Ten years since the introduction of therapeutic hypothermia in neonates with perinatal hypoxic-ischaemic encephalopathy in Spain.

INTRODUCTION: More than a decade has passed since therapeutic hypothermia (TH) was introduced in Spain; this is the only neuroprotective intervention that has become standard practice in the treatment of perinatal hypoxic-ischaemic encephalopathy (HIE). This article aims to provide a current picture of the technique and to address the controversies surrounding its use. DEVELOPMENT: In the last 10 years, TH has been successfully implemented in the vast majority of tertiary hospitals in Spain, and more than 85% of newborns with moderate or severe HIE currently receive the treatment. The factors that can improve the efficacy of TH include early treatment onset (first 6 h of life) and the control of comorbid factors associated with perinatal asphyxia. In patients with moderate HIE, treatment onset after 6 h seems to have some neuroprotective efficacy. TH duration longer than 72 h or deeper hypothermia do not offer greater neuroprotective efficacy, but instead increase the risk of adverse effects. Controversy persists around the sedation of patients during TH, the application of the treatment in infants with mild HIE, and its application in other scenarios. Prognostic information and time frame are one of the most challenging aspects. CONCLUSIONS: TH is universal in countries with sufficient economic resources, although certain unresolved controversies remain. While the treatment is widespread in Spain, there is a need for devices for the transfer of these patients and their centralisation.

Bedside and laboratory neuromonitoring in neonatal encephalopathy.

Several bedside and laboratory neuromonitoring tools are currently used in neonatal encephalopathy (NE) to assess 1) brain function [amplitude-integrated electroencephalogram (aEEG) and EEG], 2) cerebral oxygenation delivery and consumption [near-infrared spectroscopy (NIRS)] and 3) blood and cerebrospinal fluid biomarkers. The aim of the review is to provide the role of neuromonitoring in understanding the development of brain injury in these newborns and better predict their long-term outcome. Simultaneous use of these monitoring modalities may improve our ability to provide meaningful prognostic information regarding ongoing treatments. Evidence will be summarized in this review for each of these modalities, by describing (1) the methods, (2) the clinical evidence in context of NE both before and with hypothermia, and (3) the research and future directions.

Ten years since the introduction of therapeutic hypothermia in neonates with perinatal hypoxic-ischaemic encephalopathy in Spain. / Una década después de la implantación en España de la hipotermia terapéutica en el recién nacido con encefalopatía hipóxico-isquémica perinatal.

INTRODUCTION: More than a decade has passed since therapeutic hypothermia (TH) was introduced in Spain; this is the only neuroprotective intervention that has become standard practice in the treatment of perinatal hypoxic-ischaemic encephalopathy (HIE). This article aims to provide a current picture of the technique and to address the controversies surrounding its use. DEVELOPMENT: In the last 10 years, TH has been successfully implemented in the vast majority of tertiary hospitals in Spain, and more than 85% of newborns with moderate or severe HIE currently receive the treatment. The factors that can improve the efficacy of TH include early treatment onset (first 6hours of life) and the control of comorbid factors associated with perinatal asphyxia. In patients with moderate HIE, treatment onset after 6hours seems to have some neuroprotective efficacy. TH duration longer than 72hours or deeper hypothermia do not offer greater neuroprotective efficacy, but instead increase the risk of adverse effects. Unclarified aspects are the sedation of patients during TH, the application of the treatment in infants with mild HIE, and its application in other scenarios. Prognostic information and time frame are one of the most challenging aspects. CONCLUSIONS: TH is universal in countries with sufficient economic resources, although certain unresolved controversies remain. While the treatment is widespread in Spain, there is a need for cooling devices for the transfer of these patients and their centralisation.

[Neonatal hypoxic-ischemic encephalopathy: Incidence and prevalence in the first decade of the 21st century]. / Incidencia y prevalencia de la encefalopatía hipoxico-isquémica en la primera década del siglo xxi.

AIM: To examine the incidence and the prevalence of neonatal hypoxic-ischemic encephalopathy (HIE) in a tertiary Spanish center over a 9-year period, before the implementation of a hypothermia program. METHODS: All infants > or =34 weeks gestation, born between 2000 and 2008 with evidence of perinatal asphyxia and neonatal encephalopathy were identified. HIE was classified as mild, moderate or severe. Joinpoint regression model was used to identify changes in the trends of HIE incidences. RESULTS: A total of 90,963 live infants were born in La Paz Hospital between 2000 and 2008, and 23.3% of them (21.228) were admitted to the Neonatal Unit. In addition, 200 infants were referred from other centers. A total of 110 infants had HIE, of which 90% were inborn. The overall incidence of HIE was 1.088 per 1,000 live births, and the incidence of clinically significant HIE (moderate and severe grades) was 0.49 per 1,000 live births. The incidence of HIE showed a linear downward trend throughout the study period (slope=-5.37; P<0.05). Fifty-two neonates had moderate or severe HIE, this represents a prevalence of 2.42 per 1,000 infants admitted to the Neonatal Unit and means that 5-6 infants a year would have been candidates for therapeutic hypothermia. CONCLUSIONS: Neonatal HIE, and in particular significant HIE, is an infrequent condition. The low prevalence of HIE requires that these infants are referred to regional centers with sufficient experience in the use of therapeutic hypothermia, and in the management of all the medical problems associated with HIE.

[A guide to the clinical diagnosis and urgent treatment of neonatal hyperammonaemia]. / Guía clínica de diagnóstico y tratamiento urgente de hiperamonemia neonatal.

Symptomatic hyperammonaemia in newborn is a medical emergency that should be recognised in its early stages, specifically diagnosed and aggressively treated to improve the immediate and long-term prognosis of these children. The paediatrician and the neonatal doctor should have a diagnosis-therapy scheme for its urgent management.

[Impact of cardiopulmonary resuscitation on extremely low birth weight infants]. / Impacto de la reanimación cardiopulmonar avanzada en recién nacidos pretérmino de extremado bajo peso.

OBJECTIVE: To examine whether extremely low birth weight (ELBW) infants who undergo Cardiopulmonary Resuscitation (CPR) in the delivery room present poorer survival and greater short-term neurological and general morbidity than those who do not. METHODS: In a retrospective cohort of 150 ELBW infants born at our hospital between 2000 and 2004, those who needed CPR and those who did not were compared for mortality and short-term general and neurological morbidity. Infants with major birth defects, suspicion of genetic disease and those without a proactive perinatal attitude in the delivery room were excluded. CPR was defined as the administration of chest compressions and/or epinephrine in the delivery room. RESULTS: 150 infants were included, with gestational ages of 23-27 weeks (mean 25.6+/-1.2), birth weight of 425-995 grams (mean 745.2+/-132). Delivery room CPR was given to 32 infants (21.4%). No differences in perinatal characteristics were found except for lower pH and Apgar score and a higher SNAPPE score in infants who underwent CPR. Survival at discharge was similar (62.5% vs 76.3% for those without CPR). Infants who received CPR needed more surfactant, oxygen and higher median airway pressure than infants who did not. Air leaks and coagulopathy were more frequent in CPR infants (p<0.01). Prevalence of bronchopulmonary dysplasia, necrotizing enterocolitis and retinopathy was similar in the two groups. No statistical differences between ELBW infants who needed CPR and those who did not were found in prevalence of intraventricular haemorrhage (IVH) (62.5% vs 52.5%), IVH III (31.2% vs 17.7%), periventricular haemorrhagic infarction (PHI) (18.7% vs 11%) or cystic periventricular leucomalacia (PVL) (15.6% vs 11%). However, in a combined analysis of neurological morbidity (IVH III and/or PVL and/or PHI), significant differences between the two groups were found (46.7% vs 21.6%; p=0.01). CONCLUSION: This study does not support poorer survival or significant non-neurological morbidity during the neonatal period in ELBW infants who receive CPR. Although the prevalence of individual neurological problems was similar in the two groups, CPR was associated with a clear increase in general neurological morbidity, with a three-times greater risk of brain damage.

Cerebrospinal fluid leucocyte counts in healthy neonates.

OBJECTIVES: To determine the cerebrospinal fluid (CSF) white blood cell (WBC) count of normal term neonates, and compare the CSF WBC profile of normal and symptomatic infants without infection of the central nervous system (CNS). METHOD: Neonates were included if (a) they were at risk of congenital Toxoplasma infection and had undergone a lumbar puncture to assess CNS involvement, and (b) serial specific serum IgG and IgM determinations had ruled out congenital infection. According to neonatal chart reviews, 30 consecutive patients without CNS infection were classified as normal (absolutely asymptomatic) or symptomatic (any kind of symptoms). RESULTS: CSF WBC count was higher in 11 symptomatic (7/mm(3), 0-30/mm(3)) than in 19 normal (1/mm(3), 0-5/mm(3)) neonates (p<0.01). CONCLUSION: Normal neonatal CSF contains up to 5 WBCs/mm(3). Mild pleocytosis can be found in symptomatic infants without CNS infection.

[Clinical guide to the management of patients with Beckwith-Wiedemann syndrome]. / Guía clínica para el seguimiento de pacientes con síndrome de Beckwith-Wiedemann.

Beckwith-Wiedemann syndrome (BWS) is characterized by congenital overgrowth, macroglossia and omphalocele or umbilical hernia. Children with BWS may also have all or some of the following features: asymmetry (hemihypertrophy) of the limbs, torso or face, hypoglycemia, organomegaly, ear pits or creases, and embryonal tumors. The frequency of BWS is approximately 1:14,000 births. We present a guide for the management of children with BWS aimed at helping pediatricians and general practitioners or specialists in the clinical follow-up of these patients. This guide has been structured according to different age groups and is based on published evidence.

Infratentorial congenital glioblastoma multiforme. A rare tumour with a still unknown biology. / Glioblastoma multiforme congenito infratentorial. Un tumor excepcional con una biologia aun desconocida.

INTRODUCTION: Congenital glioblastoma multiforme represents only 3% of congenital central nervous system tumours and an infratentorial location is unusual. CASE REPORT: A newborn with congenital glioblastoma multiforme with no mutation in the TP53 gene or p53 nuclear immunoreactivity that infiltrated practically the whole brainstem and also invaded supratentorial structures. CONCLUSIONS: As far as we know, only four cases with an infratentorial location have been reported previously, three in the cerebellum and one in the brainstem. The biology of congenital glioblastoma multiforme is not well known and, unlike glioblastoma multiforme in adults and children, mutations in the TP53 gene are uncommon. However, this is not associated with a more favourable prognosis. These observations suggest that specific biological processes underlie fetal glioblastoma multiforme development.

TITLE: Glioblastoma multiforme congenito infratentorial. Un tumor excepcional con una biologia aun desconocida.Introduccion. El glioblastoma multiforme congenito representa solo el 3% de los tumores congenitos del sistema nervioso central, y su ubicacion infrantentorial es excepcional. Caso clinico. Recien nacido con un glioblastoma multiforme congenito sin mutacion en el gen TP53 ni inmunorreactividad nuclear p53, que infiltraba practicamente todo el tronco cerebral e invadia tambien estructuras supratentoriales. Conclusiones. Hasta donde sabemos, solo se han referido previamente cuatro casos de localizacion infratentorial, tres en el cerebelo y uno en el tronco del encefalo. La biologia del glioblastoma multiforme congenito no se conoce bien y, a diferencia del glioblastoma multiforme en la edad adulta, las mutaciones en el gen TP53 son poco frecuentes, sin que eso parezca implicar un mejor pronostico. Estas observaciones sugieren que el glioblastoma multiforme con origen en la vida fetal tiene una biologia diferente del que se presenta en otras etapas de la vida.

[Multicenter program for the integrated care of newborns with perinatal hypoxic-ischemic insult (ARAHIP)]. / Programa multicéntrico para la atención integral del recién nacido con agresión hipóxico-isquémica perinatal (ARAHIP).

INTRODUCTION: Newborns with perinatal indicators of a potential hypoxic-ischemic event require an integrated care in order to control the aggravating factors of brain damage, and the early identification of candidates for hypothermia treatment. PATIENTS AND METHODS: The application of a prospective, populational program that organizes and systematizes medical care during the first 6 hours of life to all newborns over 35 weeks gestational age born with indicators of a perinatal hypoxic-ischemic insult. The program includes 12 hospitals (91,217 m(2)); two level i centers, five level ii centers, and five level iii hospitals. The program establishes four protocols: a) detection of the newborn with a potential hypoxic-ischemic insult, b) surveillance of the neurological repercussions and other organ involvement, c) control and treatment of complications, d) procedures and monitoring during transport. RESULTS: From June 2011 to June 2013, 213 of 32325 newborns above 35 weeks gestational age met the criteria of a potential hypoxic-ischemic insult (7.4/1000), with 92% of them being cared for following the program specifications. Moderate-severe hypoxic-ischemic encephalopathy was diagnosed in 33 cases (1/1,000), and 31 out of the 33 received treatment with hypothermia (94%). CONCLUSIONS: The program for the Integrated Care of Newborns with Perinatal Hypoxic-Ischemic Insult has led to providing a comprehensive care to the newborns with a suspected perinatal hypoxic-ischemic insult. Aggravators of brain damage have been controlled, and cases of moderate-severe hypoxic-ischemic encephalopathy have been detected, allowing the start of hypothermia treatment within the first six hours of life. Populational programs are fundamental to reducing the mortality and morbidity of hypoxic-ischemic encephalopathy.

Neuron-specific enolase and myelin basic protein: relationship of cerebrospinal fluid concentrations to the neurologic condition of asphyxiated full-term infants.

OBJECTIVE: We questioned whether neuron-specific enolase (NSE) and myelin basic protein (MBP) concentrations in cerebrospinal fluid (CSF) in the first 72 hours of life are correlated with the neurologic condition of asphyxiated full-term infants in the neonatal period and at 1 year of age. PATIENTS AND METHODS: Sixty-nine asphyxiated infants were studied with serial neurologic examination, cranial ultrasonography, and neurologic follow-up. CSF samples were obtained by lumbar puncture at 12 and 72 hours of life. NSE was measured by enzyme immunoassay, and MBP was measured by radioimmunoassay. RESULTS: Twenty infants had no neonatal encephalopathy and 49 exhibited different stages of encephalopathy. NSE and MBP concentrations in CSF at 12 and 72 hours of life were related to the degree of neonatal encephalopathy. Neither NSE nor MBP levels were correlated with any perinatal factors. Infants with documented brain injury had the highest concentrations of both NSE and MBP. The concentrations of these two biochemical markers at both 12 and 72 hours correlated with adverse outcome (death or cerebral palsy at 1 year). Based on a receiver operating characteristics curve analysis for any given specificity, NSE at 12 hours was a more accurate marker than MBP at either 12 or 72 hours for distinguishing infants with motor impairment at age 1 year from infants with normal outcome at the same age. CONCLUSIONS: Our findings suggest that NSE and MBP are reliable biochemical markers for early estimates of hypoxic-ischemic brain damage in asphyctic full-term newborns, NSE being superior to MBP.

Early neurological manifestations and brain anomalies in Marden-Walker syndrome.

We report on an infant with the Marden-Walker syndrome. In addition to the consistent neurological abnormalities described previously in this syndrome, the infant had a striking neurological constellation, absence of primitive reflexes, jerky eye movements, failure to habituate to repeated stimuli, inadequate behavior development, and absence of orientation responses to visual or auditory stimuli. Muscle biopsy showed a similar pattern to the congenital fiber-type disproportion. Ultrasonograms and magnetic resonance imaging of his brain demonstrated absence of corpus callosum, colpocephaly, hypoplastic brainstem, hypoplasia of the inferior vermis and of the cerebellar hemispheres. These findings further delineate this syndrome and suggest that prenatal central nervous system (CNS) dysfunction, mainly of the cerebellum and brainstem, may play a significant role in the pathogenesis of the Marden-Walker syndrome.

Albinism and agenesis of the corpus callosum with profound developmental delay: Vici syndrome, evidence for autosomal recessive inheritance.

We report on two sibs and two other unrelated patients with agenesis of corpus callosum, oculocutaneous albinism, repeated infections, and cardiomyopathy. All manifested postnatal growth retardation, microcephaly, and profound developmental delay. Additional central nervous system anomalies present in at least one patient included hypoplasia of the cerebellar vermis, white matter neuronal heterotopia, or bilateral schizencephaly. Repeated viral, bacterial, and fungal infections were consistent with a primary immunodeficiency. However, immunological studies showed variable, nonspecific findings. Cardiomyopathy with progressive heart failure or infection led to death before age 2 years in three of the patients. This syndrome was first described by Vici et al. [1988: Am. J. Med. Genet. 29:1-8]. The four patients reported herein confirm this unique disorder. Affected sibs of both sexes born to unaffected parents provide evidence for autosomal recessive inheritance.

Rehospitalization because of respiratory syncytial virus infection in premature infants younger than 33 weeks of gestation: a prospective study. IRIS Study Group.

OBJECTIVE: To collect data on hospitalization for respiratory syncytial virus (RSV) infections and presumptive risk factors for rehospitalization among premature infants in Spain. DESIGN: Observational, prospective, longitudinal, multicenter study. SETTING: Fourteen Spanish neonatal units with an annual birth cohort of 57,000 infants. PATIENTS: All children (n = 680) born < or =32 weeks of gestational age between April 1, 1998, and March 31, 1999, and discharged from the hospital before March 31, 1999, were included in the study. A total of 96 were excluded because of administration of prophylactic treatment (n = 55) or were lost to follow-up (n = 41). Five children died during the study period, but death was related to RSV in only 1 case. METHODS AND MAIN OUTCOME MEASURES: Neonatal and demographic data were recorded at the initial visit. Infants were prospectively followed at monthly intervals up to March 31, 1999. In patients rehospitalized for respiratory disorders, further data about RSV status and morbidity were collected. A comparison was made between children rehospitalized for RSV infection and those who were not. The influence of factors on the probability of rehospitalization for RSV infection was assessed by logistic regression analysis. RESULTS: Of the 584 evaluable patients 118 (20.2%) were rehospitalized for respiratory disease during the study period. The causative pathogen was identified in 89 (75.4%) hospital admissions. Of these 59 (66.3%) were a result of RSV infection in 53 children; 6 were reinfections. In a logistic regression model significant independent prognostic variables included: lower risk of RSV hospitalization with increase gestational age [odds ratio (OR), 0.85; 95% confidence interval (CI), 0.72 to 0.99; P < 0.047]; higher risk with chronic lung disease (OR = 3.1; 95% CI 1.22 to 7.91; P < 0.016); and living with school age siblings (OR = 1.86; 95% CI 1.01 to 3.4; P < 0.048). CONCLUSION: This large descriptive study has enabled us to define the influence of specific risk factors that increase the risk of rehospitalization for RSV infection in preterm infants. Such studies help to define the appropriate role of available prophylactic interventions and establish treatment guidelines.

Changes in the long bones due to fetal immobility caused by neuromuscular disease. A radiographic and histological study.

The long bones in eleven newborn infants who had neuromuscular disease were studied and were found to be thin, hypomineralized, and elongated. In most of the bones, there were multiple diaphyseal or metaphyseal fractures, or both. By light microscopy, the outstanding findings were fractures through the growth plate and diaphysis and thinning of the cortices. The etiology of the fractures and the insufficient substance of the bone is the reduction in the intrauterine motion of the fetus, which leads to fragility of the bones and contractures of the joints. The severity of the alterations may have been related to the time of the onset of the abnormalities and to the duration and degree of the intrauterine akinesia.

Neural migration disorders studied by cerebral ultrasound and colour Doppler flow imaging.

Cerebral ultrasound and colour Doppler flow imaging (CDFI) were used to diagnose a wide spectrum of anomalies of cell migration (17 patients): presumed lissencephaly (n = 12); schizencephaly of both fused (n = 2) and open lips (n = 2); hemimegalencephaly (n = 1); and subependymal type grey matter heterotopia (n = 12). The patients with grey matter heterotopia had irregular ventricular margins (n = 10), periventricular hyperechogenic bands (n = 12), and/or periventricular hyperechogenic nodules (n = 7). Some patients had more than one type of migration disorder as well as other central nervous system malformations. Cerebral ultrasound diagnoses were confirmed by magnetic resonance imaging (MRI) or necropsy. It is concluded that colour Doppler flow imaging is a worthwhile addition to the assessment of brain surface anomalies.

Stroke in neonates with cardiac right-to-left shunt.

Neonatal focal cerebral arterial infarction has been rarely reported in the literature, in contrast to the watershed infarctions, which are common entities among asphyxiated infants. In neonatal postmortem series, thromboembolism was the commonest cause of cerebral arterial occlusion; the source of emboli was associated to different risk factors. Our four cases are the first alive patients reported with congenital heart disease and right-to-left shunt, who suffered a cerebral infarct with its clinical neurological correlates in the neonatal period. We assume that the most probable mechanism was paradoxical embolism, once pulmonary filter is obviated as a result of the altered hemodynamics in these patients. Our data demonstrate the value of ultrasound scanning for assessment of focal cerebral ischemic lesions. Thus, although abnormal neurological signs in this particular group of infants could be attributed to hypoxemia or specific treatments as prostaglandins, we suggest routine cerebral ultrasounds in neonates with congenital heart disease and neurological disabilities, as early complications could be not so infrequent.

Ultrasonographic findings in thalamus and basal ganglia in term asphyxiated infants.

Three severely asphyxiated term neonates demonstrated bilateral hyperechogenicity in the thalamus and basal ganglia. During evolution, areas of attenuated echogenicity appeared in these structures at the same time as periventricular cysts were evident in 2 patients with coexistent periventricular leukomalacia. All 3 patients developed ventricular dilatation; in the 2 patients with periventricular leukomalacia, the ventricular border was irregular in the outer (dorsal) margin, and interhemispheric fissures were widened as a manifestation of cerebral atrophy. Furthermore, the thalamic inner (ventral) margins of the lateral ventricles were irregular in all 3 patients. This previously unrecognized finding points to a particular form of cerebral atrophy localized in the gangliothalamic region that contributes to the development of ventriculomegaly. The reported sonographic sequence implies profound damage in the thalamus and basal ganglia in asphyxiated infants which undoubtedly has contributed to the poor outcomes of our patients.

Cerebral abnormalities in congenital myotonic dystrophy.

The brain structure of 14 infants born with congenital myotonic dystrophy at 2 hospitals was evaluated by cranial ultrasonography, and the findings were correlated with clinical and neuropathologic data. Ventricular dilation was diagnosed in 11 infants (78%). Seven infants died during the neonatal period; all had ventricular dilation which remained essentially static. In the ultrasound scans of the 5 infants with ventricular dilation. Of the 7 survivors, 4 had ventricular dilation born at 1 hospital, 4 had widening of the interhemispheric fissure. Macrocephaly, a previously unrecognized finding in congenital myotonic dystrophy, was present in 10 infants (71%), 8 of whom presented with ventricular dilation. None had clinical evidence of increased intracranial pressure. There was no ventricular obstruction in the 4 brains examined pathologically. Histologic examination revealed minor expression of neuronal migrational disturbances in each patient. Macrocephaly together with the ultrasonographic and neuropathologic findings in our patients suggest that these abnormalities may originate in an external hydrocephalus.

Natural history of ventricular dilatation in preterm infants: prognostic significance.

Cerebral ultrasounds were prospectively performed in 100 infants weighing 1,500 gm or less in order to evaluate the prognostic significance of ventricular dilatations and their associated findings. There was no difference in the incidence of ventricular dilatation (24%) between patients with or without periventricular hemorrhage (PVH). Although patients with PVH developed ventricular dilatation significantly earlier than infants without PVH, no differences were observed in severity, location, head circumference growth, or intracranial pressure between the groups. Ventricular dilatation was statistically related to PVH grade III and PVH with parenchymal involvement; grades moderate-to-severe of periventricular echogenicity; and cystic periventricular leukomalacia (PVL). Ventricular dilatation persisted longer than 6 weeks in 61% of infants and had irregular margins in 62%. The latter were significantly related to cystic PVL. Seventy-seven of 100 infants examined were followed until 20 months corrected age. Ventricular dilatation mainly when persistent and with irregular margins was associated with handicaps. We conclude that ventricular dilatation is frequent in very low-birth weight infants. Furthermore, its occurrence may be independent of PVH. Persistent ventricular dilatation with irregular margins, even in its mild forms, suggests a parenchymal lesion and guarded prognosis.