http://en.wikipedia.org/wiki/Retinal_degeneration_(rhodopsin_mutation)

Retinal degeneration (rhodopsin mutation)From Wikipedia, the free encyclopedia

Fundus images of retinitis pigmentosa

Retinal degeneration is the deterioration of the retina(1) caused by the progressive and eventual death of

the cells of the retina.(2) There are several reasons for retinal degeneration, including artery or vein

occlusion, diabetic retinopathy, R.L.F./R.O.P. (retrolental fibroplasia/ retinopathy of prematurity), or disease

(usually hereditary).(3) These may present in many different ways such as impaired vision, night

blindness, retinal detachment, light sensitivity, tunnel vision, and loss of peripheral vision to total loss of

vision(4). Of the retinal degenerative diseases retinitis pigmentosa (RP) is a very important example.

Inherited retinal degenerative disorders in humans exhibit genetic and phenotypic heterogeneity in their

underlying causes and clinical outcomes* (5) (6) (7). These retinopathies affect approximately one in 2000

individuals worldwide (7). A wide variety of causes have been attributed to retinal degeneration, such as

disruption of genes that are involved in phototransduction, biosynthesis and folding of the rhodopsin

molecule, and the structural support of the retina.(6) Mutations in the rhodopsin gene account for 25% to

30% (30% to 40% according to(9)) of all cases of autosomal dominant retinitis pigmentosa (adRP) (5) (20–

22) in North America (10–12) There are many mechanisms of retinal degeneration attributed to rhodopsin

mutations or mutations that involve or affect the function of rhodopsin. One mechanism of retinal

degeneration is rhodopsin overexpression. Another mechanism, whereby a mutation caused a truncated

rhodopsin, was found to affect rod function and increased the rate of photoreceptor degeneration.(9)

*For example, a single peripherin/RDS splice site mutation was identified as the cause

of retinopathy in eight families; the phenotype in these families ranged from retinitis pigmentosa

tomacular degeneration.(7)

Photoreceptor cell death[edit]

Illustration of the structure of the mammalian retina, including photoreceptor cells ; rod cells and cone cells

Photoreceptor cell death is the eventual outcome of retinal degeneration. Without proper function of

the photoreceptor cells, vision is not possible. Irreversible loss of these cells has been attributed as a

cause of blindness in many retinal degenerative disorders, including RP. The exact mechanism of

photoreceptor cell death is not clearly understood. (5)(14) Among potential causes is

the endocytosis of stable complexes formed between rhodopsin and its regulatory protein arrestin in

certain mutants. (5) Various studies have also documented that over-expression of rhodopsin itself

(mutations in genes involved in the termination of rhodopsin signaling activity have been shown to

cause degeneration by persistent activation of the phototransduction cascade (14)) causes

photoreceptor cell death and may induce photoreceptor cell loss in transgenic animals expressing

truncated rhodopsin. Yet another mechanism may be prolonged photoreceptor responses and also

abnormal rhodopsin deactivation may induce outer segment shortening and eventual photoreceptor

death (9)

In RP photoreceptor cell death is believed to occur by programmed cell death or apoptosis. (10) (11)

(15)

Retinitis pigmentosa[edit]

Photograph of United States Supreme Court building illustrating normal visual field, prior to onset of retinitis pigmentosa

Photograph of the United States Supreme Court Building, modified to illustrate the effect of visual field loss, tunnel

vision, in patients with Retinitis Pigmentosa.

Retinitis pigmentosa is a progressive neurodegenerative disorder(16), which affects 1 in 3,000

individuals (6) and affects between 50000 and 100000 people in the United States.3 Autosomal

dominant RP accounts for approximately 15% of these cases. (8) Autosomal dominant retinitis

pigmentosa (ADRP) is a genetically heterogeneous group of inherited retinal degenerations that

cause blindness in humans. (14)

RP begins with death of rod photoreceptor cells, which are the only cells in the retina to express

rhodopsin and which express it as their most abundant protein. Eventually, loss of rod cells leads to

loss of cone cells(cone photoreceptors), the mainstay of human vision (16). Symptoms of RP include

loss of sensitivity to dim light, abnormal visual function, and characteristic bone spicule deposits of

pigment in the retina. Affected individuals progressively lose visual field and visual acuity, and

photoreceptor cell death can ultimately lead to blindness. (9) A prominent early clinical feature of

retinitis pigmentosa is the loss of night vision as a result of death of rod photoreceptor cells. Proper

expression of the wild-type rhodopsin gene is essential for the development and sustained function of

photoreceptor cells.(10)

Mutations in the human rhodopsin that affect its folding, trafficking and activity are the most commonly

encountered causes of retinal degeneration in afflicted patients. A single base-substitution at

the codon position 23 in the human opsin gene (P23H) is the most common cause of ADRP in

American patients. (6)(17) ADRP due to rhodopsin mutations has a wide range of clinical presentation

and severity. Before 1991, phenotypic evidence pointed to different subsets of ADRP with

varying prognoses.(30–34) Molecular classification of ADRP and further sub-classification based on

the region of the mutation in the rhodopsin gene allowed better prediction of a particular disease

course. But even within these specific subsets, the prognosis is influenced by the specific mutation

itself.(8)

Rhodopsin and its function in vision[edit]

Three dimensional structure of rhodopsin

Rhodopsin is a transmembrane protein (Rh1) that is the primary visual pigment (photopigment) of rod

photoreceptors (which are the only cells in the retina to express rhodopsin and which express it as

their most abundant protein(16)) and forms an integral part of the visual cascade.(8)(13)(10) It is a G-

protein-coupled receptor activated by light that initiates the phototransduction cascade (visual

transduction cascade taking place in photoreceptor rod outer segments (13).) converting light signals

to electrophysiologicalsignals in retinal neurons. This photo-activated signal transduction process is

essential for vision. (10)

The structure and function of rhodopsin and the gene encoding it have been the subjects of intense

scrutiny for many years because rhodopsin serves as a useful model for understanding the largest

receptor family in the human genome, the G protein-coupled receptors, and because defects in the

rhodopsin gene are the most common cause of the most common inherited blinding disease, retinitis

pigmentosa. (16) (18)(19)

Rhodopsin Mutation[edit]

The human rhodopsin gene is the locus for numerous alleles linked to the neurodegenerative disease

retinitis pigmentosa. (16) Mutations in the rhodopsin gene account for 25% to 30% (30% to 40%

according to (9)) of all cases of autosomal dominant retinitis pigmentosa (ADRP).(8)(10)(20–22) Over

100 distinct mutations in the light-sensing molecule rhodopsin are known to cause (adRP). (6)(9)(10)

(13)(14) Most of these mutations aremissense mutations affecting single amino acid residues in the

rhodopsin protein. (10)(24) These mutations affect rhodopsin transport to the outer segments of rod

photoreceptor cells, rhodopsin folding, and rhodopsin endocytosis. Mutations in the human rhodopsin

that affect its folding, trafficking and activity are the most commonly encountered causes of retinal

degeneration in patients afflicted with RP. (6) A single base-substitution mutation of codon 23 of the

rhodopsin gene in which proline is changed to histidine (Pro23His) in the human opsin gene accounts

for the largest fraction of rhodopsin mutations observed in the United States and is the most common

cause of ADRP in American patients.(6)(8)(17)

In 1990, the Pro23His mutation of the rhodopsin gene was reported as the first mutation associated

with RP.(8)(20)(21)(24–26) This mutation has been described only in the United States, where it

continues to be the most commonly described gene defect in RP. The phenotype of the RP

associated with the P23H mutation is characteristically relatively mild but variable.(8)(20–22)(24–28)

Multiple studies have demonstrated that the degree of severity of a given mutation in the rhodopsin

gene is based in large part on its position in the rhodopsin molecule—intradiscal,transmembrane,

or cytoplasmic.(29–36) Intradiscal mutations tend to be less severe, whereas mutations affecting

cytoplasmic domains and retinol binding sites tend to be very severe.(30)(36) The severity of

cytoplasmic mutations affecting maintenance of photoreceptor cell polarity, such as those at the C-

terminus (sorting signal of rhodopsin) may result from inappropriate intracellular transport of the

molecule. (8)(13)(37)

Some research has described transgenic mouse mutants that cause degeneration by prolonged

activation of the phototransduction cascade.(38) In this research null mutations in the

rhodopsinkinase(39) and arrestin(40) genes, each of which plays a role in terminating rhodopsin

activity, caused light-dependent retinal degeneration.(14)

Rhodopsin C-terminal mutations[edit]

A fraction of rhodopsin mutations alter the C-terminal tail of the protein, such as the point

mutations P347L, P347S, P347R, and V345M.3–5 In addition, two frameshift mutations (fs 341del

and fs 341-343del) are predicted to add additional residues to the C terminus,(43) whereas Q344ter

results in a C-terminal truncation, and an intron splice mutation (N88) is thought to remove the entire

C-terminal tail of rhodopsin.(9)(41)(42)

Data indicate that expression of truncated rhodopsin negatively affects both photoreceptor function

and health, compromising rod cell survival.The presence of truncated opsin may impair synaptic

transmission or other cellular processes and eventually cause cell death. Large quantities of

mislocalized opsin may decrease the availability of functional proteins in regions where truncated

opsin is concentrated. The presence of truncated rhodopsin in the outer segments causes functional

abnormalities and localization of rhodopsin in the outer and/or inner segments induces increased

photoreceptor cell death (9)

Rhodopsin endocytosis[edit]

Like many other G protein-coupled receptors, the rhodopsin protein undergoes endocytosis following

activation (6)(44)(45). Perturbation of endocytic regulation of rhodopsin has deleterious effects on

photoreceptor cell physiology. In certain mutants, rhodopsin and its regulatory protein arrestin form

stable complexes. As mentioned these complexes have a fatal effect; when taken up during

endocytosis these complexes causes photoreceptor cell death, because the internalized rhodopsin is

not degraded in the lysosome but instead accumulates in the late endosomes. The formation of toxic

Rhodopsin- Arrestin complexes is also reported for mutants of human rhodopsin associated with

severe forms of ADRP (6)(46)(47). For example, mutations at Arg135 are associated with severe

forms of retinitis pigmentosa and exhibit a high affinity for arrestin, undergo endocytosis, and display

endosomal abnormalities.(6)

Missense mutations in the opsin gene affecting the R135 and K296 residues of the protein product

cause ADRP and result in accumulation of Rhodopsin-Arrestin complexes in the photoreceptor cell (6)

(46)(47). The R135 mutant rhodopsin is noted to form stable complex with arrestin and undergo

endocytosis resulting in aberrant endocytic vesicles in HEK cell culture system (47). Similarly, the

K296E rhodopsin is observed to bind the visual arrestin with high affinity. This abnormal interaction is

demonstrated to have pathological consequences in the retina. Besides this, the stable rhodopsin and

arrestin complexes are shown to mislocalize and accumulate in the inner segments of rod

photoreceptors of the mouse model of ADRP.(6)

Using mutants that are defective in late endosome to lysosome trafficking, it was shown that

rhodopsin accumulates in endosomal compartments in these mutants and leads to light-dependent

retinal degeneration. It was also shown that the internalized rhodopsin in dying photoreceptor cells

were not degraded but instead showed characteristics of insoluble proteins. This data led to the

implication of rhodopsin buildup in the late endosomal system as a novel trigger of death of

photoreceptor neurons. Thus failure to degrade internalized rhodopsin in a timely manner triggers cell

death of photoreceptor neurons, suggesting that lysosomal turnover of rhodopsin is vital in

maintaining photoreceptor viability. (6)

The precise mechanisms regulating the pro-cell death signaling pathways and their interconnection

with endocytosis is not well understood. It is speculated that a component innate to the

endolysosomal system plays a crucial role in regulating the cell death signals emanating from the

endosomes. This component senses the accumulation of rhodopsin and then engages the proper

machinery to execute cell death in the retina. Failure of proper protein degradation and resultant

subsequent accumulation of proteins, as in the case of rhodopsin-arrestin complexes, is a well-

recognized cause of cell death in many neurodegenerative disorders, such as retinitis pigmentosa (6)

(48).

Non-rhodopsin mutations[edit]

Mutations non-retina-specific ADRP genes that encode for proteins essential for pre-mRNA splicing

may be a major cause of ADRP. Proteins required for the formation of stable U4/U6 snRNPs and for

assembly of the U4/U6.U5 tri-snRNP have been identified, including HPRP3, PRPC8, and PRPF31,

proper function of these proteins is necessary for spliceosome performance. (10)

The rhodopsin transcript is a pre-mRNA splicing substrate affected by PRPF31 protein, meaning that

rhodopsin (RHO) is among the target splicing substrate genes for PRPF31. Thus it can be understood

that mutations in PRPF31 can cause alternative, potentially non-functional, forms of the rhodopsin

protein. It was shown that expression of these mutant PRPF31 proteins significantly reduced

rhodopsin expression in cultured retinal cells and induced apoptosis of retinal cells, establishing a link

between mutations in proteins involved in pre-mRNA splicing and the expression of a critical retina-

specific gene, rhodopsin. (10)

This shows that non-rhodopsin mutations may also be critical in presentation of retinal degenerative

disorders. It suggests a mechanism for retinal degeneration caused by non-retinal-specific genes,

such as PRPF31 mutations. (10)

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http://www.ffb.ca/eye_conditions/RD_diseases.html

Retinal Degenerative Diseases

Millions of people in North America live with varying degrees of irreversible vision loss because they have an untreatable, degenerative eye disorder like retinitis pigmentosa (RP), which affects an estimated 1.5 million people worldwide, or age-related macular degeneration, which is the leading cause of vision loss in Canada and North America. Retinal degenerative diseases affect the delicate layer of tissue that lines the inside back of the eye. This part of the eye -- the retina - is essential for vision.

Imagine the eye is like a camera. The shutter, like the iris of the eye, opens and closes to let in the right amount of light. The lens helps to focus light on the film. The retina is like film. Regardless of the perfection or quality of the rest of the camera, if the film is faulty, the developed pictures may be distorted, blurred or impossible to see.

This very large and diverse group of vision disorders affects young and old and people from many cultures, races and ethnicities. Age-related macular degeneration is distinguished by its prevalence in the senior population, and age is considered to be the major risk factor for developing this eye disease. Retinitis pigmentosa and other related conditions are inherited genetic conditions, even if a person who develops it has no previous family history of vision loss. The list of inherited retinal dystrophies (degenerations) is very long, but here are a few of the more common:

Retinitis pigmentosa

Choroideremia (affects males)

Retinoschisis, Juvenile

Stargardt disease

Usher disease

http://www.retina-international.org/eye-conditions/retinal-degenerative-conditions/amd/

What is Macular Degeneration?

Macular Degeneration is the name for several similar conditions that are characterised by a

breakdown of the macula.

The word "macula" comes from the Latin for "spot"; it is the centre portion of the retina that

makes central vision, the vision directly in front of you, possible. The macula is very small: only

about three by five millimetres (about the size of a ladybug) covering about 10 percent of the

retina.

What causes Macular Degeneration?

There are two basic types of Macular degeneration - Age-related and early onset or Juvenile -

and they will be explained in detail in separate sections.

Age-related Macular Degeneration (referred to as AMD) usually does not develop until the sixth

or seventh decade of life, although early onset cases are becoming more common in patients as

young as 40. Because of the later onset of this disease, it is difficult to determine if it is inherited,

but studies are showing familial patterns of the condition, indicating that there may be genetic

causes. There are also other aspects of your health that are risk factors for Age-related Macular

Degeneration; these will be discussed later.

Early onset Macular Degeneration appears to be largely genetic; that is, it is a condition that is

programmed into your cells and not caused by injury or infection or any other external agent.

Certain genes that are necessary for normal vision give faulty messages to the cells in the

macula, leading to their progressive degeneration and eventually to vision loss.

To understand why and how Macular Degenerations occur, scientists must look to a variety of

disciplines. Increasingly sophisticated research at the cellular level is providing insight into the

processes that cells undergo whey they die, and how one step leads to another.

The study of molecular genetics, cell biology, biochemistry, and how these and other fields

interact with each other has provided an abundance of avenues for researchers to pursue. The

symptoms of Macular Degeneration, like those of other retinal diseases, vary greatly and range

in severity from one person to another.

What is Dry AMD?

Dry AMD is the more common form of Macular Degeneration. It is also referred to as atrophic,

nonexcudative, or drusenoid form. This form accounts for 90 percent of Age-related Macular

Degenerations.

Dry AMD is characterised by the build-up of drusen, small yellowish deposits, beneath the

macula. The layer of photo receptor cells in the macula begin to atrophy, or die, as some of the

cells break down. These changes, may, in turn, result in a distortion of vision that is most

apparent when reading. Often if one eye has dry AMD, the other eye will also show some signs

of the condition. However, dry AMD does not usually cause total loss of reading vision.

What is Wet AMD?

Wet AMD accounts for 10 percent of patients with AMID. It is also called choroidal

neovascularisation, subretinal neovascularisation, exudative form, or disciform degeneration.

In wet AMD, new abnormal blood vessels begin to grow beneath the macula, in a thin layer of

tissue called the choroid. The choroid is the main source of oxygen and nutrients for the retinal

photo receptors, and it is the only blood supply for the macula. New fragile blood vessels develop

which may leak fluid and blood, and then cause the choroid and retina to deteriorate. This

causes the retinal layer to blister under the macula, and the photo receptor cells to degenerate.

At this stage, there is marked disturbance of vision in the affected eye.

What are the symptoms?

The most common symptoms are blurring of vision with particular difficulty discerning details,

both up close and from a distance. People with Macular Degeneration may have blind spots,

resulting in a dark or empty area in the centre of their field of vision. They may also notice

distortions of lines and shapes, either in everyday objects (e.g. crooked door frames) or in tests

given by the eye doctor.

Colour vision may also be diminished, although peripheral vision and night vision usually remain

unaffected. Because Age-related Macular Degeneration could begin in one eye, the remaining

good eye will take over on its own to compensate for vision loss. It may be some time before the

second eye is seriously affected enough for an individual to notice vision problems. Others do

notice a sudden loss of vision. If you experience a sudden vision loss or distortion, it is important

that you see your eye care professional immediately.

How are macular degenerations diagnosed?

The early signs of Macular Degeneration are usually detectable in a thorough eye exam even

before the disease begins affecting vision. The doctor will examine the eye with special lenses,

which help to show the interior of the eyeball through the pupil, the opening in the centre of the

iris through which light rays enter the eye. Tests for Macular Degeneration include:

Acuity tests which measure the accuracy of your reading and perception vision at specific

distances in specific lighting situations. This is the test that people are most familiar with and

typically involves a standard eye chart.

Colour testing which can help to determine the status of your cone cells. Since cone cells are

the retinal cells that interpret colour, your doctor will be better able to determine the health of

these cells through your performance on these tests. There are several types of colour tests

which measure various aspects of vision.

A dark adaptation test which will measure how well your eyes adjust to changes in lighting.

Information from this test can help the doctor to better understand the current function of your

rod cells, which are the retinal cells responsible for night vision.

A fluorescein angiogram which allows inner eye structures to be visualised. A non-toxic dye is

injected into the patient's arm and it moves through the bloodstream, including the blood

vessels in the eyes. Photos are then taken of the retina and macula, which will identify new

blood vessel growth and leakage from blood vessels. New blood vessel growth is a feature of

wet age-related Macular Degeneration, which is explained in detail in the section of this

booklet describing the different forms of Macular Degeneration.

Check your vision with an Amsler grid

The Amsler grid test may be helpful in revealing signs of wet Age-related Macular Degeneration

(AMD). It is not a substitute for regularly scheduled eye exams.

Directions:

Wear your reading glasses (if you use them).

Sit at a comfortable reading distance (12” or 30cm) from the grid in a well lit room. 

Cover one eye with your hand. Look at the centre dot at all times. If you notice any area on the

grid that is blurred, distorted, discoloured or missing, you may be exhibiting signs of AMD and

should contact your ophthalmologist promptly.

Are there any specific risk factors related to AMD?

As we have seen, AMD is related to ageing, but it certainly does not affect all older people. There

is a growing body of evidence that suggests genetic factors can determine whether or not

someone will get AMD.

Other studies have looked for additional conditions that may be associated with AMD and have

found a number of factors besides age that are associated with an increased risk of developing

AMD. 

These include a history of hypertension (high blood pressure) and/or cardiovascular disease,

smoking, a family history of AMD, hyperopia (farsightedness), light skin and eye colour, and lens

opacities (cataracts). Both men and women are at risk for this disease.

The presence of these risk factors in people with AMD has been noted, but the relationship of the

various factors to the disease itself has not been systematically studied and it is not clear just

why the links are present.

How common is AMD?

Researchers estimate that one in 2000 people in the developed world are affected by AMD.

Among non-diabetics, it is the most common problem affecting the retina, and it is the major

cause of legal blindness in individuals over the age of 65. As the population enjoys a longer life,

the number of those affected by AMD will increase as well.

How quickly does AMD progress?

Most cases of AMD progress very slowly over a period of years. Vision may remain stable

between annual eye examinations, and many patients retain a reasonable amount of peripheral

vision. However, wet AMD typically progresses much more rapidly than dry AMD. The majority of

people who experience severe vision loss from AMD have the wet form.

Do Macular Degenerations lead to total blindness?

Most people with Macular Degeneration do retain some peripheral vision, and they learn to

optimize the use of their remaining vision. Each case differs. However, many will be classified as

legally blind". Legally blind individuals are those whose best visual sharpness or acuity (with

glasses or contact lenses, if needed) is 20/200 or worse in their better eye; or whose visual field,

regardless of acuity, is restricted to a 20 degree diameter (10 degree radius).

Can people with Macular Degeneration drive?

This is a difficult question. Many people with mild forms of Macular Degeneration do drive legally,

and do not have problems. It would be best to discuss your visual limitations and their effect on

driving with your eye care professional. Driving is a symbol of independence for many people,

and individuals with progressive vision loss may be unwilling to face the fact that their vision

impairment may impede save driving. Often people with Macular and other retinal degenerations

speak of "near miss" accidents that force them to confront their vision loss and acknowledge that

it is affecting their driving. It is important to remember that your driving affects not only you but

other drivers and pedestrians, and that the results of an error can ultimately be life-threatening.

If I have drusen, will I develop AMD?

Not necessarily, although the presence of drusen may indicate that your eyes are at some risk

for developing AMD. Drusen are deposits that contain complex lipids (fats) and calcium and can

accumulate as a person ages. It is not known how they form but it has been suggested that they

are undigested waste products from RPE cells. There are two basic types of drusen: "hard" and

"soft".

Hard drusen are small, round, solid deposits that sit under the RPE without causing structural

damage. Most people start accumulating some drusen after the age of 40, and hard drusen

alone do not impair vision. However, hard drusen may advance to soft drusen, although this does

not always happen.

Soft drusen are more likely to be associated with vision loss. They are less uniform, involve a

larger area under the RPE, and contain other cellular substances in addition to lipids.

Development of soft drusen may cause the RPE to separate from other eye tissue layers.

It is important to understand the significance of drusen, particularly if you have a family history of

Macular Degeneration. There are many people with drusen in both eyes and no impairment to

their vision at all. However, it is not known who will go on to develop a vision problem and who

will not, so if your eye doctor tells you there are drusen in your eyes, you should continue to seek

eye care regularly, as well as use an Amsler grid to monitor your vision yourself.

What are retinal detachments and tears?

Retinal detachment occurs when the photo receptors (the rods and cones) separate from their

underlying tissue layers. This causes a loss of vision in the area of the separation. Retinal

detachments can sometimes be repaired or partially repaired with surgery. Retinal tears are

splits in the retina that may cause vision disturbances, such as flashes of light or floaters. Retinal

detachments and tears may be caused by physical injury or may be inherited. Although they may

occur in people with Macular Degenerations, they are not necessarily a consequence of the

disease.

Are cataracts associated with Macular Degeneration?

It is not unusual for an older individual with a Macular Degeneration to develop a cataract, which

is a clouding of the lens of the eye. Cataracts that significantly interfere with vision can be

surgically removed. While cataract surgery cannot improve the vision loss due to retinal

degeneration, it can alleviate the added loss caused by the cataract, Whether or not surgery

improves the vision often depends on the extent of retinal changes. Because surgery is not

advised for everyone, it is important to discuss the details of your individual case with an eye

care professional.

Is AMD related to other retinal diseases?

Age-related Macular Degeneration is just one type of a group of retinal degenerations that are

characterised by a breakdown of the photo receptor cells, leading to impaired vision. While AMD

is characterised by a loss of central vision, Retinitis Pigmentosa is associated with night

blindness and a progressive loss of peripheral vision leading to "tunnel" vision. These symptoms

are not the same, but as researchers get closer to uncovering the causes of these conditions,

there is increasing evidence that they are related. For example, it has been found that different

defects of the same gene are responsible for certain forms of RP and Macular Degeneration.

Will others in my family be affected?

The late onset forms of Macular Degeneration are not known to be inherited in a straightforward

pattern such as autosomal dominant or recessive. However, familial patters have been observed,

indicating that inheritance is involved to some extent. Some surveys have estimated that 15 to 20

percent of AMD patients have one or more first-degree relatives who are also affected.

AMD presents a special challenge for genetic researchers because it is difficult to determine the

exact role of genetics when a disease occurs late in life. A number of research projects are now

underway to look specifically at the role of genetics in the development of AMD.

In one study, occurrence of AMD is being compared in groups of identical and non-identical

twins. Genes from blood samples of people with Macular Degeneration are being searched for

disease-causing changes. From these and other studies, scientists hope to learn more about the

relationship between genes and Macular Degeneration.

Because it is not the same gene that causes Macular Degeneration in everyone with the

condition, but an assortment, each with its own particular variations, the hereditary pattern of

these diseases differs from family to family, although the gene mutation will be consistent within

one family. You can get the best information about the likely pattern of the disease in your own

family by consulting with a genetic counsellor or an eye care professional who specializes in

hereditary retinal degenerations. They can help you learn how the disease is inherited in your

family and the chance of passing it on to your children.

Is there any way to prevent AMD?

While research supported by the member organisations of Retina International and other private

and government agencies worldwide is adding to new understandings of AMD, at present there

is no known method of preventing its occurrence. However, there are studies that suggest that

adjustments in lifestyle may help reduce the risk of developing AMD.

Regular eye exams may allow for early diagnosis of AMD. Individuals at risk - for example, those

with degenerative vision loss in one eye, soft drusen, or positive family history - should have

regular eye examinations by an eye care professional after the age of 50 and self-monitor their

vision daily with the use of an Amsler grid. Without self-monitoring, a person may not realize his

or her vision is impaired until the disease has reached advanced stages.

How can nutrition influence the occurrence of AMD?

Researchers found that people who consumed the highest quantity of spinach, collard greens

and other dark green leafy vegetables foods that are rich in carotenoids, were less likely to have

the advanced form of AMD, compared with people in the study who ate the least amounts of

these foods. The findings also suggest that people should not rely on vitamin supplements as

their main source for vitamins, minerals and nutrients, but instead should eat a balanced diet that

includes a wide range of vegetables.

Does sunlight influence the onset of AMD?

Avoiding intense, bright sunlight may help to reduce the retinal degeneration due to AMD. Good

quality sunglasses, hats and visors can help people to protect their eyes from the sun.

Does smoking influence the onset of AMD?

Cigarette smoking has been linked to increased risk of developing AMD. It is recommended that

persons stop smoking to decrease their chance of developing AMD.

What treatment options are available for AMD?

Retina International and its members support extensive multi-disciplinary research programmes

in an effort to find the causes prevention, and possible treatment for Macular Degeneration and

other forms of retinal degenerations. Researches studying retinal degenerative diseases may

contribute to the understanding of others so that, for example, research related to RP may also

benefit those with Macular Degeneration. Information from research projects is shared with

others in the field in order to advance the goal of understanding all forms of retinal degeneration.

Listed below are details of some of the latest advances in research and treatments for AMD.

Dry AMD

Although several new drugs are being investigated and approved by regulatory agencies around

the world for the treatment of the exudative (wet) type of AMD, aside from cessation of smoking

and a healthy diet of dark green leafy vegetables and fruits supplemented by zinc and anti-

oxidant vitamins (Vitamins E, C, and beta carotene), very little is available to help patients with

atrophic or "dry" AMD to prevent progression to more serious stages of debilitating disease. A

blood filtration process, called Rheopheresis, is being marketed in Canada as a treatment for dry

AMD by OccuLogix Inc. Little is known about what causes the conversion from dry to wet AMD,

and this is the subject of ongoing research studies. Check back regularly for updates to this

website as research studies are published.

Wet AMD

At present people with macular degeneration have three possible treatment options: thermal

(heat laser); Photodynamic Therapy; or anti-VEFG drugs.

Laser Photocoagulation

Laser photocoagulation is a surgical procedure involving the application of a hot laser to seal and

halt or slow the progression of abnormal blood vessels. In the 1990's laser treatment was the

only therapy available for AMD.

Through the use of a high-energy light that turns to heat when it hits the parts of the retina to be

treated, laser photocoagulation seals the choroidal neovascularization (CNV) and inhibits the

leaky blood vessels growth, preventing further vision deterioration. A scar forms as a result of the

treatment, and this scar creates a permanent blind spot in the field of vision. Vision does not

usually improve after laser treatment and may even be somewhat worse. However, loss of vision

following laser treatment, though immediate, is generally less severe than the eventual loss of

vision that usually occurs if laser treatment is not done. In many cases, some visual distortion will

disappear after laser treatment.

Photo Dynamic Therapy (PDT)

Photodynamic Therapy (PDT) (trade name Visudyne) uses a non-thermal (or cold) laser with an

intravenous light-sensitive drug to seal and halt or slow the progression of abnormal retina blood

vessels. This treatment does not produce a blind spot on the retina. The light is shone directly at

the targeted tissue and the drug accumulates in these cells. It therefore reduces damage to

normal surrounding tissue and allows the treatment to be given again as needed. . However,

early diagnosis of AMD is key, because once vision is lost due to of the growth of abnormal blood

vessels, it cannot be reclaimed by either treatment.

Anti-angiogenesis Therapies

As of February 2006, pegaptanib sodium (trade name Macugen) is approved for use in Canada,

the United States and Europe. The United States Food and Drug Administration (FDA) approved

Macugen for treatment of neovascular (wet) age-related macular degeneration. FDA approval

came following successful clinical trials demonstrating that the drug reduced vision loss in 70 per

cent of clinical trial patients. It is also very encouraging that the drug is effective for all kinds of

wet AMD, whether in the early or late stages.

Pegaptanib sodium (trade name Macugen) is what researchers call an anti-VEGF drug, or in

other words, a drug which works by targeting the proteins which act to trigger abnormal blood

vessel growth and leakage. Anti-VEGF drugs are delivered directly to the eye by an injection,

which is repeated every four to six weeks.

Other anti-VEFG drugs on the horizon include ranubizimab (trade name Lucentis), from

Genetech and Novartis. On June 30, 2006, the US Food and Drug Administration (FDA)

announced approval of Lucentis (Ranibizumab). AMD Alliance International (AMDAI) loudly

applauded the decision, which effectively makes available in the USA a ground breaking

treatment for wet age related macular degeneration. This approval is based on the evidence

presented from several years of rigorous clinical trials, in which Lucentis was shown to maintain

vision in 95% of trial participants, and improve vision in approximately 30 to 40% of trial

participants. This decision means that treatment with Lucentis will now be widely available in the

USA through retinal specialists. The FDA approval of course only covers the USA. Introduction of

Lucentis in Europe is expected to follow in the coming year. Fighting Blindness and the AMD

Alliance International of which it is a member, applauds the introduction of new treatments, which

bring hope and help to those with macular degeneration.

Angiostatic Therapies

In other research developments, a completely different class of AMD drugs, called angiostatic

therapies, is showing promise. This class of drugs propose yet another approach to treatment of

AMD, in this case by administering a type of steroid to stop the abnormal growth of blood vessels

in the eye. Unlike the anti-VEGF treatments, angiostatic drugs are delivered through a canula, to

the back of the eye.

One possible angiostatic treatment is anecortave acetate (Retaane), from Alcon Laboratories.

Although early clinical results were not as stellar as hoped, scientists working on the treatment

believe this may be a result of drug delivery problems, not the drug itself and are making

adjustments. On May 24, 2005, the USA Food and Drug Administration released what is called

an "approvable" letter, basically meaning that the drug is approvable but some further study is

required. Alcon recently reported that their researchers and officials will "meet with the FDA to

discuss the approvable letter, the clinical studies submitted with the NDA and other ongoing

clinical studies for RETAANE® suspension to determine the steps necessary to gain final

approval for the wet AMD indication." Retaane has received market approval for use in Australia.

In early March 2006, a request for market approval in Europe was withdrawn, by Alcon, from

regulatory consideration.

Combination Therapies

Other investigations are also showing promise, including combination therapies, which combine

traditional PDT therapy with new drugs to increase the effectiveness of PDT. Combination

treatments pair one or more existing or new AMD treatments to see if the end result might be

greater than what could be achieved individually. More and more medical practitioners believe

that combination methods are the way of the future for wet AMD treatment. Usually the idea is

that one kind of treatment will take care of existing AMD in the patient, and the other will help to

prevent any future developments.

Position Statement on Avastin (bevacizumab)

The role, efficacy, and safety of anti-vascular endothelial growth factor (VEGF) therapies for use

in the treatment of age-related macular degeneration (AMD) were first established by clinical

trials of pegaptanib sodium, (Macugen, [OSI] Eyetech/Pfizer) and later by clinical trials for

ranibizumab (Lucentis, Genentech, Inc.)

Pegaptanib Sodium

Phase 3 clinical trials for pegaptanib sodium demonstrated that after 1 year of treatment,

individuals who were treated with 0.3 mg and 1 mg pegaptanib sodium experienced less vision

loss than those who were treated with a placebo. Individuals who were treated with pegaptanib

sodium experienced lasting results for 2 years. The most common side effect (occurring in

approximately 1.3% of cases) was endophthalmitis, which was caused by the injection.

Ranibizumab

Phase 3 clinical trials for ranibizumab demonstrated superior results after 1 year of treatment,

and showed that the majority of individuals who were treated with ranibizumab improved or

maintained vision 2 years later. The improvement in visual acuity endpoints in the ranibizumab-

treated groups (0.3 mg and 0.5 mg) was maintained at year 2, while individuals in the control

group continued to experience vision deterioration. At 2 years, at least 90% of individuals who

were treated with ranibizumab maintained or improved vision compared to approximately 53% of

individuals who were treated with sham injections. Treatment side effects were mild to moderate,

affected less than 3% of individuals, and included conjunctival hemorrhage, increased IOP,

vitreous floaters, and endophthalmitis.

Broadening the Anti-VEGF Theory

Ranibizumab was developed by Genentech, Inc. The company had previously developed

bevacizumab (Avastin, Genentech, Inc.) an anti-VEGF drug that is currently approved by the

Food and Drug Administration (FDA) as an intravenous therapy for metastatic colorectal cancer

patients. Bevacizumab for use in cancer therapy is currently being investigated. Ranibizumab is

a molecular fragment of an antibody, and bevacizumab is a full-length antibody. They are both

thought to work by a similar principle - the drug blocks the production of VEGF. VEGF, which is

also produced by cancer cells, prompts the abnormal growth of blood vessels, also known as

angiogenesis. Bevacizumab binds with VEGF and interferes with its ability to stimulate blood

vessel growth.

In early 2004, Philip Rosenfeld, MD, PhD, and colleagues at the Bascom Palmer Eye Institute in

Miami, Fla, initiated the use of bevacizumab in the treatment of AMD. Their first study was called

Systemic Avastin for Neovascular AMD (SANA). In this and subsequent studies, which consisted

of intravitreal injections of bevacizumab, individuals who were clinically followed reported

improvements in visual acuity comparable to ranibizumab with no serious adverse events. It is

important to note that these clinical studies were not conducted as randomised clinical trials.4,5

Based on these results, the use of bevacizumab for the treatment of AMD appears to have been

broadly accepted by retinal specialists around the world.

The use of bevacizumab in the eyes, an indication for which it is not approved, is called off-label

use. It is reasoned conjecture on the part of the AMD Alliance International that the off-label use

of bevacizumab was first suggested for reasons of economy and availability in the face of a

significant unmet need. Until the June 30, 2006 FDA approval in the USA, treatment with

ranibizumab was not available unless an individual was registered in a clinical trial, or, as is

possible in some European countries, receives the treatment on what is called a 'named-patient'

basis.

Antioxidants and Vitamin Therapies

One working hypothesis is that a cause or contributing factor to Macular Degeneration involves

the formation of chemicals in the body called free radicals. Free radicals are thought to result, in

part, from exposure to sunlight and other forms of ultraviolet light. They cause cellular damage by

taking electrons from molecules in healthy cells. This process, called oxidation, has been linked

to a variety of health problems including heart disease and cancer. Substances called

antioxidants may counteract the oxidation process; the body produces its own antioxidants, and

these are helped by antioxidants that we ingest through food or vitamin supplements. Vitamins C,

E nd carotenoids, including beta-carotene, are examples of potent antioxidants. However, which

of these is helpful to AMD is not yet known.

The work investigating a link between vitamins and Macular Degeneration is still in preliminary

stages. Recommendations regarding nutritional supplementation and light avoidance for patients

with Macular Degeneration are expected to emerge from studies now in progress.

Can an eye transplant cure Macular Degeneration?

No. Medical technology is not yet advanced enough to transplant the entire eye. It is simply

impossible to reconnect the nerves leading from the eye to the brain. What you may have heard

referred to as an "eye transplant" is probably the process of corneal transplantation, which is a

valuable vision saving procedure for some people, but unfortunately has no relationship to the

problems in the eye caused by Macular Degeneration. However, retinal cell transplantation is a

procedure that may have promise for people with Macular Degeneration in the future, although it

is still in its early experimental stages Retinal cell transplantation is described below.

Retinal Cell Transplantation

Transplantation of retinal cells has shown some encouraging results in animals, although it is

important to emphasize that this is not yet a treatment available for use in humans. Retinal cell

transplantation is still in preliminary stages of investigation in the laboratory. Before a procedure

can be tested in humans, long-term beneficial effects must be proven and possible side effects

must be determined. Such research might take several more years.

The good news is that studies so far have found that when photo receptor cells are transplanted

into the retinas of animals, some features of normal photo receptors are either maintained or

develop after transplantation. However, there is not yet conclusive evidence that retinal cell

transplants or similar procedures in animals with a retinal degeneration result in long-term

improved or restored vision. Nevertheless, the research done so far has been promising enough

for the American Foundation Fighting Blindness to expand a grant award programme aimed at

scientists who are investigating several areas of basic science that could lead to new therapies

that might repair or replace damaged retinal cells.

Special challenges in AMD research

Because AMD does not develop until late in life, and all body tissues undergo changes

associated with ageing, it is difficult to determine which eye findings are normal in those over the

age of 50, and which may be predictive of AMD. The American Foundation, along with the

American National Eye Institute, is working to define normal ageing, classify AMD types, define

genetic components, define risk factors, develop new diagnostic techniques, analyse eye tissue

layers and how they interact, and develop animal models that imitate human AMD.

Gene Therapy

As researchers identify more of the mutant genes that contribute to Macular Degeneration, it

becomes possible to think about curing the defect at the most basic cellular level. Gene therapy

is what many scientists feel is the answer of the future for many forms of retinal degenerations. It

is based on a simple logic: if a gene is defective, replace it with one that is not defective. While

this may sound simple, the actual procedure of gene therapy is very complex. 

Gene therapy might be described as a form of drug therapy in which the "good" gene itself is the

drug, which is introduced into the body to replace the "bad" gene. There are a number of reasons

that retinal degenerations are diseases that seem particularly suited to the use of gene therapy.

First and foremost, some of the defective genes for early onset inherited Macular Degeneration

have been identified. Also, there are a number of applicable animal models in which gene

therapy can be tested for effectiveness and safety. And the outcomes of gene therapy can be

tested by reliable and non-invasive visual examination of the retina. Finally, a treated eye can be

compared to an untreated eye in the same patient, giving researchers the ideal conditions for

conducting a controlled scientific experiment.

While all of the above factors make gene therapy a promising future approach for treating

Macular Degeneration, there are still many obstacles. One key question is how to actually

introduce the DNA of the good gene into diseased cells. Researchers have found that a

neutralized virus can act as a transporter of the gene to the degenerating photo receptor cells,

which seem to be particularly good targets for this type of gene transfer.

What assistance is available to help cope with AMD?

This information is helpful in learning how to physically cope with Macular Degeneration and

similar diseases. But what about emotional aspects? What assistance is available to help me and

my family cope with Macular Degeneration?

There are many devices and techniques that help people with Macular Degeneration maximize

the use of their remaining vision.

The white cane is probably the most visible aid, and some people with Macular Degeneration find

it a useful navigational aid if their vision loss progresses beyond a certain stage. The cane is a

form of non-optical aid; that is, it does not have an actual effect on your eyes, although it may

help you see or cope with vision loss. Other non-optical aids include guide dogs, audio tapes,

and large print books.

There are also electronic aids. These include closed-circuit televisions (CCTV), reading

machines, and talking computers, An increasing number of computer programmes are

addressing the needs of the visually impaired, making it possible to easily enlarge type on the

screen or provide an audio or Braille version to go with what is shown on the screen.

Optical aids are devices that work to improve your vision to some extent. These include Corning

and NOIR glasses, the Fresnel prism, telescopes and magnifiers. With advancing technology,

some of these devices are becoming increasingly sophisticated and offering new opportunities

for people with retinal degenerations to maximize their usable vision.

To determine which aids may be most useful for you, it is suggested that you get a thorough low

vision evaluation from a specialist, Contact the RP Foundation for more information on low vision

services in your area.

While research findings provide hope for the future, there is no actual treatment for people with

macular degeneration. Are there other ways that people with this condition can enhance the

quality of their lives? It is important that individuals and families know that there are resources

available to help them cope with the life-changing conditions Macular Degeneration may bring.

People with Macular Degenerations may rind it helpful to discuss their questions and concerns

with other people who have similar experiences. The RP Foundation Fighting Blindness can help

people get together to exchange information about these common issues in their lives and

explore possible solutions for some of their problems. You may also wish to speak with a mental

health professional to assist you and/or your family in dealing with the many changes that can be

related to Macular Degenerations.

How can I assist a person with AMD?

Age-related macular degeneration (AMD) is a difficult condition to understand, largely because

the eyes of a person with AMD look normal. The person with the conditions may still able to

manoeuvre around obstacles; can see a white piece of fluff on a dark carpet and yet we will walk

right by a neighbour or best friend without recognising them.

Those with AMD want people to understand that they are "visually impaired," not "clumsy,"

"standoffish," or "illiterate." They will sometimes fake "seeing" because it is easier than explaining

that they have no central vision. If a companion says, "Just look at that picture," many will reply,

"Oh yes!" rather than explaining, yet again, that they cannot see that kind of detail. Also it is

difficult to locate items for example, one could ask a family member 'Have you seen my umbrella'

answer 'yes, it's over there'. Now where is over there? The person may be pointing in the general

direction but the affected individual can not see where they are pointing so needs to a more

detailed explanation. Is it left, or is it right etc. So sometimes the entire family will need to be re-

educated.

Caregivers need to get as much information as they can about vision loss, and share that

information with the people they are caring for and their families. If you are a caregiver to

someone with any form of vision loss, we urge you to:

Become informed; learn as much as you can about the condition.

Be patient - adjusting to vision loss takes time.

Contact a member organization of Retina International.

Ensure the person you are caring for receives skills training and assessments for adaptive

tools.

Meet other people with the same condition.

Meet other caregivers.

When a person is diagnosed with AMD, it changes not only their own lives, but the lives of their

families and friends. Upon diagnosis painful emotions such as disbelief, panic, anger, and

frustration can be experienced by an individual and often family and caregivers are on the

receiving end of these feelings. What can really help an individual to come to terms with vision

loss is an increase in confidence and skill level - and that takes time.

As a carer it is important to be as informed as you can about the condition of the person

receiving care and educate their network of family and friends. Eventually, these steps will help

the affected individual feel confident, in control, and willing to accept help when needed without

feeling dependent on others.

By working together with caregivers and family members, those with AMD or any form of vision

loss can live with dignity, confidence, safety, and a strong feeling of self-worth.

http://idmgarut.wordpress.com/2009/02/02/referat-degenerasi-makula/

Referat : DEGENERASI   MAKULA Posted on Februari 2, 2009 by idmgarut

PENDAHULUAN

Degenerasi macula adalah suatu keadaan dimana macula mengalami kemunduran sehingga terjadi penurunan

ketajaman penglihatan dan kemungkinan akan menyebabkan hilangnya fungsi penglihatan sentral. Macula

adalah pusat dari retina dan merupakan bagian yang paling vital dari retina yang memungkinkan mata melihat

detil-detil halus pada pusat lapang pandang. Tanda utama dari degenerasi pada makula adalah didapatkan

adanya bintik-bintik abu-abu atau hitam pada pusat lapangan pandang. Kondisi ini biasanya berkembang secara

perlahan-lahan, tetapi kadang berkembang secara progresif, sehingga menyebabkan kehilangan penglihatan

yang sangat berat pada satu atau kedua bola mata.(1,2)

Berdasarkan American Academy of Oftalmology penyebab utama penurunan penglihatan atau kebutaan di AS

yaitu umur yang lebih dari 50 tahun. Data di Amerika Serikat menunjukkan, 15 persen penduduk usia 75 tahun

ke atas mengalami degenerasi makula itu. Terdapat 2 jenis tipe dasar dari penyakit-penyakit tersebut yakni

Standar Macular Degeneration dan Age Related Macular Degeneration (ARMD). Bentuk yang paling sering

terjadi adalah ARMD.(3,4)

Degenerasi makula terkait usia merupakan kondisi generatif pada makula atau pusat retina. Terdapat 2 macam

degenarasi makula yaitu tipe kering (atrofik) dan tipe basah (eksudatif). Kedua jenis degenerasi tersebut

biasanya mengenai kedua mata secara bersamaan. Degenerasi makula terjadi sebagai akibat dari kerusakan

pada epitel pigmen retina.(1,2,3,4)

Degenerasi makula menyebabkan kerusakan penglihatan yang berat (misalnya kehilangan kemampuan untuk

membaca dan mengemudi) tetapi jarang menyebabkan kebutaan total. Penglihatan pada tepi luar dari lapang

pandang dan kemampuan untuk melihat biasanya tidak terpengaruh, yang terkena hanya penglihatan pada

pusat lapang pandang. Gejala klinis biasa ditandai terjadinya kehilangan fungsi penglihatan secara tiba-tiba

ataupun secara perlahan tanpa rasa nyeri. Kadang gejala awalnya berupa gangguan penglihatan pada salah

satu mata, dinilai garis yang sesungguhnya lurus terlihar bergelombang.(1,3)

Diagnosis dapat ditegakkan berdasarkan gejala klinis dan hasil pemeriksaan mata. Sejauh ini belum ada terapi

untuk degenerasi makula tipe kering. Suplemen seng hanya mampu membantu memperlambat progresivitas

gangguan. Untuk beberapa kasus basah, terapi laser bisa membersihkan pembuluh darah abnormal sehingga

kekaburan penglihatan dapat dicegah. Tetapi, tidak semua kasus bisa diatasi dengan terapi laser. Saat ini

sedang dikembangkan berbagai obat dan prosedur operasi baru antara lain terapi foto dinamik.(2,3,4,5)

Faktor resiko gangguan ini selain karena usia tua, juga riwayat keluarga (genetik), ras kaukasia serta merokok.

(1,5)

II. ANATOMI DAN FISIOLOGI RETINA

Anatomi Retina

Retina atau selaput jala merupakan bagian mata yang mengandung reseptor yang menerima rangsang cahaya.

Retina berbatas dengan koroid dengan sel epitel pigmen retina dan terdiri atas lapisan : (6,7)

1. Lapisan epitel pigmen

2. Lapisan fotoreseptor merupakan lesi terluar retina terdiri atas sel batang yang mempunyai bentuk ramping,

dan sel kerucut.

3. Membran limitan eksterna yang merupakan membrane ilusi.

4. Lapisan nucleus luar, merupakan susunan lapis nucleus sel kerucut dan batang.

5. Lapisan pleksiform luar merupakan lapis aselular dan merupakan tempat sinapsis sel fotoreseptor dengan sel

bipolar dan sel horizontal.

6. Lapis nucleus dalam, merupakan tubuh sel bipolar, sel horizontal dan sel Muller.

7. Lapisan pleksiform dalam, merupakan lapis aselular merupakan tempat sinaps sel bipolar, sel amakrin dengan

sel ganglion.

8. Lapis sel ganglion yang merupakan lapis badan sel daripada neuron kedua,

9. Lapis serabut saraf, merupakan lapis akson sel ganglion menuju kearah saraf optic.

10. Membran limitan interna, merupakan membrane hialin antara retina dan badan kecil.

Retina adalah selembar tipis jaringan saraf yang semitransparan, dan multilapis yang melapisi bagian dalam dua

per tiga posterior dinding bola mata. Retina membentang ke depan hampir sama jauhnya dengan korpus siliare,

dan akhirnya di tepi ora serrata. Pada orang dewasa, ora serrata berada sekitar 6,5 mm di belakang garis

Schwalbe pada system temporal dan 5,7 mm di belakang garis ini pada sisi nasal. Permukaan luar retina

sensorik bertumpuk dengan membran Bruch, khoroid, dan sclera. Retina menpunyai tebal 0,1 mm pada ora

serrata dan 0.23 mm pada kutub posterior. Ditengah-tengah retina posterior terdapat makula. Di tengah makula

terdapat fovea yang secara klinis merupakan cekungan yang memberikan pantulan khusus bila dilihat dengan

oftalmoskop.(3,8)

Retina menerima darah dari dua sumber : khoriokapiler yang berada tepat di luar membrana Bruch, yang

mendarahi sepertiga luar retina, termasuk lapisan pleksiformis luar dan lapisan inti luar, fotoreseptor, dan lapisan

epitel pigmen retina, serta cabang-cabang dari arteri retina sentralis yang memperdarahi dua per tiga sebelah

dalam. (6,7)

Fisiologi Retina

Untuk melihat, mata harus berfungsi sebagai suatu alat optis, sebagai suatu reseptor kompleks, dan sebagai

suatu transducer yang efektif. Sel-sel batang dan kerucut di lapisan fotoreseptor mampu mengubah rangsangan

cahaya menjadi suatu impuls saraf yang dihantarkan oleh lapisan serat saraf retina melalui saraf optikus dan

akhirnya ke korteks penglihatan. Makula bertanggung jawab untuk ketajaman penglihatan yang terbaik dan untuk

penglihatan warna, dan sebagian besar selnya adalah sel kerucut. Di fovea sentralis, terdapat hubungan hampir

1:1 antara fotoreseptor kerucut, sel ganglionnya, dan serat saraf yang keluar, dan hal ini menjamin penglihatan

yang paling tajam. Di retina perifer, banyak fotoreseptor dihubungkan ke sel ganglion yang sama, dan diperlukan

sistem pemancar yang lebih kompleks. Akibat dari susunan seperti itu adalah bahwa makula terutama digunakan

untuk penglihatan sentral dan warna ( penglihatan fototopik) sedangkan bagian retina lainnya, yang sebagian

besar terdiri dari fotoreseptor batang, digunakan terutama untuk penglihatan perifer dan malam (skotopik). (6,7)

Fotoreseptor kerucut dan batang terletak di lapisan terluar yang avaskuler pada retina sensorik dan merupakan

tempat berlangsungnya reaksi kimia yang mencetuskan proses penglihatan. Setiap sel fotoreseptor kerucut

mengandung redopsin, yang merupakan suatu pigmen penglihatan fotosensitif yang terbentuk sewaktu molekul

protein opsin bergabung dengan 11-sis-retinal. Sewaktu foton cahaya diserap oleh rodopsin, 11-sis-retinal

segera mengalami isomerisasi menjadi bentuk ali-trans. Redopsin adalah suatu glikolipid membran yang

separuh terbenam di lempeng membram lapis ganda pada segmen paling luar fotoreseptor. Penyerapan cahaya

puncak oleh terjadi pada panjang gelombang sekitar 500 nm, yang terletak di daerah biru-hijau pada spektrum

cahaya. Penelitian-penelitian sensitivitas spektrum fotopigmen kerucut memperlihatkan puncak penyerapan

panjang gelombang di 430, 540, dan 575 nm masing-masing untuk sel kerucut peka-biru, -hijau, dan –merah.

Fotopigmen sel kerucut terdiri dari 11-sis-retinal yang terikat ke berbagai protein opsin. (7)

Penglihatan skotopik seluruhnya diperantarai oleh fotoreseptor sel batang. Pada bentuk penglihatan adaptasi

gelap ini, terlihat bermacam-macam nuansa abu-abu, tetapi warna tidak dapat dibedakan. Sewaktu retina telah

beradaptasi penuh terhadap cahaya, sensitivitas spektral retina bergeser dari puncak dominasi rodopsin 500 nm

ke sekitar 560 nm, dan muncul sensasi warna. Suatu benda akan berwarna apabila benda tersebut mengandung

fotopigmen yang menyerap panjang-panjang gelombang dan secara selektif memantulkan atau menyalurkan

panjang-panjang gelombang tertentu di dalam spektrum sinar tampak (400-700 nm). Penglihatan siang hari

terutama diperantarai oleh fotoreseptor kerucut, senjakala oleh kombinasi sel kerucut dan batang, dan

penglihatan malam oleh fotoreseptor batang.(7)

III. PATOFISIOLOGI

Degenerasi makula yang terkait usia tipe kering ditandai oleh adanya atrofi dan degenerasi retina bagian luar,

epitel pigmen retina, membran Bruch, dan koriokapilaris dengan derajat yang bervariasi. Dari perubahan-

perubahan di epitel pigmen retina dan membran Bruch yang dapat dilihat secara oftalmoskopi adalah drusen

yang sangat khas. Drusen adalah endapan putih kuning, bulat, diskret, dengan ukuran bervariasi di belakang

epitel pigmen dan tersebar di seluruh makula dan kutub posterior. Seiring dengan waktu, drusen dapat

membesar, menyatu, mengalami kalsifikasi dan meningkat jumlahnya. Secara histopatologis sebagian besar

drusen terdiri dari kumpulan lokal bahan eosinifilik yang terletak di antara epitel pigmen dan membran Bruch;

drusen mencerminkan pelepasan fokal epitel pigmen.(4,7,9)

Walaupun pasien dengan degenerasi makula biasanya hanya memperlihatkan kelainan non eksudatif, sebagian

besar pasien yang menderita gangguan penglihatan berat akibat penyakit ini mengalami bentuk eksudatif akibat

terbentuknya neovaskularisasi subretina dan makulopati eksudatif terkait. Cairan serosa dari koroid di bawahnya

dapat bocor melalui defek defek kecil di membran Bruch sehingga mengakibatkan pelepasan-pelepasan lokal

epitel pigmen. Peningkatan cairan tersebut dapat semakin menarik retina sensorik di bawahnya dan penglihatan

biasanya menurun apabila fovea terkena. Pelepasan epitel pigmen retina dapat secara spontan menjadi datar

dengan bermacam-macam akibat penglihatan dan meninggalkan daerah geografik depigmentasi pada daerah

yang terkena. Dapat terjadi pertumbuhan pemubulu-pembuluh darah baru ke arah dalam yang meluas ke koroid

sampai ruang subretina dan merupakan perubahan histopatologik terpenting yang memudahkan timbulnya

pelepasan makula dan gangguan penglihatan sentral yang bersifat ireversivel pada pasien dengan drusen.

Pembuluh pembuluh darah ini akan tumbuh dalam konfigurasi roda-roda pedati datar atau sea-fan menjauhi

tempat masuk ke dalam ruang sub retina.(4,7,9)

IV. ETIOLOGI

Degenerasi macula dapat disebabkan oleh beberapa factor dan dapat diperberat oleh beberapa factor resiko,

diantaranya : (6,7,8,9)

1. Umur, faktor resiko yang paling berperan pada terjadinya degenerasi makula adalah umur. Meskipun

degenerasi makula dapat terjadi pada orang muda, penelitian menunjukkan bahwa umur di atas 60 tahun

beresiko lebih besar terjadi di banding dengan orang muda. 2% saja yang dapat menderita degenerasi makula

pada orang muda, tapi resiko ini meningkat 30% pada orang yang berusia di atas 70 tahun.

2. Genetik, penyebab kerusakan makula adalah CFH, gen yang telah bermutasi atau faktor komplemen H yang

dapat dibawa oleh para keturunan penderita penyakit ini. CFH terkait dengan bagian dari sistem kekebalan tubuh

yang meregulasi peradangan.

3. Merokok, Merokok dapat meningkatkan terjadinya degenrasi makula.

4. Ras kulit putih (kaukasia) adalah sangat rentan terjadinya degenerasi makula di banding dengan orang Afrika

atau yang berkulit hitam.

5. Riwayat keluarga, resiko seumur hidup terhadap pertumbuhan degenerasi makula adalah 50% pada orang-

orang yang mempunyai hubungan keluarga penderita dengan degenerasi makula, dan hanya 12 % pada mereka

yang tidak memiliki hubungan dengan degenerasi makula.

6. Hipertensi dan diabetes.

Degenerasi Makula menyerang para penderita penyakit diabetes, atau tekanan darah tinggi gara-gara mudah

pecahnya pembuluh-pembuluh darah kecil (trombosis) sekitar retina. Trombosis mudah terjadi akibat

penggumpalan sel-sel darah merah dan penebalan pembuluh darah halus.

7. Paparan terhadap sinar Ultraviolet

8. Obesitas dan kadar kolesterol tinggi

V. KLASIFIKASI

1. Degenerasi Makula tipe non-eksudatif (tipe kering)

Rata-rata 90% kasus degenerasi makula terkait usia adalah tipe kering. Kebanyakan kasus ini bisa memberikan

efek berupa kehilangan penglihatan yang sedang. Tipe ini bersifat multipel, kecil, bulat, bintik putih kekuningan

yang di sebut drusen dan merupakan kunci identifikasi untuk tipe kering. Bintik tersebut berlokasi di belakang

mata pada level retina bagian luar. Adapun lesi klasik yang bisa ditemukan adanya atrofi geografik. Terdapat

endapan pigmen di dalam retina tanpa disertai pembentukan jaringan parut , darah atau perembesan cairan.

(11,12,13,14)

Degenerasi makula terkait usia noneksudatif ditandai oleh atrofi dan degenerasi retina bagian luar, epitel pigmen

retina, membran Bruch, dan koriokapilaris dengan derajat yang bervariasi. Dari perubahan-perubahan di epitel

pigmen retina dan membran Bruch yang dapat dilihat secara oftalmoskopis, drusen adalah yang paling khas.

Drusen adalah endapan putih kuning, bulat, diskret, dengan ukuran bervariasi di belakang epitel pigmen dan

tersebar di seluruh makula dan kutub posterior. Seiring dengan waktu, drusen dapat membesar, menyatu,

mengalami kalsifikasi dan meningkat jumlahnya. Secara histopatologis sebagian besar drusen terdiri dari

kumpulan lokal bahan eosinifilik yang terletak di antara epitel pigmen dan membran Bruch; drusen

mencerminkan pelepasan fokal epitel pigmen.(7,10)

Drusen dapat di bagi berdasarkan klinik dan histopatologi yakni drusen keras ( nodular), drusen diffus

( konfluent), drusen halus ( granular ), dan drusen kalsifikasi . Selain drusen, dapat muncul secara progresif

gumpalan-gumpalan pigmen yang tersebar secara tidak merata di daerah-daerah depigmentasi atrofi di seluruh

makula.(7,10)

2. Degenerasi Makula tipe eksudatif ( tipe basah)

Degenerasi makula tipe ini adalah jarang terjadi namun lebih berbahaya di bandingkan dengan tipe kering. Kira

kira didapatkan adanya 10% dari semua degenerasi makula terkait usia dan 90% dapat menyebabkan kebutaan.

Tipe ini ditandai dengan adanya neovaskularisasi subretina dengan tanda-tanda degenerasi makula terkait usia

yang mendada atau baru mengalami gangguan penglihatan sentral termasuk penglihatan kabur, distorsi atau

suatu skotoma baru. Pada pemeriksaan fundus, terlihat darah subretina, eksudat, lesi koroid hijau abu-abu di

makula. Neovaskularisasi koroid merupakan perkembangan abnormal dari pembuluh darah pada epitel pigmen

retina pada lapisan retina. Pembuluh darah ini bisa mengalami perdarahan dan menyebabkan terjadinya scar

yang dapat menghasilkan kehilangan pusat penglihatan. Scar ini disebut dengan Scar Disciform dan biasanya

terletak di bagian sentral dan menimbulkan gangguan penglihatan sentral permanen.(4,7,11,15,16)

VI. GEJALA KLINIS 

Gejala-gejala klinik yang biasa didapatkan pada penderita degenerasi makula antara lain : (1,4,8,9)

1. Distorsi penglihatan, obyek-obyek terlihat salah ukuran atau bentuk

2. Garis-garis lurus mengalami distorsi (membengkok) terutama dibagian pusat penglihatan

3. Kehilangan kemampuan membedakan warna dengan jelas

4. Ada daerah kosong atau gelap di pusat penglihatan

5. Kesulitan membaca, kata-kata terlihat kabur atau berbayang

6. Secara tiba-tiba ataupun secara perlahan akan terjadi kehilangan fungsi penglihatan tanpa rasa nyeri.

VII. DIAGNOSIS

Diagnosis dapat ditegakkan berdasarkan gejala klinik dan hasil pemeriksaan oftalmoskopi yang mencakup ruang

lingkup pemeriksaan sebagai berikut : (1,2,3,4,5)

1. Test Amsler Grid, dimana pasien diminta suatu halaman uji yang mirip dengan kertas milimeter grafis untuk

memeriksa luar titik yang terganggu fungsi penglihatannya. Kemudian retina diteropong melalui lampu senter

kecil dengan lensa khusus.

2. Test penglihatan warna, untuk melihat apakah penderita masih dapat membedakan warna, dan tes-tes lain

untuk menemukan keadaan yang dapat menyebabkan kerusakan pada makula.

3. Kadang-kadang dilakukan angiografi dengan zat warna fluoresein. Dokter spesialis mata menyuntikan zat

warna kontras ini ke lengan penderita yang kemudian akan mengalir ke mata dan dilakukan pemotretan retina

dan makula. Zat warna ini memungkinkan melihat kelainan pembuluh darah dengan lebih jelas.

e

VIII. DIAGNOSIS BANDING

Degenerasi macula khususnya tipe eksudat dapat di diagnosis banding dengan: (4)

1. Makroneurisme

2. Vaskulopati koroid polipoid

3. Khorioretinopati serous sentral

4. Kasus inflamasi

5. Tumor kecil seperti melanoma koroid

IX. PENATALAKSANAAN

Tidak ada terapi khusus untuk AMD noneksudatif Penglihatan dimaksimalkan dengan alat bantu penglihatan

termasuk alat pembesar dan teleskop. Pasien diyakinkan bahwa meski penglihatan sentral menghilang, penyakit

ini tidak menyebabkan hilangnya penglihatan perifer. Ini penting karena banyak pasien takut mereka akan

menjadi buta total. (2,4,8,9)

Pada sebagian kecil pasien dengan AMD eksudatif yang pada angiogram fluorosen memperlihatkan membrane

neovaskular subretina yang terletak eksentrik (tidak sepusat) terhadap fovea, mungkin dapat dilakukan obliterasi

membrane tersebut dengan terapi laser argon. Membrane vascular subfovea dapat diobliterasi dengan terapi

fotodinamik (PDT) karena laser argon konvensional akan merusak fotoreseptor di atasnya. PDT dilakukan

dengan menyuntikkan secara intravena bahan kimia serupa porfirin yang diaktivasi oleh sinar laser nontermal

saat sinar laser berjalan melalui pembuluh darah di membrane subfovea. Molekul yang teraktivasi

menghancurkan pembuluh darah namun tidak merusak fotoreseptor. Sayangnya kondisi ini dapat terjadi kembali

bahkan setelah terapi laser. (2,4,8,9)

Apabila tidak ada neovaskularisasi retina, tidak ada terapi medis atau bedah untuk pelepasan epitel pigmen

retina serosa yang terbukti bermanfaat. Pemakaian interferon alfa parenteral, misalnya, belum terbukti efektif

untuk penyakit ini. Namun apabila terdapat membrane neovaskular subretina ekstrafovea yang berbatas tegas (?

200 um dari bagian tengah zona avaskular fovea), diindikasikan fotokoagulasi laser. Dengan angiografi dapat

ditentukan dengan tepat lokasi dan batas-batas membrane neovaskular yang kemudian diablasi secara total oleh

luka-luka bakar yang ditimbulkan oleh laser. Fotokoagulasi juga menghancurkan retina di atasnya tetapi

bermanfaat apabila membrane subretina dapat dihentikan tanpa mengenai fovea. (4,8)

Fotokoagulasi laser krypton terhadap neovaskularisasi subretina avaskular fovea (? 200 um dari bagian tengah

zona avaskular fovea) dianjurkan untuk pasien nonhipertensif. Setelah fotokoagulasi membrane neovaskular

subretina berhasil dilakukan, neovaskularisasi rekuren di dekat atau jauh dari jaringan parut laser dapat dapat

terjadi pada separuh kasus dalam 2 tahun. Rekurensi sering disertai penurunan penglihatan berat sehingga

pemantauan yang cermat dengan Amsler grid, oftalmoskopi dan angiografi perlu dilakukan. Pasien dengan

gangguan penglihatan sentral di kedua matanya mungkin memperoleh manfaat dari pemakaian berbagai alat

bantu penglihatan kurang. (4,8)

Selain itu terapi juga dapat dilakukan di rumah berupa pembatasan kegiatan dan follow up pasien dengan

mengevaluasi daya penglihatan yang rendah. Selain itu dengan mengkomsumsi multivitamin dan antioksidan

( berupa vitamin E , vitamin C, beta caroten, asam cupric dan zinc), karena diduga dapat memperbaiki dan

mencegah terjadinya degenerasi makula. Sayuran hijau terbukti bisa mencegah terjadinya degenerasi makula

tipe kering. Selain itu kebiasaan merokok dikurangi dan dan pembatasn hipertensi.(4,15)

X. PROGNOSIS

Bentuk degenerasi makula yang progresif dapat menyebakan kebutaan total sehingga aktivitas dapat menurun.

Prognosis dari degenerasi makula dengan tipe eksudat lebih buruk di banding dengan degenerasi makula tipe

non eksudat. Prognosis dapat didasarkan pada terapi, tetapi belum ada terapi yang bernilai efektif sehingga

kemungkinan untuk sembuh total sangat kecil.(10)

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