Approach Considerations
Statistical prediction models can guide decisions to perform temporal artery biopsy and initiate glucocorticoids in giant cell arteritis (GCA), but do not supplant clinical judgment. [86, 87]
The laboratory hallmarks of GCA include elevation in the erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) level and thrombocytosis. The ESR usually exceeds 50 mm/h and may exceed 100 mm/h, but may be normal in 7-20% of patients with GCA. [88, 89] Therefore, a normal ESR does not rule out GCA, and the level of elevation of ESR does not correlate reliably with the severity of the disease. Because normal values of ESR are known to increase with age and are higher in women, the ESR should be appropriately adjusted. [90]
CRP is of hepatic origin. The level usually rises before ESR in most disease states, and is often elevated in GCA. It has higher sensitivity and specificity than ESR (98.6% and 75.7%, respectively) and is relatively unaffected by age, gender, and other hematologic parameters. [91]
Nonconcordance between ESR and CRP can occur (ie, either an elevated ESR with normal CRP or a normal ESR with an elevated CRP). The use of both tests provides a slightly greater sensitivity for the diagnosis of GCA (99%) than the use of either test alone. [92]
Alpha-2 globulin, fibrinogen, and other acute-phase reactants are elevated mildly but nonspecifically in 72% of patients with GCA. A study of 26 markers related to immune cells identified serum B-cell activating factor (BAFF) and interleukin-6 (IL-6) as having the strongest association with GCA; elevated levels of BAFF and IL-6 accurately distinguished patients with newly diagnosed GCA from healthy controls. [93] However, currently these tests are not readily available in most laboratories.
A complete blood cell count (CBC) should always be obtained. CBC reveals mild normochromic normocytic anemia in most patients, with a mean hemoglobin level of 11.7 ± 1.6 g/dL. Anemia has been shown to have a good negative predictive value for severe ischemic complications in GCA. [94] The leukocyte and differential counts are generally normal.
Platelet counts are mildly elevated in most patients. A platelet count greater than 400,000/µL, although not in itself diagnostic, is more helpful than an elevated ESR for ruling in GCA. [95] Conversely, a normal platelet count is more accurate than a normal ESR for ruling out GCA. [96] Additionally, in the largest population-based GCA study to date in the United States (3001 patients), the combination of elevated platelet counts and CRP levels greater than 2.45 mg/dL was associated with a positive temporal artery biopsy, while ESR results were not as specific a predictor. [95]
Liver function test results (eg, alkaline phosphatase and aspartate aminotransferase), are elevated in 20-30% and 15% of GCA cases, respectively. In addition, the prothrombin time may be prolonged. Muscle enzyme levels (eg, creatine kinase, aldolase) are normal.
In GCA, the frequency of rheumatoid factor, antinuclear antibodies, and other autoreactive antibodies is not higher than that of age-matched controls. Complement levels are normal, and cryoglobulins and monoclonal immunoglobulins are absent.
Automated visual field testing typically reveals an inferior altitudinal defect, inferior nasal sectorial defect, or central scotoma.
Temporal artery biopsy
Superficial temporal artery biopsy (TAB) is the criterion standard for diagnosing temporal arteritis. TAB should be obtained almost without exception in patients in whom GCA is suspected clinically. It is important because the treatment course for GCA is long and often complicated, and many of the nonspecific symptoms of GCA (eg, headache, body aches, fatigue) occur in myriad other disorders. A positive TAB has 100% specificity but relatively low sensitivity (15%-87%) for the diagnosis of GCA.
Imaging studies
Color duplex ultrasonography of the temporal artery has emerged as a promising alternative or complement to TAB. [97, 98, 99, 100, 101, 102, 103] Its specificity is 80%-100% when a dark halo (classic halo sign) is seen about the vessel. [99] This key diagnostic feature is believed to represent vessel wall edema. Its sensitivity is limited, however; in particular, early inflammatory changes that can be seen on TAB specimens do not produce the characteristic halo effect.
Color duplex ultrasonography is user dependent. However, experienced sonographers with proper training and equipment have been shown to provide reliable diagnosis of GCA. [104]
The prospective Temporal Arteries in the Diagnosis and Treatment of Giant Cell Arteritis (TABUL) study, which included an ultrasound training program for diagnosing GCA, analyzed 381 patients who underwent both ultrasound and TAB within 10 days of starting treatment for suspected GCA, and found that the sensitivity of TAB was 39% (95% confidence interval (CI) 33% to 46%), which was significantly lower than previously reported and inferior to that of ultrasound (54%; 95% CI 48% to 60%). However, TAB had 100% specificity (95% CI 97% to 100%), versus 81% (95% CI 73% to 88%) for ultrasound. [105]
The TABUL authors noted that performing ultrasound scans in all patients with suspected GCA and performing biopsies only on negative cases would increase the sensitivity of ultrasound to 65% while maintaining specificity at 81%, reducing the need for biopsies by 43%. Furthermore, strategies that combined clinical judgement with testing showed sensitivity and specificity of 91% for TAB and 81% for ultrasound, and specificity of 93% and 77%, respectively. Cost-effectiveness favored ultrasound, with both cost savings and a small health gain. [105]
At the very least, the use of ultrasonography to “map” the path of the artery is a very useful adjunct to the evaluation of a patient with suspected GCA, making considerably more straightforward the choice of incision site and the biopsy target segment. [106]
Rhéaume et al reported that high-resolution magnetic resonance imaging (MRI) of the scalp arteries had a sensitivity of 93.6% and a specificity of 77.9% for the diagnosis of GCA, with a corresponding negative predictive value of 98.2%. These authors suggested that MRI could be used as the initial investigation in GCA, with TAB being reserved for patients with an abnormal MRI.
Bley et al reported that high-resolution MRI and color duplex ultrasonography have comparable diagnostic power in detecting GCA. Decisions regarding which technique to use may depend on the clinical setting. [107]
Because aneurysms of the aorta or other vessels are often asymptomatic, unless they rupture, screening all patients with GCA for large-vessel disease with computed tomography (CT) is prudent. MRI can also be used to evaluate aortic involvement in GCA. [108] Vessel wall thickening and edema may be evident on T2-weighted images, and increased mural enhancement may be visible on postcontrast T1-weighted images, indicative of regional inflammation. Ultrasonography may be helpful for diagnosing and monitoring aortic involvement in GCA, including aortic aneurysms. [109]
In rare cases, serious suspicion for aortic or carotid artery disease may warrant invasive imaging studies. Aortic arch and cerebral angiography may show occlusion or alternating stenotic areas. However, temporal artery arteriography has no diagnostic value in GCA and does not aid in predicting the proper biopsy site for the temporal artery.
CT and MRI of the brain are not first-line diagnostic procedures for GCA. On CT and MRI, the brain is typically unaffected by GCA, but in patients with a multi-infarct state due to cervicocephalic arteritis, CT and MRI demonstrate multiple areas of infarction. [110, 111, 112, 113]
Positron emission tomography (PET) scanning with 18-fluorodeoxyglucose (FDG) uptake has been used to evaluate the vasculitic process within large vessels such as the thoracic aorta. [114] In a retrospective case-control study by Nielsen et al that evaluated 18-FDG PET/CT in 44 patients with GCA and 44 controls, FDG uptake in the temporal and/or maxillary artery had sensitivity of 64% and specificity of 100% for the diagnosis of GCA. Including the vertebral arteries in the assessment increased sensitivity to 82%, with specificity remaining 100%. Because of the high specificity, the authors suggest that TAB can be omitted in patients whose PET/CT shows 18F-FDG uptake in the cranial arteries. [115]
For further discussion, see Giant Cell Arteritis Imaging.
EULAR guidelines
European League Against Rheumatism (EULAR) guidelines in clinical practice, published in 2018, include the following recommendations on imaging in GCA [116] :
-
In patients with suspected GCA, early imaging is recommended to complement the clinical diagnostic criteria, assuming high expertise and prompt availability of the imaging technique. Imaging should not delay initiation of treatment.
-
In patients in whom there is a high clinical suspicion of GCA and a positive imaging study, the diagnosis of GCA may be made without biopsy or further imaging. In patients with a low clinical probability and a negative imaging result, the diagnosis of GCA can be considered unlikely. In all other situations, additional efforts towards a diagnosis are necessary.
-
Temporal artery ultrasound (US), with or without axillary artery US, is recommended as the first imaging modality in patients with suspected GCA with predominantly cranial manifestations (eg, headache, visual symptoms, jaw claudication, temporal artery swelling and/or tenderness). A non-compressible ‘halo’ sign is the US finding most suggestive of GCA.
-
If US is not available or the results are inconclusive, high-resolution MRI of cranial arteries to investigate mural inflammation may be used as an alternative for diagnosis of GCA.
-
CT and PET are not recommended for the assessment of inflammation of cranial arteries.
-
US, PET, MRI and/or CT may be used for detection of mural inflammation and/or luminal changes in extracranial arteries to support the diagnosis of large-vessel GCA. US is of limited value for assessment of aortitis.
-
Conventional angiography is not recommended for the diagnosis of GCA as it has been superseded by the previously mentioned imaging modalities.
-
In patients with GCA in whom a flare is suspected, imaging might be helpful to confirm or exclude it. Imaging is not routinely recommended for patients in clinical and biochemical remission.
-
MRA, CTA, and/or US may be used for long-term monitoring of structural damage in patients with GCA, particularly to detect stenosis, occlusion, dilatation, and/or aneurysms. The frequency of screening as well as the imaging method applied should be decided on an individual basis.
-
Imaging examination should be done by a trained specialist using appropriate equipment, operational procedures and settings. The reliability of imaging, which has often been a concern, can be improved by specific training.
American College of Rheumatology classification criteria
The following are classification criteria for GCA issued by the American College of Rheumatology in 1990 [54] :
-
Age 50 years or older
-
New-onset localized headache or localized head pain
-
Temporal artery tenderness to palpation or decreased pulsation
-
ESR of 50 mm/h or higher
-
Positive arterial biopsy results (vasculitis characterized by mononuclear infiltration or granulomatous inflammation, usually with multinucleated giant cells)
The presence of 3 or more criteria yields a diagnostic sensitivity of 93.5% and specificity of 91.2%. However, in one study, the American College of Rheumatology classication criteria misclassifed up to 25% of ophthalmology patients with GCA. [117]
Temporal Artery Biopsy
Superficial temporal artery biopsy (TAB) is the criterion standard for making a diagnosis of temporal arteritis. (See the image below.) TAB should be obtained almost without exception in patients in whom GCA is suspected clinically. It is important because the treatment course for GCA is long and often complicated, and many of the nonspecific symptoms of GCA (eg, headache, body aches, fatigue) occur in myriad other disorders.
Hematoxylin- and eosin-stained superficial temporal artery biopsy specimen, cross section. The hallmark histologic features of GCA shown here include intimal thickening with luminal stenosis, mononuclear inflammatory cell infiltrate with media invasion and necrosis, and giant cell formation in the media.
A positive TAB is diagnostic of GCA (100% specificity). The reported sensitivity of TAB has ranged widely, from as low as 15% to as high as 87%. [118] The histopathological changes on TAB often correlate with clinical features of severity. [11]
TAB should be performed as soon as possible after clinical suspicion is raised. If the index of suspicion is high, the clinician should not delay starting therapy while awaiting TAB. Failure to treat increases the risk of ischemic ocular and cerebral complications, and TAB results remain positive for characteristic GCA pathology for at least 2 weeks after treatment is started.
The reported chances of obtaining a positive biopsy after initiation of steroid treatment vary widely in the literature, from only 10% after 1 week to 86% after 4 or more weeks of treatment. [119, 120] This wide variation may relate to issues such as patient selection, differences in biopsy or pathology techniques, or differences in the disease itself in different populations.
A systematic review of the TAB literature showed that the median positive yield of TAB was 25%, with interquartile range of 17% to 34%. [121] Because of this high negative rate, and because there may be "skip lesions" with normal intervening segments of artery in GCA, some authors advocate obtaining 2- to 3-centimeter, and occasionally bilateral, TAB specimens. Surgeons should aim for the longest TAB length that is reasonably possible and compensate for possible shrinkage after fixation of the specimen.
In the pathology literature, the recommended minimum length for fixed TAB specimens has varied. Different studies suggested fixed TAB length thresholds of 0.5 cm (n=1,520 biopsies), 0.7 cm (n=966 biopsies), or 1.5 cm (n=538 biopsies) as the optimum for identifying GCA and avoiding false-negative results. [122, 123, 124] A review by Foster et al of 1190 TABs from 1163 patients suggests a 1.5–2.0 cm length as the optimal biopsy length for diagnosing GCA. This length accounts for post-fixation shrinkage. Longer lengths did not yield enough improvement in diagnosis to justify the increased risk of complications. [125, 126]
Clinicians who request TAB, but do not perform TAB themselves, may not appreciate the time required to harvest a TAB specimen, and may not appreciate that the length of the skin incision and biopsy specimen may not correspond, as the artery contracts when removed from the wound bed.
Biopsy of the most symptomatic side should be performed first. If frozen section is available, and the initial biopsy is negative, a contralateral specimen may be considered if clinical suspicion of GCA remains high. In cases in which a large TAB section is obtained from the most symptomatic side and multiple thin sections obtained, diagnosis can be made in 86% of cases with a unilateral TAB.
Studies have found that bilateral biopsies do not increase the diagnostic yield in the vast majority of patients (99%). [127, 128, 129, 130] Nevertheless, most physicians with high clinical suspicion despite an initial negative biopsy would still recommend a second contralateral biopsy, given the consequences of a missed diagnosis of GCA. [131]
The clinical significance of giant cells seen on TAB in temporal arteritis is unknown. Armstrong et al found that patients whose TAB contained giant cells had 3 times the rate of blindness and polymyalgia rheumatica compared with the group with no giant cells; although the difference was not statistically significant, it does suggest an association with giant cells and more aggressive disease. [132]
Alberts et al reported that in clinical practice, bilateral temporal artery duplex ultrasonography can serve the same function as biopsy, but without subjecting patients to the potential morbidity of a surgical procedure. TAB could be reserved for cases in which the ultrasonographic result is inconsistent with the clinical picture, in which case the biopsy result, if different, might influence the treatment decision. [98]
Several clinical studies demonstrate that the likelihood of a positive TAB in patients with GCA is greatly enhanced if temporal artery pulses are absent or diminished, even in the absence of other localizing signs. The presence of a headache and jaw claudication may also increase the yield. [133]
TAB is a safe procedure; however, risks include temporary or permanent damage to the temporal branch of the facial nerve, infection, bleeding, hematoma, skin ulceration, dehiscence, and objectionable scar. Ischemic stroke after TAB occurs in the uncommon situation where the external carotid provides critical collateral circulation to the brain.
Temporal artery biopsy procedure
TAB may be performed by ophthalmologists, general surgeons, head and neck surgeons, plastic or vascular surgeons, or dermatologic surgeons. The frontal branch of the superficial temporal artery is preoperatively identified by visualization, palpation, or Doppler ultrasonography and then marked with a pen or with dye. In approximately 16% of cases, the frontal branch is atrophic or absent, in which case a biopsy should be performed on the main trunk of the superficial temporal artery using a preauricular approach. [134]
To improve the yield and to avoid complications, proper site selection is important. Focal symptoms or signs, such as erythema, tenderness, absent pulsations, arterial nodularity or swelling, inflammation, bruit, or thickening, help guide biopsy site selection and may improve the yield of the biopsy.
Localizing findings are often absent or misleading, however; frequently, the physical examination findings correlate poorly with the biopsy results. In the absence of localized arterial findings, the zone between the tragus of the ear and the lateral canthus is usually not biopsied, to avoid damage to the temporal branch of the facial nerve. Knowledge of the anatomy and careful dissection above and within the superficial temporal fascia help prevent nerve damage during the procedure.
A small area of hair may have to be shaved. It is essential to accurately mark the location of the artery with a marking pen prior to any local anesthetic administration. If there is concern that the vessel markings will be obscured by the prep solution, the vessel location can be scratched with a needle tip prior to the antiseptic scrub. [135]
In patients with a readily visible or palpable artery, epinephrine can be included with the initial local anesthetic injection. If the artery is difficult to visualize or palpate, avoid epinephrine in the local anesthetic until after the vessel is visualized subcutaneously. Local anesthetic is administered approximately 1 cm from either side of the vessel but not into the vessel.
With the site selected and the patient under local anesthesia, a shallow incision just into the underlying fat is made directly over the artery. The artery is bluntly dissected free from within the superficial temporal fascia. To avoid nerve injury, it is important to undermine just below the dermis in the superficial fat and above the superficial fascia. [136]
A segment of artery is ligated proximally and distally, removed, and sent for histopathologic review. Hemostasis is obtained with electrocoagulation, and a layered closure is performed.
Traditionally, excision of 2-3 cm of artery is recommended to provide accurate diagnosis of temporal arteritis because some studies have noted higher positive rates with longer specimens. Temporal arteritis may have a patchy distribution among extracranial arteries and within small segments of these arteries. In general, longer biopsy specimens provide more tissue in which to demonstrate short, noncontiguous foci of giant cell arteritis, the so-called skip areas.
Skip areas are not commonly identified, but patches of arteritis as short as 0.29 mm have been clearly demonstrated on serial sectioning. Serial sectioning, proper tissue handling, and adequate specimen length are critical to ensure maximum yield from the biopsy. Surgeons should be aware that fixation results in shrinkage of the biopsy specimen. [137]
Ultrasonography
Although superficial temporal artery biopsy remains the standard for diagnosis of giant cell arteritis (GCA), color duplex ultrasonography can be used to diagnose GCA. A hypoechoic halo around the temporal artery lumen on color duplex sonograms has demonstrated high specificity for GCA, but limited sensitivity; in particular, early inflammatory changes that can be seen on TAB specimens do not produce the characteristic halo effect. [138]
Steroid treatment results in disappearance of the halo. Rarely, the halo may disappear before 2 weeks of steroid treatment; often, it persists for up to 2 months. [139]
The halo represents edema in the artery wall. Some centers consider this finding a major decision-maker in their diagnostic equation, while others do not believe that such a halo is definitive for GCA.
Cerebral Angiography
The sensitivity of cerebral angiography in GCA affecting the brain is as low as 10–20%. Consequently, angiography is not the procedure of choice in such cases. However, involvement of multiple vessels in multiple vascular beds (a high-probability angiogram) raises the possibility of RCVS (reversible cerebral vasoconstriction). Documentation of reversibility of the angiographic abnormalities, during the course of the disease, will eventually secure the diagnosis of RCVS. [140]
GCA causes granulomatous inflammation in the wall of medium-size and large arteries and preferentially affects extracranial branches of the carotid artery. [141] Occlusion of the posterior ciliary arteries occurs more commonly. Involvement of intracranial arteries is rare, and cerebral infarctions are the hemodynamic consequences of occlusion of cervical arteries.
Magnetic resonance angiography (MRA) and cerebral angiography reveal occlusion of the affected arteries. While MRA can give useful information in GCA, cerebral angiography is the criterion standard to obtain optimum information, but at the cost of potential complications.
In GCA, vertebral arteries are more likely affected than internal carotid arteries, especially in the extradural portion, where there is more elastic tissue. [142] The vertebral and external carotid arteries (including the superficial temporal artery) may show vasculitic changes of alternating stenotic segments or occlusion. The internal carotid arteries may be occluded, but they rarely demonstrate a characteristic vasculitic pattern.
Electromyographic Studies
Electromyography (EMG) is rarely needed in patients with a clinical presentation of giant cell arteritis. Elderly patients frequently have mildly abnormal nerve conduction studies and EMG findings that suggest a mild peripheral neuropathy, regardless of whether they have GCA. The relationship of such neuropathies to the systemic inflammatory state in some patients is uncertain. In other patients, antecedent ischemic mononeuropathies may occur and eventually resemble a "diffuse," severe, peripheral neuropathy.
Histologic Findings
The histopathology of the diagnostic arterial lesion in giant cell arteritis (GCA; see the image below) includes the following:
-
Intimal proliferation with resulting luminal stenosis
-
Disruption of the internal elastic lamina by a mononuclear cell infiltrate
-
Invasion and necrosis of the media progressing to involvement of the entire vessel wall (ie, panarteritis) with an inflammatory infiltrate consisting predominantly of mononuclear cells
-
Giant cell formation with granulomata within the mononuclear cell infiltrate
-
Intravascular thrombosis (less consistently found)
Hematoxylin- and eosin-stained femoral artery branch, cross section, taken from a lower limb amputation specimen. Mononuclear cell invasion and necrosis in the media of this large artery can be observed. Extensive lower limb vasculitis from GCA resulted in ischemic necrosis of the lower limb, necessitating amputation.
Involvement of an affected artery is patchy, with skip lesions and normal intervening segments. It is commonly accepted that because of the patchy involvement of the arteries, biopsies may be nondiagnostic in many patients, and nondiagnostic biopsy specimens do not exclude the diagnosis of GCA. Some authors even suggest that biopsy may not be necessary. [119]
Early cases or regions with minimal involvement
Collections of lymphocytes are confined to the region of the internal or external elastic lamina or adventitia in early cases or regions of arteries with minimal involvement. Intimal thickening, with prominent cellular infiltration, is typically present.
Late cases or regions with marked involvement
All layers are affected in late cases or regions of arteries with marked involvement. There are widespread areas of necrosis of portions of the arterial wall. The elastic laminae usually are involved, and granulomas containing multinucleated histiocytic and foreign body giant cells, histiocytes, predominantly helper T-cell lymphocytes, and some plasma cells and fibroblasts are usually present.{ref7
Weyand and colleagues have extensively described the distribution and function of inflammatory cells in the artery wall. [143] Eosinophils may be seen in the specimen section, but polymorphonuclear leukocytes (PMNs) are rare. Thrombosis may develop at the sites of active inflammation. These areas with thrombosis may recanalize later.
It has been observed that the inflammatory process is usually most marked in the inner portion of the media adjacent to the internal elastic lamina. This has led to the belief that the internal elastic lamina plays a central role in the initiation of the inflammatory process. Fragmentation and disintegration of elastic fibers occur. This is closely associated with an accumulation of giant cells, which often seem to engulf parts of the internal elastic lamina.
The giant cells are difficult to find in some cases, and their absence does not exclude the diagnosis if other features are present. Fibrinoid necrosis is seen less commonly in necrotizing arteritis.
The more sections that are examined in the area of arteritis, the more likely it is that giant cells will be found. What is needed is transmural acute and chronic inflammation for acute diagnosis or evidence of previous repair. Healed or subacute phase shows fibrosis, fragmented internal elastic lamina, chronic inflammatory cells in the intima or media, and ideally neovascularization. Long breaks in internal elastic lamina favor healed arteritis over atherosclerosis.
Intimal proliferation is often marked. However, intimal proliferation is a nonspecific feature in the elderly, and does not suggest past or present arteritis if found alone.
-
Hematoxylin- and eosin-stained superficial temporal artery biopsy specimen, cross section. The hallmark histologic features of GCA shown here include intimal thickening with luminal stenosis, mononuclear inflammatory cell infiltrate with media invasion and necrosis, and giant cell formation in the media.
-
Lumbar angiogram showing stenosis and occlusion of femoral artery branches due to vasculitis.
-
Hematoxylin- and eosin-stained femoral artery branch, cross section, taken from a lower limb amputation specimen. Mononuclear cell invasion and necrosis in the media of this large artery can be observed. Extensive lower limb vasculitis from GCA resulted in ischemic necrosis of the lower limb, necessitating amputation.
-
Hematoxylin and eosin stain, low power. Temporal artery. Note the thrombosis in the lumen, intimal hyperplasia, and infiltration of the arterial wall muscular layers with inflammatory cells. A multinucleated giant cell is seen internal to the muscularis at the area of the internal elastic lamina (upper right).
-
Anterior ischemic optic neuropathy. Image courtesy of Richard Kho, MD, Q.C. Eye Center, Quezon City, Philippines.
-
Branch retinal vein occlusion in a patient with giant cell arteritis. Image courtesy of Manolette Roque, MD, Roque Eye Clinic, Manila, Philippines.
-
Central retinal artery occlusion (CRAO).
-
Prominent temporal artery is visible on the temple of a 76-year-old woman with temporal arteritis. Courtesy of ScienceSource (https://www.sciencesource.com/).
