9. M I - Mechanisms Regulating Ocular Growth & Refractive Error Development

Question 1

Emmetropia is the ... of the eye in which, with ..., the conjugate focus of the retina is .... Thus distant object are ... of the retina; Ametropia is an eye that is ...;

Emmetropisation is the ... which are considered '...' rather than ....

Answer 1

Emmetropia is the refractive state of the eye in which, with accommodation relaxed, the conjugate focus of the retina is at infinity. Thus distant object are focussed sharply on the photoreceptor plane of the retina; Ametropia is an eye that is not emmetropic/ with refractive error; Emmetropisation is the disappearance of neonatal refractive errors which are considered 'normal' rather than an exception during early development.

Question 2

What is the distribution of ocular refraction in young Caucasian adults?

Answer 2

Emmetropic = 54%
Myopia = 27%
Hyperopia = 19%

Question 3

Describe the frequency distribution of refractive states of new borns vs 6-8 yrs.

Answer 3

Newborns have a more even distribution ranging from -6 to +10DS. Frequency peaks at around +2DS;
Children between ages of 6 and 8 have a more prominent peak at around plano.

Question 4

There is an average ...% (x...) increase in axial length from birth to adulthood, such that neonatal have an average of ...mm, whereas adults have an average of ...mm. Around ...% of this change occurs in the first ... years of life. The remaining ...% takes place in the next ... years. This is usually complete at ... years old.

Answer 4

There is an average 40% (x3) increase in axial length from birth to adulthood, such that neonatal have an average of 16.5mm, whereas adults have an average of 23.5mm. Around 85% of this change occurs in the first 3 years of life. The remaining 15% takes place in the next 10-12 years. This is usually complete at 13-15 years old.

Question 5

What are the 3 primary theories of refractive development?

Answer 5

Biological Statistical Model;
Theories of Emmetropisation;
The Use-Abuse Theory

Question 6

The Biological Statistical Model attempts to show that ... are due to the way in which .... It is proposed that there is some mechanisms ... of 4 ocular components: ..., ..., ..., ....
Theses parameter are each .... However, it is observed that .... results for the majority of individuals, meaning that they show .... This implies some ... between each component. Components of ..., ... and ... are fully co-ordinated such that the ... and ... of the eye are perfectly matched.
Ametropic results from ... of the ocular components. This model proposes a ... to explain why .... This model also suggest that ... drive the coordinated growth mechanism. However, this model doesnt explain the role of ... on ametropia.

Answer 6

The Biological Statistical Model attempts to show that all errors of refraction are due to the way in which the components of the eye combine. It is proposed that there is some mechanisms co-ordinating the post-natal growth of 4 ocular components: axial length, corneal power, lens power, anterior chamber depth.
These parameter are each normally distributed. However, it is observed that emmetropia results for the majority of individuals, meaning that they show non-normal distribution. This implies some active co-ordination of development between each component. Components of axial length, corneal power and lens power are fully co-ordinated such that the focal plane and axial length of the eye are perfectly matched.
Ametropic results from failure of coordination of the ocular components. This model proposes a direct mechanical correlation to explain why larger eyes have flatter corneas. This model also suggest that hereditary influences drive the coordinated growth mechanism. However, this model doesnt explain the role of environmental influences on ametropia.

Question 7

Theory of emmeropisation is based upon a '...' of the parameters measured for various components of the eye. Parameters are grouped according to ... between them. There are 3 main factors that appear to explain the major correlations bewteen the optical compoents in the growing eye:
* ... = corneal ... correlated with ...;
* ... = ... and ... correlated with ... (... tone proposed to adjust these parameters together);
* derailment factor = correlations between everything, representing whthere there was ..., ... or ....
* This model suggests that ..., rather than size, ultimately determines the ... (both a mouse and an elephant can be ...). It is proposed that the ... and the ... form an elastic envelope that .... The ... supplies information regarding ... to the brain, which in turn feedbacks information to the ... concerning the necessary degree of '...'. Both ... and ... influences (...) are responsible for the genesis of ... and ....

Answer 7

Theory of emmeropisation is based upon a 'factor analysis' of the parameters measured for various components of the eye. Parameters are grouped according to statistical correlations between them. There are 3 main factors that appear to explain the major correlations between the optical compoents in the growing eye:
* size factor = corneal curvature correlated with axial length;
* stretch factor = axial length and AC depth correlated with lens power (ciliary muscle tone proposed to adjust these parameters together);
* derailment factor = correlations between everything, representing whthere there was too little, just enough or too much stretch.
* This model suggests that stretch, rather than size, ultimately determines the refraction (both a mouse and an elephant can be emmetropic). It is proposed that the ciliary body and the choroid form an elastic envelope that counteracts the stretch/ effective pressure of the sclera. The macula supplies information regarding focus to the brain, which in turn feedbacks information to the cilary muscle concerning the necessary degree of 'stretch'. Both hereditary and environmental influences (feedback loop) are responsible for the genesis of ametropia and emmetropia.

Question 8

The Use-Abuse Theory suggests that excess ... strongly assocaites with ... in humans. However there is no proof of .... This theory strongly supports the role of the ... as the major factor influencing ... development. In particular, it has been proposed that ..., in response to ..., is the key driver of myopia development. This is still however, highly .... In terms of population frequency, prevalence of myopia is highest in ... > ... > ... > ....

Answer 8

The Use-Abuse Theory suggests that excess near work strongly assocaites with development of myopia in humans. However there is no proof of cause and effect. This theory strongly supports the role of the environment as the major factor influencing post-natal refractive error development. In particular, it has been proposed that over-use of accommodation, in response to near demands, is the key driver of myopia development. This is still however, highly controversial. In terms of population frequency, prevalence of myopia is highest in clinical microscopists > military cadets > college students > general population.

Question 9

What does it mean by environmental influences in myopia development? What are the caveats that we have to be aware of?

Answer 9

Environmental influences refer to the visual environment “seen” by the retina during development. Most of these evidence comes from animal models, since variables can be manipulted experimentally. But therer may be key differences compared with human/ primate visual system.

Question 10

Form deprivation myopia was demonstrated in ... macaque monkeys via .... Macaque that were raised in the light had axial length that increased ...% (-... to -...D) in the .... Macaques that were raised in total darkness .... This gives the conclusion that .... Altered environmental conditions are capable of .... Blurred image in the sutured eye causes ..., causing .... This, therefore, supports the concept that ....

Answer 10

Form deprivation myopia was demonstrated in neonatal macaque monkeys via monocular lid suture. Macaque that were raised in the light had axial length that increased 20% (-10 to -15D) in the sutured eye. Macaques that were raised in total darkness had no differences in axial length betewen control and sutured eye. This gives the conclusion that poor quality retinal image promotets axial elongation. Altered environmental conditions are capable of altering the axial elongation of the eye. Blurred image in the sutured eye causes axial elongation in attempts to obtain a clearer focus, causing form deprivation myopia. This, therefore, supports the concept that axial elongation is the "default" growth mechanism.

Question 11

To demonstrate that changing visual environment can cause changes in ..., ... was performed in chicks. Restricting VG to just lateral vision ...; restricting VF to frontal causes ... (mainly in the ...). This is similar to he ... experiment, where clear vision is needed for .... However, the results for this is ..., which indicates that ... in some individuals can mitigate the form deprivation. In chicks, it seems that ... is needed rather than ....

Answer 11

To demonstrate that changing visual environment can cause changes in refractive error, visual field restriction was performed in chicks. Restricting VG to just lateral vision has no effect; restricting VF to frontal causes axial elongation (mainly in the deprived nasal retina). This is similar to he form deprivation myopia experiment, where clear vision is needed for emmetropisation. However, the results for this is highly variable, which indicates that regulation of growth in some individuals can mitigate the form deprivation. In chicks, it seems that peripheral (nasal) retina is needed rather than central retina.

Question 12

In human infants, there are deprivation studies done based on ... and ... with .... Both of these causes .... Both observed ... coompared to control or to the control eye. There are, however, ....

Answer 12

In human infants, there are deprivation studies done based on congenital cataract and eyelid vascular tumours with significant ptosis. Both of these causes form deprivation. Both observed high myopic distribution coompared to control or to the control eye. There are, however, high variance.

Question 13

There are experiments that induce refractive error in chicks. Using an opaque occluder as a ..., causing ..., thus .... When the occluder is removed, .... If a negative lens is placed in front of the eye, .... If a positive lens is placed in front of the eye, the eye ... and it induces .... When these lenses are removed, ....This shows that emmetropisation responds to ....

Answer 13

There are experiments that induce refractive error in chicks. Using an opaque occluder as a form deprivation, causing axial elongation, thus induced myopia. When the occluder is removed, there is a recovery from myopia. If a negative lens is placed in front of the eye, it drives the eye to elongate and induce myopia. If a positive lens is placed in front of the eye, the eye shortens and it induces hyperopia. When these lenses are removed, growth was again altered to try and achieve emmetropia.This shows that emmetropisation responds to altered visual input.

Question 14

... is important in determining eye growth. An experiment that knocked out accommodation in chicks with ... (... innervation for ....) demonstrated ... of the eye compared to ... in normal eyes. However, local retinal deprivation in chicks conflicts this eveidence, where ... will cause .... This, therefore, conflicts the ..., including accommodation. This regional changes in eye growth suggest that .... There are also evidence that show that myopia occurs even after or ... with ... (but also, these are only done on chicks). It is proposed that there are ... that control ocular growth.

Answer 14

Accommodation is important in determining eye growth. An experiment that knocked out accommodation in chicks with EW lesion (parasympathetic innervation for accommodation) demonstrated unstable refractive changes of the eye compared to steady changes in normal eyes. However, local retinal deprivation in chicks conflicts this eveidence, where nasal deprivation will cause only the nasal side to grow. This, therefore, conflicts the global mechanism, including accommodation. This regional changes in eye growth suggest that myopia cannot be the result of a global process. There are also evidence that show that myopia occurs even after optic nerve section or blockade of retinal action potentials with TTX (but also, these are only done on chicks). It is proposed that there are local retino-scleral mechanisms that control ocular growth.

Question 15

What effect did atropine have on form deprivation in tree shrews?

Answer 15

Atropine prevented the development of form deprivation myopia.

Question 16

In humans, atropine is a broadband ..., which blocks ..., including all subtypes ...-... (*neurotransmitter*) with .... Atropine ... (...) and induces .... In avians, atropine is ineffective because ` ciliary muscles have … instead of …. However, atropine still appeared to … in chicks, therefore atropine acts via … to …. In humans, according to the … (ATOM) study, children with atropine treatment had …. However, as clincians, we should consider the side effects of … and …. It is proposed that atropine also acts on …, … and …. There are also M1 and M4 receptors found in …`.

Answer 16

In humans, atropine is a broadband muscarinic receptor agonist, which blocks parasympathetic activity, including all subtypes M1-M5 (ACh) with equal affinity. Atropine blocks accommodation (cycloplegic) and induces mydriasis. In avians, atropine is ineffective because ciliary muscles have nicotinic recepotrs instead of muscarinic receptors. However, atropine still appeared to prevent axial elongation in chicks, therefore atropine acts via non-accommodative mechanism to prevent axial elongation. In humans, according to the Atropine in the Treatment of Myopia (ATOM) study, children with atropine treatment had clinical significant slowing of myopia. However, as clincians, we should consider the side effects of cycloplegia and glare. It is proposed that atropine also acts on retina, choroid and sclera. There are also M1 and M4 receptors found in neural tissues.

Question 17

The protective effect of ... is seens with *drug* in tree shrews, which is a .... This has a clear ... relationship, meaning that .... In humans, although effect was significant, .... This drug is only selective at .... Its also has affinity for ... receptor.

Answer 17

The protective effect of atropine reducing axial length elongation is seens with pirenzepine in tree shrews, which is a M1 specific antagonist. This has a clear dose-response relationship, meaning that protective effect increases with dosage. In humans, although effect was significant, pirenzepine was not well tolerated. This drug is only selective at lower doses. Its also has affinity for M4 receptor.

Question 18

What are MT-3 and MT-7? What are their purposes in myopia research?

Answer 18

MT-3 = highly selelctive M4 muscarinic receptor antagonist;
MT-7 = highly selective M1 muscarinic receptor antagonist;
They can be used to identify which specific muscarinic receptors are involved in myopia inhibition produced by atropine.

Question 19

What are the results of using MT-3 and MT-7 in myopia in chicks? What relevance does this have on pirenzepine?

Answer 19

MT-3 (M4 antagonist) inhibits myopia in chicks at physiological relevant doses.
MT-7 (M1 antagonist) does not inhibit myopia in chicks at physiological relevant doses.
This indicates that pirenzipine inhibits axial myopia in the chick model via the M4 receptor.

Question 20

There are blur-sensitive genes, ... identified in a subclass of retinal ... of chicks, which can .... These genes encode proteins that are involved in ..., ... and/ or .... ZENK is a ... that can respond to different lenses.
Presentation of negative lens will cause ZENK to be ... within ... of lens application.
Presentation of positive lens will cause ZENK to be .... ZENK is therefore known as the "..." gene. This demonstrated a rapid, active, change in ... in the retina which responds to the sign of .... Atropine can ..., which is known to ... of the ... eye.

Answer 20

There are blur-sensitive genes, proto-oncogene identified in a subclass of retinal amacrine cells of chicks, which can differentially respond to positve and negative lenses. These genes encode proteins that are involved in cell division, differentiation and/ or growth. ZENK is a transcription factor that can respond to different lenses. Presentation of negative lens will cause ZENK to be downregulated within 30 mins of lens application. Presentation of positive lens will cause ZENK to be upregulated. ZENK is therefore known as the "anti-myopia" gene. This demonstrated a rapid, active, change in gene expression in the retina which responds to the sign of defocus. Atropine can increase ZENK expression, which is known to slow the elongation of the myopic eye.

Question 21

There are studies that suggest that ... retina is important in ..., even if the .... It is also found that induction of ... promotes axial elongation. Normal myopic correction gives ... at the fovea. If the curvature of the resulting image plane does not match the ..., there will be ... in the periphery. This therefore theorised that a ... is counter-productive. Studies have found that children who became myopia on he average had ... prior to onset, relative to those who did not become myopic. However, it should be noted that .... There are myopia control interventions that induce ..., such as ... spectacles e.g. ..., ..., .... These all have evidence that they ....

Answer 21

There are studies that suggest that peripheral retina is important in emmetropisation, even if the fovea is ablated. It is also found that induction of peripheral hyperopia promotes axial elongation. Normal myopic correction gives clear image at the fovea. If the curvature of the resulting image plane does not match the retinal curvature, there will be hyperopic blur in the periphery. This therefore theorised that a myopic Rx is counter-productive. Studies have found that children who became myopia on he average had more peripheral hyperopia at 2 years prior to onset, relative to those who did not become myopic. However, it should be noted that there is very weak predictive power of myopia progression. There are myopia control interventions that induce relative peripheral myopia, such as peripheral aberration control spectacles e.g. MiyoSmart, dual focus soft CLs, Orthokeratology. These all have evidence that they slow axial elongation.