Giant-cell arteritis related strokes: scoping review of mechanisms and rethinking treatment strategy?

Abstract

Stroke is a rare and severe complication of giant cell arteritis (GCA). Although early diagnosis and treatment initiation are essential, the mechanism of stroke is often related to vasculitis complicated by arterial stenosis and occlusion. Its recurrence is often attributed to early steroid resistance or late GCA relapse, so immunosuppressive treatment is often reinforced. However, many questions concerning the mechanisms of stroke remain elusive, and no review to date has examined the whole data set concerning GCA-related stroke. We therefore undertook this scoping review. GCA-related stroke does not necessarily display general signs and inflammatory parameters are sometimes normal, so clinicians should observe caution. Ischemic lesions often show patterns predating watershed areas and are associated with stenosis or thrombosis of the respective arteries, which are often bilateral. Lesions predominate in the siphon in the internal carotid arteries, whereas all the vertebral arteries may be involved with a predominance in the V3-V4 segments. Ultrasonography of the cervical arteries may reveal edema of the intima (halo sign), which is highly sensitive and specific of GCA, and precedes stenosis. The brain arteries are spared although very proximal arteritis may rarely occur, if the patient has microstructural anatomical variants. Temporal artery biopsy reveals the combination of mechanisms leading to slit-like stenosis, which involves granulomatous inflammation and intimal hyperplasia. The lumen is sometimes occluded by thrombi (<15%), suggesting that embolic lesions may also occur, although imaging studies have not provided strong evidence for this. Moreover, persistence of intimal hyperplasia might explain persisting arterial stenosis, which may account for delayed stroke occurring in watershed areas. Other possible mechanisms of stroke are also discussed. Overall, GCA-related stroke mainly involves hemodynamic mechanisms. Besides early diagnosis and treatment initiation, future studies could seek to establish specific preventive or curative treatments using angioplasty or targeting intimal proliferation.

Keywords: embolic stroke; giant cell (temporal) arteritis; stroke; stroke/physiopathology; thrombotic stroke.

Figure 1

Pathology of temporal artery biopsy. (A) False-negative temporal artery biopsy. Minimal non-specific intimal proliferation. (B) Positive temporal artery biopsy with full-thickness granulomatous inflammation and slit-like luminal stenosis related with major hyperplasia of the intima [magnified in (C)]. (D) Positive TAB with intraluminal thrombus (^*). 1: intima, 2: media, 3: adventitia. H&E staining. Bar is 0.5mm (Dr Badaro).

Figure 2

Basic structural variation of intracranial arteries. (A) Intradural arteries are characterized by the presence of large internal elastic lamina (IEL), whereas EEL disappear from the entry point into the dura mater. Extradural arteries have prominent EEL and IEL, and elastic fibers in the tunica media and adventitia. In the adventitia, vasa vasorum (VV) surround extradural arteries including the vertebral and carotid arteries, whereas VV are usually absent from the intradural arteries. (B) Classically, the transition from extra- to intra-dural artery type occurs in the cavernous portion of the carotid between the posterior (EEL always present) and anterior knees (EEL mostly absent) (113), and within the 5mm of vertebral artery around the dural entry point (111). Although EEL is considered absent from intracranial arteries, structural variations may occur in healthy subjects, and EEL may persist as a continuous or fragmented structure in the intracranial arteries [from Denswil et al. (116)]. ACA, anterior cerebral; ACoA, anterior communicating; AICA, anterior inferior cerebellar; BA, basilar; ICA, internal carotid; MCA, middle cerebral; PCA, posterior cerebral; PCoA, posterior communicating; PICA, posterior inferior cerebellar; SCA, uperior cerebellar; VA, vertebral.

Figure 3

Frequency of stenotic lesions in cervical arteries. Vertebral arteries are often involved, mainly in V3 and V4, whereas internal carotid lesions are located at the level of the siphon. External carotid branches are not depicted. Classically, lesions are localized in V1 and V4 for vertebral arteries (9, 64), or in the entire vertebral and terminal carotid arteries (not represented) (115). Heatmap based on Beuker et al. (87) and Ruegg et al. (188).

Figure 4

Risk of stroke during follow-up of GCA patients. (A) Overall risk of stroke in GCA patients compared with paired controls [from Tomasson et al. (68), Lo Gullo et al. (253) and Amiri et al. (261)]. A slightly higher incidence of stroke is observed within weeks after treatment initiation: thereafter the overall incidence remains roughly similar with paired controls. (B) The higher risk of ischemic event precedes treatment initiation, which is followed by a drop close to basal level within a week. Risk slightly increases during treatment tapering and/or GCA relapses. However, this incidence remains low compared with unrelated strokes.

Figure 5

Proposed GCA-related stroke mechanisms and treatment strategies.