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Hereditary spastic paraplegias (HSPs) are a clinically and genetically heterogeneous group of neurodegenerative disorders characterized by progressive spasticity and weakness of the lower limbs with a notable phenotypic variation and an autosomal recessive (AR), autosomal dominant (AD), and X-linked inheritance pattern. The recent clinical use of next generation sequencing methods has facilitated the diagnostic approach to HSPs, but the diagnosis remains quite challenging considering its wide clinical and genetic heterogeneity. In this scenario, magnetic resonance imaging (MRI) emerges as a valuable tool in helping to exclude mimicking disorders and to guide genetic testing. The aim of this study is to investigate the presence of possible patterns of morphostructural MRI findings that may provide relevant clues for a specific genetic HSP subtype. In our cohort, for example, white matter abnormalities were the most common finding followed by the thinning of the corpus callosum, which, interestingly, presented different thinning characteristics depending on the HSP subtype., (Copyright © 2021 Elsevier B.V. All rights reserved.)

The great majority of children with neurodevelopmental challenges do not get specific intervention until after their second birthday. This worsens their outcomes, because a great part of the entire neuroplastic window for learning is misspent. There is emerging evidence that the impact on outcomes of early goal-directed training involving the parents in infants with neurodevelopmental disabilities is significantly superior to the results achieved in older children and adults, especially if intervention commences in the first months of life. This chapter outlines the common elements of neurodevelopment and early intervention. It includes an outline of some of the primary early intervention practices and the scientific evidence driving them., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Aim: To systematically explore the relationship between type and severity of brain lesion on Magnetic Resonance Imaging (MRI) and visual function in a large cohort of children with periventricular leukomalacia (PVL)., Methods: 94 children with bilateral cerebral palsy (CP) and history of PVL were recruited at Stella Maris Scientific Institute in Pisa (Italy). We included data of participants (72) with at least one MRI after the age of three years and an evaluation of visual function including fixation, following, saccades, nystagmus, acuity, visual field, stereopsis and color perception. Brain lesions location and extent were assessed by a semi-quantitative MRI-scale for children with CP., Results: Brain lesion severity strongly correlated with visual function total score (global MRI score p = .000; hemispheric score p = .001 and subcortical score p = .000). Moreover, visual acuity, visual field, stereopsis and colour were compromised when a cortical damage was present, while ocular motricity (and in particular fixation and saccades) were compromised in presence of subcortical brain damage., Interpretation: Structural MRI is valuable for understanding the relationship between brain lesion severity and visual function in children with CP., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Children with Down Syndrome (DS) have a high prevalence of ocular disorders, and even when ophthalmological deficits (i.e. refractive errors or strabismus) are corrected, visual acuity seems to have a different developmental trend compared to typical children. Unfortunately, there is no consensus about the age at which it is fundamental to perform a first comprehensive visual assessment in this population., Aims: We analyzed early visual functions in a sample of 42 Italian children with DS, in order to achieve new insights for early surveillance and intervention., Material and Methods: DS children were evaluated with the Early Neurovisual Assessment, including Teller Acuity Cards (at 6, 12 and 18 months of age) and the Pediatric Ophthalmological Examination (within the 36th months of age)., Results: Visual acuity in our sample was lower than findings reported in the literature on healthy Italian children, but the values were within the confidence interval reported in previous studies on DS children. Moderate or severe refractive errors (> 3diopters) were present in five children (four had hyperopia and one myopia). Abnormalities in ocular motility were observed in 15 children and pathological findings for fundus oculi or lens were found in another eight. Furthermore, ophthalmological findings correlated with visual acuity at 18 months of age., Conclusion: According to our results, the Early Neurovisual Assessment at 18 months of life is a reliable tool for early detection of visual disorders in children with DS and it is useful for programming early intervention to promote their neurodevelopment., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Aminoacylase 1 deficiency (ACY1D) is a rare inborn error of metabolism characterized by increased urinary excretion of N-acetylated amino acids. Clinical phenotypes of 15 known patients with ACY1 deficiency have been described up to now. Findings are greatly variable, ranging from normality to relevant neurological and psychiatric impairments, but clinical follow up has been rarely reported. To partially fill this gap, we present a detailed clinical description and the outcome four years post-diagnosis of a patient already described, with mild intellectual disability, language delay, autistic traits and compound heterozygous mutations in ACY1., (Copyright © 2018 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

Childhood apraxia of speech (CAS) is a paediatric speech sound disorder in which precision and consistency of speech movements are impaired. Most children with idiopathic CAS have normal structural brain MRI. We hypothesize that children with CAS have altered structural connectivity in speech/language networks compared to controls and that these altered connections are related to functional speech/language measures. Whole brain probabilistic tractography, using constrained spherical deconvolution, was performed for connectome generation in 17 children with CAS and 10 age-matched controls. Fractional anisotropy (FA) was used as a measure of connectivity and the connections with altered FA between CAS and controls were identified. Further, the relationship between altered FA and speech/language scores was determined. Three intra-hemispheric/interhemispheric subnetworks showed reduction of FA in CAS compared to controls, including left inferior (opercular part) and superior (dorsolateral, medial and orbital part) frontal gyrus, left superior and middle temporal gyrus and left post-central gyrus (subnetwork 1); right supplementary motor area, left middle and inferior (orbital part) frontal gyrus, left precuneus and cuneus, right superior occipital gyrus and right cerebellum (subnetwork 2); right angular gyrus, right superior temporal gyrus and right inferior occipital gyrus (subnetwork 3). Reduced FA of some connections correlated with diadochokinesis, oromotor skills, expressive grammar and poor lexical production in CAS. These findings provide evidence of structural connectivity anomalies in children with CAS across specific brain regions involved in speech/language function. We propose altered connectivity as a possible epiphenomenon of complex pathogenic mechanisms in CAS which need further investigation.

Background: Strong evidence supports an association between high levels of homocysteine (Hcy) and lipoprotein(a) [Lp(a)] and an increased rate of ischemic vascular events., Methods: The study population comprised 162 patients (50 women [30.9%]; age, 66.71 ± 12.76 years) having a history of acute coronary syndrome within 1 year who underwent fasting blood sampling, measurement of intima-media thickness and pulse wave velocity at the common carotid and femoral arteries by Doppler ultrasound, and ankle-brachial index measurement. Cutoff values were considered 0.9 mm and 1.2 mm for carotid and femoral intima-media thickness, respectively; 12 m/s for pulse wave velocity; and <0.9 for ankle-brachial index. We included hypertension, dyslipidemia, diabetes, overweight/obesity, smoking, and family history of cardiovascular disease in the count of traditional risk factors (CRFs). Adding Hcy ≥15 μmol/L and Lp(a) ≥500 mg/L to CRFs, we obtained a new score, named TOTAL., Results: On univariate analysis, Hcy and Lp(a) were significantly associated with presence of atherosclerotic extracoronary lesions (for Hcy: β = .934; standard error = 0.178; P < .0001; for Lp(a): β = .961; standard error = 0.177; P < .0001) and compliance alterations (for Hcy: odds ratio, 13.3; 95% confidence interval, 3.9-45.3; P < .0001; for Lp(a): odds ratio, 14.6; 95% confidence interval, 5.69-37.62; P < .0001). On multivariate analysis, Lp(a) and Hcy were significantly associated with extracoronary atherosclerosis, even after correction for CRFs. The area under the curve of the TOTAL score for both atherosclerosis and vascular compliance alterations was significantly higher than the area under the curve of traditional CRFs plus only Hcy ≥15 μmol/L or plus Lp(a) ≥500 mg/L, separately added., Conclusions: The addition of evaluation of Hcy ≥15 μmol/L and Lp(a) ≥500 mg/L to the traditional CRF count does improve detection of systemic atherosclerotic burden of patients with acute coronary syndrome and can offer a new opportunity to optimize secondary prevention., (Copyright © 2016 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

The recent advance of new molecular technologies like array - Comparative Genomic Hybridization has fostered the detection of genomic imbalances in subjects with intellectual disability, epilepsy, and/or congenital anomalies. Though some of the rearrangements are relatively frequent, their consequences on phenotypes can be strongly variable. We report on a boy harbouring a de novo 8.3 Mb duplication of chromosome 1q21.1-q21.3 whose complex unusual phenotype deserves attention, due to the presence of focal cortical dysplasia, microcephaly, and epilepsy. Loss-of-function (LOF) effects of genes associated with human disease involved in the rearrangement have been only partially established, and have not been previously associated with brain malformations in several deletion syndromes. Less is known, instead, about the consequences of their duplication on neuronal migration and brain development process. Further advance in neuroimaging and genetic research will help in defining their actual role in neurodevelopment and cerebral cortex malformations., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)

Childhood apraxia of speech (CAS) is a neurogenic Speech Sound Disorder whose etiology and neurobiological correlates are still unclear. In the present study, 32 Italian children with idiopathic CAS underwent a comprehensive speech and language, genetic and neuroradiological investigation aimed to gather information on the possible behavioral and neurobiological markers of the disorder. The results revealed four main aggregations of behavioral symptoms that indicate a multi-deficit disorder involving both motor-speech and language competence. Six children presented with chromosomal alterations. The familial aggregation rate for speech and language difficulties and the male to female ratio were both very high in the whole sample, supporting the hypothesis that genetic factors make substantial contribution to the risk of CAS. As expected in accordance with the diagnosis of idiopathic CAS, conventional MRI did not reveal macrostructural pathogenic neuroanatomical abnormalities, suggesting that CAS may be due to brain microstructural alterations., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Aim: To provide first evidence of construct validity of a semi-quantitative scale for brain structural MRI (sqMRI scale) in children with unilateral cerebral palsy (UCP) secondary to periventricular white matter (PWM) lesions, by examining the relationship with hand sensorimotor function and whole brain structural connectivity., Methods: Cross-sectional study of 50 children with UCP due to PWM lesions using 3 T (MRI), diffusion MRI and assessment of hand sensorimotor function. We explored the relationship of lobar, hemispheric and global scores on the sqMRI scale, with fractional anisotropy (FA), as a measure of brain white matter microstructure, and with hand sensorimotor measures (Assisting Hand Assessment, AHA; Jebsen-Taylor Test for Hand Function, JTTHF; Melbourne Assessment of Unilateral Upper Limb Function, MUUL; stereognosis; 2-point discrimination)., Results: Lobar and hemispheric scores on the sqMRI scale contralateral to the clinical side of hemiplegia correlated with sensorimotor paretic hand function measures and FA of a number of brain structural connections, including connections of brain areas involved in motor control (postcentral, precentral and paracentral gyri in the parietal lobe). More severe lesions correlated with lower sensorimotor performance, with the posterior limb of internal capsule score being the strongest contributor to impaired hand function., Conclusion: The sqMRI scale demonstrates first evidence of construct validity against impaired motor and sensory function measures and brain structural connectivity in a cohort of children with UCP due to PWM lesions. More severe lesions correlated with poorer paretic hand sensorimotor function and impaired structural connectivity in the hemisphere contralateral to the clinical side of hemiplegia. The quantitative structural MRI scoring may be a useful clinical tool for studying brain structure-function relationships but requires further validation in other populations of CP.

Background: Infants with normal fidgety movements at 3 to 5 months after term are very likely to show neurologically normal development, while the absence of fidgety movements is an early marker for an adverse neurological outcome, mainly cerebral palsy (CP). The clinical significance of so-called sporadic fidgety movements (i.e., fidgety movements occur isolated in a few body parts and are of 1- to 3-second-duration) is not yet known., Aims: Our objective was to determine whether infants who had developed CP and had sporadic fidgety movements have a better outcome than infants who did not have fidgety movements., Study Design: Longitudinal study. Retrospective analysis of prospectively collected data., Subjects: 61 infants who developed CP (46 male, 15 female; 29 infants born preterm; videoed for the assessment of movements and postures at 9 to 16 weeks post-term age)., Outcome Measures: The Gross Motor Function Classification System (GMFCS) was applied at 3 to 5 years of age., Results: There was no difference between children diagnosed with CP who had sporadic fidgety movements at 9 to 16 weeks post-term age (n = 9) and those who never developed fidgety movements (n = 50) with regard to their functional mobility and activity limitation at 3 to 5 years of age. One infant had normal FMs and developed unilateral CP, GMFCS Level I; the remaining infant had abnormal FMs and developed bilateral CP, GMFCS Level II., Conclusions: There is no evidence that the occurrence of occasional isolated fidgety bursts indicates a milder type of CP., (Copyright © 2015. Published by Elsevier Ireland Ltd.)

Background: Down syndrome is a frequent cause of intellectual disability, with severe impact on the quality of life of affected individuals and their families, and high social costs. Intervention programs should start soon after birth but no consensus exists on specific types and timing of early interventions in this population., Aim: This pilot study explores the effects of an early multi-sensory intervention, based on body massage, on the development of visual function in infants with Down syndrome., Method: Infants were randomly allocated to either a massage or a control group. Intervention consisted of only standard care (Control Group) or standard care plus infant massage (Massaged Group). Visual acuity was assessed by Teller Acuity Cards and stereopsis by the Frisby Stereopsis Screening Test at 5, 6, 9 and 12 months., Results: Massaged Group Infants showed a significantly higher visual acuity at 6 months of age and an accelerated development up to at least 12 months; compared to Controls, stereopsis had an earlier onset in the Massaged Group followed by a faster maturation., Conclusion: Environmental enrichment, in the tested form of infant massage, seems to affect maturation of visual functions in human infants, also in the presence of a genetic disability, when applied during a period of high brain plasticity., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Functional Transcranial Doppler ultrasonography (fTCD) was used to investigate the effects of early acoustic deprivation and subsequent reafferentation on cerebral dominance for language in deaf children provided with Cochlear Implantation (CI). Twenty children with CI (13 in right ear and 7 in left ear) and 20 controls matched for age, sex and handedness were administered a fTCD animation description task. Left hemisphere dominance for language with comparable mean Laterality Indexes (LIs) was found in children with CI and controls; right-ear implanted subjects showed cerebral activation controlateral to implanted ear more frequently than left-ear implanted ones. Linguistic proficiency of CI recipients was below age expectation in comparison to controls; language scores did not significantly differ between children with left and right LI, whereas both age and side of implantation were significantly related to language outcome. Theoretical implication and potential clinical application of fTCD in CI management are discussed., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background: Deficits of motion processing have been reported in premature and very low birth-weight subjects during infancy, childhood and adolescence. Less is known about ventral stream functioning in preterms., Aim: The aim of this study is to investigate ventral stream functioning in a sample of "healthy" adolescents born preterm with normal outcome and without brain damage., Study Design: We enrolled thirty preterm-born adolescents (mean age: 14.2years, mean gestational age 28.9weeks, mean birth weight 1097g), and 34 age-matched term-born controls (mean age: 14.5years). All subjects were administered a psychophysical test known as "Form Coherence Task" and a comprehensive standardized battery of neuropsychological tests suitable for investigating ventral stream functioning including Street Completion Test, Poppelreuter-Ghent Test and the first part of the Visual Object and Space Perception (VOSP) battery. Dorsal stream visual functioning was investigated by the second part of the VOSP., Results: Preterm (PT) subjects showed the same results in all "ventral" tasks with respect to full-term controls without any correlation to gestational age or birth weight. We found a significant negative correlation between Form Coherence Task and Letters Task (p=.014) and between Form Coherence and Silhouette Tasks (p=.017). No correlation was observed between Form Coherence Task and Street and Ghent Tests. A statistical difference was instead found between PTs and controls in two tasks of the VOSP battery that mostly involve the dorsal stream., Conclusions: Preterm birth per se (in absence of evident brain lesions) is not sufficient to compromise the development of ventral pathway., (© 2013. Published by Elsevier Ireland Ltd. All rights reserved.)

Background: Several studies report a high percentage of premature infants presenting perceptual motor difficulties at school age. The new version of the Movement Assessment Battery for Children allows the assessment of perceptual-motor abilities in children from the age of 3years., Aims: To evaluate early perceptual-motor abilities in prematurely born children below the age of 4years., Study Design: The Movement Assessment Battery for Children 2nd edition was administered to 105 low-risk prematurely born children (<32weeks gestation) and in a control group of 105 term-born children matched for age and sex. All children were assessed between the age of 3years and 3years-11months., Results: 63 children (60%) had total scores above the 15th percentile, 15 (14.3%) had scores between the 5th and the 15th percentile, and 13 (12.4%) below the 5th percentile. The remaining 14 children (13.3%) refused to perform or to complete the test. The difference between preterm and control group was significant for total scores, Manual Dexterity and Aiming and Catching scores. In the preterm group there was a correlation between age at testing, total scores and Aiming and Catching subscores. The Movement ABC-2 subscores were significantly lower in children born below 29weeks., Conclusion: Perceptual-motor difficulties can already be detected on the assessment performed before the age of 4years. Prematurely born children assessed between 3years and 3years-3months appeared to have more difficulties in performing the test than the older ones or their age matched term-born peers. These findings support the possibility of a delayed maturation in the younger age group., (© 2013 Elsevier Ireland Ltd. All rights reserved.)

Background: Several studies have reported on neonatal tremors or "jitteriness" or, as described by Precthl "hyperexcitability syndrome" including tremors and increased resistance to passive movement., Aim: To describe the evolution of signs and the outcome at one year in low risk term born infants with neonatal tremors persisting beyond 10 days., Subjects: 84 low risk term born neonates with tremors at birth and persisting after 10 days, underwent a longitudinal neurological assessment paying attention to the evolution of tremors and increased resistance to passive movement., Results: At 1 month 74 of the 84 infants had persistent tremors, isolated in 27 or associated with increased resistance to passive movement in the other 47. The remaining 10 had isolated increased resistance to passive movement and none had a normal assessment. The percentage of infants with a normal assessment progressively increased at 6, 9 and 12 months (34.5%, 77%, 93% respectively)., Conclusion: Our data suggest that neonatal tremors can have a variable evolution and rate of resolution, with 70% of recovery by 9 months with a normal outcome at 24 months in all. The risk of persistence of signs (at 12 months) in infants with either isolated tremors or increased resistance to passive movements is lower than in the subgroup with both signs at one month., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

"Psychomotor" development refers to changes in a child's cognitive, emotional, motor, and social capacities from the beginning of life throughout fetal and neonatal periods, infancy, childhood, and adolescence. It occurs in a variety of domains and a wide range of theories makes understanding children's development a challenging undertaking. Different models have tried to interpret the origins of human behavior, the pattern of developmental changes over time, and the individual and contextual factors that could direct child development. No single theory has been able to account for all aspects of child development, but each of them may contribute an important piece to the child development puzzle. Although theories sometimes disagree, much of their information is complementary rather than contradictory. The knowledge of child typical development and related theories and models is greatly useful for clinical practice, leading to recognition of developmental disorders and the ways in which they can be approached and treated. In this chapter, traditional and more modern concepts around functional development of psychomotor abilities are reported, firstly more in general and then specifically in the motor domain., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Background: Several studies have reported the development of various aspects of visual function in infancy and early childhood in both preterm and term-born infants, but only a few studies have focused on the predictive power of neonatal visual findings in infants with brain lesions., Aims: To explore visual findings at term age, and at 3 and 12 months corrected age in preterm infants (gestational age <33 weeks) with and without brain lesions; to compare the assessment at term age and at 12 months; and to assess the relationship between visual findings and neurodevelopmental outcome at 12 months., Study Design: Cranial ultrasound scans (US) were classified in normal, mild or major abnormalities. One-hundred and forty-five infants were assessed with age specific tests for visual function at term age, and at 3 and 12 months. Neurodevelopmental assessment (Griffiths' Scales) was performed at 12 months., Results: A good correlation was found between early and late visual assessment and neurodevelopment outcome. Of the 121 infants with normal neonatal visual assessment, 119 were also normal at 12 months and 116 had normal developmental quotient. Of the 24 infants with abnormal neonatal visual assessment, 12 were also abnormal at 12 months. All the false positives had normalised by 3 months. Of the 35 infants with major US abnormalities, 20 had normal and 15 abnormal scores on the neonatal assessment. At 1 year 17 had normal and 18 abnormal scores., Conclusion: A normal visual assessment at term age is a good predictor of normal visual and neurodevelopmental outcome at 12 months. An abnormal visual examination in the neonatal period was a less reliable prognostic indicator, infant should be reassessed at 3 months., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

During the perinatal period, the nervous system is very vulnerable to insult. At this time, the brain undergoes fast and complex maturational processes such as synaptogenesis, arborization, and apoptosis, and the response to the insult is highly dependent on its exact timing. There is evidence that some of the neuroplastic mechanisms adopted by the young brain after damage are unavailable at a later stage of maturation. This applies, for example, to the reorganization of language, the sensorimotor system, or the visual system. Expanding our knowledge on these mechanisms could help the development of early therapeutic interventions aimed at supporting and enhancing functional reorganization at a time of greatest potential brain plasticity., (Copyright © 2011 Elsevier B.V. All rights reserved.)

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., (Copyright (c) 2010 Elsevier Ltd. All rights reserved.)

In the present paper, we address brain-behaviour relationships in children with acquired aphasia, by reviewing some recent studies on the effects of focal brain lesions on language development. Timing of the lesion, in terms of its occurrence, before or after the onset of speech and language acquisition, may be a major factor determining language outcome. However, it is still unclear which are the effects of aphasia occurring between 2 and 5 years of age, a time window which is crucial for acquiring and automatizing the basic rules of native language. A comprehensive review of the literature on acquired childhood aphasia precedes the description of long-term follow-up (20 years) of two identical twins, one of whom became aphasic at 3 years and 4 months after infarction of the left sylvian artery. Psycholinguistic analysis and fMRI data show a slow and incomplete recovery from non-fluent aphasia associated to an intra-hemispheric organization of language. These data, which support the potential but also the limits of neural plasticity during language development, are discussed in the light of the literature on the time-course and neural bases of acquired childhood aphasia.

Creatine transporter 1 (CT1) defect is an X-linked disease that causes severe neurological impairment. No treatment has been available for this condition so far. Because the transport of creatine (Cr) precursors Gly and Arg is not affected in this disorder, we tested the possible corrective effect of these two amino acids on Cr depletion in lymphoblasts lacking the transporter. Substrates enriched with Arg or Arg plus Gly increased the concentration of intracellular Cr in affected cells as well as in control cells. The greatest effect was obtained with 10 and 15 mM Arg and 10mM Arg plus Gly. These results encourage an in vivo trial with Cr precursors in CT1 defect.

Objective: To examine the reorganisation of the somatosensory system after early brain lesions., Methods: We studied 12 young patients with congenital hemiplegia. Causative lesions were brain malformations, periventricular injuries and cortico-subcortical lesions. We explored the somatosensory system using evoked potentials, fMRI during sensory stimulation and clinical assessment of sensory function. To correlate sensory and motor function, we also performed transcranial magnetic stimulation, fMRI of hand movement and assessment of motor function by means of Melbourne test., Results: Eleven patients showed a perilesional reorganisation of primary somatosensory function, as expressed by short latency potentials following stimulation of the paretic hand; in a remaining patient, delayed latency responses (N27.1) were only elicited over the ipsilateral undamaged hemisphere. Five of the eleven patients with perilesional somatosensory representation of the affected hand showed contralesional shifting of motor function, thus exhibiting sensory-motor dissociation. Significant correlation was found between sensory deficit and fMRI activation during sensory stimulation., Conclusions: In subjects with early brain lesions, somato-sensory function is generally reorganised within the affected hemisphere. A contralesional shifting is uncommon and poorly efficient in function restoration., Significance: This study confirms and further explores the difference in reorganisation capabilities of the motor and sensory system following early brain injury of different etiologies and timing.

Objective: The aim of this study was to examine the relationship between cortical development and cerebral electrical activity at early gestational ages., Methods: We obtained EEGs (7.2+/-3.8 days) and MR brain images (3.2+/-2.9 days) after birth in 17<30 week gestation infants without evidence of focal brain injury The EEGs were assessed for discontinuity and characteristic maturational features (delta brush, occipital and temporal sawtooth); cortical development was quantified from MR scans using a specially designed computer programme to measure cortical folding., Results: The inter-burst interval shortened and cortical folding increased with increasing post-menstrual age (PMA). In contrast, the minimum duration of bursts was independent of PMA and cortical folding. Delta brush (8-20 Hz activities) was seen at all PMAs; temporal and occipital sawtooth activities were always more prominent than delta brush but were seen less frequently with increasing PMA and complexity of cortical folding., Conclusion: There was a positive correlation between some but not all maturational features of the preterm neonatal EEG and the complexity of whole brain cortical folding and PMA. These relationships were strong for the inter-burst interval, a global measure of maturation, but not strongly seen for regional features such as occipital and temporal sawtooth within this gestational age range., Significance: Combining neurophysiological examination with detailed neuroimaging gives insights into developmental changes occurring in the very preterm brains and suggests further comparative studies focusing on measures of focal brain development at different gestational ages.

The study aimed to evaluate the development of awakenings during preterm and term age in 12 low-risk infants observed between 33 and 40 weeks of post-conceptional age. Waking was been detected through the analysis of body motility. Gross generalized body movements with prolonged startles, marked stretching and writhing was considered as waking, whereas vigorous, forceful abrupt body movements with high frequency tremor sometimes superimposed upon movements were considered as corresponding to crying. Total number of awakenings in the 24 h does not show significant changes with age, whereas the mean duration increases significantly, which is accounted for mainly by those awakenings starting with crying, in particular, during the day. These data suggest a developmental gap between the ability to sustain the waking state, which already starts to increase before term age, and the ability to maintain prolonged sleep episodes, which has been shown to develop later. Furthermore, the developmental difference between awakenings starting with crying and awakenings starting with wakefulness suggests that two kinds of awakenings might be modulated by different factors.

At the onset of West syndrome a specific impairment of visual function has been clearly demonstrated, while other aspects of sensorial development, and in particular of the auditory function, have been less studied. The aim of this study was to evaluate auditory function and orienting responses at the onset of West syndrome, and to relate the results with EEG patterns, visual function and neurodevelopmental competence. A prospective multicentric study was performed on 25 successively enrolled infants with West syndrome; all the patients underwent a full clinical assessment, including MRI and video-EEG, visual function and auditory orienting responses (AORs) as well as Griffiths' developmental scales. The whole assessment performed at the onset of spasms (T0) was repeated after two months (T1). AORs resulted significantly impaired both at T0 and T1. At the onset of spasms a highly significant relationship of auditory attention with visual function and neurodevelopmental competence was shown in both cryptogenic and symptomatic forms, but it was no longer present after two months. Our results may suggest a possible pervasive effect of the epileptic disorder on sensory processing, associated to a deficit of neurodevelopment. Although we failed to show a significant correlation between auditory orienting responses and EEG patterns, some evidence seems to support at least partially an influence of the epileptic disorder per se on the genesis of the sensorial impairment. A longer follow up and a larger cohort will be useful for a better clarification of these findings.

The aim of this study was to evaluate the organisation of EEG patterns in 24-h recordings of preterm and near-term neonates. In particular, the distribution of the different EEG codes at different postmenstrual ages (PMA) and the variations of sleep-related EEG pattern organisation was studied, during day (8.00 a.m.-8.00 p.m.) and night (8.00 p.m.-8.00 a.m.) time. The age of appearance of different neonatal EEG patterns, previously described in literature for short lasting records, was confirmed in this 24-h study. The medium-voltage continuous EEG pattern (pattern "3") was less represented approaching term age, in coincidence with the appearance of the two low-voltage continuous patterns ("1" and "2"), which are also related to active sleep and wakefulness. Discontinuous pattern ("7") was also less represented with age, but in day-time only. The percentage of time occupied by this pattern, related to quiet sleep, was significantly higher during day-time hours, than at night.

The neonatal behavioral observation is an important source of medical information in three domains: 1) assessment of development which can be done with the Assessment of Preterm Infant Behavior, 2) assessment of pain with the analysis of facial expression using validated pain scales such as the Neonatal Facial Coding System, 3) assessment of brain injuries with the Quality Assessment of General Movements. Such a behavioral observation of the newborn using validated tools is a useful complement of the neuro-imaging techniques.

Muscle biopsy was examined in 20 children with cerebral palsy, using immunohistochemical methods for marker of denervation neural cell adhesion molecules (N-CAM) in addition to standard techniques. Histological and histochemical study showed mild myopathic changes, type 1 predominance, and type 1 and type 2 hypotrophy, in accord with previous observations. Immunohistochemical study showed N-CAM expression in most biopsies (15/20), usually in scattered fibers, whereas in four patients aged less than 6 years it was expressed in grouped fibers. Our study supports the hypothesis of motor unit remodeling as a consequence of spasticity, especially in early phases of the disease.

Objective: To evaluate EEG maturational features in preterm infants below 27 weeks postmenstrual age., Methods: EEGs recorded from 5 preterm infants (postmenstrual age 24-26 weeks) were examined and selected maturational features were scored and quantified. The five infants also had serial cranial ultrasound scans (US) and magnetic resonance images of the brain within the first weeks after birth., Results: Background activity was markedly discontinuous in all patients and very variable. Temporal sawtooths occurred but less frequently than in older preterm infants. All 5 infants also showed a particular novel feature, characterized by rhythmic, regularly shaped, medium-high amplitude 4-7 Hz activities, lasting 0.5-3 s and located in the occipital regions. This pattern was symmetrical but sometimes asynchronous., Conclusions: Occipital sawtooth, so called because it shares shape and frequency with temporal sawtooth but has an occipital localisation, constitutes a physiological EEG pattern characteristic of premature infants between 24 and 26 weeks of postmenstrual age.

Objectives: Selected EEG features were evaluated in 21 constantly discontinuous tracings recorded on the same number of full-term neonates with hypoxic-ischaemic encephalopathy., Methods: The tracings were examined without using interval amplitude as the basis for distinguishing between burst-suppression and nonburst-suppression patterns., Results: The results were related to outcomes and other clinical parameters (severity of hypoxic-ischaemic encephalopathy, pO2 levels and drug intake)., Conclusions: Features defining the grade of EEG discontinuity (i.e. maximum interval duration, minimum burst duration and interval amplitude) significantly related to outcome and, in most cases, to the grade of hypoxic-ischaemic encephalopathy. Other features (amplitude of slow waves within the burst and incidence of abnormal EEG transients) related to PO2 levels. The consumption of anticonvulsant drugs increased EEG discontinuity, but this effect did not seem dose-related. Finally, the persistence of a constantly discontinuous EEG pattern after the first week of life is a sign of unfavourable prognosis. In full-term neonates with hypoxic-ischaemic encephalopathy quantitative analysis of all constantly discontinuous EEGs seems more useful than only describing burst-suppression patterns on the basis of interval amplitude.

Posture, quantity of spontaneous movement patterns, quality of general movements (GMs), and behavioural state organisation were studied in nine infants affected by documented brain malformations. A single 1 h video recording of five infants and two or more serial video recordings of another four infants were performed after birth. The graphic representation of single movement patterns (actogram) and of behavioural states of one video recording was performed in eight out of nine infants. The quality of GMs was assessed according to Prechtl's method in all video recordings. All nine infants showed a less variable posture than normal newborn infants and an unusual resting posture was detected in seven infants. Poor behavioural state organisation without sleep cycles was common to the nine infants and excessive wakefulness was observed in six infants. As for the quantity of single movement patterns, six infants lacked one or two movement patterns normally present in healthy newborn infants. An abnormal quality of GMs was noted in all nine infants and distinct motor abnormalities were observed in single infants. A monotonous and sometimes stereotyped sequence of different body parts involved in the movement (i.e. poor repertoire GMs) was common to all infants. In the four infants of whom two or more video recordings were available, initial poor repertoire GMs were followed by a further deterioration in movement quality. No relationship was found between the quantity of defective brain tissue, lack of a specific part of the brain, type and severity of GM and posture abnormalities.

We describe the state of the art of Prechtl's method for the qualitative assessment of general movements as a diagnostic tool for early detection of brain dysfunction. After discussing the optimal technique for video recording general movements in preterm, term and young infants, attention is focused on the proper analysis of this spontaneous motor pattern. Recently, a group of active researchers in the field reached consensus on the various qualities of normal and abnormal general movements. These definitions are reported here in full. Since it is a newly introduced method careful investigation into its reliability is required. Various groups of investigators have obtained data which demonstrate the robust character of the method (interscorer agreement: 78-98%). Finally, we discuss the validity of this early assessment method on the basis of the reports published so far. While the method's sensitivity is similar in all age groups studied (preterm, term, first month, second month, and third month age epochs), and averages 94.5%, the specificity of the method is age-dependent. It is low during the early ages, increases gradually and reaches 82 to 100% at 3 months post-term. This phenomenon is explained by spontaneous recovery of early dysfunction. In contrast, consistent abnormalities of general movements are linked to neurological deficits found at the 2 year follow-up.

The qualitative assessment of general movements (GMs) has been shown to be a better predictor of neurological outcome than the traditional neurological examination in brain-damaged preterm infants. The aim of this study was to compare the results of the two techniques in term infants. Off-line assessment of GMs from videorecordings and neurological examinations were carried out, from birth till about 6 months of postterm age, in a group of 58 term infants, the majority of which were affected by mild to severe hypoxic-ischaemic encephalopathy. The agreement between the two techniques and their predictive power, with respect to the neurological outcome at 2 years, were evaluated for four age groups. The range of agreement between neurological and GM findings was between 78 and 83%. At all ages the results of GM observation correlated highly with the neurological outcome; their sensitivity and specificity with respect to outcome were consistently slightly superior to those of neurological examination. In infants normalize after an initial period of transient abnormalities, GMs normalize earlier than the neurological results.

The correlation between MRI findings and sensorimotor development was investigated in a group of 48 infants with bilateral spastic cerebral palsy (CP). The ages at MRI examination and cognitive assessment were fairly homogeneous (mean 15 months and 17 months, respectively). The following MRI parameters were scored: size of lateral ventricles, extension of white matter lesions and of white matter reduction, thinning of corpus callosum, presence and size of cystic areas, dimension of subarachnoid spaces and presence of cortical abnormalities. Cognitive assessment included Griffiths Developmental Scales and Uzgiris-Hunt Scales. The patients were subdivided into six classes according to intellectual level (DSM-III-R). For the whole group a highly significant correlation was found between all MRI parameters and the level of cognitive development. This result was probably due to the inclusion of 14 untestable, severely mentally retarded infants, who showed very severe MRI abnormalities. However, when the untestable infants were excluded from the analysis, it was the presence of cysts and the entity of white matter reduction that correlated with both Griffiths Scales and Uzgiris-Hunt Scales. These results indicate the clinical value of MRI findings and particularly of white matter abnormalities for early identification of sensorimotor impairment in infants with bilateral spastic CP.

Background: In normal awake infants, fidgety movements are seen from the age of 6 weeks to 20 weeks. The aim of the study was to test the predictive value of absent or abnormal spontaneous movements in young infants for the later development of neurological deficits., Methods: In a collaborative study involving five hospitals we collected data on the normal and abnormal quality of fidgety movements of 130 infants and compared it with assessments of neurological development done longitudinally until the age of 2 years. On the basis of ultrasound scans infants were classified as at low-risk or at high-risk of neurological deficits. Infants were videoed for 1 h every week from birth to discharge and then for 15 min every 3 to 4 weeks; quality of general movements was assessed. Repeated neurological assessments were also done until 24 months of corrected age., Findings: 67 (96%) of 70 infants with normal fidgety movements had a normal neurological outcome. Abnormal quality or total absence of fidgety movements was followed by neurological abnormalities in 57 (95%) of the 60 infants (49 had cerebral palsy and eight had developmental retardation or minor neurological signs). Specificity and sensitivity of fidgety movement assessment were higher (96% and 95%, respectively) than of ultrasound imaging of the infants' brain (83% and 80%, respectively)., Interpretation: Our technique of assessing spontaneous motor activity can identify and distinguish between those infants who require early intervention for neurological abnormalities and those who do not. Our technique is simple, non-intrusive, reliable, quick, and can be done on very young infants.

The prognostic value of abnormal EEG transients was investigated in 362 subjects submitted to EEG recording during the neonatal age and followed-up at least until the 12th month of corrected age. The incidence of negative and positive spikes and sharp waves, of rhythmic sharp theta and delta activities and of alpha discharges were evaluated by means of a quantitative score. These abnormal EEG transients appeared to be generally rare and even absent in a large number of subjects. In infants with normal outcome their incidence tends to increase from low postmenstrual ages towards term period. Full-term newborns with abnormal neurological outcome presented a significantly higher incidence of these transients. Preterm infants with unfavourable evolution showed a higher incidence only when submitted to EEG recording at around term age. However, no difference between subjects with normal and abnormal outcome was detected in preterm infants when evaluated at low postmenstrual ages. The hypothesis that at low postmenstrual ages brain damage might, on the one hand, give rise to abnormal transients and, on the other, alter the "capability' of manifesting them (together with other EEG maturational aspects), might explain these results.

The characteristics of rhythmical kicking movements of preterm infants with documented brain damage (BD), who later showed a severe motor impairment, are described and compared with those of low-risk (LR) preterm infants. Spontaneous movements were videotaped for 60 min in the incubator or in a warmer. A first group of 6 BD and 6 LR infants was observed at 31-35 weeks of postmenstrual age (PMA) and a second group (6 BD, 6 LR) at 37-39 weeks. Bouts of rhythmical kicks, defined as leg movements repeated in the same form at least three times at regular short intervals, were analysed during periods of activity. The results indicated non-significant differences between BD and LR infants at 31-35 weeks of PMA. In contrast, some differences were observed at 37-39 weeks. These differences were not due to leg movement frequency, but to inter-leg coordination and to temporal organisation of the kicking cycles. LR infants exhibited more alternate-leg movements and fewer semi-both-leg movements (simultaneous flexion and non-simultaneous extension) than BD infants. In LR cases the duration of the pause between flexion and extension was shorter, whereas flexion and extension periods were similar for all infants. Although there were significant differences, quantitative analysis of kicking characteristics was not clinically useful because of the large overlap in findings between the two groups. On the other hand Gestalt evaluation of general movements of the same videorecordings showed a closer correlation with the presence of brain lesions and with neurological outcome.

The aim of this study is to identify normal EEG patterns of preterm infants, characteristic of early postmenstrual ages (PMAs). Quantitative features of EEG background activity have been examined in records from 83 preterm infants within the first 2 weeks of life at a PMA of 27-34 weeks. These subjects presented different cranial ultrasound findings and different outcomes. EEG quantitative data have been compared to the subsequent neurological evolution. We supposed that the features of EEG background activity which were associated with a favourable outcome should be considered as indexes of "normality" of the tracing for that specific PMA. At 27-30 weeks of PMA a high incidence of "temporal sawtooth," a particular rhythmic theta activity detectable in temporal regions, relates to a favourable evolution, therefore it can be assumed that this activity is a normal feature of EEG tracings at this age. On the contrary, a significant correlation between a high incidence of "temporal sawtooth" and an abnormal outcome is observable at 33-34 weeks and leads us to deduce that this pattern should disappear at this time. After 31 weeks other parameters (such as the incidence of 8-20 Hz activities, the length of the intervals and burst duration) show a significant correlation with the outcome.

Visual acuity testing using Teller Acuity Cards was carried out on 78 infants and children affected by cerebral palsy (CP). Age of testing was between 3 and 109 months. The aim of the study was to investigate the usefulness of acuity cards in patients with CP, and to relate visual outcome with the type of CP, MRI findings, mental levels and motor disabilities. Visual acuity estimates were obtained for 60 children: acuity values were within normal values for age for 17 and below the 5th percentile for 43. Cerebral blindness was diagnosed in 10 patients. Eight infants were not testable, mainly because of behavioural problems. The overall success rate was 88%. Visual impairment in most infants with low acuity and in all blind children was not due to ophthalmological abnormalities. Visual outcome was significantly related to the type of CP, with hemiplegic children showing the best results and tetraplegics the worst. Cerebral blindness was significantly correlated with tetraplegia, the severity of lesions in the optic radiations, and visual cortex areas, as indicated by MRI, and the degree of mental, motor and oculomotor deficit. These correlations were mainly due to the blind subjects, who consistently showed major MRI abnormalities and severe motor, mental and oculomotor impairment. Longitudinal results obtained for 45 children showed visual outcome stable over time in 64.4% of cases, improvement in 6.6% and deterioration in 28.9%.

The early development of walking was investigated in 25 normal fullterm and in 25 low-risk preterm infants. All subjects were videorecorded within 3-4 weeks of the beginning of independent walking and again 4 months later. Analysis of the videos was carried out according to a predetermined list of items, with a semiquantitative score for each. The results indicate wide interindividual differences in normal infants in the form of independent walking. Several items seemed to be associated in different ways in different individuals. Age of onset, as long as the corrected age was considered, did not differ between preterm and fullterm infants, neither did their walking patterns. Gait asymmetries were often observed in both groups and they were related with asymmetries observable in prewalking locomotor behaviour. Toe-strike often occurred at the beginning of walking, but not after 4 months; in preterm infants the toe strike pattern correlated significantly with certain motor characteristics observed during the first weeks of life.

The developmental course of spontaneous motility was investigated in a group of 26 fullterm infants, affected by mild to severe hypoxic-ischaemic encephalopathy. Serial 1-h videorecordings were carried out from birth to 15-22 weeks and a quality assessment of general movements (GMs) was made from a replay of the videos. Neurological follow-up of the infants were continued until at least 18 months of age; neonatal EEG and neuro-imaging techniques (US-scan, CT or MRI) were also carried out in all cases. The results indicate that perinatal asphyxia has important effects on the spontaneous motility of fullterm infants. Hypokinesis occurred very frequently during the first days of life, followed by a transient or prolonged (lasting longer than 15-22 weeks) abnormal quality of GMs. In the first 2 weeks the results of GM assessment did not correlate with the simultaneous findings of neurological examination, neuro-imaging and EEG, whereas they did when the results at 15-22 weeks were considered. The changes in spontaneous motility and especially GM developmental trajectories were good predictors of the neurological outcome. The predictive value of GM assessment was found to be similar to that of EEG and neuro-imaging, and better than neurological examination.

Brain magnetic resonance (MR) was performed in 29 liver cirrhosis patients without (N = 10) and with hepatic encephalopathy (HE) of chronic recurrent (N = 10) and of chronic persistent (N = 9) type. Sixty percent of the patients with chronic recurrent HE and 100% of the patients with chronic persistent HE showed a bilateral and symmetrical hyperintensity of the globus pallidus in the T1-weighted images while the T2-weighted images were normal, suggesting the possibility of the accumulation of a paramagnetic compound in this brain area during HE. Other findings of the study were evidence of brain atrophy of mild or moderate degree in 70% of patients with chronic recurrent HE and in 77% with chronic persistent HE and patients with liver cirrhosis without HE appeared normal on MR examination.

The development of spontaneous motility and posture was studied longitudinally in 14 carefully selected low-risk preterm infants. The aim of this investigation was to provide a set of data suitable for comparison with fetuses and with neurologically abnormal preterm infants. The infants were videorecorded weekly, for one hour in a supine position, from birth until their discharge from the hospital. Ten of them were thereafter also observed at home at 3-week intervals from 3 to 18 weeks of corrected age, together with 10 healthy fullterm infants. Occurrence and duration of motor patterns and postures in periods of rest and activity were obtained by off-line analysis of the videotapes. Few significant changes were found from birth until term age in the composition and quantity of the spontaneous movement patterns. Only twitches and stretches during activity periods showed a small decline approaching term age. However, notable inter-individual differences and intra-individual fluctuations from week to week were observed. Postterm development of preterm infants was similar to that of the fullterms. Both showed considerable changes in the qualities of general movements after the first postterm weeks. Only fidgety character movements occur earlier in preterm infants. No age-specific preference postures of the limbs were found in the preterm period. Midline position of the head in supine was observed at about the same postterm age in preterm and fullterm groups. Asymmetrical tonic neck postures were very inconsistently present before term age and rapidly disappeared after term, earlier so in preterm infants.