Epidemiology of Angioid Streaks-Associated Choroidal Neovascular Membranes in the United Kingdom

Background: The purpose of this study is to determine the incidence of angioid streak-associated choroidal neovascular membranes (CNV) in the UK and provide other epidemiological data, clinical characteristics, therapies used, and short-term outcomes following treatment of this condition. Procedure: This is a prospective multicenter cohort study. Patients newly diagnosed of angioid streaks- associated CNV were identified prospectively over a 14-month period (January 2009-March 2010) by active surveillance through the British Ophthalmic Surveillance Unit (BOSU). Questionnaire-based data was obtained from reporting ophthalmologists at baseline and 12 months. The main outcome measure was incidence of angioid-streak associated CNV. Secondary outcomes included clinical characteristics, treatments used, and visual outcomes. Results: Forty-four cases of angioid streak-associated CNV were reported to BOSU, giving an annual incidence of 0.057 (95% CI: 0.040-0.074) per 100,000 population. Affected patients had a mean age of 47 years (range: 24-62 years), presented with a mean (SD) LogMAR visual acuity (VA) of 0.53 (0.51) (Snellen equivalent 6/18), and had most often subfoveal CNV. At one year, the mean LogMAR visual acuity had declined to 0.73 (0.59) (Snellen equivalent 6/36). Visual acuity improved > two Snellen lines in six cases (21%) and deteriorated > two lines in 13 cases (41%). Treatments used included anti-VEGF in 25 eyes (83%), photodynamic therapy (PDT) in two (7%), and observation in three (10%). Conclusions: This study represents the first population-based prospective study evaluating the incidence of angioid streak-associated CNV in the UK. Despite new treatments for CNV, the visual outcome of patients with this disorder remains guarded.


Introduction
Angioid streaks (AS) are irregular, radiating, orange-red jagged lines that extend from around the optic nerve head into the mid-peripheral retina, including the macula. Early on in the course of the disease, AS appear as well-defined orange lines; as the disease progresses, they became less well-defined and more pigmented. They represent crackline dehiscences in Bruch's membrane [1]. AS can be associated to systemic diseases, most commonly pseudoxanthoma elasticum, Ehlers-Danlos, Paget disease, sickle cell disease, or they may be idiopathic [2]. Rarely, they may be associated with abetalipoproteinemia [2][3].
Choroidal neovascular membranes (CNVs) may develop in up to 86% of patients with AS; when left untreated, they undergo progressive scarring leading to visual loss, often to levels of < 20/200 [1,[4][5][6][7]. The age at presentation of patients with AS-associated CNVs varies between 11 to 85 years with a mean age of 44 to 59 years [1,[8][9][10][11][12][13][14]. Due to the brittle nature of Bruch's membrane in these patients, acute visual loss can occur also following minor trauma as a result of choroidal rupture and sub-macular haemorrhage [15][16]. Bilateral visual loss is not uncommon, and it has been reported to occur in 42 to 71% of patients [6,17]; legal blindness has been reported in about 50% of patients due to the occurrence of bilateral CNV [1].
The management of patients with AS-associated CNV is challenging. Several treatment modalities have been used, including laser photocoagulation [18][19], photodynamic therapy (PDT) [20][21], transpupillary thermotherapy [8,22], feeder vessel occlusion [11], and surgical removal of the CNV or macular translocation [23][24]. Poor visual outcomes are often obtained with these treatments, and a high recurrence rate is observed. Intravitreal injection of anti-VEGF (vascular endothelial growth factor) has been recently used with promising results [13,[25][26][27][28][29]. However, due to the rarity of this condition, no prospective randomised clinical trial (RCT) is available to evaluate the outcomes and complications of these treatments.
The purpose of this study was to prospectively estimate the incidence of AS-associated CNV in the general population in the UK and to gain knowledge on the aetiology, clinical characteristics, management, and response to treatment of this group of patients.

Materials And Methods
Patients with newly diagnosed AS-associated CNV were identified prospectively through active surveillance by the British Ophthalmological Surveillance Unit (BOSU) during a 14-month period from January 2009 to March 2010. BOSU operates a monthly active surveillance scheme throughout the United Kingdom (UK) [30]; it was developed to assist in the investigation of uncommon ocular conditions that are of public health or scientific importance. The surveillance scheme involves all permanently employed ophthalmologists in the UK with clinical autonomy (consultants and associate specialists) who form the reporting base. Before the initiation of a study, BOSU informs all ophthalmologists about the new ocular condition under investigation, including the specific case definition. At the end of each month, a report card is sent to each ophthalmologist, who then returns it specifying whether a new case had been seen that month or whether no cases were seen. After case notification, incident and follow-up questionnaires are sent by the investigators to reporting ophthalmologists.
The baseline incident questionnaire collected data on demographics (age, gender, and ethnicity), ocular history, visual acuity (VA), systemic associations, family history of AS, CNV location, and investigations used for diagnosis. The 12-month follow-up questionnaire collected data on VA, treatment(s) performed, complications of treatment, status of the CNV (active/inactive), whether new CNVs developed during the 12 month follow-up period in the affected and fellow eye, investigations used to assess CNV activity, and whether the case was discharged or continued to followed. Paired t-tests were used to compare visual acuity at baseline and at follow-up.
This study was conducted in accordance with the tenets of the Declaration of Helsinki. Approval was granted by the North East of Scotland Multi-centre Research Ethics and Research and Development committees.

Results
During the study period, the response rate to BOSU was 77%. There were 20 males and 13 females (gender not available in two) with a mean age of 47 years (range: 24-62 years). Thirty-three patients were of British white origin; two were Caribbean. The right eye was affected in 18 patients. AS were associated with pseudoxanthoma elasticum in 22 patients (63%) and sickle cell in one; in 12 patients (34%), AS seemed to be idiopathic. A family history of AS was present in five patients. The ASassociated CNV was subfoveal in 18 eyes, juxtafoveal in 10, and extrafoveal in seven.  LogMAR (> 2 lines) in 11 cases (44%). Patients managed by observation included one patient with extrafoveal CNV that maintained 6/6 vision at last follow-up, and two others with juxtafoveal and subfoveal CNVs that had initial VA of 6/18 and 6/12 and deteriorated to counting fingers (CF) at the 12-month followup. The two cases that were treated with PDT had 6/12 and 6/18 vision at baseline, both deteriorated to CF at one year.
At 12 months, the CNV remained active in seven eyes (23%), and it was inactive in 23 (77%); treatment was still ongoing in eight eyes (27%) and it had been stopped in 18 (68%). All but one patient remained under follow-up after one year.

Discussion
To our knowledge, this represents the first prospective, population-based study on the epidemiology of ASassociated CNV undertaken in the UK. Based on this study, the annual incidence of AS-associated CNV is estimated ~ 0.057 cases per 100,000 individuals, confirming the rarity of this condition. This study, which represents one of the largest prospective, consecutive cohorts of patients with AS-associated CNV, provides important information with regards to baseline characteristics and outcomes following treatment.
AS-associated CNV affects young individuals, and despite of treatment, many experienced marked visual loss. In keeping with data previously reported [10,20,[31][32], visual outcomes following PDT were poor; the two patients that received PDT in the current study had vision of CF at the 12 month follow-up visit. Given that visual results following laser and PDT are often disappointing [19][20], anti-VEGF therapies would appear to be the treatment of choice at present time for AS-associated CNV [27,[33][34][35][36][37][38][39][40]. Table 1 summarises currently available studies (presenting > five cases) on the use of anti-VEGF in patients with AS-associated CNV. Some of these studies reported favourable visual outcomes following treatment with stabilisation or improvement of VA in 78-100% of cases (Table 1). However, the majority of these studies were retrospective case series with numbers ranging between four and 27 patients, and some had received previous treatments prior to the one investigated. Others, however, have reported less favourable visual results similar to those presented herein ( Table 1). Artunay and colleagues [41] investigated the use of combined intravitreal ranibizumab and reduced fluence PDT in a prospective case series which included 10 treatment-naïve cases. At 12 months, they achieved stable (within two Snellen lines from baseline) or improved VA (> two Snellen lines) in 90% of cases.  In the current study, stabilisation or improvement of VA was achieved in 56% of eyes treated with anti-VEGF (n=25) with only 20% experiencing a > two Snellen lines of visual acuity improvement. This is in keeping with findings by Noda, et al. [40] and Bhatnagar, et al. [27] in their small case series, and slightly more favourable that outcomes reported by Mimoun, et al. [35], the largest series, although retrospective, published prior to the current study.

Authors Year # of Eyes # of Patients FU (Months) Design Drug Average # of Injections
Although this study has several limitations, including the small number of patients included, missing data (in 35/44 cases data available at baseline and in 30/44 cases data was available at 12 months), the short follow-up period, and the inherent limitation of any surveillance study, namely incomplete ascertainment, it provides important epidemiological data and useful information for the management and counselling of patients with this rare retinal disease.

Conclusions
Patients with AS-associated CNV have now a more favourable visual prognosis with the use of anti-VEGF therapies. Early diagnosis and treatment are essential to restore and maintain vision. Despite of anti-VEGF treatment, in a proportion of patients visual deterioration still occurs and, hence, new therapeutic options are much needed.

Additional Information Disclosures
Human subjects: Consent was obtained by all participants in this study. The North of Scotland Research Ethics Committees on 27/05/2008 issued approval # 08/S0802/66. This study was conducted in accordance with the tenets of the Declaration of Helsinki. The ethics committee waived the need for informed consent for this study. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.