Lecture #18

Retinal disease4/4/13

QUIZ on Tuesday

• 20 minutes at end of class• 10 points added to midterm grade (up to total

of 100)• Bring your calculators

Animal Wiki due midnight tonight

• Keep it simple• If you can’t find out any color vision info make

your best guess based on similar organisms• Be sure to try some wiki formatting (bullets or

colors, adding links)

Final wiki project

• Topic of interest to you• Introduction page

State topicWhy is it interesting / important?Give brief introduction or background

• 3 topic pagesDraw on primary literatureEach 500-1000 wordsMake interesting to reader so they will learn

For next week

• Identify a topic• With one sentence for each, tell me:

What is your topic?Why is it important for vision?Why is it interesting?

• Based on this I will suggest some references

Wiki project timeline

• Description of each week’s wiki project assignment is on the web4/11 - Identify topic4/18 - Make intro page and find references4/25 – 1st main page5/11 - Final project finished

Wiki project ideas

• In depth study of an animal visual system (mantis shrimp, humans, comparison of primates)

• Tetrachromatic females • Instrumentation used by optometrist to check

your vision• Characteristics of light environment

Color and polarization in the sky

More ideas• Flicker fusion frequency - temporal

perception• Depth perception• Fluorescence in the ocean• Animal coloration and camouflage• Eye research of UMd faculty

Bill Jeffery, Betsy Quinlan, Dan Butts, Hey-Kyoung Lee, Richard Payne (not KLC)

• Robotic vision

Some topics done previously

Todays topics

• Why the retina is susceptible to disease• Major retinal diseases

Diabetic retinopathyAge related macular degenerationOther genetic diseases

Structure of the retina

Pigment epithelium

Photoreceptors

Outer nuclear layer

Outer plexiform layer

Inner nuclear layer

Inner plexiform layer

Ganglion cell layer

Retina formation

• Cells form once early in developmentPrior to birth

• In mammals, if cells are damaged, they do not regenerateLost foreverThis is not true of fish where retina grows their entire life

Retina under high stress #1• High metabolism of

photoreceptorsIn dark, ion channels are open and current is constantly flowing In the dark, normal state of synapse is to release glutamate

Glutamate release

Retina under high stress #2

High energy needs are met by the choroid (blood circulation behind RPE) and retinal vasculature (above ganglion cell layer)

Retinal vasculature has hole around fovea

Few blood vessels above retina but none above macula

Most energy demanding tissue in nervous system has to get O2 and energy in and waste out by diffusion

Retina under stress #3

• Photoreceptors are exposed to high light levelsThis includes damaging UVLight sensitivity is reason for their existenceStill susceptible to light damage

Structure of the retina

mRNA goes from nucleus (n) to inner segment (m, e) where protein is made and sent to outer segment (o)

Photoreceptors

Rat rod Frog rodsGreen Red

New membrane (proteins) added at boundary of inner and outer segments

New outer segments are built up at same time

Retina does turn over outer segments (OS)

• Label photoreceptors with H3-methionine

• Used to make proteins : follow these after they are added to OS

• Outer segment turns over in 10 days (rat)

2 days

3 days 4 days

7 days 9 days

Young 1967

Tip of outer segment is removed by phagocytosis into RPE

RPE

Outer segment

Phagosomes are present in rods and cones each day

Rods shed at beginning of dayCones shed at beginning of night

Rod shedding Cone shedding

Young 1978

Retinal disease

• How is retinal health / disease diagnosed?Examine fundusPsychophysical testingElectrophysiology

Diagnosis #1

• Fundus imaging

• OphthalmoscopeInvented by Helmholtz

Ophthalmascope

• Illuminate the eye nearly on axis

• View retina on axis

Two vascular systems for retina

Choroid is behind RPE - hidden from viewRetinal vasculature - this is what see in fundus - no blood vessels on top of fovea / macula

#2 Fluoroscein angiography• Inject fluorescent dye

• Provides finer resolution of retinal vasculature

• Look for fluid loss through capillaries

#3 Higher resolution imaging : OCT

• Optical coherence tomography

• Essentially ultrasound with light

• Get microscope like resolution of the retina

Optical - uses light Coherence - interference from retinal layers compared to mirror Tomography - profile in sections

Invention and development of OCT

Optical coherence tomography

OCT normal 3D view

Blood build up on /in retina

Age related macular degeneration

Pigment epithelial detachment and drusen or deposits

#4 Psychophysics

• Behavioral response to stimulusVisual acuityIntensityTemporal responsePeripheral visionColor visionDark adapted (rod) vision

#5 Electrophysiology

• Record electrical response of the eye

• Apply electrode (as a contact lens)• Measure potential in response to light pulse

Electroretinogram

Electrical set up

Neurons of retina

Photoreceptors

Horizontal cells

Bipolar cellsAmacrine cells

Ganglion cells

Normal ERG in response to flash of light

Irregular ERG responses as a result of retinal disease

Types of retinal disease

• Most common (few % of population)Glaucoma - next classDiabetic retinopathyAge related macular degenerationAll three have both genetic and non-genetic causes

Health related information at National Eye Institute

Info on many diseases

Diabetic retinopathy

• Diabetic eye diseaseDamage to retina as result of having diabetes

• Diabetic retinopathyDamage to blood vessels of retina

May swell (aneurisms) and eventually block blood flow

As some are blocked, new vessels try to grow on surface of retina

• Leading cause of blindness in adults

Vision with proliferative retinopathy

Blood leaks from vessels growing on surface of retina

Prevention• Get eye exam

40-50% of people with diabetes have some form of retinopathy

• Keep blood sugar and blood pressure in check

Treatment

• Retinopathy can be treated with laser surgeryUse laser to shrink and seal leaking blood vessels

• May also need vitrectomy - remove blood stained vitreous

• 95% chance can prevent blindness over 5 yrs

Age related macular degeneration (AMD)

• Disease associated with aging of the eyeDestroys sharp central vision

• Leading loss of vision in people > 60 yrsAffects >1.7 M people

Two kinds of AMD

• Wet AMDBlood vessels grow under retina and lift maculaMay leak fluid which raises macula up from back of eye

Lose contact with RPE and blood supplyRapid loss of vision

SymptomStraight lines appear wavy

Two kinds of AMD

• Dry AMDPhotoreceptors degenerateResults in blurry central vision and then vision lossSymptom - blurred vision

Can’t recognize facesNeed more light for reading

May coincide with growth of drusenYellow deposits under retina

Example of vision with AMD

Prevalence

• Wet AMD - 15%• Dry AMD - 85%• But most of severe vision loss is from wet

AMDWet form always arises from first having dry form

• Risk factorsSmoking, obesity, Caucasian, female, family history

Treatment• Dry AMD

Take high doses of antioxidants and zincSlows progression

Eat vegetables

Treatment

• Wet AMDDestroy blood vessels by

Laser surgeryPhotodynamic therapy

Inject drug which is light activated to destroy blood vesselsInject anti growth factors to slow blood vessel growth

Phenotypes of AMD

Identify regions of genome which linked to susceptibility

CFH gene

Some genes found

• CFH - Complement factor H Y402H allele2.5x higher risk for heterozygote carrier and 6x for homozygoteOther alleles show association with AMD

Some causativeOthers protective

March 2013

Now many loci for AMD

Rattner et al 1999

Mendelian retinal diseases

• Single gene mutationsMendelian inheritanceEarly onsetMore severe clinical courseUntreatable

• All together infect 1:2000 people

Hereditary diseases

• Age of onsetLeber congenical amaurosis - retinal dystrophies diagnosed shortly after birth or in infancy

Dystrophy - abnormal development

Degeneration - loss after previous function

Hereditary diseases

• Pattern of visual lossLoss in periphery first - retinitis pigmentosaLoss in center first - macular degeneration

• Rod vs cone involvementRods firstCones first

Hereditary diseases

• Inheritance patternDominant -

Recessive -

Hereditary diseases

• Inheritance patternDominant - get disease if just one copy of mutant geneRecessive - need two copies of mutant gene

Example: Retinitis pigmentosa has many forms

• Result of impaired rod function• Progressive degeneration of retina beginning

in midperipherySpares central retina until late in disease

• Characteristic retinal depositCalled bone spicule pigmentary deposit

• Eventually lose rod and cone functionIf lose cones early called cone-rod dystrophy

Inheritance

• X linked• Autosomal recessive• Autosomal dominant

Genetic causes of retinal disease

Retnet Diseases

Retnet Genes

Progress in retinal disease identification

Nearly 200 known genes

Many genes are from phototransduction pathway

• Screen families of affected and unaffected individualsSequence 15 rod phototransduction genesSequence all of them since <1999 didn’t have them all mapped in humans

30% of autosomal dominant RP is caused by rhodopsin mutations

Phototransduction

Summary

Retinitis pigmentosa - causal genes2013 (36 genes)

Still more work to do

• Well studied diseases still have unknown causes40% of retinitis pigmentosa cases are unexplained

• Genetic susceptibility for degenerative diseases just beginning