Age - Related Macular Degeneration (AMD)

Age-related macular degeneration (AMD) is a leading cause of blindness in elderly population.

It destroys sharp, central vision, which is needed for seeing objects clearly and for common daily tasks such as reading and driving.   AMD may be detected with a combination of tests such as   visual acuity test, dilated eye exam, tonometry, Amsler grid and fluorescein angiogram.  This condition is not curable.

However, the progress of   the disease to an advanced stage can be prevented. Current treatment options   include laser photocoagulation, photodynamic therapy and anti- Vascular Endothelial Growth Factor (VEGF) therapy. There is a need to develop innovative drug delivery strategies to administer drugs   effectively  to the posterior segment of the eye.  This article reviews the brief patho physiology, ongoing research, and recent combination drug therapies indicated in the treatment of AMD

Introduction:

Age-related macular degeneration (AMD) is a degenerative disorder affecting the macula.  Visual loss due to age-related macular degeneration is a significant cause of posterior segment blindness and is not preventable.

AMD can be dry or wet form.   Dry AMD occurs when light-sensitive cells in the macula slowly break down, gradually blurring central vision in the affected eye.  The dry type is much more common and is characterized by drusen and loss of pigment in the retina.  Drusen are small, yellowish deposits that form within the layers of the retina.  There is no medical treatment for this type.  However, aids such as magnifiers can be helpful in reading and   in doing other small detailed tasks.  Wet AMD occurs when abnormal blood vessels under the macula start to grow behind the retina.  These new blood vessels tend to be very fragile and often leak blood and fluid. Clinically this is characterized by large soft drusen, pigmentary abnormalities of retina and retinal pigment epithelium (RPE) in the early stages.  In the later stages there is occurrence of   geographic atrophy, choroidal neovascularization (CNV), pigment epithelial detachment (PED), and fibrous scarring of the macula. ¹

Visual loss may not be measurable   in early AMD while   late AMD is associated with moderate to severe visual loss.  The clinically proven methods of treatment are laser photocoagulation of treatable lesions and subretinal surgery in selected cases.  While the visual results in the former depend on the location of the CNV, the outcome of submacular surgical removal of neovascular membrane is not very rewarding in AMD. Laser photocoagulation, photodynamic therapy and anti- Vascular Endothelial Growth Factor (VEGF) therapy are widely used.

Anatomy of eye:

The eye is shaped like a ball. The pupil is the opening, which allows light to enter the eye.   Behind the pupil is the lens, which focuses light on the retina at the back of the eye.  Light enters through the clear front surface of the eye (the cornea), passes through the opening of the pupil, through the lens and finally is  perceived by the retina at the back of the eye.  Retina is a delicate tissue, which converts light into images and sends them to the brain.  It is a   multilayered structure that lines the inside of the globe. It is made up of specialized cells that convert light to electrical impulses that travel to the brain and produce sight.   In the center of the retina, there is a tiny, extremely specialized area called macula.  It is approximately 1/8 inch in diameter and about the size of this letter "O".  Macula has the most densely packed photoreceptors and cells that collect light. They consist of rods and cones which perceive color. It   is  supplied with oxygen-rich blood that nourishes the cells.  If the macula is intact, we see the fine details of whatever is directly in front of us.  Macular degeneration involves the deterioration or breakdown of this tiny structure.  Central vision becomes   blurred or disappears. Straight lines look wavy or broken.  We see the edges of images,  but not what is in the middle. In time, the sense of color is  diminished because the cones are damaged.  The patient does not experience total blindness and there is always a ring of peripheral vision.

Normal vision                                       Same as viewed by person with   AMD

Source : US  National eye Institute

Detection And Testing:

Some common tests performed are as follows:

Ophthalmoscopy :

An ophthalmoscope is an instrument used to examine the retina and vitreous.  Ophthalmoscopy requires dilation of pupils to give the the best view of inside of the eye.

Amsler Grid Test:

A chart is held approximately 14-16 inches from the eye.  One eye is covered & the patient is told to focus at the central dot.  The possibility of AMD is indicated in case of missing areas or if grid lines do not appear straight or parallel.

Source: AgingEye Times

Fluorescein angiogram (FA)

The test is performed by injecting a special dye, called fluorescein, into a vein in the arm.  In a few seconds, the dye travels to the blood vessels inside the eye.  A camera equipped with special filters that highlight the dye is used to photograph the fluorescein as it circulates through the blood vessels in the back of the eye.  If there are any circulation problems, swelling, leaking or abnormal blood vessels, the dye and its patterns will reveal these in the photographs.  The doctor can then diagnose the condition and suggest   possible treatment options for the patient. 

Fundus photography:

Fundus photography is a highly specialized form of medical imaging. It requires a customized camera that is mounted to a microscope with intricate lenses and mirrors.  These high-powered lenses are designed so the photographer can visualize the back of the eye by focusing light through the cornea, pupil and lens.

Treatment:

Age related macular degeneration is not completely  curable. Once detected it is important to stop further deterioration using several options available depending on the severity of the condition.

Primary Therapy:

(a)  Laser Photocoagulation:

This procedure uses laser to destroy the fragile, leaky blood vessels. A high energy beam of light (argon or krypton laser) is aimed directly onto the new blood vessels and destroys them, preventing further loss of vision.  Though thermal laser treatment has been shown beneficial at reducing the likelihood of developing severe visual loss, there is usually an immediate decrease in visual acuity especially in subfoveal choroidal neovascularization (CNV). A CNV membrane is described as subfoveal if any part of the lesion lies beneath the centre of the foveal avascular zone (FAZ). The concern of   subfoveal lesions is due to the fact   that photocoagulation of such a CNV membrane necessarily results in the destruction of the overlying retina.² Moreover, thermal laser is effective only in a small subgroup of patients with small, well-demarcated lesions that include a component of classic CNV. Therefore, many alternatives to laser photocoagulation are evolving mainly for subfoveal CNV.

(b)  Photodynamic Therapy (PDT):

In 2000, USFDA approved Visudyne™ (Verteporfin for injection) for the treatment of predominantly classic subfoveal choroidal neovascularization due to AMD, pathologic myopia or presumed ocular histoplasmosis. It was the first approved drug therapy for the treatment of wet AMD. Visudyne™ is injected systemically and activated by a non-thermal laser to destroy leaking vessels.³ This therapy utilizes low-intensity light exposure (689 nm, 50 J/cm² dose, for 83 s in Verteporfin PDT) which  causes selective destruction of CNV with preservation of the overlying neuro sensory retina. There are various photosensitizing agents available for treatment. However, currently only Verteporfin is approved for the treatment of CNV. ⁴ Patients who receive this therapy become temporarily photosensitive and should avoid direct sunlight for 5 days.

(c)  Anti Vascular endothelial growth factor (anti-VEGF)

VEGF is a naturally occurring large lipoprotein molecule consisting of at least 6 structurally related proteins. Studies have shown elevated VEGF levels in areas of laser induce CNV in primates and clinically in AMD patients. Macugen (Pegabtanib) was approved in 2004 to treat wet AMD, and is used solely or in combination with other AMD treatments.

The drug Lucentis (Ranibizumab) was approved by FDA for treating AMD in June 2006.  It is   a humanized antibody fragment designed to bind and inhibit the action of VEGF and thus   prevent blood vessel growth and leakage. Avastin (Bevacizumab) is a drug similar to Lucentis that is used to treat colon cancer. Ophthalmologists may prescribe Avastin off label for the treatment of AMD.

VEGF Trap is a substance that blocks the action of vascular endothelial growth factor (VEGF), and prevents the growth of new blood vessels in a tumor. It belongs to the family of drugs called angiogenesis inhibitors. Angiogenesis is the term used to describe  the proliferation of blood vessel growth.  Substances that stop the growth of excessive blood vessels are anti-angiogenic .Bayer Healthcare and Regeneron have initiated a Phase 3 study of the VEGF Trap -Eye in the neovascular form of wet AMD. ⁵

(d)  Combination therapy of Triamcinolone  and Verteporfin

Triamcinolone acetonide has been used to modify the process of choroidal neovascularization. Corticosteroids have a multitude of anti-inflammatory effects and also seem to have direct anti-angiogenic properties. Steroids have an inhibitory effect on angiogenesis, fibrotic activity and inflammatory reaction by reducing the migration and activation of inflammatory cells. Up-regulation of extracellular matrix protein plasminogen activator inhibitor by steroids results in direct angiostatic effect. Corticosteroids stabilize endothelial and basement membranes and also reduce vascular permeability with beneficial effects.

PDT provides immediate angio-occlusion of CNV and intravitreal triamcinolone acetonide (IVTA) , prevents inflammation and up-regulation of VEGF, decreases subsequent regrowth of CNV and finally improves VA outcome. This provides substantial reasons for using verteporfin and triamcinolone in combination. ^{6, 7,8}

Significant improvements in best-corrected visual acuity (VA) after 1 month and their maintenance over a 3-month period were observed after verteporfin Photodynamic therapy combined with intravitreal bevacizumab. These results should be confirmed in larger and long-term prospective randomized trials. ⁹

Alternative Therapies:

(a) Radiation Therapy:

Radiotherapy affects the evolution of exudative macular degeneration directly by endothelial toxicity, leading to capillary closure and/or indirectly through its attenuating effects on the inflammatory response, mediated by macrophages and other inflammatory cells.¹⁰ Low-dose ionizing radiation has been shown to prevent proliferation of endothelial cells of newly formed subretinal capillaries and may induce destruction of abnormal CNV tissue.

(b) Submacular Surgery:

Surgical removal of CNV   with large subfoveal hemorrhages can limit toxicity to overlying photoreceptors by prompt evacuation of blood . ¹¹ By preserving the overlying neurosensory retina it can limit visual field defect enlargement and central vision loss.

Moreover,surgery may apply to a wide range of lesions   and adjunctive procedures such as RPE transplantation. However, the risks with submacular surgery are considerable and include acceleration of cataract, development of retinal tears and retinal / choroidal detachments.

(c) Retinal translocation:

Retinal translocation and limited macular translocation are being used with rationale to move the macular area from the underlying CNV to a healthier RPE region. The Choroidal neovascular membrane can then be treated with laser photocoagulaton, while sparing the foveal center. ¹² However, there is risk of development of intractable proliferative vitreoretinopathy, total retinal detachment, and unpredictable long-term visual prognosis.

(d) Transpupillary thermotherapy (TTT):

A slit lamp delivery system is used to project a beam of diode laser on the lesion thereby causing heat transmission to RPE and choroid. Studies by Reichel et al ¹³ showed benefit   for patients with occult CNV in terms of improvement of visual acuity and decreased exudation.

Prevention:

There is evidence that dietary supplements can help prevent the onset and progression of age-related macular degeneration. Lutein and zeaxanthin is found in leafy green vegetables, corn, egg yolk, squash, broccoli and peas. These carotenoids are proposed to reduce the risk of AMD by absorbing the blue light that could damage the macula, by preventing free radicals from damaging eye cells and by strengthening eye cell membrane. ¹⁴

Undergoing Research

Research is in progress to transiently enhance vascular permeability in PDT to selectively release an anti-angiogenic or anti-inflammatory factor to prevent recurrence of  neovasculature in  case of AMD or to release chemotherapeutic agents in the case of PDT of a malignant tumour. ¹⁵

A study was done to evaluate the safety, efficacy & durability of systemic Bevacizumab therapy for neovascular ARMD. The results were good for a small group of patients however the risks associated with systemic anti-VEGF therapy versus the safety of intra vitreal therapy deters the involvement of a large number of patients. ¹⁶

Micro and nano particulates have been used primarily on a pre-clinical basis as new drug delivery devices in experimental models of neovascular AMD ¹⁷ .The development of polymeric micelles with smart functions such as environment-sensitivity and specific tissue-targetability may enhance the activity of potent bioactive compounds, facilitating their clinical applications. Also, polymeric micelles response to external stimuli, such as light, might exert the activity of the loaded compounds in a site-directed manner, ensuring the effectiveness and safety of the nanocarrier-mediated targeting therapy. Thus, polymeric micelle-based nanocarriers will continue to hold promise for the delivery of drugs and genes . ¹⁸

All types of nucleic acids have been developed for the treatment of   infectious and cell proliferative diseases affecting mostly the posterior segment of the eye. The eye is therefore a good target for this type of molecules mainly because it is a confined compartment and their delivery is close to the target site. However, to improve the efficiency of such molecules, the use of controlled and/or targeted delivery systems is needed since they allow protection against degradation, increase intracellular penetration and permit long-term delivery avoiding repeated administrations. ¹⁹

Conclusion:

Early detection of AMD can stop the progress of the disease. Patients need to be educated about the condition and consistent follow up is   required. Drug delivery to the posterior segment of the eye still remains a   challenge. Rapid pre corneal elimination, poor corneal absorption, rapid anterior chamber elimination and large diffusional path lengths combine to prevent topically administered drugs from reaching the posterior segment of the eye.

Lot of research is  being undertaken and many Pharmacophores are being investigated. A fundamental understanding of the patho physiology of AMD integrated with a mechanistic understanding of drug delivery to the posterior segment is requisite for the design of drugs and drug delivery systems for macular degeneration.

References:

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2. Beatty et al, Photocoagulation of subfoveal choroid neovascular membrane in age related macular degeneration, British Journal of Ophthalmology (83) (1999) 1103-1104.

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7.Gillies  M.  C. ,Sompson  J.  M. ,Luo  W, Penfold  P., Hunyor  A.  B.,Chua  W.,  A randomized clinical trail of a single dose of intravitreal Triamcinolone Acetonide for neovascular age-related macular degeneration: One-year results. Arch Ophthalmol (121) (2003) 667-673.

8. Jonas  J.  B.,Kreissing  I.,Hugger  P., Sauder  G , S. Panda-Jonas, Degenring  R., Intravitreal triamcinolone acetonide for exudative age-related macular degeneration, British  Journal of  Ophthalmology (87) (2003) 462-468.

9.Lazic  R., Gabric  N., Verteporfin therapy and intravitreal bevacizumab combined and alone in choroidal neovascularization due to age-related macular degeneration, Ophthalmology (114) ( 6) (2007) 1179-1185.

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About Authors:

Varun Doshi, Varsha Pradhan, Dr.(Mrs.) Bala Prabhakar

Dr. (Mrs) Bala Prabhakar is Chairperson, Head of Department & Professor in Pharmaceutics at School of Pharmacy & Technology Management, SVKM’s NMIMS University. She has 21 years of experience in teaching and administration.

She has worked with Directorate of Health Services, Andaman & Nicobar Administration, PortBlair,  Govt College , Port Blair, C.U.Shah College of Pharmacy, SNDT Women’s University and  K M Kundnani College of Pharmacy affiliated to Mumbai University.  She has guided graduate students for the award of their post graduate degree in pharmacy.  She has presented a number of research papers at national and international conferences/symposiums and published papers in research and scientific journals.  She has worked in All India Council for Technical Education, New Delhi, (on deputation) which is the apex body of the country (established under the act of parliament for controlling the coordinated development of technical education in the country) in administrative capacity in the departments of Engineering & Technology, Management, Pharmacy, Research and Institutional Development, Post Graduate Education & Research, Quality Assurance and National Board of Accreditation.

Ms. Varsha Pradhan is a professional career of 16 years in industry & academics. She has an enriching experience with top Pharmaceutical Companies at various capacities in production & research. She has to her credit several technology transfers of Pharmaceutical products. She is a faculty & is also doing her PhD from School of Pharmacy & Technology Management, SVKM’s NMIMS University.

Mr. Varun Doshi has completed his M.Pharm.