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Prompt diagnosis, treatment, referral essential for giant cell arteritis
This condition, which manifests in the eye as arteritic ischemic optic neuropathy, can be blinding and fatal if left untreated.
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A 73-year-old white female presented to the office on an emergency basis because she could not see out of her right eye upon waking that morning. Her medical history was significant for recent polymyalgia rheumatica, and she had been on a dose of 5 mg of prednisolone daily. Seven months ago she experienced swollen knees and joint pain; minor weight loss did not alarm her. Of note was soreness in her jaw while chewing that eased after treatment with prednisolone. She denied fever or scalp tenderness; she had a high rheumatoid factor titer.
The patient’s entering visual acuities were 20/60 OD and 20/30 OS. IOP was 12 mm Hg OD and 13 mm Hg OS. Extraocular movement was full. Afferent pupillary defect was questionable in the right eye. Confrontational visual fields showed general loss except for a superior temporal quadrant in the right eye. Temporal artery pulsation appeared weak and tender to palpation. Fundus exam showed papilledema in the right eye without hemorrhage. All other findings were normal.
The patient was referred to a neuro-ophthalmologist immediately. Considering the polymyalgia rheumatica, weight loss and jaw claudication with nerve involvement, the patient was presumed to have an arteritic ischemic optic neuropathy. The prednisolone dose was quadrupled. The biopsy of the right temporal artery 2 days later was positive, so the oral prednisolone was increased to 40 mg per day. A Humphrey visual field performed 2 weeks afterward showed constriction in the right eye and a hint of altitudinal defect. Comanagement with her rheumatologist was initiated.
Giant cell arteritis (GCA), also known as cranial or temporal arteritis, is a systemically occurring inflammatory disorder of the arteries. The inflammation is granulomatous and characteristically affects large- and medium-sized arteries. The severity and extent of the inflammation depends on the quantity of elastic tissue in the media and adventitia layers of the involved arteries. Intracranial arteries are normally spared due their small amount of elastic tissue.
Susceptible arteries can be cranial and extracranial. Cranial vessels consist of the vertebral arteries (branches of the subclavian arteries), the superficial temporal and occipital arteries (both branches of the external carotid arteries), the ophthalmic arteries (branches of the internal carotid arteries) and posterior ciliary arteries (branches of the ophthalmic arteries). When the ophthalmic and posterior ciliary arteries are affected by GCA, there can be devastating unilateral or bilateral vision loss, which may be irreversible. Extracranial vessels consist of the carotids, subclavians, axillary, brachial, iliac, femoral and tibial arteries (all are major vessels that directly or indirectly branch off of the aorta).
Some life threatening sequelae of GCA include aortic dissection, aneurysms, cerebrovascular accidents and myocardial infarctions. Autopsy studies suggest GCA is more common than reported clinically, indicating that the signs and symptoms often go undetected, putting the patient at increased risk for such sequelae.
Epidemiology
The prevalence of GCA increases with each decade of life, peaking during the seventh decade (Gonzalez-Gay et al.). Individuals older than 50 years have annual incidence rates of 19 per 100,000 (Kermani et al., 2010, and Kermani et al., 2011). GCA presents with a gender bias, being two to three times more common in women than in men, as is frequently evident with many autoimmune diseases (Richards et al.). A woman’s lifetime risk is about 1%, and a man’s is about half that (Kermani et al., 2011). GCA is rarely seen among individuals of African-American, Arab and Asian descent. The highest incidence is seen among individuals of Scandinavian and Northern European descent.
Studies have revealed patterns in the incidence of GCA. Geographical variations have been noted in which urban dwellers are 2.25 times at greater risk as compared to rural dwellers (Richards and colleagues). Several independent studies have indicated the presence of seasonal clustering, and in one particular long-term study (Salvarani and colleagues), conducted in Olmstead County, Minn., a cyclic pattern was discovered where the incidence of GCA would peak every 6 to 7 years.
Numerous etiologies have been proposed. It is most widely believed that GCA is an antigen-driven autoimmune disease. Based on the patterns of incidence, environmental and infectious etiologies are suggested.
Genetic associations also have been found. The HLA class 1 and 2 genes and genes encoding various cytokines and growth factors have been studied and are now thought to play a role. Based on the numerous and varying etiologies proposed, it appears GCA has a multifactorial disease process.
Pathogenesis
Inflammatory mononuclear cells infiltrate the blood vessel wall with frequent giant cell formation. There is a predisposition for the infiltrates, which may be composed of lymphocytes, neutrophils and giant cells, to accumulate at the intima-media border of the arterial wall.
As the disease progresses, the architecture of the vascular wall takes on characteristic morphologic changes. The elastic lamina becomes progressively fragmented until it is obliterated altogether. Smooth muscle cells in the tunica media are gradually destroyed and replaced by scar tissue. Concurrently, the tunica intima becomes hyperplastic, leading to stenosis and/or occlusion of the arterial lumen. These changes in vascular morphology ultimately result in ischemia, which becomes progressively severe as the disease advances. Thrombosis may occur in the more severely affected parts of the artery, leading to further ischemia. Infarcts and ischemic strokes result from an embolus breaking free. The risk and severity of such events increase with cardiovascular and diabetic comorbidities.
Atherosclerotic risk factors are often associated with increased severity of ischemic manifestations. These risk factors include cardiovascular disease, hypercholesterolemia, hypertension, diabetes mellitus and a history of smoking.
Signs, symptoms
A patient with GCA may look and feel ill and present with or without fever. There may be a history of recent weight loss, anorexia, myalgia, arthralgia or neck pain. The patient may complain of a throbbing headache that is severe and persistent over the temporal or occipital lobes. There may be associated scalp tenderness, particularly while brushing the hair or while lying down.
Humphrey visual fields, performed 2 weeks after treatment was initiated, showed constriction in the right eye (bottom photo) and a hint of altitudinal defect.
Image: Hallak J
Pathognomonic to GCA is the presence of jaw pain and claudication. There may also be pain in the tongue, nose or ears. Often there is a medical history of polymyalgia rheumatica characterized by shoulder, neck, hip and pelvic girdle pain described as being worse upon waking or after exertion. Upon examination, the temporal artery may appear beaded or nodular and also enlarged. It may be tender to the touch, and the pulse will typically be weak or absent.
Ocular signs and symptoms include rapid and severe vision loss (<20/200 in 75% of cases, according to DelMonte and Bhatti), which may be preceded by a transient loss of vision known as a transient ischemic attack. Such an event is a warning sign and occurs in up to one-third of all cases (Hayreh). When vision loss occurs, it is usually unilateral, but simultaneous bilateral vision loss may also occur. Without treatment, those with unilateral vision loss may subsequently have involvement of the fellow eye (50% to 90% of cases, according to DelMonte and Bhatti).
Near normal visual acuity does not rule out the presence of GCA. Some individuals will present with a “silent form,” where there are pronounced systemic symptoms, often with fever of unknown origin. They will not, however, present with the typical cranial manifestations. Conversely, individuals with an “occult variant” will not manifest systemic symptoms but will have vision loss. Several sources report that the occult variant occurs in more than 21% of patients.
With ocular involvement, ischemic events occur upstream. Vision loss is typically due to an ischemic optic neuropathy (ION) located anteriorly (AION) or posteriorly (PION). On fundus evaluation, an AION will normally present with a swollen chalky white optic nerve. A PION may not be as obvious. Vascular occlusions (branch or central retinal artery occlusions) may also serve as a source of vision loss.
Vision loss may present as a decrease in visual acuity, color vision and/or contrast sensitivity. There may be a marked constriction or sectorial visual field loss.
Other neurologic symptoms may arise such as cranial nerve palsies, which may progress and result in transient diplopia. Diplopia, in such cases, is due to ischemia at the level of the brainstem or extraocular muscles. A small percentage (8%) of individuals may complain of ocular pain. Further, in the presence of asymmetric GCA, an afferent pupillary defect (APD) may be detectable. Finally, there may be signs of ischemia or inflammation in the anterior segment, leading to hypotony and exudation.
Retinal ischemia secondary to ophthalmic artery involvement may also occur. Cotton-wool spots are found in up to 33% of cases and are usually seen in the early stages. Additionally, arterial occlusions occur in up to 14% of cases (Hayreh). Choroidal ischemia may present with midperipheral dot and blot hemorrhages. Fluorescein angiography (FA) studies may reveal generalized choroidal filling delays, which typically take on wedge-shaped (triangular) defects with the base toward the equator and the apex toward the posterior pole. These filling delays tend to resolve slowly due to the presence of collateral vessels.
Diagnosing GCA
The case history is vital to the clinician, involving queries about related pertinent ocular and systemic symptoms when GCA is suspected. Physical examination includes palpation of the temporal and/or brachial arteries, observing for any pulse asymmetries, bilateral weak pulses and thready pulses. Upon auscultation, a murmur of aortic regurgitations or bruits near the clavicle, resulting from subclavian artery stenosis, may be heard.
Ruling out GCA in a differential diagnosis often involves ordering specific blood work, including erythrocyte sedimentation rate (ESR) Westgren method, C-reactive protein (CRP) and platelet cell count studies. Vascular imaging and temporal artery biopsies are performed to confirm the diagnosis of GCA.
Pertinent diagnostic tests
ESR is a nonspecific measure of inflammation in which the sedimentation rate of red blood cells is measured over the course of 1 hour.
The test relies on the presence of pro-sedimentation and anti-sedimentation factors within the blood via the interactive forces of fibrinogen and erythrocytes.
The level of fibrinogen within the blood, which causes red blood cells to aggregate and settle faster, rises during an inflammatory process and, therefore, causes an increase in the amount settling within the allotted time. In contrast, erythrocytes, which are negatively charged, will resist sedimentation.
Changes in red cell morphology (i.e., shape and/or size alteration as in sickle-cell anemia) will result in a lower ESR due to their inability to stack and subsequently settle. Conversely, individuals with normal red cell morphology suffering from severe anemia will have abnormally elevated ESRs. The use of certain medications (i.e., antiplatelets and anticoagulants) may also alter sedimentation rates.
ESR normative values are age- and sex-dependent. It is important to familiarize ourselves with the norms our laboratories utilize. The ESR is typically elevated above 50 mm/h in cases of GCA; however, there are known cases in which the ESR is normal or low.
CRP is a protein produced by the liver and is found in the blood. It functions to promote phagocytosis, clear damaged cells, reduce inflammation and protect the body from certain autoimmune diseases. The level of CRP, which elevates in response to inflammation, is not influenced by hematologic factors or age. However, the test is nonspecific and cannot identify the location or etiology of the inflammation. A healthy individual has a normal concentration of under 0.8 mg/dL. Higher levels may be found in pregnant women and in individuals with inflammation and infections.
Inflammatory markers, systemic
Statistical analysis studies have been conducted to better understand the usefulness of inflammatory markers and the reliability of systemic signs on positive temporal artery biopsies (TAB). Statistical measures of sensitivity (the probability for a test result to be correctly identified as positive among patients with the disease), specificity (the probability for a test result to be correctly identified as negative among patients without the disease), positive predictive value (the probability that a patient actually has the disease after a positive test result) and negative predictive value (the probability that a patient does not have the disease after a negative test result) aids our understanding of their correlations to GCA.
Kermani and colleagues showed that ESR and CRP are highly sensitive (86% and 87%, respectively), but that they have low individual specificities (27% and 31%). However, when ESR and CRP are used in combination, the specificity rises slightly (41%). With regard to predictive values, although they each have low positive predictive values (25% and 27%), their negative predictive values are high (87% and 89%). They did find that the ESR and CRP values were normal in 4% of confirmed GCA cases. Therefore, when the clinical suspicion of GCA is high, even in the absence of inflammatory markers, TAB is considered.
Walvick and colleagues further analyzed the effectiveness of inflammatory markers to serve as predictors of a positive TAB. They confirmed that an elevated CRP (>2.45 mg/dL) serves as the best predictor of a positive TAB and that elevated platelets may serve as better predictors than ESR. Thrombocytosis, which increases odds of a positive TAB, was defined as platelet counts above 400,000/µL. The recommendation was to look at all three inflammatory markers (ESR, CRP and platelets) together when selecting patients for TAB.
Finally, Hayreh and colleagues reviewed the presence of symptoms and the available diagnostic markers for their usefulness in predicting a positive TAB. They found that jaw claudication is the leading sign of GCA, with a ninefold chance for a positive diagnosis. Neck pain or an elevated CRP (>2.45 mg/dL) were the next two most reliable signs (3.4- and 3.2-fold increase for a positive diagnosis). An elevated ESR (>47 mm/h) and advanced age (>75 years) each had a twofold increased chance for a positive diagnosis. Finally, both anorexia and weight loss were considered significant systemic signs.
Temporal artery biopsy: gold standard
Currently, the TAB is considered the gold standard for GCA diagnosis. Biopsy should be performed as quickly as possible once GCA is suspected. However, the treatment of GCA should not be delayed while waiting to perform a biopsy. In fact, a 2- to 4-week delay in obtaining the biopsy after the start of treatment will not likely affect the results. Treat first; ask questions later.
The classic histological finding on biopsy is the presence of granulomatous inflammatory infiltrates located at the intima-media junction of the arterial wall. In addition, the arterial elastic lamina will likely be fragmented such that the normal vessel structure is divided by areas of scar tissue formation.
TAB is both highly sensitive (85%) and highly specific (100%). False negative findings typically occur secondary to the selection of the wrong artery to biopsy (in cases of unilateral temporal artery involvement) and/or the presence of skip lesions, in which there is a discontinuity of the inflammation. These false negatives can be minimized by obtaining longer specimens (1 cm to 5 cm), serial sections and bilateral biopsies.
TAB is invasive and not without risk. Complication rates are low (0.5%), according to Ball and colleagues, and include facial nerve damage, eyebrow drooping, skin necrosis, infection and stroke. For these reasons, some individuals choose to decline TAB.
Role of imaging
Imaging for the purpose of diagnosing GCA has several advantages. First, it provides for a noninvasive modality of confirmation. Second, when TABs are negative (which occurs in 42%), but the suspicion for GCA remains high, it can provide additional data to help make the proper diagnosis. Third, it is a good option in those suspected of GCA in arteries other than the temporal artery. Finally, it provides a way to monitor the effects of treatment and treatment tapering.
Two methods have been utilized to assess the superficial temporal arteries for inflammation. They include color duplex ultrasonography and magnetic resonance imaging (MRI). Extracranial artery assessment can be achieved via color duplex ultrasonography as well, but it also can be achieved with positron emission tomography (PET), magnetic resonance angiography (MRA) and computed tomography angiography (CTA).
Color duplex ultrasonography
Color duplex ultrasonography is a promising method of diagnosis and has been studied extensively. The other methods of imaging need continued studies to prove useful in the diagnosis of GCA.
This test uses a combination of real-time imaging and flow velocity determination to assess the vessel anatomy and lumen status. Inflamed arteries will take on a characteristic “hypoechoic halo” around the lumen, which is thought to reflect edema of the arterial wall.
Although it is not a standard imaging test for GCA diagnosis, the color duplex ultrasound test provides a quicker, noninvasive method of diagnosing GCA. When imaging bilaterally, a unilateral halo sign provides excellent predictive values (positive predictive value: 85%, negative predictive value: 88%). Sensitivity has been quoted as being between 68% and 82%, with specificity being between 83% and 91%. If the halo sign is present bilaterally, the specificity goes up to 100%, possibly eliminating the need for a TAB.
Upon the start of treatment, hypoechoic halo has resolved, so this type of ultrasound may serve as an important tool for follow-up care during treatment and treatment tapering. Additionally, ultrasound-directed TABs tend to improve the sensitivity of the biopsy. Although promising, the color duplex ultrasound is operator-dependent, requires expertise in conducting and analyzing, and is not yet widely available.
Treatment
Early diagnosis of GCA, accompanied by immediate administration of high-dose systemic corticosteroids, is critical for the prevention of further complications secondary to ischemia. The proper initiation of treatment allows for a dramatic reduction of pain usually occurring within hours to days from the initiation of treatment. The goals for treatment include reducing symptoms, halting further vision loss and minimizing systemic involvement. Early treatment may even allow for some visual improvement.
Intravenous methylprednisolone should be considered in the presence of ocular signs and symptoms and is currently the standard of care. However, there is limited evidence for its effectiveness. Additionally, there has been no consensus in the literature regarding the dosage requirements, with a range between 500 mg and 1,000 mg every 12 hours for 2 to 3 days having been reported, according to Borchers and colleagues.
Following IV infusion, the patient should be placed on oral prednisone with a standard dose between 40 mg/d and 60 mg/day until a reduction in the inflammatory markers (ESR, CRP and platelets) becomes evident. However, doses of more than 100 mg/d have been quoted. This high oral dose is typically maintained for 2 to 4 weeks.
Once a reduction of inflammation is noted, a slow taper should be initiated. The course of the taper is dictated by using the inflammatory markers as guides. The total length of treatment may take months to years, with some individuals requiring lifelong maintenance doses. Up to 40% or 50% of patients may relapse during the steroid taper or after withdrawal of treatment. Recurrences after complete steroid withdrawal usually occur within the first year at a rate of 20% to 30% of cases (Borchers and colleagues).
Side effects
It is widely known that long-term glucocorticoid therapy has numerous adverse effects that typically occur within the first year of treatment at a rate of 35% to 65% of cases and include the onset or worsening of diabetes and hypertension. Heart failure, gastric ulcers or bleeds, infections, avascular hip necrosis and osteoarthritis are other common sequelae. The use of high-dose steroids in the presence of osteoarthritis increases the risk of bone fractures in a population that is already frail. Therefore, calcium, vitamin D and, if necessary, bisphosphonates, are recommended as protective measures.
Ocular side effects include the formation of or increased progression of posterior subcapsular cataracts, as well as increased risk of glaucoma secondary to a steroid response with subsequent increase in intraocular pressures. Still, a high-dose glucocorticoid regimen is the first line of treatment and most direct. Side effects of glucocorticoids will be handled as they arise later.
As a result of the significant side effects of long-term steroid use, potential steroid-sparing treatment methods have been under investigation. This includes the use of antimetabolites such as methotrexate, which has been used in the treatment of cancer and autoimmune disease. Methotrexate has been shown to reduce the risk of relapse and allows for a significant reduction of cumulative corticosteroid doses, but one’s risk for steroid-induced side effects has not been shown to decrease. Furthermore, methotrexate has its own possible adverse effects, most commonly gastrointestinal upset, altered liver function tests, hematological abnormalities, respiratory symptoms and skin abnormalities. Promising studies are underway on the use of other immunosuppressive agents.
Some clinicians may choose to incorporate the use of antiplatelet medication such as a daily low-dose aspirin, for patients not already on such treatment. Using antiplatelets is thought to aid in the reduction of cranial ischemic events secondary to GCA. It may also play a role in producing a steroid-sparing effect. Aspirin therapy, in conjunction with glucocorticoids, should be considered in patients who have no contraindications.
Case report follow-up
Our patient’s visual acuity improved to 20/30 OD and 20/20 OS. The improvement in vision in the left eye points to the possibility of subclinical involvement of that eye as well as the early questionable absence of APD in the right eye. However, the more affected right eye (AION) resulted in mild APD secondary to nerve pallor. The patient is comanaged closely with her rheumatologist.
As primary care practitioners, optometrists and ophthalmologists are in the position to potentially save the life of their patient if the warning signs are recognized. Classically, a case of GCA will occur in an elderly Caucasian female who appears frail and ill. She may present with a sudden loss of vision in one eye and complain of a throbbing headache that is severe and persistent. Upon further questioning she may also have symptoms of jaw claudication. With this picture in mind, one must expect some deviations. The disease entity crosses all ethnic and racial barriers.
Additional signs and symptoms to watch for include other neurologic features (i.e., diplopia, extra-ocular muscle restriction and APD) and signs of ischemia, ocular and elsewhere. Once suspected, immediate blood work must be ordered.
Upon confirmation of the presence of inflammation (through elevated levels of CRP, platelets or ESR), the clinician must initiate treatment with high-dose corticosteroids. If blood work fails to provide conclusive evidence of the presence of disease, yet the suspicion for GCA remains high, it is imperative to begin treatment while searching for confirmation via TAB or imaging studies. Immediate neuro-ophthalmology consult is a must. Timing and individualized treatment are critical to the final outcome.