5 Chapter 7: Emmetropization

7A. Emmetropization – Normal Refractive

Development

[1.] Emmetropization and Emmetropia 

“Emmetropization refers to the developmental process that
matches the eye’s optical power to its axial length so that
the unaccommodated eye is focused at distance” – International Myopia Institute 

Emmetropia is the term used for patients with effectively NO refractive error.  This is typically considered between the ranges of -0.75 and +0.75 D.

Emmetropization is the biological development process used by the eye to minimize refractive error from birth through childhood.  

[2.] Focal point of the eye is set by the anterior optics of the eye (cornea and lens)

At birth, the anterior optics of the lens and cornea set the focal point of the eye.  On average, the axial length at birth is about 2.00 D hyperopic, but can vary from low myopia to high hyperopia.  At this stage, the normal retina, through signaling we will discuss later, detects the location of the defocus and grows longer to meet the focal point.  Below is a figure showing the distribution of refractive error in 3 month old infants.  

We know that the axial length changes to meet the optical focus of the eye through longitudinal studies measuring all the components of eye.  Below is one of those studies.  If we look at the correlation of change in refractive error in infants to the change in axial length, lens power and corneal power, there is no correlation with the CHANGE in refractive error in infants and change in the corneal or lens power.  However, change in refractive error is associated with the change in axial length.

If we look at what happens as the infants age into childhood, the eyes begin to approach zero refractive error or slightly hyperopic. At 3 months of age, 95% of all patients were between -1.50 and +5.00 D with an average around +2.00 D.   By 9 months of age, it has shifted more myopic (or less hyperopic) with a range of -1.00 to +4.00 D and an average of +1.50 D.  By 3 years, it has shifted even more to myopic/less hyperopic with a range of -1.75 to +1.75 D and an average of +0.50 D. 

[3.] Errors in emmetropization result in myopia or hyperopia

When the eye fails to grow to the proper length, the result is spherical refractive error.  Myopia is due to the eye growing too long compared to its total focal power.  Hyperopia is caused by the eye not growing enough for the focal power.

Astigmatism is unaffected by emmetropization as it has multiple focal locations.  The source of astigmatism is always corneal, lenticular or both.  

7B. Emmetropization – Visual Regulation of Eye Growth

[1.] Emmetropization  and Visual Input 

As discussed in the previous section, the eye at birth has a wide range of refractive errors, though hyperopic on average.  At birth, visual input guides emmetropization to match the eye length with the optics of the eye.  Errors biologically or optically can interrupt this process. This is true for all vertebrate species including humans, fish, primates, mice, and chickens.  Look at the figure below.  As can be seen, for all animal models the eyes grow longer over the first year after birth.  To put into context, a 1 millimeter change in length of the human eye equates to an approximate 3 diopter change in refractive error.

Using lenses (see above), we can defocus the image in developing animals.  If a negative lens is used, it decreases the power of the eye and puts in the image BEHIND the retina.  If a positive lens is used, it increases the power and puts in the image IN FRONT of the retina. When this is done at birth in animal models, the animal eyes will grow to the new location.  See below for examples in primates, guinea pigs, and chickens.  When a plus lens is put in front of a developing animal eye, the eye will grow SHORTER to find the image that is in front of the retina.  When a minus lens is put in front of a developing animal eye, the will grow LONGER to find the image that is behind the retina.

[2.] Form Deprivation Leads to Myopia

 A reasonable person might ask “what crazy person would put glasses on a chicken?”.  The answer would be that researchers did not start putting lenses on animals until they discovered form deprivation causes myopia.  Form deprivation is when the eye is given no visual input either through a cataract or lids blocking the line of sight (both can happen in infants). Initially, they were looking for a model of amblyopia so they began sewing lids shut to induce amblyopia in animals.  The ultimate result of this is it caused myopia (in addition to amblyopia.) Below, we can see that eyes in chickens, monkeys and humans with form deprivation become highly myopic.    

With form deprivation, there is NO focal point in front, behind or on the retina. Without visual input, the eye continues to grow to try to find a focal point that does not exist.  This along with amblyopia is why it is critical to detect cataracts in infants and young children before development processes reduce vision permanently. When form deprivation is removed, normal emmetropization resumes allowing the refractive error to return to close to baseline.

[3.] Visual Input at the Retinal Level, NOT the Brain, Drives Emmetropization

A logical assumption would be that processes in the brain must be responsible for detecting the direction of the blur and growing appropriately.  This however would be WRONG.  When the connection to the brain is cut either by optic nerve or the ciliary nerve, the eye still responds the same to blur and form deprivation.  This means the biological mechanisms that control emmetropization are at a local level in the retina.

[4.] Visual Input at the Local Retinal Level, NOT the Foveal

Localized areas of the retina are capable of changing their own axial length without changing the entire eye.  This was discovered by a number of experiments, by using either form deprivation or by lenses to block only part of the visual field and leave the remaining portion clear and in focus.  The locations of the retina with form deprivation or minus lenses induced local increases in axial length.  Below is an example using MRI and partial form deprivation.  The areas with the form deprivation show increased length compared to complete form deprivation where the entire eye became longer.   

One might think that the fovea is the driver of emmetropization, but that would be incorrect.  Regardless of whether an animal has a fovea (predator) or one without (prey), optimizing visual acuity is necessary for survival.  To illustrate that point, researchers have looked at how animals with and without foveas respond to negative and plus lenses.  In the example below, the fovea was laser ablated (destroyed) in one eye only and then given minus lenses/diffusers.  Both eyes ended up the same length regardless the presence or absence of a fovea. 

 [5.] Why does this matter clinically?

Prescribing too much minus power in children will result in the image being focused behind the retina.  If the child is still developing, this will signal the eye to grow.  Ultimately, this will cause a permanent change in the child’s prescription to more myopia, as we can not undue the eye growth.  This also works in the opposite.  Prescribing too much plus places the image in front of the retina, thereby inhibiting eye growth.

How do we know this will work in people?  Because researchers tried it.  In what would now be consider unethical experimentation, researchers fitted children with more plus in one eye than was needed.  (In all fairness, it was to treat an accommodative disorder.) The result was that the eyes with more plus grew less.  It ultimately resulted in inducing anisometropia in the children.  

7C. Emmetropization – Anatomy and Biology

[1.] Emmetropization is a biological process 

Previously we learned that emmetropization is a process that requires visual input to minimize refractive error and maximize visual acuity.  This process is done at the local eye level without input from the brain.  The brain does this first by detecting the sign of defocus, i.e. is the image in front or behind the retina.  Once the sign of defocus is detected, neurotransmitters, growth factors and signaling molecules must pass through the RPE, choroid, and sclera to initiate growth. Below is the best model for how this process works.  

[2.] Retina (Detecting the Sign of Defocus)

The growth signals can detect the sign (i.e. location of defocus) and grow in the appropriate direction to optimize vision.  The retina is the primary tissue where the information of optical defocus sign is converted in molecular signals for growth.  Form deprivation and lens induced defocus cause large changes in expression of genes and proteins.

[3.] Choroid and Sclera 

Looking at the optical coherence images below of myopic and emmetropic retinas, we can see the structural changes occurring with axial elongation.  As the eye elongates, all structures of the eye must stretch and/or grow to accommodate the change in eye size.  One of the more striking features of the more myopic eyes is the thinning of the choroid.  The choroid provides the oxygen supply for the outer retina.  As the eye gets longer, the choroid gets thinner and thinner.  In the images below, the emmetropes show a relatively normal choroid and the high myopes show almost no choroid visible.

Ultimately, the scleral must remodel or thin as well due to the increase in axial elongation.  When scleral thickness is measured relative to the amount of refractive error, research shows that it thins with increasing amounts of myopia.  In very high myopia (15 D or more) it can result in ruptures of the sclera/choroid, and such significant thinning that it is visible with the naked eye.  Thankfully, these events are extremely rare and individuals with these amounts of myopia typically have underlying genetic diseases of the collagen.  

[4.] Ramifications for ocular disease

Ultimately, this lengthening results in anatomical changes in the eye that have ramifications for other ocular diseases.  the anterior chamber depth increases.  This, along with changes in the optic nerve head has effects on the development and detection of glaucoma. Changes in the choroidal and retinal blood flow increase the risk for macular neovascularization. The stretch on the retina increases the risk of retinal detachment and macular holes.

7D. Emmetropization: Signal Components for Growth

[1.] Defocus

Defocus, which we typically think of as spherical refractive error, is critical to the emmetropization process.  It gives the SIGN of defocus to signal the direction of growth. 

Myopic defocus results in the image in front of the retina.  This signals to the eye during development that it needs to stop growing (or ideally shorten.)  The confusing part is the difference between correcting myopia, where we give MINUS lenses to reduce the total power of the eye and improve vision.  To give the eye a myopic defocus to slow/stop growth, we need to give PLUS power to imitate myopia. 

Hyperopic defocus results in the image being behind the retina.  This signals to the eye during development that it needs to grow further back to find the focal position.  In this situation, the eye needs less power to create/simulate hyperopic defocus.  We would give PLUS lenses to correct hyperopia, but to induce hyperopic defocus, we must give MINUS power.  This is at the core of why we do not give too more minus power than is needed to a child.  If we give too much minus, we reduce the power to the point the image is placed behind the retina, and thereby stimulate further growth, leading to even MORE myopia.

[2.] Temporal Processing of the Signal for Growth

What is probably running through some people’s minds is “If I or a child look through a minus lens for a short period, will it cause my eyes to grow longer?”  The short answer is no.  The length of time the eye sees the defocus signal matters.  Brief viewing through the wrong lens power has no effect on growth.  The length of time needed to cause growth is something we can temporal processing.  Essentially, how long does the signal need to be viewed to cause growth. 

Below is an experiment where monkeys wore minus lenses creating hyperopic defocus.  When the lenses were worn 24 hours a day, the monkey’s eyes grew longer than average.  When the lenses were removed 4 times a day for 15 minutes at a time, the eyes grew normally like the hyperopic defocus was never there.  The big point is that brief periods of good focus prevent abnormal growth.

[3.] Competitive Focus 

Using bifocal/multifocal/fresnel contact lenses, we can put the focus of light in different locations at the same time.  This is called dual focus or competitive focus.  Look at the images above.  In both the animal experiment on the left and the commercially available contact lens on the right, light is focused to multiple locations.  In the example on the right in animals, they focused light in multiple different locations to determine which would slow axial elongation (and myopia) versus which would speed elongation.   In the myopia control lens on the right, light is focused ON the retina and IN FRONT of the retina at the same time.

The data from experiments using dual/competitive focus are below.  Essentially, in the experiments, animals are given 50% percent of the image focused on the retina, and the other 50% focused either myopically (in front of the retina) or hyperopically (behind the retina). There are two critical parts to the results of the experiment outlines in yellow and blue boxes.  When part of the image is focused behind the retina (yellow box), the eye does not elongate or develop myopia.  This tells us that even partial well focused vision stops axial elongation.  If we then look at the blue box, the focus is  now 50% myopic or in front of the retina and 50% on the retina.  This results in a shortening of the eye.  The big picture is that the signals to grow longer and grow shorter are not equal and the eye favors stopping/shortening growth over elongation.  This is one of the two theories how contact lenses light the MiSight lens above can slow/stop myopia progression.  We will discuss myopia control in more detail later in this course.

[4.] Luminance, i.e. light level     

The amount of light in the environment or visual targets also seems to effect emmetropization.  Looking at the above image, when animals are given low versus high levels of luminance while being form deprived (it is also true of defocus), the higher luminance negates decreases the axial elongation.  So high light levels are stop or slow growth.  This is in animal models, so how does this apply to humans. First, if you look below at a table of the luminance in our normal environments, the difference in luminance is enormous between indoors and outdoors.

This can even be seen seasonally.  Children progress into more myopia during winter months when people are indoors less and the total luminance is lower.  During summer months, myopia progresses less, possibly due to the higher levels of luminance and spending time outdoors.  This could also be due to accommodation/near work.  We will discuss theories of myopia development later in this course.