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The research story so far
By John Sanders
This article was first published in 2007 in the Nystagmus Network newsletter and may not be reproduced or quoted without the permission of the author.
If anyone ever writes a history of congenital nystagmus, I would like to suggest two events which should be included. One is the international research workshop we organised in September 2005, when for the first time ever nearly 30 scientific and medical experts met to discuss nystagmus. More of that meeting in Abingdon later.
The other event didn’t seem so important at the time. It’s scribbled in my diary simply as “Gt Ormond St, 3.00 pm.” The only other thing my diary tells me about Friday, November 19th, 1993 is that my shift as a journalist at Reuters started at 7.15 am.
But I remember that grey, overcast winter’s day in London well. Fellow NN committee member Sue Ricketts and I had been invited to talk to staff in Great Ormond Street Hospital’s Department of Ophthalmology. Until then, NN had received little recognition from the medical profession, so it was a big step forward for us.
One of the people we met there was Chris Harris, then a vision researcher and now a professor and one of NN’s scientific advisers. In February this year, I asked Chris how things had developed since 1989 when, backed by ophthalmologist David Taylor, he set up his research lab at Great Ormond Street and saw his first case of nystagmus.
The first breakthrough
It’s hard to imagine now, but back in the 1980s hardly anyone realised that congenital nystagmus could be the result of something else wrong with a baby’s eyes. The view then was that nystagmus was either caused by albinism or was “idiopathic”, in other words “we just don’t know what the cause is.”
From 1989 that view gradually began to change for two reasons. One was that many complex cases were referred to Great Ormond Street from other centres, so staff there saw far more children with nystagmus than any other hospital in the UK. As a result, researchers at the hospital began to identify patterns that no-one else had seen.
The other reason was that Chris Harris was working alongside a colleague, Tony Kriss, who was a pioneer in the use of electrophysiology to diagnose eye problems. Since then, electrophysiology has been used increasingly by Great Ormond Street and other centres to identify the underlying causes of nystagmus in both children and adults.
Chris soon noticed that a lot of the children presenting with nystagmus also had another eye defect, for example childhood cataracts or cone dystrophy. “It was quite obvious that they had sensory problems. It wasn’t just albinism. It was all sorts of things.”
Ultimately that observation led to the definition of sensory defect nystagmus (SDN) and a research paper “Nystagmus in Infancy” published in the British Journal of Ophthalmology in 1992. That landmark paper also argued that a sizeable number of children had nystagmus because of neurological diseases (covering a range of metabolic diseases and malformations) and provided us with the diagnosis of “neurological nystagmus” or NN.
Basically, those definitions (sensory defect nystagmus and neurological nystagmus) are what we use today. Unfortunately, even now we cannot explain every case of nystagmus, so some people are still left with the label of “congenital idiopathic nystagmus”, often abbreviated to CN or CIN.
So what?
The cynics among you may say: “Big deal. You’ve got some fancy names and acronyms for nystagmus, but how does this help people who actually have the condition?” That’s a very valid question. What has happened since the early 1990s? In terms of treatments or cures, the honest answer is probably very little.
Surgery does appear to help in some cases, but does not cure nystagmus and the research findings to support surgical interventions are limited. In general, surgery is an option favoured more in the US than the UK and is a subject we may return to at some point in the future.
However, on the positive side, the number of centres researching nystagmus has increased. In the UK, they include Leicester, London, Manchester, Cardiff, Southampton and Plymouth. Unfortunately, little is being done in the rest of Europe, but we have made contact with researchers in the US and Australia.
Also, it is worth noting that over the last 15 or 20 years experts have more or less come to agree on some of the basic principles of congenital nystagmus. That may not sound very important, but -- without some consensus on what nystagmus is -- progress in understanding it will be very slow.
Remember that back in the 1980s most people were not aware that sensory defects can cause nystagmus. It takes a long time to convince people of developments like that. Even now, as some of you know from experience, some medics still have very outdated ideas about nystagmus.
With the help of Chris and his colleagues in Plymouth and their Social Impact Survey, we have also made progress in highlighting the problems caused by nystagmus. That has been very important, because until doctors and researchers accept how debilitating nystagmus can be, they are reluctant to spend time or money trying to do anything about it.
Hugely important
It was to build on this emerging consensus and to give research some added momentum that we organised the world’s first workshop to discuss nystagmus. With the help of Chris Harris and Professor Richard Abadi (another longstanding nystagmus researcher), we gathered experts from around the world to meet for a few sunny days on the banks of the River Thames in Abingdon in September 2005.
At the outset, we estimated the workshop could cost us up to £30,000, making it our biggest commitment to date. Thanks to the efforts of past and present members of the Nystagmus Network, we had the money in the bank and were able to press ahead with our plans. As it was, the final bill was lower than our initial estimate, much to the relief of treasurer Peter Leon.
What did we get for our money? Well, here’s what Chris Harris had to say: “The workshop was hugely important. It brought together all the big names. It showed other people what was going on and that there are things going on. I think it actually created a bit of competition as well, which is a good thing.”
Certainly, even in the 18 months since Abingdon, some of that research has started to open up some very interesting possibilities in drug treatment and genetics for example. But the workshop also showed how our understanding of nystagmus and its underlying mechanisms is developing. In the long term that could take nystagmus research in new directions, as we will see in the next issue of Focus.
One theme of the Abingdon workshop was the importance of studying how nystagmus develops in very young babies. The key phrase here is developmental plasticity. The evidence suggests the existence of a critical period during the development of a baby’s vision. If babies have a visual defect during that critical early period, then they may well develop congenital nystagmus (CN) too. However, once they are past this critical period, they will not develop CN.
In an attempt to discover what happens during this early developmental phase, Chris Harris is working on a developmental model to explain the process. “This model is trying to understand plasticity itself. Plasticity is not random. It tries to develop things that are good and useful.” Put simply, his model suggests that nystagmus may be the best thing for a baby’s eyes to do if the baby has a visual defect. However, the nystagmus then gets locked in and is not the ideal way to see when the baby grows up.
New mathematics
Other researchers are modelling nystagmus too, but in a different way. They make eye movement recordings of adults and children with nystagmus, which are stored on a computer. These eye movements and the wave forms they produce can then be compared and analysed. The goal is to use these eye movements recordings to explain what has happened to cause nystagmus.
Modelling involves very complex mathematics, known as “new mathematics.” In the UK and the US a number of groups are researching nystagmus using modelling, Although the mathematics approach does not really explain why nystagmus happens or what you can do about it, says Chris, “it can reveal mechanisms that you wouldn’t see in the conventional way and that’s the beauty of this technique.”
Anatomy
Another way to study nystagmus is through anatomy. This involves looking at the visual system in detail to see if there are any subtle defects no-one has yet identified. The fact that some people have congenital nystagmus, but we don’t know why means that we must be missing something somewhere. To shed some light on this question, we invited a number of experts, including anatomists Jan Provis from Australia and Jean Buettner-Ennever from Germany, to the workshop.
Jan specialises in the development of the fovea (the part of the retina used for detailed vision) in babies. She explained how foveal development depends on vascular development. This raises the question that perhaps some children with nystagmus experience a vascular problem with the development of their fovea.
Jean Buettner-Ennever introduced the idea that nystagmus could somehow involve receptors in the muscles, something known as proprioreception. Similarly, John Leigh, a British ophthalmologist based in the US, suggested that congenital nystagmus may sometimes be due to a membrane disorder.
Gene jigsaw
The anatomical approach raises interesting questions, but needs more research. In the field of genetics, on the other hand, we have already had a significant development since the workshop. In October 2006, a team led by Professor Irene Gottlob of Leicester University announced that they had identified the FRDM7 gene as being implicated in at least some cases of congenital idiopathic nystagmus.
Researchers in Leicester and Southampton are trying to find out what FRDM7 does to cause nystagmus. Chris Harris believes that this and other genes may well provide answers to some of the questions about what goes wrong in the development of the vision of a baby with nystagmus. Since genes control plasticity, one possibility is that a gene mutation could cause the plastic process to go wrong.
“For example, it could allow eye movements to become precocious, to develop more quickly than they should. That could then explain why some children get idiopathic nystagmus. If you looked at such a person, you wouldn’t find any visual defects, because it’s just a mis-timing in development,” explains Chris.
Genetic researchers are now hunting for other nystagmus causing genes. This work should further reduce the number of people left with an “idiopathic” diagnosis and could hold out the prospect of gene therapy in the future. Finding out what genes do and what triggers them could herald a whole new era of nystagmus research, says Chris.
Drug discoveries
Another promising avenue, once again being pursued by Irene Gottlob, is drug therapy for congenital nystagmus. Drugs have long been used to reduce nystagmus in people who develop the condition in later life, so called Acquired Nystagmus (AN). A small trial using gabapentin and memantine on adults with congenital nystagmus has produced some promising results. That trial was completed in 2006 and Irene now hopes to carry out a larger study if she can get the funding.
However, there are still lots of unanswered questions about these drugs. For example, what are the long term side effects if any and what is the ideal dose? Chris also has another concern: “Is this something you take for life or do you just take the drug to pass your driving test? That worries me.”
On a more positive note, just as with the gene discovery, a better understanding of what these drugs do could have wider significance, he says. “It might give us clues as to the mechanisms for congenital nystagmus, if these drugs act in different ways, and we may be able to understand more about the circuitry involved.”
Drug therapy even opens up the intriguing prospect of being able to reverse congenital nystagmus. Chris Harris wouldn’t put money on that possibility, but acknowledges that we will not know unless we try: “If you take the drugs long enough, maybe you can kick the system out of its nystagmus mode.”
Stress
Separately, researchers in Cardiff are also casting doubt on the accepted wisdom that once you have nystagmus, nothing can be done about it. Debbie Wiggins and Jon Erichsen at Cardiff University have been looking at the effects of visual demand and stress on nystagmus. In a paper to be published this year, Debbie overturns the assumption that when people with nystagmus have visual demand and look at things carefully their nystagmus gets worse.
“That’s what everyone thought and that’s what happens,” says Chris. “But what Debbie has shown is that what is causing that increased nystagmus is the stress of that task. Not the actual task itself. If anything your nystagmus gets slightly better when you have to look at details. So that totally turns things around.”
This research is important for two reasons. Firstly, it confirms that stress mechanisms are involved in nystagmus. As most of us know, nystagmus gets worse if you’re nervous or tired. But, more interestingly, it also shows that nystagmus is still adaptive – even in adulthood.
Joining up the dots
That brings us back to gabapentin and memantine. Is the benefit they bring due to stress reduction? We don’t know, but Chris believes that the various research strands are not as separate as they may at first seem. “You can see lots of threads here. They all go round and round a little, but there are threads.”
Moreover, all this activity means that he is more optimistic now than at any time since he started work on nystagmus in 1989. “We didn’t have any of that before. Why? Because we were stuck with anecdote and lack of experiment and people who didn’t want to do anything. This is why it’s a really important time now. We’ve moved on from arguing over diagnosis and wave-forms and are now really trying to understand the processes involved.”
The increase in the volume of activity and the range of different approaches certainly mean that nystagmus research has undergone a step change in the last two decades. However, although the pace of change looks set to continue, Chris remains cautious about the possibility of finding a cure. “Whether it will lead to a cure, I still have my doubts. But who knows? I reckon in a couple of years’ time we will have a very different view on nystagmus. I hope we do.”
© John Sanders, 2007
Email: John Sanders
Professor Harris’s HarrisLab website
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