Temporal/Giant Cell Arteritis 

Giant cell (temporal) arteritis (GCA) confronts the neurologist in many ways. It should always be considered in the differential diagnosis of a new-onset headache in an elderly patient with an elevated erythrocyte sedimentation rate (ESR). Neuroophthalmologic complications, such as anterior ischemic optic neuropathy (AION), generally are well recognized, but many other neurologic problems can complicate the clinical course of GCA. Timely diagnosis and steroid treatment are essential for the prevention of potentially irreversible ischemic end-organ damage.

Temporal arteritis was first described in the Western literature by Hutchinson in 1890, and the histopathologic features were reported by Horton in 1932. Visual loss associated with temporal arteritis was first reported by Jennings in 1938, and Birkhead first introduced the effectiveness of systemic corticosteroid therapy in preventing blindness.

Age and female sex are established risk factors for polymyalgia rheumatica and giant cell arteritis, a genetic component seems likely, and infection may have a role. One school of thought considers giant cell arteritis and polymyalgia rheumatica to be different manifestations of the same disease process, while others see them as closely related but different diseases.^[1] The term giant cell arteritis is sometimes used to describe temporal arteritis only, but is sometimes used to refer to both temporal arteritis and polymyalgia rheumatica.

The image below depicts stenosis and occlusion of femoral artery branches due to vasculitis.

GCA is primarily a disease of cellular immunity. The vasculitic damage is mediated by activated CD4⁺ T helper cells responding to an antigen presented by macrophages. The primary inflammatory response affects the internal elastic lamina. Multinucleated giant cells, which are a histologic hallmark of GCA, may contain elastic fiber fragments. The actual inciting antigen remains unknown, but elastin remains an important suspect.^[2]

The superficial temporal artery is involved in most patients, providing a convenient biopsy site, but this is only the "tip of the iceberg." The topographic distribution of GCA, which reflects its predilection for the internal elastic lamina, includes the aortic arch and its branches.

GCA does not cause a widespread intracranial cerebral vasculitis, because intracranial arteries lack an internal elastic lamina. GCA does involve cervicocephalic arteries, including the carotid and vertebral arteries. It commonly affects arteries in the following pattern:

• Common, external, and internal carotid artery involvement is usually extracranial; rarely, proximal intracranial segments have been affected.
• Intraorbital branches, especially the posterior ciliary and ophthalmic arteries, commonly are affected.
• Vertebral arteries are involved as frequently as the superficial temporal arteries in fatal cases, although basilar artery involvement is rare.
• Vertebral arteritis is extracranial, but it may extend intracranially for roughly 5 mm beyond dural penetration.
• Subclavian, axillary, and proximal brachial arterial involvement produces a characteristic angiographic pattern of vasculitis, consisting of long, smooth, stenotic segments that alternate with nonstenotic segments and tapered occlusions.
• Involvement by GCA of the ascending aorta can lead to aortic rupture, and coronary arteritis may result in myocardial infarction (MI).
• Less often, the descending aorta and mesenteric, renal, iliac, and femoral arteries can be affected, with attendant complications of intestinal infarction, renal infarction, crural infarction, and ischemic mononeuropathies.
• Pulmonary arterial involvement has also been described.

Pathogenesis and histopathologic findings

The pathogenesis of GCA is not known but probably has an idiopathic autoimmune etiology. A cellular immune reaction to elastin and an abnormality of the tunica media of affected vessels have been implicated.

In support of the elastin theory, disease severity has been shown to correlate with the amount of elastic tissue within the vessels, with the arteries most commonly affected being the superficial temporal, ophthalmic, occipital, vertebral, posterior ciliary, and proximal vertebral arteries. The intracranial circulation is typically spared because these arteries have very little elastic tissue. The theory also is supported by histopathologic findings of a disrupted, fragmented internal elastic lamina in affected vessels and the presence of characteristic giant cells close to the internal elastic lamina. Along with elevated serum levels of neutrophil elastase, deposition of elastase along the damaged internal elastic lamina has been described.

In patients with GCA abnormality of the tunica media of affected vessels is probably caused by ischemia, and presumably as a result of an immune-mediated response to the injured smooth muscle cells, secondary damage to the elastic lamina occurs. Histologically, the presence of macrophages and giant cells closely attached to the smooth muscle cells has been shown.

While evidence for humoral immunity includes elevated levels of circulating immunoglobulin and complement, and also immune complex/immunoglobulin and complement deposition in the inflamed vessel wall, support for cellular immunity includes the presence of giant cells, macrophages and monocytes, and lymphocytes in the inflammatory infiltrate. Increased frequencies of the HLA haplotypes B8, DR3, DR4, DR5, and DR(beta)1 are seen in patients with GCA.

Intimal macrophages produce platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF) leading to intimal proliferation. Medial macrophages generate metalloproteinases leading to the destruction of vascular elements, including the internal elastic lamina. Adventitial macrophages produce interleukin-6 (IL-6), augmenting the inflammatory response. This results in inflammation with local vascular damage and intimal hyperplasia leading to stenosis and occlusion.^[3]

The expression of MxA protein in arteries from patients with polymyalgia rheumatica and temporal arteritis shows that noninflamed and inflamed vessel walls are influenced by IFN-I. Further studies are required to elucidate whether IFN-I plays a role in the initiation of polymyalgia rheumatica and/or temporal arteritis.^[4]

Matrix metalloproteinase-2 (MMP-2) and -9 (MMP-9) have a role in the pathophysiology of giant cell arteritis because of their ability to degrade elastin. In addition, MMP-9 is also associated with intimal hyperplasia, subsequent luminal narrowing, and neoangiogenesis.^[5]

Frequency

United States

The incidence of GCA in Olmsted County, Minnesota, increased between 1950 and 1975 from 5.1 to 17.4 incident cases per 100,000 population per year in persons aged 50 years and older. The increase was attributable to greater clinical awareness and improved rate of accurate diagnosis. On January 1, 1975, the prevalence was 133 cases per 100,000 in persons aged 50 years and older.

International

Few epidemiologic studies of GCA outside the US have been published, but incidence rates are not thought to vary significantly within the defined age-susceptible groups. The highest incidence is reported in Scandinavia, where 23.3-33.6 per 100,000 people older than 50 years are affected.

Prevalence heavily depends on the number of individuals aged 50 years or older; the mean age of onset is 75 years. Countries with a lower life expectancy have a lower prevalence.

Mortality/Morbidity

GCA has not been associated with a statistically significant increase in rates of death, stroke, or MI compared to an age-matched, community-based control population; however, it can lead to these outcomes.

• GCA leads to death by one of these mechanisms in roughly 2% of cases.
• As would be expected, the topographic extent and severity of the vasculitis is greater in fatal than in nonfatal cases.
• More difficult to quantify are the number of patients whose deaths are related directly or indirectly to chronic corticosteroid use and its attendant complications (eg, hip fracture).

Race

No racial predisposition to GCA is known, although existing epidemiologic studies are limited because they have been performed on predominantly Caucasian populations, suggesting that it is more common among them.

Sex

The female-to-male ratio is roughly 3.7:1.

Age

The median age of onset is 75 years. The age range in one series of 166 cases proven by temporal artery biopsy (TAB) was 55-92 years. Rarely described in those younger than 40 years, it is the most common systemic vasculitis affecting elderly patients.

The following conditions are histologically similar but nosologically distinct from GCA and occur in different age groups: Juvenile temporal arteritis affects children; primary CNS vasculitis (originally termed granulomatous angiitis of CNS) can strike at any age, but it is far more likely than GCA to affect young adults.