Case
A 75-year-old Caucasian woman presents to her ophthalmologist with acute visual loss in her right eye (OD). Her past medical history includes hypertension that is well controlled with an angiotensin converting enzyme inhibitor, as well as a hysterectomy. She takes a baby aspirin a day. She had undergone cataract extraction and lens placement in both eyes (OU) 10 years previously. She does not drink alcohol or use tobacco.
Optic discs of a 75-year-old woman with acute visual loss in the right eye (right optic disc on left, left optic disc on right). The right optic disc has mild pallid swelling and there is a nerve fiber layer infarct at 9 o’clock. The left optic disc is normal with cup:disc ratio of 0.5
Introduction
GCA is the most common primary vasculitis of the elderly in the Western world [1]. Visual symptoms due to GCA is a neuro-ophthalmic emergency. In up to 60% of patients, acute vision loss occurs [2]. There is an increased prevalence in Caucasian women over 50 years old [3]. There is evidence to suggest an increase in the number of patients being investigated for GCA [4]. Prompt diagnosis and urgent intervention with corticosteroids are of paramount importance to prevent blindness and stroke.
GCA affects large and mid-sized arteries, with a preferential effect on branches of the internal and external carotid arteries [5]. Headache, the most common symptom in patients with GCA, is believed to be due to inflammation of branches of the external carotid artery [6]. Jaw claudication, which has been shown to be the most specific symptom of GCA, is a consequence of ischemia to the masseter muscle supplied by the maxillary artery [7]. Ischemia of the retrolaminar portion of the optic nerve occurs at a watershed zone supplied by the short ciliary arteries and the ophthalmic artery [8]. On temporal artery biopsy the classic findings include necrosis of the internal elastic lamina of the vessel wall with granulomas containing multinucleated histiocytes and lymphocytes are seen. This marked inflammation causes direct occlusion or thrombotic occlusion of the affected vessels [9].
Arteritic anterior ischemic optic neuropathy (AAION) is the most common cause of visual loss due to GCA [10]. Other causes of visual loss include posterior ischemic optic neuropathy (PION), central and branch retinal artery occlusion, and choroidal infarction [11]. In contrast to nonarteritic AION, in AAION, the visual loss is often profound [12]. Disc edema may be present or absent (AION vs. PION respectively). When present, its classic appearance is one of chalky pallor, oftentimes associated with cotton-wool spots due to ocular ischemia. Additionally, the intraocular pressure may be reduced, and strabismus may be seen secondary to cranial nerve palsies, all secondary to ischemia [13, 14]. This case (Fig. 4.1) does not have the small “disc-at-risk” usually seen in NAION and thus the suspicion of AAION must increase considerably.
General Diagnostic Considerations
Acute visual loss in the elderly should be considered as temporal arteritis until proven otherwise. In these patients it is important to ask about a history of headaches, malaise, jaw claudication, fevers, and recent unintentional weight loss.
What Clinical Features Prompt You to Consider GCA?
Most patients with AAION present with acute and profound visual loss. Patients may also complain of prodromal symptoms of amaurosis, pain, or diplopia. The case presented with a history of preceding transient visual loss is especially important in that typically non-arteritic anterior ischemic optic neuropathy (NAION) is sudden, and not preceded by transient visual symptoms (e.g., amaurosis fugax). Any visual symptoms in the other eye are very worrisome and second eye involvement in untreated GCA can occur in up to 75% of untreated patients within days [11]. Patients may have headache, jaw claudication, scalp tenderness, fever, malaise, and unintentional weight loss [15]. A large proportion have coexisting polymyalgia rheumatica [15].
Up to a fourth of patients with GCA will have visual complaints only, without systemic symptoms (i.e., “occult” GCA) [16] and present a diagnostic challenge [17]. Therefore, ophthalmologists and other health care providers need to always have GCA on their “clinical radar”, and consider ESR and CRP testing even in patients who voice no systemic complaints.
What Investigations Do You Typically Order When You Are Concerned About GCA?
Immediate (STAT) lab tests include Erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), as well as a complete blood count (CBC) with differential (platelets in particular). Fundus fluorescein angiography (FFA) can be ordered to look for delayed choroidal perfusion (especially in PION). Sane et al. has demonstrated with FFA that sluggish retinal circulation can occur in GCA due to partial and reversible thrombotic occlusion or vasospasm of the central retinal artery [18]. Temporal artery ultrasound can be obtained. Of course, temporal artery biopsy (TAB) should be done to establish definitive diagnosis. The decision to proceed with TAB depends on the results of the investigations, but importantly, this decision is based on the entire presentation and laboratory results. A patient may have GCA even with normal blood tests.
Diagnostic Approach
- 1.
Evidence of extracranial circulation ischemia (AION, PION, CRAO, ophthalmic artery occlusion),
- 2.
New onset headache,
- 3.
Abnormal laboratory results (ESR, CRP, platelets),
- 4.
Jaw claudication,
- 5.
Abnormal superficial temporal artery (pulseless, localized pain),
- 6.
Constitutional symptoms (fatigue, malaise, fever, weight loss), and
- 7.
Polymyalgia rheumatica.
Patients who have one positive finding have low clinical suspicion, and an alternative diagnosis must be sought. If the TAB is negative in patients with high clinical suspicion for GCA, a contralateral TAB should be considered [19]. In most cases, a unilateral TAB is sufficient in suspected cases of GCA [20], but in 3–5% of cases, there can be significant differences in the pathologic grade of disease from one side to the other [21]. In an editorial review of the subject, Miller discussed the lower risk of the TAB compared with the significant risk of vision loss due to a missed diagnosis of GCA and concluded that bilateral simultaneous or sequential TAB should be considered [22]. Clinical judgment is also important, and not every patient with a low suspicion of GCA needs bilateral TAB [23]. Because of “skip-lesions” (portions of artery not effected by inflammation), a long TAB length is recommended [24].
Of note, normal ESRs can be estimated as (age × 0.5) for men, and ((age + 10) × 0.5) for women. An elevated ESR is a non-specific test, and can be found to be elevated in the setting of renal disease, lowered in patients taking non-steroidal anti-inflammatory agents and statins, and can be normal even in TAB proven GCA [25]. An elevated CRP is more sensitive test than ESR in the diagnosis of GCA [26], and when both CRP and ESR are elevated, there is a 97% specificity for the diagnosis of giant cell arteritis [27]. Non-invasive vascular studies such as ultrasound of the superficial temporal artery are not sensitive and specific enough to be considered as providing significant diagnostic yield in the setting of GCA, and have yet to be used as a standard of care in the United States [28].
Treatment
Immediate high dose glucocorticoids are required to protect the vision [2], the preferred route of either intravenous or oral differs considerably between doctors and practices. Some find admission to hospital can be helpful to facilitate the evaluation, and initiate intravenous pulse therapy with 1 g intravenous (IV) methylprednisolone administered for 3 (and for some up to 5) consecutive days in those with visual symptoms and/or other risk features of ischemic vasculitic complications. High dose oral prednisone such as 80 mg is used alternatively to IV.
Some studies have demonstrated an improvement in vision with corticosteroid treatment, and this was found to be more significant in patients treated initially with intravenous corticosteroids versus oral steroids [29]. The debate continues with some authors arguing that immediate administration of IV corticosteroids shows no greater benefit than do oral corticosteroids in the treatment of GCA [30, 31]. There is some consensus that a patient presenting with severe vision loss should be given at least one dose of intravenous steroids [32].
The majority agree a slow oral steroid taper over 12–18 months is appropriate. Some use 1 mg/kg, decreasing by approximately 10% every 2–4 weeks, others suggest 80 mg prednisone and taper each month in the following manner: 60–40–30–20–15–10–5 and stay at 5 mg at least for the duration of 12 months after initial diagnosis. This is dependent on the patient’s symptoms, examination findings, and acute phase reactants during the medication taper, while observing for a resurgence of features suggesting active disease, although in the authors experience a visual flare after 2 weeks is rare. Regular follow up on a weekly (initially) to monthly basis over the course of 12–18 months with close communication with either the patient’s family physician, or a rheumatologist depending on the case. The goal of the co-managed care approach is to manage steroid-related side effects in a team-based manner, while aiming to preserve the patient’s remaining vision.
Visual recovery for patients with GCA is generally poor [33] and progression can occur despite treatment with corticosteroids [34]. Despite the devastating visual consequences, a recent review of visual performance and quality of life measures in GCA patients showed no significant difference in disability between patients with and without vision loss when only one eye was affected [35].
Despite careful corticosteroid tapering, there are cases of GCA that are refractory to treatment [36, 37]. Additionally, recurrence of visual loss was observed in patients on maintenance doses of prednisone, up to 3 years after initial GCA diagnosis [38, 39]. These cases present a therapeutic challenge.
What Adjunctive Treatments Would You Recommend, If Any, for Patients with GCA?
A Cochrane review investigated the use of aspirin, as an adjunctive treatment in GCA, and found there wasn’t enough evidence to comment on its benefit in GCA [40]. That said, many GCA patients are already using aspirin when they are diagnosed and the therapy is generally not discontinued.
Are There Alternative Treatments for GCA?
The immunopathology of GCA is under investigation for the consideration of future targeted therapies [41]. Stone and associates reported results of a Phase III study known as the GiACTA study [42], that evaluated tocilizumab, an interleukin-6 receptor antagonist, in people with GCA. The study met its primary and key secondary endpoints, showing tocilizumab, initially combined with a 6-month corticosteroid regimen, was more effective in achieving sustained remission through 1 year compared to a 6 or 12-month steroid-only regimen in people with newly diagnosed and relapsing GCA. However, their corticosteroid dosing regimen [43] was not what we would consider standard of care for GCA and their relapse rates were far higher than is our experience utilizing a less aggressive corticosteroid taper. Only 14% and 18% of their patients treated with prednisone alone for 26 and 52 weeks respectively achieved remission at 52 weeks. In addition, the medication is extremely expensive and the duration of treatment is not definitely known. Further study of tocilizumab is underway to address some of these concerns.
There has been recent interest in the potential role of anti-viral treatment for GCA because virological analysis of temporal artery specimens from biopsy positive and negative GCA patients have revealed the presence of Varicella zoster virus (VZV) antigen [44]. These findings have led to the hypothesis that VZV may play a role in triggering GCA immunopathology [44]. No controlled trials have been conducted to determine whether combination therapy with antiviral agents (oral or intravenous) and corticosteroids confers any additional benefit to GCA patients as compared to corticosteroids alone.
Comments by Susan P. Mollan, FRCOphth
GCA continues to present a diagnostic challenge to clinicians, due to the heterogeneous nature of presentation and the overlap in the clinical sub-types from Cranial to Large Vessel GCA. In some centres in the United Kingdom (UK) and in parts of Europe cranial ultrasound is clinically helpful in reducing the number of patients requiring temporal artery biopsy [45, 46]. Fluoro-deoxyglucose positron emission tomography (PET) may have a role in assessing disease activity and extent in GCA with those having evidence of subclinical large vessel inflammation in up to 80% GCA and 33% of polymyalgia rheumatic (PMR) [47]. Other non-invasive imaging modalities, such as MRI [48], are showing promise but currently are not adopted widely and remain in the research arena.
There are no randomized controlled trials (RCT) to support or direct the use of glucocorticoids in GCA however the main intervention is immediate administration of high dose glucocorticoids [49, 50]. Before glucocorticoid studies documented between 30% and 60% going blind from GCA [51], now the rate of visual loss is somewhere between 5% and 20% [52–54].
In the UK, the British Society of Rheumatology GCA guidelines [49] and in Europe, the EULAR guidelines [55], are both widely used by clinicians to help give a framework for the oral taper in conjunction with the clinical symptoms, signs, and acute phase serological markers. They recommend the use of gastric and bone prophylaxis, commend the use of methotrexate in those with co-morbid cardiac and metabolic disease or those with extended oral taper due to flares and they judge the evidence for adjunctive treatment.
The morbidity associated with high cumulative doses of glucocorticoids is well established [56, 57]; with over 85% experiencing at least one side-effect. Common corticosteroid induced side-effects being diabetes mellitus, osteoporosis and fractures [58]. GCA, the disease and the GC side effects, confers a significant health related economic burden [59]. Trials investigating corticosteroid sparing agents have been disappointing. Azathioprine was shown to be effective at reducing the overall steroid dose failed due to higher rates of discontinuation of azathioprine compared to corticosteroids [60]. Evidence for the use of Methotrexate is conflicting [61–63] and on meta-analysis showed modest benefit [64]. The RCTs investigating Tumor Necrosis Factor antagonists such as infliximab [65], and other targeted therapies Etanercept [66] and Adalimumab [67] did not confer a significant enough benefit to change from standard treatment.
There has been more success recently. Interleukin (IL)-6 receptor inhibition presents a promising approach and Tocilizumab, a recombinant, humanised anti-IL-6 receptor monoclonal antibody, has undergone RCTs to show efficacy and safety for use in GCA [42, 68]. There are a number of factors that remain unanswered, such as the role of Tocilizumab in immediate emergency treatment in sight threatening disease and as yet to be determined is how to maintain sustained remission long term [69].
In the next years there will be further breaking news for GCA therapeutics. A trial investigating use of concurrent Abatacept (CTLA-4–IgG1 fusion protein) with corticosteroids showed at 12 months 48% were in remission for those receiving abatacept and 31% for those receiving placebo (p = 0.049) [70]. Other agents under investigation are Leflunomide [71, 72]; this inhibits dendritic cell maturation and decreases production of IL-6, TNF, IL-12 and IL-17. It is currently undergoing Phase 3 RCT for GCA and PMR in UK and Europe. Baricitanib, which is an oral selective and reversible inhibitor of JAK1 and JAK2 is currently recruiting to phase 2 study [73]. Modern treatment will help target the disease more efficiently, potentially reduce toxicity and prevent long-term late complications of GCA.