Studies about Therapy for Amblyopia (Lazy eye)

News Release to above study:

Drops for Lazy Eye as Effective as Patch

Scientists have found that atropine eye drops given once a day to treat moderate amblyopia, or lazy eye, work as well as the standard treatment of patching one eye. The finding could lead to more success in correcting amblyopia by helping children avoid the social stigma of wearing an eye patch and making it easier for parents to help their kids stick to the treatment.

Amblyopia is the most common vision problem in children, affecting two or three of every 100 children. It can be caused by any condition that causes the brain to favor one eye such as crossed eyes, different focusing ability between the two eyes or childhood cataracts (clouding of the eye lens). The preferred eye becomes dominant and the weaker, "amblyopic" eye becomes ignored by the brain. The visual system in the brain for the amblyopic eye often fails to develop properly, and at some time between the ages of five and ten the condition can become permanent.

Patching the unaffected eye has been the standard treatment for amblyopia, but many kids don't like the teasing or the skin irritation that comes with wearing an eye patch. An alternative treatment – an eye drop called atropine – has been known for almost a century. This drug dilates the pupil and blurs the image seen by the dominant eye, forcing the brain to use the weaker eye. This method is often used when patching doesn't work, but few doctors try it at the beginning. NIH's National Eye Institute (NEI), therefore, funded a study to see whether atropine was as effective as patching for treating amblyopia in children under seven years of age. The study was conducted by a network of eye care professionals at universities in North America and in local community offices.

Two hundred and fifteen children received patching, and 204 received atropine eye drops once a day. The researchers found that 79 percent of those receiving the eye patch were treated successfully, while 74 percent receiving the atropine were treated successfully – a difference that isn't clinically significant. Vision in the amblyopic eye improved faster in the patching group, but the difference in the two groups at six months was not significant. Side effects were minimal for both groups.

Study chairman Dr. Michael Repka, professor of ophthalmology and pediatrics at the Wilmer Eye Institute of Johns Hopkins University School of Medicine in Baltimore, says, "This study shows that one drop a day of atropine works as well as patching the eye for some children with amblyopia. Since both patching and atropine work equally well, the choice of treatment can be made by the eye care professional in consultation with the parent."

Note from web master: The results of this study have been published (JAAPOS, Oct 2004), but as of 12/18/2004 have not been added to the NIH web site. The edited JAAPOS abstract follows:

Amblyopia is the most common cause of monocular visual impairment in both children and young and middle-aged adults. Patching has been the mainstay of amblyopia therapy. It is generally held that the response to treatment is best when it is instituted at an early age, particularly by age two or three, and is poor when attempted after eight years of age.

Patching the unaffected eye of children with moderate amblyopia for two hours daily works as well as patching the eye for six hours. This research finding should lead to better compliance with treatment and improved quality of life for children with amblyopia, or "lazy eye," the most common cause of visual impairment in childhood. These results appear in the May issue of Archives of Ophthalmology.

"These results will change the way doctors treat moderate amblyopia and make an immediate difference in treatment compliance and the quality of life for children with this eye disorder," said Paul A. Sieving, M.D., Ph.D., director of the National Eye Institute, one of the Federal government's National Institutes of Health and the agency that sponsored the study. "This is very important, because it is estimated that as many as three percent of children in the U.S. have some degree of vision impairment due to amblyopia."

After four months of treatment, children with moderate amblyopia who wore an adhesive patch daily for two hours over their unaffected eye showed the same improvement in vision as those who wore a patch for six hours. Placing an opaque adhesive patch, or eye bandage, over the unaffected eye for six hours daily is considered one of the standard treatments for moderate amblyopia. Both groups of children in the study performed one hour a day of "near" work, such as coloring, tracing, reading, and crafts, while their eye was patched.

Amblyopia, which usually begins in infancy or childhood, is a condition of poor vision in an otherwise healthy eye because the brain has learned to favor the other eye. Although the eye with amblyopia often looks normal, there is interference with normal visual processing that limits the development of a portion of the brain responsible for vision. The most common causes of amblyopia are crossed or wandering eyes or significant differences in refractive error, such as farsightedness or nearsightedness, between the two eyes.

"Prior to these results, many children with amblyopia had to wear an eye patch during school hours," Dr. Sieving said. "For these children, the accompanying social and psychological stigma was very real. Many were stared at and teased by other children, which made them feel different. Now, children can look forward to attending school without the patch. This will make them feel better about themselves."

Dr. Sieving said it is crucial for young children to comply with the recommended treatment because visual impairment can persist into adulthood if amblyopia is not successfully treated in early childhood. Amblyopia is the most common cause of monocular (one eye) visual impairment among children and young and middle-aged adults.

"Because the daily burden to administer treatment for amblyopia falls on the parent, the findings from this study will immediately affect families that have young children with this eye disorder," said study chairman Michael Repka, M.D., professor of ophthalmology and pediatrics at the Wilmer Eye Institute of Johns Hopkins University School of Medicine in Baltimore. "The findings make it much easier for parents to monitor their children and encourage children to successfully comply with treatment. Timely and successful treatment for amblyopia in childhood can prevent lifelong visual impairment."

Patching the unaffected eye has been the mainstay of amblyopia treatment for decades. In March 2002, the same researchers reported the effectiveness of a second treatment, which involved using atropine eye drops that dilated the unaffected eye, temporarily blurring vision. Both treatments force the child to use the eye with amblyopia, stimulating vision improvement in that eye by helping the part of the brain that manages vision to develop more completely. However, with patching, opinions varied widely on the number of daily hours it should be prescribed. No prior study had provided conclusive evidence of the optimal number of patching hours.

In this study, 189 children less than seven years old with moderate amblyopia were randomly assigned to receive either two hours or six hours of daily patching. The average age of the children was 5.2 years. Both groups showed significant improvement in the vision of the eye with amblyopia. "After four months, we found that 79 percent of children in the two-hour group and 76 percent of the patients in the six-hour group could read at least two more lines on the standard eye chart," Dr. Repka said. "The study also found that parents of children who wore the patch for six hours were more concerned about social stigma than the parents of children who wore the patch for two hours."

Dr. Repka said having the child perform one hour of "near," or close-up, work per day while patched was an important part of the prescribed treatment. He said it remains unclear if the same amount of visual improvement would occur with patching alone. "We are planning a clinical trial to address the importance of near work in the treatment of amblyopia," he said.

National Eye Institute
National Institutes of Health

Prescribing six hours of daily patching for the unaffected eye of children with severe amblyopia works as well as prescribing full-time patching. This research finding should lead to better compliance with treatment and improved quality of life for children with severe amblyopia, or "lazy eye," the most common cause of visual impairment in childhood. The findings appear in the November issue of Ophthalmology.

These research results will change the way doctors treat severe amblyopia and make a difference in treatment compliance and the quality of life for children with this eye disorder. It is estimated that as many as three percent of children in the U.S. have some degree of vision impairment due to amblyopia. The study was funded by the National Eye Institute (NEI), part of the National Institutes of Health.

Amblyopia, which begins in infancy or childhood, is a condition of poor vision in an otherwise healthy eye because the brain has learned to favor the other eye. Severe amblyopia is defined as amblyopia causing a reduction in visual acuity ranging from 20/100 to 20/400. Placing an opaque adhesive patch, or eye bandage, over the unaffected eye full time has been considered one of the standard treatments for severe amblyopia. It is crucial for young children to comply with the recommended treatment because visual impairment can persist into adulthood if amblyopia is not successfully treated in early childhood.

In this study, conducted at 32 clinical centers nationwide, 175 children less than seven years old with severe amblyopia were randomly assigned to receive either six hours of prescribed daily patching or full-time prescribed patching. Both groups of children performed one hour a day of "near" work, such as coloring, tracing, reading, and crafts, while their unaffected eye was patched. After four months, both groups showed similar and substantial improvement in the vision of the eye with amblyopia. These findings make it easier for parents to monitor their children and encourage children to successfully comply with treatment. Timely and successful treatment for amblyopia in childhood can prevent lifelong visual impairment.

Advances in Strabismus, Amblyopia, and Visual Processing Research - 1999-2006

From the National Eye Institute - National Institutes of Health

(for a complete report go to: http://www.nei.nih.gov/strategicplanning/NEI_ProgressDoc.pdf)

The Strabismus, Amblyopia, and Visual Processing Program supports clinical and laboratory research on visual development, neural processing, eye movement, and other disorders involving output of the retina and other portions of the brain that serve vision. Knowledge of the normal visual system provides a foundation for understanding the causes of impaired vision and developing corrective measures.

Amblyopia

Amblyopia is the medical term used when the vision in one eye is reduced because the eye and the brain are not working together properly. The eye itself looks normal, but it is not being used because the brain is favoring the other eye. This condition is also sometimes called lazy eye. Amblyopia is a common cause of visual impairment in childhood. The condition affects approximately 2 to 3 out of every 100 children. Unless it is successfully treated in early childhood, amblyopia usually persists into adulthood, and is the most common cause of monocular (one eye) visual impairment among children and young and middle-aged adults.

Treatment Options

Eye patching has been a mainstay of treatment for children with amblyopia. Patching the stronger eye forces the use of the weaker eye and can improve or, if caught early, completely reverse the condition. Two patching regimens are commonly prescribed in clinical practice. One is minimal occlusion for two hours per day and the other is use of occlusion for six or more hours per day. Until recently, there were no data available to favor the use of one regimen over the other and compliance with patching varied widely.

To address the clinical issue of the optimal number of patching hours for moderate amblyopia, a clinical trial comparing two hours versus six hours of daily patching for children with moderate amblyopia was conducted by the Pediatric Eye Disease Investigator Group (PEDIG), a network of eye care professionals involved in determining the best treatments for various eye problems in children. The results from this clinical trial revealed that patients in both groups showed substantial improvement in the eye with amblyopia. At four months, 79 percent of patients in the two-hour patching group and 76 percent of patients in the six-hour patching group had improved by two or more lines on the eye chart.

Children who wear patches often feel socially stigmatized, making the treatment an emotionally uncomfortable experience. This often interferes with compliance as children remove the patch to avoid the associated psychological burden. However, the two-hour regimen will allow children to wear the patch in the privacy of their homes.

In a parallel study conducted by PEDIG investigators, children with severe amblyopia who were less than 7 years of age were treated with either full-time patching or 6 hours of patching in combination with one hour of near work like reading or coloring. Researchers found that 6 hours of patching with an hour of near work was as effective in improving visual acuity as full-time patching¹¹². Both of these studies should lead to better compliance with treatment for children with amblyopia. These results will change the way doctors treat moderate and severe amblyopia and make an immediate difference in treatment compliance and the quality of life for children with this eye disorder.

Childhood Screening for Common Eye Diseases

Healthy vision is an important part of a child’s success in school. A great deal of classroom instruction is conveyed visually through books, computer screens and chalkboards. Children who enter school with eye diseases or visual impairments are at a distinct disadvantage when encountering visually-based instruction. Childhood visual impairment can also result in developmental delays, the need for special education programs, social services and a lifetime of irreversible visual impairment. It is estimated that 20 percent of preschool children ages 3-4 have a treatable eye condition. While many states are developing guidelines for preschool screening programs, none of the commonly used vision tests have been evaluated in a research-based environment to establish their effectiveness.

Vision Screening Tests for Preschoolers

Results from the NEI-sponsored Vision in Preschoolers (VIP) Study found that 11 commonly used screening tests vary widely in identifying children with symptoms of common childhood eye conditions such as amblyopia, strabismus, and significant refractive error. When the best tests are used by highly skilled personnel in a controlled setting, approximately two-thirds of children with one or more of the targeted disorders were identified. These better tests were able to detect 90 percent of children with the most severe visual impairments. The VIP study will provide state and local agencies with data to select the most effective vision screening exams that are currently available. The VIP study will also help ensure that more children are detected and treated at an early stage when therapy is most effective .

Amblyopia Treatment Study

NEI-supported researchers found that Atropine eye drops work as well as patching the eye in the treatment of amblyopia¹¹³. Atropine is used to blur vision in the stronger eye in order to force use of the weaker eye. Atropine offers an alternative to eye patching for children who do not want to wear eye patches. This research finding may lead to better compliance with treatment and improved quality of life in children with this eye disorder. Patients will continue to be followed in this study to better assess the long term effects these treatments have on visual acuity.

Strabismus and Neural Development

Strabismus is a common eye disorder resulting in improper alignment of the eyes. Although strabismus has a clear tendency to run in families, the underlying genetic mechanisms involved in its pathogenesis are poorly understood. This stems, at least in part, from the variety of different forms of strabismus. There are, however, rare forms of strabismus that are inherited as classic genetic disorders, and are more approachable using current genetic techniques. Uncovering the genetic basis of these rare disorders has the potential to provide insight into the pathogenesis of more common forms of strabismus and to provide a foundation for the development of new interventions and treatments.

This year, NEI-funded clinician scientists have identified two genes, KIF21A and ROBO3, which are altered in rare, genetic forms of strabismus. In both cases, strabismus appears to result from developmental defects in neuronal axons that are involved in sending impulses to extraocular muscles. Further study will help target the exact role of these genes in neuronal development and may contribute insight into other forms of strabismus. Additionally, these genes may contribute toward our understanding of repairing motor neuron circuits.

Control of Eye Development

Development of the vertebrate eye is controlled by specific genes that operate in a hierarchy of expression. Some of these genes have been identified as “master controls.” In Drosophila, the fruit fly, loss of any one master control gene results in the failure to form an eye, while the misexpression of any of these genes is sufficient to form an eye in aberrant body locations. One of these Drosophila master genes, called eyeless, is similar to a human gene, Pax-6. Pax-6 mutations result in aniridia, a congenital malformation of the eye associated with improper development of the iris and with the formation of cataracts. Pax-6 and eyeless genes are found in other embryonic tissues, and they are crucial to the formation of other organ systems, such as the nose and antenna.

In an effort to understand the function of master genes and the factors, which turn on each tissue-specific developmental program, NEI-supported scientists recently identified two signaling pathway receptors in Drosophila that act before the eyeless gene to specify eye formation. One is the transmembrane receptor Notch that promotes eye formation. The second is the epidermal growth factor (EGF) receptor that blocks eye formation in favor of antennae. These findings are the first to suggest a mechanism of global control of eye development. Continuation of this line of research is essential to the understanding of the developmental hierarchy controlling ocular development and will enhance our under-standing of the molecular basis of congenital diseases of the eye.

Sleep and Brain Development

Recent research on the developing visual system in animals has pro-vided direct evidence that sleep in early life plays a crucial role in brain development. In normal animals the numbers of cortical neurons dominated by inputs from each eye are roughly equivalent. Neurons receiving input from the same eye are grouped in aggregates in the visual cortex called ocular dominance columns. NEI-sponsored researchers used monocular deprivation (MD) in animal models, i.e., temporarily blocking the visual input to one eye, to develop an assay for the effects of sleep on neural plasticity. In a control group, experimental measurements of ocular dominance in the cortical surface were done after a standard MD treatment. Experimental groups were given one of three different treatments for a six-hour period following MD. One group was allowed to sleep at will in total darkness, a second group was kept awake in total darkness, and a third group was kept awake in the light.

The control animals showed the expected shift in [ocular] dominance toward the open eye. Sleep enhanced the effects of MD on visual cortical responses, but wakefulness, even in complete darkness, did not do so. The researchers theorized that sleep is a period of low sensory input during which the brain consolidates events of recently acquired tasks and that during development, sleep allows the consolidation of changes in ocular dominance evoked by short-term visual experience. Sleep deprivation prevents consolidation of the visual experience and appears to allow accumulated changes to reverse.

The results provide the first direct evidence that sleep and sleep deprivation modify experience-dependent changes in the brain, and also suggest that synaptic circuits are modified during sleep. Additional research exploring the mechanisms underlying sleep may provide a clearer understanding of the function of sleep.

Visual System Plasticity

Ocular dominance columns are columns of nerve cells in the visual cortex that respond to visual input and activity from one eye or the other in binocular animals. In studies of visual system plasticity (its ability to be molded by visual input) changes in the ocular dominance columns in the visual cortex are a hallmark indicator of plastic changes during development. The long standing belief has been that ocular dominance columns emerge de novo during development from an initial state where visual inputs from the part of the brain known as the lateral geniculate nucleus (LGN), representing the two eyes, change from an overlapping representation to separate columnar aggregates each representing the input from one eye. This process is believed to take place during a limited period in development called the critical period. Experimental observations of this organization were made using injections of nerve tracers that were restricted to single layers of the LGN, with each layer of the LGN receiving its input from one eye . However, interpreting these observations are complicated by the fact that the presence of a continuous band of label in the young cortex could either be due the absence of segregated ocular dominance columns, or due to spillover to more than one layer of the LGN.

In a recent study, scientists showed that ocular dominance columns in the visual cortex of the ferret appear long before the columns can be modified by visual experience during brain development. The use of the ferret as an experimental model was critical for this new observation. The visual system of the ferret is at a much earlier stage of development at birth than the cat, commonly used for these studies. Unlike the cat, the projection of the nerve processes from the LGN to the visual cortex develop after birth in the ferret, allowing studies that would otherwise be difficult. Tracer injections confined to individual LGN layers produced clearly segregated patches of labeled cells in the developing cortex as early as postnatal days 16 to 18 in the ferret. Projections from restricted injections to both layers of the LGN gave rise to separate labeled patches in the cortex at this early stage of development in the ferret. The labeled cortical patches have all the characteristics of ocular dominance columns observed in the adult.

To further test the effects of imbalanced inputs of visual activity on ocular dominance columns, monocular enucleations (i.e., eye removal) were done on young animals. In all cases, the patchy cortical labeling arising from injections in the LGN persisted. These observations show that ocular dominance columns appear much earlier than previously thought, and at a much earlier stage of visual cortical development. Earlier studies on the monkey suggest a similar finding. Newborn monkeys have ocular dominance columns very similar to those in the adult. Ocular dominance columns appear to be established before they can be modified by visual experience, or put another way, the plastic changes associated with visual experience during the critical period act on pre-existing cortical columns. This new research suggests that neural activity is not required for the establishment of cortical columns; instead molecular cues guide their formation, although neural activity clearly modifies them later during the critical period. These results may also suggest that the establishment and plasticity associated with ocular dominance columns are at different stages of visual system development.