Haim Bassan

Does Cerebellar Injury in Premature Infants Contribute to the High Prevalence of Long-term Cognitive, Learning, and Behavioral Disability in Survivors?

OBJECTIVE. Although cerebellar hemorrhagic injury is increasingly diagnosed in infants who survive premature birth, its long-term neurodevelopmental impact is poorly defined. We sought to delineate the potential role of cerebellar hemorrhagic injury in the long-term disabilities of survivors of prematurity. DESIGN. We compared neurodevelopmental outcome in 3 groups of premature infants (N = 86; 35 isolated cerebellar hemorrhagic injury, 35 age-matched controls, 16 cerebellar hemorrhagic injury plus supratentorial parenchymal injury). Subjects underwent formal neurologic examinations and a battery of standardized developmental, functional, and behavioral evaluations (mean age: 32.1 ± 11.1 months). Autism-screening questionnaires were completed. RESULTS. Neurologic abnormalities were present in 66% of the isolated cerebellar hemorrhagic injury cases compared with 5% of the infants in the control group. Infants with isolated cerebellar hemorrhagic injury versus controls had significantly lower mean scores on all tested measures, including severe motor disabilities (48% vs 0%), expressive language (42% vs 0%), delayed receptive language (37% vs 0%), and cognitive deficits (40% vs 0%). Isolated cerebellar hemorrhagic injury was significantly associated with severe functional limitations in day-to-day activities. Significant differences were noted between cases of cerebellar hemorrhagic injury versus controls on autism screeners (37% vs 0%) and internalizing behavioral problems (34% vs 9%). Global developmental, functional, and social-behavioral deficits were more common and profound in preterm infants with injury to the vermis. Preterm infants with cerebellar hemorrhagic injury and supratentorial parenchymal injury were not at overall greater risk for neurodevelopmental disabilities, although neuromotor impairment was more severe. CONCLUSIONS. Cerebellar hemorrhagic injury in preterm infants is associated with a high prevalence of long-term pervasive neurodevelopment disabilities and may play an important and underrecognized role in the cognitive, learning, and behavioral dysfunction known to affect survivors.

Positive Screening for Autism in Ex-preterm Infants: Prevalence and Risk Factors

OBJECTIVE. The survival of very low birth weight infants has increased markedly in recent years. Unfortunately, the prevalence of significant and lifelong motor, cognitive, and behavioral dysfunction has remained a major problem confronting these children. The objective of this study was to perform screening tests for early autistic features in children with a history of very low birth weight and to identify risk factors associated with a positive screening result. METHODS. We studied 91 ex-preterm infants ≤ 1500 g at birth. Infants underwent conventional MRI studies at preterm and/or term-adjusted age. We collected pertinent demographic, prenatal, intrapartum, acute postnatal, and short-term outcome data for all infants. Follow-up assessments were performed at a mean age of 21.9 ± 4.7 months, using the Modified Checklist for Autism in Toddlers, the Vineland Adaptive Behavior Scale, and the Child Behavior Checklist. RESULTS. Twenty-six percent of ex-preterm infants had a positive result on the autism screening tool. Abnormal scores correlated highly with internalizing behavioral problems on the Child Behavior Checklist and socialization and communication deficits on the Vineland Scales. Lower birth weight, gestational age, male gender, chorioamnionitis, acute intrapartum hemorrhage, illness severity on admission, and abnormal MRI studies were significantly associated with an abnormal autism screening score. CONCLUSIONS. Early autistic behaviors seem to be an underrecognized feature of very low birth weight infants. The results from this study suggest that early screening for signs of autism may be warranted in this high-risk population followed by definitive autism testing in those with positive screening results.

Late Gestation Cerebellar Growth Is Rapid and Impeded by Premature Birth

Objective. Cognitive impairments and academic failure are commonly reported in survivors of preterm birth. Recent studies suggest an important role for the cerebellum in the development of cognitive and social functions. The objective of this study was to examine the impact of prematurity itself, as well as prematurity-related brain injuries, on early postnatal cerebellar growth with quantitative MRI. Methods. Advanced 3-dimensional volumetric MRI was performed and cerebellar volumes were obtained by manual outlining in preterm (<37 weeks) and healthy term-born infants. Intracranial and total brain volumes were also calculated. Results. A total of 169 preterm and 20 healthy full-term infants were studied; 145 had preterm MRI (pMRI), 75 had term MRI (tMRI), and 51 underwent both pMRI and tMRI. From 28 weeks’ postconceptional age to term, mean cerebellar volume (177%) in preterm infants increased at a much faster rate than did mean intracranial (110%) or mean brain (107%) volumes. Smaller cerebellar volume was significantly related to lower gestational age at birth and to intracranial and total brain volumes. Mean cerebellar volume of preterm infants at tMRI was significantly smaller than the volumes of term-born infants. Cerebellar growth impairment was correlated strongly with associated brain injuries, even in the absence of direct cerebellar injury. Conclusions. Our data suggest that the growth of the immature cerebellum is particularly rapid during late gestation. However, this accelerated growth seems to be impeded by premature birth and associated brain injury. The long-term neurodevelopmental disabilities seen in survivors of premature birth may be attributable in part to impaired cerebellar development.

Complete Sequence of a Novel Protein Containing a Femtomolar‐Activity‐Dependent Neuroprotective Peptide

Abstract : The vulnerability of neurons and the irreversibility of loss make discoveries of neuroprotective compounds fundamentally important. Here, the complete coding sequence of a novel protein (828 amino acids, pl 5.99), derived from mouse neuroglial cells, is revealed. The sequence contained (1) a neuroprotective peptide, NAPVSIPQ, sharing structural and immunological homologies with the previously reported, activity‐dependent neurotrophic factor ; (2) a glutaredoxin active site ; and (3) a zinc binding domain. Gene expression was enriched in the mouse hippocampus and cerebellum and augmented in the presence of the neuropeptide vasoactive intestinal peptide, in cerebral cortical astrocytes. In mixed neuron—astrocyte cultures, NAPVSIPQ provided neuroprotection at subfemtomolar concentrations against toxicity associated with tetrodotoxin (electrical blockade), the β‐amyloid peptide (the Alzheimers disease neurotoxin), N‐methyl‐D‐aspartate (excitotoxicity), and the human immunodeficiency virus envelope protein. Daily NAPVSIPQ injections to newborn apolipoprotein E‐deficient mice accelerated the acquisition of developmental reflexes and prevented short‐term memory deficits. Comparative studies suggested that NAPVSIPQ was more efficacious than other neuroprotective peptides in the apolipoprotein E‐deficiency model. A potential basis for rational drug design against neurodegeneration is suggested with NAPVSIPQ as a lead compound. The relative enrichment of the novel mRNA transcripts in the brain and the increases found in the presence of vasoactive intestinal peptide, an established neuroprotective substance, imply a role for the cloned protein in neuronal function.

Fluctuating Pressure-Passivity Is Common in the Cerebral Circulation of Sick Premature Infants

Cerebral blood flow pressure-passivity results when pressure autoregulation is impaired, or overwhelmed, and is thought to underlie cerebrovascular injury in the premature infant. Earlier bedside observations suggested that transient periods of cerebral pressure-passivity occurred in premature infants. However, these transient events cannot be detected reliably by intermittent static measurements of pressure autoregulation. We therefore used continuous bedside recordings of mean arterial pressure (MAP; from an indwelling arterial catheter) and cerebral perfusion [using the near-infrared spectroscopy (NIRS) Hb difference (HbD) signal) to detect cerebral pressure-passivity in the first 5 d after birth in infants with birth weight <1500 g. Because the Hb difference (HbD) signal [HbD = oxyhemoglobin (HbO2) − Hb] correlates with cerebral blood flow (CBF), we used coherence between MAP and HbD to define pressure-passivity. We measured the prevalence of pressure-passivity using a pressure-passive index (PPI), defined as the percentage of 10-min epochs with significant low-frequency coherence between the MAP and HbD signals. Pressure-passivity occurred in 87 of 90 premature infants, with a mean PPI of 20.3%. Cerebral pressure-passivity was significantly associated with low gestational age and birth weight, systemic hypotension, and maternal hemodynamic factors, but not with markers of maternal infection. Future studies using consistent serial brain imaging are needed to define the relationship between PPI and cerebrovascular injury in the sick premature infant.

Impaired Trophic Interactions Between the Cerebellum and the Cerebrum Among Preterm Infants

Background. Advanced neuroimaging techniques have brought increasing recognition of cerebellar injury among premature infants. The developmental relationship between early brain injury and effects on the cerebrum and cerebellum remains unclear. Objectives. To examine whether cerebral parenchymal brain lesions among preterm infants are associated with subsequent decreases in cerebellar volume and, conversely, whether primary cerebellar injury is associated with decreased cerebral brain volumes, with advanced, 3-dimensional, volumetric MRI at term gestational age equivalent. Methods. Total cerebellar volumes and cerebellar gray and myelinated white matter volumes were determined through manual outlining for 74 preterm infants with unilateral periventricular hemorrhagic infarction (14 infants), bilateral diffuse periventricular leukomalacia (20 infants), cerebellar hemorrhage (10 infants), or normal term gestational age equivalent MRI findings (30 infants). Total brain and right/left cerebral and cerebellar hemispheric volumes were calculated. Results. Unilateral cerebral brain injury was associated with significantly decreased volume of the contralateral cerebellar hemisphere. Conversely, unilateral primary cerebellar injury was associated with a contralateral decrease in supratentorial brain volume. Cerebellar gray matter and myelinated white matter volumes were reduced significantly not only among preterm infants with primary cerebellar hemorrhage but also among infants with cerebral parenchymal brain injury. Conclusions. These data suggest strongly that both reduction in contralateral cerebellar volume with unilateral cerebral parenchymal injury and reduction in total cerebellar volume with bilateral cerebral lesions are related to trophic transsynaptic effects. Early-life cerebellar injury may contribute importantly to the high rates of cognitive, behavioral, and motor deficits reported for premature infants.

PRRT2 mutations cause benign familial infantile epilepsy and infantile convulsions with choreoathetosis syndrome.

Benign familial infantile epilepsy (BFIE) is a self-limited seizure disorder that occurs in infancy and has autosomal-dominant inheritance. We have identified heterozygous mutations in PRRT2, which encodes proline-rich transmembrane protein 2, in 14 of 17 families (82%) affected by BFIE, indicating that PRRT2 mutations are the most frequent cause of this disorder. We also report PRRT2 mutations in five of six (83%) families affected by infantile convulsions and choreoathetosis (ICCA) syndrome, a familial syndrome in which infantile seizures and an adolescent-onset movement disorder, paroxysmal kinesigenic choreoathetosis (PKC), co-occur. These findings show that mutations in PRRT2 cause both epilepsy and a movement disorder. Furthermore, PRRT2 mutations elicit pleiotropy in terms of both age of expression (infancy versus later childhood) and anatomical substrate (cortex versus basal ganglia).

Cerebellar Hemorrhage in the Preterm Infant: Ultrasonographic Findings and Risk Factors

Cerebellar hemorrhage (CBH) in premature infants is increasingly diagnosed secondary to improved neuroimaging techniques and survival of very small preterm infants. Information is limited, however, on the incidence, topography, and risk factors for CBH in the preterm infant. Objectives. To define the incidence of CBH in preterm infants diagnosed by neonatal cranial ultrasound (US), describe the sonographic features of CBH, and identify maternal and perinatal risk factors associated with this lesion. Methods. A systematic electronic database search identified preterm infants born 1998–2002 with US diagnosis of CBH. For 35 cases of CBH we double-matched (according to gestational age, gender, and year of birth) 70 preterm controls with normal cranial USs and performed detailed medical-record reviews for both patients and controls. Results. Unilateral CBH was seen in 25 patients (71%), vermian hemorrhage was seen in 7 (20%), and combined bihemispheric and vermian hemorrhage was seen in 3 (9%). Isolated CBH occurred in 8 patients (23%); the remaining infants had associated supratentorial lesions. The incidence of CBH in preterm infants weighing <750 g at birth showed significant increase over the study period. Univariate analyses identified maternal, intrapartum, and early postnatal hemodynamic risk factors; multivariate regressions indicated that emergent caesarian section, patent ductus arteriosus, and lower 5-day minimum pH independently increased the odds of CBH. Neonatal mortality and morbidity were significantly higher among patients with CBH compared with preterm controls. Conclusions. CBH is an important complication of extreme preterm birth and has been underrecognized in surviving preterm infants. Predictors of CBH seem to be multifactorial and include combined maternal, intrapartum, and early postnatal factors.

Experimental intrauterine growth retardation alters renal development

Abstract Vascular placental insufficiency is considered a common pathogenic factor in human intrauterine growth retardation (IUGR), resulting in small-for-gestational-age, asymmetric newborns. IUGR neonates experience higher morbidity and mortality rates, as well as a possible contribution towards late sequelae, such as hypertension, and cardiovascular disease in adulthood. To simulate vascular placental insufficiency, an experimental rabbit IUGR model was used. Intrauterine growth retardation was achieved by ligation of 25–30% uteroplacental vessels of half of the fetuses during the last third of gestation. Ischemic fetuses were significantly small, asymmetric, and had a disproportionately small body with a relatively large head. The kidneys from all groups were analyzed for relative estimated glomeruli number (REGN) using an unbiased blind design. The glomeruli number was significantly reduced in the asymmetric IUGR rabbit fetuses, probably due to decreased renal vascular supply. Our results support the concept that the reduced number of glomeruli may contribute to impaired renal function, thus predisposing to neonatal renal dysfunction and late sequelae, such as adult hypertension. This study emphasizes the clinical importance of early IUGR diagnosis and prevention.

Identification of pressure passive cerebral perfusion and its mediators after infant cardiac surgery.

Cerebrovascular pressure autoregulation (CPA) regulates cerebral blood flow (CBF) in relation to changes in mean arterial blood pressure (MAP). Identification of a pressure-passive cerebral perfusion and the potentially modifiable physiologic factors underlying it has been difficult to achieve in sick infants. We previously validated the near-infrared spectroscopy–derived hemoglobin difference (HbD) signal (cerebral oxyhemoglobin − deoxyhemoglobin) as a reliable measure of changes in CBF in animal models. We now sought to determine whether continuous measurements of ΔHbD would correlate to middle cerebral artery flow velocity (CBFV), allow identification and quantification of pressure-passive state, and help to delineate potentially modifiable factors. We enrolled 43 infants (2 d to 7 mo old) who were undergoing open cardiac surgery and cardiopulmonary bypass. At 6 and 20 h after surgery, we measured changes in HbD, CBFV (by transcranial Doppler), and MAP at different end-tidal CO2 levels. We assigned a pressure-passive index (PPI) to each study on the basis of the relative duration of significant coherence between ΔMAP and ΔHbD. We found a significant relationship between ΔHbD and ΔCBFV at both time points. At 6 h after surgery, we showed high concordance (coherence >0.5; PPI ≥41%) between ΔMAP and ΔHbD, consistent with disturbed CPA in 13% of infants. End-tidal CO2 values ≥40 mm Hg and higher MAP variability both were associated with increased odds (p < 0.001) of autoregulatory failure. This approach provides a means to identify and quantify disturbances of CPA. High CO2 levels and fluctuating MAP are two important preventable factors associated with disturbed CPA.