Ординатура / Офтальмология / Английские материалы / Essentials in Ophthalmology Pediatric Ophthalmology Neuro-Ophthalmology Genetics_Lorenz, Borruat_2008

Summary for the Clinician

■Giant cell arteritis can cause a variety of constitutional symptoms as well as symptoms related to focal ischemia.

■The typical clinical presentation of GCA is easy to recognize (elderly patient with aches and myalgias, anorexia, new headache and jaw claudication) but is absent in as many as half of cases.

■Elderly patients should be specifically questioned about a pain or ache in their jaw that occurs only after a few minutes of continuous chewing because jaw claudication is the single most specific symptom of GCA.

13.3 Visual Manifestations of GCA

Visual manifestations are common in patients with GCA, though the exact frequency is variable and ranges from 14% to 70% amongst different studies [47]. In Hayreh’s prospective study [25] of 170 biopsy-positive cases of GCA diagnosed at a single referral center in the midwestern United States, 50% (85/170) of the patients had ocular findings or visual symptoms at their initial visit and in the vast majority (97.7%) of these patients, visual loss in one or both eyes was the most commonly reported symptom [25]. Gonzalez-Gay et al. [20] reported their retrospective series of 161 biopsy-positive patients followed at a single institute in northwestern Spain, and 26% had visual manifestations at diagnosis [20]. HLA phenotyping was performed in 62 of these patients with biopsy-proven GCA and the authors found that the frequency of ischemic visual complications was 3 times higher in the patients carrying the HLA DRB1*04 allele, suggesting that genetic differences may influence the phenotypic profile [20].

Ocular involvement and visual symptoms may be the first or sole manifestation of GCA, emphasizing the importance of maintaining a heightened awareness of this disease in any elderly patient with a new visual disturbance.

13.3  Visual Manifestations of GCA 233

13.3.1 Transient Visual Loss

Visual loss in GCA can be transient or permanent. Among patients with visual manifestations of GCA, a history of transient visual loss is reported by 30%–54% of patients [17, 20, 25]. In some patients, transient visual loss may be the only visual symptom. Transient monocular blindness, or amaurosis, in GCA is not a trivial symptom but rather should be considered an ominous sign of impending blindness [25, 39]. It occurs as a result of insufficient perfusion of the optic nerve, retina or choroid and precedes the development of permanent visual loss in more than half (50%–64%) of untreated cases [20, 25]. Thus, amaurosis in a patient known or even suspected to have GCA is considered an ophthalmologic emergency and immediate high-dose steroid treatment is recommended in an effort to prevent permanent visual loss which follows in the majority of untreated cases [20, 25]. Additionally, hospitalization and strict bed rest during treatment initiation is advised as even small, posturally mediated decreases in perfusion in already compromised arteries may precipitate an ischemic complication [39].

In a patient who presents with transient monocular blindness with little or no systemic symptoms of GCA, the difficulty lies in distinguishing GCA amaurosis from classical amaurosis fugax due to retinal emboli. Clues that the transient visual loss is due to GCA include a relatively short duration of visual loss (1–2 min or less), multiple recurrences in the same eye over a short period of time and brief episodes of visual dysfunction precipitated by a change in posture such as standing up or bending over. A history of amaurosis alternating between the two eyes is rarely due to retinal emboli and should be considered GCA. Funduscopic examination sometimes demonstrates evidence of retinal or disc ischemia, which further substantiates a diagnosis of GCA in patients with amaurosis. There may be cotton-wool spots (CWS), intraretinal hemorrhages, observable sludging of blood in the retinal arterioles, or optic disc edema. Even in patients with no visual complaints, isolated CWS have been found [17].

234 Giant Cell Arteritis

Summary for the Clinician

■Giant cell arteritis should be in the differential diagnosis of transient visual loss in an elderly patient.

■A history of transient visual loss in a patient suspected to have GCA should prompt immediate treatment with highdose steroids until a diagnosis is confirmed or refuted.

13.3.2Anterior Ischemic Optic Neuropathy

By far the most common cause of permanent visual loss due to GCA is anterior ischemic optic neuropathy (AION). GCA-related AION, also called arteritic AION, is due to inflammatory occlusion of the short posterior ciliary arteries which provide blood flow to the optic disc, the choroid and, in some persons, a small part of the retina supplied by the cilioretinal artery. As such, arteritic AION (infarction of the prelaminar and

13 laminar portion of the optic nerve head) is frequently accompanied by choroidal ischemia or ciliary artery occlusion which may be evident on funduscopic examination or by fluorescein angiography (Fig. 13.2) [25]. The more common form of AION, called non-arteritic AION, is due to insufficient perfusion through the terminal paraoptic branches of the short posterior ciliary artery causing optic disc ischemia. Thus, non-ar- teritic AION is not accompanied by evidence of choroidal ischemia.

A diagnosis of AION is clinically based on acute visual loss accompanied by optic disc edema. The importance in distinguishing between arteritic versus non-arteritic AION in a timely manner lies in the immediate prognosis for the other eye. Among patients with arteritic AION, 25%–50% will suffer a similar event in the other eye, typically within 1–14 days, if left untreated [39]. In this acute setting, the clinician must use clinical indices to determine if the AION is likely to be GCA-related. Certain historical features favor a diagnosis of arteritic AION: age greater than 70 years, preceding amaurosis, very severe visual loss in range of count-

ing fingers or worse, new headache and positive systemic review of systems particularly jaw claudication. On examination, the following features are considered diagnostic for arteritic AION until proven otherwise: severe pallid disc edema or a “chalky white” disc swelling, a normal or large optic cup in the contralateral eye, an associated cilioretinal artery occlusion or the presence of retinal ischemic findings such as CWS or retinal edema (Fig. 13.3) [25, 39]. The presence of retinal ischemic lesions in the presence of AION (optic disc ischemia) is highly suggestive of a systemic inflammatory vasculopathy such as GCA because two different vascular territories of the eye (the central retinal arterial circulation and the posterior ciliary arterial circulation) are implicated.

Recurrent episodes of ischemic optic neuropathy are considered rare once the systemic symptoms, sedimentation rate and acute-phase reactants have normalized. A recent report by Chan et al. found an unexpectedly high 10% recurrence rate (7 of 67 patients) [10]. The recurrences were all ipsilateral and occurred 3–36 months (median 8 months) after the initial episode. In six of the seven patients with recurrent ischemic optic neuropathy, recurrent visual loss was associated with a relapse of systemic symptoms or re-eleva- tion of acute-phase reactants.

Fig. 13.2.  Fluorescein angiogram in a patient with arteritic anterior ischemic optic neuropathy (AION). There is delayed and patchy choroidal perfusion indicating occlusion of the short posterior ciliary artery supplying the optic disc

Summary for the Clinician

■Acute visual loss in a patient with GCA is most likely due to anterior ischemic optic neuropathy and if the patient is not treated with steroids immediately, bilateral visual loss will occur in up to half of these patients within the next days or weeks.

■The older the patient, the more likely an episode of AION will be due to GCA.

■A swollen optic disc plus any retinal ischemic findings in a patient over age 50 years is GCA until proven otherwise.

13.3.3Other Types

of Ischemic Visual Loss

Visual loss in GCA can be due to ischemia affecting any aspect of the anterior visual pathway from retina to occipital lobe. Anterior ischemic optic neuropathy is by far the commonest cause of visual loss (78%–99%) [9, 20, 25]. Central retinal artery occlusion is the second most common cause of visual loss in GCA, affecting about 10%–13% of patients. Other less common causes include posterior ischemic optic neuropathy,

cilioretinal artery occlusion, choroidal infarction and, rarely, ischemia to the chiasm or postchiasmal visual pathway [39]. Occipital lobe infarction due to vertebrobasilar artery involvement occurs in less than 5% of patients with visual loss [20]. In patients with cortical visual loss, visual hallucinations may arise in the area of visual field loss and generally disappear spontaneously after several weeks. They may resolve abruptly with steroid initiation.

13.3.4 Diplopia

Diplopia is the second most common visual symptom related to GCA but occurs far less frequently than visual loss. Transient or constant diplopia was reported to occur in 5.9%–21% of patients with visual manifestations [17, 20, 25]. In some patients, the diplopia may be a harbinger of subsequent visual loss [17]. In others, the diplopia is transient and the sole visual manifestation of GCA [25]. Ischemia of the extraocular muscles, of the cranial nerves and of brainstem ocular motor pathways has been implicated as the mechanism of diplopia in GCA. Thus, weakness of a single extraocular muscle, an isolated cranial nerve III, IV or VI palsy (partial or complete), combined cranial nerve palsies, skew de-

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viation, internuclear ophthalmoplegia, one-and- a-half syndrome and upgaze palsy have all been described to occur with GCA [39].

13.3.5 Orbital Manifestations

The more unusual ocular manifestations of GCA include efferent pupil abnormalities (tonic pupil, Horner pupil), acute hypotony, ocular ischemic syndrome, orbital ischemia, and, rarely, orbital infarction syndrome [39]. Signs of orbital inflammation such as red eye, chemosis or proptosis accompanied by pain typically evoke consideration of a more common condition known as orbital pseudotumor, which is also treated with steroids. However, the steroid requirement for orbital pseudotumor is lower in dosage and shorter in duration than that used for GCA, so caution must be taken to exclude GCA in any older patient with an orbital inflammatory syndrome [35]. In a review of 13 cases of GCA-re- lated orbital manifestations, Lee et al. [35] noted that all patients had proptosis and only 2 patients had pain. Chemosis, lid edema, ophthalmople-

13 gia, visual loss and episcleritis were other findings. The outcome was reported as “improved” in 8 of these 13 patients.

13.4 Clinical Subtypes of GCA

Patients with GCA can be grouped into three clinical subtypes which are defined by the signs and symptoms that predominate the patient’s clinical picture. These clinical subtypes are probably related to different levels of expression of different cytokines, and, as such, identification of characteristic cytokine patterns in the serum and biopsy specimen is being investigated as a potential means of predicting who might be at risk for ischemic complications and where the complication might occur [7, 36, 57].

systemic inflammation in the absence of focal ischemic symptoms. Such patients have asthenia, arthralgias, myalgias, achiness, anorexia, weight loss, and night sweats. A fever of unknown origin which may be low-grade or spiking up to 40°C is common and often generates concern and investigations for an underlying systemic infection or malignancy. Serologically, these patients typically have high sedimentation rates, elevated acute-phase reactants such as C-reactive protein, haptoglobin and fibrinogen, elevated liver function tests, low albumin levels, thrombocytosis and a normocytic normochromic anemia [37]. The serum level of the inflammatory cytokine interleukin-6, which derives from circulating monocytes, is also a sensitive indicator of active systemic inflammation [47, 57].

13.4.2 Cranial Arteritis

This clinical subtype of GCA is dominated by localized vasculitis and focal tissue ischemia. The inflammation primarily involves the branches of the carotid arteries, hence the name “cranial arteritis.” Common symptoms of cranial arteritis include headaches or facial pain, even carotidynia, scalp tenderness, jaw claudication, painful dysphagia, hoarseness, and visual loss. Necrosis of the scalp or tongue necrosis are dramatic but rare manifestations of cranial GCA, inaugural in 1% of cases or fewer (Fig. 13.4) [3, 8]. In the world

13.4.1Systemic Inflammatory Syndrome

This subtype of patients is characterized by non-specific constitutional symptoms related to

Fig. 13.4.  Hemorrhagic necrosis of the scalp in GCA. Reprinted from Clinical and Experimental Dermatology, volume 28, Campbell FA et al. [8], Scalp necrosis in temporal arteritis, pp. 488–490, 2003 with permission from Blackwell Publishers

literature, tongue necrosis has been described in 46 cases of GCA since 1959 [49]. Their relative infrequency is related to the abundant vascular supply to these tissues. Scalp necrosis occurs only when all four supplying arteries are occluded, indicating an extensive vasculitis and portending a grim prognosis. In patients with scalp necrosis, the associated mortality rate related to cerebral or coronary artery occlusion is 41% and the incidence of irreversible visual loss is 67% [8].

13.4.3 Large-Vessel Vasculitis

The third clinical subtype of GCA is a localized vasculitis that primarily involves the subclavian and axillary arteries and/or the aorta. This form of GCA has been termed “large-vessel arteritis or large-vessel vasculitis.” Because the inflammatory process is localized, the temporal artery biopsy is negative in at least half of these patients with large-vessel vasculitis [7, 36, 57], and the diagnosis requires vascular imaging. In contrast to cranial arteritis which leads to arterial stenosis and obstruction, aortitis leads to dilation and aneurysm formation, most commonly of the thoracic aorta. Local stenosis develops in the superior branches of the aortic arch, particularly the subclavian artery and axillary artery. Involvement of the large arteries to the lower extremities is rare, reported in less than 1% of patients [43].

On angiography, the characteristic finding is bilateral stenosis of large arteries or occlusion of large arteries with a smooth tapering proximal and distal to the occlusive lesion. Compted tomography (CT) scan can demonstrate aortic involvement (thickening of the wall) and aortic aneurysm formation [30]. Magnetic resonance imaging (MRI) findings consistent with aortitis are aortic wall thickening, wall edema, increased mural contrast enhancement, and vascular stenosis of aortic branch points. MRI has the advantage of easily combining angiographic images of the aortic branches to provide a comprehensive evaluation for large-vessel vasculitis (Fig. 13.5) [7, 40]. Positron emission tomography (PET) scanning has shown encouraging results for detecting and monitoring large-vessel vasculitis [6, 38]. However, one important and unresolved issue with PET is ascertaining whether increased

13.4  Clinical Subtypes of GCA 237

vascular uptake is a finding specific to vasculitis or if it is simply a marker of any type of wall injury [7]. There is no gold standard test for largevessel vasculitis and imaging is selected on individual considerations.

Large artery involvement is an under-ap- preciated aspect of GCA. It may occur as the predominant clinical subtype in which patients chiefly have ischemic symptoms in their arms and shoulders. It may also occur as a subclinical process in patients with a systemic inflammatory syndrome or cranial arteritis. The reported rate of large-vessel arteritis reaches 27% of patients with GCA [14, 43, 52], and even if an aortic aneurysm is not present at the initial presentation, it can develop later. In 94 patients with GCA followed longitudinally at one institution, 9 (9.6%) had a thoracic aneurysm in a median of 5.8 years after diagnosis, raising questions about the need for serial assessments for the development of large-vessel disease [14].

PET scan suggests that subclinical aortitis is even more common than suspected, although the specificity of the PET scan for detecting vasculi-

Fig. 13.5.  Magnetic resonance imaging arteriogram of large-vessel vasculitis. Abnormal findings are a proximal high-grade stenosis in the left subclavian artery, stenosis in the region of the left subclavian–axil- lary junction and mild long segment narrowing of the proximal right subclavian artery. From Current Opinion in Rheumatology, volume 8, Bongartz T, Matteson EL [7] Large-vessel involvement in giant cell arteritis, pp. 10–17, 2006 with permission from Lippincott, Williams and Wilkins

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tis remains in question. One study demonstrated increased uptake in the aorta in more than half of 35 patients tested [6] and an autopsy series suggests that the frequency of aortic involvement during the course of GCA reaches an amazing 70% [44]. Such numbers have led to the speculation that aortitis may be the rule rather than the exception in GCA. Nonetheless, the clinical symptoms of aortitis are rare (3%–11%) [7, 36]. Symptoms related to large-vessel occlusion are limb claudication, peripheral paresthesias, Raynaud phenomenon and rarely tissue gangrene [36, 57]. The limb claudication is frequently bilateral and may have an acute onset. Physical signs include diminished or absent pulses, asymmetric blood pressure readings and bruits over the carotid, axillary, brachial or subclavian arteries. Aortitis with subsequent aneurysm formation is often clinically silent until a complication occurs, i.e., aortic valve insufficiency, aortic rupture or aortic dissection, heralded by symptoms of acute chest pain, shortness of breath, and hypotension [7].

Patients considered high-risk for aortic aneurysm have a murmur of aortic insufficiency, poly- 13 myalgia rheumatica plus ESR >100 mm/h, or any two of the following: hypertension, hyperlipidemia, polymyalgia rheumatica, and coronary artery disease [7]. Such patients are recommended to have CT/MR angiography and abdominal ultrasound at the time of their diagnosis of GCA and again 1 year later with an annual chest radiograph and transthoracic echocardiogram thereafter [7]. All other patients are recommended to have at least an annual abdominal ultrasound,

chest radiograph, and echocardiogram.

Summary for the Clinician

■Large-vessel involvement in GCA is often clinically silent at the time of diagnosis and is an underappreciated aspect of the disease.

■Stenosis of the aortic branches causes claudication and gangrene in the arms whereas aortitis leads to aneurysm formation and dissection years after initial diagnosis.

Summary for the Clinician

■Vascular imaging is necessary to detect large-vessel vasculitis. Aortitis can be detected with CT, MRI or PET scanning.

■There is no established protocol for screening patients for large-vessel involvement; some authors recommended annual testing.

13.5Laboratory Investigations in GCA

13.5.1Erythrocyte Sedimentation Rate

It is well known that an elevated erythrocyte sedimentation rate (ESR) strongly supports a clinical suspicion of GCA. But it is equally well accepted that a normal ESR does not rule out a diagnosis of GCA. According to the American College of Rheumatology, an ESR by the Westergren method is elevated if it is ≥50 mm/h. Approximately 85% of patients have ESR ≥50 mm/h and almost all patients have an ESR greater than 20 mm/h [53]. Yet, ESRs as low as 4 mm/h have been reported in patients with symptomatic, biopsy-positive disease [23]. In interpreting the significance of a given ESR, it is important to consider other factors which raise or lower the ESR. Conditions known to elevate the ESR are increasing age, female gender, pregnancy, anemia, inflammatory disorders, infection, connective tissue disorders, trauma, hypercholesterolemia and malignancy [23]. Conversely, a very low ESR occurs in polycythemia,hereditaryspherocytosis,impaired hepatic protein synthesis, hypofibrinogenemia, congestive heart failure and use of antiinflammatory drugs [23, 47]. Some patients with GCA consistently demonstrate a low or normal ESR despite active disease, and they have no other condition which might lower the ESR. In such patients, a genetically programmed inhibition of the initiation of the cellular and cytokine cascades may be one possible explanation. Despite these shortcomings, the low cost and universal availability of the ESR make it a useful

laboratory test in the diagnosis and management of patients with GCA.

Recent studies have focused on the potential prognostic value of the pre-treatment ESR but results have not been wholly consistent. Some investigators have noted that the presence of a strong acute-phase response with fever, weight loss and high ESR >85 mm/h confers a low risk of cranial ischemic complications, but others have not corroborated this relationship [11, 27]. Hernandez-Rodriguez et al. [27] reported that patients with systemic symptoms and a high ESR are more refractory to treatment (requiring higher cumulative steroid doses and longer duration) in contrast to Liozon et al. [37] who noted that such patients have an excellent response to steroids with rapid control of symptoms. In sum, further studies are needed to define if and how the ESR might be used as a prognosticator for risk of ischemic events and response to treatment.

13.5.2 C-Reactive Protein

C-reactive protein (CRP) is a single protein quantification whose level rises more rapidly than the ESR in response to inflammatory activity (within 4–6 h). It is not influenced by age, gender, or hematologic factors. Several studies have found the CRP to be a more sensitive indicator (sensitivity generally at 100%) of active GCA compared to the ESR [19, 23]. Like the ESR, an elevated CRP is a non-specific finding but the specificity increases to 97% when both the ESR and CRP are elevated in a patient suspected to have GCA [23]. Its disadvantages include the higher cost of testing compared to ESR and perhaps a relative unfamiliarity amongst clinicians with the test.

13.5  Laboratory Investigations in GCA 239

lower hemoglobin and albumin. In other studies as well, thrombocytosis appears to correlate well with the ESR, but opinion regarding its predictive value for a diagnosis of GCA remains conflicted. Costello et al. [12] compared the laboratory results between patients with arteritic AION (n=121) and patients with non-arteritic NAION (n=287). The patients with GCA had higher median levels of ESR, CRP, platelets and white blood cells (WBC) with lower levels of hemoglobin and hematocrit. The presence of thrombocytosis did not have a greater predictive ability than either ESR or CRP for diagnosing GCA [12]. Foroozan et al. [16] found differently in their retrospective series of 91 patients suspected of GCA: 47 (52%) patients had positive biopsy results and 27 of these patients had thrombocytosis (defined as platelet count greater than 400×103/µl), yielding a sensitivity of 57%. However, the specificity of thrombocytosis was 91% compared to 27% for an elevated ESR. Furthermore, thrombocytosis had a higher positive predictive value than the ESR (87% compared to 54%) and a relatively high negative predictive value of 67%. These authors concluded that the presence of thrombocytosis is a helpful corroborative finding for GCA in a suspected patient with an elevated ESR [16].

Summary for the Clinician

■ThrombocytosisGCA. is common in active

■In a patient with suspicious clinical symptoms and a high ESR, the presence of thrombocytosis is highly specific for a diagnosis of GCA. However, a normal platelet count is not sufficient to rule out GCA in this setting.

13.5.3 Thrombocytosis

An elevated platelet count is a common laboratory finding in GCA. Gonzalez-Gay and colleagues [19] recently reviewed the laboratory findings of 240 patients with biopsy-positive GCA. It was found that 48.8% of patients (most of whom had constitutional symptoms) had thrombocytosis at presentation, and thromobocytosis was associated with a higher ESR and CRP and

13.5.4Interleukin-6

and Other Cytokines

Cytokines are the messenger proteins within the cellular immune system and mediate a variety of functions. In GCA, cytokines play an important role in regulating the intensity of cellular proliferation and the direction of cellular differen-

240Giant Cell Arteritis

tiation, which ultimately determines the nature and magnitude of the inflammatory response. Interleukin-6 (IL-6) is a cytokine found both in inflamed arterial walls and the blood circulation. Interleukin-6 is a chief stimulator of the systemic inflammatory response and the production of most acute-phase proteins. Serum levels of IL-6 are highly elevated in active GCA and respond rapidly to steroid treatment. Weyand et al. [56] prospectively followed the acute-phase markers in 25 patients with biopsy-positive GCA. At the time of diagnosis (before treatment initiation) the ESR was elevated in 76% of patients and plasma IL-6 was elevated in 92%. Within 1 month of steroid treatment, all patients experienced symptomatic resolution and normalization of the ESR. The plasma IL-6 did decrease but did not return to normal levels. During a clinical relapse of disease, the ESR was elevated in 58% of patients whereas the plasma IL-6 was elevated in 89%. Thus, the authors concluded that plasma IL-6 appears to be a more sensitive indicator than ESR for diagnosing and monitoring GCA

patients [56].

How does IL-6 compare to CRP? Hayreh et al. 13 [23] found a linear relationship between levels of IL-6 and CRP, suggesting that IL-6 is comparable but not superior to CRP for monitoring the sys-

temic inflammatory response.

In addition to being a diagnostic marker for GCA, another proposed usefulness of the cytokines is to serve as a prognostic indicator. As mentioned previously, it has been speculated that the pattern of cytokines in the biopsy specimen and in the blood may be helpful in distinguishing clinical subsets of the disease and predicting disease evolution. Hernandez-Rodriguez et al. [27] noted that patients with an exuberant systemic inflammatory response (measured by high ESR, anemia, presence of fever and weight loss) had elevated levels of circulating IL-6 as well as tumor necrosis factor (TNFα). Such patients required higher steroids doses and longer duration of treatment. In follow-up studies, these authors measured tissue cytokine levels using quantitative polymerase chain reaction (PCR) of mRNA and immunostaining with anti-cytokine antibody. They found that, in general, IL-6 levels in tissue and in serum were lower in patients who suffered ischemic complication. No differences

were found in levels of TNFα or IL-1β expression among patients with and without ischemia. However, there was a correlation between tissue TNFα and IL-1β and longer duration disease, i.e., patients relatively refractive to steroid treatment [28]. Measurement of serum cytokines is a commercial ELISA technique of limited availability and is not widely used of among clinicians who care for patients with GCA.

13.5.5 Anemia

A normocytic, normochromic anemia of mild- to-moderate degree (< 12 g/dl) is frequently observed in patients with GCA as a result of decreased hematopoiesis related to the acute-phase response. An unexplained anemia may even be the presenting manifestation of GCA. Some recent studies have reported that the presence of anemia at presentation is associated with a reduced incidence of ischemic events [11, 19].

13.5.6 Others

Other laboratory tests that may be abnormal in GCA include WBC count, liver enzymes, other acute-phase reactants (fibrinogen, haptoglobin), albumin, gamma globulin, anticardiolipin antibodies, plasma viscosity, and amyloid A apolipoprotein [19, 47].

13.6 Diagnosis of GCA

There is no single laboratory value, imaging procedure or even biopsy sample that is positive in all patients and there is no one symptom or sign that is pathognomic of GCA. Giant cell arteritis is a syndrome in which characteristic symptoms accompanied by objective signs of inflammation and vasculopathy are used to define the clinical diagnosis. Histopathologic evidence of inflammation in arterial tissue provides definitive diagnostic evidence and should be sought whenever possible as the commitment to treatment is not a trivial matter, often long in duration and fraught with medication side-effects.

13.6.1 Temporal Artery Biopsy

The temporal artery biopsy is the most common method of histopathologic testing for GCA. It is generally agreed that an adequate biopsy specimen should have a minimum length of 2 cm [9]. Longer specimens (3–5 cm) are preferable and multiple fine (0.25–0.5 mm) sections are necessary due to the presence of skip lesions and the potential effect of post-fixation shrinkage [52]. In many situations, a unilateral temporal artery biopsy is performed and the frozen section is immediately examined. If the initial examination is negative and the clinical suspicion is high, then a sequential biopsy is completed during the same procedure. Thereafter, a more critical examination of a paraffin-embedded biopsy specimen should be performed under light and electron microscopy. Reliance on frozen sectioning alone has a high rate of false negatives [42]. If the clinical suspicion for GCA is high and the first biopsy is negative, the chances of a second biopsy demonstrating positive histopathology is rather low, ranging from 5% to 9% [23, 45]. If the clinical suspicion is low, a unilateral biopsy appears to be sufficient to rule out the diagnosis [21, 23]. Findings which should raise clinical suspicion for the diagnosis and which tend to predict a positive biopsy include: presence of jaw claudication, CRP >2.45 mg/l, elevated ESR >47 mm/h, neck pain, white or pale disc edema, systemic symptoms other than headache, temporal artery abnormalities, and elevated platelet count [21, 23].

The chief pathologic finding is a panarteritis consisting mostly of lymphocytes and macrophages. Granuloma formation may be present. The intima is thickened and the internal elastic lamina is fragmented. Infiltration by mononuclear cells and multinucleated giant cells (present in 50% of specimens) is concentrated around the inner half of the media, characteristically along the disrupted internal elastic lamina [42, 57]. The presence of active arteritis remains for up to 6 weeks after initiation of corticosteroids [9]. Fibrinoid necrosis is rarely found in GCA and should raise suspicion of other vasculitides. The healed or chronic phase of GCA is characterized by foci of lymphocytes, fibrosis and vascularization with continued evidence of intimal disruption.

13.6  Diagnosis of GCA 241

Although the temporal artery biopsy is considered the gold standard test for diagnosis, it is important to remember that a negative biopsy result may be found in up to 10%–15% of cases [53]. Particularly when GCA assumes a localized form, such as large-vessel vasculitis, and the arterial inflammation occurs in the relative absence of systemic inflammation, the gold standard temporal artery biopsy is negative in at least 50% of patients [7, 57]. In such instances, the diagnosis of GCA must be taken from clinical indices, supportive laboratory findings and corroborative imaging. Insistence on positive histopathology in these patients may lead only to multiple negative biopsy specimens (from both temporal arteries, the occipital artery, other extracranial arteries, etc.) and unnecessary delay in treatment.

Summary for the Clinician

■Histologic confirmation of diagnosis is recommended in all patients who are treated for GCA.

■If one temporal artery biopsy is negative but the clinical suspicion for GCA remains high, a second biopsy of the contralateral side is recommended despite the low yield. If the clinical suspicion is low, a single negative biopsy is sufficient to rule out the diagnosis.

■Steroid treatment should never be delayed in suspected patients as pathologic features of active arteritis can still be detected on biopsy samples for up to 6 weeks after treatment.

■A biopsy length of 2 cm or more is recommended.

13.6.2American College

of Rheumatology Criteria

In 1990, the American College of Rheumatology (ACR) developed a set of criteria which have been used to diagnose GCA [32]. These are listed in Table 13.1 and, in brief, consist of advanced age, new headache, temporal artery abnormali-

Fig. 13.7. Color Doppler ultrasonography of temporal arteries. Longitudinal (top) and transverse (bottom) view of superficial temporal artery branch showing the hypoechoic rim (arrows) around the perfused lumen, representative of edematous wall swelling in active arteritis. From Schmidt WA [53], Current diagnosis and treatment of temporal arteritis, in Current Treatment Options in Cardiovascular Medicine 2006; 8, 145–151

ties, high ESR and positive biopsy (Fig. 13.6). The presence of any three of these five criteria permitted a diagnosis of GCA with a sensitivity of 93.5% and a specificity of 91.2% based on a population of patients (n=807) with rheumatologic disease [47]. A note of caution should be taken when applying these ACR criteria to the general clinical population because the criteria were primarily developed to distinguish patients with GCA (n=214) from patients with other vasculitides (n=593) and for classifying patients with rheumatologic disorders for research purposes. It is thus possible that patients who lack typical systemic symptoms and present with an ischemic complication (so-called occult GCA)

may not have been accurately represented in the ACR study as they are more likely to seek the care of a non-rheumatologic specialist. From the ophthalmic perspective, Hayreh et al. [24] found that among 85 patients who presented with ocular symptoms due to biopsy-positive GCA, 21% had no systemic symptoms or signs of GCA. In these patients, the diagnosis was suspected on clinical grounds (AION in a patient aged 50 years or older) and confirmed by histologic findings (biopsy), so strictly speaking this would meet only two of the five ACR criteria. Likewise in the setting of large-vessel arteritis, imaging the vascular territories of interest may prove most fruitful in aiding the diagnosis.