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

Study Overview
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Brief Summary
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Background. Early diagnosis of cerebral palsy is important as intervention becomes possible at a time where neuroplasticity is at the highest. Current mean age at diagnosis is 13 months in Denmark. Recent research has documented that implementation of an early-diagnosis set-up can lower diagnostic age of cerebral palsy. The aim of the current study is to show that the response to the early intervention program added to standard care is superior to standard care alone in a Danish multi-site setting in children from both a newborn and infant detectable risk pathway. Methods The current study CP-EDIT (Early Diagnosis and Intervention Trial) with the GO-PLAY intervention included (Goal Oriented ParentaL supported home ActivitY program), aims at testing feasibility of an early diagnosis and intervention set-up in four paediatric centers. In a prospective cohort study design, we will consecutively include a total of 500 infants. We will systematically collect data at inclusion and follow a subset of participants with definite cerebral palsy or high risk of cerebral palsy until they are two years of age. The focus is on eight areas related to implementation and the perspective of the families: Early MRI; early genetic testing; implementation of the General Movements Assessment method; early prediction of cerebral palsy; comparative analysis of the Hand Assessment for Infants method and evaluation by Hammersmith Infant Neurological Examination, MRI, and the General Movements method; analysis of the GO-PLAY early intervention; parental perspective of early intervention; and parental perspective of having an early diagnosis. Discussion Early screening for CP is increasingly possible and an interim diagnosis of high risk of CP is recommended but not currently used in our clinical care. There is a need to accelerate identification in mild or ambiguous cases to facilitate appropriate therapy early. The majority of studies on early diagnosis focus on identifying CP in infants below five months corrected age. Little is known about early diagnosis in the 50% of all CP cases that are discernible later in infancy, which is also addressed in this study. The study aims at improving care of patients with cerebral palsy even before they have the diagnosis established.

Detailed Description
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Cerebral palsy (CP) is the most common cause of lifelong motor impairment in children and is defined by the Surveillance of Cerebral Palsy in Europe (SCPE) as a group of permanent but not unchanging disorders of movement and/or posture and of motor function, which are due to a non-progressive interference, lesion, or abnormality of the developing/immature brain. An early diagnosis is important in order to start relevant intervention, when neuroplasticity is highest. Research suggests that early intervention programs have a positive influence on cognitive and motor outcomes and is a parental request. In 2004, the Danish Cerebral Palsy Follow-up Program (CPOP) was introduced, with the aim of establishing a standardized follow-up program. The CPOP guarantees that children with CP are followed annually and aims to document, monitor, and improve the quality of health care for children with CP in Denmark. A previous Danish nationwide study from birth years 1995-2003 found that the median corrected diagnostic age of Danish children with CP was 11 months based on first mention in the patient journal. In an novel analysis we have found that for children with CP in birth years 2010-2013 the diagnostic age was 13 months based on first registered diagnosis. The best predictive tools for early diagnosis of CP has been found to be the Prechtl Qualitative Assessment of General Movements (GMA), Hammersmith Infant Neurological Examination (HINE) and cerebral MRI. These tools can be used to diagnose CP before the corrected age of five months. The method Hand Assessment for Infants (HAI) has in recent publications been found promising to complement these tests, but little evidence on HAI has been published. Feasibility of an early-diagnosis set-up of a systematic approach with neurological assessment, GMA/HINE and neuroimaging has been evaluated in several studies, but not yet in Denmark and not in a setting where both the newborn- and infant-detectable risk pathways were included. Neonates may have obvious risk factors at birth/in the neonatal period, but in the present study infants with findings suggesting CP emerging in the first year of life are also included. For more than 80% of children with CP neuroimaging performed with MRI is abnormal. It has been recommended for many years to use MRI while diagnosing CP. A review from 2007 showed that 86% of the MRIs performed on children with CP were abnormal and for the majority gave clues to the pathogenesis of CP. In a previous Australian study of children with CP specific MRI patterns varied depending on parity, gestational age, level of neonatal care, Apgar score and time to established respiration. Diagnostic MRI of newborns and infants with suspected brain damage are today based on structural images with the focus on identifying major structural brain pathology, such as periventricular leukomalacia or white matter damage. However, advanced research MRI-sequences can be sensitive to detect brain damage and 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. MRI will be offered earlier than regular clinical practice for participants in this research project and for a subset of patients repeat MRI will be possible. Many gene variants may play a role in the development of CP. Previous research with genetic testing has shown that genetic aetiology, while often seen in children with no previous gestational or neonatal risk factor, is not limited to this group nor those with other neurodevelopmental comorbidities such as epilepsy or intellectual disability. One study has suggested an association between CP and genes that hinder early brain development and also predispose to susceptibility to environmental risk factors. The cause for the various CP types, including the most prevalent spastic subtype and the rare ataxic or dyskinetic CP, are different. In some cases, the cause is obvious, such as asphyxia during labour, cerebral bleeding, or infection, but in many cases the cause is unknown. However, in an increasing number of patients it is now possible to identify the underlying cause, since it has become clear that several treatable metabolic and genetic diseases such as dopa-responsive dystonia may be misdiagnosed as CP. Identifying the cause makes it possible to provide genetic counselling and direct specific treatment, e.g., with nutrient-specific diets or medications, which can interrupt disease progression and hinder further injury. In the current study extensive genetic testing with whole genome sequencing will be performed in participants with definite CP or high risk of CP. Receiving an early diagnosis of CP or high risk of CP is a parent priority and both parents and care providers agree that early access to interventions is important for the child. Parents of children with CP may experience high stress levels, depression, and chronic sorrow symptoms. Intensive home-based approaches addressing cognitive and motor improvement increasingly involve parents as treatment providers, supervised by therapists. This can lead to both a positive parental outcome such as motivation, knowledge, and increased competences, as well as negative outcomes, because parents may be overwhelmed by the burden of responsibility and the feeling of insufficiency and lack of confidence. The current study CP-EDIT (Early Diagnosis and Intervention Trial) with the GO-PLAY intervention included ( Goal Oriented ParentaL supported home ActivitY program, that will be registered separately at ClinTrials), aims at testing feasibility of an early diagnosis and intervention set-up in four neuropaediatric centers in Denmark with focus on eight areas related to implementation and the perspective of the families: Early MRI, early genetic testing, implementation of the GMA method, early prediction of CP, comparative analysis of the HAI and HINE, MRI, and GMA methods, analysis of the GO-PLAY early intervention, and parental perspective of intervention and early diagnosis.

Official Title
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Multi-center Prospective Cohort Study CP-EDIT: Cerebral Palsy - Early Diagnosis and Intervention Trial

Conditions
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Cerebral Palsy

Intervention / Treatment
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* Diagnostic Test: Early intervention program


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Group A: 'Newborn-detectable risk-pathway' Preterm birth with gestational age below 32 or birth weight below 1500 g and clinical concern Moderate to severe brain injury (Papile grade 3 to 4 intraventricular haemorrhage, cystic periventricular leukomalacia, neonatal stroke, term hypoxic-ischaemic encephalopathy (≥35 weeks gestation at birth) or other significant neurological condition) History (e.g. neonatal seizures, Extra Corporal Membrane Oxygenation, meningitis, kernicterus, severe hypoglycemia) or neurological risk factors (brain malformation, increased tone) Parental concern and one of the factors above Group B: 'Infant detectable risk-pathway' Inability to sit independently by age 9 months Hand function asymmetry or crawl asymmetry Inability to take weight through the plantar surface of the feet History (as above) or neurological risk factors Parental concern and one of the factors above Exclusion Criteria: 1) Infants with progressive or neurodegenerative disorders or genetic disorders not associated with CP, 2) Infants with other disability diagnoses e.g. Down Syndrome.

Ages Eligible for Study
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Minimum Age: 3 Months
Maximum Age: 12 Months

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Cohort I<br>500 participants screened by history and interview with parents to assess if they are to proceed to cohort II. This will be assessed by steering committee. | |
| Cohort II<br>Participants (n=300) who meet the inclusion criteria from Cohort I, is assessed at enrollment visit and will proceed to cohort III if they meet any two of the following criteria: Neuroimaging predictive of a motor disability 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 Infants will also be included if they meet both of the following criteria: Unilateral brain injury on neuroimaging predictive of CP Clinical signs of asymmetry Studies/objectives related to Cohort II Evaluation of MRI GMA implementation - To assess the feasibility of GMA in a multi-center Danish hospital setting. Prediction of CP - To determine the clinical utility of the MRI, HINE, HAI, and GMA to predict a confirmed diagnosis of CP at 24 months GMA/HINE/MRI vs. HAI - To compare diagnostic accuracy of HAI and GMA/HINE/MRI. | |
| Cohort III<br>Participants (n=160) will be included in cohort III if infants are considered CP or at high risk of CP Participants are followed at enrolment, and ages six, 12, 18 and 24 months. Blood sample for trio-whole genome sequencing is offered to participants with definite or high risk of CP. Studies/objectives related to Cohort III e) Evaluation of genetics f) GO-PLAY. To analyse the effect of the GO-PLAY intervention with early family-centred set-up for children with definite or high risk of CP. g) Parents perspective on intervention. To explore parents' perspectives on barriers and facilitators involved in early intervention. h) Parents perspectives of early diagnosis - To analyse interviews of parents' perspectives of gains and concerns when having an early diagnosis of high risk of CP. | Diagnostic Test: Early intervention program<br>* At enrollment visit: History and examination, MRI, evaluation of comorbidities, medication and genomic testing. HINE, GMA (if below 5 mo), AIMS, SHAI, PSS and DASS-21 questionnaire. At 6 mo visit: Examination and evaluation of comorbidities, medication and HINE and AIMS At 12 mo visit: Examination and evaluation of comorbidities, medication and HINE, AIMS, HAI, PSS and DASS-21 questionnaire. At 18 mo visit: Examination and evaluation of comorbidities, medication and HINE At 24 mo visit: Examination and evaluation of comorbidities, medication and HINE, PDMS-2, GMFM-66, BSID-IV-cog, MPOC-20 ,PSS, and DASS-21 questionnaire. GMFCS and Mini MACS if CP.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| MRI | 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 | MRI at enrollment in cohort II | 
| Whole genome sequencing | 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. | Genetics at enrollment in cohort III | 
| Hammersmith Infant Neurological Examination (HINE) | 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. | At enrollment visit | 
| General Movement Assessment (GMA) | 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. | At enrollment visit if < 5 months of corrected age | 
| Screening Hand Assessment for Infants (SHAI) | 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. | At enrollment visit | 
| Clinical assessment of CP diagnosis | 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 | at 24 months corrected age | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Motor function - The Gross Motor Function Classification System - Expanded & Revised (GMFCS - E&R) | 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) | at 24 months corrected age | 
| Motor function - The Mini-Manual Ability Classification System (Mini-MACS) | 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. | at 24 months corrected age |