort were the presence of developmental delay, abnormal neurological examination, abnormal EEG, and abnormal MRI (P &lt; 0.001). Conclusion: Our study described the etiological spectrum of infantile-onset epilepsy, with the most common being acquired cause because of perinatal and postnatal insult to the developing brain. Early-onset seizures have a high possibility of intractability, especially if it is associated with developmental delay, abnormal neurological examination, EEG, and neuroimaging.

Significance of Polyspikes on Electroencephalography in Children with Focal Epilepsy

Purpose: Epilepsy is one of the most common neurological disorders in both adults and children. After detailed history-taking, electroencephalography (EEG) is the most important investigation in the evaluation of epilepsy patients. Polyspikes, defined as a sequence of two or more spikes, are among the findings that can be seen on EEGs of epilepsy patients, but the literature on their significance in focal epilepsy patients is scarce. Therefore, in the current study, we investigated the significance of polyspikes on EEG in childhood focal epilepsy. Methods: A retrospective analysis was conducted of data from children who were diagnosed with focal epilepsy and received anti-seizure medications at Pusan National University Children’s Hospital. Results: Among the 1,125 children included in this study, 468 (41.6%) showed interictal polyspikes on their EEGs. In the multivariate analysis, only the presence of brain magnetic resonance imaging (MRI) abnormalities was significantly associated with the presence of interictal polyspikes on EEGs. Among patients with brain MRI abnormalities, localized polyspikes were significantly associated with focal cortical dysplasia, while multifocal polyspikes were significantly associated with perinatal insults (hypoxic-ischemic encephalopathy and destructive encephalomalacia). Conclusion: Focal epilepsy patients with interictal polyspikes were more likely to have a structural etiology. Furthermore, patients with localized polyspikes were more likely to have focal cortical dysplasia as the structural etiology, while patients with multifocal polyspikes were more likely to have perinatal insults as the structural etiology. This study demonstrates that focal polyspikes can be used as markers of the possible presence of a structural etiology in routine practice.

Clinical spectrum and neuroimaging findings in children with seizures: A five-year retrospective study.

ObjectivesSeizures are the most common neurological illness in the pediatric population and account for 1% of all emergency department (ED) visits and 2% of all visits to children’s hospital EDs. Pediatric epilepsy presents with various diagnostic challenges. Neuroimaging, especially structural neuroimaging and preferably MRI brain, plays an essential role in diagnosing, managing, and guiding pediatric epilepsy treatment.The study aimed to estimate the clinical spectrum of seizures in children and examine the neuroimaging findings in children with seizures.Materials & MethodsThe study was a hospital-based retrospective observational study. The hospital case records of all children belonging to the age group 1 month to 12 years with 'seizures' were reviewed for 5 years from Jan 2016 to Dec 2020. Clinicodemographic profiles and neuroimaging (CT/MRI) findings were obtained, and descriptive statistics were applied.ResultsA total of 838(11%) children in the age group 1 to 144 months (mean±SD: 32.57±32.65) presented with seizures, of whom 515(61.5%) were boys and 323(38.5%) girls. Of 596(71.1%) children under five years, 409(68.6%) had febrile seizures. Generalized onset-motor seizures were the predominant type of seizures seen in 666(79.4%) children, of whom 434(65.1%) had febrile seizures.Neuroimaging (CT/MRI) was normal in 335(40%) and abnormal in 124(14.8%) children. Perinatal insult (7%) was the most common abnormality, followed by CNS infections (2.8%). ConclusionNeuroimaging, preferably MRI brain, is the most helpful tool for the etiological diagnosis of afebrile seizures.In our study, seizures secondary to perinatal insult/hypoxic insult followed by infections were major causes. Improvement in peripartum and perinatal care coupled with a targeted Tuberculosis control program may help in reducing these potentially preventable causes

C3a Receptor Signaling Inhibits Neurodegeneration Induced by Neonatal Hypoxic-Ischemic Brain Injury.

Hypoxic-ischemic neonatal encephalopathy due to perinatal asphyxia is the leading cause of brain injury in newborns. Clinical data suggest that brain inflammation induced by perinatal insults can persist for years. We previously showed that signaling through the receptor for complement peptide C3a (C3aR) protects against cognitive impairment induced by experimental perinatal asphyxia. To investigate the long-term neuropathological effects of hypoxic-ischemic injury to the developing brain and the role of C3aR signaling therein, we subjected wildtype mice, C3aR deficient mice, and mice expressing biologically active C3a in the CNS to mild hypoxic-ischemic brain injury on postnatal day 9. We found that such injury triggers neurodegeneration and pronounced reactive gliosis in the ipsilesional hippocampus both of which persist long into adulthood. Transgenic expression of C3a in reactive astrocytes reduced hippocampal neurodegeneration and reactive gliosis. In contrast, neurodegeneration and microglial cell density increased in mice lacking C3aR. Intranasal administration of C3a for 3 days starting 1 h after induction of hypoxia-ischemia reduced neurodegeneration and reactive gliosis in the hippocampus of wildtype mice. We conclude that neonatal hypoxic-ischemic brain injury leads to long-lasting neurodegeneration. This neurodegeneration is substantially reduced by treatment with C3aR agonists, conceivably through modulation of reactive gliosis.

Lenticulostriate Vasculopathy in Very-Low-Birth-Weight Preterm Infants: A Longitudinal Cohort Study.

Background: The pathogenesis and clinical significance of lenticulostriate vasculopathy (LSV) are unclear. Our study aimed to determine the prevalence, presentation, and evolution of LSV, and the perinatal risk factors associated with LSV among very-low-birth-weight (VLBW) preterm infants. Methods: One-hundred-and-thirty VLBW preterm infants were retrospectively enrolled in this study. Serial cranial ultrasound examinations were performed regularly from birth until a corrected age of 1 year. Infants with LSV were assigned to early-onset (≤10 postnatal days) and late-onset (>10 postnatal days) groups. Data describing the infants’ perinatal characteristics, placental histopathology, and neonatal morbidities were collected, and the groups were compared. Results: Of the VLBW infants, 39.2% had LSV before they were 1 year old. Linear-type LSV was the most common presentation, and >50% of the infants had bilateral involvement. LSV was first detected at 112 ± 83 postnatal days, and its detection timing correlated negatively with gestational age (GA) (R2 = 0.153, p = 0.005) and persisted for 6 months on average. The infants with and without LSV had similar perinatal characteristics, placental pathologies, cytomegalovirus infection rates, and clinical morbidities. The late-onset LSV group comprised 45 (88.2%) infants who had a significantly higher rate of being small for gestational age (SGA) and used oxygen for longer than the infants without LSV. After adjusting a multivariable regression model for GA and SGA, analysis showed that the duration of oxygen usage was an independent risk factor for late-onset LSV development in VLBW infants (odds ratio: 1.030, p = 0.032). Conclusion: LSV may be a nonspecific marker of perinatal insult to the developing brains of preterm infants. Prolonged postnatal oxygen usage may predispose VLBW preterm infants to late-onset LSV development. The long-term clinical impacts of LSV should be clarified.

Abstract 9081: Fatal Occlusive Pulmonary Vasculopathy in Rats Late After Perinatal Hypoxia: Hyperproliferative and Pro-Inflammatory Phenotypes and Related Differential Dna Methylation in Cultured Pulmonary Arterial Smooth Muscle Cells as the Potential Substrate

Background: Perinatal insults increase the risk of developing various adult-onset vascular diseases. Although we recently established a fatal SU5416/hypoxia-induced model with worsening pulmonary vascular disease (PVD) in rats late after exposure to perinatal hypoxia, the mechanisms are elusive. Hypothesis: In rats with fatal occlusive PVD late after perinatal hypoxia, cultured pulmonary arterial smooth muscle cells (PASMCs) from rats before SU5416/hypoxia treatment exhibit phenotypic and epigenetic changes. Methods: PVD was induced in 7-week-old rats exposed to perinatal hypoxia or ambient air by injecting SU5416 followed by exposure to hypoxia for 3 weeks (SU5416/hypoxia). Rats were assessed at the baseline (7 weeks of age) and 8 weeks after SU5416 injection (15 weeks of age). Proliferation, cytokine production and genome-wide DNA methylation profile were evaluated in PASMC isolated from the baseline rats with/without perinatal hypoxia. Results: In SU5416/hypoxia rats, perinatal hypoxia reduced body weight gain and survival, and increased right ventricular systolic pressure, Fulton index and occlusive PVD (p&lt;.05), which were associated with an increase in perivascular macrophages, expression of prepro-endothelin-1 mRNA and eNOS protein in the lung (p&lt;.05) but not with impaired alveolarization or worsening right ventricular fibrosis. In PASMCs isolated from the baseline rats, perinatal hypoxia enhanced PDGF-BB-induced cell proliferation and phosphorylation of extracellular signal-regulated kinase as well as TNFα-induced expression of IL-6, monocyte chemotactic protein 1 and phosphorylation of p38 (p&lt;.05). DNA methylation profiling identified 35 differentially methylated regions (DMRs). Methylation in the region encoding phosducin like protein (Pdcl) was associated with decreased PDGF-BB-induced expression of Pdcl mRNA in PASMCs with perinatal hypoxia. Functional enrichment analysis of DMRs revealed the relation to cell proliferation and inflammatory process (ie, Wnt5A and ROR1). Conclusions: In SU5416/hypoxia rats late after perinatal hypoxia, hyperproliferative and pro-inflammatory phenotypes and functionally related differential DNA methylation in PASMCs may be the substrate for the fatal occlusive PVD.

Oligodendrocyte Development and Implication in Perinatal White Matter Injury.

Perinatal white matter injury (WMI) is the most common brain injury in premature infants and can lead to life-long neurological deficits such as cerebral palsy. Preterm birth is typically accompanied by inflammation and hypoxic-ischemic events. Such perinatal insults negatively impact maturation of oligodendrocytes (OLs) and cause myelination failure. At present, no treatment options are clinically available to prevent or cure WMI. Given that arrested OL maturation plays a central role in the etiology of perinatal WMI, an increased interest has emerged regarding the functional restoration of these cells as potential therapeutic strategy. Cell transplantation and promoting endogenous oligodendrocyte function are two potential options to address this major unmet need. In this review, we highlight the underlying pathophysiology of WMI with a specific focus on OL biology and their implication for the development of new therapeutic targets.