Idiopathic subretinal neovascularisations
In subjects under 50 years of age, the finding of a sub-retinal neovascular membrane (CNV) should promote investigations to rule out associated causes, first pathological myopia, then angioid striae, then posterior segment inflammation (post-inflammatory CNV) (1), or traumatic choroid rupture, iatrogenic (2), optic nerve aplasia (3), choroid osteoma (4), choroidal nevus (5-6), radiation retinopathy (7). Where all these causes have been ruled out, the diagnosis of idiopathic CNV is made. Idiopathic CNVs have a natural history with a benign course, tend to self-limit and regress spontaneously, irrespective of lesion site, with a useful functional residual in most cases (75% ? 20/60), and rare occurrence of recurrence (8-9).
An indication of spontaneous regression and a positive prognostic factor appears to be the presence of a hypofluorescent borderline in ICGA, which is not always visible on ophthalmoscopy and FAG, corresponding to a multi-layered proliferation of the EPR, a sign of an involutional process demonstrated in the animal model and in humans in pseudohistoplasmosis CNVs (10).
Idiopathic CNVs are classified as type 2 according to Gasswith growth above the retinal pigment epithelium: in young subjects the close anatomical adhesion between EPR and Bruch's membrane could explain this growth pattern, and the integrity of the EPR could account for the prognostic evolution better than in other forms of CNV (9, 11).
The ICGA also shows focal areas of distant vascular hyper-permeability independent of the CNV similar to those observed in central serous chorio-retinopathy, and suggests a predisposing subclinical inflammatory condition also in these forms with an etiopathogenesis that is still discussed. The OCT confirms the position above the EPR with integrity of the hyperreflective band relative to the EPR itself and shows two main patterns of behaviour: a 'protruding' appearance, associated with elevation of the macular profile, and a 'fusiform' appearance in which the hyperreflectivity of the EPR-Bruch complex is confused with that of the lesion itself. The former refers to the activity phase, while involution is indicated by the latter (12-13).
The discussed inflammatory origin of juvenile idiopathic forms finds strength in the clinical response to the steroid therapyeither by os or by the subtenonial or intravitreal route (14).
For extra-foveal forms, the choice of direct argon or krypton photocoagulation remains possible, but with no data showing a better final functional result than natural history (9).
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Ph. 1 - idiopathic CNV pre PDT[/caption]
La photodynamic therapy (PDT) in idiopathic CNV has shown efficacy in stabilising and improving visus in over 65% of patients with a low rate of treatment recurrence (mean 1.1-2.1), albeit with the associated risk of atrophic changes in the EPR in the treatment area (Figs. 1-2). The association with steroid administration resumes the rationale of the likely inflammatory aetiology, and a randomised trial showed a significantly better clinical response if PDT is combined with steroid per os (15-20).
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Ph. 2 - CNV Idiopathic post PDT[/caption]
The therapeutic alternative is thesurgical excision which makes it possible to predict good functional results due to the type of neovascularisation (Gass type 2) and the integrity of the underlying EPR(21-22)
Finally, the introduction of the injection therapies with anti-VEGF drugs expanded the therapeutic spectrum for these forms of subretinal neovascularisation as well, with a response to single or multiple monthly administrations of bevacizumab in terms of improvement in visual acuity and absence of angiographic leakage at six months in 70-100% of cases and an improvement in visual acuity of at least two Snellen lines in 60-75% of cases. The therapeutic efficacy of bevacizumab was also observed in cases that had not responded to other therapeutic modalities (23-25).
La trans-pupillary thermotherapyin the only work highlighted in the literature, showed efficacy in improving and stabilising the visus in 81% of 21 treated patients (26).
However, we would point out that for none of the therapies listed above are there any randomised controlled efficacy studies and the indications arise from observational studies on groups of patients that are in any case limited in number and without control groups; moreover, the good prognosis of the natural history makes it obligatory in our opinion to inform the patient about the possibility of simply adopting an observation strategy.
Post-inflammatory subretinal neovascularisations
[caption id="attachment_1949" align="alignleft" width="150"]
Ph. 3 - CNV post toxo[/caption].
Subretinal neovascularisation (CNV) is a possible although rare complication of uveitis (1), both chorioretinitis and uveopapillitis, whether infectious or immunological in nature. No but sporadic data on the frequency of this complication are known, but it has been described associated with sarcoidosis and Behçet's disease (1), toxoplasmic chorioretinitis (2-3) (Figs. 3-4), perhaps the best known form together with the form complicating multifocal choroiditis (4), but also more rarely a complication of presumed histoplasmosis, multifocal choroiditis, choroiditis serpiginosa (1), Vogt-Konayagi-Harada syndrome (5) and rubella (6).
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Ph. 4 - CNV post toxo[/caption].
In the multifocal choroiditis an incidence of 22% is reported, and CNV is the leading cause of severe visual impairment in this cohort of patients (45% of cases), preceded by cystoid macular oedema and epiretinal membranes, associated with reduced visual acuity in three quarters of patients (<20/50) (1). If the duration of the disease is directly correlated with the risk of developing cystoid macular oedema, no such correlation seems to exist with the risk of developing CNV, so that subretinal neovascularisation can be considered an even early complication of the disease. Immunosuppressive therapy (azathioprine, cyclosporine, mycophenolate mofetil, etc.) seems to reduce the risk of CNV recurrence by 83%, but there are no data on the reduction of the risk of CNV occurrence itself; on the contrary, chronic use of low-dose steroids has no protective function against all posterior complications (1).
L'surgical excision is reported to be effective in cases of CNV complicated with presumptive histoplasmosis (7), multifocal choroiditis, serpiginous choroiditis, Behçet's disease (1), toxoplasmic retinochoroiditis (8). The therapeutic success of surgical excision can be explained by the condition of type 2 membranes according to Gass, similarly to what occurs in idiopathic forms, which lie above the otherwise healthy retinal pigment epithelium and with a natural cleavage plane given by the strong adhesions between EPR and Bruch's membrane (8).
However, in the face of the general abandonment of the surgical approach for CNVs, the photodynamic therapy has been used in single clinical evaluations in cases of rubella (9), Vogt-Konayagi-Harada syndrome (10), multifocal choroiditis (11-12), internal punctate choroiditis (13-15), presumptive histoplasmosis (14) and serpiginous choroiditis (15). PDT appears to be satisfactorily effective in these patients in stabilising visus and in inducing scarring of the lesion, with a mean retreatment rate of 2.6 (9-16).
However, we still consider the correctness of the indication to be a matter of debate: photodynamic therapy is per se 'inflammatory' and in applying it to these forms of neovascularisation, which recognise inflammation as the primum movens, it should at least be combined with steroid therapy in concert, either intravitreally or per os (13,17). Greater rationale for proposing the antiVEGF drug therapyVEGF is known to play a role in posterior eye inflammation and probably also in the occurrence of neovascular complications (18). Even for this therapy there are only occasional reports of treatment of small groups of patients, but no standardised treatment schemes. In a single scientific paper, bevacizumab shows therapeutic efficacy in 100% of cases in terms of clinical silence of the neovascularisation and in 90% of cases in terms of improvement of visual acuity, with the remaining 10% achieving visual stabilisation even after only one injection (19).
It is therefore appropriate to emphasise the current arbitrariness of any form of treatment for these neovascular forms in the absence of efficacy trials, which are, moreover, not easily achievable due to the limited incidence of this pathology. Rather, it would be desirable for tertiary referral structures for uveitis to plan common treatment strategies to be able to support a scientific comparison of efficacy between various protocols. In our opinion, the most correct current indication remains that of photodynamic therapy always associated with a steroid (per os, intravitreal), because the efficacy of the combination seems to be supported by the largest relative number of studies. However, the rationale for anti-VEFG drug therapy is present and convincing, although to date strengthened by only one case series study. Treatment strategies may be further changed by the expected market introduction of slow-release intravitreal cortisone devices.
Dr Maria Vadalà ,
Dr. Stefano Cipolla
Department of Clinical Neuroscience, Section of Ophthalmology, University of Palermo
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Dr. Carmelo Chines
Direttore responsabile
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