Francesca Tinelli

Plasticity of the visual system after early brain damage

The aim of this review is to discuss the existing evidence supporting different processes of visual brain plasticity after early damage, as opposed to damage that occurs during adulthood. There is initial evidence that some of the neuroplastic mechanisms adopted by the brain after early damage to the visual system are unavailable at a later stage. These are, for example, the ability to differentiate functional tissue within a larger dysplastic cortex during its formation, or to develop new thalamo‐cortical connections able to bypass the lesion and reach their cortical destination in the occipital cortex. The young brain also uses the same mechanisms available at later stages of development but in a more efficient way. For example, in people with visual field defects of central origin, the anatomical expansion of the extrastriatal visual network is greater after an early lesion than after a later one, which results in more efficient mechanisms of visual exploration of the blind field. A similar mechanism is likely to support some of the differences found in people with blindsight, the phenomenon of unconscious visual perception in the blind field. In particular, compared with people with late lesions, those with early brain damage appear to have stronger subjective awareness of stimuli hitting the blind visual field, reported as a conscious feeling that something is present in the visual field. Expanding our knowledge of these mechanisms could help the development of early therapeutic interventions aimed at supporting and enhancing visual reorganization at a time of greatest potential brain plasticity.

Oral propranolol for retinopathy of prematurity: Risks, safety concerns, and perspectives

OBJECTIVE To evaluate safety and efficacy of oral propranolol administration in preterm newborns affected by an early phase of retinopathy of prematurity (ROP). STUDY DESIGN Fifty-two preterm newborns with Stage 2 ROP were randomized to receive oral propranolol (0.25 or 0.5 mg/kg/6 hours) added to standard treatment or standard treatment alone. To evaluate safety of the treatment, hemodynamic and respiratory variables were continuously monitored, and blood samples were collected weekly to check for renal, liver, and metabolic balance. To evaluate efficacy of the treatment, the progression of the disease (number of laser treatments, number of bevacizumab treatments, and incidence of retinal detachment) was evaluated by serial ophthalmologic examinations, and plasma soluble E-selectin levels were measured weekly. RESULTS Newborns treated with propranolol showed less progression to Stage 3 (risk ratio 0.52; 95% CI 0.47-0.58, relative reduction of risk 48%) or Stage 3 plus (relative risk 0.42 95% CI 0.31-0.58, relative reduction of risk 58%). The infants required fewer laser treatments and less need for rescue treatment with intravitreal bevacizumab (relative risk 0.48; 95% CI 0.29-0.79, relative reduction of risk 52 %), a 100% relative reduction of risk for progression to Stage 4. They also had significantly lower plasma soluble E-selectin levels. However, 5 of the 26 newborns treated with propranolol had serious adverse effects (hypotension, bradycardia), in conjunction with episodes of sepsis, anesthesia induction, or tracheal stimulation. CONCLUSION This pilot study suggests that the administration of oral propranolol is effective in counteracting the progression of ROP but that safety is a concern.

Study protocol: safety and efficacy of propranolol in newborns with Retinopathy of Prematurity (PROP-ROP): ISRCTN18523491

BackgroundDespite new therapeutic approaches have improved the prognosis of newborns with retinopathy of prematurity (ROP), an unfavourable structural and functional outcome still remains high. There is high pressure to develop new drugs to prevent and treat ROP. There is increasing enthusiasm for anti-VEGF drugs, but angiogenic inhibitors selective for abnormal blood vessels would be considered as an optimal treatment.In an animal experimental model of proliferative retinopathy, we have recently demonstrated that the pharmacological blockade of beta-adrenoreceptors improves retinal neovascularization and blood retinal barrier breakdown consequent to hypoxia. The purpose of this study is to evaluate the propranolol administration in preterm newborns suffering from a precocious phase of ROP in terms of safety and efficacy in counteracting the progression of retinopathy.Methods/DesignPreterm newborns (gestational age at birth lower than 32 weeks) with stage 2 ROP (zone II-III without plus) will be randomized, according to their gestational age, to receive propranolol added to standard treatment (treatment adopted by the ETROP Cooperative Group) or standard treatment alone. Propranolol will be administered until retinal vascularization will be completely developed, but not more than 90 days. Forty-four participants will be recruited into the study. To evaluate the safety of propranolol administration, cardiac and respiratory parameters will be continuously monitored. Blood samplings will be performed to check renal, liver and metabolic balance. To evaluate the efficacy of propranolol, the progression of the disease, the number of laser treatments or vitrectomies, the incidence of retinal detachment or blindness, will be evaluated by serial ophthalmologic examinations. Visual function will be evaluated by means of behavioural standardized tests.DiscussionThis pilot study is the first research that explores the possible therapeutic role of beta blockers in ROP. The objective of this research is highly ambitious: to find a treatment simple, inexpensive, well tolerated and with few adverse effects, able to counteract one of the major complications of the prematurity. Any favourable results of this research could open new perspectives and original scenarios about the treatment or the prevention of this and other proliferative retinopathies.Trial RegistrationCurrent Controlled Trials ISRCTN18523491; ClinicalTrials.gov Identifier NCT01079715; EudraCT Number 2010-018737-21

Motion perception in preterm children: role of prematurity and brain damage

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.

Safety and efficacy of topiramate in neonates with hypoxic ischemic encephalopathy treated with hypothermia (NeoNATI)

BackgroundDespite progresses in neonatal care, the mortality and the incidence of neuro-motor disability after perinatal asphyxia have failed to show substantial improvements. In countries with a high level of perinatal care, the incidence of asphyxia responsible for moderate or severe encephalopathy is still 2–3 per 1000 term newborns. Recent trials have demonstrated that moderate hypothermia, started within 6 hours after birth and protracted for 72 hours, can significantly improve survival and reduce neurologic impairment in neonates with hypoxic-ischemic encephalopathy. It is not currently known whether neuroprotective drugs can further improve the beneficial effects of hypothermia. Topiramate has been proven to reduce brain injury in animal models of neonatal hypoxic ischemic encephalopathy. However, the association of mild hypothermia and topiramate treatment has never been studied in human newborns. The objective of this research project is to evaluate, through a multicenter randomized controlled trial, whether the efficacy of moderate hypothermia can be increased by concomitant topiramate treatment.Methods/DesignTerm newborns (gestational age ≥ 36 weeks and birth weight ≥ 1800 g) with precocious metabolic, clinical and electroencephalographic (EEG) signs of hypoxic-ischemic encephalopathy will be randomized, according to their EEG pattern, to receive topiramate added to standard treatment with moderate hypothermia or standard treatment alone. Topiramate will be administered at 10 mg/kg once a day for the first 3 days of life. Topiramate concentrations will be measured on serial dried blood spots. 64 participants will be recruited in the study. To evaluate the safety of topiramate administration, cardiac and respiratory parameters will be continuously monitored. Blood samplings will be performed to check renal, liver and metabolic balance. To evaluate the efficacy of topiramate, the neurologic outcome of enrolled newborns will be evaluated by serial neurologic and neuroradiologic examinations. Visual function will be evaluated by means of behavioural standardized tests.DiscussionThis pilot study will explore the possible therapeutic role of topiramate in combination with moderate hypothermia. Any favourable results of this research might open new perspectives about the reduction of cerebral damage in asphyxiated newborns.Trial registrationCurrent Controlled Trials ISRCTN62175998; ClinicalTrials.gov Identifier NCT01241019; EudraCT Number 2010-018627-25

Visual function in infants with West syndrome: correlation with EEG patterns.

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.

Impaired Visual Size-Discrimination in Children with Movement Disorders.

Multisensory integration of spatial information occurs late in childhood, at around eight years (Gori, Del Viva, Sandini, & Burr, 2008). For younger children, the haptic system dominates size discrimination and vision dominates orientation discrimination: the dominance may reflect sensory calibration, and could have direct consequences on children born with specific sensory disabilities. Here we measure thresholds for visual discrimination of orientation and size in children with movement disorders of upper limbs. Visual orientation discrimination was very similar to the age-matched typical children, but visual size discrimination thresholds were far worse, in all eight individuals with early-onset movement disorder. This surprising and counterintuitive result is readily explained by the cross-sensory calibration hypothesis: when the haptic sense is unavailable for manipulation, it cannot be readily used to estimate size, and hence to calibrate the visual experience of size: visual discrimination is subsequently impaired. This complements a previous study showing that non-sighted children have reduced acuity for haptic orientation, but not haptic size, discriminations (Gori, Sandini, Martinoli, & Burr, 2010). Together these studies show that when either vision or haptic manipulation is impaired, the impairment also impacts on complementary sensory systems that are calibrated by that one.

Cortical visual function in preterm infants in the first year.

OBJECTIVE To assess visual function in low-risk preterm infants at 3, 5, and 12 months corrected age to determine whether the maturation of visual function in the first year is similar to that reported in term-born infants. STUDY DESIGN Seventy-five low-risk infants (25.0-30.9 weeks gestation) underwent ophthalmological examinations and a battery of tests (fix and follow, visual fields, acuity, attention at distance, and fixation shift) designed to assess various aspects of visual function at 3, 5, and 12 months corrected age. RESULTS The results were comparable with normative data from term-born infants in all tests but fixation shift, suggesting that maturation of most aspects of visual function is not significantly affected by preterm birth. In contrast, >25% of preterm infants failed the fixation shift test at 3 months, with a higher percentage of failing at 5 and 12 months. CONCLUSIONS There is a specific profile of early visual behavior in low-risk preterm infants, with a high percentage of infants failing a test that specifically assesses visual attention and provides a measure of cortical processing.

Numerosity but not texture-density discrimination correlates with math ability in children

Considerable recent work suggests that mathematical abilities in children correlate with the ability to estimate numerosity. Does math correlate only with numerosity estimation, or also with other similar tasks? We measured discrimination thresholds of school-age (6- to 12.5-years-old) children in 3 tasks: numerosity of patterns of relatively sparse, segregatable items (24 dots); numerosity of very dense textured patterns (250 dots); and discrimination of direction of motion. Thresholds in all tasks improved with age, but at different rates, implying the action of different mechanisms: In particular, in young children, thresholds were lower for sparse than textured patterns (the opposite of adults), suggesting earlier maturation of numerosity mechanisms. Importantly, numerosity thresholds for sparse stimuli correlated strongly with math skills, even after controlling for the influence of age, gender and nonverbal IQ. However, neither motion-direction discrimination nor numerosity discrimination of texture patterns showed a significant correlation with math abilities. These results provide further evidence that numerosity and texture-density are perceived by independent neural mechanisms, which develop at different rates; and importantly, only numerosity mechanisms are related to math. As developmental dyscalculia is characterized by a profound deficit in discriminating numerosity, it is fundamental to understand the mechanism behind the discrimination. (PsycINFO Database Record

Cognitive competence at the onset of West syndrome: correlation with EEG patterns and visual function

The aim of this study was to evaluate cognitive development at the onset of West syndrome (WS) with regard to electroencephalogram (EEG) patterns and visual function. Twenty-five patients (14 males, 11 females) at the onset of spasms (T0) in WS and 2 months later (T1) underwent a full clinical evaluation, including neuroimaging, cognitive assessment, video-EEG, and visual function. Mean age of the patients at spasm onset was 5.9 months (SD 2.5; range 2 to 13mo). Cognitive development, assessed with Griffiths Mental Development Scales (GMDS), was generally impaired at T0 and was significantly related to visual function (p<0.001) at both T0 and T1. In general, there was a specific major impairment in the eye-hand coordination scale of the GMDS which tended to disappear after 2 months in less severe cases. At the onset of spasms, sleep EEG organization seemed to be better related to cognitive abilities than awake hypsarrhythmia. These results support a close link between visual function and cognitive competence in WS and provide additional information to improve the understanding of possible mechanisms underlying cognitive impairment.