Visual Involvement in Giant Cell Arteritis

Giant-cell arteritis (GCA) is an idiopathic inflammatory condition affecting medium- and large-sized arteries. This condition typically affects females over 50, with a peak incidence in the eighth decade of life. It is a rare disease, with an annual incidence in southern Europe (including Italy) of approximately 12/100000 inhabitants aged > 50 years. This clinical condition has considerable heterogeneity among patients, with different clinical phenotypes recognised, predominantly involving the large vessel (LV-GCA) and the medium-sized arteries of the cephalic district (cGCA). The main complications of cephalic involvement are ischaemic events such as stroke and optic involvement. Visual involvement is a minor but the main prognostic factor in patients with GCA, as it can lead to irreversible vision loss. Patients with visual involvement often exhibit other disease features but with a less intense inflammatory response compared to subjects without visual involvement. Ocular involvement occurs with a wide clinical spectrum of ocular manifestations, from amaurosis fugax and diplopia to permanent loss of visual capacity. This irreversible or partially reversible visual impairment is mainly linked to three mechanisms:

• Arteritic anterior ischaemic optic neuropathy (A-AION), which is present in 90% of cases of irreversible vision loss; it is secondary to ischaemic involvement of the short posterior ciliary arteries that supply the optic nerve head; direct ophthalmoscopy shows typically an oedematous and pale optic disc, with a resolution in cupping characteristics like in glaucomatous optic neuropathy after 4 weeks. In the presence of cilio-retinal artery, the vascular territory of this arterial variation could be involved. This ophthalmological image is being considered for differential diagnosis with non-arteritic anterior ischemic optic neuropathy (NA-AION). NA-AION is caused by a compartment syndrome that occurs at the level of the optic nerve head. This is triggered by even transient hypoperfusion that causes ischemic swelling in an area with little room to expand at the level of the lamina cribrosa. As the therapy is completely different, the differentiation between A-AION and NA-AION is crucial: Hayreh et al. differ these conditions according to the extra-ocular features of GCA and the ophthalmological characteristics (presence of pallor/papillary haemorrhages, cilio-retinal occlusion if arising from a territory with choroidal ischaemia and evidence of choroidal ischaemia or delayed choroidal perfusion).
• In 15% of cases, internal retinal ischaemia occurred during GCA due to involvement of the central retinal artery (CRAO) or one of its branches (BRAO). Direct ophthalmoscopy shows peripheral retinal whitening in contrast to the cherry-red macula. Sub-occlusive involvement of the retinal vasculature provides necrotic spots of certain retinal layers, providing superficial cottony exudates and deep paracentral acute middle maculopathy (PAMM). PAMM was first described in 2013. A single study about 52 patients with visual GCA observed PAMM in 26% of patients, either isolated or in association with other forms of visual involvement. However, this diagnosis requires evaluation by Optical Coherence Tomography (OCT).
• In 5% of cases of GCA, posterior ischemic optic neuropathy (PION) occurs due to altered circulation in the retrobulbar optic nerve. No typical retinal or optic nerve changes are evident on direct ophthalmoscopy.

Various unmet needs in the ophthalmological literature could impact on the management of patients with acute visual impairment in suspected GCA:

1. Semeiological aspects of the rare visual phenotypes are described in studies with sample sizes ranging between 8 and 85 subjects. Multicenter studies with the largest sample sizes and ten-year recruitment do not explain deeply all ophthalmological pictures meanwhile small studies interfere with a clear description of the entire spectrum of ophthalmic semeiotic manifestations, highlighting only the most frequent phenotypes and making diagnosis very complex to date. In this center, among 60 patients enrolled in the last 3 years, 5 patients with PAMM and 2 with atypical A-AION were described, complicating the diagnostic-therapeutic procedure.
2. Types of enrolled GCA patients are a limiting aspect, due to the evolution of vasculitis definition, diagnosis and management (i.e. last updated in American College of Rheumatology guidelines of 2022) and awareness about diagnosis delay and visual prognosis. Therefore, it is important to define ophthalmological manifestations and frequency distributions in enrolled patients according to recent criteria and current clinical practices.
3. Many studies with an ophthalmological focus were published several years ago. New ophthalmological clinical pictures have been recognised (such as PAMM, in 2013) and ophthalmology-focused instrumental technology has advanced considerably, such as high-OCT, Optical Coherence Resonance (OCR) and angio-Optical Coherence Tomography (OCT-A). Moreover, considering that extra-ocular manifestations of GCA may be absent in approximately 20% of patients with visual involvement, it is particularly important to update semeiological knowledge and predictive and prognostic values.
4. PAMM in GCA was described in a few epidemiological studies with a small sample size. Although PAMM could represent the second most frequent form of visual impairment in GCA, OCT is not yet widely used and/or practised in comparison with traditional methods such as ophthalmoscopy and fluoroangiography.

This observational study aims to improve the ophthalmological description of different visual involvement phenotypes in GCA. This will be achieved by utilizing state-of-the-art technology and nosographic knowledge to improve patient diagnosis and prognostic stratification.

The primary objective is a comparison of the frequency of the various semeiological findings by multi-parametric evaluation, among the main pathological ocular alterations of arteritic and non-arteritic aetiology (e.g. A-AION Vs. NA-AION, CRAO from arteritis Vs. CRAO from other causes). The second objectives are:

• Prevalence of the GCA visual phenotypes, including the potential co-existence of several of them (e.g. paracellular retinal ischemia as in PAMM, choroidal and papillary ischemia).
• Integration of clinical findings with ophthalmological methods such as visual acuity, campimetry, retinal fluorangiography, OCT, and OCT-A in various pathological visual conditions.
• Temporal evolution of the visual acuity and semeiological findings after therapy and correlation with prognosis.

This prospective study enrolls patients referred to the emergency room or ophthalmology outpatient clinic for new-onset visual symptoms, for which they will perform the clinical, laboratory and instrumental examinations required by existing clinical practice. For patients with suspected GCA, venous blood samples (18 ml per sample) are scheduled at baseline, and at times 7 days, 3 months and 6 months.

Clinical management and treatment will follow international recommendations per the 2021 American College of Rheumatology (ACR) and 2018 European Alliance of Associations for Rheumatology (EULAR) guidelines, due to the progression of acute visual impairment leading to permanent visual loss. Ophthalmological assessment will be scheduled at baseline (T0), which is repeated after 48-72 hours (T1), 7 ± 2 days (T2), 4 ± 1 weeks (T3), 12 ± 2 weeks (T4) and 26 ± 2 weeks (T5). At each time point, the evaluation includes an assessment of visual acuity, fundus, and visual field. The ophthalmologist frequently recommends fluorescein (FAG) and indocyanine green angiography (ICGA), OCT with high-resolution technique, and OCT-A. In addition to the ophthalmological assessment, patients will also undergo an internal and immuno-rheumatological evaluation to address the management and treatment of the underlying condition causing the visual impairment. Internal or immuno-rheumatology follow-up will depend on the underlying diagnosis and follow normal clinical practice.

In case of suspected ocular flare-up, the ophthalmologist may consider performing a full or partial ophthalmological work-up based on clinical need. The clinical-instrumental data obtained from the ophthalmological assessments will be collected in a standardised electronic database according to the variables described in the case report form (CRF).