Clinical signs and symptoms of GCA The classic presentation of GCA is a combination of vascular insufficiency and systemic inflammation (Table 3). Almost all patients have evidence of a systemic inflammatory syndrome, which is associated with an intense acute phase response (42). Signs and symptoms of vascular disease may be less obvious and physicians need to actively search for them. Since vascular stenosis/occlusions can lead to irreversible tissue ischemia, such as blindness or stroke, prompt diagnosis and management is an absolute requirement and the level of suspicion to not miss GCA must be high. Extravascular GCA The most frequently encountered extravascular manifestation is polymyalgia rheumatica (PMR), a condition of muscle pain and stiffness affecting the neck, the shoulder girdle, the pelvic girdle and, only occasionally, the trunk. About 40% of patients with GCA will develop PMR along the course of the disease. It may precede, coincide or follow the diagnosis of arteritis. Typically, the forearms, hands and peripheral lower extremities are spared. Myalgias are associated with pronounced stiffness, especially in the morning hours. Patients report difficulties in getting out of bed, brushing their teeth and rising from the toilet seat. PMR frequently appears in treated patients in whom corticosteroids are lowered and is a useful clinical sign to estimate disease activity. PMR occurs in patients with no signs of active arteritis and such isolated PMR is about tenfold higher in incidence than GCA. However, a subset of patients with PMR has findings of arteritis on histologic evaluation. Careful examination and monitoring of such patients is necessary to not miss GCA. The risk of evolving arteritis appears higher when immunosuppressive therapy is discontinued. Constitutional symptoms caused by GCA include anorexia, malaise, weight loss and occasionally fever (43). Fever of unknown origin is a frequent reason for referral to a vasculitis specialist. Such patients typically have completed a work-up for an occult malignancy. Clinical findings suggestive of GCA may be minimal and temporal artery biopsy should be pursued even when the arteries appear normal on physical examination. Some evidence suggests that GCA is dominated by systemic inflammation, and constitutional symptoms are pathogenic subsets of disease. Granulomatous inflammation of the vessel wall may be less severe. Possibly, this translates into lower risk of emerging ischemic complications but this remains a subject of further research. Biopsy should be pursued as inflammatory manifestations may be subtle and microscopic examination of arterial tissue has a central place in establishing the diagnosis. Laboratory signs indicative of acute phase reaction, including a marked elevation of the sedimentation rate and CRP, are helpful in distinguishing patients with inflammatory activity from those with noninflammatory conditions. Such laboratory abnormalities may be the indication for a search for vasculitis and remain important when screening for arteritis. Medium and large vessel GCA Depending on the primary vascular territory affected by the granulomatous arteritis, two categories of GCA have been identified: 1) cranial arteritis characterized by involvement along the distribution of the external carotid artery, typically manifesting in the 2nd-5th branches, and 2) large-vessel GCA targeting the aorta, the subclavian artery, the axillary artery and the vertebral artery. Occasionally, more peripheral upper extremity arteries have arteritic lesions, and, infrequently, GCA manifests in the lower extremity vessels. Arteritic stenosis or occlusions of carotid branches dominate the clinical picture. Typically, patients present with headache, scalp tenderness, and prominent temple vessels. The occasional patient has involvement of the occipital artery. Patients describe the headaches as different from all other headaches they have had previously, more intense, with only partial relief when taking analgesics. Inability to rest the head on the pillow, difficulties combing the hair or wearing glasses are useful clues. The patient may have noticed tenderness, swelling and nodularity of their temporal vessels. While headaches are a nonspecific sign, pain in the masseter muscles when chewing or talking (jaw claudication) is virtually pathognomic. Jaw claudication results from restriction of blood flow to the masseter muscles. Limited blood supply can also lead to painful dysphagia and pharyngeal soreness. A nonproductive cough, occasionally the sole referral reason for a vasculitis work-up, has been interpreted as a manifestation of insufficient blood flow to branches of the pulmonary artery. Neuro-Ophthalmic manifestations of GCA Because several of the arteries supplying the eye, optic nerve and brain can be affected, GCA is associated with a broad spectrum of neuro-ophthalmic manifestations (Table 4) (44). Ischemic damage of the optic nerve or other structures of the orbit, classically dependent on blood supply from the internal carotid artery, dominate ocular GCA. GCA-induced occlusion of the short posterior ciliary artery leads to anterior ischemic optic neuropathy, which is characterized by optic nerve head ischemia, edema, and splinter hemorrhage (45). Cotton-wool spots, fluffy, white patches in the retinal nerve fiber layer due to ischemia-induced axoplasmic stasis, can be a presenting sign of GCA (46). The posterior ciliary arteries also supply the choroid and, if affected, may lead to cilio-retinal artery occlusion. Anterior ischemic optic neuropathy associated with significant choroidal ischemia or cilioretinal artery occlusion is presumed to be due to GCA until proven otherwise. Localized involvement of the submacular choroid has been reported to cause isolated, bilateral maculopathy and central scotomas (47, 48). Hypoperfusion or, less commonly, emboli, involving the central retinal artery can cause central scotoma from central retinal artery occlusion. Ischemia in the ophthalmic artery territory can cause vision loss and ocular ischemia syndrome. Posterior ischemic optic neuropathy occurs from involvement of the ophthalmic and orbital arteries, although at a much lower frequency. Inflammatory lesions in the orbita or arteritis at neuroanatomic sites along the visual axis may be a consequence of GCA. The typical GCA patient comes to attention with sudden onset of painless vision loss, which is partial or complete. Awaking in the morning with sight impairment is not unusual. A stuttering course of transient visual obscuration or amaurosis fugax precedes severe vision loss in about one third of cases (49). Most patients present with unilateral involvement, but there is a high risk of progression and involvement of the second eye, necessitating swift diagnostic and therapeutic decisions. GCA can cause diplopia from extraocular muscle ischemia, cranial nerve palsies, or brainstem involvement. GCA needs to be on the list of differential diagnoses in at-risk individuals presenting with diplopia and ophthalmoplegia. Homonymous visual field loss results from arteritis-induced ischemia of the brain, such as infarction of the occipital lobe from involvement of the posterior circulation. Brainstem ischemia from vertebral and basilar vasculitis can be associated with hemiplegia, diplopia, dizziness and other neurologic issues. Notably, the vertebral and basilar arteries are extracranial. Intracranial vessels are typically unaffected by GCA and different types of vasculitic syndromes need to be considered in patients with intracranial vasculitis. Large vessel GCA GCA of the aorta and its primary branches displays many similarities with Takayasu’s arteritis except that the age at disease onset is strikingly different (50, 51). Preferred target regions for GCA are the ascending and descending aorta as well as the arch while the abdominal aorta is rarely affected. Lesions in the subclavian and axillary arteries result in aortic arch syndrome, pulselessness and asymmetry of pulses and blood pressure measurements. This may be an incidental finding or the patients come to attention because of upper extremity ischemic symptoms. Inability to hold up the arms for extended periods, difficulties playing the piano or cutting vegetables are typical complaints. Gangrenous tissue damage is the exception. Lower extremity GCA is difficult to distinguish from atherosclerotic peripheral vascular disease. Even imaging studies may not be able to unequivocally separate an atherosclerotic and vasculitic pathogenesis. A similar problem complicates the diagnosis of GCA aortitis. Here, the primary source of information often comes from tissue examination of the aortic wall following the surgical repair of aortic aneurysm in otherwise asymptomatic patients. While granulomatous inflammation of medium-sized arteries predictably leads to luminal occlusion, the complications of aortic wall inflammation are those of vessel wall destruction, aneurysm formation, dissection, rupture and aortic insufficiency. The risk of individuals with a diagnosis of GCA to develop aortic aneurysm, dissection or rupture is much higher than in the general population and patients need to be actively screened for evidence of large vessel involvement. Atypical GCA Since the stakes of unrecognized and untreated GCA are high, physicians need to be alert to the possibility of encountering this vasculitis. Typical presentation with temporal headaches, abnormal temporal arteries and ischemic complications is not always the case.