# Giant Cell Arteritis and Arteritic Ischemic Optic Neuropathy

## Giant Cell Arteritis (GCA)

### Overview

Giant cell arteritis is a large-vessel granulomatous vasculitis that affects medium and large arteries, with a predilection for branches of the external carotid artery (particularly the temporal and occipital arteries) and the ophthalmic artery. It is the most common systemic vasculitis in adults over the age of 50 and constitutes an ophthalmic emergency: untreated GCA can cause irreversible bilateral blindness.

### Epidemiology

GCA occurs exclusively in patients over 50, with a mean age of onset around 72 years, and risk increases with advancing age. There is a 2 to 3:1 female predominance. The highest incidence is in populations of Northern European descent, particularly Scandinavia. Polymyalgia rheumatica is associated with GCA in 40 to 60% of cases.

### Pathophysiology

The hallmark is granulomatous inflammation of the vessel wall. CD4+ T cells and macrophages infiltrate the adventitia and media, triggering intimal hyperplasia that narrows the vessel lumen and produces downstream ischemia. Multinucleated giant cells are found in approximately 50% of positive temporal artery biopsies. Fragmentation of the internal elastic lamina is a characteristic histological finding.

## Clinical Presentation

### Systemic Symptoms

Patients typically present with new-onset headache that is temporal, often severe, and frequently unilateral. Scalp tenderness -- pain with combing hair or lying on a pillow -- is common. Jaw claudication, defined as pain with sustained chewing that resolves with rest, is the most specific symptom for GCA, with a positive predictive value of approximately 90%. Constitutional symptoms include fever, malaise, weight loss, and fatigue. Polymyalgia rheumatica symptoms of bilateral proximal muscle stiffness and pain in the shoulders and hips are present in a substantial proportion of patients. On examination, the temporal artery may be tender, thickened, and non-pulsatile.

### Ophthalmic Manifestations

Arteritic anterior ischemic optic neuropathy (A-AION) is the most common ocular manifestation of GCA. It presents with severe, sudden, painless vision loss, often to the count-fingers level or worse, with chalky white (pallid) disc edema and an altitudinal visual field defect. Without treatment, the fellow eye becomes involved in 50 to 75% of cases within one to two weeks. Other ophthalmic manifestations include central retinal artery occlusion with the classic cherry-red spot, cilioretinal artery occlusion (which may be an early warning sign), posterior ischemic optic neuropathy (rare, with a normal disc initially that later becomes atrophic), diplopia from cranial nerve III, IV, or VI palsies caused by vasa nervorum ischemia, and amaurosis fugax -- transient monocular vision loss that serves as a critical warning sign preceding permanent loss. Choroidal ischemia may be detected as triangular hypofluorescent areas on fluorescein angiography.

<image>Fundus photograph of arteritic anterior ischemic optic neuropathy showing chalky white pallid disc edema, compared to non-arteritic AION with typical segmental hyperemic disc edema</image>

## Diagnosis

### Laboratory Studies

The erythrocyte sedimentation rate is typically markedly elevated, usually above 50 mm/hr and often exceeding 100. However, a normal ESR does not exclude GCA -- it is normal in approximately 5% of biopsy-proven cases. C-reactive protein is elevated and is more sensitive than ESR alone. The combination of ESR and CRP achieves a sensitivity of approximately 97%. The complete blood count may show reactive thrombocytosis and normocytic anemia. Liver function tests may reveal an elevated alkaline phosphatase. Interleukin-6 levels are elevated and may be useful for monitoring disease activity.

### Temporal Artery Biopsy (TAB)

Temporal artery biopsy remains the gold standard for diagnosis. A specimen of at least 2 cm should be obtained, as skip lesions -- segments of normal artery interspersed between affected areas -- can produce false-negative results on shorter specimens. Unilateral biopsy has a sensitivity of approximately 87%, and contralateral biopsy adds 3 to 5% additional yield. Histological findings include transmural granulomatous inflammation, giant cells, intimal thickening, and disruption of the internal elastic lamina. The biopsy should ideally be performed within two weeks of starting corticosteroids, as histological inflammation persists for this period. Critically, treatment must never be delayed while awaiting biopsy results.

### Temporal Artery Ultrasound

Temporal artery ultrasound can demonstrate the "halo sign," a hypoechoic ring around the artery representing mural edema and inflammation. Sensitivity ranges from 68 to 77% with specificity of 82 to 100%, though results are operator-dependent. Advantages include its non-invasive nature, rapid availability, and ability to assess bilateral temporal and axillary arteries simultaneously. The TABUL trial and EULAR recommendations have increased acceptance of ultrasound, and it may replace biopsy in some centers when a clear halo sign is present. Limitations include dependence on operator expertise and inability to identify skip lesions with certainty.

### Additional Imaging

PET-CT can assess large-vessel involvement including aortitis and subclavian artery inflammation. MRI or MRA of the temporal arteries can demonstrate vessel wall enhancement. CT angiography is useful for detecting large-vessel complications such as aortic aneurysm.

## Treatment

### Acute Corticosteroid Therapy

Treatment must be initiated immediately upon clinical suspicion of GCA -- waiting for biopsy results is unacceptable. For patients without vision loss, oral prednisone at 1 mg/kg/day (typically 60 to 80 mg daily) is appropriate. For patients with vision loss or amaurosis fugax, intravenous methylprednisolone at 1 gram daily for three days should be given, followed by oral prednisone at 1 mg/kg/day. The primary goal of treatment is to prevent fellow eye involvement and further vision loss. Vision already lost at presentation is usually irreversible; the urgency of treatment lies in protecting the contralateral eye.

### Steroid Taper

The initial dose is maintained for two to four weeks until symptoms resolve and ESR and CRP normalize. A gradual taper is then undertaken over one to two years. A typical regimen reduces the dose by 10 mg per month down to 20 mg, then by 2.5 mg per month down to 10 mg, then by 1 mg per month thereafter. ESR, CRP, and symptoms must be monitored throughout the taper, and the dose should be increased if disease flares occur. The relapse rate during tapering is 40 to 60%.

### Steroid-Sparing Agents

Tocilizumab, an anti-interleukin-6 receptor antibody, has transformed the management of GCA. The GiACTA trial demonstrated that tocilizumab combined with a prednisone taper achieved sustained remission at 52 weeks in 56% of patients receiving weekly dosing and 53% with every-two-week dosing, compared with only 14% on placebo. Tocilizumab significantly reduced the cumulative steroid dose and is now considered the first-line steroid-sparing agent. An important caveat is that tocilizumab suppresses both CRP and ESR, so these markers cannot be used for disease monitoring during treatment. Side effects include hepatotoxicity, diverticulitis, and neutropenia.

Methotrexate has shown modest benefit across three randomized controlled trials with mixed results and is used when tocilizumab is contraindicated. Low-dose aspirin (75 to 100 mg) may reduce ischemic complications, though the evidence is weak.

### Steroid Side Effects to Monitor

Prolonged high-dose corticosteroid therapy carries significant morbidity. Patients must be monitored for diabetes and hyperglycemia, osteoporosis (with prophylactic calcium, vitamin D, and bisphosphonate therapy initiated from day one), gastric ulceration (with PPI prophylaxis), adrenal suppression, weight gain, insomnia, mood changes, and immunosuppression.

<image>Temporal artery biopsy histopathology showing granulomatous inflammation with multinucleated giant cells, intimal hyperplasia causing luminal narrowing, and fragmentation of the internal elastic lamina</image>

## Non-Arteritic Anterior Ischemic Optic Neuropathy (NA-AION) -- Comparison

### Key Differences from A-AION

| Feature | A-AION (Arteritic) | NA-AION (Non-Arteritic) |
|---------|-------------------|------------------------|
| Age | >70 typically | >50 |
| Vision loss | Severe (CF or worse) | Moderate (20/40-20/200) |
| Disc appearance | Pallid (chalky white) edema | Hyperemic (segmental) edema |
| Pain | Headache, jaw claudication | Usually painless |
| Fellow eye risk | 50-75% in weeks if untreated | 15-20% over 5 years |
| ESR/CRP | Markedly elevated | Normal |
| Disc size | Normal | Small, crowded ("disc at risk") |
| Treatment | Urgent high-dose steroids | No proven treatment |

### NA-AION Key Points

Non-arteritic AION characteristically occurs in eyes with a small, crowded optic disc with a small cup-to-disc ratio -- the so-called "disc at risk." Risk factors include hypertension, diabetes, sleep apnea, and nocturnal hypotension. No treatment has been proven effective: the Ischemic Optic Neuropathy Decompression Trial showed that optic nerve sheath surgery was not beneficial, and steroids remain unproven. Aspirin has no evidence for preventing fellow eye involvement. Obstructive sleep apnea should be screened for and treated, as CPAP may reduce the risk of involvement of the fellow eye.

## Clinical Pearls

GCA is a clinical diagnosis that requires immediate treatment; the biopsy serves to confirm the diagnosis but must never determine whether to initiate therapy. Jaw claudication is the most specific symptom and should be actively asked about in every patient over 50 with new headache or visual symptoms. A normal ESR does not rule out GCA -- CRP must also be checked. Fellow eye involvement in arteritic AION can occur within hours to days of the initial event, which is the reason for the extreme urgency of treatment. Amaurosis fugax in a patient over 50 with headache should be considered GCA until proven otherwise. Temporal artery biopsy remains positive for up to two to four weeks after starting corticosteroids, so treatment should never be delayed to schedule the biopsy. Tocilizumab, based on the GiACTA trial, has transformed the steroid-sparing approach to GCA management. The distinction between arteritic and non-arteritic AION is critical, as the treatment, prognosis, and urgency are fundamentally different. Bone protection with calcium, vitamin D, and bisphosphonate therapy should be initiated from the first day of corticosteroid treatment.

## References

- Hayreh SS. Ischemic optic neuropathies -- where are we now? Graefes Arch Clin Exp Ophthalmol. 2013;251(8):1873-1884.
- Stone JH, et al. Trial of tocilizumab in giant-cell arteritis (GiACTA). N Engl J Med. 2017;377(4):317-328.
- Hunder GG, et al. The American College of Rheumatology 1990 criteria for the classification of giant cell arteritis. Arthritis Rheum. 1990;33(8):1122-1128.
- Luqmani R, et al. The role of ultrasound compared with biopsy of temporal arteries in the diagnosis and treatment of giant cell arteritis (TABUL). Health Technol Assess. 2016;20(90):1-238.
- American Academy of Ophthalmology. Basic and Clinical Science Course, Section 5: Neuro-Ophthalmology.