Clinical manifestations of giant cell arteritis

INTRODUCTION — Giant cell arteritis (GCA, also known as Horton disease, cranial arteritis, and temporal arteritis) is categorized as a vasculitis of large- and medium-sized vessels because it can involve the aorta and great vessels. It also shares some histopathologic features with Takayasu arteritis, the other major "large vessel" (LV) vasculitis. Systemic symptoms are common in GCA and vascular involvement can be widespread, causing stenosis and aneurysm of affected vessels. It is the targeting of the tiny muscular arteries from cranial branches of the aortic arch, however, that gives rise to many of the most characteristic symptoms of GCA. The most feared complication, visual loss, is one potential consequence of the cranial phenotype of GCA.

The clinical manifestations of GCA will be reviewed here. The pathogenesis, diagnosis, and treatment of this disorder are discussed separately. (See "Pathogenesis of giant cell arteritis" and "Diagnosis of giant cell arteritis" and "Treatment of giant cell arteritis".)

EPIDEMIOLOGY — Giant cell arteritis (GCA) is the most common idiopathic systemic vasculitis [1]. In the United States, the lifetime risk of developing GCA has been estimated at approximately 1 percent in women and 0.5 percent in men [2].

The greatest risk factor for developing GCA is aging. The disease almost never occurs before age 50 years, and its incidence rises steadily thereafter, peaking between the ages of 70 to 79 [3], with over 80 percent of patients older than 70 years of age [4,5]. One study found the mean age at incidence of GCA to be 76.7 years [6].

In addition to age, ethnicity is a major risk factor for GCA. The highest incidence figures are found in Scandinavian countries and among Americans of Scandinavian descent. In Olmsted County, Minnesota, the annual incidence of GCA was 15 per 100,000 persons over the age of 50, similar to that in Scandinavian countries [3,7]. This similarity probably reflects shared genetic risk factors, as many of the inhabitants of Olmsted County during the period of study were descended from Scandinavians and northern Europeans. In Southern Europe and Mediterranean countries, incidence rates are lower, with less than 10 per 100,000 persons over the age of 50 [5,8,9]. GCA is less common in Latin American, Asian, Arab, and African American populations, though formal data on these populations are scant [10].

Autopsy studies suggest that GCA is more frequent than reported in studies of clinically diagnosed cases. A study from Sweden found arteritis in 1.6 percent of 889 postmortem cases in which sections of the temporal artery and two transverse sections of the aorta were made [11].

As with many systemic rheumatic diseases, females are affected more frequently than males, in a ratio of almost 3:1 in populations of Scandinavian descent [3]. The ratio of women to men is lower in Mediterranean countries. Familial aggregation of GCA is not unusual [12]. (See "Pathogenesis of giant cell arteritis", section on 'Predisposing factors'.)

Most studies have found that life expectancy is not, or is only marginally, reduced in GCA [13-15], with the exception of the subset of patients who develop aortic aneurysm or aortic dissection or rupture [16]. (See 'Large vessel involvement' below.)

ASSOCIATION WITH POLYMYALGIA RHEUMATICA — Polymyalgia rheumatica (PMR) is characterized by aching and morning stiffness about the shoulder and hip girdles, in the neck, and in the torso. PMR is closely linked to giant cell arteritis (GCA), occurring in approximately 40 to 50 percent of patients with GCA [17]. Conversely, GCA is found in approximately 10 percent of patients with PMR. (See "Clinical manifestations and diagnosis of polymyalgia rheumatica".)

The precise nature of the relationship between GCA and PMR is not completely understood. In some patients, symptoms and signs of the two conditions occur simultaneously, while in others they appear separately over time.

CLINICAL FEATURES — The onset of symptoms in giant cell arteritis (GCA) tends to be subacute, but abrupt presentations over a few days can occur. Although many of the clinical manifestations of GCA are nonspecific, some characteristic findings strongly suggest the diagnosis (table 1).

Constitutional symptoms — Systemic symptoms associated with GCA are frequent and include fever, fatigue, and weight loss. Fevers occur in up to one-half of patients with GCA and are usually low-grade. However, in approximately 15 percent of patients, fevers exceed 39ºC (102.2ºF), often leading to misdiagnoses of infections [18]. One study found that one in six fevers of unknown origin in older adults was due to GCA [19]. Anorexia and weight loss are usually minor, but, like fever, may be significant [20].

We estimate that in approximately 10 percent of patients with GCA, constitutional symptoms and/or laboratory evidence of inflammation dominate the clinical presentation and may be the only clues to the diagnosis (see 'Laboratory findings' below). Thus, in an older adult with fever or constitutional symptoms not explained by an initial evaluation for infection or malignancy, a diagnosis of GCA warrants consideration.

Headache — Headache is a common presentation of GCA, occurring in more than two-thirds of patients [17,21]. The quality of headache in GCA, apart from the occasional specific complaint of tenderness of the scalp to touch, has no defining characteristics. Its salient feature is that it is new. Although headache is the chief complaint in many patients presenting with GCA, in some this symptom must be elicited by direct questioning.

Classically, headaches due to GCA are located over the temples, but they can also be frontal, occipital, unilateral, or generalized. The headaches can progressively worsen, wax and wane, or sometimes recede before treatment is started.

Jaw claudication — Nearly one-half of GCA patients experience jaw claudication, a symptom that involves mandibular pain or fatigue brought on by mastication and relieved by stopping. In some cases, patients note a trismus-like symptom, with either perceived or actual limitation of temporomandibular joint excursion. Claudication symptoms occasionally affect the tongue during eating or with repeated swallowing.

In an analysis of the diagnostic value of temporal artery biopsies, which correlated positive biopsies with clinical symptoms, jaw claudication was the symptom most highly associated with a positive biopsy [22]. Among 134 patients who underwent temporal artery biopsy, jaw claudication was present in 54 percent of those with positive biopsies, compared with only 3 percent of those whose biopsies were negative.

Ocular involvement

Transient visual loss (amaurosis fugax) — Transient monocular (and, rarely, binocular) impairment of vision can be an early manifestation of GCA. With transient monocular visual loss (TMVL), affected patients typically note an abrupt partial field defect or temporary curtain effect in the field of vision of one eye. Patients with polymyalgia rheumatica (PMR) or GCA are often sensitized to the potential for vision loss. It can be useful in the course of evaluating the possible significance of a reported visual disturbance to inquire if the patient tried to cover each eye; explicit monocular visual loss would heighten concern for GCA. Transient visual loss can be a harbinger of permanent visual loss, and thus mandates urgent attention in a patient with suspected PMR or GCA. (See "Amaurosis fugax (transient monocular or binocular visual loss)", section on 'Other causes of ischemia'.)

Permanent vision loss — Unquestionably the most feared complication of GCA remains that of permanent loss of vision, which commonly is painless and sudden, may be partial or complete, and may be unilateral or bilateral. Even in the era of effective therapy, the incidence of permanent partial or complete loss of vision in one or both eyes due to GCA as described from multiple centers has ranged from 15 to 20 percent of patients [23-28]; a more recent report found a lower incidence of 8.2 percent [29]. Though permanent visual loss may be preceded by single or multiple episodes of transient visual loss, it can also occur with devastating swiftness. Once established, visual loss is rarely reversible [30]. Moreover, it has been estimated that within one week, further loss of vision in the unaffected eye ensues in 25 to 50 percent of untreated patients [31]. If vision is intact, however, the prompt initiation of adequate glucocorticoid treatment virtually abolishes the subsequent risk of sight loss. If there is preexisting visual loss, such treatment will markedly reduce the risk of further deterioration, but will not improve established visual loss [32]. Fast-track clinics for the diagnosis of GCA might help to identify patients sooner and therefore initiate adequate treatment before complications such as blindness occur. (See "Treatment of giant cell arteritis".)

Risk factors — To date, no definite ways of stratifying risk factors for permanent visual loss in GCA have been established. Age, hypertension, thrombocytosis, jaw claudication, and other features have been proposed as risk factors, but in most studies, only prior transient visual loss has been identified as the strongest predictor for subsequent permanent visual loss [25-28,32,33].

Several studies have found a reduced risk of visual complications in patients with GCA who have heightened inflammatory status, as indicated by fever, elevations of the acute phase reactants, and anemia [34-36]. Pretreatment levels of the erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) in GCA, for example, correlate inversely with the risk of visual symptoms. A strong inflammatory response could protect against ischemic lesions by two means: first, patients with pronounced inflammatory features might be seen sooner in the clinic and thus receive more prompt treatment, and, second, interleukin (IL) 6, a key inflammatory cytokine, is endowed with angiogenic properties, and might therefore counteract arteritis-induced ischemia [32].

Causes of vision loss — Permanent loss of vision in GCA results from arteritic anterior ischemic optic neuropathy (AION), central or branch retinal artery occlusion (CRAO/BRAO), posterior ischemic optic neuropathy (PION), or, rarely, cerebral ischemia [37-39].

●Anterior ischemic optic neuropathy – At least 85 percent of cases of vision loss in patients with GCA are caused by AION. The ischemic insult in arteritic AION is typically the consequence of occlusion of the posterior ciliary artery, a branch of the ophthalmic artery from the internal carotid artery, and the main arterial supply to the optic nerve.

Only a small percentage of the total occurrences of AION are due to GCA. Most AION is nonarteritic and commonly secondary to atherosclerotic disease [40]. Approximately 40 percent of patients who suffer nonarteritic AION regain some amount of visual acuity, in contrast to visual loss due to GCA, which is more often massive and irreversible [28]. The concurrence of AION with occlusion of the cilioretinal artery, an anatomic variant present in approximately one-fifth of the population, is almost always due to arteritic disease [41].

●Central retinal artery occlusion – CRAO is a less common cause of visual loss in GCA. Atherosclerosis, especially involving the carotid arteries, accounts for the bulk of cases of CRAO. BRAOs, though reported, are unusual in GCA. (See "Central and branch retinal artery occlusion", section on 'Other inflammatory disease' and "Central and branch retinal artery occlusion", section on 'Central retinal artery occlusion'.)

●Posterior ischemic optic neuropathy – PION, which results from interruption of blood flow to the retrobulbar portion of the optic nerve, is an unusual occurrence in GCA, but should be considered in the differential diagnosis of PION presenting in an older adult. (See "Posterior ischemic optic neuropathy".)

●Cerebral ischemia – Homonymous hemianopia is a visual field defect involving either the two right or the two left halves of the visual fields of both eyes. The most common cause in GCA is an occipital lobe infarction resulting from a lesion in the vertebrobasilar circulation. In rare cases, bilateral occipital lobe involvement leads to bilateral homonymous field defects and to the development of cortical blindness (see "Homonymous hemianopia"). GCA rarely affects the intracerebral vessels, which is discussed further below. (See 'Central nervous system involvement' below.)

Ophthalmic syndromes

●Diplopia – Extraocular motility disorders occur in approximately 5 percent of patients with GCA [42]. In the context of other symptoms suggestive of GCA, diplopia has a high specificity for the disease [43]. Diplopia, which is usually transient, can result from ischemia to almost any portion of the oculomotor system, including the brainstem, oculomotor nerves, and the extraocular muscles themselves [39,44].

●The Charles Bonnet syndrome – The Charles Bonnet syndrome refers to the phenomenon of visual hallucinations in psychologically normal individuals who have visual loss due to lesions in either peripheral or central visual pathways. Its occurrence in GCA is rare [45].

Musculoskeletal involvement — Symptoms of PMR occurring in a patient with GCA include characteristic proximal polyarthralgias and myalgias, sometimes accompanied by peripheral synovitis, and on occasion, distal extremity swelling with pitting edema (also known as remitting seronegative symmetrical synovitis with pitting edema [RS3PE]) [46]. (See "Clinical manifestations and diagnosis of polymyalgia rheumatica", section on 'Differential diagnosis'.)

Large vessel involvement — Large vessel (LV) GCA refers to involvement of the aorta and its major proximal branches, especially in the upper extremities. The clinical consequences of LV GCA comprise aneurysms and dissections of the aorta, particularly the thoracic aorta, as well as stenosis, occlusion, and ectasia of large arteries. Subclinical LV GCA can also underlie systemic presentations of GCA, where fever and other constitutional symptoms predominate, without cranial symptomatology. (See 'Constitutional symptoms' above.)

A variety of imaging modalities have demonstrated the frequency and extent of LV involvement (image 1 and image 2 and image 3). In a study of 35 consecutive patients with biopsy-proven GCA, fluorodeoxyglucose positron emission tomography (FDG-PET) showed vascular uptake of FDG at the subclavian arteries in 74 percent and at the thoracic aorta in 51 percent [47]. Computed tomographic (CT) angiography of 40 patients with newly diagnosed, biopsy-proven GCA found evidence of arteritis in two-thirds of patients, mainly affecting the aorta (65 percent), but also affecting the brachiocephalic trunk (47 percent), subclavian arteries (42 percent), and femoral arteries (30 percent) [48]. Studies using color-coded duplex ultrasonography have regularly identified involvement of the subclavian, axillary, or brachial arteries in at least 30 percent of patients with GCA [49-51]. (See "Noninvasive diagnosis of upper and lower extremity arterial disease", section on 'Duplex ultrasound'.)

Symptomatically evident LV involvement is less commonly observed; a fair estimate of its incidence will require prospective studies incorporating standardized imaging protocols. But the clinical take-home point is important: Subclinical LV involvement is present in a significant percentage of patients with GCA.

The clinical phenotype of LV-GCA differs somewhat from that of cranial arteritis. One study compared the clinical features of 74 patients with angiographically diagnosed subclavian or axillary involvement of GCA (or LV GCA) with those of 74 patients with biopsy-proven temporal artery GCA (or cranial artery GCA) [52]. In contrast to those with cranial artery GCA, patients with LV GCA were younger at disease onset (66 versus 72 years), less likely to have headaches (14 versus 57 percent), and more likely to have arm claudication at presentation (51 versus 0 percent). Among the 57 patients with LV GCA in whom a temporal artery biopsy was eventually performed, positive biopsy findings were detected in only 33 patients (58 percent). Another larger retrospective study from the same tertiary care institution comparing 120 patients with radiographic evidence of subclavian artery vasculitis with 240 patents with positive temporal artery biopsies found similar results [53]. The patients with LV vasculitis were younger (68 years versus 76 years), had a longer duration of symptoms prior to the diagnosis of GCA (median 3.5 months versus 2.2 months), fewer cranial symptoms (41 versus 83 percent), and less sight loss (4 versus 11 percent). Temporal artery biopsies, performed in 79 of the 120 patients with LV vasculitis, were positive in only one-half (52 percent).

Clinical features of the cranial and LV phenotypes overlap. Systematic screening of patients with the cranial phenotype can demonstrate large artery involvement. On the other hand, temporal artery biopsies are positive in only approximately one-half of patients with LV GCA, underlining the essential role of imaging for the diagnosis of this phenotype. (See "Diagnosis of giant cell arteritis", section on 'Evaluation for large vessel giant cell arteritis'.)

●Systemic presentation of GCA – Systemic symptoms and signs can accompany the clinical presentation of both the cranial and LV phenotypes. Temporal artery biopsy or ultrasound is required to diagnose the former, imaging for the latter. In a study utilizing FDG-PET/CT for the evaluation of 240 patients with fever or inflammation of unknown origin, LV vasculitis accounted for 21 percent of 190 patients with a finalized diagnosis [54].

●Aortic aneurysm – The incidence of aortic aneurysms in GCA is heavily influenced by the methodologies used for detection and definition of aneurysms [55]. Clinical recognition of aortic aneurysms/dilatation has been described in 10 to 20 percent of cases [56-59], most studies favoring the lower figure. The thoracic aorta, especially the ascending aorta, is affected more often than the abdominal aorta. In these cases, there is often little or no clinical or laboratory evidence of systemic activity of GCA.

Estimates of the magnitude of increased risk for aortic aneurysms in GCA compared with the general population vary. An early population-based cohort study of 96 patients with biopsy-proven GCA suggested that patients with GCA were 17 times more likely to develop thoracic aortic aneurysms and 2.4 times more likely to develop isolated abdominal aortic aneurysms than were persons of the same age and sex [60]. Another study of a large database in the United Kingdom examined the cumulative incidence of aortic aneurysms based on diagnostic codes; while corroborating the increased risk of aortic aneurysms in patients with GCA, the relative risk of aortic aneurysms compared with controls was found to be 2.0 [61].

Aortic dilatation has been reported both in the early and late course of GCA (15 to 23 percent of newly diagnosed GCA patients and 22.2 and 33.3 percent of patients after a median disease duration of 5.4 and 10.3 years, respectively) [48,58,62-64]. The time course between the diagnosis of the GCA and the discovery of aortic aneurysm varies, often depending on whether systematic imaging is obtained, but clinical recognition of an aortic aneurysm is delayed in the majority of patients. In a descriptive study of 41 patients with GCA who developed thoracic aortic aneurysms, three patients developed aneurysms before GCA was diagnosed, GCA and aneurysms were diagnosed simultaneously in five patients, and in the remaining 33 patients, aneurysms were detected a median of seven years after the diagnosis of GCA [65]. Additional studies confirm that aortic aneurysm are a late complication of GCA, appearing 5 to 10 years after initial diagnosis [16,56,59].

Histopathologic examination of specimens obtained from surgery or autopsy shows a range of findings, from fibrosis to varying degrees of active aortitis, including giant cells. These findings suggest two mechanisms of disease: chronic or late recrudescent aortitis causing elastin and collagen disruption, or mechanical stress on an aortic wall that had been weakened in the early active phase of the disease.

Whether the behavior of aneurysms in GCA resembles or differs from aneurysms of other etiologies is uncertain. One study has suggested that the rate of growth of aneurysms due to GCA is more rapid than those of degenerative etiology [59]. Unfortunately for the clinician, predictive factors for the development of aortic aneurysms in GCA have not been clearly delineated. Inconsistencies in classification and data collection make it difficult to assign with confidence prognostic roles for age, sex, duration, and such traditional risk factors as smoking, hypertension, and hyperlipidemia. Aneurysms in GCA have not correlated with intensity and duration of glucocorticoid therapy [16,56].

●Aortic dissection – While subclinical or clinical aortitis is common in GCA, the related major complications, namely aortic dissection and/or rupture, occur less frequently. In two retrospective studies from large referral centers, aortic dissection or rupture was identified in 1 and 6 percent of all patients with GCA [56,57].

Aortic dissection, which mainly affects the ascending thoracic aorta, can occur early or late in the course of disease. Aneurysm size does not appear to be a predictor of aortic dissection or rupture, while active aortitis may play a role [59,66]. Although longevity in GCA is overall unaffected, epidemiologic data indicate that survival of the subset of patients with aortic aneurysm and dissection is decreased (standardized mortality ratio 2.63; 95% CI 1.78-3.73) [16].

Risk factors for aortic dissection due to GCA have not been clarified.

●Other large artery involvement – GCA can affect the subclavian arteries distal to the take-off of the vertebral arteries and extend through the axillary arteries to the proximal brachial arteries. Arterial bruits, diminished or absent blood pressures, and arm claudication can develop. Cold intolerance of the involved extremity is common, but explicit digital ulcerations and gangrene are rare because of adequate collateral arterial supply.

On imaging, upper-extremity arterial involvement in GCA is characteristically bilateral. Gradual tapering of vessels, with occasional occlusion, is typical (image 4) [67]. The vessel wall is circumferentially affected, in contrast to the eccentric appearance of atherosclerosis.

Clinically evident lower-extremity arterial involvement can occur but is uncommon [68].

Less common manifestations

Central nervous system involvement — Stroke is uncommon in GCA. In descriptive cohorts, the frequency of stroke within the first four weeks of the diagnosis of GCA, and thus construed as potentially disease-related, has ranged from 1.5 to 7.5 percent [27,69,70]. Clinical experience is most consistent with the lower end of these ranges.

GCA is an unusual cause of ischemic stroke. In a population-based stroke registry, only 0.15 percent of 4086 cases of ischemic stroke satisfied criteria for the diagnosis of GCA [71].

Stroke due to GCA has two notable clinical features: Vertebrobasilar involvement is frequent, and intracranial involvement is rare [32].

Though strokes due to GCA can occur in the distribution of both the internal carotid and vertebrobasilar arteries, they are conspicuously more common in the latter location [69,72,73]. More than one-half of strokes attributable to GCA occur in the vertebrobasilar system [69,72]. This figure contrasts with population-based studies of transient ischemic attacks and stroke overall, which occur five times more often in the territory of the internal carotid arteries compared with the vertebrobasilar arteries [74]. Arteritic involvement of the vertebral arteries can result in vertigo, ataxia, dysarthria, homonymous hemianopsia, or bilateral cortical blindness [44]. Bilateral vertebral artery involvement, which causes rapidly progressive brainstem and/or cerebellar neurologic deficits with high mortality, is highly suggestive of GCA [75].

Documented involvement of intracranial vessels in GCA is limited [44,76,77]. In 1 review of 463 patients with a clinical diagnosis of central nervous system vasculitis at the Mayo Clinic, only 2 patients had compelling evidence of intracranial GCA [76]. In a subsequent case series of 185 patients with GCA evaluated at Mayo Clinic, 9 cases of GCA with intracranial involvement were identified [77]. The major findings were a high incidence of neurologic deficits and poor prognosis despite treatment. Other clinical cases of intracranial involvement in the setting of GCA are described [78], and 3 Tesla (3T) magnetic resonance imaging (MRI) has shown vessel wall enhancement of intradural arteries in a small number of GCA patients [79].

Though reported, other neurologic problems including peripheral neuropathy, myelopathy, higher cortical dysfunction or dementia, and pachymeningitis are uncommon complications of GCA [80-82].

Upper respiratory tract symptoms — Patients with GCA can present upper respiratory tract symptoms, in particular a nonproductive cough [83]. The cause of cough is unknown, but may result from vasculitis in the area of cough receptors, which are located throughout the respiratory tree, or vasculitis of the ascending pharyngeal artery, a branch of the external carotid artery. Vasculitis of the bronchial arteries has been observed in the postmortem examination of a patient with disseminated GCA [84].

Other head and neck involvement — Branches of the external carotid artery are often affected in GCA (figure 1), including the superficial temporal artery (figure 2). Jaw claudication results from arteritic involvement of the muscles of mastication (masseter, temporalis, and medial and lateral pterygoid muscles), all of which are supplied by the branches of the external carotid artery. Involvement of other branches of the external carotid artery accounts for many of the other extracranial symptoms that can accompany the presentation of GCA, including:

●Maxillary and dental pain

●Facial swelling

●Throat pain

●Tongue pain and macroglossia [85]

Lingual infarction (causing ulceration of the tongue) and scalp necrosis are uncommon, owing to the rich collateral circulation of these tissues, but occasionally are seen, usually in neglected cases of longstanding duration [86,87].

Atypical features — A variety of unusual presentations of GCA have been reported, including:

●Dysarthria [88]

●Sensorineural hearing loss [89]

●Breast mass [90]

●Female genital tract involvement (ovary, fallopian tubes, or uterus; usually found by chance on histopathologic inspection of surgical specimens) [91]

●Mesenteric ischemia [92]

●Pericarditis [93]

PHYSICAL EXAMINATION FINDINGS

Cardiovascular findings

●Abnormal pulses – In the setting of large vessel (LV) disease, diminished pulses and discrepant blood pressure in the arms can occur. On each visit, the carotid, brachial, radial, femoral, and pedal pulses should be palpated, and blood pressures in both arms measured.

●Temporal artery abnormalities – The frontal or parietal branches of the superficial temporal arteries may be thickened, nodular, tender, or occasionally erythematous (picture 1). Pulses may be decreased or absent. The occipital arteries and, less often, the postauricular or facial arteries may be enlarged or tender.

A meta-analysis performed to identify the utility of various clinical features in the diagnosis of GCA included 21 studies reported between 1996 and 2000 [43]. The studies represented a total of 2680 patients who had undergone temporal artery biopsy, of whom 1050 (39 percent) had biopsy-proven GCA. Likelihood ratios (LR) for positive temporal artery biopsies were calculated for various features of the physical examination. The following observations were made:

•A prominent or enlarged temporal artery – LR 4.3 (ie, a patient with such a finding was more than four times as likely to have a positive temporal artery biopsy than one without such a finding)

•An absent temporal artery pulse – LR 2.7

•Temporal artery tenderness – LR 2.6

Though these findings illustrate the potential value of the physical examination in evaluating patients with possible giant cell arteritis (GCA), in a sizeable number of patients with biopsy-proven GCA, clinical examination of the temporal arteries is unremarkable; conversely, prominence of the frontal branches of the temporal arteries in older adults is not infrequent or of pathologic consequence.

●Bruits – Auscultation for bruits should be regularly performed. Bruits can be heard on auscultation of the carotid or supraclavicular areas, over the axillary, brachial, or femoral arteries, and over the abdominal aorta.

●Heart murmur – Murmurs of aortic regurgitation may signal the development of an ascending aortic aneurysm with secondary dilatation of the aortic valve.

Ocular findings — Fundoscopy is indicated in patients with subjective change in visual acuity. In a patient with transient monocular visual loss (TMVL), the ophthalmologic examination can be entirely normal. Some patients have cotton wool spots in the retina, indicative of local, retinal ischemia, depending upon the site of critical vascular lesions.

In patients with acute visual loss from arteritic anterior ischemic optic neuropathy (AION), ophthalmoscopic examination shows changes of ischemic optic neuropathy with a swollen pale disc and blurred margins (picture 2). In patients with permanent visual loss, later findings include optic disc pallor.

Fundoscopy can be valuable in differentiating nonarteritic AION from arteritic AION, as occurs in GCA. The affected swollen optic nerve is often pale immediately in GCA, whereas pallor is delayed in nonarteritic AION. The finding of associated retinal or choroidal ischemia in addition to AION is highly suggestive of GCA. Finally, the absence of a crowded optic disc in the unaffected eye of a patient with AION should make the diagnosis of nonarteritic AION unlikely and should increase the probability of arteritic AION [40].

In posterior ischemic optic neuropathy (PION), acuity is reduced but the appearance of the optic nerve on ophthalmoscopic examination is normal in the acute phase because the ischemic insult has occurred well behind the optic disc. A relative afferent pupillary defect (APD), an objective means of identifying ipsilateral optic nerve dysfunction, will be present unless both eyes have symmetrical optic nerve dysfunction. In PION, the finding of an APD can be a useful sign to implicate optic neuropathy as a probable cause of visual loss even when the optic nerve appears normal.

Diplopia is typically transient but if present, can be associated with reduced extraocular movements; diplopia due to a brainstem stroke results in skew deviation.

Musculoskeletal findings — In patients who also have polymyalgia rheumatica (PMR), active range of motion of the shoulders, neck, and hips can be limited, which in some patients can also be accompanied by distal synovitis, especially affecting the wrists and metacarpophalangeal joints. (See "Clinical manifestations and diagnosis of polymyalgia rheumatica".)

LABORATORY FINDINGS — Laboratory findings useful in the assessment of giant cell arteritis (GCA) include routine hematologic testing, selected serum chemistry tests, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP).

Hematologic abnormalities — A normochromic anemia is often present prior to therapy and improves promptly after the institution of glucocorticoids. The anemia is occasionally profound [94]. Many patients also have a reactive thrombocytosis [95,96]. The leukocyte count is usually normal or minimally elevated, even in the setting of widespread systemic inflammation.

Erythrocyte sedimentation rate and C-reactive protein — A characteristic laboratory abnormality in many patients with GCA is a high ESR, which can reach 100 mm/hour [43,96]. The CRP is nearly always commensurately elevated, though prospective head-to-head studies on the use of the ESR and CRP for the diagnosis and management of GCA are lacking. Among patients with a paraproteinemia or some other cause of a spuriously elevated or depressed ESR, the CRP level is more reliable. (See "Acute phase reactants", section on 'Clinical use'.)

Less striking elevations of the ESR [43], however, may also occur. In a population-based study of 167 patients from Olmsted County, 18 (11 percent) had an ESR less than 50 mm/hour and 9 (5 percent) less than 40 mm/hour before treatment was initiated. The patients with an ESR less than 40 mm/hour were less likely to experience systemic symptoms such as malaise, fever, or weight loss; nevertheless, their clinical manifestations, including risk of visual loss, were indistinguishable from those in patients with a higher ESR [97]. In another series of 173 biopsy-proven cases, 12 patients (5.8 percent) had ESR values less than 46 mm/hour [98].

An additional retrospective study from Olmsted County found normal values for both the ESR and CRP in 4 percent of 177 patients with biopsy-proven GCA at the time of diagnosis [99].

Neither the ESR nor the CRP is a specific biomarker for GCA. Abnormalities in the ESR and CRP can help calibrate the diagnostic probability of GCA, but normal values do not absolve the clinician of the responsibility to pursue the diagnosis in an appropriate clinical setting, nor do marked elevations certify that a diagnosis of GCA is correct. (See "Diagnosis of giant cell arteritis".)

Other laboratory abnormalities — Elevated serum concentrations of hepatic enzymes, especially the alkaline phosphatase, occur in 25 to 35 percent of patients. The elevations are typically modest and revert to normal with glucocorticoid therapy. The serum albumin level is often moderately decreased at diagnosis but responds quickly to the institution of glucocorticoids.

Elevated serum interleukin (IL) 6 concentrations appear to be related closely to clinical disease activity in GCA [100] and may better correlate with clinical relapse than the ESR [101]. However, IL-6 assays are not routinely available, and their clinical utility remains unproven.

IMAGING FINDINGS — The posterior-anterior (PA) and lateral chest radiograph can show aneurysmal dilation of the ascending aorta, but has limited sensitivity. A detailed discussion of the other imaging modalities used to evaluate the extent of involvement of the aorta and large arteries is presented separately. (See "Clinical manifestations and diagnosis of thoracic aortic aneurysm", section on 'Imaging diagnosis'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Giant cell arteritis and polymyalgia rheumatica".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Polymyalgia rheumatica and giant cell arteritis (The Basics)")

●Beyond the Basics topics (see "Patient education: Vasculitis (Beyond the Basics)" and "Patient education: Polymyalgia rheumatica and giant cell arteritis (Beyond the Basics)")

SUMMARY

●Epidemiology – The major risk factor for developing giant cell arteritis (GCA, also known as Horton disease, cranial arteritis, and temporal arteritis) is aging. The disease almost never occurs before age 50 years, and its incidence rises steadily thereafter. Although systemic manifestations are characteristic of GCA and although vascular involvement can be widespread, clinical manifestations of the disease most frequently result from involvement of the cranial branches of arteries originating from the aortic arch. The most sinister complication of GCA, visual loss, is one potential result of the major phenotype of the disease, that of cranial arteritis. (See 'Introduction' above and 'Epidemiology' above.)

●Clinical features and association with polymyalgia rheumatica – The onset of symptoms in GCA tends to be subacute, but abrupt presentations occur in some patients. When taking the patient's history, the clinician must ask about the following types of symptoms: systemic symptoms, such as fever, fatigue, and weight loss; headache; jaw claudication, which is the symptom most highly predictive of a positive temporal artery for the diagnosis of GCA; visual symptoms, particularly transient monocular visual loss (TMVL or amaurosis fugax) and diplopia; and symptoms of polymyalgia rheumatica (PMR). Other symptoms can also be present. (See 'Clinical features' above and 'Association with polymyalgia rheumatica' above.)

●Ocular involvement – A variety of ocular syndromes are associated with GCA. The most common are TMVL and anterior ischemic optic neuropathy (AION). It is estimated that bilateral blindness will develop in 25 to 50 percent of untreated patients who present with loss of vision in one eye. (See 'Permanent vision loss' above.)

●Large vessel involvement – Subclinical involvement of the aorta and large arteries is frequent, a delayed clinical consequence of which can be aortic aneurysm. (See 'Large vessel involvement' above.)

●Physical examination findings – Careful temporal arteries palpation, measurement of the blood pressures in both arms, and assessment of the arterial tree by palpation and auscultation should be performed in all patients with suspected GCA. (See 'Physical examination findings' above.)

●Laboratory findings – Laboratory findings useful in the assessment of GCA include routine hematologic testing, selected serum chemistry tests, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP). (See 'Laboratory findings' above.)

ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges William P Docken, MD and James T Rosenbaum, MD, who contributed to an earlier version of this topic review.