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2012-13 Texas Focus

Congenital Conditions Affecting Cones

March 31, 2013

10:30 AM -12:00 PM

Presented by

David Lewerenz, OD, FAAO

Assistant Professor, Chief of Low Vision Services, Northeastern State University Oklahoma

College of Optometry

lewerenz@nsuok.edu

Developed for

Texas School for the Blind & Visually Impaired

Outreach Programs

Hereditary Cone Disorders

David Lewerenz, OD, FAAO

Northeastern State University

Oklahoma College of Optometry

Overview

• Rods, cones, vision and the ERG

• Achromatopsia

• Progressive cone dystrophy

• Cone-rod dystrophy

• Compare with other conditions

• Stargardt disease

Retina

The retina is the light sensitive layer. Photoreceptors are one of the outer layers and point outwardly.

[pic]

Figure 3 Drawing of the eye and its components.

The Normal Eye

• Normal fundus

o Uniform background

o Pinkish-orange optic nerve

o Small excavated, pale area at center of optic nerve

o Medium sized blood vessels

o Pigmented central, "macular" area

o Foveal reflex

[pic]

Figure 4 Image of the normal fundus.

Layers of the Retina

Direction of light ↓

Figure 5 Image showing layers of the retina From Remington, Clinical Anatomy of the Visual System, 2005

Rods and Cones

• Contain visual photopigments that are activated by light, a process called phototransduction

• Two types

o 5 million cones (not always cone shaped) increase in relative density toward the macula and are more active in bright illumination: photopic

▪ Provide sharp, detailed vision and color vision

o 92 million rods increase in relative density toward a point about 15-20 degrees from the fovea and are more sensitive to light, so they are more active in dim illumination: scotopic

▪ Provide vision in the dark

Photoreceptor Morphology

[pic]

Figure 6 Illustration of photoreceptor from Oyster, The Human Eye: Structure and Function,1999.

Photoreceptors

Large dots in image are cones, small dots are rods, except at fovea.

One square mm of retina has 200,000 cones at the fovea!

Figure 7 Image showing photoreceptors from Oyster, The Human Eye: Structure and Function, 1999.

Creating a Composite Image

[pic]

Figure 8 Image of sculpture and path of eye movements from Oyster, The Human Eye: Structure and Function, 1999.

We make many small, quick eye movements ("saccades") without realizing it, especially when reading and examining an object for detail

Photoreceptors Function

[pic]

Figure 9 Diagram showing the photorecptors function from Oyster, The Human Eye: Structure and Function, 1999. A series of waves labled Blue cone 419, Rod 496, Green cone 531, and Red cone 558 appear. A box with the words,”Only 5-10% of cones” is connected to the blue cone wave by an arrow.

Retinal Pigments

• Melanin

o Makes retinal pigment epithelium dark in color

o Same pigment that darkens tissue throughout the body

o Absorbs stray light

• Xanthophylls

o Lutein and Zeathanthin make the macular area darker and provide protection from degenerative changes

• Lipofuscin

o Result of retinal metabolic processes

o Buildup can cause damage to the retina

Electroretinography

• Electroretinogram (ERG) is a response to light from the cells in the retina

• Recorded by an electrode in a contact lens or foil on surface of the eye

Electroretinography

• Can isolate the cones in a photopic ERG

o In a light adapted retina and with a bright flash the rods are washed out and do not respond

o A light that flickers on and off 30 times per second will also stimulate the cones selectively (rods respond only up to 20 Hz)

• Can isolate the rods in a scotopic ERG

o After dark adapting for 30 minutes and using a dim flash the rods are stimulated exclusively

Color Vision Deficiency

• X-linked recessive

• Otherwise visually normally sighted individuals

• Two levels of severity – both 20/20

o Dichromacy – More severe

▪ One cone type not functional

▪ 2% of males

o Trichromacy – Less severe

▪ One cone type not fully functional

▪ 6% of males

Hereditary Cone Disorders

Common Characteristics

• Bilateral

• Reduced visual acuity

• Poor color vision

• Light sensitivity (“photophobia”)

• Light adaptation problems

• Better vision at dusk/night

• Temporal optic nerve pallor

• Nystagmus can occur if early onset

Achromatopsia

• Poor/no cone function; Present at birth, non-progressive

Reduced visual acuity, poor color vision, light sensitive

• Rod Monochromatism

o No cone function

o Autosomal recessive

▪ Complete

▪ ~20/200

▪ Incomplete

▪ ~20/100

• Blue Cone Achromatopsia

o 1 cone type present

o X-Linked recessive

Achromatopsia

All Types

• Decreased or absent cone function at or near birth

o Cones appear to be present, but not functional

• May be assumed at first to have congenital nystagmus or (because lightly pigmented fundus in many cases) ocular albinism if ERG not done

o Not progressive

▪ May even improve slightly over time

• No treatments in clinical trials per

• Profoundly impaired cone (photopic) ERG, normal rod (scotopic) ERG

Achromatopsia ERGs

[pic]

Figure 12 Image showing ERGs including Scotopic (Rods), Max, 30 Hz Flicker (Cones) and Phototopic (Cones) information from Taylor and Hoyt, Pediatric Ophthalmology and Strabismus, 2005..

Achromatopsia

All Types

• Nystagmus – typically rapid frequency and low amplitude

• May decrease by age ten and may become latent

• Light adaptation problems

• Photophobia - Light sensitivity

• Day blindness – poor vision in bright light

• Poor to no color vision

• Two major types

o Rod monochromatism

o Blue cone achromatopsia

Achromatopsia

All Types

[pic]

Figure 13 Images showing retina of 9-year-old with achromatopsia with subtle foveal atrophy and temporal optic nerve pallor. From Albert Jakobec’s Principles and Practice of Ophthalmology, 3rd edition, Ed. by Albert and Miller, Saunders, 2008.

• Reduced foveal reflex

• May have pigment mottling in central and/or mid peripheral retina

• May have temporal disc pallor

Nerve Fiber Layer

[pic]

Figure 14 Image of the nerve fiber layer. from Oyster, The Human Eye: Structure and Function, 1999.

Papillomacular bundle is reason for temporal optic nerve pallor.

Achromatopsia

Rod Monochromatism

• All cones have reduced or no function

• High hyperopia is often present

• Affects about 1 in 30,000 to 50,000 people

• Two forms

o Complete

o Incomplete

Achromatopsia

[pic]

Figure 16 Toddler wearing glasses looks at a child's picture book.

Rod Monochromatism – 2 Types

• Complete Rod Monochromatism

o Visual acuity ~20/200

o Little or no color vision

o Severe photophobia

• Incomplete Rod Monochromatism

o Visual acuity ~20/80 to 20/200

o Moderate loss of color vision

o Moderate photophobia

Achromatopsia

[pic]

Figure 17 Image of genetic material.

Rod Monochromatism

• Autosomal recessive inheritance

• Three genes responsible for most cases

• CNGA3 – 20-30%

• CNGB3 – 40-50%, also linked

o to progressive cone dystrophy

o Location within the gene

▪ can determine severity and

▪ even the type of condition

• GNAT2 - Rare

Oligocone Trichromacy

• All three cone types are present, but function is poor in all the cones

o Like a very incomplete form of rod monochromatism

▪ Mild visual acuity loss – 20/40 to 20/80

▪ Mild photophobia

▪ Normal looking retinas

▪ No nystagmus

▪ Normal color vision

▪ Occurrence is extremely rare

▪ Autosomal recessive

Achromatopsia

Blue Cone Achromatopsia

• Blue cone achromatopsia has rods plus the "S" cones that are maximally sensitive to blue light

o Only 5-10% of cones are S cones

o There are no blue ("S") cones in the fovea

o The "M" cones (maximally sensitive to green) and the "L" cones (maximally sensitive to red) are non functional

▪ Unable to prove this histologically

o A form of incomplete achromatopsia

o X-Linked Recessive ("XLR Incomplete A.")

Distribution and Number of Blue ("S") Cones

[pic]

Figure 18 Observed fraction of cone separations from Hafer H, Carroll J, Neitz J, Neitz M, Williams DR, Organization of the Human Trichromatic Cone Mosaic, The Journal of Neuroscience, Oct. 19, 2005, 25(42): 96669-9679.

Achromatopsia

Blue Cone Achromatopsia

[pic]

Figure 19 Photo of the Blue cone monochromatism: pale tilted optic dic with myopic fundus from Taylor and Hoyt, Pediatric Ophthalmology and Strabismus, 2005.

Achromatopsia

Blue Cone Achromatopsia

• Clinical picture is similar to rod monochromatism, except

o Less loss of visual acuity and color vision than in rod monochromatism

o Vision can be as good as 20/60, can be worse

o Often myopia is present

o Macular changes often progress after age 40, especially if better than 20/100 as a child

o Occurrence is rare, < 1 in 100,000 people

Achromatopsia

How to Tell Type

• Blue Cone A. can be distinguished from rod monochromatism by

o Blue Cone A. occurrence is mostly in males

o Blue Cone A. often myopic, Rod Monochromatism often hyperopic

o Special ERG using blue flash stimulus against yellow background

o Special color vision test (Berson test)

▪ Problem with cone dystrophy

o OCT – People with Blue Cone A. have thin foveal area

o Genetic testing

Achromatopsia

Well known achromats

Rachel Scdoris

• Legally blind from achromatopsia

• Completed Iditarod 1,200 mile Alaska dog sled race in 2006

John Kay

• Founder and lead singer of Steppenwolf

Progressive Cone Dystrophy

• Overall decline of cone function throughout the retina

• Not limited to the macula/fovea

• Develops in childhood or early adulthood

• Fine or no nystagmus

• Amount of vision loss varies greatly, but usually results in worse than 20/200

• Profoundly reduced light adapted (“photopic”) ERG and nearly normal dark adapted (“scotopic”) ERG

Progressive Cone Dystrophy ERG

Cone Dystrophy - Normal

Scotopic (Rods)

Max

30 Hz Flicker (Cones)

Photopic (Cones)

Pattern ERG (Cones)

Figure 22 ERG comparing Cone Dystrophy (left sets) and Normal vision (right sets). Sets of pictures from top to bottom show: Scotopic (Rods), Max, 30 Hz Flicker (Cones), Photopic (Cones), and Pattern ERG (Cones) from Taylor and Hoyt, Pediatric Ophthalmology and Strabismus, 2005.

Progressive Cone Dystrophy

[pic]

Figure 23 Image of the retina from Basic and Clinical Science Course: Retina and Vitreous, AAO, 2008

• Affects about 1 in 30,000 people

• No treatments in clinical trials per

• Retina appears normal early

o Loss of foveal reflex

o Foveal atrophy

o Bull's eye maculopathy late

• In some cases there can be a glistening green appearance to the retina

Progressive Cone Dystrophy

[pic]

Figure 24 Four images of the retina from upper left showing early pigment mottling, upper right golden sheen in XLR, lower left Bull's Eye maculopathy, and bottom right geographic atrophy from Kanski and Bowling, Clinical Ophthalmology: A systematic approach, 7th ed., 2011

Progressive Cone Dystrophy

[pic]

Figure 25 Two images of the retina showing a baseline and "after 3 hrs. DA" from Basic and Clinical Science Course: Retina and Vitreous, AAO, 2008

• Appearance of retinal sheen may change in dark adaptation (Mizuo-Nakamura phenomenon) in X-linked form

• Color vision defect (usually red-green) will sometimes precede loss of visual acuity

• Peripheral visual fields are normal

• Often rods affected later, resembling cone-rod dystrophy

Progressive Cone Dystrophy

• Inheritance can be variable

o Autosomal dominant – GUGA1A gene

o Autosomal recessive – RDH5 gene

o X-Linked recessive – RPGR and COD2 genes

o It is not known why mutations in some of these genes, which encode proteins in both rods and cones, affect cones only

o There is no family history in many cases

Cone-Rod Dystrophy

• Sometimes described as an atypical form of retinitis pigmentosa (RP)

• Should not be confused with those forms of RP (usually syndromal) that affect cones along with rods

• Difference from achromatopsia

o Not present at birth – Occurs from childhood to age 20

o Progressive loss of vision

• Affects about 1 in 40,000 people

Cone-Rod Dystrophy

• Symptoms

o Reduced visual acuity

o Light sensitivity (“photophobia”)

o Reduced color vision

o Reduced night vision later

• There is a wide variety of expression, from mild to very severe

Cone-Rod Dystrophy

• Signs

o Retina can appear normal early in the disease

o Macular degeneration, sometimes bulls eye maculopathy

o Attenuation of retinal arterioles

o Bone spicule pigmentation in some cases, resembling retinitis pigmentosa

• ERG is profoundly reduced in cones and moderately reduced in rods

Cone-Rod Dystrophy

Cone-Rod Dystrophy

• Inheritance can be variable

o Autosomal dominant

o Autosomal recessive

o X-Linked recessive

• Many genes have been linked

• The ABCA4 gene (autosomal recessive) is also linked to Stargardt disease, progressive cone dystrophy and retinitis pigmentosa

Differential Diagnosis

• Can be difficult to distinguish between

o Cone-rod dystrophy

o Cone dystrophy

o Subset of retinitis pigmentosa that affects cones along with rods (often syndromal)

▪ Worst prognosis for retaining useful peripheral vision

• ERG can be important

• Following changes over time helps identify the condition

o Especially visual fields

• Genetic testing

Confusing Terminology

• Some sources categorize cone dystrophy and cone-rod dystrophy together

• Achromatopsia sometimes called a stationary cone dystrophy

• Rod-cone dystrophy is a term applied to retinitis pigmentosa and Leber's congenital amaurosis

• Some forms of retinitis pigmentosa (mostly syndromal) affect cones equally with rods and are sometimes referred to as cone-rod dystrophy

Stargardt Disease

• "Juvenile Macular Degeneration"

• Not specifically a cone disorder, but the macula is affected, where there is a high density of cones

o Since cones are not targeted, photophobia is less of a problem than in the other conditions discussed

• The most common inherited macular degeneration – about 1 in 10,000 people

Stargardt Disease

[pic]

Figure 27 Image of the retina from Basic and Clinical Science Course: Retina and Vitreous, AAO, 2008.

Two conditions or one?

1. Fundus flavimaculatis: White-yellow irregular flecks scattered throughout the retina

2. Atrophy of macula: Slightly oval bulls-eye pattern, later may resemble "beaten bronze" appearance and later still pigmentary degeneration

• These often occur together, but can have either or both

• Disagreement about classification into two disorders or one

Stargardt Disease

[pic]

Figure 28 Four images of the retina show in upper left early pigment mottling, upper right "Snail Slime" macula + flecks, lower left Bull's Eye maculopathy, and lower right Fundus flavimaculatus from Kanski and Bowling, Clinical Ophthalmology: A systematic approach, 7th ed., 2011.

Stargardt Disease

• Loss of visual acuity in both eyes during teens

o Sometimes there are no visible changes in the retina when vision loss begins, resulting in accusation of malingering

o Visual acuity often declines from 20/40 to 20/100 in about 5 years and stabilizes at about 20/200

o No nystagmus, since later onset

Stargardt Disease

• There is a buildup of lipofuscin in the retina pigment epithelium

o This not only damages the retina, but blocks light from going through it, resulting in "dark retina" in fluorescein angiography

• Central blind spot ("scotoma") results

• Red-green color vision deficiency sometimes develops

• Full field ERG often normal

o May be reduced in fundus flavimaculatis

o Foveal ("multifocal") ERG abnormal

Stargardt Disease

• One clinical finding that indicates Stargardt disease is a "dark choroid" on fluorescein angiography

o Present in at least 80% of Stargardt cases

o Brightness of the choroid background is masked by lipofuscin

Stargardt Disease

[pic]

Figure 30 Two images of the retina with the one on the right showing the "dark choroid with window defects" from Taylor and Hoyt, Pediatric Ophthalmology and Strabismus, 2005.

Stargardt Disease

[pic]

Figure 31 Image of the retina from Yanoff and Duker, Ophthalmology, 2008.

• Usually autosomal recessive

o ABCA4 gene is one of at least three genes that may be the cause

▪ Also implicated in autosomal recessive forms of cone-rod dystrophy and retinitis pigmentosa

• A rare autosomal dominant form has been described

Stargardt Disease

• Treatments in clinical trials

o Portland, OR and Paris, France: Gene transfer,, Phase I/II, Oxford BioMedica

o Los Angeles, Philadelphia, UK: Transplant of human embryonic stem cells, Phase I/II, Advanced Cell Technology

o Italy: Saffron supplementation

• Completed or closed clinical trials

o 4-Methylpyrazole, which inhibits dark adaptation, completed 2006, results not promising

o DHA supplementation – one completed, one closed

Best Disease

[pic]

Figure 32 Two images of the retina with upper image showing “Adult Onset Disease” from Kanski and Bowling, Clinical Ophthalmology: A systematic approach, 7th ed., 2011

• Also called vitelliform (egg-like) macular dystrophy

• Like Stargardt disease, not a disease of cones, but a disease of the macula, which is where there is a high density of cones

• Usually occurs in childhood or early adulthood

o Sometimes not present until middle age

Best Disease

[pic]

33 Two images of the retina from From Basic and Clinical Science Course: Retina and Vitreous, AAO, 2008.

• Four stages

1. Previtelliform – Near normal retinal appearance and vision

2. Vitelliform – Macula resembles egg yolk, visual acuity has mild decrease

3. Pseudohypopyon – Yellow egg yolk appearance concentrates in lower portion of macular lesion

4. Scrambled egg appearance – Scattered yellow areas, possible fibrosis and neovascularization

• Yellow "egg yolk" material is lipofuscin

• Visual acuity usually better than expected from retinal appearance

Best Disease

[pic]

34 Six Images of the retina: top left Vitelliform stage II, top right Blocked choroidal background, mid left Material in RPE, mid right Multifocal disease, bottom left Pseudohypopyon III, bottom right Vitelliruptive stage IV from Kanski and Bowling, Clinical Ophthalmology: A systematic approach, 7th ed., 2011.

Prevalence = 1 to 9 out of 100,000 people, per

Best Disease

• Mild to moderate vision loss

• 88% will have at least one eye with 20/40 or better

• Only 4% will have visual acuity worse than 20/200

• Electro-oculogram (EOG) light/dark (Arden) ratio is reduced

o Sometimes EOG is normal

o Full-field ERG usually normal

o Foveal (multifocal) ERG is usually reduced

• Often hyperopic

• Autosomal dominant inheritance – VMD2 gene

• No treatments in clinical trials per

Relative Prevalence

|Disorder |1 in |Texas |United States |

|Aniridia |70,000 |375 |4,200 |

|Ocular Albinism |50,000 |500 |5,900 |

|Achromatopsia |40,000 |650 |7,500 |

|Cone-Rod Dystrophy |40,000 |650 |7,500 |

|Leber's Congenital Amaurosis |40,000 |650 |7,500 |

|Progressive Cone Dystrophy |30,000 |850 |9,800 |

|Best Disease (approximate) |22,000 |1,300 |15,000 |

|Oculocutaneous Albinism |17,000 |1,500 |18,000 |

|Optic Nerve Hypoplasia |10,000 |2,600 |30,000 |

|Stargardt Disease |10,000 |2,600 |30,000 |

|Retinitis Pigmentosa |3,750 |7,400 |85,000 |

Rehabilitation – Core Needs

• Magnification for detailed vision

o Near vision

o Distance vision

• Photophobia & glare management

o Outdoors – sunlight

o Indoors – artificial lighting

• Coping with color vision loss

• Mobility

• General support

Magnification at Near

• Three ways to magnify at near, such as reading

o Make the print larger

▪ Relative size magnification

o Use a magnifier

▪ Angular magnification

o Bring the print closer

▪ Relative distance magnification

Making the Print Larger

Normal print might require magnification to make reading comfortable or even possible, but may lead to greater independence

Large print is usually about twice the size as normal print.

• Advantages

o Easy

• Disadvantages

o Large print books are large, heavy and expensive

o Few large print resources may be available after student leaves school

o Limited magnification

Making the Print Larger

• From the Council for Exceptional Children, "The voice and vision of special education"

o Division on Visual Impairments position paper, "Access to Print"

• "It is recommended that individuals with visual impairments resulting in low vision use standard rather than large print whenever possible and when appropriate to the task and ease of use."

• This position has been maintained and rewritten since 1984

Using a Magnifier

• Advantages

o Makes everything large print

o Available in many powers

• Disadvantages

o Must carry with you

o Small field of view

o Lots of misunderstanding

Bring the Print Closer

• Advantages

o Wide field

o Portability

o Minimizes effect of scotoma

• Disadvantages

o May require glasses with bifocal to relieve focusing fatigue

Minimizing Effect of Scotoma

By using relative distance magnification

(The presenter created a complex drawing to show how magnification can minimize the effect of scotoma).

Magnification at Near

• Choosing a magnification device is not a trial and error process

• Recommendation of magnification devices should be made by people who understand their optics

o They need to listen to and respond to the feedback of educators, parents, and vision rehab. professionals concerning students' needs and the performance of recommended devices

• No magnification device works best for all people

• No magnification device works best for all tasks

Magnification at Distance

• Telescopes are the only optical devices that can magnify at a distance

• Types

o Handheld

o Spectacle mounted

▪ Bioptic

Magnification at Distance

[pic]

Figure 39 A young woman adjusts a telescope.

• Telescopes are used for spotting

• Telescopes extend the "visual reach"

• Telescopes require training

• Nystagmus does not preclude the use of telescopes

• Powers: 2X to 10X

• In general field of view decreases as telescope power increases

Magnification at Near & Distance

Many electronic devices available

Electronic books offer large print and speech options

Magnification at Near & Distance

[pic]

Figure 41 Photo of a Kindle Figure 42 Photo of IPad

• Kindle – less glare

• IPad – better contrast

Photophobia & Glare

[pic][pic]

Figure 43 Two photos: one showing a little boy wearing dark glasses and another showing two pairs of glasses with yellow and dark amber lenses.

• No firm guidelines for filter selection

• Often gray or brown for outdoors

• Often yellow or orange for indoors

• Plum used by many

• Red contact lenses have found success*

• Don't forget importance of hat or visor

*Park WL, Sunness JS. Red contact lenses for alleviation of photophobia in patients with cone disorders. Am J Ophthalmol 2004; 137:774-5.

Color Vision Loss

• Limited treatment options

• X-Chrome contact lens

• Electronic color identification tool

• Color identification app

o Color ID 2 by GreenGar

Mobility

[pic]

Figure 46 Photo of a woman and her O&M instructor traveling a city street.

• Not needed in all cases, but…

• Don't neglect just because there might not be peripheral visual field loss

General Support

• Medical eye care

• Parental education

• Support organizations

• Educational consultation

• School for the blind and visually impaired

• Mainstream school

• Educational / Rehabilitation services

• Driving / Transportation advice

o Bioptics legal in the state?

General Support

• Counseling

o Importance of a peer group

o "Passing"

• Post-secondary education options

• Career counseling

• Genetic counseling

Thanks for your attention!

David Lewerenz, OD, FAAO

Northeastern State University

Oklahoma College of Optometry

lewerenz@nsuok.edu

918-444-4090

Texas School for the Blind & Visually Impaired

Outreach Programs

[pic]

Figure 24 TSBVI logo.

"This project is supported by the U.S. Department of Education, Office of Special Education Programs (OSEP). Opinions expressed herein are those of the authors and do not necessarily represent the position of the U.S. Department of Education.

Figure 25 IDEA logo

-----------------------

Figure 1 Image of the retina.

Figure 2 Photo of boy using print magnifier.

Only 5-10% of cones

Figure 10 Two images showing an electroretinography.

Figure 11 Two images showing color vision screening tests.

Figure 15 Two photographs of people reading.

Figure 20 Two photographs of Rachel Scdoris: as an adult and as a child.

Figure 21 Pictures of John Kay and the Steppenwolf album cover for Born to Be Wild.

Figure 26 Three images of retinas from left two show moderate Cone-Rod Dystrophy and Right advanced Cone-Rod Dystrophy.

Figure 29 Three images showing retina (middle image of “dark choroid”) from Basic and Clinical Science Course: Retina and Vitreous, AAO, 2008.

Figure 35 Two photos showing students using magnifiers.

Figure 36 Four pictures of different kinds of magnifiers

Figure 37 A young boy uses and hand held telescope.

Figure 38 A woman uses a spectacle mounted magnifier.

Figure 40 Six pictures of various print enlargement devices for reading.

Figure 44 Electronic color identification tool

Figure 45 X-Chrome contact lens

Figure 47 Two images showing Northeastern State University, Oklahoma College of Optometry and logo.

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