Ординатура / Офтальмология / Учебные материалы / Uveitis Text and Imaging Text and Imaging Text and Imaging 2009

late phase. In contrast, in case of inflammatory CNVs there is an early hyperfluorescence that progressively increases in later angiographic times. In case of haemorrhage there can be a hypofluorescent rim around the neovascular membrane as haemorrhage is usually surrounding the CNVs. For the differentiation between CNV and a new focus of retinochoroiditis however ICGA was found to be particularly useful showing early and increasing hyperfluorescence instead of the early and remaining hypofluorescence that would have been produced by a new inflammatory focus. As indicated earlier, typically CNVs develop at the border of a quiescent toxoplasmic scar with its typical angiographic signs of early hypofluorescence and late staining for the atrophic areas and late hypofluorescence when pigment clumps are present. The adjacent CNV has the typical dirty grey aspect on funduscopy, is early hyperfluorescent and progressively more fluorescent on FA and is early hyperfluorecent and progressively more fluorescent on ICGA. As stated earlier, in very rare cases, CNV can occur concomitantly with a reactivation of retinochoroiditis.

Optical coherence tomography (OCT) is very useful for the appraisal of CNV,51 showing liquid within the adjacent or overlying retina. It is also useful to verify efficacy of therapy of CNV.

As far as treatment is concerned, in the rare cases where CNV is associated with recurrent retinochoroiditis the classical association antitoxoplasmic antibiotics with corticosteroids should be given.52 The

evolution of CNV should be monitored by FA, ICGA and OCT and additional CNV therapy should be considered if progression is found.

As far as CNV in a quiescent stage is concerned, therapeutic attitudes are rapidly evolving. Argon laser therapy53 is probably no more justified even in extrafoveal CNV when taking into consideration the easy and efficient intravitreal anti-VEGF therapy. The same is probably true for the use of photodynamic therapy (PDT) although PDT may have been useful in the past on the basis of reported cases of toxoplasmic CNV.54 In the pre-anti-VEGF era, PDT was shown to be a reasonably effective strategy for the management of CNV. Mauget-Faÿsse et al54 evaluated the efficacy and safety of PDT for CNV associated with toxoplasmic retinochoroiditis. All eight patients considered were treated with PDT and were followed up prospectively. The mean visual acuity increased from 20/225, up to 20/123 with a mean follow-up period of 25 months using a mean number of 1.75 treatments. Nowadays, however, the treatment that seems to become the method of choice for probably all types of CNVs is intravitreal anti-VGEF therapy.

The overwhelming efficacy especially of Avastin® has shown promising results: recently, it was shown that a single injection of Avastin® scarred down toxoplasmic CNVs in a case that received no other treatment as well as in a case where neovessels were not controlled by PDT. Follow-up was more than 15 months in both cases.55

FUNGI

Systemic mycoses can cause a variety of health problems including digestive difficulties, skin problems, bronchopulmonary disorders. Most systemic mycoses are from opportunistic fungi. They are saprocyctes (organisms which live on decaying matter) that are usually innocuous, but become pathogenic when the host becomes abnormally susceptible to infection.55-60 Most part of fungal diseases have been described as potential pathogen for the eye: several reports described the severe complications of various fungi, such as Candida albicans, Cryptococcus Neoformans, Aspergillus Fumigatus and Histoplasma Capsulatum.

Candida albicans

Candida albicans can provoke severe endogenous endophthalmitis in immune-depressed patients, or in subjects with dangerous behaviour, such as intravenous drugs’ users, or in patients sustained with parenteral nutrition.61

In such cases, FA can be a valid tool to better define the extension and the degree of CNV activity. No studies or case series are available on ICGA and OCT. Although argon laser photocoagulation is the only one technique described,61 the combination of antimicrobial drugs with PDT or new anti-VEGF drugs may be considered.

Histoplasma capsulatum

Histoplasma capsulatum is a fungus, which is endemic in some areas of the United States. The ocular histoplasmosis syndrome or presumed ocular histoplasmosis syndrome (POHS) is characterised by disciform macular detachment associated with peripheral chorioretinal scars and peripapillary atrophy, which are the classical triad of this disease.63 POHS seems to be an immune-reaction possibly triggered by the fungus itself. The primary cause of visual impairment in POHS is the occurrence of CNV in the macula, which results in exudation and subsequent scarring.

Several treatments have been advocated for patients with POHS including argon laser photocoagulation, PDT and surgical removal of the novascular membrane.

The treatment is decided on the basis of the location of the CNV with respect to the center of the foveal avascular zone. Color picture can show a gray-green lesion (Figure 9) beneath the retina, generally anterior to the pigment epithelium. FA proves the CNV, showing early hyperfluorescence of CNV with late leakage of fluorescein dye (Figure 10); while there is the evidence that ICGA can be useful for the evaluation of choroidal involvement, there are not studies of its use in CNV evaluation, even though it can be a valid

Figure 10: Case 3 (part 1): CNV secondary to POHS. 28- year-old woman affected by POHS was referred for metamorphopsia and severe visual loss from the casualty. The patient underwent a full ophthalmic examination and a POHS associated with CNV was diagnosed. The FA confirmed the diagnosis; early (A), mid (B) and late (C) phases show well the activity of the CNV

Figure 11: Case 3 (part 2): The patient received 1g of intravenous methylprednisolone for 3 days, followed by oral prednisone at the dose 1 mg/kg/day coupled with azathioprine at the start dose of 1 mg/kg/day, up to 2 mg/kg/day in 4 weeks. After 5 months follow-up, the patient had an evident improvement and the FA showed inactive CNV with no signs of dye leakage. The patient continued the treatment with micophenolate mofetil at the same dosage and reduced systemic steroids down to 5 mg/day. No adverse events have been reported to date

tool in assessing the clinical response to a medical treatment for CNV.

As the disease can be considered auto-immune, Dees et al63 reported the use of immunesuppressant for the control of CNV secondary to POHS; patients were treated with the association of steroids, cyclosporine A and, in some cases, azathioprine (Figure 11), achieving a good control in all cases considered.

Although laser ablation of CNV has been demonstrated effective for extrafoveal neovascular membranes64 and Krypton laser has been proven effective in reducing visual impairment in patients with juxtafoveal CNV,65 new techniques are potentially safer and more effective.

PDT66-68 has been studied for the control of CNV secondary to POHS: visual acuity seems to improve and fluorescein angiographic leakage decreases after PDT therapy. Surgery should be considered only when CNV is wide and located near the optic nerve head.69 Even though no publications are available on antiVEGF agents for the treatment of CNV secondary to POHS, there is a strong rationale to suggest such technique.

HELMINTHES

Helmithes are parasitic worms, which can affect humans and, potentially, affect the eyes.

In the wide spectrum of possible parasites triggering neoangiogenesis of choroid, only toxocara canis may rarely generate choroidal lesions leading to the neoangiogenesis.

The CNV typically occurs near an active or quiescent choroidal granuloma, showing early hyperfluorescence and late leakage of the dye at fluorescein angiography (Figure 12). The ICG can demonstrate an occult CNV underlying the area close to the granuloma.70

The cases described in the literature are only reports70,71 and there are no indications on a possible method, which can offer a good control of the CNV.70

NONINFECTIOUS UVEITIS

Posterior pole uveitis can be a severe disease, threatening the visual acuity directly or secondarily by its complications. In this section we briefly expose posterior uveitis entities most often associated with CNV.

MULTIFOCAL CHOROIDITIS (INCLUDING

HISTOPLASMA CAPSULATUM NEGATIVE POHS)

Multifocal choroiditis and panuveitis was described in 1973 by Nozik and Dorsch,72 reporting 2 cases resembling POHS. More than 10 years later, Dreyer and Gass

described 28 additional cases with anterior uveitis, vitritis and multiple lesion in the posterior pole, which they called “multifocal choroiditis and panuveitis”. Today it should probably more simply be called multifocal choroiditis (MFC) as the panuveitis is usually absent.

MFC is the posterior uveitis that has the highest rate of CNV formation which is found in 32 to 46 percent of patients.73-75

CNV generally appears to be anterior to the retinal pigment epithelium and can be partially fed by retinal vessel. CNV can occur in the macular region or in the peripapillary area (Figure 13). It may originate from an old chorioretinal scar or from an inflamed area. The reason why CNV is so frequent in MFC may be explained by the widespread involvement of the choriocapillaris in many of these cases. ICGA very often shows large areas of non perfusion causing ischemia that could be the trigger of neovessel formation. FA and ICGA in MFC show the classical angiographic signs of neovessels. Sometimes FA reveals a thick hypofluorescent rim, indicating hyperplastic RPE, which surrounds totally the CNV area. ICGA plays an important role in the evaluation of choroidal involvement in MFC: Slakter et al76 observed that choroidal involvement was better detected by ICGA than FA. OCT is helpful as in all CNV in studying the position of CNV with reference to the RPE and giving information on the presence of liquid in the overlying or adjacent retina.

PUNCTATE INNER CHOROIDOPATHY

Punctate inner choroidopathy (PIC) is a subentity of MFC characterised by multiple choroidal spots, low grade myopia, and CNV.

Active, yellowish spots can be characterised by an overlying serous detachment of the neurosensory retina,77 corresponding to those areas where the patient complains of scotomas and/or metamorphopsias. Choroidal spots can evolve into faded chorioretinal lesions or atrophic chorioretinal scars. Yellowish lesions tend to depigment and to become yellow-whitish, surrounded by a hyperpigmented edge. The focal chorioretinal scars can be the site where the CNV originates. CNV is as frequently complicating PIC as in MFC and occurence of CNV was estimated at 17 to 40 percent of eyes, causing often severe and permanent visual impairment.77,78 Clinical and angiographic aspects are similar to CNV in MFC as it is the same type of disease (Figures 14 and 15). As in MFC, ICGA (Figure 15) is the best modality to prove choroidal involvement,79 which is usually found to be prominent.

OCT is helpful as in all CNV in studying the position of CNV with reference to the RPE and giving information on the presence of liquid in the overlying or adjacent retina (Figure 16).

SERPIGINOUS CHOROIDITIS

Serpiginous choroiditis (SC) is a rare, severe, recurrent and, generally, bilateral disease which is thought to primarily involve the choriocapillaris, and secondarily the RPE and the rest of the choroid.80,81 The disease typically starts from the peripapillary region and tends to progress centrifugally to the macula, assuming the typical serpiginous pattern.

The first description was in 1932 by Junius81 and several reports added more cases in the following years.80,81,83,84 CNV is a well recognised complication of serpiginous choroiditis in 10-25 percent of affected patients.85-88

CNV generally occurs near the border of both active and inactive lesions; FA can be helpful in proving the CNV and should always be performed. During the active stage of the disease, CNV can be

missed as it shows a hyperfluorescence similar to the hyperfluorescent borders of the disease. The latter hyperfluorescence comes from exudation from inner retina capillaries of areas with ischemic outer retina due to choriocapillaris non perfusion in areas of disease progression.

The role of ICGA is pivotal in the evaluation of choroidal involvement and for the longitudinal

management of SC as FA usually underestimates the areas involved (Figure 17A). ICGA allows far better delineation of choroidal lesions than corresponding fluorescein frames, showing subclinical abnormalities of the choroid appearing as a hyperfluorescent areas in the late phases of ICGA with a weak leakage89 (Figure 17B). This allows to put forward the hypothesis that subclinical, low-

Figure 16: Punctate inner choroidopathy: the OCT shows the CNV and the atrophic area

grade inflammation may be one reason leading to neovessels (Figure 17C).

OCT is helpful as in all CNV in studying the position of CNV with reference to the RPE and giving information on the presence of liquid in the overlying or adjacent retina.

OTHER INFLAMMATORY DISEASES ASSOCIATED WITH CNV

Any posterior pole ocular inflammation can be complicated by CNV which has been described for

subretinal fibrosis and uveitis syndrome91 (SFU, Figure 18), acute posterior multifocal placoid pigment epitheliopathy (APMPPE),92 birdshot chorioretinopathy (BC),97 multiple evanescent white dots syndrome (MEWDS),93,94 Vogt-Koyanagi-Harada disease (VKH),95 sympathetic ophthalmia (SO),96 Behçet uveitis97 and sarcoidisis.98

The clinical characteristics of CNV in all these entities are similar to those observed in other posterior uveitides and are generally type 2 membranes.

Choroidal neovascularization without signs of retinal scars, AMD lesions or high myopia is defined as “idiopathic” (ICNV). CNV appears as a yellowish lesion surrounded by a dark rim of fresh blood.

FA is not contributory in understanding a clinical pattern, which can be evocative of posterior pole ocular inflammation. CNV is the only reliable finding in the retina and no other abnormalities are reported.

The role of inflammation in the pathophysiology of ICNV has been postulated on the basis of ICGA,99-101 further supported by the preceding publications, which showed CNV as a possible sequela.14

Recently, Fukuchi et al102 proposed a staging system for the clinical assessment of ICNV: they divided the clinical course of ICNV into active, intermediate, cicatricial stage.

The supposed role of inflammation in ICNV is important for the treatment strategy: more than in other CNVs, ICNV should be treated as an inflammatory neovascularization.103,104

TREATMENT OF NONINFECTIOUS CNV

CNV occurring in noninfectious choroidal inflammation have common characteristics: the histopathological features, the pathophysiology and the preliminary results of some studies, suggest a relatively unique method for the management.105

Several techniques have been proposed for the management of CNVs, such as argon laser photocoagulation,106 periocular107 and systemic steroids,108 PDT,109 immunesuppression63 and surgical removal.110

When PDT was introduced, the laser treatment deeply changed, limiting argon laser photocoagulation to extrafoveal neovascular membranes to reduce the risk of hiatrogenic damages. PDT has been used following different startegies: some patients have been treated electively with PDT only,113,114 or when they did not achieve the control of CNV with other strategies;109 other series described the effects of PDT coupled with medical therapy.107

Other trials reported the safety and efficacy of immunesuppression63 for the control of choroidal new

Figure 18: Case 7: CNV secondary to subretinal fibrosis and uveitis syndrome. A 28-year-old woman was referred to the ocular inflammation unit of the Eye Clinic, Ospedali Riuniti di Ancona. The patient had the following complaints: progressive, severe visual impairment, associated with metamorphopsia and a central grey scotoma. The posterior pole examination presented diffused subretinal fibrinous streaks with a central neurosensory detachment. The diagnosis of subretinal fibrosis and uveitis syndrome has been done. The FA showed a diffuse streaky hyperfluorescence with a central hyperfluorescent area with late dye leakage, which was suggestive of a subfoveal CNV

(A). The patient received a rescue therapy with a pulse of intravenous methylprednisolone at the dose of 1g/day for three days, followed by oral steroids (1 mg/kg) associated with mycophenolate mofetil (1g twice a day). At 3 months followup, the patient had an evident improvement of symptoms and the FA proved the complete resolution of both the inflammation and CNV activity (B). The patient had no further relapses after 19 months follow-up; the dose of steroids was tapered down to 5 mg/day and the mycophenolate mofetil remained with the same dosage to date

vessels in uveitis. Although surgical removal has been reported as safe and effective,110 the introduction of less invasive methods, such as intraviteal anti-VEGF drugs99 have limited surgery to extensive and peripapillary membranes, as suggested by the results of a retrospective study on POHS by Almony et al.65 As there are not guidelines for the management of inflammatory choroidal neovascular membranes, there is not a flow-chart, which can be followed to treat CNV. All the proposed methods present the results as safe and effective, but it is not clear which one could offer more advantages: no randomized control trials are available on the direct comparison between different techniques, and no trials on CNVs secondary to a specific uveitis entities are available.

The rationale for combined therapy lies in the pathophysiology of the inflammatory CNV itself. Indeed the association of medical treatment with other methods offers both the control of the triggering factor of inflammation as well as the neovascular process.

The use of systemic steroids should be considered mandatory, as the inflammatory process is not only loco-regional, but there is the evidence of involvement of the whole immune system.113

The choice of the immunesuppressant should be established on the basis of the characteristics of the drug itself: some immunosuppressive drugs, such as cyclosporine A114 FK506 and Sirolimus,115 are known to produce nephrotoxicity114 inducing the overexpression of soluble mediators that have an important role in CNV pathogenesis. The steroid-sparing drug that is gaining consideration in this area is mycophenolate mofetil (MMF), which has proven to be effective in reducing such biomechanisms,114 improving arteriolopathy and decreasing the amount of soluble mediators involved in CNV pathophysiology. In the series considered in our center115 at the Ospedali Riuniti di Ancona, we treated 9 patients (12 eyes) affected by juxta/subfoveal CNV secondary to noninfectious uveitis, which did not respond to traditional immunosuppressants. All patients stopped previous immune-suppressive drugs before entering the study, and then received intravenous methylprednisolone at the dose of 1 g daily for 3 days, followed by prednisone at the dose of 1 mg/kg daily, coupled with MMF (1 g twice/day). At baseline, mean BCVA was 0.3± 0.17 standard deviation (SD). At one year, all eyes considered had a BCVA improvement (p < 0,05) and the mean BCVA improved up to 0.62± 0.21 SD. At

12 months, all eyes had a reduction of CNV size (p < 0.05). An oral dose of prednisone <10 mg/day was achieved in a median time of 4 months (range, 3–6 months). The series analysed in our center suggests a certain role played by MMF in controlling uveitic CNV, and the combination of high dose of systemic steroids and MMF seems to offer a safe and effective profile for

the management of CNV secondary to noninfectious uveitis. Even though there are no direct comparisons between different treatments, the rationale may suggest medical treatment as first choice for juxta/ subfoveal CNV and, when this fails in controlling the CNV activity, anti-VEGF intravitreal drugs should be introduced (Figure 19), with or without PDT.