From the fundamentals of a healthy diet to the complexities of nanosecond laser technology and genetically-engineered DNA injections, science has opened our eyes to the very real possibility that wet AMD can be treated to improve visual acuity. Despite treatment for dry AMD remaining beyond our reach, the future for AMD treatment has never looked more exciting. This second part of our three-part series on AMD focuses on ‘advances in treatment of AMD’.
In days not so long gone, the ‘treatment’ of age related macular degeneration (AMD) was merely the careful documentation of declining vision, occasionally interrupted by laser therapy. With the revolution of anti-vasoendothelial growth factor agents (anti-VEGF) the goal of treatment of AMD is not only to prevent loss of vision but to actually improve acuity. This quantum leap in therapy still only applies to wet AMD. Treatment of dry AMD remains out of reach, but is the subject of many current research attempts.
All forms of mild to moderate AMD should be treated at the initial diagnosis by prescribing antioxidant supplements. The efficacy was proven in the U.S. National Eye Institute’s Age-Related Eye Disease Study (AREDS) I trial.
There are a number of preparations on the market but the product Macuvision is representative. The role of beta carotene has become increasingly controversial and that substance is not included. The subject of the AREDS II is the use of lutein/zeaxanthine in AMD. While these luteal pigments have been available for a number of years in various preparations, their efficacy has yet to be demonstrated.
The management of wet AMD has evolved enormously in the past 10 years
Clearly, cessation of smoking is crucial and there are, of course, numerous other health benefits from this behavioural change.
Importance of Diet
A diet high in leafy, green vegetables is highly recommended, including spinach, bok choy, broccoli, leek, capsicum, sweet corn, silver beet and turnip greens. Interestingly, there is emerging evidence that carrots are not beneficial. However, good quality nuts are, especially almonds, unroasted brazil nuts, walnuts and pine nuts. Fish is important to the diet and should be consumed at two meals each week, preferably with salmon in one meal. Tinned sardines and tuna are good sources of Omega 3 fatty acids.
In general, diets should be low fat with a low glycaemic index. Pan fry or grill meat and avoid all deep fried food, palm oil, and potato crisps. Use virgin olive oil for cooking.
Retinal regeneration in dry AMD, through the use of nanosecond laser treatment, is the subject of a clinical trial underway in Australia. Fourteen patients with bilateral high risk drusen have been followed for six months. At six months, the majority of patients experienced improvement in visual function and drusen reduction. Drusen decreased in 70 per cent of treated eyes and 56 per cent of non-treated eyes. Central visual function improved in 50 per cent of treated eyes and 36 per cent of non-treated eyes. In addition, retinal imaging confirmed that there was no evidence of laser damage to the photoreceptor cells. These are encouraging early results but a previous study of laser on drusen was abandoned due to an increase in conversion to wet AMD.
Course of Dry AMD
A number of agents are being investigated for their potential to influence the course of dry AMD. One is the role of ciliary neurotrophic factor (CNTF). Genetically engineered human retinal pigment epithelial cells are programmed to secrete human CNTF. These are placed in a slow release delivery system implanted into the vitreous cavity.
In a recent phase-two study involving patients with geographic atrophy, CNTF implants stabilised best corrected visual acuity at 12 months, with 96 per cent of treated-patients losing fewer than three lines of vision versus 75 per cent of the patients in the control group. Other researchers are also looking at intravitreal implants of brimonidine, a neuroprotective drug, fenretinide, a softgel oral preparation, which reduces vitamin A metabolism, and glatiramer acetate, which reduced drusen area by 50 per cent at three months in a pilot study. This is given as a weekly vaccination.
Wet AMD Management
The management of wet AMD has evolved enormously in the past 10 years. In the past, thermal laser photocoagulation of choroidal neovascular membranes (CNVM) was the mainstay of treatment in wet AMD. This is still used infrequently today for select CNVM which are remote from the fovea. Photodynamic therapy with verteporfin (Visudyne) became the treatment of choice for the large number of patients with CNVM involving the fovea. However, its benefit was relatively marginal. The anti-VEGF drugs bevacizumab (Avastin) and ranibizumab (Lucentis) became available and suddenly sub-foveal CNVM finally became treatable. Ranibizumab has been the subject of a large number of clinical trials and today it is the gold standard of therapy for wet AMD around the world.
Wet AMD is the development of fibrovascular membranes under the retina/retinal pigment epithelium in the macula. These membranes disrupt the function of photoreceptors by a wide variety of mechanisms. The anti-VEGF drugs act by reducing the formation of the membranes and their attendant leakage and bleeding. They work by directly binding to VEGF secreted in the eye and thus block its action on capillaries. Ranibizumab is given as an injection into the vitreous cavity. This procedure is normally done in the office with local anaesthetic to numb the conjunctiva and episclera. A volume of 0.05ml is given and typically a single injection has a half-life of about a month. For this reason, the injections need to be repeated at regular intervals.
The large studies found that the best visual outcomes were obtained by monthly injections but, naturally, this becomes burdensome for both the patients and the doctors. Thus many studies have looked at alternative dosing schedules. Currently the following facts are accepted. Firstly, monthly dosing is the gold standard. Secondly, cessation of therapy will eventually result in a recurrence of neovascularisation and loss of all visual gains. Thirdly, treatment intervals may be cautiously extended once the neovascular membrane has stabilised. The maximal interval is probably only three months. Fourthly, for many patients, treatment with Lucentis is likely to be indefinite. Finally, while it is the subject of a trial currently in progress, Avastin which is being used effectively to treat different forms of cancer, is probably just as effective as Lucentis for wet AMD.
Apart from the logistics and expense associated with intensive treatment such as outlined above, there are a number of other issues. There is a small but definite risk of infective endophthlamitis associated with each injection. Postoperative topical antibiotics are normal protocol.
Another possible complication is damage to intraocular structures by the needle. Traumatic cataract due to needle contact, retinal tear or even retinal detachment are possible sequelae. One hazard that occasionally arises is occlusion of the central retinal artery by high pressure induced by the volume load. Normally the surgeon checks that the artery is patent after the injection. If the artery is occluded, then fluid can be drained from the anterior chamber to normalise pressure.
Perhaps the main problem with the injections is the relatively common occurrence of corneal epithelial toxicity from the Betadine antiseptic fluid used immediately prior to injection. This typically causes quite severe eye pain between four and six hours after an injection. The corneal epithelium develops severe punctate erosions, not dissimilar to a welding arc exposure. To reduce the incidence of this problem, it is important to thoroughly lavage the eye once the injection has been given.
The results of treatment have been very good. Most people respond to ranibizumab and maintenance of normal acuity is achievable. The other parameter used to monitor the outcome of treatment is central retinal thickness as measured by OCT scanning. The original study showed the treated subjects gained on average six letters of acuity compared to controls, who lost 15 letters at two years. Forty per cent of treated patients had 6/12 acuity at one year, compared to 11 per cent of controls.
The surgical approaches to wet AMD have almost all been discarded. Subretinal excision of neovascular membranes is rarely done. Macular translocation surgery had a very high complication rate. Occasionally, intravitreal injections of clot-lysing agents such as plasminogen, combined with gas can be used to displace large haemorrhages away from the macula.
An Exciting Future
While ranibizumab is widely used, there are a number of other agents being studied. The use of VEGF-trap, focal radiotherapy, proton beam irradiation, combination therapies, genetically-engineered DNA injections, pegaptanib, squalamine, tyrosine kinase inhibitors, and bevasirinib, to name but a few. Most exciting is the prospect of topical eyedrop therapy for wet AMD. ATG-3 (mecamylamine, CoMentis) has antiangiogenic function. OC-10X (Ocucure) has both antangiogenic and angiolytic activity. Watch this space.
For further information on AMD contact the Macular Degeneration Foundation on (AUS) 1800 111 709 or go to www.mdfoundation.com.au.
Dr. David McKay trained at the Sydney Eye Hospital before graduating with the Fellowship of the RoyalAustralian College of Ophthalmologists in 1988. He undertook further training in surgery and diseases of the retina at the Lions’ Eye Institute in Perth, WA before working in the U.S.A. in ocular oncology with Professor Jerry Shields. David returned to Sydney in 1991. He is in private practice in Macquarie St Sydney, Concord Hospital Medical Centre, and in Bathurst and Orange.