Ocular Manifestations of Giant Cell Arteritis

Introduction

Giant cell arteritis (GCA) can have highly variable clinical manifestations and there is limited coverage in the literature on its ocular manifestation. GCA is a large vessel vasculitis classically affecting the branches of the common carotid artery and is associated with end organ ischemia that could precipitate blindness if left untreated. The incidence of GCA is approximately 52 cases per 100,000 people according to a large meta-analysis and it is typically seen in middle-aged to elderly females.¹ The clinical manifestations of GCA include malaise, weight loss, fever, night sweats, proximal muscle pain, headaches, scalp tenderness, jaw claudication, and visual loss.² Current existing diagnostic criteria, established by consensus from the American College of Rheumatologists (ACR) and the European League against Rheumatism (EULAR) include clinical, laboratory, and ultrasound criteria which have not been updated for some time, and therefore could potentially lead to inaccurate diagnosis and risk stratification.³ As the population continues to age, the incidence and mortality of GCA are expected to increase and lead to permanent vision loss in the absence of prompt diagnosis and treatment.

GCA patients may be initially seen in departments other than ophthalmology owing to the diversity of its clinical manifestations. Consequently, clinicians from all specialties should be familiar with the ocular manifestations of GCA to allow for a prompt diagnosis, which relies on laboratory values, temporal artery biopsy (TAB), and some form of vascular imaging for best pre-test probability.⁴ Immediately upon diagnosis, high-dose glucocorticoids should be administered in order to prevent the worsening of ischemic manifestations.⁵ Although immunosuppressive monoclonal antibody therapy such as with tocilizumab can be used for maintenance management for GCA,⁵ ongoing clinical studies are currently being conducted to help determine the comparative efficacy of various classes of immunosuppressive medications and adequate treatment duration to prevent relapse. This review focuses on the ocular manifestations of GCA while discussing current and upcoming diagnostic and management strategies. Increased awareness of diagnostic pathways of GCA can improve the disease prognosis and prevent permanent blindness in many patients.

Ocular Manifestations of GCA

Ocular Symptoms

The incidence of any form of visual symptoms such as ocular pain, diplopia, amaurosis fugax, or vision loss in GCA can vary widely according to published studies.^6,7 Transient ophthalmic manifestations such as amaurosis fugax and diplopia are commonly associated with GCA. Amaurosis fugax is a form of transient vision loss that can either be monocular or binocular, typically due to decreased perfusion of the optic nerve or retina.⁸ Diplopia is also another transient ocular symptom that can occur with GCA due to involvement of the arterial branches of the ophthalmic artery supplying oculomotor nerves or muscles.^8,9 Prior studies have found that a notable number of patients that experienced these ocular symptoms subsequently suffered from permanent vision loss.^8–10 Many of these patients can also present with ocular symptoms without any additional systemic findings indicative of GCA, which may add another layer of complexity. Given that these transient ocular symptoms can often be an early sign of impending blindness, it is crucial to consider GCA in patients presenting with amaurosis fugax or diplopia to allow for timely treatment.

Ophthalmic vessel involvement

Table 1 lists publications the various cohort studies on GCA and ophthalmic vessel involvement. The most common ophthalmic condition associated with GCA is arteritic anterior ischemic optic neuropathy (A-AION) and is responsible for approximately 80% of patients’ prognosis of permanent vision loss.^8,11 Since the posterior ciliary artery (PCA) is the main source of blood supply to the optic nerve head which lacks anastomoses with surrounding arteries, any blood flow interruption could lead to optic nerve head infarction and atrophy with cupping.¹² Figure 1 demonstrates the blood supply to the retina. Under ophthalmoscopy, the optic disc can appear chalky due to edema and cotton wool spots (Figure 2B) or choroidal ischemia can also be visualized in the posterior fundus.^13,14 Choroidal ischemia as an ocular manifestation of GCA has been well demonstrated in the past.¹⁵

Table 1.

List of most recent cohort studies for GCA and visual outcomes

First Author	Title of case	Number of cases/patients	TAB (yes/no)	Findings On Ophthalmic Imaging	Imaging	Treatment	Visual Outcome
Anaël Dumont64	Characteristics and Outcomes of patients with ophthalmologic involvement in GCA	409 patients, 104 with visual symptoms	Yes	Optic disc edema, AION	FA, FP	IV pulses of MP, oral medication	Vision loss, amaurosis fugax, diplopia, and blurred vision
Qian Chen65	GCA presenting with ocular symptoms: Clinical Characteristics and Multimodal Imaging in a Chinese Case Series	15 patients	Yes	Optic disc edema with thickening GCC and RNFL	OCT, CDUS, MRI	IV pulses of MP, oral medication	Most patients had poor visual function but could still perceive light and less than half had permanent vision loss
Emman-uel Héron66	Ocular Complications of Giant Cell Arteritis: An Acute Therapeutic Emergency	54 patients	Yes	Chalky white optic disc edema, cilioretinal artery occlusion, cotton wool spots	FP, CDUS, MRI	Corticosteroids	Amaurosis fugax and permanent blindness
Mariana Portela67	Giant cell arteritis: Is there a link between ocular and systemic involvement?	51 patients	Yes	N/A	CDUS	Corticosteroid	Ocular migraines, diplopia, occipital seizures, and permanent vision loss
Carlo Salvarani57	Risk factors for visual loss in an Italian population – based cohort of patients with giant cell arteritis	136 patients	Yes	N/A	N/A	Oral and IV corticosteroids	Amaurosis fugax, diplopia, permanent vision loss
Antonio Casella15	Choroidal ischemia as one cardinal sign in giant cell arteritis	8 patients	Yes	Choroidal ischemia, paracentral acute middle maculopathy lesions, cotton wool spots, AION, and CRAO	FP, FA, OCT, and OCT-A	Corticosteroids	Amaurosis fugax, permanent vision loss
Alexandre Dentel68	Use of Retinal Angiography and MRI in the Diagnosis of Giant Cell Arteritis with Early Ophthalmic Manifestations	25 patients	Yes	Choroidal ischemia, cilioretinal artery occlusion, AION, CRAO	FA, ICG, MRA	N/A	Amaurosis fugax, diplopia, and permanent vision loss

Figure 1:

Blood supply to the retina. From Stroke.2021;52:e282-e294 ©2021 American Heart Association, Inc., with permission.⁶²

Figure 2:

[A] is a normal OPTOS widefield image of the right eye which is the unaffected eye. [B] is an OPTOS widefield image of the left eye, which was affected with a cilioretinal artery occlusion. The cotton wool spot (yellow arrow) can be appreciated along the inferior aspect of the macula. [C] is an optical coherence tomography of the left eye affected with the cilioretinal artery occlusion and a paracentral acute middle maculopathy (red arrow) can be appreciated by the hyperreflective (whitening) band-like lesion in the inner nuclear layer of the retina along the inferior aspect of the macula. [D] is a fluorescein angiogram of the left eye affected with the cilioretinal artery occlusion demonstrating delayed filling (green arrow) in the inferior aspect of the macula.

Another ischemic condition affecting the optic nerve in GCA patients include arteritic posterior ischemic optic neuropathy (A-PION); this occurs less commonly than A-AION.⁸ A-PION is due to ischemia in the posterior segment of the optic nerve. This portion of the optic nerve is supplied by the pial capillary plexus, which contains many collateral branches that provide anastomoses with one another therefore decreasing the visibility of optic nerve abnormalities (pallor, edema) on ophthalmoscopy.¹⁶ To further aid in the diagnosis of these ischemic ocular conditions of the optic nerve, testing for visual acuity, direct visualization of the optic nerve, and visual field testing with Humphrey visual field should be deployed. These ocular conditions associated with GCA is an ophthalmic emergency and requires prompt treatment to prevent further irreversible vision loss.

The central retinal artery (CRA) is a branch of the ophthalmic artery that can be occluded in GCA patients, resulting in central retinal artery occlusion (CRAO) and permanent blindness. During fundoscopic examination of CRAO, there is a distinct cherry-red spot visible at the maula from ischemia leading to paleness of the retina. In a prior study, the incidence of CRAO was 12% of the eyes in GCA patients.⁸ This is a result of the CRA branching from the ophthalmic artery with an anastomosis with the PCA; however, the anastomosis is not enough to prevent ischemia.¹⁷ Another artery that branches directly or indirectly from the PCA is the cilioretinal artery which can also become occluded (Figures 2A – 2D). For such a rare ocular presentation, there are limited numbers of studies describing cilioretinal artery occlusion being associated with GCA.^18,19 These case presentations describe optic disc pallor with the addition of a retinal infarct along the region of the cilioretinal artery leading to choroidal hypoperfusion.^18,20 To enhance the diagnosis of retinal artery occlusive conditions, direct fundus visualization for retinal whitening and ancillary diagnostic ophthalmic imaging should be utilized. A prior study demonstrated that visual outcome of patients with GCA due to CRAO is poor even after steroid treatment.⁷ Even though prognosis is poor, timely diagnosis and recognition of GCA associated retinal ischemia is essential to prevent vision loss in the fellow eye.

Diagnostic Approaches for GCA

To diagnose GCA, it is essential to have a complete clinical framework of recognizing clinical symptoms, laboratory testing, diagnostic imaging, and histopathological findings. The symptom of jaw claudication appears to be the most specific symptom as the odds of a positive TAB were nine times greater when presenting with this symptom.²¹ The non-specific inflammatory markers of erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels can aid in the diagnosis. CRP was shown to be more sensitive (100%) than ESR (92%) for the detection of GCA, but the combination of both laboratory results give the specificity (97%) for GCA.²¹

There are various imaging modalities that can aid in the diagnosis of GCA including color doppler ultrasound (CDUS), computed tomography angiography (CTA), magnetic resonance angiography (MRA), and positive electron tomography-computerized tomography (PET-CT). Although each of these imaging modalities has its own advantages and disadvantages, there is a current lack in the literature of comparative diagnostic effectiveness data. The detection of the halo sign on ultrasound (Figure 3), which is a dark area surrounding the lumen of the temporal arteries on CDUS has good accuracy for the diagnosis of GCA.²² CTA and MRA can be utilized to better visualize larger arteries in order to diagnose GCA if the temporal arteries are not affected.²² The Vessel Wall Imaging Study Group of the American Society of Neuroradiology recently outlined the utilization of black-blood MRI which suppresses the signal of blood flow therefore allowing enhancement of the vessel walls to detect inflammation.²³ One prior study utilized the black-blood MRI technique in detecting GCA and found that imaging demonstrated inflammatory findings within the orbit.²⁴ Another study also supports this imaging modality as the results showed good diagnostic accuracy and reliability when it comes to detecting GCA in the superficial cranial arteries.²⁵ The use of MRA as the first imaging examination followed by ultrasound or ophthalmic imaging has been shown to have the best diagnostic performance for identifying GCA.²⁶ PET-CT has also been shown to help aid in the early diagnosis of GCA with high sensitivity and specificity. There appears to be a positive correlation between the development of angiographic change in GCA with PET activity.²⁷ However, it has also been demonstrated that the initiation of corticosteroids can lead to a false negative result, although there may be some benefit from utilizing this modality to monitor GCA disease activity after treatment initiation.²⁸ According to a prior study, the use of tocilizumab for patients with GCA demonstrated reduction of vascular inflammation measured with PET and this shows that it could be a useful tool to monitor response to certain treatments for GCA.²⁹ In contrast, there have also been varying reports about the utility of FDG-PET to monitor disease activity suggesting interpretation of FDG-PET is less reliable once immunosuppressive therapy was initiated and reporting persistence of FDG uptake in absence of clinically active disease.^30,31

Figure 3:

CDUS of a TAB specimen demonstrating classical hypoechoic halo sign of GCA (arrows). (Left) Cross sectional view. (Right) Longitudinal view. From “The impact of temporal artery biopsy on surgical practice” by A. Cristaudo 2016 with permission.⁶³

Furthermore, the use of ophthalmic imaging modalities such as fluorescein angiography (FA), optical coherence tomographic angiography (OCT-A), and laser speckle fluoroscopy (LSFS) can also aid in the diagnosis of GCA. The use of FA can visualize the retinal vasculature, which has shown to be useful in diagnosing GCA in addition to imaging the temporal artery. On FA, choroidal filling delay is an established sign of GCA due to the thrombosis that occurs in the PCA, which is more proximal to the choroidal vasculature.^15,32 It has been shown that the choroidal filling time was delayed by approximately one minute in a biopsy-confirmed GCA group compared to a non-arteritic AION group.³³ The OCT-A imaging technique is another modality that can be utilized to visualize the microcirculation of the retina and choroid, which allows for the isolation of vascular pathology and individual analysis of each vascular plexus.³⁴ OCT-A has proven useful in diagnosing and monitoring choroidal ischemic pathologies.³⁵ LSFS is another scanning modality that can help diagnose GCA by quantifying the relative changes in blood flow. It was initially created to measure blood flow within the retina and now is a technique commonly used in research of systemic conditions that affect microcirculation such as diabetes, ischemic stroke, peripheral artery disease, and coronary artery disease.^36,37 There are currently no studies in the literature investigating the utilization of OCT-A and LSFS in the diagnosis of GCA, but these imaging modalities can be a promising tool given their ability to diagnose choroidal ischemia, which is a known ocular manifestation of GCA.

Despite the various imaging modalities available to assist in the diagnosis of GCA, TAB remains the gold standard. On histology, a lymphocytic inflammatory infiltrate can be seen within the arterial wall with destruction of the internal elastic lamina.³⁸ This test yields a sensitivity of 77% and a specificity of 100%; however, it is not a mandatory criteria as outlined by the American College of Rhuematology.^3,39 There have also been instances of false-negative biopsies as there can be inactive areas of arteritis on the temporal artery or the sample length acquired during biopsy was too small.⁴⁰ Prior studies have shown that corticosteroid treatment has limited effects on TAB results.^41,42 It is important to initiate treatment of high-dose corticosteroids when GCA is suspected as the risk of irreversible vision loss is far more detrimental to the patient.

Treatment and Management

The initial treatment for GCA consists of high dose oral or intravenous corticosteroids. Corticosteroids often result in early improvement within hours to days of initiating treatment and have demonstrated a significant reduction in the risk of permanent visual loss by up to 80%.⁴³ The dosing recommendation vary widely in prior literature with higher doses reserved for patients with neuroophthalmological symptoms of GCA.⁴⁴ When comparing the differences between oral or intravenous corticosteroids, visual improvement was seen in both groups with no significant differences, but early treatment is the most important prognostic factor to prevent further visual loss.^7,45 However, according to the EULAR recommendations for the management of GCA, it is best to use high dose intravenous pulse methylprednisolone for three days prior to switching to oral formulations in order to preserve vision in the contralateral eye.⁴⁶ Small retrospective cohort studies have demonstrated the superiority of utilizing high dose intravenous glucocorticoids to prevent visual involvement in contralateral eyes, but the recommendations remain controversial.^47,48 Additional prospective studies are necessary to determine the use of oral compared to intravenous corticosteroids for GCA with visual involvement.

Additional forms of management include immunomodulators that are steroid sparing such as tocilizumab. Tocilizumab is a recombinant antibody against the interleukin-6 receptor with immunosuppressant activity. Studies have demonstrated that tocilizumab used as monotherapy or in association with glucocorticoids can be clinically beneficial^49,50; however, additional studies are needed to standardize treatment guidelines. Methotrexate, for example, is another immunomodulator that can reduce relapses and the need for glucocorticoids for treatment.⁵¹ No other disease modifying anti-rheumatic drugs have been tested extensively in clinical trials for the use of GCA to date.

To effectively manage GCA, it is essential to have a multidisciplinary team consisting of rheumatologists, radiologist, and ophthalmologists. Rheumatologists have extensive experience in managing systemic inflammatory conditions and overall corticosteroid regimen by monitoring for systemic side effects. Radiologists play an integral role in the diagnosis of GCA as imaging studies can have significant positive predictive diagnostic value. Ophthalmologists directly evaluate ocular manifestations of GCA by monitoring the response of visual symptoms to corticosteroid treatment and identify associated ocular complications such as cataracts or steroid-induced glaucoma. Multidisciplinary collaboration maximizes the probability of early detection and treatment, which is crucial to prevent impairment of vision. Since GCA is a chronic condition with potential for relapse, multidisciplinary management is the most effective holistic approach to the patient’s health.

Treatment response and detection of recurrent disease

Relapses can frequently occur within the first year during the corticosteroid taper affecting up to 50% of patients.⁵² Major relapses are defined as reactivation that may lead to another ischemic event resulting in ophthalmologic damage, jaw claudication, or scalp necrosis; however, patients can also experience mild clinical symptoms in the form of minor relapse.³ A study revealed normal ESR and CRP values in patients who experience relapses, raising concern about a lack of reliable prognostic markers available to monitor the disease.⁵³ Though corticosteroids have significant benefits in the treatment of GCA, their significant side effects are such that it is critical for clinicians to find the right balance in the delivery of treatment. Adverse effects of steroids are often dose-dependent and duration-dependent with some common adverse effects including osteoporosis, metabolic syndrome, infections, and even adrenal insufficiency.⁵⁴

Biomarkers for disease status and treatment response monitoring

There are limitations to the use of PET-CT to monitor GCA. Currently, studies are underway to address the lack of accurate blood biomarkers of GCA, necessitating the assessment of all inflammatory markers for the diagnostic workup. A highly specific biomarker could improve diagnostic accuracy, patient management, and even reduce or obviate the need for a temporal artery biopsy. Several categories of biomarkers are being investigated in the diagnosis of GCA. Currently, CRP, ESR, leukocytes, and platelets are being utilized to help with risk stratification for GCA diagnosis, but there is only moderate agreement between the values.⁵⁵ Biomarkers involved in inflammation, vascular involvement, macrophage involvement, extracellular remodeling, lymphocyte activation, and cell migration can be indicative of inflammation processes that are specific for GCA.⁵⁶ Some of these biomarkers could possibly play a role in monitoring disease status and/or treatment response in the future.

Biomarkers may also be predictive of complications or treatment options for GCA. A higher ESR at diagnosis has been linked to a smaller risk of large vessel stenosis.⁵⁷ It has been postulated that CRP and ESR levels may not be an accurate way to measure the severity of GCA since some patients can present with normal levels.⁵⁶ When evaluating the risk for complications, one study found that GCA patients with ischemic complications had lower IL-6 levels both in serum and in the temporal artery at diagnosis compared to patients who had no complications.⁵⁸ The loss of self-tolerance in the adaptive immune system, specifically in the NOTCH pathway has demonstrated to be an immunosuppressive pathogenesis of GCA.⁵⁹ Another study has shown that the loss of function in inhibitory immune checkpoints CD155-CD96 can contribute to aberrant activation of IL-9 production also contributing to GCA.⁶⁰ The GM-CSF signaling cascade is another pathway that plays an vital role in GCA, which is currently being investigated as a target for pharmacotherapy.⁶¹ All these checkpoint inhibitors and signaling pathways are integral in the prevention and development of therapeutic management for autoimmune diseases like GCA. Treatment response can ultimately be difficult to monitor as there are currently no well-studied biomarkers that can accurately determine severity. Additional studies will need to evaluate these newly discovered biomarkers in GCA and their specific role in ocular involvement.

Summary

GCA can have a highly variable clinical presentation, which can cause difficulties and delays in reaching the diagnosis. Patients who are not diagnosed in a timely manner may experience ocular manifestations that could possibly result in permanent unilateral or bilateral vision loss. Prompt diagnosis and treatment are crucial in GCA as any form of delayed treatment can have dire consequences to a patient’s visual prognosis. Currently, there are limited studies evaluating the visual outcomes and ophthalmic manifestations in patients with GCA. No standardized guidelines have been developed to determine the best strategy in detecting visual relapse. There also appears to be continued debate on treatment modality, treatment duration, and the role of maintenance therapy. We anticipate that the discovery of additional ophthalmic biomarkers will aid in better earlier recognition of GCA and decrease the incidence of vision loss

Key Points:

• Jaw claudication is a hallmark of GCA and plays a critical role in its diagnosis.

• Ocular involvement in GCA can result in irreversible vision loss; prompt treatment is essential to preserve vision.

• Early administration of intravenous corticosteroids is crucial for managing ocular involvement in GCA.

Synopsis:

Giant cell arteritis (GCA) is a large-vessel vasculitis that can present with ocular manifestation and lead to irreversible blindness if left untreated. Initially, patients can present with a wide array of systemic symptoms and ophthalmic manifestations varying from jaw claudication to amaurosis fugax. The use of ancillary ophthalmic imaging can be promising in aiding the diagnosis of GCA. Accurate and early diagnosis of GCA is critical in guiding prompt treatment with corticosteroids to preserve vision. Studies are currently underway to determine the best treatment regimen for GCA to prevent relapse and vision loss.

Abbreviations:

GCA

giant cell arteritis

TAB

temporal artery biopsy

A-AION

arteritic anterior ischemic optic neuropathy

A-PION

arteritic posterior ischemic optic neuropathy

ESR

erythrocyte sedimentation rate

CRP

C-reactive protein

CDUS

color doppler ultrasound

MRA

magnetic resonance angiography

CTA

computed tomographic angiography

PET-CT

positron emission tomography-computed tomography

FA

fluoresceine angiography

OCT-A

optical coherence tomographic Angiography

LSFS

laser speckle fluoroscopy