|Year : 1998 | Volume
| Issue : 2 | Page : 67-80
Choroidal neovascular membrane
NS Bhatt, JG Diamond, S Jalali, T Das
Bombay Hospital and Medical Research Centre, Mumbai, India
N S Bhatt
Bombay Hospital and Medical Research Centre, Mumbai
Source of Support: None, Conflict of Interest: None
Choroidal neovascular membrane in the macular area is one of the leading causes of severe visual loss. Usually a manifestation in elderly population, it is often associated with age-related macular degeneration. The current mainstay of management is early diagnosis, usually by fundus examination, aided by angiography and photocoagulation in selected cases. Various other modalities of treatment including surgery are being considered as alternate options, but with limited success. The purpose of this review is to briefly outline the current concepts and the management strategy from a clinician's viewpoint.
Keywords: Choroidal neovascular membrane, age-related macular degeneration, fluorescein angiography, laser photocoagulation
|How to cite this article:|
Bhatt N S, Diamond J G, Jalali S, Das T. Choroidal neovascular membrane. Indian J Ophthalmol 1998;46:67-80
The choroidal neovascularisation is a manifestation of the diseases affecting choroid, Bruch's membrane and retinal pigment epithelium (RPE). Choroidal neovascular membrane (CNVM) originates from the choroida[l] and is located initially within the layers of Bruch's membrane; subsequently it may penetrate the RPE and grow under neurosensory retina. CNVM may occur as an idiopathic entity or in association with number of pathological conditions like age-related macular degeneration (ARMD), ocular hisptoplasmosis, pathologic myopia, angiod streaks, choroidal tears and in certain inflammatory diseases of choroid and retina (Table). It can cause severe visual loss due to leakage, haemorrhage and scar tissue formation damaging the photoreceptors and the RPE.
| Age-Related Macular Degeneration|| |
ARMD is a clinical diagnosis and may be defined by presence of drusen, geographic atrophy, pigment epithelial detachment (PED) or CNVM in a patient over the age of 50 years with diminished vision. The varied manifestation of ARMD may be divided into two categories: non-neovascular (dry, atrophic) and neovascular (wet, exudative). Non-neovascular type is more common and accounts for majority of cases (80-90%).
It is characterized by presence of drusen and pigment epithelial atrophy. ARMD usually begins as non-neovascular type and a small number (10%) progress to neovascular type. The neovascular type account for majority (90%) of severe visual loss in ARMD.,
ARMD is a multi-factorial syndrome with different causative factors damaging the macula and results in a common manifestation that we recognize clinically as ARMD. Risk factors implicated in clinical and laboratory studies include drusen, photic injury, antioxidant and vitamin/mineral deficiency. Neovascular type of ARMD characterized by CNVM occurs in older patients who are more likely to show evidence of non-specific cardiovascular problems. Hypertension and smoking are associated with development of neovascular ARMD as well as with recurrence of CNVM following laser photocoagulation.
In clinical studies, certain types of drusen have been identified as risk factors for the development of CNVM. Multiple, large and confluent soft drusen are associated with significantly increased risk for developing exudative disease, [Figure:1]a and [Figure:1]b. Focal hyperpigmentation associated with drusen is another high-risk factor.
The frequency of developing neovascular maculopathy in the second eye ranges between 12% and 34%., Using Kaplan-Meir life table analysis, Strahlman et al have calculated a cumulative risk of 4%, 10% and 17% at 12, 24 and 36 months, respectively. In the Macular Photocoagulation Study (MPS ) 128 fellow eyes developed CNVM with a 5-year cumulative incidence rate of 28% and an estimated average annual incidence rate of 6% per year.
Blurred distance and distorted near vision are the most frequent symptoms. Patients may also complain of metamorphopsia or a scotoma. However, many times they volunteer no symptoms or offer only vague visual complaints.
Detailed examination of macula with stereoscopic slit lamp biomicroscope using either 90 or 78 D lens or a corneal contact lens is essential to evaluate the subtle clinical finding of CNVM. It appears as a dirty gray-green colour lesion, deep to retina [Figure:2]. The gray-green appearance is believed to be due to hyperplastic response of RPE. It may be accompanied by sub retinal haemorrhage and/or lipid, serous or haemorrhagic PED, neurosensory exudate detachment, macular oedema and cystoid macular changes [Figure:3]a and [Figure:3]b.
Retinal pigment epithelial detachment
Serous PED appears as orange-yellow round, oval or bean-shaped elevation of the RPE with smooth, convex surface contours [Figure:1]a. Some resorb or flatten spontaneously leading to RPE disturbances including geographic atrophy. [20,21] PED in younger patients have generally a benign course. However, one third to one half of the serous PED in patients >50 years of age will develop CNVM with severe visual loss. Certain characteristics of PED are associated with increased risk of developing CNVM. They are old age (>65 years), associated sensory detachment, larger PED size (>1 disc diameter) and notching. Blood and lipids within or surrounding PED implies the presence of CNVM [Figure:4]. Similarly chorioretinal folds under PED also indicate presence of CNVM.
RPE tears have been described as a complication associated with PED, with or without laser photocoagulation. Tears are usually located at the junction of the attached and detached RPE; it occurs when the fluid forces from the underlying CNVM outstretch the sub-RPE space. When the RPE tears, the free edge of the RPE retracts and rolls toward the mound of fibrovascular tissue.
Fibrovascular scar involving the choroid, RPE and sensory retina is the end stage of CNVM. Disciform scar is white or yellow in colour with pigmentary changes. It is frequently associated with sub retinal fluid, haemorrhage and / or lipid due to leakage form CNVM [Figure:5]. Severe and extreme exudation of lipid from CNVM is called "Senile Coat's Syndrome". A disciform scar occasionally distorts the inner choroid and RPE into a series of folds or wrinkles.
Massive subretinal haemorrhage
This rare complication of CNVM is attributed to use of anticoagulant or antiplatelet drugs. However, the MPS group did not observe any increased risk of haemorrhage associated with the use of aspirin. Hence patients with macular degeneration who need to be on aspirin therapy could continue to do so without unnecessary fear of massive haemorrhage.
Occasionally patients may present with vitreous haemorrhage due to extension of blood from subpigment epithelial or subretinal space. The most frequent symptom is severe and sudden visual loss. This may be accompanied by pain believed to result form stretching of the nerve fibres within the choroid. Any patient with a massive vitreous haemorrhage in one eye and features of ARMD in the fellow eye should be suspected of harbouring CNVM in the eye with the vitreous haemorrhage. Ultrasonography often helps to establish the diagnosis [Figure:6].
Fluorescein angiography (FA) is an important test for the diagnosis and treatment of CNVM. Whenever one suspects CNVM, high-quality fluorescein angiography should be performed without delay. It helps to determine the location, extent, definition of CNVM and its relation to centre of fovea, factors with prognostic importance and treatment implications.
CNVM can be divided according to angiographic appearance into those membranes that are well-defined and those that are poorly defined. In well defined CNVM the entire extent of the CNVM can be determined from the angiogram. This is important since the benefits of photocoagulation treatment have been substantiated only for CNVM in which the entire extent of the membrane can be determined and treated.
Well defined classic CNVM
The classic CNVM shows a distinct area of choroidal hyperflourescence with well-demarcated borders that can be seen in the choroidal and early arterial phase of the fluorescein angiogram [Figure:7]a. A lacy network or cart wheel-like capillary plexuses is infrequently seen in ARMD [Figure:7]b. In the mid phase of angiogram, the intensity and the extent of hyperflourescence increases. In the late phase progressive leakage of the dye and pooling in the overlying subsensory retinal space typically obscures the boundaries of the CNVM and details of capillary plexus [Figure:7]c.
Poorly defined occult CNVM
The entire extent of CNVM may be difficult to define on angiogram either because the leakage is poorly defined or because the hyperflourescene and leakage are blocked. Unfortunately, many patients with ARMD do not show well-defined membranes., Contiguous subretinal haemorrhage, hyperplastic pigment, fibrous tissue or serous PED may obscure the area of hyperflourescence from CNVM and hinder the definition of the CNVM's extent of proximity to foveal centre.
Several patterns of occult CNVM can be described from their fluorescein angiographic appearance. The "diffuse ooze" type of occult CNVM is characterized by multiple punctate dots or regions of hyperflourescence with no discrete well demarcated source for the fluorescein leakage. The choroidal leakage becomes apparent only between two and five minutes after injection. The leaking points may not be contiguous, do not correspond to areas of drusen or atrophy of RPE and may not be associated with significant sensory retinal detachment [Figure:8]. The hyperflourescent dots may blend with areas of hyperflourscence form fluorescein-stained drusen or RPE atrophy. Thus, their borders tend to be ill-defined making the extent of the CNVM difficult to establish.
Fibrovascular PED is another form of occult CNVM. Fibrovascular PED is characterized by areas of irregular elevation of the RPE observed on stereoscopic views of the angiogram. By two minutes after injection, a stippled area of hyperfluorescence can be appreciated. Persistence of fluorescein staining or leakage within this area or into overlying subsensory retinal space is seen at 10 minutes after injection. Usually the borders are difficult to define precisely because of irregular fluorescein intensity within the area of elevated RPE; the borders of elevated RPE may gradually slope and blend into adjacent flat RPE.
Occult CNVM in serous PED
Identifying CNVM within a PED can be challenging. In haemorrhagic PED, blood within PED appears as blocked fluorescence. Accompanying CNVM may show hyperflourescence either within the PED or contiguous to it. Usually, the haemorrhage and the PED itself obscure the definition of the underlying CNVM. In PEDs that appear to be pure serous, there are several angiographic characteristics that strongly suggest underlying occult CNVM. These include, irregular hyperflourescences usually due to blockage from underlying pigment or blood within PED, an area of hyperflourescence not due to overlying transmission defect (hot spot) and a notch.,, Unfortunately, the precise extent of the CNVM within the sub-RPE space of PED cannot be defined using present techniques. Video indocyanine green angiography may permit better definition of the underlying CNVM.
Retinal pigment epithelium tears have a characteristic fluorescein angiographic appearance. The denuded RPE displays marked early hyperfluorescence. Later staining of the sclera may be observed. The rugate pigment epithelial mound blocks the fluorescence.
Indocyanine green videoangiography
Digital indocyanine green (ICG) videoangiography is a new tool for the evaluation of the choroidal circulation., ICG is a water-soluble tricarbocyanine dye and has been used to measure cardiac output since 1957. ICG is highly protein bound (98%) and is excreted by the liver via bile. It does not cross placenta. It is relatively safe dye but should not be used on patients who are allergic to iodine, since ICG contains approximately 5% iodine by weight.
ICG videoangiography has two major advantages over fluorescein angiography in its ability to image the choroidal circulation. First, the emission and fluorescence spectra of ICG are in the near infrared region, so light can better penetrate blood, exudate, serous fluid, xanthophyll and the retinal pigment epithelium. Second, ICG is highly bound to serum protein in the blood and therefore is more likely to be retained within normal and abnormal choroidal blood vessels in comparison to fluorescein, which is only partially protein bound. These features of ICG provide a more sensitive means of identifying CNVM.
Preliminary observations suggest that ICG videoangiography is particularly useful in detecting CNVM obscured by haemorrhages or by PED containing serosanguinous fluid. ICG videoangiography has also shown to improve the delineation of poorly defined CNVM and the delineation of persistent or recurrent CNVM that are observed after laser treatment. A recent study has shown that up to 40% of occult or poorly defined CNVM in fluorescein angiography could be reclassified into well-defined CNVM by ICG videoangiography. FA images well-defined CNVM and ICG images occult CNVM; hence the best imaging strategy for detecting CNVM is to perform both FA and ICG.
CNVM appears as a neovascular sprout growing under or through the RPE via breaks in the Bruch's membrane [Figure:3]b. Bruch's membrane typically is thin in the region around the break. Following penetration of the inner aspect of Bruch's membrane, the new vessels proliferate laterally between the RPE and the Bruch's membrane. As the neovascular twigs mature, they develop a more organized vascular system stemming from the trunk of feeder vessels off the choroid. The endothelial cells in the arborizing neovascular tufts lack the barrier function of more mature endothelial cells. Hence these new vessels leak fluid in the neurosensory, subsensory and the RPE layer of the retina.
CNVM associated with ARMD tends to result in more macular destruction than when associated with other pathologic conditions for several reasons. First, CNVM associated with ARMD at initial presentation have a greater tendency to be large and under the centre of the foveal avascular zone (FAZ). In ARMD there is diffuse thickening of the inner aspect of Bruch's membrane, and in association with the soft drusen it presumably predisposes Bruch's membrane to develop cracks through which ingrowth of new vessels from the choriocapillaries can occur. This hypothesis is supported by the finding of CNVM in other pathologic entities in which breaks in the Bruch's membrane occur, such as pathological myopia and angiod streaks. However, breaks in the Bruch's membrane can also be seen without ingrowth of CNVM. Endothelial cells of growing CNVM may actually produce the breaks in the Bruch's membrane rather than grow through pre-existing breaks. Finally an inflammatory component seen in association with ARMD may also play a role in development of CNVM. The presence of macrophages and lymphocytes near breaks in the Bruch's membrane suggest their possible role in induction of CNVM growth and the release of collagenases from the endothelial cells. It is postulated that leucocytes may initially stimulate neovascular proliferation, promote release of factors leading to breakdown of Bruch's membrane and even affect the dilatation of new vessels. Neovascular formation may result form the imbalance between stimulating and inhibiting chemical modulators. The RPE has been implicated as the source of these factors, but they may also act indirectly through the attraction of macrophages.
The natural history of untreated CNVM in ARMD is one of severe visual loss, secondary to the involvement of the centre of fovea and sequel of CNVM. Many classic CNVM begin outside fovea and later extend into the fovea as they grow. Most (75%) extrafoveal untreated CNVM extend under the centre of fovea in one year. Hence effort should be directed to diagnose CNVM early and prevent its spread to fovea. It is mandatory to order for fluorescein angiography immediately and plan for laser photocoagulation as soon as CNVM is suspected. Delay in treatment can be disastrous, because CNVM can grow from an extrafoveal location to a subfoveal location in a very short time., Fluorescein angiographic studies have documented growth of CNVM at an average rate of 10-18 μm per day. Also the importance of early examination and prompt diagnosis is exemplified by various studies which reported that patients with acute visual loss from ARMD are more likely to have treatable CNVM if they are examined within the first month after the onset of symptoms., Thus, if the interval between the onset of new visual symptoms and the initiation of treatment is reduced to a minimum there may be an increased likelihood that a treatable CNVM lesion can be identified.,
In 1979, the National Institute of Health initiated the Macular Photocoagulation Study (MPS), a multicentre, randomized, prospective clinical trial designed to evaluate whether laser photocoagulation prevents or delays severe visual loss due to CNVM of various aetiologies. In the MPS the patients were assigned randomly to prompt laser treatment or observation. The MPS evaluated laser treatment of well defined a) extrafoveal CNVM, b) juxtafoveal CNVM, c) subfoveal CNVM, and d) peripapillary CNVM [Figure:9].
Eligibility criteria for laser photocoagulation
According to MPS protocol there should be an angiogrpahic evidence of well defined CNVM 200 μm to 2,500 μm from centre of FAZ in eyes with a baseline visual acuity of 6/30 or better [Figure:10a] and [Figure:10b]. These lesions account for up to 25% of those neovascular lesions threatening central vision.
Once extrafoveal, well defined CNVM is diagnosed, prompt treatment should be given. The goal of treatment is to close the neovascular lesion and prevent severe visual loss rather than to restore normal visual acuity. Prior to treatment, a detailed discussion about the disease, treatment goal, side effect such as permanent scotoma, corresponding to treatment and long-term follow up with repeat angiography should be emphasized.
A recent fluorescein angiogram (<72 hours old) is used as the guide for treatment. Because the CNVM may grow, a fluorescein angiogram older than few days may not depict accurately the extent of CNVM. Ideally, a suitable frame (early frame for classic well defined CNVM and late frame for treatable occult CNVM) should be displayed on a projection device located on the laser console top, or alternately, projected on a screen behind the patient. The angiogram thus displayed permits rapid and accurate orientation of critical retinal vascular and CNVM landmarks. Many times, a frame from original negative provides maximum details.
Retrobulbar or peribulbar anaesthesia is necessary to ensure that neither ocular mobility nor patient discomfort compromise the success of treatment by preventing the clinician from delivering laser energy of sufficient intensity and duration. A suitable contact lens such as Goldmann fundus lens or Mainster standard lens is used to obtain a clear and magnified image. However, Mainster lens provides an inverted image as opposed to the erect image of Goldmann lens.
According to MPS recommendation, area of hyperfluorescence due to well defined CNVM and any adjacent blood, pigment or blocked fluorescence should be completely covered with laser burns of sufficient intensity to cause a uniformly white lesion. Also the laser treatment should extend 100-125 μm beyond the neovascular complex on all sides. Large laser burns of longer duration are preferred as it would reduce complication of rupture of Bruch's membrane and choroidal haemorrhage. Using a 200 μm spot size of 0.2-0.5 seconds duration, a test burn is placed along the membrane periphery away from the foveal edge or in normal retina to determine the laser settings. Then the foveal border of the CNVM is treated with overlapping burns. Care is taken to avoid treating retinal vessels; instead the laser burns should straddle the retinal vessels to reduce the chances of closing the vessel and causing haemorrhage [Figure:10]c.
Argon and krypton laser photocoagulation are established standard methods of treatment. The tunable dye laser offers theoretical advantages. Argon blue-green should be avoided due to greater absorption by foveal xanthophyl. Some prefer to combine Krypton red and Argon green, presumably enhancing the likelihood of CNVM closure., Initially deep choroidal burns are created with Krypton red laser supplemented by Argon green laser over it which is absorbed by haemoglobin in CNVM. Laser photocoagulation acts by causing coagulative necrosis or by altering RPE presumably producing inhibitors of neovascularization.,
Complications of treatment are uncommon. Choroidal haemorrhage is a major complication, but can be avoided by using spot sizes no smaller than 200 μm and duration of 0.2 seconds or longer. It is more common with Krypton laser due to its increased uptake by choroid. In case of bleeding, moderate pressure is applied on the globe with the contact lens and additional laser photocoagulation is done over the bleeding site. Inadvertent treatment of the foveola is the most serious complication and it can be minimized by concurrent comparison of vascular landmarks in the fundus to that seen on angiogram. Krypton laser appears to cause delayed perfusion of choroidal vessels thought to result from vascular spasm and there is increased risk of RPE tears as compared to argon laser. Late loss of visual acuity should prompt careful evaluation for recurrence, but may result from late RPE atrophy due to "run-off" or spread of laser energy.,
Beginning with the first postoperative day, patients should be instructed to monitor the size of the resulting scotoma and surrounding distortion by observing Amsler chart. Any increase in the scotoma size or in the surrounding distortion from the baseline should prompt a call to the treating ophthalmologist. Such a change may indicate persistence of CNVM.
Regular follow up is essential to detect and treat persistent or recurrent CNVM. In the first one or two weeks following treatment residual oedema and retinal vasculitis prevents adequate interpretation of angiogram forwarded. Hence, we prefer to review 3 weeks after laser treatment. Thereafter, follow up is done at 6 weeks, 3 months, 6 months, and at one year. Further examination is done at longer intervals if CNVM is well treated. For first several follow-ups, fluorescein angiography is repeated. An adequate treated membrane will show hypofluorescence [Figure:l0]d. The edge of the laser scar will show evenly hyperfluorescent rim, due to staining emanating from the adjacent untreated area. This need not be confused with persistence, which will appear as focal hyperfluorescene. Leakage in the centre of the treatment that has a broad rim of surrounding hyperfluorescence need not be retreated. These areas usually resolve spontaneously, so treatment is avoided unless follow-up examination shows that the central hypofluorescent is enlarging. Clinically, well treated CNVM will show a dry, flat scar without any evidence of activity [Figure:10]e.
In 1982, the MPS group reported that argon blue-green laser photocoagulation treatment applied with intensity to whiten the retina and for an extent to cover and obliterate discrete extrafoveal CNVM lesion and contiguous blood, significantly improved the visual prognosis when compared to natural course of the disease. [52,53] At 18 months follow-up, laser photocoagulation reduced the risk of severe visual loss (decrease in visual acuity by ≥6 lines from baseline) from 69% in untreated eyes to 25% in treated eyes. Two other randomized prospective clinical trials in France and UK reached similar conclusion. Although the benefits of laser photocoagulation were greatest during the first post-treatment year, the treatment effect demonstrated in the MPS still has held over 5 years; 64% of untreated versus 46% of treated eyes progressed to severe visual loss.
Despite proper laser treatment, recurrence of CNVM do occur. By the end of 5 years, recurrence of CNVM has been observed in 54% of laser treated eyes, and 80% of recurrence occurred within one year of treatment. Recurrence of CNVM was responsible for most of the visual deterioration seen in the treatment group. The average visual acuity in eyes without recurrence was 6/12 at 1 year and 6/15 at 3 years following the treatment. In contrast the average visual acuity in eyes with recurrences was 6/37.5 at 1 year and 6/75 at 3 years following treatment.
Cigarette smoking, CNVM located closer to the centre of the fovea on initial presentation, and CNVM with very light pigmentation are known risk factors for recurrence. [69,70] Recent reports suggest that large or confluent drusen and disciform scar in the fellow eye are also risk factor.
The krypton laser photocoagulation trial for extrafoveal CNVM, not eligible for the argon laser treatment, was designed in 1981 by MPS. The krypton red laser allows one to treat within the FAZ with theoretically less risk of damaging the fovea due to lack of uptake by the foveal xanthophyll. In addition krypton laser spares the inner retina. Eligibility criteria for the study were angiographic evidence of CNVM, posterior edge between 1-199 μm from the FAZ centre (but not under it) or CNVM 200 μm or further from the FAZ centre with blood and/or blocked fluorescence extending within 200 μm of FAZ. Some thin blood or blocked fluorescence could extend through the entire avascular zone provided the extent of CNVM could be defined on the angiogram.
The treatment method for krypton and laser photocoagulation was similar to that for argon blue-green treatment of extrafoveal CNVM with few modifications. The goal was to cover the area of hyperfluorescence completely with laser burns of sufficient intensity to produce uniform whitening of the overlying retina. Treatment of areas of blood and/or blocked fluorescence associated with the neovasculari-zation was not required. Clinically, well treated CNVM produced dry and flat laser scar.
At 3 years after randomization, 49% of treated eyes compared to 58% of untreated eyes had lost ≥6 lines of visual acuity. The average visual acuity at 5 years was 6/60 in the treated eyes and 6/75 in the untreated eyes. Laser treatment showed its greatest benefits in patients without systematic hypertension, but showed reduced or no benefits in patients with highly elevated blood pressure and in those treated with antihypertensive medication.
In 1986, the MPS group initiated two additional randomized trials to evaluate laser treatment in eyes with subfoveal CNVM. The first, termed the subfoveal study, evaluated the effect of laser treatment (argon green or krypton red, assigned randomly) compared to observation in previously untreated ARMD eyes with well-defined CNVM, a portion of which was directly beneath the centre of FAZ. The neovascular lesions could be no larger than 3.5 standard disc areas. Total area of treatment (extending 100μm beyond all borders of the lesion) could not exceed 4 disc areas. Because of the high rate of persistence and recurrence in the argon and krypton trials and their association with poorer visual outcome, a companion study, the subfoveal recurrence study, was started to evaluate laser treatment versus observation of subfoveal recurrent neovascularization developing along the perimeter of a scar after earlier treatment of extrafoveal or juxtafoveal CNVM. In the recurrent subfoveal study, the total area treated (previous laser scar and new laser treatment) could not exceed 6 disc areas. Additionally, some area within the central 4 disc areas had to be left untreated.
The results published in 1991 suggested that laser treatment of subfoveal lesions meeting eligibility criteria was better than observation alone in preventing large losses of acuity, provided the patient and the ophthalmologist were prepared for a substantial decrease in visual acuity (3 lines, on average) immediately after treatment. By 24 months some treatment benefit was noticed but the mean visual acuity was 6/90. Treated eyes retained contrast sensitivity and fasloc reading speed compared to the untreated eyes. Patients in certain subgroups showed better treatment benefits such as those with pretreatment visual acuity of <6/60 and those with CNVM of <1 disc area. Recurrence was noted in 51% of the eyes in 2 years.
Despite the marginal benefit of laser photocoagulation over observation, it is not a panacea for treatment of subfoveal CNVM. It is often difficult to convince the patient of long term treatment benefit, when there is immediate decrease of visual acuity following laser photocoagulation of subfoveal CNVM. Hence, many retinal specialists treating CNVM are hesitant to photocoagulate subfoveal CNVM. Due to these limitations, alternative ways to manage this condition are tried and newer methods are evolving.
Alternative treatment modalities for subfoveal CNVM They include perifoveal laser photocoagulation in selected cases, ICG enhanced treatments,, interferon alpha 2a,, ionizing radiation, thalidomide and fumagillin,, and photodynamic therapy.[84-85] Of these procedures, ICG enhanced treatment using ICG dye and semiconductor diode laser, and photodynamic therapy using benzoporphyrin derivative appear to hold promise currently.
Surgical removal of CNVM
Considering the poor natural history and limitations of laser photocoagulation in subfoveal CNVM, surgical removal of the membrane without overt damage to the memosensary retina is an alternate option. Initial attempts of submacular surgery used large retinotomics, till it was demonstrated by Thomas and Kaplan that small retinotomies are equally effective and less damaging. Subsequently there are several reports of CNVM removal of in ARMD., However, this has very limited visual benefit because most subfoveal CNVM have grown beneath RPE or have caused extensive scarring. Thus, the majority of eyes with ARMD will probably not be candidates for surgical removal as good results are obtained only when the CNVM is anterior to the RPE. Presence of foveal RPE and choriocapillaries is also essential for good central visual function. RPE transplantation may help to restore function of neurosensory retina in eyes with defective or damaged RPE. Bhatt et al has shown that it is possible to rescue the photoreceptors in experimental animal by transplanting fetal RPE on collagen substrate. Both RPE transposition and RPE transplantation have been attempted along with removal of ARMD related fibrovascular scar. These are preliminary which need further refinement.
Peripapillary CNVM constitute a small minority of CNVM seen in ARMD, but it can lead to severe visual loss by encroaching under the fovea. Drusen are typically seen nasal to the disc in ARMD with peripapillary CNVM.
Eyes with peripapillary CNVM are eligible for laser photocoagulation if at least 1.5 clock hours of peripapillary nerve fibre layer adjacent to the temporal half of the disc can be spared. Krypton laser is preferred as it spares inner retina and hence damage to papillomacular bundle can be minimized. Also, 100 μm of peripapillary retina adjacent to disc border should be spared to prevent damage to the optic nerve head.
| Other Conditions Associated with CNVM|| |
Virtually any disease that results in an abnormality at the level of the RPE-Bruch's membrane-choriocapillary complex, can be associated with CNVM and a subsequent disciform process. Some of these conditions are discussed below.
The incidence of CNVM in pathological myopia is approximately 5%. The basic abnormality in pathological myopia is axial elongation. The continued stretching and degeneration of the choroid causes these eyes to develop the linear breaks in the Bruch's membrane (lacquer cracks) which may predispose these eyes to the development of CNVM. Two types of fluorescein angiographic patterns are reported in the CNVM of myopic eyes. In one, the dye did not leak beyond the edges of the initially outlined CNVM, and these eyes were associated with quiescent atrophic scars. In the second type, the dye leaked beyond the edges of initially outlined CNVM and these eyes formed exudative fibrovascular scars causing serous elevation of retina or RPE. The first type occurred in eyes with severe chorioretinal degeneration and the second type occurred in eyes with mild grades of degeneration. It is thought to be due to severe haemodynamic changes in the choriocapillaries of eyes with severe degenerative myopia where the blood flow is delayed and hence dye leakage is minimal. The aggressiveness of the CNVM thus appears to be inversely related to the degree of degenerative myopia; the greater the degeneration and the thinner the choroid, lesser the extent of CNVM.
The laser treatment of CNVM complicating pathological myopia remains controversial, particularly because the natural history appears to be variable. Laser therapy is probably efficacious to stabilize the vision, although difficult, and is associated with significant potential for complication. Several factors unique to myopia CNVM pose a particular challenge in laser treatment. First, choroidal new vessel often begin very close to the fovea. Second, there is considerable atrophy of RPE. Third, lacquer cracks occasionally extend during the application of laser therapy. Finally, the extent of retinal and RPE atrophy after laser treatment may increase substantially, potentially involving the fovea.
Angiod streaks have been associated with several systemic diseases, including pseudoxanthoma elasticum, Paget's disease of bone, Ehlers-Danlos syndrome, sickle cell disease, thalassemia, and other blood dyscrasias. [99,100] In about 50% there is no associated systematic abnormality. The reported incidence of CNVM is 60% to 86% in eyes with angiod steak., Unlike, ARMD, the exudative form is more common. Also CNVM is frequently located in the papillomacular bundle. Both, successful and disappointing results [98,100] of laser treatment for CNVM associated with angiod streaks are reported in the literature. Laser treatment may give good results initially but recurrences are common and may be higher than that seen in eyes with CNVM form other causes. Although there has been no prospective randomized controlled trial of laser photocoagulation for CNVM associated with angiod streaks, it seems reasonable to consider laser treatment of well-defined CNVM outside the foveal avascular zone.
Presumed ocular hisptoplasmosis syndrome
CNVM in the macular area is a major cause of visual loss in presumed ocular histoplasmosis syndrome (POHS). Usually, CNVM occurs at the edge of an old healed chorioretinal scar. Generally, reactivation of old lesions accounts for new CNVM with a 20%-30% activation rate. FA is indicated in all patients of POHS who develop new symptoms such as metamorphosia, central scotoma and micropsia.
The MPS group recommends laser treatment to extrafoveal and juxtafoveal CNVM.,  There was no study carried out to ascertain the effect of laser photocoagulation to subfoveal CNVM. Surgical removal of subfoveal CNVM is possible and results are better than CNVM secondary to ARMD.,
CNVM occurs in other inflammatory conditions like multifocal choroiditis, serpiginous choroiditis, and certain other inflammatory diseases.
When CNVM develops in the absence of atrophic chorioretinal scar, drusen or another retinal abnormality, it is termed idiopathic. Laser treatment of extrafoveal and juxtafoveal idiopathic CNVM is beneficial to observation., The magnitude of the treatment benefit was somewhat intermediate between the treatment benefit for POHS and ARMD.
Traumatic ruptures of the Bruch's membrane are commonly seen following severe contusion injuries to the eye. Late loss of central vision following trauma can occur due to development of CNVM. In these cases the initial trauma is associated with submacular haemorrhage. FA helps to distinguish between healed scar and CNVM. The scar stains slowly with little leakage while CNVM shows classical early leak which increases in late film. Successful laser photocoagulation of such CNVM is possible.
This a benign ossifying tumour of the eye which is often associated with CNVM. If the CNVM occurs at the edge of the osteoma it is more amenable to laser treatment than if it is subfoveal in location. The CNVM should be distinguished from the branching vascular tufts seen on the inner surface of the tumour. The latter are not associated with subretinal fluid, haemorrhage or disciform scar and show no dye leakage on fluorescein angiography.,
Argon and krypton laser have been used with moderate success in causing regression of the CNVM in choroidal osteoma and generally multiple treatment sessions are required., It is presumed that the difficulty in closing the new vessels results from the lack of melanin in the tumour and very thinned, degenerated pigment epithelial-Bruch's membrane complex.
| Summary|| |
Choroidal neovascularization occurs in many diseases affecting retinal pigment epithelium-Bruch's membrane-choriocapillaries complex. It has a propensity to involve the macula and hence causes visual loss.
The MPS group study on CNVM secondary to ARMD, POHS and idiopathic causes has helped us define and understand the disease process better. This study has also helped in uniform fluorescein angiographic interpretation and finally indicated treatment criteria for laser photocoagulation. It is imperative for ophthalmologists to diagnose this entity in early stage and advise prompt evaluation and treatment. The CNVM diagnosed early, has a good likelihood of being treated and preservation of some useful vision.
Despite all the efforts, still there are large number of cases (almost 50%) that are not eligible for laser treatment, mainly because CNVM is not well defined. ICG videoagiography combined with FA will be able to define many more CNVM and make treatment possible. Newer treatment modalities are being tried. ICG-enhanced diode laser photocoagulation is one such modality. Photodynamics therapy with newer photosensitiser holds promise to selectively ablate CNVM. Surgical removal of CNVM is possible in selected cases.
Future work on pathogenesis and treatment of CNVM must advance along several fronts, including a deeper understanding of normal cellular aging changes, pathophysiology, and treatment. To do this it is necessary to develop animal models.
| References|| |
Ohkuma H, Ryan SJ, Vascular casts of experimental subretinal neovascularization in monkeys. Invest Ophthalmol Vis Sci
Ferris FL, Fine SL, Hyman LG. Age related macular degeneration and blindness due to neovascular maculopathy. Arch Ophthalmol
Leibowitz HM, Krueger DE, Maunder LR, Milton RC, Kini MM, Kahn HA, et al. The Framingham Eye Study Monograph; an ophthalmological and epidemiological study of cataract, glaucoma, diabetic retinopathy, macular degeneration and visual acuity in a general population of 2631 adults, 1973-1975. Surv Ophthalmol
Tso MO. Pathogenetic factors of aging macular degeneration. Ophthalmology
Handelman GJ, Dratz EA. The role of antioxidants in the retina and retinal pigment epithelium and the nature of prooxidant-induced damage. Adv Free Radic Biol Med
Bray TM, Bettger WJ. The physiological role of zinc as an antioxidant. Free Radic Biol Med
Krinsky NI. Antioxidant functions of carotenoids. Free Radic Biol Med
Hyman LG, Lillienfeld AM, Ferris III FL, Fine SL. Senile macular degeneration: a case-control study. Am J Epidemiol
Macular Photocoagulation Study Group. Recurrent choroidal neovascularization after argon laser photocoagulation for neovascular maculopathy. Arch Ophthalmol
Smiddy WE, Fine SL. Prognosis of patients with bilateral macular drusen. Ophthalmology
Bressler NM, Bressler SB, Seddon JM, Gragudas ES, Jacobson LP. Drusen characteristics in patients with exudative versus non exudative age-related macular degeneration. Retina
Bressler SB, Maguire MG, Bressler NM, Fine SL. Relationship of drusen and abnormalities of retinal pigment epithelium to the prognosis of neovascular macular degeneration. Arch Ophthalmol
Chandra SR, Gragoudas ES, Friedman E, van Buskirk CM, Klien ML. Natural history of disciform degeneration of the macula. Am J Ophthalmol
Gregor Z, Bird AC, Chisholm IH. Senile disciform macular degeneration in the second eye. Br J Ophthalmol
Strahlman ER, Fine SL, Hills A. The second eye of patients with senile macular degeneration. Arch Ophthalmol
Macular Photocoagulation Study Group. Five-year follow-up of fellow eyes of patients with age-related macular degeneration and unilateral extrafoveal choroidal neovascularization. Arch Ophthalmol
Fine AM, Elman MJ, Ebert JE, Prestia PA, Starr JS, Fine SL. Earliest symptoms caused by neovascular membranes in the macula. Arch Ophthalmol
Doyle WJ, Davidorf FH, Makley TA, Dierut WJ. Histopathology of an active lesion of ocular histoplasmosis. Ophthalmic Forum
Gass JDM. Pathogenesis of disciform detachment of the neureopithelium. I. General concepts and classification. Am J Ophthalmol
Elman MJ, Fine SL, Murphy RP, Patz A, Auer C. The natural history of serous retinal pigment epithelium detachment in patients with age-related macular degeneration. Ophthalmology
Meredith TA, Braley RE, Aaberg TM. Natural history of serous detachments of retinal pigment epithelium. Am J Ophthalmol
Cantril HL, Ramsay RC, Knoblock WH. Rips in the pigment epithelium. Arch Ophthalmol
Decker WL, Sanborn GF, Ridley M, Annesley WH, Sorr EM. Retinal pigment epithelial tears. Ophthalmology
Green SN, Yarian D. Acute tears of retinal pigment epithelium. Retina
Hoskin A, Bird AC, Sehow K. Tears of detached retinal pigment epithelium. Br J Ophthalmol
Yeo JH, Marcus S, Murphy RP. Retinal pigment epithelial tear: patterns and prognosis. Ophthalmology
Gass JDM. Radial chorioretinal folds: a sign of choroidal neovascularization. Arch Ophthalmol
El Bada F, Jaretts II WH, Harbin IS, Fine SL, Michel RG, Schachat AP, et al. Massive haemorrhage complicating age-related macular degeneration. Ophthalmology
Klein ML. Macular degeneration: is aspirin a risk for progressive disease? JAMA
Kreiger AE, Steriling JH. Vitreous haemorrhage in senile macular degeneration. Retina
Tani PM, Brettner H, Robertson DM. Massive vitreous haemorrhage and senile macular choroidal degeneration. Am J Ophthalmol
Koenig F, Soubrane G, Coscas G. Angiographic aspects of senile macular degeneration: spontaneous course. J Fr Ophthalmol
Bressler NM, Bressler SB, Gragoudas ES. Clinical characteristics of choroidal neovascular membranes. Arch Ophthalmol
Folk JC. Aging macular degeneration: clinical features of treatable disease. Ophthalmology
Macular Photocoagulation Study Group. Subfoveal neovascular lesion in age-related macular degeneration: guidelines for evaluation and treatment in the Macular Photocoagulation Study. Arch Ophthalmol
Poliner LS, Oik RJ, Burgess D, Gordon ME. Natural history of retinal pigment epithelium detachment in age related macular degeneration. Ophthalmology
Gass JDM. Serous retinal pigment epithelium detachment with a notch: a sign of occult choroidal neovascularisation. Retina
Guyer DR, Puliafito CP, Mones JM, Friedman E, Chang W, Verdoones SR. Digital indocyanine green angiography in chorioretinal disorders. Ophthalmology
Yannuzzi LA, Slakter JS, Sorenson JA, Guyer DR, Orlock DA. Digital indocyanine green videoangiography and choroidal neovascularization. Retina
Fox IJ, Wodd CH. Applications of dilution curves recorded form the right side of the heart or venous circulation with the aide of a new indicator dye. Proc Mayo Clin
Young RW. Pathophysiology of age-related macular degeneration. Surv Ophthalmol
Green WR, Key SN. Senile macular degeneration: a histopathology study. Trans Am Ophthalmol Soc
Green WR, MacDonnel PM, Yeo JH. Pathologic features of senile macular degeneration. Ophthalmology
Sarks SH. Aging and degeneration in macular region: clinicopathological study. Br J Ophthalmol
Sarks SH. Drusen and their relationship to senile macular degeneration. Aust J Ophthalmol
Sarks SH, van Driel D, Maxwell L, Killingworth M. Softening of drusen and subretinal neovascularization. Trans Ophthalmol Soc UK
Heriot WJ, Henkind P, Bellhorn RW, Burns MS. Choroidal neovascularization can digest Bruch's membrane: a prior break is not essential. Ophthalmology
Loffer KU, Lee WR. Basal linear deposit in the human macula. Graefe's Arch Clin Exp Ophthalmol
Penfold PL, Provis JM, Billson FA. Age-related macular degeneration:ultrastructural studies of the relationship of leucocytes to angiogenesis. Graefe's Arch Clin Exp Ophthalmol
Glaser BM. Extracellular modulating factors and control of intraocular neovascularization. Arch Ophthalmol
Coscas G, Soubrane G. Photocoagulation des neovaisseux sous-retiniens daus la degeurescence maculaire senile par laser a argon: resultats de l'etude randomisee de 60 cas. Bull mem Soc Fr Ophthalmol
Macular Photocoagulation Study Group. Argon laser photocoagulation for neovascular maculopathy: three year results form randomized clinical trails. Arch Ophthalmol
Macular Photocoagulation Study Group. Argon laser photocoagulation for senile macular degeneration: results of randomized clinical trial. Arch Ophthalmol
Moorfield Macular Study Group. Treatment of senile disciform macular degeneration: a single blind randomized trial by argon laser photocoagulation. Br J Ophthalmol
Singerman LJ, Hionis R. In discussion:Vander J, Morgan C, Schatz H. Growth rate of subretinal neovascularization in age-related macular degeneration. Ophthalmology
Vander J, Morgan C, Schatz H. Growth rate of subretinal neovascularization in age-related macular degeneration. Ophthalmology
Klein ML, Jorizzo TA, Watzke RC. Growth features of choroidal neovascular membranes in age-related macular degeneration. Ophthalmology
Grey RHB, Bird AC, Chistaolm IH. Senile disciform macular degeneration: features indicating suitability for photocoagulation. Br J Ophthalmol
Teeters UW, Bird AC. The development of neovascularization in senile disciform macular degeneration. Am J Ophthalmol
Singerman LJ, Kalski RS. Tunable dye laser for choroidal neovasuclarization complicating age-related macular degeneration. Ophthalmology
Singerman LJ. Red krypton laser therapy of macular and retinal vascular diseases. Retina
Yannuzzi LA, Shakin JL. Krypton red laser photocoagulation of ocular fundus. Retina
Miller H, Miller B, Ryan SJ. The role of retinal pigment epithelium in the involution of subretinal membrane. Invest Ophthalmol Vis Sci
Glaser BM, Compochairo PA, Davis JL, Sato M. Retinal pigment epithelium cells release an inhibitor of neovascularization. Arch Ophthalmol
Cohen SMZ, Fine SL, Murphy RP, Finkelstein D, Patz A. Transient delay in choroidal filling after krypton red laser photocoagulation for choroidal neovascular membranes. Retina
Morgan CM, Scarz H. Atrophic creep of the retinal pigment epithelium after local macular photocoagulation. Ophthalmology
Rice TA, Murphy RP, Fine SL. Stability of size of argon laser photocoagulation scars in ocular hisptoplasmosis. In: Fine SL, Owen SL, editors. Management of Retinal Vascular and Macular Disorders.
Baltimore: Williams and Wilkins; 1983. p 187-90.
Macular Photocoagulation Study Group. Argon laser photocoagulation for neovascular maculopathy after five years: results from randomized clinical trials. Arch Ophthalmol
Macular Photocoagulation Study Group. Recurrent choroidal neovascularization after argon laser photocoagulation for neovasuclar maculopathy. Arch Ophthalmol
Sorenson JA, Yannuzi LA, Shawn JK. Recurrent subretinal neovascularization. Ophthalmology
Macular Photocoagulation Study Group. Persistent and recurrent neovascularization after krypton laser photocoagulation for neovascular lesion of age-related macular degeneration. Arch Ophthalmol
Macular Photocoagulation Study Group. Krypton laser photocoagulation for neovascular lesion of age-related macular degeneration: results of randomized clinical trial. Arch Ophthalmol
Macular Photocoagulation Study Group. Laser photocoagulation of subfoveal neovascular lesions in age-related macular degeneration: results of randomized clinical trials. Arch Ophthalmol
Macular Photocoagulation Study Group. Laser photocoagulation of subfoveal recurrent neovascular lesions in age-related macular degeneration: results of randomized clinical trial. Arch Ophthalmol
Coscas G, Soubrane G, Ramahestasolo C, Fardean C. Perifoveal laser treatment of subfoveal choroidal new vessels in age-related macular degeneration: results of a randomized clinical trial. Arch Ophthalmol
Balles MW, Puliafito CA, D'Amico DJ, Jacobson JJ, Birngruber R. Semiconductor diode laser photocoagulation in retinal vascular diseases. Ophthalmology
Reichel E, Puliafito CA, Duker FS, Guyer DR. Indocyanine green dye enhanced diode laser photocoagulation of poorly defined subfoveal choroidal neovascularization. Ophthalmic Survey
Fung WE. Interferon alpha 2a for treatment of age-related macular degeneration. Am J Ophthalmol
Gillies MC, Sarks JP, Beaumont PE, Hunyou AB, McKay D, Kearns M, et al. Treatment of choroidal neovascular membrane in age-related macular degeneration with interferon alpha 2a and alpha 2b. Br J Ophthalmol
Kirkpatrick JNP, Dick AD, Forester JR. Clinical experience with interferon alpha 2a for exduative ARMD. Br J Ophthalmol
Chakravarthy U, Houston RF, Archer DB. Treatment of age-related macular degeneration by teletherapy: a pilot study. Br J Ophthalmol
D'Amato RJ, Loughnan MS, Flynn E, Folkman J. Thalidomide is an inhibitor of angiogenesis. Proc Natl Acad Sci USA
Ingber D, Fujita T, Kishimoto S, Sudo K, Kamarao T, Brem H, et al. Synthetic analogues of fumagillin that inhibit angiogenesis and suppress tumor growth. Nature
Miller JW, Walsh AW, Kramer M, Hasan T, Michaud N, Floote TJ, et al. Photodyanamic therapy of experimental choroidal neovascularization using lipoprotien-delivered Benzoporphyrin. Arch Ophthalmol
Asrani S, Zeimer R. Feasibility of laser targeted photocclusion of ocular vessels. Br J Ophthalmol
de Juan Jr E, Machemer R. Vitreous surgery for hemmorrhagic and fibrous complication of age-related macular degeneration. Am J Ophthalmol
Blinder KJ, Peyman GA, Paris CL, Gremillion CMJ. Submacular scar excision in age-related macular degeneration. Int Ophthalmol
Thomas MA, Kaplan HJ. Surgical removal of subfoveal neovascularization in the presumed ocular hisptoplasmosis syndrome. Am J Ophthalmol
Thomas MA, Grand GM, Williams DF, Lee CM, Pesin Sr, Lowe MA. Surgical management of subfoveal choroidal neovascularization. Ophthalmology
Lambert HM, Capone A, Aaberg TM. Surgical excision of subfoveal neovascular membranes in age-related macular degeneration. Am J Ophthalmol
Bhatt NS, Newsome DA, Fenech T, Hessburg TP, Diamond JG, Miceli MV, et al. Experimental transplantation of human retinal pigment epithelial cells on collagen substrates. Am J Ophthalmol
Algevere PV, Berglin L, Gouras P, Sheng Y. Transplantation of fetal retinal pigment epithelium in age-related macular degeneration with subfoveal neovascularization. Graefe's Arch Clin Exp Ophthalmol
Grossniklaus HE, Green WR. Pathologic findings in pathologic myopia. Retina
Green WR, Retina. In: Spencer WH, editor. Ophthalmic Pathology: An Atlas and Textbook.
Philadelphia: WB Saunders Co;1996. Vol 3. p 964-73.
Noble KG, Carr RE. Pathologic myopia. Ophthalmology
Hotchkiss ML, Fine SL. Pathologic myopia and choroidal neovascularization. Am J Ophthalmol
Avila MP, Weiter JJ, Jalkh AE, Trempe CL, Pruett RC, Schepens CL. Natural history of choroidal neovascularization in degenerative myopia. Ophthalmology
Fried M, Siebert A, Meyer-Schwickerath G. Natural history of Fuch's spot: a long term follow-up study. Doc Ophthalmol Ser
Clarkson JG, Altman RD. Angiod streaks. Surv Ophthalmol
Gas JDM, Clarkson JG. Angiod streaks and disciform macular detachment in Paget's disease (osteitis deformans). Am J Ophthalmol
Shields JA, Federman JL, Tomer TL, Annesley Jr WH. Angiod streaks: ophthalmoscopic variations and diagnostic problems. Br J Ophthalmol
Piro PA, Scheraga D, Fine SL. Angiod streaks: natural history and visual prognosis. In: Fine SL, Owens S, editors. Management of Retinal Vascular and Macular Disorders.
Baltimore:Williams and Wilkins;1983. p 136-39.
Singerman LJ, Hatem GF. Laser treatment of choroidal neovasuclar membranes in angiod streaks. Retina
Meislik J, Neldner K, Reeve EB, Ellis PP. Laser treatment in maculopathy of pseudoxanthoma elasticum. Can J Ophthalmol
Kayazawa F. A successful argon laser treatment in macular complications of angiod streaks. Ann Ophthalmol
Guyer DR, Gragoudas ES, D'Amico DJ. Angioid streaks. In: Albert DM, Jackobiec FA, editors. Principle and Practice of Ophthalmology.
Philadalphia: WB Saunders Co; 1994. Vol 2. p 852-60.
Lewis ML, van Newkirk MR, Gass JDM. Follow up study of presumed ocular histoplasmosis syndrome. Ophthalmology
Morgan CM, Schatz H. Recurrent multifocal chroiditis. Ophthalmology
Jampol LM, Orth D, Daily MJ, Rabb MF. Subretinal neovascularization with geographic (serpiginous) choroiditis. Am J Ophthalmol
Smith RE, Kelley JS, Harbin TS. Late macular complication of choroidal rupture. Am J Ophthalmol
Fuller B, Gitter KA. Traumatic choroidal rupture with late serous detachment of macula-report of successful argon laser treatment. Arch Ophthalmol
Sheilds CL, Sheilds J, Augsburger JJ. Choroidal osteoma. Surv Ophthalmol
Gass JDM. New observations concerning choroidal osteomas. Int Ophthalmol
Burke JF, Brockhurst RJ. Argon laser photocoagulation of subretinal neovascular membrane associated with osteoma of the choroid. Retina
Grand MG, Burgess DB, Singerman LJ, Ramsey J. Choroidal osteoma: treatment of associated subretinal neovascuar membranes. Retina