The Functional RPE:

Does the RPE die during detachment in the periphery?

*Atrophic (dry) Retinal Detachment* --> There is a wet and dry Retinal Deatachment just like how there is Wet and Dry AMD. Wet comes from the blood, usually systemic disease is involved. This can pull the entire RPE off the tight junctions? --> Dry is more common in both Retinal Detachment and AMD -Not always as they would in Retinal artery occlusion -In peripheral detachment the receptors can live due to the diffusion of nutrients and metabolic waste across the fluid between the receptors and the REP for atleast a while -When the Peripheral Retina Detaches a ratio of 300 PR to 1. Retinal cell is lost. --> The cells are not as metabolically intense, especially rods, and they can float in the vitreous where there can be diffusion across and they may be able to regional the peripheral after having the retina surgically reattached. --> Macula on and Macula off

Genetic RPE Failure: Retinitis Pigmentosa

- Diffuse damage to RPE, which anchors the PR, occurs in many hereditary diseases -Initial stages of the disease the patient will develop loss of night vision -The periphery is where there is a 300:1 ratio of bone spicules to peripheral retina and the central retina is hanging on with reduced and this is due to phytotoxicity if RP patients are raised I caves you would the longer visual life.

What is Iatrogenic Correctopia?

- During glaucoma shunt surgery many patients developed progressive correctopia and ectropium uvae developed because of the adherence of the iris to the silicon tube at the iris root. -When the patient got glaucoma the condition would stabilize.; no adverse outcomes except for the minimal cosmetic effect.

What can Glaucoma Medication do to the iris?

- It can make it darker -Latanoprost -There is no superficial changes (Type 2 change) in the iris just the color gets changed to a darker color -E.g peripheral Hyperpigmentation with a granular appearance (Type 1)

How does the Retina Function after Retinal Detachment

- The PR can stay alive for a while especially if the *macula remains attached* -In detached retina the *outer segment* of the PR degenerated but the *inner segment* remains intact for days. The inner segment survives because thats where the nuclei are. -The receptors were about *40% normal* by two weeks after detachment with scleral buckling -150 days later the outer segments grew back to normal length in the retinal periphery

Why do you think our retina is backwards?

- This is because the receptors have to be in contact with the pigmented cells for a reason

What is the Treatment for Visual Snow? **

-*Acetozolamide*: Carbonic anhydrase inhibitor causes water to decrease in the eye and this in turn will cause pressure to drop. This can be used for malformations that cause diplopia. --> Prescribe 250 mg a day -*Clonazepam*: Off label medication with similar effect. This is used for seizures and pain disorders. This works for persistent without infarction aura. -Or we could try and treat the underlying systemic reason which would be low blood pressure such as hypotension causing lack of blood flow and the aura to appear. -*Lamictal* : --> Used as an anticonvulsant and anti-epileptic --> Treat seizures in children and adults --> Delay bipolar episodes --> Not for children younger than 16 --> Could be used for visual snow because sometimes the visual snow can be like a tiny subclinical seizure. Doesn't work for everyone and this is a little bit controversial.

How can drugs affect the RPE?

--> These meds effect and build and tell the PR they are seeing color and they are not 1. Snowy Vision from *Digitaliz* or from the foxglove plant (for heart pain and angina) 2. Amphetamines, Plaquenil (lupus and autoimmune disease), oral contraceptives and Viagra can cause blue vision = *Cyanopsia* 3. Oral Atropine, Ergotamine (migraine), Sulfa Drugs, and Cyclopentolate can cause red vision (Erythopsia) --> can be used for Nerve Gas to keep heart beating because they are sympathomimetics 4. Digoxin as well as thiazide are diuretics involved in HTN and can also cause yellow vision (Xanthopsia) and visual snow

How do other species handle this problem?

-Cats, Dogs, Deer, Cows and other animals like this "fish" use the "carpet of light" -Reflective layer behind the receptors -Sacrifice acuity for sensitivity (good for nocturnal)

Review: What is the Sheer Phenomenon

-Caused by WBC -WHIte spots -Only present in day light -Dissapears when eye closure -No function imparmetn -No psychological strain -Rare association with other symptoms

Chronic RPE failure: Best Disease

-Drusen in the foveal region signify death of retinal pigment epithelium and accumulation of lipofuscin -Best Disease (yellow lesion in the central macular to viteliform dystrophy = eggy yolk appearance because lipofluscin build up -This can change into scrambled egg because of dramatic separation of the layer of the retina due the lipofluscien that had leaked in between

How does Lipfuscin act as a toxin shield?

-Exists in clumps and increases in amount with age (As in age spots on the skin) -Aging Pigment -Left over garbage after the RPE eats the outer segment of the PR and it is thought to play a role in AMD development - Fluoroscein can now be used to find deposition of lipofuscin in the RPE. -You can see the build up of lipofluscin tossed away in older patients these can lead to AMD.

How Long does Disc Renewal Take? When does it occur for Rods vs Cones?

-In rats = 5-10 days -remember that 300-400 rods are in each RPE cell -Each RPE cell must phagocytize 20,000 to 50,000 discs per day -Rods do not slough at a constant rate all day -Burst of sloughing at sunrise (or when room lights go on) -Cones slough there disks at sunset (or lights go off)

What is the Retinal Rail Road?

-In the light there is a lot of retinal in the RPE cells -In the dark there is a lot of retinal in the Rhod receptors -In the light, worn out photopigment is broken down and transported to the RPE cells for regeneration -In the dark, the recycled photopigment is all in the receptors waiting for light --> The recycling of photopigment to the RPE is via active transport through the tight junction and goes to the choriocapillaires and back again with oxygen and nutrients to keep the disk process of recycling happening everyday

How does an Ectopic Pupil affect Amblyopia? How can this affect the Bruckners Test?

-Lets say that the pupil is dragged off center during development the cone PR that are aligned with the new exit pupil will take over and in that sense the Stiles Crawford Effect can help prevent lazy eye that comes from Ectopic Pupils. -The bruckners test looks for a difference in brightness of the red reflex --> If one pupil is brighter, the macular pigment is not visible, due to misalignment or worse cause of leukoria --> Left eye is the amblyopic

What is the Stiles Crawford Effect? **

-Light that is entering a receptor (only cones) on axis is more likely to be absorbed than light hitting a receptor on an angle. -Type 2 -Not for rods; only the cones need to be in line with exit pupil of the eye to absorb the light

Who is the late Dr. Hubel and Living Dr. Wiesel?

-Made discoveries about the cortex by accident -There is a Cat who's head is positioned in one way with a wire. You show the cat different pictures and it didn't react until you showed it a picture with a slide with a crack on it = it reacted. It reacted because this picture lined up with the simple cell that the micro pipet was lined up too.

VEGF Inhibitors and the Toxin Shield?

-Melanin in the RPE absorbs free radicals by getting them to stick to its surface --> Shields photoreceptors from toxins -Hard to get drugs to receptors (short of virtual injection) -When an oral pharmaceutical crosses the blood brain barrier it can ALSO be absorbed there -ANTI VEGF drugs: E.g Lucentis and Avastin ( Avastin < Lucentis $$) -These get into the aqueous directly and because of the Blood Retinal Barrier they are able to remain in the aqueous of the vitreous.

What causes Visual Snow?

-Migraine HA and Lingual Gyrus -The flashing that we witness usually happens from the lingual gyrus

RPE detachment and Autofluorescence:

-More visible -Detachment of RPE is more likely with wet retinal detachment due to hemmorage

What are some Risk Factors For myopia?

-Myelinated nerve fibers have a feathery appearance and follow the course of the NFL -There may be a slight elevation of the visual field threshold in the affected area -->Myelinated nerve fibers can get in the way of vision by blocking light and they can act like a translucent corneal scar. The eye now perceives a blurry image and assumed hyperopia and it will grow and this could result in an anisomotropic eye.

Why do we have microvilli? **

-Outside of the Fovea there are greater amount of receptors inserted into the RPE -RPE cells send microvilli down between receptor outer segments, because RPE cells contain unique features --> Metabolic machinery (ribosomes for protein, mitochondria for active transport) --> Melanin --> If you lose a single RPE cell in the fovea you lose about 20 foveal cones

-This is the same picture but one is lit up with Blue Laser Autoluorescence.

-Pseudoxanthoma elasticicum -Fundus autoflouresence may reveal structures you wouldn't know there was hypoflourescent body over the optic nerve and macula

How does voltage affect the eye and how is this related to the RPE?

-RPE cells generate an electrical voltage which changes depending on the amount of light entering the eye -Cornea = Postive charge and more light increases the voltage -This is the basis for the (electrooculogram) (EOG), a test of eye health -*Mueller cells* are a link in conducting this voltage and guiding light fiber optically so it doesn't get blocked by other neurons that could potentially get in the way. -The cornea has about a 6mv charge which is carried while the retina has negative charge -The emmetropization process is an electrical process because the mueller cells guiding the light help eye grow. This signal can start from the ciliary body and this is when the eye is growing from hyperopic to emmetropic and this is a process of electrical activity along the mueller cells.

How does the RPE act as a Toxin Shield?

-RPE is one cell layer thick with 4-6 million per eye -RPE cells form tight junctions with one another to create a waterproof layer = Important in metabolism --> We need Opaque RPE to act as a toxin shield, the blood retinal barrier which would be considered a part of the blood brain barrier. The circulation from the choroid will result in waste leaving and O2 answering. -R membrane: Is an electrostatic seal that is brought upon by the RPE

What is a clinical application of a single unit Recording?

-Retinal transplants may not be possible because there are 1.2 million optic nerve fibers and lots of photoreceptors that require connections -A better possibility is to by pass them is to by pass them with some wireless device -This device may be able to give a low contrast pixilating vision for patients who need it E.g Provide vision for a patient who's photoreceptors have been destroyed. Through a camera mounted in a spectacle frame and image is transmitted to a micro electrode array tacked onto the retinal nerve fiber layer. ---> electrode stimulate ganglion cells axons, mimicking signals produced when PR are activated. --> Stimulates the outer aspects of retinal ganglion and bipolar cells. Early data suggests that retinal implants can restore rudimentary vision in blind patients.

Why do the Discs Slough off?

-Rod and cone discs degenerate because they get indigestion from toxic produce like free radical oxygen -E.g: Rats kept in continuous light reading levels for 24/7 will have PR degeneration -*Toxic Product Hypothesis* -rate of degeneration is dependent on the light wavelength (shorter; worse) and duration (longer is worse) -The receptors can become toxic and come apart due to UV

6. The RPE and Pigment Regeneration:

-Rods have discs like a stack of coins -Cones have indented disks like comb teeth (at least in the lower 1/3 to 2/3 of each cone) -These discs have to be renewed (sloughed) on a regular basis -One of the most important reasons for a backwards retina is to regenerate pigment -The average rod is bigger than the average cone -The difference between these disks is where pigment is regenerated E.g Rhodopsin and cone pigment --> Rods: The pigment disks are encased --> Cones: Pigment disks are invaginated -Notice a difference in synapse at the pedicle for cones vs spherule for rods. The pedicle synapse is open to listing neurotransmitter and the spherical shielded synapse doesn't allow neurotransmitter space because under star light conditions it can not afford to lose photons.

How is our Retina Backwards?

-Some of the layers are thicker than others -Our retina is backwards; you want the light and the detector of light to be next to one another; however we have it opposite we have a lot of stuff in front blocking the vision. Because of this not all of the light is getting absorbed by the PR; and even after the PR it has to go back to the optic nerve to create a neural signal.

How does Lasik affect the Stiles- Crawford Effect?

-Sometimes with Lasik you can experience large pupils and see halos. -These are due to peripheral aberration and diffraction -Here the Stiles Crawford affect is still trying to light and focus it in one spot but the swelling makes it seems as if the the light is coming to multiple exit pupils in the eye -In order to try and prevent these measure the pupils in the dark with a blacklight (UV) -This allows you to see pupils with crystalline lens auto-flourscence without causing pupil constriction -Wavefront LASIK can also diminish these problems by customizing the stromal ablation in the periphery to match the corneal topography

What are 2 diseases who have Disruption of the RPE?

-Stargardt and Best Disease Autofluorescence --> Show up well on autofluorsciene and this is a build up of lipfluscin and the failure of filtering out toxins. -->Peripheral vision is untouched

What is the visual snow Simulation?

-Static Vision -Most common cause is LOW BP -Orthostatic Hypotension particularly when you are lying down in a hot bath tub and you get up abruptly. -Entoptic Static- Make vision static - blood flow problem - distinguish from blue phenomenon

1. What is the Toxin Shield of the Retina?

-The Choroid -Active transport from the choriocapilaries to and from the receptors = toxin shield -The RPE cells provide the major source for nutrition to receptors therefore if they where to get separated they could potentially die -E.g This is an albino patients with no melanin in the RPE but you can see the choroidal vasculature against the white sclera with absence of pigment

The RPE, Mueller Cells, and Retinal Growth Factor

-The RPE cells are electrically active and continuous with the iris -Raptors have striated muscle in there iris and can accommodate by squeezing their entire eyeball to a new shape. --> Their muscles go deep around the eyeball -In humans its the Mueller cells the conduct electricity for retinal growth factor --We have the PR at the Botton and light coming in from the top and the a full thickness of yellow cells (mueller cells) (not as one of the 6 layers of the retina) and this has to do with structural integrity and also to conduct electricity to help the eye grow.

3. The RPE and Receptor Alignment:

-The absorption of light is dependent on the angle and which light hits our pupils. Therefore our PRE aligns our photoreceptors at the exit pupil of the eye, not the real pupil. -This alignment can be effected if the pupil becomes off centered. -For patients with correctopia; this is a full thickness iris defect it can be traumatic or congenital, due to Axenfeld Geiger syndrome,. -Now the problem is going to stem from the the fact that the pupil, apertures of the eye, and RPE receptors are not in lined up.

What is Electro-Oculography?

-The cornea holds a standing charge of about 6 mV greater than the retina -this difference is greatest in light and abut half as great in the dark -Certain eye disease affect the EOG even when their appearance on the retina is not pathoneumonic -We can measure the standing voltage of the eye using EOG surface electrodes along the temporal canthus, nasal and the ear. --> By looking left and right at a red light you can measure the voltage across the eyeball -The electric retinogram can also do this

2. The RPE as a Light Shield:

-The pupil is black because the uvea is a great light absorber this is very beneficial because it this reduces the scatter of light before it goes to the retina. -The RPE does help a little bit to reduce glare not a lot in humans -E.g The animal with the horizontal pupil will absorb light and be able to objects across with small diameters. The pupil need to be black because if it was white it would be like a cataract and unable to allow light to pass through and bounce to the back of the eye. -During the day we give up the amount of light taken in to gain visual acuity. We do this by having RPE cells cut down the oblique light by having small traces of pigment on the outer segments of receptors -At night we are able to take in light from any angle and therefore our acuity suffers. At night we trade off acuity for sensitivity therefore we do not need the light shield. *This is why there is no light shield for Rods* -Owls have *reflective* not *absorptive* retinas. Therefore a night time animal would not want a light shield because light is scarce at night and they would want as much as they can get to come in.

4. The RPE and Anchoring the Receptors

-The receptor-RPE boundary is the *weakest* --> Detachment occurs here 3 Holding Forces: a) Physical Barbs on receptors or RPE cells b)Mucopolysacharide (gluey acid) c) Pressure of globe contents In the RPE we have holes, inserted in these holes are receptors which are held in place by *microvilli* -The number of RPE cells is the lowest in the fovea ( 20:1) -This increases beyond 5 degrees of the macula. -The fourth reason we have a backwards eye is to prevent retinal detachment; the RPE works as an anchor and PR outer segment have barbs on them and a gluey acid. With all of this we also have the vitreous trying to hold the retina in place. -Retinal detachment can happen at the PR and the RPE

What are Ocular Ventricles? How do they act as Toxin Shields?

-The vitreous and aqueous closely resemble the CSF --> The CSF nourishes the brain amydygla singular gyrus --> They are sealed the same way ventricles are --> Aqueous has constituents that blood doesn't have because the muller cells are playing a role in sealing off the ventricle -The retinal vasculature is identical to the embryological retina -The sub retinal space is the ocular ventricle -Try and thinking of the RPE and a ventricle lining

How is the Stiles-Crawford effect manifested with Opaque Colored CL?

-These only come in one Base curve however some patients will still wear them. It may make the patient look strabismic and there pupil could be decentered. -Because of the stiles Crawford effect they may be able to handle it.

How are Misaligned Pupils affected by the Stiles Crawford Effect? **

-This image shows that a dilated pupil will give the illusion of an off centered pupil and the vision is still fine for the patient and this is because the cones are able to reorient them selves towards the new exit pupil of the eye and if the contact lens is removed, the cones will go back to there original position. In reality their are other cones in that position that are picking up light at the new exit pupil. -However if the pupil is correctopic this won't work because their will be two entry points for light

What does Iatrogenic mean?

-This is something that happened surgically -In this they lost optic nerve integrity because it caused pupillary drag in the direction of the shunt -Used antimetabolite to prevent scarring it effects the ciliary body causing it to contract and the drag the pupil in the same direction as the contraction

What is Retinal Growth Factor?

-This is the name given to the neurotransmitters released by this process and is thought to the use of axial lengthening of the eye -Since most infants are born hyperopic, retinal growth factor usually results in emmetropization (lengthening of the farsighted eye to minimize refractive error) -involves dopamine and melatonin -Even if the optic nerve the eye can grow in response to light. The RGF is neurochemical (electrical and neural) soup that makes the eye change axial length in response to the wavelength and focus of the light.

What does a Thiner Retina Mean?

-This means a Thicker Visual Cortex -Singe unit recording helped us to sort out all of the structures and their neurological function -Helps us understand why our retinas are thinner than some species but our visual cortex is thicker; in the absence of the striate cortex we would need a much thicker retina -He was the first look at structures and discover function

What can cause Acute RPE failure?

-UV --> UV-A : 320 to 400nm Melanogenic (produces tanning) and can cause sunburn an cataracts --> UV-B 280 to 320 nm Skin cancer and cataracts --> UV-C 200 -280 nm Absorbed by cornea and can cause photokeratitis and *maybe AMD at elevation* --> Inuits use snow goggles in elevations because there are shorter wavelengths meaning deeper penetration in order to deal with snowblindness.

How does Melanin Act as a Toxin Shield? **

-Uvea ( Iris and choroid) and RPE cells all have melanin. -RPE cells are still the same amount in all ethnicities however Africans have twice the melanin in the choroid than caucasians -Pigmented structures absorb toxins E.g treating the common cold with charcoal -Iris and the back of the eye, where there is melanin located, can absorb pigment -The ciliary body is considered the liver of the eye because it has the ability to filter out toxins E.g when you put drops in the front of the eye ; the ciliary body will filter it out -The RPE is the same from person to person it does not differ. Melanin differs from individual to individual but the RPE is the same therefore it is not a determinant of the color of the retina.

-The optometrist Schwartz defines visual perceptions "Conscious expression of neural activity within the neural structures of the visual system"

-We know this because all nerves communicate exactly the same way with electrical potentials -This picture is a lampshade and it is concave and convex depending on what your brain tells your eyes to look for.

Eye Structure and Function:

-We've seen how other species see - 2 types of eyes found I nature (Vertebrate and Compound) -Know how obstructions in the eye such as the avian pectin result in perception of objects in space -Structure doesn't explain cataract pt. who complains of marked reduction in vision but see's 20/20 -The vertebrates retina is put together backwards

How can you differentiate Sheer Phenomenon with visual snow?

-White, black or other colors -TV-like static most often randomly distributed in the entire VF -Present in all light conditions often more intense in the dark -Phenomenon persist with eye closure -Often function impairment E.G reading difficulties or impaired night vision -Mild to severe psychological strain -Frequently associated with other perceptual disturbances (e.g. vision loss, increased after images, tinnitus)

What is single unit recording?

-use of a glass micropipette filled with a weak electrolyte solution to record the action potentials from a single living neuron -With single unit recording neurons in the retina, LGN, Striate Cortex, can be testing for their response to light -Hubel and Weisel used this technique to record the electrical activity in the primary visual cortex of cats

But what are the Functional Layers?

1. Pigment Epithelium 2. PR layer 3. Horizontal Cell Layer 4. Amacrine Layer 5. Bipolar Cell layer 6. Ganglion Cell Layer --> 5 Neurons --> 1 RPE RPE --> PR out segment --> PR inner segment --> Outer Limiting Membrane --> Outer Nuclear Layer --> Outer plexiform Layer --> Inner nuclear layer --> Inner Plexiform Layer --> Ganglion Cell Layer --> Nerve Fiber Layer

What are the 6 reasons for the RPE? **

1. Toxin Shield 2. Light Shield 3. Alignment of the receptors 4. Anchoring the receptors 5. Retinal Growth Factor 6. Photopigment Regeneration

Where Does Retinal Detachment Occur?

Between the Inner segments of the receptors (along the cilium) and the RPE (outer segment of PR still there with RPE) --> Associated with posterior vitreous detachment --> Hole in retina, due to systemic cause, water leaks in = detachment --> Curtain over vision --> Harder to repair when macula comes off

How many Layers does the retina have? --> Labeled

NFL: Nerve Fiber Layer OPL: Outer plexiform Layer ILM: Internal Limiting Membrane ONL: Outer Nuclear layer GCL: Ganglion cell layer ELM: External limiting Membrane IPL: Inner Plexiform Layer IS: Photoreceptor Inner Segment INL: Inner nuclear Layer OS: Receptor Outer Segment RPE: Retinal Pigmented Epithelium IS/OS: Interface between IS and OS

What layer of the retina is responsible for macular degeneration?

RPE

Tight Junctions and the Toxin Shield?

The choroid not the CRA provides the RPE blood supply Wherever there is blood supply there is oxygen RPE is sealed in the inside by BBB (mueller cells) -CRA Occlusion can give you the appearance of a cherry red spot because it is seen in contrast to a white edematous retina. An intact cilioretinal artery continues to nourish this region of the retina