Emerging neuroprotective interventions in periventricular leukomalacia - A systematic review of preclinical studies.

INTRODUCTION: Periventricular leukomalacia (PVL) is a result of various antenatal, intrapartum, or postnatal insults to the developing brain and is an important harbinger of cerebral palsy in preterm neonates. There is no proven therapy for PVL. This calls for appraisal of targeted therapies that have been investigated in animal models to evaluate their relevance in a clinical research context. AREAS COVERED: This systematic review identifies interventions that were evaluated in preclinical studies for neuroprotective efficacy against PVL. We identified 142 studies evaluating various interventions in PVL animal models (search method is detailed in section 2). EXPERT OPINION: Interventions that have yielded significant results in preclinical research, and that have been evaluated in a limited number of clinical trials include stem cells, erythropoietin, and melatonin. Many other therapeutic modalities evaluated in preclinical studies have been identified, but more data on their neuroprotective potential in PVL must be garnered before they can be considered for clinical trials. Because most of the tested interventions had only a partial efficacy, a combination of interventions that could be synergistic should be investigated in future preclinical studies. Furthermore, since the nature and pattern of perinatal insults to preterm brain predisposing it to PVL are substantially variable, individualized approaches for the choice of appropriate neuroprotective interventions tailored to different subgroups of preterm neonates should be explored.

A gastric outlet thickened mucosal fold associated with cytomegalovirus infection in an extremely preterm infant managed by surgical resection.

Non-bilious vomiting in preterm neonates discharged from neonatal intensive care units is a common complaint and is often associated with benign conditions such as gastro-oesophageal reflux. A neonate of 27 weeks gestation who presented later with vomiting owing to gastric outlet obstruction is described. He was discharged at 11 weeks of age and required re-admission 1 week later. He had persistent non-bilious vomiting from 7 weeks of age, failure to thrive and metabolic alkalosis. Clinical examination demonstrated visible gastric peristalsis, and hypertrophic pyloric stenosis was suspected. Ultrasound of the gastric pylorus and upper gastro-intestinal contrast studies were negative. Exploratory laparotomy after failure of conservative management revealed a thickened mucosal fold in the gastric pylorus, which was excised. Histopathology demonstrated inclusion bodies which are pathognomonic of cytomegalovirus infection. He was treated with valganciclovir for 6 weeks and was asymptomatic and thriving well at follow-up. Gastric outlet obstruction can be one of the manifestations of CMV infection of the gastro-intestinal tract. Diagnosis can be confirmed only by histopathology.Abbreviations: BPD: bronchopulmonary dysplasia; CMV: cytomegalovirus; H&E: haematoxylin and eosin; IHC: immunohistochemistry; IHPS: infantile hypertrophic pyloric stenosis; NEC: necrotising enterocolitis; PCR: polymerase-chain reaction; VGP: visible gastric peristalsis.

Risk Factors for Periventricular Leukomalacia in Preterm Infants: A Systematic Review, Meta-analysis, and GRADE-Based Assessment of Certainty of Evidence.

BACKGROUND: We analyzed the certainty of evidence (CoE) for risk factors of periventricular leukomalacia (PVL) in preterm neonates, a common morbidity of prematurity. METHODS: Medline, CENTRAL, Embase, and CINAHL were searched. Cohort and case-control studies and randomised randomized controlled trials were included. Data extraction was performed in duplicate. A random random-effects meta-analysis was utilizedused. CoE was evaluated as per Grading of Recommendations Assessment, Development and Evaluation (GRADE) guidelines. RESULTS: One hundred eighty-six studies evaluating 95 risk factors for PVL were included. Of the 2,509,507 neonates assessed, 16,569 were diagnosed with PVL. Intraventricular hemorrhage [adjusted odds ratio: 3.22 (2.52-4.12)] had moderate CoE for its association with PVL. Other factors such as hypocarbia, chorioamnionitis, PPROM >48 hour, multifetal pregnancy reduction, antenatal indomethacin, lack of antenatal steroids, perinatal asphyxia, ventilation, shock/hypotension, patent ductus arteriosus requiring surgical ligation, late-onset circulatory collapse, sepsis, necrotizing enterocolitis, and neonatal surgery showed significant association with PVL after adjustment for confounders (CoE: very low to low). Amongst the risk factors associated with mother placental fetal (MPF) triad, there was paucity of literature related to genetic predisposition and defective placentation. Sensitivity analysis revealed that the strength of association between invasive ventilation and PVL decreased over time (P < 0.01), suggesting progress in ventilation strategies. Limited studies had evaluated diffuse PVL. CONCLUSION: Despite decades of research, our findings indicate that the CoE is low to very low for most of the commonly attributed risk factors of PVL. Future studies should evaluate genetic predisposition and defective placentation in the MPF triad contributing to PVL. Studies evaluating exclusively diffuse PVL are warranted.

Hypothyroxinaemia in refractory shock: a clue to diagnose hypopituitarism.

The rarity of congenital hypopituitarism (CHP) makes it essential for clinicians to be aware of its varying clinical manifestations. We report a neonate with one such unique presentation. A preterm girl baby was managed for respiratory distress. Diffuse cutis marmorata was present since birth; septic screens were positive with placental histopathology showing chorioamnionitis. Newborn screening showed low free thyroxine and normal TSH. Transient hypothyroxinaemia of prematurity was considered. Her respiratory status worsened on day 9, followed by refractory shock. She was treated for sepsis. Further evaluation for absent heart rate variability in response to vasopressor resistant shock led to the detection of hypocortisolism. Low cortisol along with hypothyroxinaemia made hypopituitarism the working diagnosis. Owing to the variable clinical spectrum of CHP, diagnosis is challenging. We highlight a few clinical and laboratory features, which would help in earlier diagnosis of CHP.

Diagnostic Dilemma of an Umbilical Mass in a Newborn Infant - a Twin or a Tumor?

BACKGROUND: We present the diagnostic dilemma of a neonate with two umbilical soft tissue masses. Case report: The baby had an umbilical mass herniating through the umbilical cord, and another mass hanging from the umbilical mass by a string of tissue. Both masses were amorphous solid soft tissues and the hanging mass had hair on the surface. Clinical diagnosis was umbilical cord teratoma. However, histopathological examination of the masses showed that tissues representing various organs were arranged in cephalocaudal order as in a fetus, revealing that it was a parasitic twin. The hanging mass was probably the cephalic part and the umbilical mass was malformed torso and limbs. Conclusion: This parasitic omphalopagus heteropagus parasitic twin presented as two amorphous masses without externally identifiable anatomic structure, The parasitic twin of omphalopagus heteropagus may have unusual presentations. Histopathological examination was essential to diagnose whether it is a twin or a tumor.

MRI at term equivalent age for predicting long-term neurodevelopmental outcome in preterm infants - a cohort study.

Purpose: Preterm infants are at increased risk of adverse neurodevelopmental outcome (NDO). Cranial ultrasound has limited predictability. The purpose of the study is to evaluate whether magnetic resonance imaging (MRI) done at term equivalent age (TEA) predicts NDO at 18-22 months of corrected gestational age (CGA).Materials and methods: This cohort study of preterm infants born at ≤32 weeks of gestation and/or birth weight <1500 grams between April 2011 and August 2012 was conducted in a tertiary care institute in India. MRI done at TEA was reported using objective scoring. NDO at 18-22-month CGA was assessed using Bayley Scale of Infant Development (BSID) version III. Composite score (CS) < 85 in motor, language, or cognition domain was taken as adverse NDO. Association between individual MRI subscores and NDO was evaluated using multiple linear regressions by backward elimination method. Validity of MRI abnormality in predicting adverse NDO was assessed.Results: Out of 94 infants who had MRI at TEA, 56 (60%) underwent BSID III. Mean gestational age was 29.8 ± 2.1 weeks. Median CS of all domains was lower with higher total MRI score. Predictive accuracy for various subscores ranged from 55 to 73%. By multiple regression analysis, signal abnormality was associated with motor delay (ß -8.4; p .02) and cystic white matter (WM) changes with motor delay (ß -7.3; p .003) and cognitive delay (ß -6.1; p .005).Conclusions: Although specificity and negative predictive value were moderate to high across all subscores in MRI to predict the NDO, the accuracy has been only low to moderate, which limits its use as sole predictor.

Meconium Peritonitis: A Rare Treatable Cause of Non-Immune Hydrops.

Meconium peritonitis as a cause of non-immune hydrops in neonates is rarely reported. Here we report such a rare occurrence. In our case, a routine antenatal scan at 25 weeks revealed isolated ascites. By 31 weeks of gestation, all features of hydrops were observed in scans. However, antenatal workup for immune and non-immune hydrops was negative. Subsequently, a preterm hydropic female baby was delivered at 32 weeks. She required intubation and ventilator support. An X-ray revealed calcification in the abdomen suggestive of meconium peritonitis. Ultrasound showed gross ascites, a giant cyst compressing the inferior vena cava, and minimal bilateral pleural effusion. Emergency laparotomy revealed meconium pellets and perforation of the ileum. Double-barrel ileostomy was performed, and the edema resolved and activity improved. The baby was discharged after 3 weeks. Ileostomy closure was done at follow-up. The baby is growing well.

Novel clinical phenotype of generalised lymphatic dysplasia in a neonate: a missed diagnosis.

We report a preterm neonate who had a large cervical cystic hygroma and right chylothorax. She was operated on day-21 and a near-complete resection of cystic hygroma was done. She developed refractory hypoxemia and shock post surgery and died after 24 hours. During autopsy, the chest cavity was found to be filled with chyle. Histopathological examination showed dilated lymphatics in the pleura, hepatic capsule, serosa of stomach and intestines, peri-pancreatic regions, peri-renal capsule and peri-adrenal tissues suggestive of generalised lymphatic dysplasia. Clinical exome sequencing did not reveal any pathogenic mutation in the genes involved in primary lymphatic dysplasia, noonan syndrome or rasopathies.

Neonate with haemophagocytic lymphohistiocytosis secondary to dengue infection: a case report.

We report the first case of haemophagocytic lymphohistiocytosis (HLH) in a neonate secondary to primary Dengue virus infection. This neonate presented in the third week of life with fever, shock and hepatosplenomegaly and was diagnosed to have Dengue infection by serology and HLH was confirmed on bone marrow.

Correlation among Magnetic Resonance Imaging Parameters of Brain in Preterm Neonates at Term Equivalent Age.

OBJECTIVES: To assess the spectrum of Magnetic Resonance Imaging (MRI) abnormalities among preterm babies at term equivalent age using objective scoring and to study the association among MRI variables. METHODS: Ninety-four preterm babies born at ≤32 wk of gestation and / or birth weight ≤ 1500 g at term equivalent age who underwent cranial MRI between April 2011 and August 2012 and the MRI interpreted by experienced radiologists were studied. In 2014, the MRI was retrospectively re-interpreted by the same radiologists using an objective scoring system described by Kidokoro. Spectrum of MRI abnormalities, their association with perinatal variables and correlation among white matter (WM), grey matter and cerebellar scores were analyzed. RESULTS: MRI abnormalities observed were WM signal abnormality (24 %), lateral ventricular dilatation (16 %), WM cystic abnormality (13 %), deep grey matter signal abnormality (9 %), cerebellar volume reduction (9 %) and deep grey matter volume reduction (8 %). Sepsis was significantly associated with occurrence of WM and cerebellar abnormalities (p < 0.05). WM scores did not show significant correlation with cortical grey matter and deep grey matter scores while cerebellar scores showed a weak positive correlation with WM (r = 0.33), cortical grey matter (r = 0.27) and deep grey matter scores (r = 0.22). CONCLUSIONS: MRI abnormalities are common in preterm infants, with 60 % showing some abnormality at term equivalent age. Among perinatal characteristics, sepsis was identified as risk factor for WM and cerebellar injury. Grey matter abnormality occurs independent of WM abnormality. Cerebellar abnormalities appear to coexist with either WM or grey matter changes.