Abstract
Introduction
Angioid streaks is a rare retinal condition with pathological fissures in Bruch's membrane due to an abnormal and calcified Bruch's membrane. The condition can occur idiopathic or in association to other conditions. Development of macular neovascularization (MNV) in these angioid streaks, and MNV-related exudation, development of atrophy or in rare cases traumatic rupture can lead to visual symptoms.
Case description
This report describes a case of angioid streaks which was diagnosed after a blunt trauma that lead to visual symptoms and further examination revealed MNV with traumatic rupture. Anti-vascular endothelial growth factor treatment using faricimab was commenced with three injections at four weeks intervals. Family history raised suspicion of a systemic disease, and genetic work-up led to a diagnosis of pseudoxanthoma elasticum. The MNV treated with faricimab led to excellent visual results and no exudative recurrence during a follow-up period of 8 months after the last injection.
Conclusion
This case report presents a clinical approach for managing MNV with traumatic rupture secondary to angioid streaks and is also the first case to present results of faricimab use for these lesions.
Keywords
Introduction
Angioid streaks are pathological fissures in Bruch's membrane, typically presenting as irregular, radiating lines extending from the optic disc toward the peripheral retina. These lines may appear grey, reddish-brown, or dark red upon fundoscopic examination and can resemble retinal blood vessels due to their color and orientation. Histologically, angioid streaks correspond to breaks in an abnormal and calcified Bruch's membrane. These fissures can facilitate the ingrowth of fibrovascular tissue from the choroid into the sub-retinal pigment epithelial (sub-RPE) space, particularly where the RPE is thinned. This process may result in subretinal hemorrhage, macular neovascularization (MNV), and disciform scarring. Angioid streaks are typically bilateral and may coexist with other abnormalities such as optic disc drusen and atrophic changes in the retinal pigment epithelium.
While angioid streaks can appear idiopathically, many cases are associated to other conditions. Popularly, the mnemonic PEPSI is used to remember its associations: Pseudoxanthoma Elasticum, Paget's disease of bone, Sickle cell disease, and Idiopathic. The most common associated condition is pseudoxanthoma elasticum, which is characterized by progressive calcification and degeneration of elastic fibers in tissues such as the dermis, Bruch's membrane and vascular walls.1,2 Because of an increased risk of cardiovascular disease and cerebrovascular infarcts, pseudoxanthoma elasticum can be potentially life-threatening. 2 Previously, Ehler-Danlos Syndrome was given for the E in the mnemonic, however, recent large-cohort investigations were able to show that this single-report based fact is not validated in larger cohorts.3,4 The other associated conditions (Paget's disease of bone, and sickle cell disease) also increases risk of early death. Thus, for angioid streaks, a thorough work-up to identify a potentially associated condition may be lifesaving.
Although angioid streaks itself remain asymptomatic, involvement of the fovea, with disruption of the RPE or photoreceptors, or the development of MNV may lead to visual symptoms including metamorphopsia and reduced central visual acuity. Management of MNV secondary to angioid streaks has largely mirrored that of neovascular age-related macular degeneration (AMD), with anti-vascular endothelial growth factor (anti-VEGF) agents such as ranibizumab, bevacizumab, and aflibercept demonstrating efficacy in controlling neovascular activity and stabilizing or improving vision. 1 5–7
This case report presents a case of a patient with angioid streaks unaware of this condition and without any symptoms until receiving a tennis ball to the eye. Retinal examination revealed a traumatic choroidal rupture in relation to a presumed previously inactive MNV. The MNV was treated using faricimab (6.0 mg/0.05 ml) (F. Hoffmann-La Roche, Basel, Switzerland), to which there is no reports to date for its use on MNV secondary to angioid streaks. Faricimab is a bispecific monoclonal antibody which targets both VEGF-A and angiopoietin-2 (Ang-2). This dual inhibition addresses both neovascularization and vascular instability. Faricimab has shown promising results in the treatment of neovascular AMD and other exudative retinopathies. 8 The decision to treat with faricimab rather than other anti-VEGF agents was based on our local treatment protocol which employs faricimab as a first line therapy for all MNVs. The patient underwent work-up to identify an associated condition, and the patient was diagnosed with pseudoxanthoma elasticum.
Case description
A 30-years old Caucasian man seeked a local general ophthalmologist because of central scotoma after receiving padel tennis ball towards the right eye. The general ophthalmologist finds unremarkable anterior segment in both eyes, unremarkable fundoscopy in the left eye, and subretinal hemorrhage in the right eye. The patient is conservatively observed for two months and then referred to our tertiary center ophthalmology department due to persisting subretinal hemorrhage in the right eye.
At the first examination at our department, the patient described that the central scotoma in the right eye had changed into blurry vision and metamorphopsia. He had no history of ocular or systemic comorbidities. The best-corrected visual acuity (BCVA) right eye (RE) / left eye (LE) was measured to 0.8/1.2 Snellen and the intraocular pressure (IOP) RE/LE was 17/19 mmHg. The anterior segment of both eyes were unremarkable. Retinae were examined using fundoscopy, optical coherence tomography (OCT) (Topcon Triton OCT, Tokyo, Japan), OCT angiography (Topcon Triton OCT, Tokyo, Japan), scanning laser ophthalmoscopy-based fundus pseudocolor photography (OPTOS California, Nikon, Tokyo Japan), and fundus autofluorescence (OPTOS California, Nikon, Tokyo Japan) (Figure 1). In both eyes, the patient had optic disc drusen and angioid streaks. Macula of the right eye had subretinal hemorrhage and subretinal fluid in the superior and temporal part of the fovea extending towards the superior peripapillary area. OCT angiography revealed an underlying type 1 MNV (Figure 2). Angioid streaks on the left eye were without any exudative findings or MNV in OCT angiography. Although the patient had no history of systemic comorbidities, family history revealed that his father and paternal uncle died at an early age from acute myocardial infarction, and his paternal grandfather died at age 40 from the same cause. They were all of Caucasian race and were never diagnosed with any inherited diseases. No clear skin lesions were presents. The patient agreed for a genetic testing for which we applied a broad retinal dystrophy genetic panel including ABCC6 with whole exome sequencing for the suspicion of pseudoxanthoma elasticum. The genetic test identified heterozygote presence of the variant ABCC6 c.2787 + 1G > T, which is associated with pseudoxanthoma elasticum. The patient was diagnosed with pseudoxanthoma elasticum and referred to clinical genetics for further counseling and cardiological assessment.
Retinal examination of both eyes (right eye in the left column, left eye in the right column) with rows illustrating (from top to bottom): OPTOS scanning laser ophthalmoscopy (SLO)-based fundus pseudocolor photography, OPTOS-based fundus autofluorescence (FAF), color fundus photography with indication of the optical coherence tomography (OCT) scan area, and central OCT scan. SLO-based photography reveals the presence of angioid streaks in both eyes as dark irregular lines that radiate from the optic disc. Macula of the right eye also presents with subretinal hemorrhages and white lesions in the superior and temporal part of the fovea extending towards the superior peripapillary area which is suggestive of an underlying macular neovascularization (MNV). FAF images show hyper-FAF in both eyes in the nasal and superior part of the optic disc from the optic disc drusen, hypo-FAF in both eyes corresponding to the angioid streaks, and hypo- and hyper-FAF in the right eye in the superior and temporal part of the fovea extending towards the superior peripapillary area corresponding to the MNV. SLO-based photography and true-color fundus photography of the right eye illustrates areas of subretinal hemorrhages and indicative of a choroidal rupture. OCT shows subretinal fluid and subretinal hyperreflective material in the right eye corresponding to the MNV and is without any exudative findings in the left eye.
Top series of images show baseline optical coherence tomography (OCT) angiography-based diagnosis of subretinal macular neovascularization (MNV) in the right eye with respect to the spaces of the underlying fovea-near angioid streaks. The en face OCT-angiography segment corresponding to the outer retina and the choriocapillaris clearly shows the MNV in the superior and temporal part of the fovea extending outside of the scanning area towards the superior peripapillary area. Bottom series of images show follow-up OCT angiography 2 months after the last faricimab therapy, which shows a fibrotic MNV lesion without any subretinal fluid or other signs of activity.
Faricimab treatment was commenced as 3 intravitreal injections with 4 weeks apart, and a follow-up visit 4 weeks after the last injection. At the follow-up visit, the BCVA in the right eye was 1.0 Snellen, and the subretinal fluid and the subretinal hemorrhages were resolved and the MNV lesion was fibrotic (Figure 3). OCT angiography-based examination 2 months after the last injection also showed a fibrotic inactive MNV lesion (Figure 2). No further treatment was planned, as the patient was enrolled in an “as-needed” treatment protocol, and the patient was observed closely throughout follow-ups (Figure 3). Further extrafoveal and lesion centered scans also showed extrafoveal resolution of the subretinal fluid and subretinal hemorrhages (Figure 2). The patient described that injection therapy had stabilized vision on the right eye, but that he still could see the difference between the right and the left eye. The patient was followed closely for a total of 8 months after the last faricimab therapy with subjective stability in vision, objective stability in BCVA in the right eye with 1.0 Snellen at all follow-up visits, and anatomic stability without recurrence of fluid (Figure 3).
Faricimab therapy was commenced on the day of first visit to our department as intravitreal injections with 4 weeks apart, with a follow-up visit 4 weeks after the last injection. At the first follow-up, the subretinal fluid and the subretinal hemorrhages were resolved and the macular neovascular lesion had become fibrotic. No further injections were given. Anatomical stability was observed at all of the following follow-ups.
Because of the apparent stability, the patient was recommended annual retinal examinations with advice to contact the ophthalmologist earlier upon any recurrence of visual symptoms. In Denmark, cases with inactive MNV and anatomic stability for at least 6 months after the last anti-VEGF injection are followed by a local ophthalmologist within the Danish public eye care system as per national guidelines.
Conclusions
An important clinical diagnostic take-away from this case description is that family history revealed several cases of cardiovascular diseases as a cause of early death, which is highly suggestive of the condition being associated to a systemic and inherited condition rather than an idiopathic case of angioid streaks. In our case, the patient history and clinical findings led to genetic work-up, and the patient was diagnosed with pseudoxanthoma elasticum. In our setting, clinical geneticists follow these patients and ensure cardiological assessment and counseling for the prevention and active treatment of cardiovascular diseases. In doing so, this may improve the survival of our patient and potentially also his children.
MNV is the most common and vision-threatening complication in patients with angioid streaks, especially when the foveal region is involved. These abnormal neovascular complexes can result in central visual loss and metamorphopsia. Prompt treatment is critical to prevent irreversible structural damage, including subretinal fibrosis and permanent foveal scarring. 6 Compared to AMD, patients with PXE need treatment for exudative MNV occurs about 15 years earlier and are more often bilaterally. 9
In the present case, a young male patient with trauma-associated subretinal hemorrhage and MNV in the right eye in the setting of bilateral angioid streaks was treated with three intravitreal injections of faricimab. MNVs can be secondary to both angioid streaks and traumatic choroidal rupture. In this case, our hypothesis is that an inactive MNV was already present prior to the trauma, and that the trauma led to choroidal rupture and activation of the MNV. We hypothesize this because of the short period from trauma to retinal examination, and that it can be considered unlikely for such a well-formed MNV to develop in such a brief period. Treatment led to full anatomical resolution of subretinal fluid and hemorrhage, stabilization of the MNV lesion, and improvement in best-corrected visual acuity from 0.8 to 1.0 Snellen. No recurrence or adverse events were observed during an 8-month follow-up period. Martinez-Serrano et al. did a 4-year follow-up of seven cases of MNV secondary to angioid streaks treated with either bevacizumab (1.25 mg/0.05 ml) or ranibizumab (0.5 mg/0.05 ml) and found that cases regularly exhibited exudative recurrence which necessitated additional anti-VEGF therapy. 5 Based on a pro re nata regimen, mean time between the injections was 3.8 ± 2.7 months (range 1.9–5.8 months). 5 It is unclear whether faricimab in such cases may provide a lower recurrence rate as demonstrated in our case. One important limitation of our case report is that our follow-up time from the last anti-VEGF treatment was 8 months. Larger case series with longer follow-up period is needed.
The optimal treatment regimen or follow-up interval in cases with MNV secondary to angioid streaks remains to be determined. The recurrence rates seen in the Martinez-Serrano et al. study indicates the need for continuous follow-up in a pro re nata regimen when treating with either bevacizumab or ranibizumab. In a large study of 168 eyes with angioid streaks and MNVs, Cicinelli et al. found that during a 5-year follow-up time, 65% of type 1 MNVs remained non-exudative and 36% evolved into exudative. 10 Raming et al. reported the outcomes of 108 eyes with angioid streaks with MNV of patients diagnosed with pseudoxanthoma elasticum and followed for a median of 77 months. 9 Eyes received a single anti-VEGF injection (bevacizumab, ranibizumab, or aflibercept) and then followed monthly in a pro re nata regimen. 9 During the first year, a median of 5.5 injections were necessary to manage this condition, and the median number of injections per patient during the follow-up period was 28. 9 Altogether, these studies indicate that long-term exudative recurrence is likely to occur in a substantial proportion of the patients.
Footnotes
Acknowledgements
None.
Ethical considerations and Consent for publication
The patient gave oral and written consent to publish this case. No further approvals are needed for case reports according to Danish law.
Funding
The authors received no financial support for the research, authorship, and/or publication of this article.
Declaration of conflicting interests
The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Author Y.S. declares to have received speakers fee from Bayer and Roche, and to be the inventor of a patent related to the use of biomarkers of polypoidal choroidal vasculopathy (WO2020007612A1), not related to this work. All other authors declare that no potential conflicts of interests exist in relation to this work.
Data availability statement
All data are contained in the manuscript.