Introduction

Giant cell arteritis (GCA) is an inflammatory disorder of the branches of the aorta and, occasionally, the ascending aorta itself. The inflammatory response appears to begin as a reaction to an antigen in the artery, which activates cytotoxic (TH1) lymphocytes that enter the vessel wall through the vasa vasorum in the adventia of the arteries. These activated TH1 cells release cytokines, especially IL-6 and interferon gamma, which, in turn, activate macrophages. The macrophages produce proteolytic enzymes and toxic oxygen radicals that cause destruction of the internal elastic membrane and damage the media of the artery as well. The macrophages fuse their membranes to become the pathognomic giant cells of the disorder. It is these giant cells that appear to produce growth factors, which leads to fibrosis of the intima of the vessels, as well as neovascularization.

While the nature of the antigen remains unknown, there is some evidence to support actinic (i.e., resulting from UV light) damage to the internal elastic membrane of the temporal and ciliary retinal arteries as being an important initiator of the process. The branches of the external carotid artery are most frequently affected in GCA. Though less frequent, the vertebral, subclavian and coronary arteries have all been the target of the inflammatory process in this disorder and may give rise to symptoms of ischemia in the tissues that they supply. In addition, the ascending aorta may be a site of inflammation, leading to aortic dissection, aortic rupture and aortic valvular insufficiency. While thrombosis of the vessel lumen is seen in some pathological specimens, the rapid reversibility of some of the ischemic manifestations, including visual loss, suggests that there is an element of vasospasm involved as well.

Clinical Presentation

Headache is the most common presenting symptom in GCA. However, headaches are extremely common (bordering on universal) and it is, therefore, very understandable that most physicians do not undertake an extensive work up in every patient with a new headache of only a few days duration. It is equally understandable that most physicians do not always think immediately about giant cell arteritis (formerly known as temporal arteritis) when confronted with a patient complaining of a headache. While most of the time, this approach is correct, both clinically and economically, failure to diagnose GCA can have devastating consequences, as untreated GCA can cause irreversible visual loss early in its course.

Diagnosis

Giant cell arteritis occurs exclusively in patients over the age of 50 and its incidence increases with aging. It is uncommon in Blacks, more common in females and in fair skinned individuals of northern European extraction, though these are only weak factors and are not very helpful in the individual patient.

The headache of GCA is unilateral and usually localized in the distribution of the temporal artery. The headache is often described as sharp or burning and not pulsatile. Visible swelling and redness over the temporal arteries may accompany the headache. Patients will usually be able to recognize this headache as very different from their previous headaches that they have may have experienced from hypertension, sinusitis, migraine or other causes.

Sudden monocular blindness, a catastrophic complication of GCA, usually occurs very early in the course of the disease and can be the presenting manifestation of the disease. Treatment should be begun immediately with high doses of intravenous methylprednisolone within 24 hours of visual loss because such treatment has been reported to restore vision in a small number of patients. In addition, loss of vision in the second eye is most frequently seen in first several days after the involvement of the first eye.

New onset of diplopia in an elderly patient, with or without a headache, may be caused by GCA and is also correlated with impending visual loss.

Unilateral pain in the temporal muscles brought on by chewing (jaw claudication) is seen in approximately one fifth of patients with biopsy proven GCA. It is an important symptom to recognize because it appears to be present early in the course of GCA and is highly correlated with the risk of visual loss.

The presence of painless areas of dark atrophic skin over the temples represent scalp necrosis and, when present, are important signs of GCA.

Almost all patients with GCA have evidence of an acute phase response in their blood - an elevated Westegren sedimentation rate (ESR) - usually over 50 mm/hour. The sensitivity of the test is better than 95% and, therefore, represents an excellent cost-effective screening test for GCA. In addition to the ESR, the C-reactive protein (CRP) levels are usually greatly elevated. Recently, it has been reported that the circulating levels of IL-6 are elevated in GCA and more accurately predict flares of the disease than the ESR.

While many patients with GCA have stiffness and pains in their pectoral and pelvic muscles, consistent with polymyalgia rheumatica, this symptom complex carries a relatively low risk of visual loss. Involvement of the vertebral and basilar arteries, prior to their penetration of the dura mater, can lead to infarction of the posterior portions of the brain - typically, the posterior lobes, cerebellum and, occasionally, the medulla. Therefore, ischemia of these areas of the CNS in a normotensive elderly patient, who is in normal sinus rhythm and has a high ESR should lead to a work up for GCA.

Other unusual signs and symptoms of GCA are listed in Table 1. In an elderly patient with an unexplained high ESR and one of these findings, a temporal artery biopsy is a reasonable consideration.

Table 1. Unusual presenting manifestations of giant cell arteritis

• Scalp tenderness
• Formed visual hallucinations
• Inappropriate ADH secretion (SIADH)
• Fever of unknown origin
• Claudication of the upper extremities
• Vertebral artery steal syndrome

Treatment

A biopsy of a temporal artery that demonstrates the inflammatory and proliferative changes noted above is the gold standard for the diagnosis of GCA. It is generally agreed, however, that the biopsy may be falsely negative in anywhere from 10 - 25 percent of patients who otherwise have the disorder. Negative biopsies have been blamed on skip lesions in the arteries, though this has not been proven in any controlled study. Another possible explanation for a false negative biopsy is that the pathology has been altered by steroid treatment.

A number of strategies have been proposed for increasing the sensitivity of the temporal artery biopsy:
1. Performing biopsies on the side that the patient has arteritic symptoms.
2. Performing biopsies within 72 hours of the institution of corticosteroid therapy.
3. Including periarterial lymphocytic foci as criteria for a pathological diagnosis.
4. Using magnetic resonance angiography of the temporal arteries to localize the site of arteritis.
5. Using high-resolution ultrasonography of the temporal arteries to localize the site of arteritis.
6. Using positron (PET) scanning in a similar fashion.

From a practical standpoint, only the first two suggestions help to increase the yield of positive biopsies. An extension of these observations is that, in a patient with a clinical picture highly suggestive of GCA, treatment should be continued in the face of a negative biopsy.

Patients with suspected GCA should be started on 80 mg of prednisone (or an equivalent dose of methylprednisolone) daily. This should be continued for a minimum of three weeks and, then, gradually tapered by no more than five mg decrements every five days until the patient reaches 40 mg per day, at which point the interval between five mg decrements should be extended to every ten days. Patients with very recent visual loss should receive 500 mg of intravenous methylprednisolone every six hours for the first two days. Patients should be concomitantly treated with medications such as diphosphonates to prevent rapid bone resorption and some experts recommend the routine use of an H2 antagonist or a proton pump inhibitor for these patients while they are on high doses of corticosteroids. Patients should also be monitored for the development of hyperglycemia and hypertension, both of which should be treated with appropriate oral medications.

Dapsone, azathioprine and methotrexate have been advocated as steroid sparing agents, but have not yet been shown to be efficacious in prospective controlled studies. An immediate fall in the ESR, after initiating corticosteroid therapy, is often helpful in confirming the diagnosis and reassures the treating physician that the patient is receiving an appropriate dose. However, it is probably not a good idea to use the ESR as a guide to therapy because patients have been known to flare up without a rise in the ESR. Moreover, the ESR can increase from a number of intercurrent problems other than GCA - most notably infection, for which additional corticosteroids would be contraindicated. Patients with GCA may have persistently elevated IL-6 levels in the face of normal ESR, indicating ongoing subclinical inflammation that may contribute to some of the late vascular complications of the disorder, such as aortic rupture and dissection.

In conclusion, GCA is a serious condition of the elderly that can usually be diagnosed and treated successfully when the physician is attuned to the cardinal manifestations of the disease.

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