Stroke Secondary to Giant Cell Arteritis in a Moroccan Population-Based Cohort of 40 Patients with Giant Cell Arteritis and Literature Review

Background: Ischemic stroke, less common than visual lesions, is a rare but important complication that occurs in 3% to 4% of patients with giant cell arteritis (GCA) and is typically due to stenosis of carotid and/or vertebral arteries.

Material and Methods: We conducted a multi-center retrospective study in a cohort of 40 patients with GCA, from January 1991 through December 2008, from 2 different neurology departments in Marrakech. 3 patients presented GCA- related cerebrovascular accidents (CVA). All patients with intracranial (IC) involvement received treatment with oral or intravenous glucocorticoids, in combination with an immunosuppressant agent, methotrexate or tocilizumab.

Results: In our series, the main clinical presentations in patients GCA with CVA were headache (66.6%), and alteration of visual acuity (100%). Abnormal findings of temporal artery examination were present in 2 patients (66.6%). CVA was more frequent in patients with visual involvement (P = 0.02), especially permanent VL. Furthermore, The the patients with intracranial involvement less frequently presented with elevated ESR (33.3%). Posterior circulation arteries were affected in 1 (33.3%) and anterior circulation arteries in 2 (66.6%). Despite treatment, outcomes for patients with IC-GCA were poor. 1 patient (33.3%) with vertebrobasillar ischemic stroke had a rapid progressive disease course and died. The median mRS at follow-up 6 months after discharge in these patients was 3.  Our results support the existence of a clinical subset of GCA patients who are more susceptible to the development of ischemic manifestations. 

Discussion: Stroke in GCA patients is directly related to the inflammatory involvement of the internal arotid arteries (ICA), vertebral arteries (VA), and more seldom intracranial arteries, and is an uncommon manifestation of GCA, in which the absence of inflammatory syndrome and vision complications seems to be real predictors. Patients with neurologic symptoms and intracranial involvement may have a poor prognosis and fulminant course, even when treated with glucocorticoids and classical immunosuppressive agents, and strokes have been reported to be associated with significant morbidity and mortality as well as residual neurologic deficits in many survivors.

Conclusion: Further studies are needed to draw an increasingly accurate picture of the pathogenesis of GCAs. Such data will be needed to identify new diagnostic biomarkers, improving the diagnostic accuracy of GCAs, and to set up increasingly effective therapies that may avoid severe morbidity and high early mortality in such cases.

Giant cell arteritis (GCA) is is a large-vessel vasculitis which affects persons over the age of 50 years, and is known to be common in Nordic populations. Several predisposing genetic factors have been identified, but it has emerged that epigenetic factors are essential in triggering the onset of the disease. It was therefore underlined that GCA should be classified into a cranial form (c-GCA) and an extracranial or large vessel form (LV-GCA). LV-GCA mainly involves the thoracic aorta and its branches and is the main cause of noninfectious aortitis in humans. Despite the systemic nature of involvement, GCA is considered a neuro-ophthalmologic emergency.  Intracranial involvement in GCA (IC-GCA) is a rare and highly aggressive disease that is often resistant to steroid monotherapy. Ischemic stroke, less common than visual lesions, is a rare but important complication that occurs in 3% to 4% of patients and is typically due to stenosis of carotid and/or vertebral or basilar arteries. Despite immunosuppressive therapy, patients with intracranial involvement may have a fulminant course with neurological decline and progressing to death. It can be speculated that additional therapies may be available in the future that take advantage of new insights into the pathogenesis of GCA. We report 3 GCA patients with cerebrovascular accidents (CVA), and severe prognosis despite immunosuppressants.

We conducted a multi-center retrospective study in a cohort of patients with GCA with intracranial involvement, from January 1991 through December 2008, from 2 different neurology departments at the Mohamed V Military Hospital in Rabat and Avicenne Military Hospital in Marrakech (Morocco). We included 40 patients with the diagnosis of GCA who met the American College of Rheumatology (ACR) classification criteria for GCA. Clinical (average age, sex, GCA symptoms), laboratory and radiological features of all patients with GCA with (n=3) and without (n=37) intracranial involvement included in the study after screening are depicted (Table 1 and 2). In the present study, we analyzed a large series of patients, in order to 1) assess the frequency, clinical features, clinical characteristics radiological characteristics, pattern of arterial involvement and response to treatment of cerebrovascular ischemic events with outcomes, 2) identify the best predictors for CVA in patients with GCA. Patients with GCA without intracranial involvement (n=37) served as controls. 

Treatment and outcome information of patients with GCA with intracranial involvement (n=3) included in the study are depicted (Table 3).

Demographics and clinical features

The baseline characteristics of the study population are shown in Table 1. We included 3 patients who developed stroke at the same time they presented with GCA symptoms and 37 patients with GCA without intracranial involvement. The median time from symptom onset until diagnosis of GCA was 5 days and did not differ between patients with and without involvement of intracranial arteries. Demographic characteristics did not differ between these two groups.

Table 1: Baseline characteristics of GCA study population

The most frequent symptoms at the time of GCA presentation in patients with cerebrovascular accidents (CVA) were new-onset headache (66.6%), alteration of visual acuity (100%), jaw claudication (33.3%), STA abnormalities (66.6%), constitutional syndrome (33.3%). Polymyalgia rheumatica symptoms were present in 33% of patients. CVA was more frequent in patients with visual involvement (P = 0.02), especially permanent VL. The CVA occurred shortly after the ocular symptoms (median 2.0 days), and the patients with intracranial involvement less frequently presented with elevated ESR (33.3%). 

Diagnostic studies

In patients with GCA with intracranial involvement, focal neurological deficits due to intracranial vasculitis at disease onset mainly consisted of motor (33.3%), speech (33.3%) and cerebellar (33.3%) deficits (table 2). Of 3 patients with GCA with intracranial involvement, neuroimaging showed supratentorial ischemic strokes in 2 (66.6%) patients and infratentorial ischemic stroke in 1 patient (33.3%). Brain magnetic resonance imaging (MRI) performed demonstrated schemic stroke in the territory of the internal carotid artery in 1 patient, middle cerebral artery in one patient, explaining the motor deficit found, and ischemic stroke in the vertebrobasilar territory (cerebellar stroke) in a one patient. Intracranial angiographic imaging modalities used included magnetic resonance angiography and computed tomography angiography (CTA). The most frequently affected arteries were the internal carotid artery (ICA; 33.3%), the vertebral artery (33.3%) and the middle cerebral artery (33.3%) (Table 2). The patient with cerebellar infarction had bilateral vertebral artery stenosis. Abnormal CSF was found in 1 (33.3%) patient including increased total protein. 

Table 2: CNS affection in patients with GCA with intracranial involvement

Treatment and outcomes

All patients with intracranial involvement received treatment with oral or intravenous glucocorticoids (1000 g daily for 5 days), in combination with an immunosuppressant agent, methotrexate or tocilizumab and 160 mg daily of Aspirin (Table 3). The mean starting dose of oral prednisone was 52.2 mg daily. Tocilizumab was added to the regimen for the patient with cerebellar infarction. Table 3 illustrates the clinical disease course and treatment strategies in these patients.  Response to treatment was characterized by spectacular improvement of symptoms in all patients without intracranial involvement and no relapse during long term follow up (100%). However, despite treatment, outcomes for patients with IC-GCA were poor. In our study, the patient with cerebellar infarction had a rapid progressive disease course characterized by recurrent ischemic events and died within 3 months despite aggressive corticosteroid and supportive therapy. Follow-up 6 months after hospital discharge, showed higher level of disability in GCA patients with intracranial involvement (Table 3).

Table 3: Treatment and outcome of patients with intracranial involvement.

GC, glucocorticoids; MTX, methotrexate

Giant cell arteritis (GCA) is the most common primary vasculitis affecting the elderly population and constitutes an emergency due to possible devastating neurologic and ophthalmologic complications of the disease. Depending on the arteries primarily involved, the clinical presentation of GCA may vary from constitutional symptoms to amaurosis fugax, jaw, arm or leg claudication, headache, scalp tenderness and eventually stroke [1,2,3]. Severe cranial ischaemic complications (sCIC) , are defined as either severe vision complications [diplopia, transient vision loss and permanent vision defects (permanent vision loss PVL and partial vision field/acuity defect PVF/AD)] or stroke. [4] Visual manifestations of this disease are estimated between 26 and 30%, of whom 14.9

Cerebrovascular accidents secondary to GCA are an uncommon, difficult-to-treat and are usually associated with significant morbidity and mortality as well as residual neurologic deficits in many survivors. An improved understanding of the risk factors for ischaemic complications and early diagnosis of this disease is beneficial for the patient. Further studies are needed to draw an increasingly accurate picture of the pathogenesis of GCAs. Such data will be needed to identify new diagnostic biomarkers, improving the diagnostic accuracy of GCAs, and to set up increasingly effective therapies that may avoid severe morbidity and high early mortality in severe cases of GCA-related stroke.

Limitations of the study

Interpretation and comparison of response to treatment is limited by the retrospective design of the study and the comparably small simple size.

Funding

This research received no external funding. 

Conflicts of Interest

The authors declare no conflicts of interest

Abbreviations

AION: anterior ischaemic optic neuropathy 

AxAV: axillary artery vasculitis 

AZA=azathioprine 

CA=carotid arteries

CFX=cyclophosphamide

CIEs=cranial ischaemic events 

CRP=C-reactive protein

ESR=erythrocyte sedimentation rate

FP = fusion protein 

GCs= glucocorticoids 

GCA=giant cell arteritis

GM-SSF = granulocyte-macrophage colony-stimulating factor

IC= intracranial

IHD: ischaemic heart disease

 IL = interleukin 

JAK = Janus kinase 

MOAB = monoclonal antibody 

MMF=mycophenolate mofetil 

mRS=modified Rankin Scale

NIHSS=National Institutes of Health Stroke Scale

PCA=Posterior circulation arteries.

PMR=polymyalgia rheumatic

PVL=permanent visual loss 

R = receptor 

RRA = recombinant receptor antagonist 

RTX=rituximab 

S: stroke 

SMOL = small molecule 

STA=superficial temporal artery

TCZ=tocilizumab

TVL: transient vision loss 

VA=vertebral arteries

VC: vision complication 

↓: lower

↑: higher