Early rehabilitation for children with visual processing dysfunctions from 1 year of age: a Randomized Controlled Trial protocol

An increasing amount (VPD). At present, there is a lack of evidence-based rehabilitation methods that can be used early in development. We developed a visual rehabilitation protocol suitable from 1 year of age. The protocol contains objective, quantitative outcomes and is structured, comprehensive and individually-adaptive. Our aim is to investigate effectiveness of this first visual rehabilitation program for young children with (a risk of) VPD. We conduct a single-blind, placebo-controlled trial that is embedded within standard clinical care. The study population consists of 100 children born very or extremely preterm (<30 weeks) of 1 year of corrected age (CA), of whom 50% are expected to have VPD. First, children undergo a visual screening at 1 year CA. If they are classified as being at risk of VPD, they are referred to standard care: an ophthalmic and visual function assessment and a (newly developed) visual rehabilitation program. This program consist of a general protocol (standardized and similar for all children) and a supplement protocol (adapted to specific needs of the child), and employs quantitative parameters of visual outcome. Children are randomly allocated to an intervention group (starting upon inclusion at 1 year CA), or a control group (postponed: starting at 2 years CA). The control group will receive a placebo treatment. The effectiveness of early visual rehabilitation will be examined with follow-up visual and neurocognitive assessments after 1 year (upon completion of the direct intervention) and after 2 years (upon completion of the postponed intervention). The they from 1 In an ongoing longitudinal study we found elevated risks of visual attention and processing problems in this population(15, 16), driving the urgency for rehabilitation. However, we expect outcomes to be applicable to other young children at risk of brain damage-related VPD. After positive results have been obtained, the visual rehabilitation program can be investigated in other risk groups. The aim of this study is to investigate the effectiveness of early rehabilitation of VPD in children born very or extremely preterm from 1 year CA. To this end, we developed a structured yet tailored visual rehabilitation protocol and will test its effectiveness in enhancing visual development in a randomized controlled trial. Unique features of the present approach are the objective outcome measures that are assessed from a young age, broad quantitative and qualitative data collection to assess the full spectrum of visual and neurodevelopment, and its embedding within standard neonatal and visual clinical care. This protocol was written in accordance with the Standard Protocol Items: Recommendations for Intervention Trials (SPIRIT) guidelines. Additional file 1 contains the SPIRIT checklist.


Abstract
Background An increasing amount of children suffer from brain damage-related visual processing dysfunctions (VPD). At present, there is a lack of evidence-based rehabilitation methods that can be used early in development. We developed a visual rehabilitation protocol suitable from 1 year of age. The protocol contains objective, quantitative outcomes and is structured, comprehensive and individually-adaptive.
Our aim is to investigate effectiveness of this first visual rehabilitation program for young children with (a risk of) VPD.

Methods
We conduct a single-blind, placebo-controlled trial that is embedded within standard clinical care. The study population consists of 100 children born very or extremely preterm (<30 weeks) of 1 year of corrected age (CA), of whom 50% are expected to have VPD. First, children undergo a visual screening at 1 year CA. If they are classified as being at risk of VPD, they are referred to standard care: an ophthalmic and visual function assessment and a (newly developed) visual rehabilitation program. This program consist of a general protocol (standardized and similar for all children) and a supplement protocol (adapted to specific needs of the child), and employs quantitative parameters of visual outcome. Children are randomly allocated to an intervention group (starting upon inclusion at 1 year CA), or a control group (postponed: starting at 2 years CA). The control group will receive a placebo treatment. The effectiveness of early visual rehabilitation will be examined with follow-up visual and neurocognitive assessments after 1 year (upon completion of the direct intervention) and after 2 years (upon completion of the postponed intervention).

Discussion
Through this RCT we will establish the effectiveness of a new and early visual rehabilitation program.
Combining a general and supplement protocol enables structured comparisons between participants and groups, and custom rehabilitation that is tailored to the children's specific needs. The design ensures that all included children will benefit from participation by advancing the age at which they start receiving rehabilitation. We expect results to be applicable to all children with (a risk of) VPD early in life.

Background
Over the past decades, survival rates of children who experienced adverse perinatal events (e.g., preterm birth, hypoxia/ischemia; hemorrhages) have increased due to the intensive, high quality care that they receive. As a consequence, the number of children that sustains neurological damage has increased as well. Because about 40% of the brain is involved in processing visual information, there is a high chance that these children will develop problems in the visual domain.
Visual dysfunctions with a cerebral origin,i.e. cerebral visual impairment (CVI), have become common in children: conservative estimates range from 10-22 cases per 10000 births in developed countries, to 40 per 10,000 in developing countries (1). Brain damage-related visual dysfunctions are now the primary cause of low vision in children (2,3).
Given the large underlying visual and oculomotor network, children with these impairments can suffer from a variety of problems, e.g. visual sensory, oculomotor or visual perception problems. What they have in common is dysfunctions with properly processing incoming visual information, i.e. visual processing dysfunctions (VPD). The problem is particularly urgent for young children, because early visual dysfunctions can severely delay or disrupt their neurocognitive, motor and behavioral development (4)(5)(6). To alleviate early-onset problems, prevent later growing-into-deficit and maximize developmental opportunities, detection and rehabilitation of VIP problems early in life is crucial (7,8).
Early in development, high levels of cerebral plasticity enable recovery or take-over of function. Therefore, it is assumed that the sooner visual rehabilitation programs start, the higher the chances are that they will enhance visual processing development. Although there are a large number of infant studies in the field of early detection that rely on this assumption, the effectiveness of early rehabilitation in the visual domain has never been proven.
Early rehabilitation starts with early detection of problems. Before the age of 4-5 years, it used to be challenging to assess the functional consequences of damage to the brain's visual system. There have been advances in the early detection of (a risk of) visual problems, for example the early assessment of basic visual function in neonates as early as 31 weeks PMA in preterm infants (9), and a functional vision battery with cognitive and integrative aspects, to use between one and four years of age (10). These batteries involve various aspects of visual function and rely on behavioral observations. In addition, more quantitative, computer-based methods have been developed, such as an eye tracking-based task for attention in toddlers (11). Building on these innovations, our group developed a method to quantify the efficiency of visual processing in a nonverbal manner in children, using an eye tracking-based approach (12,13). We showed that children with (a high risk of) neurological damage (e.g. children with visual disorders or children born preterm) are prone to develop VPD (14)(15)(16). These VPD were particularly strongly correlated with brain damage-related visual problems (cerebral visual impairment; CVI) (17,18).
Theseinnovative early and nonverbal assessments can fulfill the need for scientifically strong psychometric tools to evaluate the effectiveness of early intervention. Hence, besides providing an early characterization of VPD that was previously unavailable, they also open up the possibility to monitor or rehabilitate VPD in these children at a young age. One can even argue that early detection of problems is only useful if it leads to advancing support and rehabilitation. Hence, the essential next step in the field of pediatric visual dysfunctions is to provide affected children with effective early rehabilitation programs.
A major problem is that there is no evidence-based rehabilitation for VPDfrom1 year of age: this area is severely understudied (19) and quality of evidence is low (20)(21)(22). Available (visual) interventions lack a standardized approach and/or systematic objective evaluation (23)(24)(25), and ideas about their effectiveness merely stem from clinical impressions, not from randomized and carefully controlled studies. The available evidence has predominantly been found in older children, for a limited range of visual functions (i.e., visual acuity and/or contrast sensitivity) (26), without incorporation of functional vision measures, using only stimulation and no training (24,26), and without objective outcome measures. Studies that did use a comprehensive and structured training approach had a small sample size (27,28). Although these existing studies provide important information on approaches and possibilities to rehabilitate visual problems, the effectiveness of such visual rehabilitation programs for children younger than 4 years has not yet been investigated with an RCT. VPD in children can arise from many different conditions, e.g. perinatal asphyxia or hypoxia, focal lesions, cranial trauma, infections, or hemorrhages. Therefore, the general population with VPD is a highly diverse group of children. In the present study, we focus on children born very or extremely preterm (i.e. born <30 weeks of gestation) from 1 year of corrected age (CA). In an ongoing longitudinal study we found elevated risks of visual attention and processing problems in this population (15,16), driving the urgency for rehabilitation. However, we expect outcomes to be applicable to other young children at risk of brain damage-related VPD. After positive results have been obtained, the visual rehabilitation program can be investigated in other risk groups.
The aim of this study is to investigate the effectiveness of early rehabilitation of VPD in children born very or extremely preterm from 1 year CA. To this end, we developed a structured yet tailored visual rehabilitation protocol and will test its effectiveness in enhancing visual development in a randomized controlled trial. Unique features of the present approach are the objective outcome measures that are assessed from a young age, broad quantitative and qualitative data collection to assess the full spectrum of visual and neurodevelopment, and its embedding within standard neonatal and visual clinical care. This protocol was written in accordance with the Standard Protocol Items: Recommendations for Intervention Trials (SPIRIT) guidelines. Additional file 1 contains the SPIRIT checklist.

Study design
Randomized single-blind, placebo-controlled intervention study (RCT), embedded within standard clinical care.

Study setting
The study will be executed at the Neonatology department of an academic medical center, in collaboration with the department of Pediatric Ophthalmology and with four regional centers of a center of expertise for blind and partially sighted people that provides visual diagnostics and rehabilitation.

Participant characteristics & timeline
It is expected that 25-50% of the very/extremely preterm population is at risk of VPD at 1 year CA (15,16). Therefore, all infants who have been born extremely or very preterm (i.e. before 30 weeks gestational age) and who participate in the clinical follow-up program of the dept. Neonatology, Erasmus MC-Sophia Children's Hospital, will be available for inclusion around 1 year CA. We aim to include: N = 100 children from 1 year CA, born very or extremely preterm (< 30 weeks of gestation). About 50% are expected to be at risk of VPD (and eligible for the intervention) N = 100 children born at term without VPD from 1 year of age, to add to an existing database of typically developing children (healthy control group).
The study population can be divided in 3 groups: The eye tracking-based exam is designed to be visible with a visual acuity of 0.05 or higher.
High chance of epileptic activity during assessment More than 2 attacks in the previous year or when using the anti-epileptic Vigabatrin (which may lead to visual dysfunctions).
Retinopathy of prematurity (ROP) of grade 3 or higher, assessed by a pediatric ophthalmologist, as this will account for their visual dysfunctions.

Participant inclusion and baseline
Children born very or extremely preterm (< 30 weeks GA) will be recruited around the corrected age (CA) of 1 year at the department of Neonatology of an academic medical center. After obtaining written informed consent (see Additional file 2), a visual assessment is performed to identify the prevalence and nature of visual processing problems. This assessment consists of an eye trackingbased test of visually-guided orienting behavior and a checklist for neurological dysfunction. The visual assessment results are compared to normative references to identify the children with a risk of visual processing dysfunctions (VPD). The children who are identified as being at risk of VPD will first undergo an orthoptic and ophthalmic exam (dept. Pediatric Ophthalmology). Next, they will be referred to a visual advisory and rehabilitation center in order to receive standard care, consisting of a visual function assessment (VFA) and a visual rehabilitation program. The VFA is used to evaluate visual sensory functions (e.g., visual acuity, visual field, contrast sensitivity, ocular motility), and observe the functional visual behavior of the child. This assessment is performed by experienced orthoptists/optometrists and behavioral therapists, and together they will determine the visual level of the child (these levels are adapted from earlier work) (

Intervention
To reliably examine the effectiveness of this visual rehabilitation program with an RCT, children who are at risk of VPD will be randomly allocated to one of two groups:

Intervention group (direct)
This group consists of preterm children who are at risk of VPD and who will start the visual rehabilitation program upon referral to the visual rehabilitation center (i.e. around 1 year CA). The program consists of a general protocol (standardized across participants) and a supplement protocol (tailored to the child's specific VPD), and lasts ~1 year.

Control group (postponed & sham/placebo)
This group consists of preterm children who are also at risk of VPD, but for whom the visual rehabilitation program will be postponed for the duration of 1 year. These children will be placed on a waiting list for the duration of the direct visual rehabilitation (i.e. ~1 year). However, during this first year they will receive a placebo intervention: general developmental support that is aimed at monitoring the child's developmental progress without providing specific visual rehabilitation. As soon as the follow-up assessments of the direct intervention group are completed, children in the control group will start visual rehabilitation (i.e. around 2 years CA).
Importantly, this study design ensures that all children at risk of VPD will receive visual rehabilitation at an earlier age than is the case in current standard care (i.e. where only a small number of young will be referred based on obvious ocular disorders, and others will not receive rehabilitation beforẽ 4y of age)), while the RCT design enables a reliable and controlled comparison of the effectiveness of visual rehabilitation within this group. For a detailed outline of the visual rehabilitation protocol we refer to Additional file 3; template visual rehabilitation protocol.

Follow-up after 1 year
One year after inclusion, the children at risk of VPD will repeat the visual function assessments, and all included children (with and without VPD risk) will repeat the eye tracking-based visual screening, and undergo a neurodevelopmental assessment (that is standard care at most Neonatology departments, from 2 years CA).
That way, the specific effects of early visual rehabilitation on visual processing and neurocognitive development are compared and evaluated.

Postponed intervention
After this first follow-up, the children in the postponed intervention group will start their visual rehabilitation program, which will also be evaluated 1 year later. In addition, the results of the visual screening are again evaluated for all children, to identify new cases with a risk of VPD who will then also qualify to start visual rehabilitation. Differences in effectiveness of direct and postponed early visual rehabilitation are assessed. The intervention study will have a duration of either 1 year or 2 years, depending on the visual rehabilitation group.

Medical information
Medical and demographic information will be extracted from the medical records available at the hospital.

Visual screening-A0
All included children will be screened for a risk of VPD, which consists of 1) an eye tracking-based assessment, and 2) a neurological checklist.
The eye tracking-based assessment is used to measure visual processing functions. The assessment will be combined with an existing appointment for standard outpatient visits at the Neonatology information. This is the main study parameter (12,13,30,31

Inventories for daily life visual functioning-B0
The PAI-CY questionnaire(32) will be filled in by parents upon inclusion. This questionnaire assesses daily visual functioning and can be used to investigate and monitor rehabilitation needs of visually impaired young children. It is the only available questionnaire for young children and its psychometric properties are currently under investigation.

Determining the risk of VPD
Abnormal visual orienting behavior, indicated by abnormal RTF values on one or more visual stimuli AND/OR the presence of at least one neurological risk factor for VPD. The children at risk of VPD are referred to standard care for children with suspected visual dysfunctions, i.e.: 1.
They will undergo an ophthalmic exam to evaluate eye and orthoptic function, 2.
They will become clients of the visual advisory and rehabilitation center where they undergo a visual function assessment and are enrolled in the visual rehabilitation program.
Ophthalmic exam (standard care; group 2A and 2B)-C0 All children at risk of VPD will be referred to the Pediatric Ophthalmology department to evaluate of visual acuity, refractive error and ocular alignment. This evaluation is performed by ophthalmologists and/or research orthoptists. Total time of the exam is approximately an hour.
Visual function assessment (VFA; standard care; group 2A and 2B)-D0 All children at risk of VPD will undergo an extensive VFA. This assessment is part of standard care and will be done by an experienced orthoptist or optometrist. All assessments will be performed according to a standardized protocol that ensures similar assessments, choice of tests, and scoring by the various examiners. The following functions will be assessed: ocular alignment and fixation preference, binocular vision, presence of nystagmus, oculomotor function (fixation, saccades, pursuit, motility), convergence, visual acuity, visual field, contrast sensitivity and color vision. Performance per function is classified as normal or abnormal for the child's (developmental) age.
First follow-up (T1): Starting one year after inclusion, i.e., from 2 years CA, the following assessments are repeated: Visual screening (study-specific; all groups)-A1 The visual assessment (eye tracking-based exams) will be repeated in all included children, and will be combined with an existing appointment for standard outpatient visits the Neonatology department.

Inventories for daily life visual functioning (study-specific)-B1
Will be given to, or sent to, parents around the first follow-up.

Visual function assessments (VFA; standard care)-D1
The VFAs will be repeated in the children at risk of VPD (independent of the visual rehabilitation group they are in), as part of standard care at the visual advisory center. there is no regular follow-up as part of standard care, study-specific appointments will be made at the academic hospital or in the form of home visits. In addition, the children at risk of VPD who have been referred to Visio will undergo the visual function assessment again (D2), as part of standard care.

Neurodevelopmental assessment (standard care Neonatology)-E
By embedding this study within standard clinical care, close collaboration with involved medical and rehabilitation specialists, and planning participation together with regular appointments or in the form of home visits, we expect to maximize participants' completion of the follow-up measurements.
Intervention: visual rehabilitation protocol (Additional 13 file 3) We developed a structured visual rehabilitation protocol using a two- Active (top-down-modulated) visual perceptual training that is contingent on children's abilities (28,38,40) e. can be individually-tailored by adapting materials and activities to children's preferences/capabilities (25) f. incorporates children's systems through active caregiver involvement (33,41) Second, we examined the clinical and practical requirements for a rehabilitation protocol by consulting professionals about, e.g., which types of rehabilitation, in which (developmental) domains, which elements, materials and objects, minimum duration and frequency, and how to deal with parental motivational and resistance issues. The answers to these questions were grouped and analyzed in order to extract common themes and the most important clinical features the protocol should contain.
The result of this two-step process is a visual rehabilitation program that consists of: 1. a general protocol that is identical for all children, and 2. a supplement protocol that is tailored to the specific VPD of the child.
Both parts are designed to adhere to the basic visual skills a child presents with, and to their cognitive, motor and socio-emotional developmental level. Importantly, the parent-child relationship will be taken into account in order to support, involve and stimulate the parents in executing the rehabilitation program at home. processing of contrast and color information, will get additional training for the processing of form and motion-related visual information that is integrated within the visual rehabilitation program itself; in order to comprehensively support the child.

Additional components:
Focus moments. These sessions with video feedback, evaluation with the parents and reporting behavioral observations, are done three times throughout the intervention period to determine whether the program suffices or needs adaptations.
Stepping cards. An instruction for parents given after each session that contains a specific goal, instruction, observational points, and evaluation for their daily practice sessions.
Logbook for therapists (per session) and parents (to be completed weekly). The logbooks are used to keep track of the frequency/intensity and content of the therapy sessions and the daily practice sessions by parents.
Protocol for Activities & Materials to be used, based on chapter 5 (29) Criteria for discontinuing or modifying interventions Modifying intensity of rehabilitation: after the second focus moment (around week 16), it is determined whether the child still benefits from sessions every week or every two weeks. If this rehabilitation intensity is no longer indicated/ no longer needed, the intensity is brought down to once every 4 or 6 weeks, to keep monitoring (visual) development, and to enable a frequency adaptation again when needed. This will be done until the end of the program.
Modifying the content/focus of rehabilitation: this is based on the evaluations with parents and the observations after each therapy session. If a modification is warranted, only the supplement protocol will be modified, the standard protocol remains as is.

Improving and monitoring intervention adherence
All rehabilitation activities are demonstrated and explained by the therapists to the parents, with the goal that they understand the content and the motivation, in order for them to practice daily with their child. Parents will participate in all therapy sessions: they do not only receive practice instructions but will also be educated on the visual development of their child. The parents are asked to log their daily practice session in order to evaluate them in the therapy sessions. These evaluations will give insights in improvements and/or changes in visual performance of the child, which is known to motivate parents and enhance intervention adherence.

Permitted concomitant care
Participating children will not be restricted in receiving care as usual. If applicable, they are allowed to engage in additional neurodevelopmental training programs during this study. However, participation in such programs will be carefully registered and monitored to take into account interference with the possible effects of the visual rehabilitation program. In addition, children in the control intervention group will, in the first year, be provided with general developmental support and monitoring that does not include specific visual training components. This program consists of visits by a psychologist-intraining (under supervision of neuropsychologists from the academic hospital and visual advisory center) and aims at monitoring developmental achievements of preterm children from 1 to 2 years of corrected age. That way, we directly involve all parents in the study, and enable a structured and controlled investigation of the effectiveness of specific visual rehabilitation. After concluding the study, the children who are at risk of VPD and have been referred to the visual rehabilitation center will remain clients there. This means that their treatment does not necessarily stop, but that this depends on the indications and judgement of the therapists and psychologists.
Outcome measures To answer our main research question about the effectiveness of early visual rehabilitation in young preterm children, we will compare visual outcomes between the intervention and control group. We   (16), and in 9 to 23% of children in a cross section of the preterm population at 1y CA (15). In addition, between 25% and 33% of children with CVI have prematurity as contributing factor (42). However, the prevalence of risk factors for VPD (brain damage, perinatal events) is much higher than 50% in our study population. Therefore, we expect that each year at least 50 newborn preterm children from the Neonatology department (i.e., 50%) are at risk of VPD and thus eligible for inclusion in the intervention study.

Recruitment strategies
Children will be recruited from the current medical follow-up program for children born preterm that is ongoing at the department of Neonatology. Children's eligibility for inclusion will be screened by a multidisciplinary team (project leader and project members from Neonatology). The project leader and/or other investigators will approach their parents first by telephone, to ask for permission to send an information leaflet about the study. Two weeks after sending the study information, parents will be contacted again to ask for their permission to include their child in the study. The baseline assessment (i.e. the visual screening) and the 1-year follow-up assessment will be scheduled together with an existing appointment at Neonatology, to minimize burden for children and parents. Children in the control group (group 3) will be recruited through daycare centers. The parents will receive study information by mail and are asked to contact the project leader if they are willing to participate. If they give their consent, an appointment for the visual assessment will be made.

Randomization & treatment allocation
Prior to recruitment of participants, a randomization scheme has been designed in which the order of visual rehabilitation groups (either direct or postponed) is randomized using an online tool (Sealed Envelope Ltd. 2016; https://www.sealedenvelope.com/simple-randomiser/v1/lists).
Randomization is blocked, to ensure a balance in sample size across groups over time, and stratified, to control and balance the influence of covariates (43). Covariates in the current study are: the presence of brain damage and gestational age (<28 weeks or 28-30 weeks).
After this computer-generated randomization, preterm children who are classified as being at risk of VPD will be assigned a participant number and concurrently be allocated to one of the visual rehabilitation programs. The order of allocation corresponds with the date and order of inclusion. This allocation will be done by the principal investigator and remains concealed to all other investigators, the participating children, and their parents. All participant numbers will be separately placed in opaque envelopes that contain a note with the assigned visual rehabilitation group. Revealing the group allocation to parents will be done by opening the opaque envelopes in their presence.

Blinding
The study set-up is single-blind. Intervention allocation will be known by the project leader managing the contacts between all involved parties, and by the behavioral therapists of Visio who will execute the interventions. Parents cannot be blinded to intervention allocation either, as they will actively participate in the intervention programs. However, the allocation will be blinded for the researchers and/or master students and orthoptists who perform the baseline and follow-up visual assessments, and for the researchers performing data analyses.
Prior to analyzing results of the visual rehabilitation (i.e. analyzing results of the follow-up visual assessments), participant numbers will be converted into a new participant code and visual intervention group will be coded into a new variable (group A or B). That way, group allocation remains concealed and bias during data analysis will be prevented (44).

Data management
All data will be handled confidentially and anonymously. Communication about participating children between the various participating departments and organizations will only be done using codes, not names or other personal identifying information. All data will be coded, and only a separate coding list will link study data to personal identifying information of a specific subject. The coding list is password-protected and only accessible by the main investigator(s). Data files will be stored on a PC and will only be accessible with a password. This password is only known to the main investigator(s).
Paper documents will be stored in a locked cupboard of which only the main investigator(s) have a key. The investigator(s) will remain blind to the participants' outcomes during the course of the study.
All data will be anonymized prior to analyses and publications. Group allocation and randomization will not be revealed until after the statistical analyses have been finished.

Withdrawal
Subjects can leave the study at any time for any reason if they wish to do so without any consequences. The investigator can decide to withdraw a subject from the study for urgent medical reasons. When subjects withdraw from the visual rehabilitation program they will not be replaced, to ensure adherence to the randomization protocol for the RCT. Withdrawal of subjects will be taken into account during data analyses, by using intention-to-treat (ITT) analyses. Subjects withdrawn from the visual rehabilitation program will be followed-up with a short questionnaire (assessed by telephone) in which they are asked for their reasons and circumstances of their withdrawal.

Statistical analyses
Sample size calculation

Effectiveness of visual rehabilitation program
In children at risk of VPD who have been allocated to a visual intervention group, differences in viewing behavior parameter RTF between T0 and T1 are analyzed with a Repeated Measures ANOVA.
A p-value of 0.05 will be considered statistically significant. Covariates are the medical and demographic factors and the RM analyses will be done with and without them to obtain their contribution to the main effect. All analyses are done according to the intention-to-treat principle Other effects of visual rehabilitation on VPD (other parameters) Secondary study parameters are the differences in other eye tracking-based parameters of viewing behavior and the outcomes of visual function assessments (e.g., visual acuity, contrast sensitivity, extent of visual field). RM ANOVAs with a p-value of 0.05 will be considered statistically significant.
After finding a main effect of group on the viewing behavior parameters, post-hoc comparisons will be done to establish which of the 5 visual stimuli significantly differ from each other in parameter values.
For these comparisons, Bonferroni's correction will be applied to the viewing behavior variables to correct the p-value for the number of comparisons.

Harms
In accordance with section 10, subsection 4 of the WMO, the sponsor will suspend the study if there is sufficient ground that continuation of the study will jeopardize subject health or safety. The sponsor will notify the accredited METC without undue delay of a temporary halt including the reason for such an action. The study will be suspended pending a further positive decision by the accredited METC.
The investigator will take care that all subjects are kept informed.

Ethics & dissemination
The present study has been approved by Participant confidentiality will be protected through our data management policy (see section Data Management). The main investigator(s) and the participating medical and clinical specialists will have access to the final trial dataset. There are no contractual agreements that limit such access for investigators. During the course of the study the principal investigator will have no access to patientidentifying data and communication will only be done using participant codes.
The involved researchers and sponsors have no financial or other competing interests for the overall trial nor for each study site.
No harm is expected from trial participation, in particular since most study components are part of standard clinical care. Therefore ancillary and post-trial care are suspected to be non-applicable.
Nature and extent of the burden, risks and benefits associated with participation Plans for granting public access to full protocol, dataset and statistical code Public access to the full protocol will be given through this paper. All results will be published open access. The dataset will not be made publicly available given the patient identifying information it contains. Statistical code will be made available upon request.

Discussion
The aim of this RCT is to investigate the effectiveness of an innovative and comprehensive visual rehabilitation program for children from 1 year of age. We have developed a visual rehabilitation protocol that adheres to recent scientific insights regarding rehabilitation and that conforms to standard clinical care for children at visual rehabilitation centers in the Netherlands.
The present study provides a solution to some notorious problems in the (early) rehabilitation domain.
Firstly, an underlying problematic paradox in the execution of rehabilitation studies is that the content of visual rehabilitation has to be tailored to the individual child in order to exert effects, but that establishing scientific evidence for effectiveness requires structured and controlled designs with homogeneous groups. With this protocol, we can achieve visual rehabilitation that is not only structured and evidence-based, but also individually tailored and adaptive to a child's level of functioning. Parts of the general visual protocol are currently used in visual practice but they have never been structured into one comprehensive protocol, and have never been subject of scientific investigation. Since there is a lack of evidence-based visual intervention or training programs (20,22), but clinical experiences are good, these programs are considered best clinical practice. In addition, the supplement visual protocol and additional components were specifically designed for this study and satisfy the need for individually adaptive programs.
Secondly, in order to obtain true evidence for the effects (does improvement occur as a result of the rehabilitation or as result of 'normal' visual development?) an RCT is needed in which children with visual dysfunctions are randomly allocated to an intervention or control group. However, a difficulty with conducting RCTs in (young) patient groups is the ethical consideration with randomization of treatment allocation, which means that one group is withheld treatment. Our RCT design circumvents this problem. We start with providing rehabilitation to all participants a couple of years earlier than is currently possible within clinical visual care (from about 4y of age). That way, both the intervention (from 1y of age) and control group (from 2y of age) will receive earlier care than usual and are both expected to benefit from participation in this study.
This study has the potential to satisfy a great clinical and scientific need for early and evidence-based visual rehabilitation options. Up to now, several reviews of visual interventions in children mentioned a lack of evidence-based programs. One showed some evidence for visual training as opposed to, more passive, visual stimulation (20). Another focused on several strategies for visual improvement in children with frequently co-occurring visual and neurodevelopmental problems (22). The strongest evidence was found for visual aids (e.g. spectacles) and environmental modification to compensate for visual loss. Less evidence was found for functional behavioral methods that focused on actually improving visual function, and it was stressed that more information on this subject is needed. Given the increasing prevalence of children with corrected low vision, i.e. for whom spectacles cannot provide more functional visual improvement, the availability of behavioral training programs is of the utmost importance.
It is important to note that the present study not only concerns early rehabilitation but also early screening of a VPD risk. A combined approach of detecting and rehabilitating VPD in children will benefit from the multidisciplinary collaboration of involved neuroscientists, neuropsychologists, and behavioral therapists. Upon achieving the study goals, this set-up also ensures immediate dissemination in the form of clinical implementation of the visual rehabilitation program. The proposed training programs contain a unique combination of elements that ensures incorporation of a widely-advocated system approach (33,41). This will not only improve VPD and development, but also support the parent-infant relationship and improve infant self-regulation and later independence. With implementing this new program, we expect that more children will gain opportunities for learning, development, and daily independence earlier in development. These are invaluable and essential steps toward an inclusive society that maximizes children's opportunities.
The broader scope of this new rehabilitation program lies in monitoring and supporting the development of children at risk not only in the visual domain, but also in behavioral, cognitive and social-emotional domains. Focusing our attention on the early development of children born preterm will help set the good circumstances for further learning and development up to school age.
Ultimately, we expect the outcomes to be applicable in all types of pediatric patients at risk of visual processing dysfunctions/ VPD (e.g., comorbid with syndromes or developmental disorders). The possibility to train visual functioning brings us closer to enhancing neurodevelopment in prevalent neurological risk groups, and will optimize recovery or compensation on a functional and daily level.

Study design challenges and limitations
An important challenge is to determine the right age to start interventions: how early is too early?.
This is yet unknown, which is why we chose to start at 1 year CA when basic visual and neurodevelopment has completed and more elaborate development emerges. We expect that careful monitoring of visual assessment outcomes, not only related to interventions but also in the placebo control group, and in the form of yearly follow-up measurements, will reveal the age(s) at which children start to show specific VPD. This will inform future clinical applications or new studies about the possible best developmental stages to start visual intervention programs. In addition, it was difficult to estimate the risk of VPD in this specific population of children born <30 weeks at 1 year CA. The precise number will determine the inclusion and sample size of the rehabilitation leg of the study. However, besides investigating effectiveness of visual rehabilitation in children born preterm, the present protocol provides a solid basis for other studies and/or applications in different pediatric populations at risk of VPD early in life. Lastly, the study population is a relatively vulnerable risk group, particularly because of their young age. Children born very or extremely preterm generally go through a rough first start in the neonatal period, putting a medical and psychological burden on both the children and their parents. Therefore we start recruiting at 1y of CA, when for the majority of children the most intense periods are behind them.

Consent for publication
Not applicable.

Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request Competing interests