Laura Bassi

Probabilistic diffusion tractography of the optic radiations and visual function in preterm infants at term equivalent age

Children born prematurely have a high incidence of visual disorders which cannot always be explained by focal retinal or brain lesions. The aim of this study was to test the hypothesis that visual function in preterm infants is related to the microstructural development of white matter in the optic radiations. We used diffusion tensor imaging (DTI) with probabilistic diffusion tractography to delineate the optic radiations at term equivalent age and compared the fractional anisotropy (FA) to a contemporaneous evaluation of visual function. Thirty-seven preterm infants (19 male) born at median (range) 28(+4) (24(+1)-32(+3)) weeks gestational age, were examined at a post-menstrual age of 42 (39(+6)-43) weeks. MRI and DTI were acquired on a 3 Tesla MR system with DTI obtained in 15 non-collinear directions with a b value of 750 s/mm(2). Tracts were generated from a seed mask placed in the white matter lateral to the lateral geniculate nucleus and mean FA values of these tracts were determined. Visual assessment was performed using a battery of nine items assessing different aspects of visual abilities. Ten infants had evidence of cerebral lesions on conventional MRI. Multiple regression analysis demonstrated that the visual assessment score was independently correlated with FA values, but not gestational age at birth, post-menstrual age at scan or the presence of lesions on conventional MRI. The occurrence of mild retinopathy of prematurity did not affect the FA measures or visual scores. We then performed a secondary analysis using tract-based spatial statistics to determine whether global brain white matter development was related to visual function and found that only FA in the optic radiations was correlated with visual assessment score. Our results suggest that in preterm infants at term equivalent age visual function is directly related to the development of white matter in the optic radiations.

Magnetic resonance imaging of white matter diseases of prematurity

Periventricular leucomalacia (PVL) and parenchymal venous infarction complicating germinal matrix/intraventricular haemorrhage have long been recognised as the two significant white matter diseases responsible for the majority of cases of cerebral palsy in survivors of preterm birth. However, more recent studies using magnetic resonance imaging to assess the preterm brain have documented two new appearances, adding to the spectrum of white matter disease of prematurity: punctate white matter lesions, and diffuse excessive high signal intensity (DEHSI). These appear to be more common than PVL but less significant in terms of their impact on individual neurodevelopment. They may, however, be associated with later cognitive and behavioural disorders known to be common following preterm birth. It remains unclear whether PVL, punctate lesions, and DEHSI represent a continuum of disorders occurring as a result of a similar injurious process to the developing white matter. This review discusses the role of MR imaging in investigating these three disorders in terms of aetiology, pathology, and outcome.

Diffusion tensor imaging in preterm infants with punctate white matter lesions

Our aim was to compare white matter (WM) microstructure in preterm infants with and without punctate WM lesions on MRI using tract-based spatial statistics (TBSS) and probabilistic tractography. We studied 23 preterm infants with punctate lesions, median GA at birth 30 (25–35) wk, and 23 GA- and sex-matched preterm controls. TBSS and tractography were performed to assess differences in fractional anisotropy (FA) between the two groups at term equivalent age. The impact of lesion load was assessed by performing linear regression analysis of the number of lesions on term MRI versus FA in the corticospinal tracts in the punctate lesions group. FA values were significantly lower in the posterior limb of the internal capsule, cerebral peduncles, decussation of the superior cerebellar peduncles, superior cerebellar peduncles, and pontine crossing tract in the punctate lesions group. There was a significant negative correlation between lesion load at term and FA in the corticospinal tracts (p = 0.03, adjusted r2 = 0.467). In conclusion, punctate lesions are associated with altered microstructure in the WM fibers of the corticospinal tract at term equivalent age.

Magnetic resonance imaging assessment of brain maturation in preterm neonates with punctate white matter lesions

IntroductionEarly white matter (WM) injury affects brain maturation in preterm infants as revealed by diffusion tensor imaging and volumetric magnetic resonance (MR) imaging at term postmenstrual age (PMA). The aim of the study was to assess quantitatively brain maturation in preterm infants with and without milder forms of WM damage (punctate WM lesions, PWML) using conventional MRI.MethodsBrain development was quantitatively assessed using a previously validated scoring system (total maturation score, TMS) which utilizes four parameters (progressive myelination and cortical infolding, progressive involution of glial cell migration bands and germinal matrix tissue). PWML were defined as foci of increased signal on T1-weighted images and decreased signal on T2-weighted images with no evidence of cystic degeneration. A group of 22 preterm infants with PWML at term PMA (PWML group) were compared with 22 matched controls with a normal MR appearance.ResultsThe two groups were comparable concerning gestational age, birth weight and PMA. TMS was significantly lower in the PWML group than in the control group (mean TMS 12.44 ± 2.31 vs 14.00 ± 1.44; P = 0.011). Myelination (mean 2.76 ± 0.42 PWML group vs 3.32 ± 0.55 control group, P = 0.003) and cortical folding (3.64 ± 0.79 vs 4.09 ± 0.43, P = 0.027) appeared to be significantly delayed in babies with PWML.ConclusionConventional MRI appears able to quantify morphological changes in brain maturation of preterm babies with PWML; delayed myelination and reduced cortical infolding seem to be the most significant aspects.

Neonatal cerebral sinovenous thrombosis

Cerebral sinovenous thrombosis (CSVT) is an uncommon condition among paediatric patients involving major sinuses, with a preponderant occurrence in neonates. The clinical presentation is unspecific, either early, within 48h from birth, or later. An early presentation may be accompanied by several comorbidities (respiratory distress, poor tone, fetal distress, asphyxia), whereas a later presentation is more often associated with conventional neurological signs such as seizures, lethargy, apnoea and poor feeding. These differences in clinical presentation render the neuroradiological diagnosis difficult, in particular before the introduction of magnetic resonance imaging. The interest in CSVT is based on the complex pathogenesis, often resulting from a combination of inherited and acquired thrombophilic patterns. In addition, the course of CSVT can be influenced by medical treatment, currently based on the consensus of experts more than on randomised trials.

Visual performance and brain structures in the developing brain of pre-term infants

The presence of abnormal visual function has been related to overt lesions in the thalami, peritrigonal white matter (such as cavitational-necrotic periventricular leucomalacia) and optic radiations, and also to the extent of occipital cortex involvement. The normal development of visual function seems to depend on the integrity of a network that includes not only optic radiations and the primary visual cortex but also other cortical and subcortical areas, such as the frontal or temporal lobes or basal ganglia, which have been found to play a topical role in the development of vision. Therefore, the complex functions and functional connectivity of the developing brain of premature infants can be studied only with highly sophisticated techniques such as diffusion tensor tractography. The combined use of visual tests and neonatal structural and functional neuroimaging, which have become available for newborn infants, provides a better understanding of the correlation between structure and function from early life. This appears to be particularly relevant considering the essential role of early visual function in cognitive development. The identification of early visual impairment is also important, as it allows for early enrolment in intervention programmes. The association of clinical and functional studies to newer imaging techniques, which are being increasingly used also in neonates, are likely to provide further information on early aspects of vision and the mechanisms underlying brain plasticity, which are still not fully understood. Early exposure to a difficult postnatal environment together with early and unexpected removal from a protective milieu are exclusive and peculiar factors of prematurity that interfere with the normal development of the visual system in pre-term babies. The problem is further compounded by the influence of different perinatal brain lesions affecting the developing brain of premature babies. Nevertheless, in the last few decades, there have been considerable advances in our understanding of the development of vision in pre-term infants during early infancy. This has mainly been due to the development of age-specific tests assessing various aspects of visual function, from ophthalmological examination to more cortical aspects of vision, such as the ability to process orientation or different aspects of visual attention [1-7]. Improvements in understanding very early and specific neurological impairments in neurological functions have been reported in pre-term infants, known to be at risk of developing visual and visual-perceptual impairment. These impairments are due not only to retinopathy, a common finding in premature infants, but also to cerebral (central) visual impairment, secondary to brain lesions affecting the central visual pathway.

Neonatal neuroimaging: Going beyond the pictures

The cerebral ultrasound has been used many years for the diagnosis of brain lesions in term and preterm newborns. Major improvements were obtained by the combination of different imaging modalities such as Magnetic Resonance Imaging with the Diffusion Weighted Imaging (DWI) and the new quantitative Diffusion Tensor Imaging (DTI). The clinical use of MRI has been validated over some years especially to depict the perinatal asphyxia lesions in term newborns, but its use in order to diagnose the typical diseases of preterm babies is very recent and useful in identifying a marker able to predict neurological outcome. The imaging correlates for motor impairment are well recognized (periventricular white matter cavitations), but no any imaging correlate for cognitive impairment and neurobehavioral disorders. While DWI has been used in term newborns to identify the ischemic areas with restricted diffusion, it may be also used to characterize brain development in preterm infants with the Apparent Diffusion Coefficient (ADC) and may allow us to detect abnormalities responsible for the non-motor impairments. Recent datas showed that in infants without focal lesions higher ADC values in WM were associated with poorer neurodevelopmental assessment at 2 years. The DTI also allows to detect the Fractional Anisotropy (FA) that measures the microstructure. DTI can also be used to map the WM tracts in the immature brain and may be applied to understand the normal development or the response of the brain to injury. Some WM regions in the preterm brain have a lower FA suggesting that widespread WM abnormalities are present in preterms even in the absence of focal lesions. The complexity of the developing brain can be explained by the new tractography that can assess the connectivity of different WM regions and the association between structure and function, such as optic radiations microstructure and visual assessment score. Technological advances in neonatal brain imaging have made a major contribution to understand the neurobehavioral disorders of the developing brain that have the origin in the early structural cerebral organization and maturation.

From germinal matrix to cerebellar haemorrhage.

Abstract For many years cerebellar development after preterm birth has been poorly investigated and has been studied without taking germinal matrix-intraventricular haemorrhage into account. Advanced neuroimaging techniques like magnetic resonance imaging, as well as the use of various acoustic windows (mastoid fontanelle, occipital foramen) have allowed for in vivo diagnosis of acquired focal haemorrhagic lesions in the cerebellum of very preterm babies. The vulnerability of the cerebellum also seems to be related to specific gestational ages, i.e., between 23 and 27 weeks, when rapid growth in cerebellar volume occurs and at a much faster rate than mean brain volume increase. In this paper, the contribution of the cerebellum in long-term motor cognitive, learning and behavioural functions, including psychiatric ones, is discussed.

Neurological examination in healthy term infants aged 3-10 weeks.

Objectives: The neurodevelopmental progress of newborn term infants is checked routinely at around 6 weeks of postnatal age. The maturation of neurological signs in this age range however has not been systematically studied and normative data are not available. The aim of this study was to document any changes in posture, tone, reflexes, behaviour and movements in low-risk full-term infants between 3 and 10 weeks of postnatal age. Study Design: We performed a structured neurological examination previously standardised in full-term newborns in the first 48 h after birth. In the current study, a total of 76 examinations were performed between 3 and 10 weeks of age in low-risk full-term infants. Results: The results of the examinations were divided according to postnatal age. In most items, the scores changed with time, with a definite shift in their distribution occurring around 6 weeks. At this age, a reduction in flexor tone of the limbs was observed, together with an increase in active neck tone. Visual orientation in contrast had already improved by 3 weeks when all infants were able to follow a target in a full circle compared to newborns that are often only able to follow a target in an arc. Conclusions: Our results suggest that 6 weeks post-term birth is an important milestone for changes in neurological signs, particularly those related to muscle tone and posture, probably reflecting maturation of the nervous system. These findings provide important guidelines for the interpretation of the neurological examination performed at this age.

Efficacy of sodium channel blockers in SCN2A early infantile epileptic encephalopathy

BACKGROUND Recent clinical evidence supports a targeted therapeutic approach for genetic epileptic encephalopathies based on the molecular dysfunction. PATIENT DESCRIPTION A 2-day-old male infant presented with epileptic encephalopathy characterized by burst-suppression EEG background and tonic-clonic migrating partial seizures. The condition was refractory to phenobarbital, pyridoxine, pyridoxal phosphate and levetiracetam, but a dramatic response to an intravenous loading dose of phenytoin was documented by video-EEG monitoring. Over weeks phenytoin was successfully switched to carbamazepine to prevent seizure relapses associated with difficulty in maintaining proper blood levels of phenytoin. Genetic analysis identified a novel de novo heterozygous mutation (c.[4633A>G]p.[Met1545Val]) in SCN2A. At two years and three months of age the patient is still seizure-free on carbamazepine, although a developmental delay is evident. CONCLUSIONS Sodium channel blockers represent the first-line treatment for confirmed or suspected SCN2A-related epileptic encephalopathies. In severe cases with compatible electro-clinical features we propose a treatment algorithm based on a test trial with high dose intravenous phenytoin followed in case of a positive response by carbamazepine, more suitable for long-term maintenance treatment. Because of their rarity, collaborative studies are needed to delineate shared therapeutic protocols for EIEE based on the electro-clinical features and the presumed underlying genetic substrate.