CP-EDIT: Cerebral Palsy - Early Diagnosis and Intervention Trial

MRI scans will be described clinically by radiologists at the participating hospitals. The findings will be categorised according to SCPE criteria (Surveillance of Cerebral Palsy in Europe). In participants where ultrasound or CT scanning of the patients have already been performed as part of clinical follow-up, the results will be gathered, and additional MRI may be optional. Repeat MRI at ages 12 and 24 months will be optional for participants in cohort III as part of the complementary NIBS-CP project (NeuroImaging of Babies during natural Sleep to assess typical development and Cerebral Palsy), which may provide important biological information about myelination, microstructure, and connectivity of the white matter fibre tracts, as well as the metabolic profile, including markers of neuronal integrity and glial markers, of the brain tissue

Blood samples will be obtained from participants with definite or high risk of CP (n=160) upon inclusion in CP-EDIT cohort III after informed, written consent has been obtained by the parents. The parents will also be asked to provide a blood sample and written consent for genome sequencing (trio-analysis). A clinical geneticist and clinical laboratory geneticist will perform the data analysis and result interpretation. Results will be categorised as either: I) Pathogenic CP-explaining variant, II) Likely pathogenic CP-explaining variant, III) Variant of uncertain significance, IV) Likely benign variant, V) Benign variants (according to the ACMG guidelines) and VI) Pathogenic variant, non-CP disease. Only data from the proband will undergo a full analysis. De novo variants in gene with no known clinical association may be submitted to GeneMatcher.

The HINE is a standardized neurological examination for infants aged 3-24 months. It includes three sections: 1) Neurological Examination - Assessment of cranial nerve function, posture, movements, tone, reflexes and reactions 2) Motor Milestones - head control, sitting, grasping, rolling, crawling, standing and walking and 3) State of Behavior - consciousness, emotional state and social orientation. The HINE global score ranges from a minimum of 0 to a maximum score of 78. A score < 73 indicates high risk of CP and < 40 indicates abnormal outcome, usually CP. HINE cut off scores for high risk infants indicating CP are: score < 57 at 3 months, <60 at 6 months, < 63 at 9 months and, < 66 at 12 months. The HINE asymmetry-score, also provides insight into CP topography (unilateral vs bilateral) and CP motor severity (ambulant vs non-ambulant, GMFCS I-III vs IV-V). The HINE is performed by a neuro pediatrician or physiotherapist.

GMA is an observation that evaluates the quality of an infant's early spontaneous movement patterns. GMA is categorised in writhing movements (from preterm until 6-9 weeks post term age) and fidgety movements (from 9 to 20 weeks post term age). Absent fidgety movements (FM) at 3 months post-term age is highly predictive of CP in 'high-risk' infants and may be a marker for other adverse neurodevelopmental outcomes. FMs are classified as follows: Normal, defined as circular movements of small amplitude, moderate speed, and variable acceleration of neck, trunk, and limbs in all directions. Abnormal FMs: (a) absent, when normal FMs are never observed from age 9 to 20 weeks post term age; (b) sporadic , when FMs can be detected but less than 3 sec. (c) exaggerated, when FMs are of large amplitude, high speed, and jerkiness are seen.

SHAI is developed to facilitate screening for risk of unilateral CP in infants aged 3-12 month at risk of CP. The sHAI measures the manual actions performed with each hand separately, test procedure comprises a semi-structured video-recorded play session lasting 5 min, with assessment of 6 unimanual items (including quality of holding, grasping from easy position, object location, finger movements and quality of movement). All items are scored on a three-point rating scale (0-2) and the scores of the unimanual items are summed to the Each Hand Sum score (EaHS) with a range of 0-12 raw scores. The EaHS of the better functioning hand and the lesser functioning hand is used to calculate an asymmetry index (0-100) where a higher percentage indicates a larger asymmetry.

Definitely CP' encompasses participants that fulfil SCPE CP clinical criteria and guided by fulfilling the following: 4/5 for children <5 months, and 3/4 for children ≥ 5 months of the following at screening.

• Delayed motor development without signs of neuromuscular disease (floppy infant, absent reflexes)
• GMA test with absent fidgety GMs at fidgety age
• HINE scores <57 at 3months or <60 at 6months or <63 at 9 months or <66 at 12 months
• MRI or ultrasound of brain with a lesion in one or more of the following structures: sensori-motor cortex, basal ganglia, posterior limb of the internal capsule, pyramidal tracts
• Focal neurological symptoms (hyperreflexia, clonus, dystonia, ataxia, intention tremor) or clinical signs of asymmetry

GMFCS - E&R is a 5-level classification system that describes the gross motor function of children and youth with CP based on their self-initiated movement with particular emphasis on sitting, walking, and wheeled mobility. Distinctions between levels are based on functional abilities, the need for assistive technology, including hand-held mobility devices (walkers, crutches, or canes) or wheeled mobility, and to a much lesser extent, quality of movement. The GMFCS - E&R contains 5 age bands (under 2 years, 2-4 years, 4-6 years, 6-12 years, and 12-18 years) and is categorized into five levels from walking without limitation (level I) to non-ambulatory function (levels IV and V)

Mini-MACS describes how children with CP aged 1-4 years use their hands when handling objects in daily activities. Ability is ranked on five levels based on the children's self-initiated ability and their need for assistance or adaptation when handling objects. The five levels are categorized from able to handle objects easily and successfully (level 1) to does not handle objects and has severely limited ability to perform even simple actions (level 5). Mini-MACS is a functional description that can be used as a complement to the supposed diagnose of CP and its subtypes.

MOS-R is the detailed GMA for 3-5-month-old infants. The MOS-R comprises the following five subcategories: (1) Quality of fidgety; (2) Observed movement patterns; (3) age-adequate movements (4) Observed postural patterns and (5) movement character. The MOS score ranges from a minimum of 5 to a maximum score of 28. An MOS ranging from 25 to 28 is considered to be optimal; scores from 20 to 24 are mildly reduced and an MOS below 20 requires intervention. A score below 9 indicates a very high risk for neurodevelopmental disabilities, especially for non-ambulatory CP.

AIMS is an observational assessment scale constructed to measure gross motor maturation in infants from birth through independent walking. 58 items are generated and organized into four positions: prone, supine, sitting and standing. Each item describes three aspects of motor performance weight-bearing, posture and antigravity movements. The overall score ranges from a minimum of 0 to a maximum of 58.

PDMS-2 is a standardized, norm-referenced measure used to evaluate the gross and fine motor development of children aged birth to 6 years. The gross motor component is comprised of four subtests: reflexes (raw score range 0-16), stationary (raw score range 0-60), locomotion (raw score range 0-178) and object manipulation (raw score range 0-48). Two subtests, grasping (raw score range 0-52) and visual-motor integration (raw score range 0-144), form the fine motor component. The total Motor Quotient (TMQ) is formed by a combination of the results of the gross and fine motor subtests. The PDMS-2 TMQ range from 90-165 (indicating average or above average age-normed motor abilities) to 89-35 (indicating below average to very poor age-normed motor abilities).

GMFM-66 is a criterion-referenced tool designed and evaluated to measure changes in gross motor function over time or with intervention in children with CP. It consists of 5 dimensions rolling, sitting, walking, running, and jumping. The 66 items are organized in increasing difficulty order from 0 (low capacity) to 100 (high capacity) along an interval scale. Each item is scored on a four-point Likert scale (0-3). It can be used from 5 months of age, and a 5- year-old typically developing child is expected to achieve a score of 100.

BSID-4 is a standardized and norm-referenced assessment, which measures the cognitive, motor, language and social-emotional development of infants and toddlers aged 0-3. Raw scores of successfully completed items are converted to scale scores and to composite scores. These scores are used to determine the child's performance compared with norms taken from typically developing children of the same age.

The HINE is a standardized neurological examination for infants aged 3-24 months. It includes three sections: 1) Neurological Examination - Assessment of cranial nerve function, posture, movements, tone, reflexes and reactions 2) Motor Milestones - head control, sitting, grasping, rolling, crawling, standing and walking and 3) State of Behavior - consciousness, emotional state and social orientation. The HINE global score ranges from a minimum of 0 to a maximum score of 78. A score < 73 indicates high risk of CP and < 40 indicates abnormal outcome, usually CP. HINE cut off scores for high risk infants indicating CP are: score < 57 at 3 months, <60 at 6 months, < 63 at 9 months and, < 66 at 12 months. The HINE asymmetry-score, also provides insight into CP topography (unilateral vs bilateral) and CP motor severity (ambulant vs non-ambulant, GMFCS I-III vs IV-V).

HAI is an assessment developed for infants at risk of developing CP in the age range 3-12 months. The test procedure comprises a semi-structured video-recorded play session lasting 10- 15 min. A test kit of toys is presented to the infant to encourage and elicit exploration, making a wide range of a unilateral and bilateral hand movements observable. The HAI measures the degree and quality of goal directed actions performed with each hand separately as well as both hands together. It provides a separate score for each hand (Each Hand Sum Score 0-24), a score for both hands (Both Hands Sum Score 0-58), an asymmetry index in % illustrating possible asymmetric hand use as well as criterion referenced measure of general upper limb ability (HAI-units 0-100)

DASS-21 is an adult self-report designed to measure the emotional states of depression, anxiety and stress. It is a 21-item questionnaire and will be used to measure parent emotional well-being

PSS is an 18-item questionnaire assessing parents' feelings about their parenting role, exploring both positive (emotional benefits, personal development) and negative aspects (demands on resources, feelings of stress) of parenthood. The overall score ranges from a minimum of 18 to a maximum of 90

ASQ-2 pinpoints developmental progress in children between the age of one month to 5 ½ years. It has a parent-centric approach and is used as a developmental screener

MPOC-20 is a self-report measure of parents' perceptions of the extent to which the health services they and their child(ren) receive are family-centered. The 20 items consist of 5 domains; enabling and partnership, providing general information, providing specific information about the child, respectful and supportive service, and coordinated and comprehensive care.