Infants at high neurological risk for cerebral palsy: new pathways for early diagnosis and early intervention

Cerebral palsy (CP) is still recognized to be the most prevalent childhood-onset motor disorder, despite the advances in technology that have improved survival rates for infants with perinatal adverse events. Given the developmental nature of this complex disorder an early diagnosis is mandatory to obtain a prompt referral to appropriate intervention pathway and achieve the best levels of functional outcome. The early diagnostic and habilitative approaches to this chronic disease have been my field of interest during the attendance to the PhD program. As for the diagnostic approach, a specific focus was set on early Unilateral Cerebral Palsy (UCP) detection in infants with perinatal unilateral brain damage which is still challenging before 6 months of age, while as concern the habilitative approach, early intervention proposals based on the family-cantered care framework have been explored. The research activity fully took place at the “Neurologia Prima Infanzia” section of the Unit 1 of the IRCCS Fondazione Stella Maris. The Section 1 of the thesis addresses the UCP diagnostic issue, with the following research studies: • Systematic review of the literature on the early signs of UCP: the main aim was to collect information on the predictive validity of the available clinical tools in assessing the risk of developing UCP after a unilateral perinatal brain injury. The recommended diagnostic algorithm for early diagnosis of CP (MRI+ General Movement Assessment and/or Hammersmith Infant Neurological Examination), has been hypothesized to be less effective and reliable for UCP detection. The absence of fidgety was found to have a good sensitivity and a quite high specificity in the detection of UCP in a population at risk, even if lower than the very high rate of sensitivity and specificity reported in the literature for the detection of CP in general. Asymmetries in tone, postures, or movement during the HINE administration were reported, with a moderate sensitivity and a quite high specificity in detecting a later diagnosis of UCP. A standardized asymmetries detection in neurological examination and in fidgety scoring itself seem still lacking in the evaluation of infants with perinatal unilateral brain lesions. • Observational longitudinal study on early motor signs of UCP: the aim was to collect preliminary data on the characteristics of the early motor organization in a sample of infants with predominantly unilateral brain lesion by means of a videorecording of the spontaneous motricity and the Hammersmith Infant Neurological Examination administration with a focus on the detection of asymmetries at 3 months of age (chronological or corrected). Early MRI data were collected and analysed. Results found that infants at low-risk of developing UCP according to their MRI brain lesion pattern reported a normal fidgety, while infants with UCP outcome, generally reported different expressions of pathological fidgety. Asymmetrical fidgety was reported in 6 out of 9 infants later diagnosed with UCP, 2 infants reported a normal intermittent fidgety and 1 reported a sporadic fidgety. A preliminary evaluation of these data suggested that asymmetrical fidgety reported a high sensitivity and specificity in detecting UCP. Looking for a possible correlation between fidgety subtypes and MRI brain lesion patterns we speculate that asymmetrical fidgety was more likely to be expressed when the lesion is extended to hemispheres, thalamus and/or basal ganglia. We hypothesised that asymmetrical fidgety could be considered as a “miswiring biomarker”, expression of a cortical-subcortical mismatch subsequent to an early vascular accident. • Multicentric retrospective study on the possible correlation between asymmetry in sleep spindles and the motor outcome in infants with unilateral brain injury: the aim was to determine whether interhemispheric difference in sleep spindles in infants with perinatal unilateral brain injury could link to a pathological network reorganization that underpins the development of UCP. Sleep spindles were detected and quantified with an automated algorithm from electroencephalograph records performed at 2-5 months of age. The clinical outcomes after 18 months were compared to spindle power asymmetry (SPA) between hemispheres in different brain regions. A significantly increased SPA in infants who later developed UCP was found, with the most robust interhemispheric difference seen in the central spindles. The best individual-level prediction of UCP was seen in the centro-occipital spindles with an overall accuracy of 93%. An empiric cut-off level for SPA at 0.65 gave a positive predictive value of 100% and a negative predictive value of 93% for later development of UCP. Results suggests that automated analysis of interhemispheric SPA provides a potential biomarker of UCP at a very early age. The Section 2 of the thesis addresses the early intervention topic, with the following research studies: • Systematic review on the available data on early parent-infant interactions in infants at high-risk of CP: the aim was to systematically review data on early parent-infant interaction assessments in population of infants at high-risk of developing CP.Eighteen articles were selected and a high level of heterogeneity in terms of infant neurological risk, infant age, and tools assessing interactive behaviors were found. Both infant and maternal behaviors within the investigated interactive exchanges were reported to be compromised, leading to subsequent overall impairment of the dyadic patterns. The review did not yield a clear picture of early dyadic interactions in high-risk infant populations suggesting that further observational studies are needed to provide a more accurate knowledge of the early dyadic exchanges as they might provide a critical opportunity for early family centered habilitative interventions. • Feasibility study of a home-based and parent-delivered intervention based on infant massage in infants at high risk of CP: the main aim of this study was to assess the feasibility, acceptability and usability of IM, carried out by parents at home, on infants at high risk for CP. An IM daily diary and an ad hoc questionnaire Infant Massage Questionnaire Parent-Infant Experiences were developed. The parents were trained to carry out the IM with a home-based course, conducted by an expert therapist. Data collection consisted in the selection of the variables around the characteristics of the infants and of the mothers, IM dosage and frequency, different body parts of the infants involved and questionnaire scores. Results provide evidence of the feasibility of IM at home on infants at high risk for CP. In conclusion, data collected in the Section 1 of the project, could contribute to define potential early biomarkers in infants at risk for developing UCP to stratify the levels of intervention. Data collected in the Section 2 corroborate the hypothesis that early interactions may represent a valuable first field of intervention for infants at risk of CP and their parents and more protocols specifically aimed to longitudinally investigate this dimension are required as well as case-control study aimed to prove the efficacy of models of early intervention based on the principle of the family-centered care in comparison with standard care.