Detecting and measuring eye movement abnormalities in children with neurometabolic disease
Aim and background
The original goal of this two-year project was to develop a method for eliciting calibrated saccadic eye movements from infants and children who were too immature to co-operate with standard eye movement recording techniques. This included children with cognitive regression as seen in degenerative conditions such as neurometabolic diseases, children with developmental delay due to other neurological disorders, and healthy infants and young children who are simply too young for standard procedures.
Saccadic eye movements allow us to shift gaze from one visual object to another. Serendipitously, saccades happen also to be very stereotyped behaviours that are present from birth in healthy neonates. In adults and older children, as the amplitude (size) of saccades increases, the duration and peak velocity of saccades also increase in a remarkably reproducible way that is similar across all healthy individuals, called the ‘main sequence’. However, in some neurological diseases, saccades may be slower than normal usually reflecting brainstem disease. By measuring saccade speed (peak velocity and duration), it is possible to quantify the degree of brain dysfunction. The reason for the focus on saccadic eye movements in young children was threefold; a) there is little known about the main sequence in young children because of the difficulties in recording calibrated saccades from minimally co-operative participants; b) saccade speed was being used as a primary measure in clinical trials for treatments of neurometabolic disease but children were being excluded because they could not comply with demanding standard (adult) procedures in the protocol; and c) saccades are frequently affected in neurological disease but are difficult to assess clinically.
Young healthy children from the Plymouth area were recruited by advertising throughout the city and through local radio and television. Children with neurological conditions were recruited mostly from local special needs schools and by word-of-mouth. Children with specific disorders (metabolic diseases and Dancing Eyes syndrome) were recruited via family support groups within existing extensive contacts from the past.
The project required considerable exploration, mostly by trial and error, of different (and often subtly different) protocols to find the best procedure for measuring saccades. This was time-consuming and participant-consuming, but eventually we succeeded. The problem was solved by breaking it into two sub-problems; 1) finding a simple way to calibrate eye movements; 2) eliciting saccades reflexively. Both procedures require minimal co-operation and can be applied at any age. We will describe the new method and then discuss how we have validated the technique on adult control subjects.
Method
The conventional approach is to ask the subject to look between two or more visual targets with known angular separation, so that a conversion from voltage to degrees of eye movement can be obtained. Unfortunately, this is very difficult and unreliable in young infants, or toddlers who do not co-operate, or in children with attention deficits. Moreover, many children with neurological problems also have a condition called saccade initiation failure (SIF) (also known as ‘ocular motor apraxia’). Children with SIF have great difficulty triggering saccades (regardless of whether they are slow or not) and prefer to shift gaze with moving the head, thus making the procedure impossible or unreliable at best. This is a real obstacle to the goal as SIF is common in paediatric neurological conditions.
The new strategy is to keep the subjects attention on a single visual target and move the head through a known angle. Provided attention is maintained on the target, the eye movement will be determined by the amount of head rotation. To move the head, the child was placed on the lap of the parent who sits on a motorised chair and holds the child’s head still. The chair was then rotated backand- forth through a known fixed angle. Trial and error found that pure sinusoidal oscillation through 20-30 degrees yields the most reliable results.
It is not possible to precisely position the young child on the chair so that the eyes are on the axis of rotation. Children and parents come in different sizes, and usually the child’s eyes are forward of the axis of rotation. This introduces a parallax error since the eyes need to move through a greater angle than the angle of chair rotation. After some exploration, this error was corrected by video recording the child’s face during the calibration procedure. The excursion of the reference electrode on the child’s forehead during oscillation provides a measure of the parallax, this correction is typically about 10%.
Eliciting Saccades
As with calibration, the conventional method for eliciting saccades is to ask the subject to look between targets of different angles. To obtain a main sequence, it is necessary to elicit very many saccades of different magnitudes. This requires the subjects to sit upright (usually with a helmet clamped on the head) and watch small points of light jump around a monitor screen for 30-45 minutes. Even healthy young children find this task very boring and extremely difficult. It is virtually impossible with infants and sick children. To circumvent this problem, vestibulo-optokinetic nystagmus was induced, by spinning the child and parent completely around a few cycles in each direction. This nystagmus is reflexive and is present from birth. It requires no co-operation whatsoever. Analysis of the nystagmus quick phases (which are saccadic eye movements) used software specifically developed by the investigators. By applying the calibration, the main sequence from any infant or child with only minimal co-operation, can be measured.
Control groups of 20 adults and 20 healthy children (3-48 months), undertook the whole procedure, for comparison, no significant statistical difference was found. Therefore, we may conclude that the new procedure is accurate.
Children with neurological conditions
Twenty seven children aged 11 months to 11 years with various neurological disorders were examined, it is emphasised that it would not normally be possible to record eye movements from these patients using conventional techniques. The new method, obtained a main sequence from 23, and was unsuccessful in 4 children. Two of these had no eye movements due to their advanced disease (Tay Sachs, and congenital myasthenia), hence there is no main sequence to measure. One had congenital nystagmus and very poor vision. One was dramatically unco-operative and became hysterical during attempts to attach the electrodes.
In the remaining 23, the technique worked very well. As there are no meaningful statistics because of the wide range of disorders, the results from 4 children illustrate different points.
Results
An 8 year old girl suffering from Niemann Pick type C disease.
This girl was diagnosed at age 2 and has been continuously declining since. Currently, she can no longer speak, is wheelchair-bound, is doubly incontinent, and cannot comprehend the conventional procedure. The new method found the main sequence to be remarkably normal in spite of a complete absence of vertical saccades.
Comment: This child was recruited onto the miglustat trial but failed to provide any data due to her cognitive decline. If the new technique had been available, data could have been obtained, not only from her, but probably also from another 4 children who failed recruitment onto the trial due to cognitive decline.
A 5 year old boy, having suffered a near-drowning episode at 22 months, in which his heart stopped for at least 2 hours.
He was eventually revived, but suffered serious brain damage. He exhibited no visual response and was unable to move his head. He had a tracheostomy and gastrostomy because of his inability to swallow. He was presumed blind. We obtained a main sequence for leftward saccades, which showed severe slowing consistent with abnormal left brainstem function. He also exhibited severe SIF to the right, probably due to severe right-sided brainstem damage. In addition, we were able to observe optokinetic response for visual stimulus drifting to the right.
Comment: This child was the most disabled that we have seen to date. Not only were we able to measure saccade speed using the new procedure, but we were also able to demonstrate some degree of vision in an otherwise completely unresponsive child.
An 8 year old boy diagnosed with cerebral palsy and with a history of hydrocephalus, strabismus, and epilepsy.
Although some degree of vision was present, there were concerns about his inability to learn to read (his spoken language was excellent). It was found that his main sequence was normal. However, he exhibited clear signs of SIF in which there was a dearth of quick phases causing the eyes to reach the limit of gaze when rotating in the chair (compare to his twin brother).
Comment:
This boy demonstrates SIF, which is a sub-cortical problem. It means that at least some of his problems may be unrelated to any visual problems. It is uncertain as to why this occurs in CP but it is believed to be quite common (based on the literature), and it has considerable implications for assessing and educating CP children.
An 11 month old girl, diagnosed with a chromosome deletion at 14q31/2. She has dysgenesis of the corpus callosum, plagiocephaly, microcephaly, global developmental delay and cortical visual impairment.
The main sequence was abnormal, indicating severe brainstem pathology. Some optokinetic nystagmus was observed, indicating some degree of cortical vision.
Comment:
This is a new clinical finding and demonstrates how little we know about neural function in the very young.
Discussion
The goal of the research project has not only been achieved, but the new procedure exceeded initial hopes. It is remarkably robust and easy to use with any child of any age. The only requirement is that the child can open his/her eyes and fixate a single visual target. This can be achieved by the vast majority of children, even those with profound delay.
The new procedure could be used to measure horizontal saccadic eye movements as an outcome measure in future clinical trials for neurometabolic disease. Unfortunately, the current trials of miglustat using the conventional procedure have been disappointing with no significant improvement. It is not clear whether this was due to the difficulties in conventional procedures or true failure of the drug, but it has clearly discouraged affected families from joining trials. New drugs for metabolic diseases are currently reaching phase 3 status, and it is possible that our new method will be used in the future.
The new method has been used on some children with non-metabolic disorders with surprising but welcome results. It is now possible to record from children with even profound developmental delay and visual unresponsiveness. This opens up a completely new way of examining these children, which may help in diagnosis and charting the natural history of developmental disorders. At present there is virtually no data on the eye movement abilities of these children (or even healthy age-matched controls), and further ways are being sought to continue research in this area.
Most surprising, and perhaps most significant, is that the new procedure enables eliciting and quantifying eye movements in children who were thought to be ‘cortically blind’ (cortical/cerebral visual impairment, CVI). Finding some degree of cortical visual function has been of considerable encouragement to the children’s parents and teachers. Even being able to demonstrate a lack of visually driven eye movements has been useful, as it has allowed an objective statement of CVI to be made, and allowed various social and educational services to be accessed. Current lack of thorough clinical evaluation of vision in these children has meant that many parents and teachers have extremely limited knowledge of the child’s visual impairments. It is hoped that the new procedure will be incorporated into each child’s clinical and educational work-up, and it is hoped that liaison with local eye hospitals and local sensory impairment groups will achieve this end.
Dissemination
Dissemination is an important aspect of this work because others in the UK and other countries need to be aware of this new avenue for examining children with neurological problems. The new technique has already been demonstrated to a variety of UK and international groups. As a consequence, both Cardiff University and Bristol Eye Hospital have expressed considerable interest in the technique, and they are exploring collectively how to take this forward. The investigators were also interviewed and featured on the BBC ‘Spotlight’ television programme which was then placed on their website.
The most important international scientific meetings in paediatrics occur every 2 years, and there will be an opportunity to present this year, submissions have been made to present this work at three major international meetings. A paper describing our technique is nearing completion and will be submitted to a paediatric medical journal. A further update will be sent when these planned disseminations have been realised.
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