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Importance: Cerebral palsy (CP) is the most common childhood physical disability. Early intervention for children younger than 2 years with or at risk of CP is critical. Now that an evidence-based guideline for early accurate diagnosis of CP exists, there is a need to summarize effective, CP-specific early intervention and conduct new trials that harness plasticity to improve function and increase participation. Our recommendations apply primarily to children at high risk of CP or with a diagnosis of CP, aged 0 to 2 years. Objective: To systematically review the best available evidence about CP-specific early interventions across 9 domains promoting motor function, cognitive skills, communication, eating and drinking, vision, sleep, managing muscle tone, musculoskeletal health, and parental support. Evidence Review: The literature was systematically searched for the best available evidence for intervention for children aged 0 to 2 years at high risk of or with CP. Databases included CINAHL, Cochrane, Embase, MEDLINE, PsycInfo, and Scopus. Systematic reviews and randomized clinical trials (RCTs) were appraised by A Measurement Tool to Assess Systematic Reviews (AMSTAR) or Cochrane Risk of Bias tools. Recommendations were formed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) framework and reported according to the Appraisal of Guidelines, Research, and Evaluation (AGREE) II instrument. Findings: Sixteen systematic reviews and 27 RCTs met inclusion criteria. Quality varied. Three best-practice principles were supported for the 9 domains: (1) immediate referral for intervention after a diagnosis of high risk of CP, (2) building parental capacity for attachment, and (3) parental goal-setting at the commencement of intervention. Twenty-eight recommendations (24 for and 4 against) specific to the 9 domains are supported with key evidence: motor function (4 recommendations), cognitive skills (2), communication (7), eating and drinking (2), vision (4), sleep (7), tone (1), musculoskeletal health (2), and parent support (5). Conclusions and Relevance: When a child meets the criteria of high risk of CP, intervention should start as soon as possible. Parents want an early diagnosis and treatment and support implementation as soon as possible. Early intervention builds on a critical developmental time for plasticity of developing systems. Referrals for intervention across the 9 domains should be specific as per recommendations in this guideline.

To investigate the feasibility of a study based on treatment with topiramate (TPM) added to moderate hypothermia in newborns with hypoxic ischemic encephalopathy (HIE).Multicenter randomized controlled trial. Term newborns with precocious metabolic, clinical and electroencephalographic (EEG) signs of HIE were selected according to their amplified integrated EEG pattern and randomized to receive either TPM (10 mg/kg once a day for the first three days of life) plus moderate hypothermia or hypothermia alone. Safety was assessed by monitoring cardiorespiratory parameters and blood samples collected to check renal, liver, metabolic balance and TPM pharmacokinetics. Efficacy was evaluated by the combined frequency of mortality and severe neurological disability as primary outcome. Incidence of magnetic resonance injury, epilepsy, blindness, hearing loss, neurodevelopment at 18-24 months of life was assessed as secondary outcomes.Forty-four asphyxiated newborns were enrolled in the study. Twenty one newborns (10 with moderate and 11 with severe HIE) were allocated to hypothermia plus TPM and 23 (12 moderate and 11 severe HIE) to hypothermia. No statistically or clinically significant differences were observed for safety, primary or secondary outcomes. However, a reduction in the prevalence of epilepsy was observed in newborns co-treated with TPM.Results of this pilot trial suggest that administration of TPM in newborns with HIE is safe but does not reduce the combined frequency of mortality and severe neurological disability. The role of TPM co-treatment in preventing subsequent epilepsy deserves further studies.

Visual functions are often impaired in preterm infants with periventricular haemorrhagic infarction, because of the involvement of the region where the optic radiations are located. In some cases an unexpected sparing of the visual fields has been described, and related to the plasticity of thalamo-cortical afferents that are supposedly able to bypass the lesion when it occurs in the early third trimester of gestation. We systematically reviewed the literature in the field to determine the limits and potentials of this type of reorganization. We found four studies meeting our criteria, from which we extracted case reports on 19 individuals with intraventricular haemorrhagic infarction. Eleven of the 19 did not have visual field defects, five had a bilateral visual field defect, and the remaining three had a unilateral visual field defect. The involvement of the optic radiations was often associated with normal visual fields as only one of the four individuals with damaged optic radiations showed visual field defects. Conversely, the presence of basal ganglia/thalamus involvement apparently prevented such reorganization, as the only two individuals with unilateral field restriction and available magnetic resonance imaging data both showed abnormalities in those structures. Consistent with this, we report on a further individual in which visual field restriction was associated with abnormal tractography on brain magnetic resonance imaging. Overall, this review supports the existence of effective mechanisms of plastic reorganization that allow a rewiring of geniculo-calcarine connections with restoration of full field vision but which are hindered by the involvement of the basal ganglia and thalamus.

Aim Early intervention programmes based on the manipulation of the extra-uterine environment have been used in preterm infants with the aim of improving development and functional outcome. Infant massage, among them, has proved effective for weight gain and reduced length of stay in the neonatal intensive care unit. We have recently shown that infant massage accelerates brain maturation of low-risk preterm infants without brain abnormalities as measured by global parameters of electroencephalography (EEG) activity. In the present study we further analyse the same cohort of preterm infants, testing the hypothesis that massage determines changes in EEG spectral activity, a highly sensitive index of brain maturation. Method Infants were randomly allocated to a massage or comparison group. Intervention consisted of standard care only (comparison group) or standard care plus infant massage (massage group). Massage was started at around 10 days after birth and was provided for 12 days during a 2-week period. EEG was performed at around 1 and 4 weeks, i.e. before and after intervention. Spectral EEG analysis was performed on 80 seconds of active sleep, applying the fast Fourier transform on the signal obtained from eight monopolar derivations. Results The modification in global EEG spectral power between the two assessments was significantly different for the two groups, especially for the delta band activity; the spectral power did not change in massaged infants although, not surprisingly, it decreased significantly in the comparison group, as shown by previous studies. Interpretation We propose that massage intervention affects the maturation of brain electrical activity and favours a process more similar to that observed in utero in term infants.

Objective The aim of this study was to evaluate the epileptic and developmental evolution in infants with West syndrome. Methods A prospective study of 21 infants was performed, with a follow-up at 2 years. Serial assessment included long-term EEG monitoring, visual and auditory evaluation and assessment of neurodevelopment. Results Neurosensory and developmental impairments at the spasm onset were transitory in seven cases, including four cryptogenic forms. In all other cases, there was a progressive worsening in neurosensory and developmental impairments. The epileptic evolution was generally better: in 11 of the 16 infants without seizures at outcome, spasms had already disappeared by 2 months after disease onset. Statistic analysis of results showed a correlation between neurosensory impairment and development throughout the whole follow-up. In addition, visual function at T1 resulted significant predictor of developmental outcome. Among the epileptic features, disorganization of slow sleep was an unfavorable prognostic factor. Conclusion Some forms of West syndrome are confirmed to have a benign evolution: among them there are not only cryptogenic cases but also symptomatic ones without significant neurodevelopmental impairment. Abnormalities of sleep organization, expression of the pervasive epileptic disorder, seem to play a role in determining a developmental deterioration. Neurosensory impairment since the onset of the disease could be a relevant cause of the developmental disorder.

It has been controversial whether electrophysiology offers better precision than behavioural techniques in measuring visual acuity in children with brain damage. We investigated the concordance between sweep VEPs and Acuity Cards (AC) in 29 children with periventricular leukomalacia (PVL), the most common type of brain damage in preterm infants. An overall good correlation was shown but with relatively better behavioural acuity values. VEP/AC ratio was significantly correlated to corpus callosum posterior thinning. We propose that this result reflects the efficacy of the compensatory mechanisms following early brain damage which may differentially affect the two methods.

Background Strabismus is one of the most common visual disorders in infancy. While there is a great attention on the effects of the timing of surgery as to the development of binocular vision, little is known about the possible influence of congenital strabismus on perceptual-motor and more generally, on neuromotor development. Aims Aim of this study was to investigate perceptual-motor and motor coordination abilities of 19 children with essential congenital esotropia who underwent a late surgery (after 4 years), compared to 23 age-matched controls. Methods Children were tested using the Movement Assessment Battery for Children (Movement ABC) that were performed both 1-week before surgery (T1) and about 3 months (±2 weeks) after surgery (T2). Results and conclusions At T1, abnormal or borderline results were found in more than half of the children with strabismus, as opposed to only about 17% of the controls. At T2 none of the children showed abnormal Movement ABC total scores and there was no difference in global scores between the study and the control group. The two groups also did not show any significant difference in individual items of the movement ABC with the exception of those assessing ball skills. Our results suggest that surgical correction of strabismus, even when performed after the 4th year of life, appears to be effective in improving perceptual-motor and motor function.

Psychological tests based on visual information processing have shown to be promising in predicting neurodevelopmental outcome in infants at risk. In the present study we prospectively investigated the early development in a group of 20 high-risk preterm infants by means of i) the Fagan Test of Infant Intelligence at 7, 9, and 12 months postterm and ii) a detailed battery for the early assessment of visual functions at 6 and 10 months postterm. The results were then correlated to the Griffiths development scales at two years. At around 7 months no correlation was found in our infants between the Fagan test and neurodevelopmental outcome, possibly as a consequence of the influence of abnormal oculomotor behaviour. At around 9 months most of the visual abnormalities were no more present and the Fagan test was significantly correlated with the outcome. At 12 months postterm a decline of the predictive value of the FTII was observed. In conclusion, nine months postterm age appears to be the best age for the early assessment of neurodevelopmental outcome in high-risk preterm infants, as the maturation of the attentional and visual systems allows a more reliable evaluation.

Environmental enrichment (EE) was shown recently to accelerate brain development in rodents. Increased levels of maternal care, and particularly tactile stimulation through licking and grooming, may represent a key component in the early phases of EE. We hypothesized that enriching the environment in terms of body massage may thus accelerate brain development in infants. We explored the effects of body massage in preterm infants and found that massage accelerates the maturation of electroencephalographic activity and of visual function, in particular visual acuity. In massaged infants, we found higher levels of blood IGF-1. Massage accelerated the maturation of visual function also in rat pups and increased the level of IGF-1 in the cortex. Antagonizing IGF-1 action by means of systemic injections of the IGF-1 antagonist JB1 blocked the effects of massage in rat pups. These results demonstrate that massage has an influence on brain development and in particular on visual development and suggest that its effects are mediated by specific endogenous factors such as IGF-1.

Background. The effects of renin-angiotensin system blockade on nitric oxide (NO), especially in pathological conditions, are far from being established. The influence of kinins and angiotensin type 2 receptor are largely speculative and based mainly on animal studies. This study was aimed to address these aspects in humans. Methods. Eight IgA nephropathy patients with documented clinical and histological indicators of poor prognosis were given 50 mg of losartan, 10 mg of enalapril, and 40 mg of the NO donor isosorbide 5 mononitrate (as a control of NO generation) in randomized order for 7 days each. Treatment periods were separated by washout periods of 7 days each. Laboratory investigations were performed before and after each study period. Seven healthy controls received losartan and enalapril according to the same study design. Results. Glomerular filtration rate remained stable while effective renal plasma flow increased with each treatment (P

Summary: While a variety of immunologic factors are likely to be involved in the initial acute phlogistic events in IgA nephropathy (IgAN), progression to renal failure occurs through a relatively silent course histologically related to prevalent sclerotic changes. In this phase of IgAN, haemodynamic mechanisms are likely to play the most important role. Among the others, angiotensin II and endothelin 1 are thought to be critical mediators. Angiotensin II promotes mesangial cell contraction, modulates membrane permselectivity and induces glomerular hypertension. Evidence for a local angiotensin II hyperactivity in IgAN (especially in patients at definite risk of progression) has been previously provided by our group. Endothelin 1 is mitogenetic for mesangial cells and increases matrix production. Moreover, it exerts local vasoconstrictor effects and induces mesangial cell contraction, both resulting in glomerular afterload. Again, plasma and urinary endothelin 1 are elevated in IgAN. Moreover, those patients with increased risk of progression show an increased ratio between urinary endothelin 1 and cyclic guanosine 3′,5′ monophosphate (GMP), a local messanger with counterbalancing effects. Several data of clinical benefits of angiotensin-converting enzyme inhibitors in IgAN have been reported. Less is known about the intrinsic mechanism of the antiproteinuric action, either reduction of filtration fraction or changes in glomerular permselectivity. The clinical usefulness of factors counterbalancing endothelin 1 effects, such as nitric oxide donors, remains to be established. A sample of eight IgAN patients with poor prognostic indicators was enrolled to examine the renal haemodynamic effects of angiotensin receptor antagonism, angiotensin-converting enzyme inhibition and administration of an exogenous source of nitric oxide. Study periods (7 days each) were randomized and spaced out by one week wash-out. Data showed that angiotensin receptor antagonism and angiotensin-converting enzyme inhibition were equally effective in modifying renal haemodynamics, but only the latter condition significantly reduced albuminuria, possibly indicating a prevalent action on membrane permselectivity in the short time period of the study. The antiproteinuric effects of nitric oxide donors were strictly confined to patients with increased urinary endothelin 1/cyclic GMP ratio. Finally, each treatment condition was found to be associated with an increased nitric oxide production, which appeared to be an additional factor in modulation of filtration fraction changes.

We tested 26 school-aged children born preterm at a gestational age below 34 weeks, 13 with and 13 without periventricular brain damage, with four different visual stimuli assessing perception of pure global motion (optic flow), with some form information (segregated translational motion) and form-defined static stimuli. Results were compared with a group of age-matched healthy term-born controls. Preterm children with brain damage showed significantly lower sensitivities relative to full-term controls in all four tests, whereas those without brain damage were significantly worse than controls only for the pure motion stimuli. Furthermore, when form information was embedded in the stimulus, preterm children with brain lesions scored significantly worse than those without lesions. These results suggest that in preterm children dorsal stream-related functions are impaired irrespective of the presence of brain damage, whereas deficits of the ventral stream are more related to the presence of periventricular brain damage.

Consensus has been reached on the concept that infantile cerebral palsy (CP) is a complex disorder which is limited neither to motor disability nor to the simple association between motor disability and possible disorders of other functions. Conversely, as extensively shown in this book, CP is currently considered as the result of the interaction between the different residual motor, sensorial, perceptive, or cognitive abilities or functions and their adaptative transformation grounded on evolution, that is to say a “continuously evolving disability of an individual who is continuously evolving”. The issue of visual-perceptive development (and of its disorders) in CP must be viewed within this frame-work, also considering the central role it plays in the child’s neuromotor, cognitive, and affective development, becoming the first tool for the interaction with the surrounding world.

Summary: Purpose: Several studies have reported behavioral and electrophysiological evidence of visual impairment during the active stage of West syndrome. The underlying mechanisms are, however, poorly understood, and little has been reported about the correlation between visual impairment, EEG patterns, and brain lesions. The aim of the study was to assess visual function at the onset of spasm and 2 months thereafter and relate visual findings to brain lesions and EEG features. Methods: Twenty-five infants with West syndrome were enrolled and studied with (a) a full clinical assessment including a battery of tests specifically designed to assess visual function, (b) a video-polygraphic study, and (c) brain magnetic resonance imaging (MRI). Besides brain neuroimaging and EEG comparison with visual function, an intra-EEG analysis was performed to investigate the possible relation of EEG patterns to fluctuating visual behavior (fixation and following). Results: Twenty-two children had at least one abnormal result on one or more of the tests assessing visual function at T0. Visual impairment at the spasm onset was related to the sleep disorganization rather than to the hypsarrhythmic pattern in awake EEG. After 2 months, both EEG features become significantly linked to visual function. Visual function improved in several cases after 2 months, in parallel with the seizure regression. No relation was found between EEG patterns and fluctuating visual behavior. Conclusions: The study supplies new evidence of the involvement of visual function in West syndrome. The presence of abnormal visual findings in infants without lesions on brain MRI suggests that visual abnormalities are due not only to brain injury but also to epileptic disorder per se. New insight is also provided into the possible mechanisms underlying clinical and EEG abnormalities.

This is a study of the biodynamics of the lower cervical spine in relation to the global function of the spine. The lower cervical spine has therefore been investigated with reference to both the maintenance of the neutral posture, and to its responses to various functional stresses.