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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 (1012) 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.(3034) 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 Gprotein-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)(2426) 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)(2428) 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.(2936) 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 Cterminus (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.35 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 wellrecognized 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 retinaspecific 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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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

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.

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 antioxidant 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.

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.

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 ranibizumabtreated 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 reeducated. 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.


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 perubahanperubahan 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 orangorang 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) DAFTAR PUSTAKA 1. Degenerasi Makula. Medicastore Online. 9125.162.255.115 2. Macular Degeneration. [ Online ]. [ Cited on 2007, Januari 17th ].Available from : URL: 3. Degenerasi Makula. IDI Online-Iptek Kedokteran. 4. Liesegang TJ., Skuta GL., Cantor LB,. Retina and Vitreous. Basic and Clinical Course.Section 12 . San Fransisco, California : American Academy of Ophthalmology. 2003-2004. 5. Degenerasi Makula. IDI Online-Iptek Kedokteran. 6. Sidarta I,. Anatomi dan Fisiologi Mata. Dalam : Ilmu Penyakit Mata Edisi kedua. Jakarta : BP-FKUI. 2002 7. Hardy RA,. Retina dan Tumor Intraokuler. Dalam : Vaughan D.G, Asbury T., Riordan E.P, Editor. Oftalmologi Umum Edisi 14. Jakarta : Widya Medika. 2000. 8. Degenerasi Makula dan Mata Anda. Klinik Mata Nusantara Online. (diakses tanggal 6 Maret 2007) 9. James C., Chew C., Bron A. Retina dan Koroid. Dalam : Oftalmologi Edisi Kesembilan. Yakarta : Penerbit Erlangga. 2006 10. Maturi R.K,. Aging Relation Macular Degeneration. [Online]. [ Cited on 2007, Januari 17th ]. Available from : URL: 11. Macular Degeneration. [Online]. [ Cited on 2007, Januari 17th ]. Available from : URL: In : Eye Condition. 12. Age-Related Macular Degeneration. [Online]. [ Cited on 2007, Januari 17th ]. Available from : URL: 13. Macular Degeneration. [Online]. [ Cited on 2007, Januari 17th ]. Available from : URL:

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