Year : 2000 | Volume
: 48 | Issue : 4 | Page : 263--78
New approaches in the management of choroidal neovascular membrane in age-related macular degeneration.
L Verma, T Das, S Binder, WJ Heriot, B Kirchhof, P Venkatesh, I Krebs, U Stolba, C Jahn, H Feichtinger, L Kellner, H Krugluger, I Pawelka, U Frohner, A Kruger, W Li, HK Tewari
R.P Centre for Ophthalmic Sciences, AIIMS, New Delhi, India
R.P Centre for Ophthalmic Sciences, AIIMS, New Delhi
Age-related macular degeneration (AMD) is a leading cause of blindness in the elderly population. The prevalence is reported to be 1.2-1.4% in several population-based epidemiological studies. Currently 25-30 million people worldwide are blind due to AMD. With the aging world population it is bound to increase significantly, and could become a significant public health problem in next two decades, with serious socio-economic implications. Several strategies are today available to treat the wet form of AMD, which is responsible for significant visual loss. These were until recently confined to laser photocoagulation, and subretinal surgery, but today two other modalities, namely, radiation and photodynamic therapy, are available. These treatment modalities however, are aimed at preservation of vision only, and not at reversing the process of the disease. Further research on antiangiogenic drugs and gene therapy could significantly help AMD patients.
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Verma L, Das T, Binder S, Heriot W J, Kirchhof B, Venkatesh P, Krebs I, Stolba U, Jahn C, Feichtinger H, Kellner L, Krugluger H, Pawelka I, Frohner U, Kruger A, Li W, Tewari H K. New approaches in the management of choroidal neovascular membrane in age-related macular degeneration. Indian J Ophthalmol 2000;48:263-78
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Verma L, Das T, Binder S, Heriot W J, Kirchhof B, Venkatesh P, Krebs I, Stolba U, Jahn C, Feichtinger H, Kellner L, Krugluger H, Pawelka I, Frohner U, Kruger A, Li W, Tewari H K. New approaches in the management of choroidal neovascular membrane in age-related macular degeneration. Indian J Ophthalmol [serial online] 2000 [cited 2022 Aug 8 ];48:263-78
Available from: https://www.ijo.in/text.asp?2000/48/4/263/14844
Age-related macular degeneration (AMD) is a degenerative disorder affecting the macula. Clinically this is characterized by large soft drusen, pigmentary abnormalities of the retina and retinal pigment epithelium (RPE) in the early stages, and by geographic atrophy, choroidal neovascularization (CNV), pigment epithelial detachment (PED), and fibrous scarring of the macula in the late stages. While there may not be measurable visual loss in early AMD (modest visual loss detected by psychophysical and electrophysiologic testing), late AMD is associated with moderate to severe visual loss. Geographic atrophy is considered to be the dry form of AMD, and the CNV, PED, and disciform scar are the wet form of AMD.
Visual loss due to age-related macular degeneration is a significant cause of posterior segment blindness and is presently not preventable. 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. In the last few years renewed efforts have been made to evolve a more rewarding treatment modality for this disease, which is a major cause of blindness in the aging population. This communication reviews the recent developments in treatment of AMD and looks at future directions in research. We also briefly review the current state of knowledge of AMD, with particular reference to epidemiology, natural history, and clinically established treatment methods of AMD and associated CNV.
Three population-based studies-the Beaver Dam Eye Study (USA), the Blue Mountain Eye Study (Australia), and the Rotterdam Study (The Netherlands)-have addressed the prevalence of late AMD in the respective populations. Utilising a similar standard protocol of objective grading using colour fundus photographs, the prevalence of AMD was 1.7% (1.2% exudative; 0.5% geographic atrophy) in the Beaver Dam study, 1.4% in the Blue Mountain study, and 1.2% in the Rotterdam Eye study. Similar population-based studies are not available in India and other Asian countries. The prevalence of AMD in the south Indian population over 70 years is estimated to be 1.1%. Apart from advancing age, the probable risk factors include gender (women are more at risk), cigarette smoking, hypertension, and dyslipedimia. In most studies Caucasians have been found to be more at risk. A prevalence of 1% or less is reported in many population-based studies involving black races.[6-8] The racial difference in late AMD has been attributed to the possible protective effect of melanin pigments. It is probable that melanin acts as a free radical scavenger, protecting the outer layers of the retina and the inner layers of the choroid from degenerative changps.
Clinically AMD is characterised by the presence of drusen, RPE abnormalities, CNV, PED, geographic atrophy, and disciform scar. Presence of drusen and RPE abnormalities together represent the early stage of AMD, with the other characteristics representing the late stage of AMD. The neovascular component of AMD consists of CNV and PED. The geographic atrophy and disciform scar are the terminal stage of the disease process.
Drusen are extracellular deposits that lie between the basement membrane of the RPE and the inner collagenous zone of Bruch's membrane. They represent lipidization of a few RPE cells or localized deposits of an eosinophilic material within Bruch's membrane with overlying hypopigmentation or atrophy of the RPE. Clinically drusen vary considerably in size, shape, number, colour, distinctness of borders and elevation. Several varieties of drusen are described; two varieties - hard and soft -are quite apparent ophthalmoscopically and the soft drusen have a distinct relation with wet AMD.[12,13]
Geographic atrophy is ophthalmoscopically characterized by a large (> 175 μ) well demarcated hypopigmented patch over the macular area; choroidal vessels are often apparent in this lesion.
Choroidal neovascularization (CNV) is growth of new choroidal vessels into the subretinal space through breaks in the Bruch's membrane. Ophthalmoscopically the CNV appears as a greenish-gray lesion, often with a detachment of sensory retina, subretinal blood, and exudates. CNVs are classified into the classic, and occult variety based on characteristics of fluorescein angiography. An area of hyperfluorescence with well demarcated borders in the early phase (a lacy network of vessels with classical sea-fan or cartwheel pattern), and progressive dye leakage obscuring the boundaries of CNV in the late phase of angiography characterizes a classic CNV. Two varieties of occult CNV described by the Macular Photocoagulation Study (MPS) include (a) fibrovascular pigment epithelial detachment, and (b) late leakage of the fluorescein dye from an undetermined source. The number of sources of CNV varies; up to 90% of them have one to three sources. The occult CNVs are best imaged with indocyanine green (ICG) angiography. Three ICG angiographic features are described in occult CNVs; they are: focal spots, plaques, and the combination The reported incidences of these imaging features are 29%, 61%, and 8% respectively.
Based on anatomic location in relation to the foveola, the CNVs are classified as extrafoveal, juxtafovaeal, and subfoveal. Extrafoveal CNV are at or beyond 200μ from the foveola; juxtafovaeal CNVs are within 200μ of the foveola; and subfoveal CNVs are at the foveola [Figure:1]. Both fluorescein angiograterphic character and location of the CNV influence the treatment modality and the outcome.
Serous detachment of RPE, unrelated to CNV, typically appears as a round or oval, yellow or yellow-orange, sharply demarcated elevated mound of RPE on ophthalmoscopy. On fluorescein angiography, a sharply demarcated area of uniform fluorescence develops rapidly under the dome of the PED, and there is persistent staining in the later phases of the angiography. Occult CNV may be responsible for serous detachment of RPE, and bleeding from the CNV could also cause haemorrhagic detachment.
Disciform scar is the end result of CNV replacing the outer sensory retina and the RPE. The process of choroidal neovascularisation is complex and includes an interplay of several factors such as metabolic and mechanical factors released from the tissues and vessel walls, physical and chemical properties of extravascular matrix, pericyte-endothelial interaction and finally, influence of various peptide-signaling molecules.
Two treatment modalities, laser photocoagulation, and subretinal surgery are currently used to treat CNV in AMD. One large multicentre randomized treatment trial, the Macular Photocoagulation Study (MPS), and one multicentric pilot trial, the Subretinal Surgery Trial (SST), have addressed these treatment strategies from a scientific perspective.
Focal photocoagulation is indicated for well defined extrafoveal, juxtafoveal, and selected subfoveal CNVs. The primary goal of photocoagulation is complete obliteration of the CNV complex with confluent burns of intensities sufficient for vessel closure, and the desired end point is a uniform whitening of the overlying retina. The treatment parameters of extra, juxta and subfoveal membrane are outlined in [Table:1]. Recurrent membranes are treated with similar laser parameters, used for extra, juxta, and subfoveal membranes, but the treatment should extend 300μ into the previous treatment scar. Further, it should include treatment of feeder vessel, if present.
Topical anaesthesia is often adequate unless the patient is extremely sensitive. In subfoveal lesions peribulbar or retrobulbar anaesthesia is preferred to stabilise the globe. Alternately, pressure against the globe applied through the hand-held contact lens could be equally useful. The additional benefit of this moderate pressure is that the blood flow through the membrane may be slowed down enough to allow more efficient absorption of laser energy, and greater destruction of the neovascular complex. In all probability the wavelength specificity for laser photocoagulation of the CNV is not as critical as the completeness of treatment. Argon green laser (514 nm) is the wavelength recommended by MPS. Diode infrared laser can be of advantage when the membrane is covered by a thin layer of haemorrhage.
Pre-treatment preparation includes a thorough clinical examination including stereo biomicroscopy, a good quality fluorescein angiography, and fundus photography. Stereo fundus photography and angiography have added advantages, and ICG angiography is sometimes useful. However, the most useful and often practical approach is a colour coded drawing of the lesion traced on a clear acetate overlay obtained from an appropriate fluorescein angiogram. The drawing is repeated to evaluate the completeness of treatment and also to treat recurrent neovascular lesions. The angiography should not be older than 72-96 hours. Several studies have shown that the average rate of growth of neovascular membrane is 5-10μ per day, and hence a serious error of judgement could occur with a delay of more than four days.
Post-treatment care consists of avoiding oral aspirin and lifting of heavy weights till the neovascular membrane is completely regressed. The follow-up visits are scheduled at 6 weeks, 12 weeks, and thereafter at an interval of 3 to 6 months. It is essential that fluorescein angiograms be repeated at all the visits in the first year of treatment since most recurrences occur during this period, and thereafter whenever recurrence is clinically suspected.
While the laser photocoagulation of CNV in AMD is currently the mainstay of treatment, it has several limitations: (a) only a minority of patients with exudative AMD meet strict MPS criteria; (b) majority of patients with subfoveal CNV do not benefit from laser photocoagulation; and (c) nearly half of the patients in the MPS had persistent or recurrent new vessels.[26-28]
Briefly, the surgery for CNV in AMD consists of complete vitrectomy including removal of the posterior hyaloid; a small temporal retinotomy is made as close as possible to the subretinal neovascular complex with a subretinal pick; a small bolus of balanced salt solution is injected beneath the retina; the membrane is stroked from side to side to release it from its attachments; subretinal forceps are used to grab the membrane and slowly pull it out while the height of the infusion bottle is increased to raise the intraocular pressure and control intraoperative bleeding.
Subretinal surgery is still an evolving technique. Since the first conceptual publication several changes have been made in the surgical technique and instrumentation to achieve better anatomical and functional results. The changes include reducing the retinotomy size, design of finer instruments and other innovations such as subretinal endophotocoagulation and autologous iris pigment transplantation. It has also been realised that the numerous pre- and sub-RPE attachments of the neovascular complex in AMD in contrast to the neovascular complex in ocular histoplasmosis, increase risk of damage to the underlying RPE thereby resulting in poorer visual outcome.
Several new modalities of treatment are under investigation. While clinical experience in some of these new modalities is limited, many of them hold a great deal of promise. Some of these methods are radiation therapy, photodynamic therapy, macular rotation surgery, and retinal transplantation. Antiangiogenic compounds, micronutrients, and gene therapy have also been explored either for treatment of or prophylaxis against CNV in AMD.
Radiation therapy has been proposed as an alternative treatment for exudative AMD because of the known radiosensitivity of vascular endothelial cells. Ionizing radiation is used in neoplasia to inhibit cellular proliferation and is particularly lethal for rapidly dividing cells. In-vitro studies have indicated that proliferating endothelium is particularly radiosensitive. Though the mechanism of radiation therapy as an antiangiogenic agent is unclear, it has been shown that a single radiation of 5 Gy was sufficient to arrest 99% of cultured retinal endothelial cells. (Chakravarthy U, McQuaid M. Radiosensitivity of retinal capillary endothelial cells and pericytes. Paper presented at Association Eye Research Meeting, Montpelier, 1989.) In-vivo experiments in rats have shown that the rod photoreceptors are most radiosensitive; cell death does not seem to occur at doses less than 10 Gy; and with a single large dose of 15-20 Gy there is capillary closure.[33,34] Animal models have also demonstrated choriocapillaries occlusion with sparing of larger choroidal vessels.
Two different techniques are currently used for medical radiation. They are teletherapy and brachytherapy. Teletherapy [also called external beam radiotherapy (EBRT)] refers to delivery of radiation from a distance. The linear accelerator is the most commonly used device for EBRT. Brachytherapy refers to the use of sealed radioactive material to deliver the radiation at a short distance; plaque brachytherapy uses isotopes to deliver radiation to a small field. EBRT may expose the surrounding ocular tissues to radiation toxicity if precise care is not taken to accurately focus on the target tissue. Plaque brachytherapy may require surgical exploration of the site, suturing of the requisite size of the plaque, and its removal. Currently both EBRT and plaque brachytherapy are being explored to deliver radiation for AMD. However, EBRT is the most commonly used approach.
The treatment essentially involves both the ophthalmologist and radiologist. After a thorough ophthalmic examination, the radiotherapist examines the patient. Simulation and custom design face-masks are crucial in ensuring the safety of the procedure. A computed tomogram (CT scan) of the patient's head in the treatment position (treatment is given in supine position) with the head-positioning device is used for small field treatment target localization. The total radiation dose is fractionated into several small fractions and delivered over a number of days.
There are several non-randomized[36-41] and a few randomized[42,43] clinical trials studying the treatment of classic, occult, or mixed subfoveal CNVs, showing both beneficial[36-39,42] and no-beneficial[38-40,43] effects. While it is beyond the scope of this article to review each of these treatment modalities, it is clear that the published results are not conclusive enough to currently recommend radiotherapy in AMD outside the protocol of experimental treatment. A randomized controlled clinical trial is necessary to determine if a therapeutic window exists.
Photodynamic therapy (PDT) relies on photochemical injury to the vessel wall and selective damage to the target tissue while sparing the adjacent normal tissue. Since photocoagulation ablates both the CNV and the overlying neural retinal tissue, PDT could offer an effective therapeutic alternative. It involves the use of photoactivable compound (photosensitizer), which accumulates in, and is retained by, proliferating tissues. When this molecule is activated by light of appropriate wavelength, active forms of oxygen and free radicals are generated, causing photochemical damage to the cells. Photodynamic therapy has been tried in extraocular malignancies with encouraging results.
Photodynamic therapy essentially requires two components - the photosensitizer that accumulates in the neovascular tissue, and a specific laser light corresponding to the absorption peak of the dye. Several chemical compounds are tested as photosensitizing agents in treatment of CNV. They are Benzoporphyrin derivative[45,46] (BPD- Verteporfin; Ciba Vision AG, Balateh, Switzerland & QLT Phototheraputics, Vancouver, Canada); Tin ethyl etiopuritin[47,48] (SnET2- Purlytin; Miravant, Santa Barbara, USA.), and Lutetiumtexaphyrin (Lu-tex; Alcon Laboratories, Fort Worth, Tx, USA). The light characteristics required to sensitize these compounds are 690 nm for BPD, and 664 ran for SnET2 and 732 run for Lu-tex [Table:2].
In PDT photochemical reaction ensues when the photosensitizer molecule in the ground state is excited to a higher energy triplet state following light absorption. The triplet state molecules are short lived. They transfer their energies via two pathways to cause cytotoxicity; these are (a) free radical mechanism to form cytotoxic intermediates (Type I reaction), and (b) conversion to singlet oxygen (Type II reaction). The released free radicals and singlet oxygen either alone or together damage the neovascular complex possibly by three mechanisms-cellular, vascular, and immunologic.
Photodynamic therapy requires two steps. First the photosensitizing dye is injected, and second, a specific wavelength of light is shown over a fixed spot for a predetermined time. To avoid photosensitization of other parts of the body the patients are required to avoid bright light including sunlight for a day or two to weeks depending on the clearance of the dye.
In the TAP (Treatment of AMD with Photodyanamic therapy) study using verteporfin a diode laser at 690 nm with a slitlamp delivery system was designed to deliver 60 J/cm2 at an intensity of 600 mW/cm2 over 83 seconds. Verteporfin at a dose of 6 mg /m2 body surface area (30 ml solution) was injected intravenously over a period of 10 minutes, and five minutes after completion of infusion the laser light was beamed for 83 seconds to the CNV lesion. The treatment spot size was the greatest linear diameter (GLD) of the entire CNV lesion plus an addition of 1000μm (500 μm margin for additional treatment around the lesion). Retreatments were done using similar parameters after 3 months in eyes for recurrent CNVs after thorough clinical and fluorescein angiographic evaluation.
In phase I and II PhotoPoint trial using SnET2 dye 0.5-0.75 mg/kg of the dye and 664 nm low power diode laser was used to deliver a light dose of 36 J/ cm2. The dye was injected as an intravenous infusion, followed by a large spot application of laser light for 60 seconds. The spot size calculations was similar to the measurements used in the TAP study. Phase I and II human clinical trials using Lu-tex have been completed in Europe, and further studies are underway in the United States.
The clinical experience of PDT is largely available for BPD. The one year results of TAP study is published. The initial report has demonstrated PDT is followed by early closure of CNV secondary to AMD, reduction in macular oedema and exudation resulting in stabilization, and even limited improvement of vision [Figure:2]. However, recurrences are common and hence repeat treatment is necessary. This treatment modality is currently being extended to other forms of CNV.
Macular rotation surgery
Since the pathogenesis of AMD is not yet known it seems justified to replace the diseased submacular RPE either by transplantation of pigment cells or by relocation of the fovea to an adjacent area of intact RPE and choriocapillaries.
In 1993 Machemer and Steinhorst suggested macular translocation to relocate the fovea on the intact RPE. The retina was detached by trans-scleral subretinal injection of fluid, followed by a 360° peripheral retinotomy. The retina was then rotated around the optic disc under silicone oil for 10-45°. In recent years many other surgeons have developed techniques for producing macular translocation. Wolf et al[51,52] use intraoperative perfluorinated and semifluorinated liquid fluorocarbons to facilitate retinal translocation and retinal reattachment. Eckardt et al supplement retinal translocation with counter rotation of the whole eye by extraocular muscle surgery. Strabismus surgery consists of partial transposition of all four recti muscles and folding and retropositioning of the oblique muscles. Counter-rotation of the globe is performed at the time of macular translocation; alternately, counter-rotation can be postponed to the time of silicone oil removal. The two-step approach aims to limit the postoperative inflammatory response of the anterior segment such as synaechiae formation and ischaemia. Ninomiya et al confine the retinal translocation to a temporal retinal flap, thereby reducing the extent of retinotomy to 180° de Juan and later Lewis replaced retinotomy with scleral shortening. In their technique the temporal half of the retina is detached by transretinal injection of balanced salt solution (BSS) into the subretinal space using a 39-gauge flexible needle. The superior temporal sclera is then shortened either by means of pre-placed mattress sutures (de Juan) or by special clips (Lewis). Finally fluid gas exchange and positioning of the patient from the supine intraoperative position via the temporal side to the upright postoperative position slides the fovea downward by 350-1500 μ. The extent of translocation is less in myopic than in emmetropic eyes. Limited translocation allows shift of primary subfoveal CNV to the adjacent extrafoveal site; thus following surgery the membrane is amenable to conventional laser photocoagulation in early postoperative period. Fujikado et al recommend removal of the CNV at the time of limited macular translocation.
Visual acuity. Postoperative recovery is gradual and usually it takes 6-12 months to reach the maximum visual acuity. In general, vision improves more than 2 lines in one-third eyes, decreases by more than 2 lines in another one-third eyes and vision gets stabilized in the remaining patients.[53,54] Functional prognosis seems to be independent of the type of translocation, but appears to depend on the initial visual acuity. It appears that the reading vision can be improved or maintained only when surgery is performed within 4 months of loss of reading vision (Eckardt, personal communication). The current aim of macular translocation is to preserve or regain reading vision.
Tilted image. The angle of translocation may be as little as 10-15° following limited translocation, but cyclotropia can occur up to 50° or more after 360° retinotomy. The small angle of limited macular translocation is likely to be compensated spontaneously; but the tilted vision from higher angles of rotation regresses over 3-6 months. Since the axis of retinal rotation (optic disc) differs from the axis of counter rotation of the eye (visual axis), strabismus surgery can not fully compensate for diplopia. Therefore, the indication for Machemer type of macular rotation is currently confined to "one eyed" individuals.
Proliferative Vitreoretinopathy (PVR). Besides the long operating time of 2-4 hours, postoperative PVR is the main concern in these elderly patients with AMD. The rate of PVR was as high as 30% in the earlier series of Wolf et al and Eckardt et al. de Juan and Lewis believe that the larger area of RPE exposure to the vitreous cavity as well as intraoperative seeding of the RPE cells were significant risk factors for preretinal membrane formation. Consequently, limited translocation avoided retinotomy all together. The rate of PVR after limited translocation is around 4% (+10% incidence of retinal detachment). Alternately, the surgeons who prefer the 360° retinotomy type of translocation attribute retinal trauma as the main cause of PVR. Retinal injury occurs during retinotomies and stretching-pulling of retina in the initial steps of inducing retinal detachment in translocation surgery. Less traumatic means of induction of retinal detachment have been tested. A few are described here.
Number and size of retinal perforations for transretinal fluid injection are reduced and the new flexible 39-gauge needle causes little damage to the retina.
A chandelier light allows bimanual manipulation in the eye. The retina can simultaneously be pulled and brushed off the RPE. Flute needle drainage of the vitreous cavity at time of subretinal fluid injection avoids increase in intraocular pressure and risk of retinal incarceration into the sclerotomy sites or the infusion port.
Mg+ and Ca+ free vitrectomy infusion fluid weakens the static retinal attachment factor; thus retinal manupulation can be less forceful, less time consuming and more efficient. Mg+ and Ca+ are a prerequisites for cell to cell attachment. In an environment free of Ca+, Mg+, RPE micro villi retract and interdigitations between RPE and photoreceptors open up.
Recurrence of subfoveal CNV. The rate of CNV recurrence is reported up to in 10% of eyes[52,53] following the Machemer type of translocation. CNV recurrence following "limited rotation" is equally common. Philipps has noted a recurrence rate of 48% of eyes by nine months following limited translocation. This high rate of recurrence argues against limited translocation, because recurrent CNV being nearly always subfoveal compromises surgical success. Recurrent CNVs are usually of a classic type, located in juxtafoveal region; hence they may be promising to retreat by photodynamic therapy. The CNVs following the Machemer type of translocation can usually be treated by conventional laser therapy. Eckardt et al recommend rotation of the retina to an extent that the fovea is overlapped by at least one disc diameter of intact RPE at its new location. This safety margin leaves sufficient space for eventual laser photocoagulation [Figure:3]. The high risk of CNV recurrence with limited translocation is possibly related to small CNVs. The capillary network is most dense under the fovea. Destruction of small CNV leaves behind a more dense rim of capillaries and neovascular component compared to destruction of large CNV.
Late macular oedema. Macular oedema is a major complication of the Machemer type of translocation. Its pathogenesis is not clearly understood. It is found in 10-60% of eyes.[52,53] It appears weeks to months after surgery and significantly reduces visual acuity. The fluorescein angiography appears as diffuse or cystoid macular oedema, or as a stippled area of deep foveal leakage [Figure:4]. It does not respond to oral corticosteroids and spontaneous regression is rare. Macular oedema does not seem to be a major problem with limited translocation; thus it is speculated that the pathogenesis of late macular oedema could be related to the extensive translocation procedures, to extensive surgery and / or to the larger rotation of the retina.
Ocular hypotony. Ocular hypotony occurs in about 30% of eyes. This complication is confined to the Machemer type translocation. Although none of the eyes usually progress to phthisis bulbi, intraocular pressure could be as low as 5-7 mm Hg. The mechanism of hypotony is unclear. Possibly resection of peripheral 360° retina increases the facility of posterior aqueous out flow to the choroid. A more peripheral scissors retinotomy instead of the vitreous cutter assisted retinotomy may help to overcome this problem.
The RPE transplantation aims to replace the sick cells in the macular region which have lost their junctions and adhesive matrix with the healthy cells. This ideally would lead to restoration of the foveal area and vision. In animal models three different techniques have been developed during the last 15 years, which have been tried clinically.
Turner and Blair transplanted fragments of embryonic retina into the sub retinal space. The formation of rosettes was described, but it was also demonstrated that parts of the transplanted retina could survive longer. However, most of the tissue lost its organization and degenerated after 4-5 months, del Cerro et al used a suspension of enzymatically dissolved retinal cells for subretinal transplants. These transplants showed a lower degree of organization than the fragments, but it was shown that they could restore function in the animal model. Later it was successfully shown in patients with retinitis pigmentosa. Silvermann and Huges developed a transplant of gelatine-embedded photoreceptors, where the other layers were shaved off with a vibratome. Primarily good results were obtained, but reproducibility was difficult. In human eyes the safety of this technique was confirmed, but no functional improvement was demonstrated.
These experiments established the superiority of embryonic tissue, good differentiation of embryonic transplants and absence of an acute immune reaction. They, however, also left many unanswered questions about transplant morphology, long-term survival and host-recipient interaction. The future of retinal transplantation will clearly depend on proven long lasting clinical success.
Immunologic aspects of retinal transplants
The anterior chamber and the subretinal space of the eye represent relatively immunologic privileged sites; however, this privilege is not absolute, and immune reactions do occur. In foetal RPE transplants in human eyes Algvere et al found no visual improvement, presumably due to a delayed immune reaction.
To avoid immune reaction autologous material was considered for transplantation, thereby gaining some therapeutic benefit. One disadvantage in autologous transplantation is that aged cells carrying the same genetic information are used. However, one could propose that cells relatively better preserved and transplanted into a different environment might behave and develop differently. The possible pigmented autologous materials are iris pigment epithelial cells (IPE)[68-71] and the RPE cells. IPE cells have the ability to digest photoreceptor outer segments, and can also delay photoreceptor degeneration in the RCS rat.[72,73] Whether they also possess this ability in a situation where the host RPE is degenerated is unclear. Recent experimental work has shown that the ability of IPE to digest photoreceptor outer segments is slower than the RPE.
IPE Transplantation. IPE cell transplantation was first introduced by Gelance et al[68,69] in 1993 and is now performed by different groups in Europe and Japan. IPE transplantation is done as one or two-step surgery. In one-step surgery the IPE is harvested from one or two basal iridectomies at the beginning of surgery, and re-injected into the subretinal space in 20% serum at the end of vitrectomy. In this technique 20,000-50,000 cells with a viability of 70-80% are injected. In two-step surgery IPE cells are harvested through an iridectomy; these cells are cultured until their optimal number is reached without losing their characteristics. After a few weeks they are reinjected into the subretinal space close to the macula, following vitrectomy and removal of the neovascular membrane. In this technique 20, 000 - 200,000 cells are injected.
RPE Transplantation. In autologous RPE cells transplantation, the cells are harvested from the nasal retina. This site is chosen because a retinotomy at this site is less likely to cause a retinal detachment and can be tamponated easily with a gas bubble. It was also demonstrated that the RPE is denser in the nasal quadrant than in the other three quadrants and that morphologically the cells are similar to the central retina. Drusen are rarely present in the nasal retina and autofluorescence as an indicator of lipofuscin deposition is mainly observed between the temporal great vascular arcades in AMD patients.
After vitrectomy is completed, the posterior hyaloid is removed by active suction over the disc. A retinotomy is performed supertemporal to the membrane; hydrodissection of the neovascular membrane is done before it is removed very slowly with the subretinal forceps under elevated intraocular pressure to avoid bleeding. The intraocular pressure is then lowered and a second retinotomy performed nasal to the optic disc. A shallow retinal detachment is created by subretinal injection of BSS. With a blunt instrument the RPE cells are gently mobilised over an area of 3-5 disc diameters, taking care to avoid any bleeding. Then the cells are aspirated with a micro-pipette connected to a tuberculin syringe and two thirds of the harvested RPE cells are immediately injected very slowly via the first retinotomy used for removal of neovascular membrane. The remaining one-third of the RPE cells in the syringe are sent for cell count and vitality studies. If the RPE cell harvest is low, the procedure is repeated, so that between 2,000 and 4,000 RPE cells are transplanted. An air or gas bubble at the end of surgery serves as a tamponade for the two retinotomies. The patient is positioned in a prone posture for next few days. The surgery is often combined with cataract surgery (phacoemulsification and acrylic posterior chamber lens implantation) if there are signs of cataract or the patient is 75 years or above.
The clinical experience of both IPE and autologous RPE transplantation have been limited to exudative AMD only. Marginal improvement in visual acuity is reported following cultured IPE transplantation.
Our experience (Binder et al) is limited to autologous RPE transplants. Since January 1999 we have operated 28 eyes of 27 patients (at the time of reporting). The transplant cells varied from 2,000 to 10,000 RPE cells. A minimal follow up of 6 months is now available in 12 cases.
Inclusion criteria for the study were:
Age: 45 - 85 years
CNVM: subfoveal classic and/or occult not suitable for photocoagulation by MPS criteria.[26-28]
Documented rapid growth in last 3-9 months.
Fellow eye: some form of AMD.
Consent to participate.
Exclusion criteria were:
Presence of other retinopathies, chronic glaucoma or optic atrophy of any aetiology
Patient suffering from a severe general disease
Patient under cytostatic or immune suppressive therapy
Refusal to participate.
Pre-and postoperative examinations included best corrected visual acuity for distance and near, biomicroscopy of the anterior and posterior segment, applanation tonometry, FFA and ICG, autofluorescence, scotometry and fixation tests (SLO). Multifocal ERG and OCT examinations are currently done from January 2000.
The surgery was uneventful in all cases. Postoperatively a slight intravitreal haemorrhage occurred in 2 eyes, intravitreal haze and flare of the anterior chamber in 3 eyes and transient elevated IOP in 3 eyes. After a minimal follow up of 6 months and a maximum of 13 months (median: 8.9 months) distant visual acuity improved by more than 2 lines in 5 eyes; the corresponding near vision was J1, J3, J4 in one eye each and J8 in two eyes. In four eyes there was only one line improvement and in three eyes vision remained unchanged [Table:3]. During follow up there was no increase in size of the atrophic area on fluorescein angiography and ICG demonstrated further loss of the choriocapillaries - choroidal complex [Figure:5][Figure:6].
Recurrent membrane was not observed till the time of reporting in these eyes, but slight fibrotic alterations occurred in some cases. Autofluorescene[78,79] was observed in the transplanted area in some cases.
Central fixation was present in the 3 eyes with good reading ability, and extra foveal fixation was present in 6 other cases. On multifocal ERG improvement of function could be demonstrated in most of the cases after one month [Figure:7] but the period of observation is too short to arrive at a final conclusion.
tPA in submacular haemorrhage in AMD-CNV
Extensive submacular haemorrhage, one of the worst complications of AMD, creates a large central scotoma and poor visual acuity.[80-84] Initial attempts to remove submacular blood involved vitrectomy, retinotomy and mechanical removal of the formed clot with intravitreal forceps. Injection of tissue plasminogen activator (tPA) into the subretinal space to lyse the clot facilitated aspiration, but the tPA took as long as 45 minutes to achieve lysis and often the remaining clot necessitated forceps extraction.[87-90] Surgical complications, notably retinal detachment with proliferative vitreo-retinopathy, were relatively frequent and significant.[90,91] The benefit of surgery was limited because most patients remained legally blind due to the causal macular pathology. In management of AMD any treatment given should have a low risk and be easily tolerated by elderly patients given the limited visual benefit of intervention.
A simple technique that significantly reduces the complication rate while effectively removing the blood from the macula is pneumatic displacement of liquid subretinal blood. The technique is similar to pneumatic retinopexy. The original concept was based on two clinical observations: (a) that intravitreal injection of tPA (without direct injection into the subretinal space) appears to liquefy subretinal blood, together with (b) my (WJH) clinical observation that liquid blood in the subretinal space is often displaced inferiorly by intravitreal gas. The combination of intravitreal injection of tPA and a gas bubble displaces liquefied blood away from the macula. The original tPA dosage selected was 100 μg for a concentration of 25 μg/ml but cases of probable toxicity (from the arginine buffer) have been observed. Many surgeons now prefer to inject a total dose of 25-33 μg.[95-100] Effective displacement of subretinal blood with a gas bubble alone has also been reported in fresh hemorrhages.[101-103]
The original technique was based on standard protocol for intravitreal injection, for example the, pneumatic retinopexy. This included
- Topical Benoxinate and retrobulbar or subconjunctival 2% lidocaine anaesthesia,
- Irrigation of the conjunctival sac with 5% Povidone iodine,
- Anterior chamber (AC) paracentesis.
- During the paracentesis, the eye is compressed gradually with a sterile cotton bud on the nasal conjunctiva and the pressure maintained after the needle has been removed.
- Intravitreal injection of 25-100 μg in 0.1 ml of tPA (slowly) followed by a separate intravitreal injection of 0.3 ml of either SF6 or C3F8 as compression with the cotton bud is released.
- Both intravitreal injection are 4 mm posterior to the limbus into the mid-vitreous cavity with 30 g needles.
- The optic nerve head is then examined by an indirect ophthalmoscope to assess ocular perfusion
- If necessary, another paracentesis is performed after 5 minutes
- Antibiotic ointment is applied followed by a sterile pad and the patient is allowed to go home. The patient is instructed not to adopt any specific position for 6-12 hours but then to look face down that evening and all the following day.
- The patient is reviewed 48 hours post injection
- Fluorescein angioraphy is performed if a potentially treatable lesion is ophthalmoscopically visualised.
Since the initial six cases presented (Heriot WJ. An outpatient procedure for the displacement of submacular blood by intravitreal gas and tPA. Presented in the Vail vitrectomy meeting, March 1996), many patients have been treated with very few side effects although endophthalmitis, retinal tears and retina detachment have occurred.[95-100]
The gas bubble displaces liquid blood to the periphery of bubble-retinal contact and the majority is displaced inferiorly from the macula [Figure:8]. This gradually reabsorbs leaving some stippling of the RPE and mild choroidal atrophy [Figure:9]. The benefit of anterior chamber paracentesis prior to gas injection is to maximize gas volume. Injecting gas into a normal pressure or firm eye causes the gas to compress within the syringe hub and needle lumen. The compressed gas remains within the syringe as the needle is withdrawn thus greatly reducing the gas volume injected.
Although some pigmentary changes inferiorly occurred in the initial patient group, widespread RPE changes suggestive of significant toxicity were reported by Gilbert (Gilbert HD. Pigmentary retinopathy following intravitreal injection of tissue plasminogen activator. Presented in the Vitreous Society Meeting 1997). Although this complication is infrequent and not visually significant in most, a lower dose of tPA is currently recommended (see below). The lower dose may not be as effective for longer duration clots (S. Stenkula, personal communication) but the observation that blood displacement can occur with gas alone[101,102] warrants an initial trial of the gas injection for fresh haemorrhages.
The optimal dose and timing of intravitreal tPA in humans is yet to be established. Benner et al injected a range of tPA concentrations into the subretinal space of cat eyes and demonstrated that 2.5 mg/ L to 200 mg/ L were well tolerated, while l000mg/ L caused severe irreversible toxic effects to the photoreceptor-RPE complex. The original dose of 100 μg in the vitreous cavity (volume: 4cc is 25 mg/ ml or 25 mg/ L) is well within the safe range documented in cats. But it assumes an even distribution of tPA throughout the vitreous cavity; however, this would vary depending on the state of the vitreous gel and possibly other factors. The toxic effect of tPA is due to the arginine buffer, and not the tPA itself.
The kinetics of tPA migration into the subretinal space are not clear. Coll et al have proposed that tPA (70 kD) and albumin (68 kD) may have similar kinetics and albumin can cross the human retina. In other study tPA did not enter the subretinal space in the rabbit eye but the tPA kinetics were compared to labeled dextran (20kD), not albumin; so the validity of the rabbit eye model itself is unproven. Clinical experience has shown that there is no displacement or reduction of sub-RPE blood (haemorrhagic PED). The attachments of the RPE to Bruch's membrane would limit blood migration and tPA would not cross the apical tight junction barrier of the RPE.
Breakthrough haemorrhage into the vitreous cavity can occur and the incidence is more benign than untreated large subretinal haemorrhages. If the breakthrough is due to erythrocyte diapedesis through the retina, it is more likely to occur if the erythrocytes are not enmeshed in the subretinal fibrin. Treatment of this complication/ association is a simple vitrectomy to clear the visual axis. No retinotomy is necessary, thus reducing the risks of postoperative retinal detachment and PVR.
In conclusion the prevalence of AMD is associated with age. As the proportion of older people increases over time in both developed and developing countries, more aged individuals are likely to have AMD. The socioeconomic impact is enormous. No preventive treatment exists, but there are indications that micronutrient supplementation could delay or prevent AMD. In the 1990s, laser photocoagulation was the only clinically proven treatment available, but it can benefit only a small proportion of selected individuals. Today photodyanmic therapy holds greater promise. Newer surgical stratagies such as macular rotation or translocation appears more beneficial atleast in selected individuals. Trials are also continuing for treatment of dry AMD. The outcome of ongoing research on antiangiogenic drugs and gene therapy is likely to substantially alter our approach to AMD in future. With accumulation of experience and research results, we strongly believe that a rational, scientifically correct and individually tailored approach in treatment of CNV in AMD will be soon established.
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