[First SIBEN clinical consensus: diagnostic and therapeutic approach to patent ductus arteriosus in premature newborns]. / Primer consenso clínico de SIBEN: enfoque diagnóstico y terapéutico del ductus arterioso permeable en recién nacidos pretérmino.

OBJECTIVE: To report the process and results of the first neonatal clinical consensus of the Ibero-American region. DESIGN AND METHODS: Two recognized experts in the field (Clyman and Van Overmeire) and 45 neonatologists from 23 countries were invited for active participation and collaboration. We developed 46 questions of clinical-physiological relevance in all aspects of patent ductus arteriosus (PDA). Guidelines for consensus process, literature search and future preparation of educational material and authorship were developed, reviewed and agreed by all. Participants from different countries were distributed in groups, and assigned to interact and work together to answer 3-5 questions, reviewing all global literature and local factors. Answers and summaries were received, collated and reviewed by 2 coordinators and the 2 experts. Participants and experts met in Granada, Spain for 4.5 h (lectures by experts, presentations by groups, discussion, all literature available). RESULTS: 31 neonatologists from 16 countries agreed to participate. Presentations by each group and general discussion were used to develop a consensus regarding: general management, availability of drugs (indomethacin vs. ibuprofen), costs, indications for echo/surgery, etc. Many steps were learnt by all present in a collaborative forum. CONCLUSIONS: This first consensus group of Ibero-American neonatologists SIBEN led to active and collaborative participation of neonatologists of 16 countries, improved education of all participants and ended with consensus development on clinical approaches to PDA. Furthermore, it provides recommendations for clinical care reached by consensus. Additionally, it will serve as a useful foundation for future SIBEN Consensus on other topics and it could become valuable as a model to decrease disparity in care and improve outcomes in this and other regions.

[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.

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.

Cerebral haemodynamics in preterm infants after exposure to dexamethasone.

AIM: To determine changes in brain haemodynamics produced by dexamethasone; to evaluate the pathophysiological conditions involved in the effect of dexamethasone. METHODS: A prospective study was made of 12 ventilated preterm infants who received dexamethasone (0.25 mg/kg/12 hours) for ongoing chronic lung disease or extubation failure. Cerebral blood flow (CBF), absolute cerebral blood volume (CBV), and cerebral blood volume changes (delta CBV) were estimated by near infrared spectroscopy, before and 10, 30, 60, 120, 180 and 240 minutes after the first, third, and fifth doses of dexamethasone. All patients were monitored continuously using pulse oximetry, transcutaneous blood gases, and blood pressure. RESULTS: There were significant short term changes in delta CBV on each day of the study; delta CBV increased significantly at 240 minutes compared with values before the first dose, and from 120 minutes onward during the third and fifth doses. However, mean CBV values averaged over 240 minutes after the first, third, and fifth doses did not vary. Mean CBF values averaged over 240 minutes increased progressively up to the fifth dose (significant differences between the first and fifth dose). The short term changes in CBF consisted of a significant increase 60 minutes after dexamethasone administration compared with the before and 10 minute values in every study. Blood pressure was significantly higher in the third and fifth doses than in the first dose. Blood pressure showed no short term changes. There was no correlation between CBF and blood pressure changes. TcPCO2 (transcutaneous PCO2) decreased significantly throughout the study period, with the average mean value in the fifth dose significantly lower than in the first dose. Nevertheless, no short term changes in TcPCO2 were observed. CONCLUSIONS: Postnatal systemic dexamethasone administration produced significant changes in cerebral haemodynamics that seemed to be related to both a direct effect on regional vessel walls and the cumulative effect of dexamethasone.

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.

Central nervous system vasculopathy in neonatal lupus erythematosus.

Central nervous system involvement in neonatal lupus erythematosus (NLE) has not been previously reported. We report four patients with NLE, all with complete congenital heart block and three with cerebral ultrasound and color Doppler flow imaging (CDFI) studies demonstrating evidence of associated vasculopathy in the gangliothalamic vasculature. CDFI confirmed blood flow through the affected vessels, indicating that blood flow was not compromised at this early stage. Short-term follow-up revealed no signs of progression of the vasculopathy, focal ischemia, gangliothalamic atrophy, or neurological impairment. Nevertheless, the implications of this finding with respect to the natural history of NLE remain to be defined, particularly in cases in which the disease develops into systemic lupus erythematosus later in life. Besides specific diagnostic studies for NLE, cerebral ultrasound, and CDFI studies are mandatory in all cases of complete congenital heart block, regardless of whether mothers are diagnosed as having connective-tissue disease or not. Neonates with signs of vasculopathy in the gangliothalamic region should be examined for NLE.

Postnatal adaptation of brain circulation in preterm infants.

Global and regional postnatal cerebral circulatory changes in stable preterm infants were studied, and their relation to brain injury was assessed. Thirty-five preterm infants were studied on the first and second days of age. Cerebral blood flow (CBF) (mL/hg per min) and cerebral blood volume (CBV) (mL/hg) were measured using near-infrared spectroscopy. The cerebral blood flow velocity (cm/second) (peak systolic, diastolic flow, mean flow) and resistance index (RI) were determined in the internal carotid, anterior cerebral, and striate arteries by color Doppler flow imaging. Serial cerebral ultrasound studies were performed to detect changes in brain parenchymal echogenicity or intraventricular hemorrhage (IVH); the maximum severity of these findings was considered. CBF and cerebral blood flow velocity increased significantly with time, and such changes were independent of mean blood pressure, PO(2), PCO(2), hematocrit, or glycemia. In contrast, CBV and RI remained unchanged. According to the results of sonograms, no differences were found in postnatal CBF and cerebral blood flow velocity changes, regardless of whether patients had or did not have parenchymal lesions or IVH. However, higher CBV values were found on the second day in infants with IVH compared with infants without IVH. Early coupling of CBF and metabolic demands is independent of blood pressure. Improved venous return, instead of vasodilation, could be important in this adaptation.

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.

New pattern of hyperechogenicity in thalamus and basal ganglia studied by color Doppler flow imaging.

Thirty-seven infants whose cerebral real-time B-mode ultrasound (CUS) documented hyperechogenic areas in the thalamus and basal ganglia (HTBG) either of linear or fine punctate pattern, were studied prospectively by color Doppler imaging (CDI). This study aimed to establish a relationship between these areas and the regional vasculature, to analyze associated disorders to establish pathogenesis, and to determine clinical significance. HTBG were diagnosed in the first 4 days of life in all but 7 infants. Different patterns of HTBG were observed: punctate in 11 infants, linear in 12, and mixed in 14. The basal ganglia were affected in all patients, 9 also had involvement of the thalamus. CDI confirmed that HTBG were allocated along the gangliothalamic vessels. Blood flow velocity waves were obtained at this level in all patients. Real-time spectral analyses were performed in 35 patients and compared with a control group of 20 healthy neonates. Differences were not significant. Computed tomography and magnetic resonance imaging failed to indicate this abnormality. Necropsy revealed basophilic deposits in the walls of involved arteries. Congenital infections manifested in 5 patients, chromosomal abnormality in 1, dysmorphic syndromes in 9 (3 unidentified), isolated congenital defects in 5, and diverse congenital disorders in 3. In the remaining 14, no congenital disorders nor infections were found. This CDI study demonstrates the vascular location of these HTBG. Supported by early CUS diagnosis, it is speculated that vascular injury in that region has a prenatal origin. This abnormality does not appear to alter regional blood flow. HTBG are associated with very heterogeneous disorders and in most patients the etiology and pathogenesis remain unclear.

[Non-invasive monitoring of cerebral hemodynamics in the newborn]. / Monitorización no invasiva de la hemodinámica cerebral en el recién nacido.

INTRODUCTION AND DEVELOPMENT: The regulation of cerebral blood flow (CBF) is a determinant factor amongst the mechanisms involved in the development of neonatal brain lesions. Therefore it has been the main objective of many investigators in recent decades, seeking reliable techniques for measurement of cerebral haemodynamic parameters. However, the use of different techniques to assess brain haemodynamics has been limited by various factors including: harmlessness of the technique, its ease of use and accuracy of measurement. In this paper we aim to show how, using these techniques, together with sufficient understanding of neonatal pathophysiology, we can obtain better understanding of antenatal and perinatal factors responsible for cerebral damage, and the effect of this lesion on development. Besides using these findings to prevent specific disorders, we will obtain the advantage of an appropriate medical and neurosurgical treatment, with lower risk of neurological sequelae.

[Cerebellar hypoplasia in the newborn: association with respiratory control disorders and mental retardation]. / Hipoplasia cerebelosa en el recién nacido: asociación con alteraciones del control respiratorio y retraso mental.

Cerebellum malformations are frequently diagnosed since the advent of the neuroradiological studies (computed tomography, magnetic resonance imaging and ultrasonography). Cerebellar hypoplasia is found in association with a wide variety of neurologic and systemic disorders. Clinical picture in newborn may be different than in other periods of life. Two characteristics are interesting in neonatal period: their relation with abnormal respiratory control and mental retardation. The pathophysiology of cerebellar hypoplasia is uncertain, however experimental studies suggest than an abnormality of the Bergman glia may lead to the observed granulle cell layer deficiency in this malformation. It is tempting to speculate that a similar migrational abnormality in the cerebrum accounts for the intellectual impairment seen in some affected patients. Respiration is a complex neural function requiring precise coordination of numerous neural circuits. Cerebellar hypoplasia may be important in the pathogenetic mechanism of abnormal respiratory control due to cerebellar respiratory control disturbance. Also diaphragmatic dysfunction may occur in association with cerebellar atrophy. We report two newborns with cerebellar hypoplasia (vermis and hemispheres) associated with central respiratory and neurological dysfunction, and mental retardation.

[Severe apparent life-threatening event during "skin-to-skin": treatment with hypothermia]. / Episodio aparentemente letal neonatal durante el «piel con piel¼. Tratamiento con hipotermia.

'Skin-to-skin' in healthy newborn infants is currently routine practice in Spanish maternity wards. This practice has shown benefits in increasing the duration of breast-feeding and maternal bonding behaviour with no significant adverse events. Early sudden deaths and severe apparent life-threatening events (ALTE) during the first 24 hours of life are infrequent, but well recognised. Risk factors during 'skin to skin' have been established. These events can lead to high neonatal morbidity and mortality. Hypothermia is now the standard of care for moderate to severe hypoxic-ischaemic encephalopathy and has shown to reduce mortality and neurological morbidity in children with hypoxic-ischaemic brain injury. Although there are no clinical trials that evaluate hypothermia after a severe ALTE, neonates who suffer it should be considered for this treatment. We present a case of a healthy newborn who had an ALTE during skin-to-skin with his mother and was treated with hypothermia.