Macular degeneration

Macular degeneration
Specialty	Ophthalmology

Human eye cross-sectional view. Courtesy NIH National Eye Institute

Normal vision. Courtesy NIH National Eye Institute

The same view with age-related macular deneneration.

Macular degeneration is a medical condition in which the light sensing cells in the macula malfunction and, over time, cease to work. According to the American Academy of Ophthalmology, it is the leading cause of central vision loss (blindness) in the United States today for those over the age of fifty years. Although some macular dystrophies that affect younger individuals are sometimes referred to as macular degeneration, macular degeneration generally refers to age-related macular degeneration (AMD).

Age related macular degeneration

Age-related macular degeneration begins with characteristic yellow deposits in the macula (central area of the retina) called drusen. Most people with these early changes have good vision. People with drusen can go on to develop advanced AMD. The risk is considerably higher when the drusen are large and numerous and associated with disturbance in the pigmented cell layer under the macula.

Advanced AMD, which is responsible for profound vision loss, has two forms: dry and wet. Central geographic atrophy, the dry form of advanced AMD, causes vision loss through loss of photoreceptors and cells supporting the photoreceptors in the central part of the eye. Currently, no treatment is available for this condition. Neovascular or exudative AMD, the wet form of advanced AMD, causes vision loss due to abnormal blood vessel growth under the macula. Bleeding, leaking, and scarring from these blood vessels eventually cause irreversible damage to the photoreceptors and supporting cells, if left untreated. New, effective treatments for the neovascular form of AMD are now available.

Risk factors

• Aging: Approximately 10% of patients 66 to 74 years of age will have findings of macular degeneration. The prevalence increases to 30% in patients 75 to 85 years of age.
• Smoking: The only environmental exposure clearly associated with macular degeneration is tobacco smoking.
• Family history: The lifetime risk of developing late-stage macular degeneration is 50% for people who have a relative with macular degeneration vs. 12% for people who do not have relatives with macular degeneration, i.e. a four fold higher risk.
• Macular degeneration gene: Complement factor H (CFH) and complement factor B (CFB) genes have been determined to be strongly associated with a person's risk for developing macular degeneration. CFH is involved in inhibiting the inflammatory response of C3b by binding C3b and cleaving it to its inactive form: C3bi. C-reactive protein and heparin normally increase the affinity of CFH for C3b. But the mutation in CFH(Tyr402His) reduces the affinity of CFH for heparin and CRP. This change results in reduced affinity of CFH for C3b and leads to increased inflammatory response against the retina.
• Hypertension: Also known as high blood pressure.
• Cardiovascular status - high cholesterol, obesity.
• High fat intake is associated with an increased risk of macular degeneration in both women and men. Fat provides about 42 % of the food energy in the average American diet. A diet that derives closer to 20-25 % of total food energy from fat is probably healthier. Reducing fat intake to this level means cutting down greatly on consumption of red meats and dairy products such as milk, cheese, and butter. Eating more cold-water fish (at least twice weekly), rather than red meats and eating any type of nuts may help macular degeneration patients.
• Oxidative stress: It has been proposed that age related accumulation of low molecular weight, phototoxic, pro-oxidant melanin oligomers within lysosomes in the retinal pigment epithelium may be partly responsible for decreasing the digestive rate of photoreceptor outer rod segments (POS) by the RPE. A decrease in the digestive rate of POS has been shown to be associated with lipofuscin formation - a classic sign associated with macular degeneration.
• Race Macular degeneration is more likely to be found in whites than in blacks.
• Exposure to sunlight especially blue light. There is conflicting evidence as to whether exposure to sunlight contributes to the development of macular degeneration. A recent study in the British Journal of Ophthalmology on 446 subjects found that it does not. High energy visible light (HEV) has been implicated as a cause of age-related macular degeneration.

Signs

• Drusen
• Pigmentary alterations
• Exudative changes: hemorrhages, hard exudates, subretinal/sub-RPE/intraretinal fluid
• Atrophy: incipient and geographic
• Visual acuity drastically decreasing (two levels or more) ex: 20/20 to 20/80.

Symptoms

File:Amsler.jpg

Image courtesy AgingEye Times

• Blurred vision: Those with nonexudative macular degeneration may by asymptomatic or notice a gradual loss of central vision, whereas those with exudative macular degeneration often notice a rapid onset of vision loss.
• Central scotomas (shadows or missing areas of vision)
• Distorted vision (i.e. metamorphopsia) - A grid of straight lines appears wavy and parts of the grid may appear blank. Patients often first notice this when looking at mini-blinds in their home.
• Trouble discerning colors; specifically dark ones from dark ones and light ones from light ones.
• Slow recovery of visual function after exposure to bright light

The Amsler Grid Test is one of the simplest and most effective methods for patients to monitor the health of the macula. The Amsler Grid is essentially a pattern of intersecting lines (identical to graph paper) with a black dot in the middle. The central black dot is used for fixation (a place for the eye to stare at). With normal vision, all lines surrounding the black dot will look straight and evenly spaced with no missing or odd looking areas when fixating on the grid's central black dot. When there is disease affecting the macula, as in macular degeneration, the lines can look bent, distorted and/or missing.

The traditional Amsler grid test is a black and white pattern that may miss early defects (references at www.ixm.us). Since treatment and vision preservation in macular degeneration is facilitated by early detection of the disease, a more sensitive blue-on-yellow Amsler grid test pattern has recently been introduced (IXMUS Home Test).

'Vision loss' or 'blindness' in macular degeneration refers to the loss of 'central vision' only. The peripheral vision is preserved. Blindness in macular degeneration does not mean 'inability to see light' and even with far advanced macular degeneration, the peripheral retina allows for useful vision.

The loss of central vision profoundly affects visual functioning. It is not possible, for example, to read without central vision. Pictures which attempt to depict the central visual loss of macular degeneration with a black spot do not really do justice to the devasting nature of the visual loss. This can be demonstrated by printing letters 6 inches high on a piece of paper and attempting to identify them while looking straight ahead and holding the paper slightly to the side. Most people find this surprisingly difficult to do.

Diagnosis

Fluorescein angiography allows for the identification and localization of abnormal vascular processes. Ocular coherence tomography is now used by most ophthalmologists in the diagnosis and the followup evaluation of the response to treatment by using either Avastin or Lucentis which are injected into the vitreous of the eye at various intervals.

Treatment

Most of the treatments that are available now and and currently being studied are aimed at stopping the neovascular (or wet) form of AMD.

In June 2006, the drug ranibizumab (Lucentis) has been approved by the FDA for use in the treatment of AMD. Ranibizumab has been shown to not only halt the progession of the disease, but also works to reverse its effects—and over time improve the patient's vision. Ranibizumab has been shown to improve vision 3 lines or more in approximately 40% of patients and has a very favorable safety profile. Ranibizumab is given as an injection into the eye. The initial studies required an injection every 4 weeks for 2 years.

Bevacizumab (Avastin), a drug approved for use in colon cancer, has been used by ophthalmologists in the treatment of wet macular degeneration. Before Lucentis was available, Avastin was widely used by ophthalmologists who treat macular degeneration, and some of their experiences with relatively small numbers of patients with short follow-up times were recently published. No randomized controlled clinical trial with systematic safety data collection has been performed to validate its efficacy and safety. Bevacizumab, when administered at the usual cancer treatment doses, has been shown to cause systemic adverse effects. The most common adverse effect was hypertension, but severe hemorrhages have also occurred. In addition, there is no evidence that the full-length antibody can actually penetrate all layers of the retina. There is continued interest as the Avastin for use in the eye can be obtained for about 300-500 dollars per dose while Lucentis costs about $2,000 per dose. The National Eye Institute is planning a head-to-head Lucentis vs. Avastin, randomized, controlled clinical trial for treatment of macular degeneration.

Macugen or pegabtanib was approved in 2004 for treatment of neovascular AMD. It targets certain forms of VEGF molecules and is injected directly into the eye like ranibizumab or bevacizumab. Although this was shown to decrease the risk of vision loss signficantly compared to no treatment, it is felt to be relatively ineffective compared to the newer treatments.

Photodynamic therapy (PDT) with Visudyne (verteporfin) had been the treatment of choice for neovascular AMD until recently. This was the first treatment shown to decrease the chance of severe vision loss in 2 years in patients with neovascular AMD without first causing immediate vision loss at the time of the treatment. A photosenstive dye with affinity for the abnormal blood vessels are first injected through the veins. A low-energy activating laser is then directed toward the abnormal blood vessels, causing selective damage to those blood vessels. This has also fallen out of favor as newer, more effective treatments became available.

Direct laser treatment for neovascular AMD was shown to decrease the chance of profound vision loss at 2 years in patients with neovascular AMD but it is seldom used as the treatment itself causes significant vision loss immediately. Infrequently, abnormal blood vessels outside of the center part of the macula are detected. Direct laser treatment can be an effective way to treat these patients with acceptable morbidity.

In a study published in the journal Nature, researchers working with mice at the University College London Institutes of Ophthalmology and Child Health and Moorfields Eye Hospital, transplanted mouse stem cells which were at an advanced stage of development, and already programmed to develop into photoreceptors, into mice that had been genetically induced to mimic the human conditions of retinitis pigmentosa and age-related macular degeneration. These photoreceptors developed and made the necessary neural connections to the animal's retinal nerve cells, a key step in the restoration of sight. Previously it was believed that the mature retina has no regenerative ability. This research may eventually lead to using transplants in humans to relieve blindness.[1]

Prevention

Although there is currently no accepted way to prevent age-related macular degeneration, several macular degeneration clinical trials are currently underway. The most promising approach is the anti-angiogenesis treatment for wet macular degeneration. Different anti-angiogenesis strategies that block VEGF-mediated choroidal neovascularization are being evaluated in clinical trials. Drugs currently approved for wet macular degeneration include: pegaptanib (Macugen) and Lucentis Drugs under investigation include: ranibizumab, anecortave (Retaane), bevacizumab (Avastin), squalamine (Evizon) and siRNA. Second generation antisense oligonucleotides iCo-007 targeting the Raf-1 kinase are also under investigation as a target for broad inhibition of multiple pro-angiogenic signals. The most promising of these treatments, ranibizumab (Lucentis), is the 1st drug tested that has shown significant improvement in visual acuity in multiple phase III trials. Radiation therapy (brachytherapy) and rheopheresis are also being evaluated for wet macular degeneration. Ophthalmologists are using Avastin in the eye "off-label", since it was approved by the FDA for cancer and not eye disease

Recent studies suggest that statins, a family of drugs used for reducing cholesterol levels, may be effective in prevention of AMD, and in slowing its progression.

The Age-Related Eye Disease Study concluded that high levels of antioxidants and zinc can reduce some people's risk of developing advanced AMD by about 25 percent. In 2006 AREDS II is under way to study the effects of Genistein (a derivative in Soyabeans).

The use of antioxidants is believed to protect against AMD by filtering out high energy blue light and scavenging for harmful free radicals also known as reactive oxygen species. These species bond to anything, transforming them, and changing their properties. Lutein and zeaxanthin are the only antioxidants found in the macula and lens, and are therefore the only ones that can protect the eyes from these harmful things.

Juvenile macular degeneration

Juvenile macular degeneration is not a term in standard usage at this time. Preferred term for conditions that affect the macula in younger individuals related to genetics is macular dystrophy. Examples of these include:

• Best's disease
• Doyne's honeycomb retinal dystrophy
• Sorsby's disease
• Stargardt's disease

Impact

Macular degeneration, especially the more aggressive wet form, can result in legal blindness, resulting in a loss of driving privileges and an inability to read all but very large type. Perhaps the most grievous loss is the inability to see faces clearly or at all.

Some of these losses can be offset by the use of adaptive devices. A closed-circuit television reader can make reading possible, and specialized screen-reading computer software, e.g., JAWS for Windows, can give the blind person access to word processing, spreadsheet, financial, and e-mail access.

External links

• Macular Degeneration Research
• Macular Degeneration 3000 word report A Patients Guide to AMD
• BBC News — AMD from a European perspective
• Macular Degeneration Foundation
• VisionSimulations.com | What the world looks like to people with various diseases and conditions of the eye
• ARMD Cook | Recipes using medical guidelines for the prevention and possible reversal of MD and ARMD
• Wellman Center for Photomedicine at Massachusetts General Hospital MGH and Harvard Medical School information on the use of photomedicine as treatment
• Age Related Macular Degeneration amdcanada.com
• "Scientists seek to restore sight". BBC News Scotland. 2006-07-11. Retrieved 2006-07-13. {{cite web}}: Check date values in: |date= (help); Cite has empty unknown parameters: |accessyear=, |month=, |accessmonthday=, and |coauthors= (help)