BACKGROUND/AIMS Teletherapy has been proposed as a possible treatment for choroidal neovascular membranes (CNV), secondary to age related macular degeneration (AMD) not amenable to laser photocoagulation. The aim of this prospective study has been to investigate the effect of teletherapy on isolated occult choroidal neovascular membranes of subfoveal location.
METHODS 28 AMD patients presenting with retrofoveal isolated occult CNV demonstrated by fluorescein angiography were treated by external beam radiation. A complete ophthalmological examination, fluorescein angiography, and indocyanine green angiography (ICG) were performed within 15 days before treatment and repeated at follow up. A total dose of 16 Gy was applied in four sessions of 4 Gy using a 4 MeV photon beam. Follow up ranged from 6 to 9 months (mean follow up 6.4 months).
RESULTS Visual acuity was found to be stable in 68% of the cases. The decrease in visual acuity was of 3–6 lines in 18% and of more than 6 lines in 10% of the eyes at last examination. On fluorescein angiography the size of the lesion area was found to be stable in 67%, decreased in 13%, and increased in 20% of the cases. On ICG angiography the size of the CNV was stable in 93% and increased in 7% of the cases. All the eyes experiencing a visual acuity decrease showed either no change or an increase in size of the membrane on fluorescein angiography and/or on ICG.
CONCLUSION According to this study with strict inclusion criteria, external beam radiotherapy seems to have a beneficial effect on the evolution of isolated occult subfoveal CNV.
- age related macular degeneration
- occult subfoveal neovascularisation
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Age related macular degeneration (AMD) is the major cause of legal blindness in the developed countries in people aged 50 years or more.1 2 The prevalence of AMD increases with aging to a prevalence of about 30% in people older than 75 years.2 3 As it is estimated that the section of the population over the age of 85 will be five million by the year 2000 in the USA and tripled by the middle of the next century, it is expected that AMD will be an even greater health problem in the future.4 The most severe visual loss occurs in patients with AMD complicated by neovascular membranes.1 3 Such patients account for 12% of AMD, but for 88% of legal blindness cases.1
Neovascular membranes complicating AMD are subdivided into well defined and occult on fluorescein angiography. Well defined choroidal neovascular membranes (CNV) are characterised by a well demarcated area of early hyperfluorescence with progressive leakage in the late phase.5 Occult CNV lack the typical features of well defined CNV. They show either areas of early hyperfluorescence (that are neither as discrete nor as bright as areas of well defined CNV) followed by stippled hyperfluorescence with staining of the fibrovascular tissue and leakage within the neurosensory retinal space during the late phase, or late phase fluorescein leakage of an undetermined source, which appears as speckled hyperfluorescence with pooling of dye in the overlying subsensory retinal space.5-7
Differentiating well defined from occult CNV is of fundamental clinical significance. At present laser photocoagulation remains the only worldwide demonstrated treatment for well defined neovascular membranes (of extrafoveal, juxtafoveal, and subfoveal location)5 8-15 complicating AMD. However, laser photocoagulation failed to demonstrate any significant benefit in eyes with occult CNV.7 16-18 As it is estimated that 60–70% of the CNV in AMD are occult at the time of diagnosis,19 20 there is strong need for new therapies. Radiotherapy is a treatment method that has been recently proposed to treat subfoveal CNV in AMD. Pilot studies showed a beneficial effect in well defined or partially well defined CNV,21-26 but only scarce evidence is available on its effect on occult CNV alone.26 We present here the first results of a pilot study conducted to investigate the effect of radiotherapy on isolated occult CNV of subfoveal location before initiating a large randomised trial.
Patients and methods
Twenty eight consecutive patients with isolated occult subfoveal CNV, referred to the University Eye Clinic of Créteil, were included in this study. The eligibility criteria are summarised in Table 1. Briefly, all patients were over the age of 50 and had evidence of AMD. Fluorescein angiography showed isolated subfoveal occult CNV, thus making the patients ineligible for laser photocoagulation. The patients were informed of the nature of their condition, as well as of the experimental nature and the potential complications of ocular radiotherapy. All the patients agreed to participate in the study.
BASELINE AND FOLLOW UP EVALUATION
All recruited patients were subjected to an ophthalmic examination including best corrected distance visual acuity, biomicroscopic fundus examination, and fluorescein angiography. Indocyanine green angiography (ICG) was additionally obtained in 15 cases. Examinations were performed within 15 days before the beginning of radiotherapy and repeated every 3 months during follow up. Follow up ranged from 6 to 9 months for all patients. Changes in visual acuity from baseline examination were graded as mild (decrease or increase of 3–6 lines) and severe (decrease or increase of more than 6 lines). The size of each lesion on the fluorescein angiogram was determined by superimposing a transparent sheet with circles of 1–12 disc areas determined from each patient’s red free photograph. A difference in size of at least 0.5 disc area was considered significant. To avoid bias in evaluation, baseline and follow up photographs were assessed in a masked fashion by one of the authors.
Comparison of subgroups with respect to lesion size on fluorescein and ICG angiography and changes in visual acuity were assessed with the Student’s test (independent t test). The significance level was chosen at p=0.05.
Teletherapy was carried out using a technique similar to that previously described by others.21 22 25 Briefly, a 4 MeV photons beam was used to deliver a total dose of 16 Gy in four sessions of 4 Gy. The total dose (100%) was administered to an area of 1 cm2 in the macular region; outside this area the dose decreased progressively to 50% at the posterior pole of the lens. The lateral field beam was tilted at 15° in order to reduce irradiation to the contralateral eye (less than 10% of the total dose).
Baseline characteristics are summarised in Table 2. Most of the patients were between 70 and 79 years of age, 54% of them being males and 46% females. Distribution of initial visual acuity ranged from 20/25 to 20/200, 25% with 20/40 or better, 36% between 20/50 to 20/80, 25% between 20/100 to 20/150, and 14% with 20/200. Biomicroscopic examination showed neurosensory retinal detachment in all eyes, intraretinal and/or subretinal haemorrhages were present in 57% of the eyes and serous pigment epithelial detachment (PED) in 11% of the cases. Fluorescein angiograms showed occult CNV involving the centre of the fovea in all cases. In addition, ICG showed a late staining hyperfluorescent plaque involving the centre of the fovea in all cases.
CHANGES IN VISUAL ACUITY FROM BASELINE EXAMINATION
Change in visual acuity from baseline are summarised in Table 3: 72% of the eyes had no decrease or even an increase in visual acuity, 18% experienced a moderate (between 3 and 6 lines), and 10% a severe (more than 6 lines) decrease in visual acuity.
RELATION BETWEEN MORPHOLOGY AND CHANGES IN VISUAL ACUITY
The changes in visual acuity in relation to morphological features at baseline are summarised in Table 3. The groups of eyes presenting with blood or serous PED at baseline had a significantly poorer outcome than those without: five (34%) eyes suffered a significant decrease in visual acuity, versus three (25%) in the group presenting without blood or serous PED. Statistical analysis of the visual acuity changes confirmed a significative difference between the outcome in the two groups (mean initial visual acuity in the group presenting with blood and/or serous PED at baseline 0.3 (SD 0.1), mean final VA 0.2 (0.1), p=0.036, mean initial VA in the group presenting without it 0.4 (0.3), mean final VA 0.4 (0.2), p=0.77).
CHANGES IN LESION SIZE
The changes in size at follow up compared with baseline measured on fluorescein and ICG are summarised in Table 4: 19 (67%) eyes showed either no change or even a slight decrease in size of the lesion area on fluorescein angiography (Figs 1 and 2). Statistical analysis showed no significant difference between initial and final size of the lesion area (mean size of disc areas initially 4.2 (SD 2.6),v finally 4.6 (2.8), p=0.88). Moreover, in the group of patients in which ICG was obtained the size of the hyperfluorescent plaque was stable in 14 (93%) eyes. Statistical analysis confirmed the absence of any significant difference between initial and final size of the lesion area (mean size in disc areas initially 3.8 (2.6), v finally 3.8 (2.4), p=1). Comparison of the size of the lesion obtained on ICG and fluorescein angiography (mean size in disc areas initially 4.8 (2.7), finally 5.1 (3.1)) showed no significant difference (p=0.25 for the initial size, p=0.17 for the final size). The size of the lesion area on ICG was the same or less than the one measured on fluorescein angiography in all cases both at baseline and at follow up. A decrease or increase in the size of the lesion area on fluorescein angiography was not significantly correlated with changes in the size of the late staining plaque on ICG.
CHANGES IN LESION CHARACTERISTICS
Blood and/or serous PED observed at baseline in 19 (68%) eyes (see Table 1) regressed in all cases but one at follow up. Of the nine eyes that presented without blood or serous PED at baseline two (22%) had significant bleeding during follow up, which was still present at final examination. Some neuroretinal detachment was present in all cases at baseline (see Table 1). It persisted in 23 (82%) eyes at the follow up on biomicroscopic examination. Fluorescein angiography showed persistent leakage of dye to some extent in all eyes (Fig 2 A); however, at final follow up examination a significant degree of chorioretinal atrophy was observed in four (15%) of the eyes which corresponded to a significant decrease in the lesion area on fluorescein angiography. Development of some fibrous tissue occurred in only one of the eyes presenting with either blood or serous PED at baseline examination.
RELATION BETWEEN LESION CHARACTERISTICS AND VISUAL ACUITY
Visual acuity was found to be stable in 50% of the eyes showing no changes in size of lesion area on fluorescein angiography and/or on ICG. No significant decrease in visual acuity was observed in the eyes showing a decrease in size of lesion area on fluorescein angiography. Finally, all the eyes suffering a decrease in visual acuity at follow up examination showed either no change or an increase in size of lesion area on fluorescein angiography and/or on ICG.
Studies on the natural history of eyes with subfoveal occult neovascular membranes have shown that long term visual outcome is poor.6 7 18 27 At present there is no treatment of proved value for occult subfoveal CNV. Confluent or scatter laser photocoagulation was shown to be of no benefit in occult subfoveal CNV.7 16 17 Perifoveal laser photocoagulation has been shown to preserve visual acuity in the short term in occult subfoveal CNV, but the long term visual outcome was still poor. Among experimental therapies, interferon alfa-228 was shown to be of no benefit in the treatment of CNV in AMD. Surgical excision only addresses well defined subfoveal CNV29-32 and photodynamic therapy is currently under investigation. Radiotherapy is another alternative treatment for subfoveal CNV in AMD. Since the original publication of Chakravarthy et al,21 there has been increasing interest in this treatment as it is non-invasive and is reported to have no systemic or local side effects at the low doses used.21-23 25 26Most of the current studies report concerned well defined subfoveal CNV21-25 33 34 Only scarce and controversial results are available on the effect of radiotherapy on a well selected group of eyes with occult subfoveal CNV.26 35
According to our data, external beam radiotherapy seems to have a stabilising effect on the growth of subfoveal occult CNV as judged by the observed modifications in lesion size. Firstly, most of the eyes (80%) showed either a decrease or no change in size during follow up on fluorescein angiography. Eyes presenting without blood or serous PED at baseline did significantly better, 100% showing either no change or a decrease in size. This result differs from the reports on natural history of occult CNV that showed an increase in size in all the cases after at least 6 months of follow up.6 20 Secondly, significant fibrovascular proliferation was observed at follow up in only one eye that presented with blood at baseline, an event that was previously reported to occur after at least 6 months of observation in 22% of the eyes presenting with the same characteristics at baseline.20 Thirdly, no case of growth of well defined CNV was observed, a complication previously reported to occur in as many as 50% of the eyes during natural history of occult CNV after 9–12 months of follow up.7 20 Finally, the onset of an atrophic scar was observed in 15% of the cases. These results are in accordance with previous reports on the evolution of well defined subfoveal CNV after radiotherapy.24 Occult CNV, as well defined CNV, react to external beam irradiation with a reduction of the trend of growth and of disciform scar formation.36
In the present study 72% of the eyes had stable or increased vision at follow up examination, 18% suffered from a mild decrease, and 10% from a severe decrease in visual acuity. Indeed, the natural course of such lesions has been shown to be deleterious for the visual function with a longer follow up as only 37% of eyes have been shown to retain a stable visual acuity, 21% suffering a mild and 42% a severe decrease in visual acuity after at least 6 months of follow up.6 7 20 However, final visual acuity was slightly worse (68% of eyes showing no significant change in visual acuity) than previously reported by others.26 As inactive and self limiting CNV have been reported to occur relatively frequently among occult lesions,37 this could be due to the fact that some of the lesion included in previous studies were inactive and self limiting choroidal CNV. Identification of the prognostic factors for functional visual outcome in eyes presenting with occult CNV is therefore necessary. The presence of blood was recently suspected as being such a factor, but could not be demonstrated.20 In our study, eyes presenting with blood and/or serous PED at baseline had a significantly worse functional outcome at follow up than eyes without blood and/or serous PED. Therefore, the results of the present study show that external beam irradiation has a beneficial effect on the visual acuity of eyes with occult subfoveal CNV, presenting with a spontaneous unfavourable aspect at baseline. Moreover, it suggests that occult subfoveal CNV, presenting with blood or serous PED on biomicroscopic examination may constitute a subgroup with a particularly bad prognosis. Such cases had a significantly less favourable evolution after radiotherapy than eyes presenting with only a decrease in visual acuity and a neuroretinal detachment at baseline.
RELEVANCE OF ICG IN THE EVALUATION OF OCCULT CNV
ICG has recently been shown to allow visualisation of CNV being defined as occult on fluorescein angiography,38-40 ICG allowing a more precise delineation of the lesion. In our study, the size of the lesion was similar on ICG and on fluorescein angiography at baseline and at follow up, and 93% of the eyes showing no changes in lesion size at follow up. However, changes in size on fluorescein angiography could not be correlated with modifications in size on ICG. As hyperfluorescent plaques on ICG are thought to represent active CNV,39 this indicates that changes in fluorescein angiography, and particularly changes in the size of the leakage area, may occur without modifications in the size of the active CNV, therefore suggesting that ICG angiography could be more valuable than fluorescein angiography in the evaluation of the evolution of occult CNV.
SIDE EFFECTS OF RADIOTHERAPY
Various methods have been used including external beam radiation with dose regimens ranging from 8 to 24 Gy.21-23 25 26Fraction schedules also varied widely ranging from 2 to 8 Gy.21-23 25 26 33 34 Cumulated doses ranging from 10 to 15 Gy have been shown to be effective without causing any local or systemic side effects.21 25 We used a total dose of 16 Gy in four sessions of 4 Gy. According to previous reports,26no short term complications were observed during follow up that might preclude radiotherapy for occult subfoveal CNV.
In conclusion, external beam radiotherapy seems to have a beneficial effect on the evolution of occult subfoveal CNV. However, longer follow up is essential to evaluate final visual outcome and scar formation (as occult CNV have a slow natural history) to exclude any late onset side effect such as radiation induced retinopathy.