Characteristics and Prognosis of Binocular Diplopia in Patients With Giant Cell Arteritis

Methods: All consecutive patients diagnosed with GCA from January 2015 to April 2021 in a French tertiary ophthalmologic center were retrospectively reviewed. GCA diagnosis relied on a positive temporal artery biopsy or high-definition MRI. Results: Among 111 patients diagnosed with GCA, 30 patients (27%) had diplopia. Characteristics of patients with diplopia were similar to other GCA patients. Diplopia resolved spontaneously in 6 patients (20%). Diplopia was attributed to cranial nerve palsy in 21/24 patients (88%), especially third (46%) and sixth cranial nerve (42%). Ocular ischemic lesions occurred in 11 of the 30 patients with diplopia (37%); 2 patients developed vision loss after initiation of corticosteroids. In the remaining 13 patients, diplopia resolved after treatment onset in 12 patients (92%) with a median delay of 10 days. Patients treated intravenously tended to have a quicker improvement than those treated orally, but with a similar resolution rate of diplopia at 1 month. Two patients had relapse of diplopia at 4 and 6 weeks after an initial treatment course of 24 and 18 months, respectively. Conclusions: Diplopia is a rare feature at GCA diagnosis, but should raise clinician suspicion for GCA when associated with cephalic symptoms and prompt the initiation of corticosteroids to prevent ocular ischemic complications.

Original Contribution Section Editors: Clare Fraser, MD Susan Mollan, MD Characteristics and Prognosis of Binocular Diplopia in Patients With Giant Cell Arteritis Thibaud Chazal, MD, Gaelle Clavel, MD, PhD, Tifenn Leturcq, MD, Manon Philibert, MD, Augustin Lecler, MD, PhD, Catherine Vignal-Clermont, MD Background: Giant cell arteritis (GCA) is a large vessel vasculitis associated with a risk of permanent ophthalmologic complications. Data about diplopia prognosis in GCA are scarce. This study was designed to better characterize diplopia in newly diagnosed GCA patients. Methods: All consecutive patients diagnosed with GCA from January 2015 to April 2021 in a French tertiary ophthalmologic center were retrospectively reviewed. GCA diagnosis relied on a positive temporal artery biopsy or high-definition MRI. Results: Among 111 patients diagnosed with GCA, 30 patients (27%) had diplopia. Characteristics of patients with diplopia were similar to other GCA patients. Diplopia resolved spontaneously in 6 patients (20%). Diplopia was attributed to cranial nerve palsy in 21/24 patients (88%), especially third (46%) and sixth cranial nerve (42%). Ocular ischemic lesions occurred in 11 of the 30 patients with diplopia (37%); 2 patients developed vision loss after initiation of corticosteroids. In the remaining 13 patients, diplopia resolved after treatment onset in 12 patients (92%) with a median delay of 10 days. Patients treated intravenously tended to have a quicker improvement than those treated orally, but with a similar resolution rate of diplopia at 1 month. Two patients had relapse of diplopia at 4 and 6 weeks after an initial treatment course of 24 and 18 months, respectively. Conclusions: Diplopia is a rare feature at GCA diagnosis, but should raise clinician suspicion for GCA when associated with cephalic symptoms and prompt the initiation of corticosteroids to prevent ocular ischemic complications. Journal of Neuro-Ophthalmology 2024;44:87–91 doi: 10.1097/WNO.0000000000001912 © 2023 by North American Neuro-Ophthalmology Society G iant cell arteritis (GCA) is a large-vessel vasculitis usually affecting individuals over 50 years old and typi- Internal Medicine Department (TC, GC, TL), Neuro-Ophtalmology Department (MP, CV-C), and Neuroradiology Department (AL), Hopital Fondation Adolphe de Rothschild, Paris, France The authors report no conflicts of interest. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s Web site (www. jneuro-ophthalmology.com). Address correspondence to Thibaud Chazal, Service de Médecine Hospitalière, 29 rue Manin, Hopital Fondation Adolphe de Rothschild, 75019 Paris, France; E-mail: [e-mail] Chazal et al: J Neuro-Ophthalmol 2024; 44: 87-91 cally involving aorta and its large arterial branches, particularly the branches of the external carotids, leading to headache, jaw claudication, scalp tenderness, and temporal artery thickening.1 Involvement of cranial vessels, especially ophthalmic arteries, may expose patients to visual impairment ranging from transient visual loss or blurred vision to complete and definite blindness, sometimes affecting both eyes. Involvement of the posterior ciliary arteries leads to acute anterior ischemic optic neuropathy (AION), whereas involvement of the central retinal artery, less frequently, leads to central retinal artery occlusion, both with a significant risk of definite and severe vision loss.2 Treatment of GCA relies mainly on corticosteroids which should be started immediately to prevent further damage, particularly in the eyes. Binocular diplopia is a rare symptom of GCA at diagnosis with a reported occurrence of 2%–15% of patients.3–6 Affected patients may present with transient or constant diplopia and may also experience vision loss. The pathophysiology of diplopia in GCA is multifactorial and the underlying mechanism is rarely understood in a clinical setting. Ischemia of the ocular motor cranial nerves secondary to vasculitic occlusion has been described, as well as ocular muscle involvement.7 Clinical profile of patients who present with diplopia related to GCA has been described in several series including less than 30 patients,8,9 but data about its prognosis are scarce. International guidelines recommend the use of intravenous corticosteroids in case of ocular involvement in GCA, but there are no specific guidelines for patients with binocular diplopia.10 Our study was designed to describe the characteristics of patients with binocular diplopia related to GCA in a tertiary ophthalmologic center and evaluate the prognosis of diplopia after treatment initiation. METHODS We conducted a retrospective study that included all consecutive patients diagnosed with GCA in a French tertiary ophthalmologic center from January 2015 to April 2021. Characteristics of patients with transient and persistent binocular diplopia before the diagnosis of GCA were 87 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution obtained by chart review and compared with patients with GCA, but without diplopia. Transient binocular diplopia was defined as a diplopia lasting less than 24 hours and persistent as a diplopia lasting more than 24 hours. Cephalic symptoms included headaches of recent onset, jaw claudication, and scalp tenderness. Polymyalgia rheumatica was defined as the presence of moderate-to-severe pain lasting for at least 2 weeks and morning stiffness in at least 2 of the following areas: neck, shoulder, and pelvic girdles. Large vessel involvement was defined as the involvement of the aorta or its branch on CT-scan, MRI, or Positron Emission Tomography scan. Demographic, clinical, laboratory, and radiologic data of all patients were extracted from clinical records at diagnosis and during follow-up. All patients with persistent ophthalmologic symptoms were referred to further detailed ophthalmologic examinations. GCA diagnosis was made according to 2018 European Alliance of Associations for Rheumatology criteria with a positive temporal artery biopsy (TAB) or a high-resolution fat-suppressed contrastenhanced 3D-T1 MRI suggestive of the diagnosis.10,11 Results are expressed as mean ± 1 SD for variables with a normal distribution, or as median and interquartile range (IQR) otherwise. Student t test and Mann–Whitney U test were used to compare demographic and laboratory data depending on the distribution of the variable. Fisher exact test or chi-squared test were used to compare categorical data when applicable. Analyses were performed using SSPS (IBM Corp. Released 2019. IBM SPSS Statistics for Windows, Version 26.0. Armonk, NY: IBM Corp). This study was approved by our center’s ethic committee (IRB 00012801). Patients were informed of this study, but written consent was not necessary given the retrospective design. RESULTS Patients’ Characteristics One hundred and eleven patients were diagnosed with GCA over the study period, including 30 patients (27%) with binocular diplopia. Diplopia was transient in 3 patients (10%) and persistent in 27 patients (90%). Characteristics of patients with diplopia are shown in Table 1. Mean age was 74 years old with a female predominance (70%). Most patients had cephalic symptoms (87%) with associated polymyalgia rheumatica in 7 patients (23%). Four patients (13%) had large-vessel involvement. GCA diagnosis was confirmed in 9 patients by TAB and in 21 patients by high-resolution fat-suppressed contrastenhanced 3D-T1 MRI. There were no differences in comorbidities or clinical presentation between patients with and without diplopia. C-reactive protein was elevated in all patients with diplopia vs. 93% of patients without diplopia (P = 0.19). 88 Diplopia Characteristics Median delay between diplopia onset and GCA diagnosis was 10 days (IQR 4–19). Twelve patients (40%) had diplopia for less than a week at GCA diagnosis. Detailed examination of ocular motility was available in only 24 patients (80%). Among them, 11 (46%) were diagnosed with third cranial nerve palsy, 10 (42%) with sixth cranial nerve palsy (including 2 patients with both third and sixth cranial nerve palsy), and 2 patients (8%) with fourth cranial nerve palsy (Table 2). Three patients (13%) did not have cranial nerve palsy: 1 patient had orbital apex syndrome and the mechanism was not precisely understood in 2 patients. Highresolution MRI was performed in 28 patients (93%) and did not find cerebral or brainstem ischemic lesion. Extraocular muscles were described as normal in all patients. Four patients with clinical signs of third cranial nerve palsy had signal abnormalities of the third cranial nerve on highresolution MRI. Diplopia Prognosis Three patients (10%) had transient diplopia and 3 more patients had persistent diplopia, which resolved spontaneously before first examination. Ocular ischemic complications occurred in 11 patients (37%) with diplopia vs. 60% in patients without diplopia (P = 0.02). Of the 11 patients who presented with diplopia and then developed ocular ischemia, 5 had bilateral visual impairment and 2 developed ischemia after initiation of steroids (unilateral AION at day 4 in 1 patient treated with intravenous corticosteroids and bilateral sequential AION at day 10 and day 14 in another patient, who initially received oral corticosteroids). Characteristics of ocular symptoms and ocular ischemic events are shown in Table 2. Seven patients (64%) had major vision impairment (LogMAR .1) in 1 eye and 2 patients (18%) had bilateral blindness at 1 month visit. Patients with diplopia and visual impairment (n = 11) had similar characteristics to patients without ocular ischemia (n = 19) except for a higher frequency of high blood pressure (82% vs 32%, P = 0.02) (See Supplemental Digital Content, Table S1, http://links.lww.com/WNO/A710). A total of 13 patients (43%) had persistent diplopia without loss of vision. In these patients, median duration of diplopia after treatment initiation was 10 days (IQR 5–24). Diplopia (dysmotility) ultimately resolved in 12/13 patients (92%). Only 1 patient had persistent unilateral abduction limitation more than 6 months after the onset of therapy. Six patients (40%) received intravenous pulses of methylprednisolone, whereas 9 patients (60%) received only oral corticosteroids. Median duration of diplopia was 6 days (IQR 4–28) in patients treated intravenously vs. 11 days (IQR 6–13) in patients treated orally (P = 0.81) (See Supplemental Digital Content, Table S2, http://links.lww. com/WNO/A710). The resolution rate of diplopia at 7 days was 67% in patients treated intravenously vs. 33% in Chazal et al: J Neuro-Ophthalmol 2024; 44: 87-91 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution TABLE 1. Baseline characteristics of GCA patients with and without diplopia Age, years Female sex (%) Comorbidities, n (%) Hypertension Diabetes mellitus Hyperlipidemia Symptoms, n (%) Cephalic symptoms Headache Scalp tenderness Jaw claudication Polymyalgia rheumatica Temporal arteries induration Laboratory studies, n (%) Elevated C-reactive protein (. 5 mg/L) C-reactive protein, mean (mg/L) Elevated fibrinogen (. 4 g/L) Thrombocytosis (. 450.000/mm3) GCA diagnosis (% of exams suggestive of GCA) Temporal artery biopsy High-resolution MRI Large vessel involvement, n (%) P GCA With Diplopia (n = 30) GCA Without Diplopia (n = 81) 74 (SD ± 8.1) 21 (70) 77 (SD ± 7.8) 49 (60) 0.09 0.36 15 (50) 4 (13) 8 (26) 43 (53) 12 (15) 22 (28) 0.77 1 0.96 26 (87) 25 (83) 14 (47) 17 (57) 7 (23) 11 (37) 73 (90) 62 (77) 36 (44) 47 (58) 19 (23) 37 (46) 0.73 0.44 0.83 0.90 0.99 0.39 30/30 (100) 54.4 (SD ± 41.7) 20/21 (95) 8/24 (33) 74/80 (93) 50.3 (SD ± 37.2) 55/59 (93) 30/77 (39) 0.19 0.64 1 0.62 9/12 (75) 21/28 (75) 4/26 (15) 24/45 (53) 63/71 (88) 9/70 (13) 0.18 0.16 1 GCA, giant cell arteritis. patients treated orally (P = 0.31). At 1 month, the resolution rate of diplopia was 66% and 78%, respectively (P = 1). Five patients received tocilizumab at GCA diagnosis, because of visual symptoms progression after the onset of corticosteroids in 2 patients and as a corticosteroid sparing agent in 3 patients with ischemic ocular lesions. Among the 13 patients with persistent binocular diplopia and without ocular ischemic lesions, none received tocilizumab. Median follow-up was 21 months (IQR 14–31). Two patients (7%) died during follow-up with a median delay between diagnosis and death of 12 months. Seven patients (23%) experienced a GCA relapse during follow-up including 2 patients with binocular diplopia recurrence at 4 and 6 weeks after treatment discontinuation. These patients had received treatment for 18 and 24 months, respectively. Diplopia resolved in both patients after treatment was resumed. DISCUSSION We showed that binocular diplopia was not an exceptional feature at GCA diagnosis, accounting for 27% of our patients in our tertiary ophthalmologic French center. This number is higher than other series published in the literature, which may be because of a recruitment bias in our center where patients are referred for ophthalmologic symptoms, thus overestimating patients with visual signs of GCA.8,9 The underlying mechanism of diplopia in our study was mostly cranial nerve palsy, especially third or sixth cranial Chazal et al: J Neuro-Ophthalmol 2024; 44: 87-91 nerve. Most patients had high-definition MRI at GCA diagnosis and none had ocular myositis, although it has been discussed in previous series as a potential cause of diplopia in GCA patients.12 In a recently published study by Mournet et al,13 high-definition MRI was shown to have excellent diagnostic sensitivity and specificity to detect signal abnormalities of the third cranial nerve in GCA patients presenting with third CN impairment, confirming the implication of cranial nerves in the pathophysiology of diplopia in GCA. We did not find clinical, biological, or morphologic differences between patients with and without diplopia at GCA diagnosis. Specifically, we did not find a difference in cardiovascular comorbidities, thus suggesting a different pathophysiology than microvascular cranial nerve palsy, the most common cause of diplopia in patients over 50 years old.14 Data about the prognosis of diplopia in GCA are contradictory. Some studies indicate a low rate of ocular ischemic complication, whereas others found that patients presenting with diplopia at GCA diagnosis had a more severe visual prognosis than others.9,12,15 In our study, around one third of patients with diplopia ultimately developed ocular ischemic complications with subsequent permanent vision loss, almost exclusively before the initiation of treatment and often after several days in the course of diplopia. These results indicate that diplopia is not associated with a better visual prognosis and should raise clinicians’ awareness of the need to rapidly start an adequate treatment if GCA is 89 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution TABLE 2. Ophthalmologic features and prognosis of patients with binocular diplopia at GCA diagnosis GCA With Diplopia (n = 30) Characteristics of diplopia Transient diplopia, n (%) Persistent diplopia, n (%) Delay between diplopia onset and GCA diagnosis, days (median, IQR) Oculomotor examination (n = 24) Third nerve palsy, n (%) Fourth nerve palsy, n (%) Sixth nerve palsy, n (%) Other mechanisms, n (%) Ocular ischemic lesions, n (%) AION, number of eyes (%) CRAO, number of eyes (%) PAMM, number of eyes (%) Bilateral lesions, n (%) Outcomes Median follow-up, months (IQR) Spontaneous resolution of persistent diplopia, n (%) Severe loss of vision, 1 eye (logMAR . 1) Severe loss of vision, 2 eyes (logMAR . 1) GCA relapse, n (%) Diplopia relapse, n (%) Death, n (%) 3 (10) 27 (90) 10 (4–19) 11 (46) 2 (8) 10 (42) 3 (13) 11 (37) 11 (50) 4 (18) 1 (3) 5 (45) 21 (14–31) 3 (10) 7/11 (63) 2/11 (18) 7 (23) 2 (7) 2 (7) AION, anterior ischemic optic neuropathy; CRAO, central retinal artery occlusion; GCA, giant cell arteritis; IQR, interquartile range; MAR, minimal angle of resolution; PAMM, paracentral acute middle maculopathy. suspected. Although our data suggest that patients with diplopia had ocular ischemic complications less frequently than controls (37% vs 60%), these results are to be considered cautiously because most patients were referred to our center for visual impairment, affecting the frequency of ocular ischemic lesions in our control group. In patients without ocular ischemic complications, diplopia prognosis is good with a resolution in almost all patients (92%) in less than a month after the beginning of corticosteroids. Although there is no study in the literature comparing both situations, it seems that diplopia associated with GCA has a shorter course after initiation of therapy (median duration of 11 days in our study) compared with diplopia secondary to microvascular cranial nerve palsy, which tends to resolve in 4–12 weeks.16,17 Our study suggests that diplopia resolution tends to be quicker in patients treated intravenously compared with patients receiving oral corticosteroids. However, patients treated with oral corticosteroids did not have more ocular ischemic events than patients treated intravenously (1 patient in each group) and the recurrence rate of GCA was not different between groups after a median follow-up of 9 months (IQR 4–23) and 12 months (IQR 6–26), respectively (See Supplemental Digital Content, Table S2, http://links.lww.com/WNO/A710). Our study has some limitations because of its retrospective and monocentric design. Duration of diplopia was 90 difficult to establish precisely because of the fact that it relied on self-assessment only. We were not able to assess the efficacy of tocilizumab in patients with diplopia given the low number of patients treated with anti-IL6-receptor antibodies. Larger prospective studies are needed to better define patients with diplopia at risk of visual complication and study the impact of anti-IL6 receptor agents on preventing ocular ischemic complications in these patients. 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