Retrospective, Multicenter Comparison of the Clinical Presentation of Patients Presenting With Diplopia From Giant Cell Arteritis vs Other Causes

Background: Although giant cell arteritis (GCA) is a well-known cause of transient and permanent vision loss, diplopia as a presenting symptom of this condition is uncommon. We compared symptoms and signs of patients presenting with diplopia from GCA to those from other causes. Methods: This was a multicenter, retrospective study comparing the clinical characteristics of patients presenting with diplopia from GCA with age-matched controls. Demographic information, review of symptoms, ophthalmic examination, and laboratory data of biopsy-proven patients with GCA were compared with those of age-matched controls presenting with diplopia. Results: A total of 27 patients presented with diplopia from GCA, 19 with constant diplopia, and 8 with transient diplopia. All patients with constant diplopia from GCA were matched with 67 control subjects who had diplopia from other etiologies. Patients with GCA were more likely to describe other accompanying visual symptoms (58% vs 25%, P = 0.008), a greater number of systemic GCA symptoms (3.5, GCA vs 0.6, controls, P < 0.001) such as headache (94% [17/18] vs 39% [23/67]; P < 0.001), jaw claudication (80% [12/15] vs 0% [0/36]; P < 0.001), and scalp tenderness (44% [7/16] vs 7% [3/43]; P < 0.001). Ocular ischemic lesions (26% vs 1%, P < 0.001) were also common in patients with diplopia from GCA. Inflammatory markers were elevated significantly in patients with GCA vs controls (erythrocyte sedimentation rate: 91% [10/11] vs 12% [3/25], P < 0.001; C-reactive protein: 89% [8/9] vs 11% [2/19], P < 0.001). Conclusions: GCA is a rare but serious cause of diplopia among older adults and must be differentiated from other more common benign etiologies. Our study suggests that most patients with diplopia from GCA have concerning systemic symptoms and/or elevated inflammatory markers that should trigger further work-up. Moreover, careful ophthalmoscopic examination should be performed to look for presence of ocular ischemic lesions in older patients presenting with acute diplopia.

Original Contribution Retrospective, Multicenter Comparison of the Clinical Presentation of Patients Presenting With Diplopia From Giant Cell Arteritis vs Other Causes Ahmara G. Ross, MD, PhD, Imran Jivraj, MD, Geoffrey Rodriguez, MD, Maxwell Pistilli, MS, Med, John J. Chen, MD, PhD, Robert C. Sergott, MD, Mark Moster, MD, Claire A. Sheldon, MD, PhD, Grant T. Liu, MD, Rod Foroozan, MD, Melissa W. Ko, MD, Courtney E. Francis, MD, Zoë R. Williams, MD, Andrew G. Lee, MD, Collin M. McClelland, MD, Kenneth S. Shindler, MD, PhD, Sushma Yalamanchili, MD, Benjamin Osborne, MD, Thomas R. Hedges III, MD, Gregory P. Van Stavern, MD, Ernest Puckett, MD, Mohammed Rigi, MD, Msc, Ignacia García-Basterra, MD, Madhura A. Tamhankar, MD Background: Although giant cell arteritis (GCA) is a wellknown cause of transient and permanent vision loss, diplopia as a presenting symptom of this condition is uncommon. We compared symptoms and signs of patients presenting with diplopia from GCA to those from other causes. Methods: This was a multicenter, retrospective study comparing the clinical characteristics of patients presenting Department of Ophthalmology (AGR, MP, GTL, KSS, MAT), Scheie Eye Institute, University of Pennsylvania, Philadelphia, Pennsylvania; Department of Ophthalmology (IJ), University of Toronto, Toronto, Ontario, Canada; Department of Ophthalmology (GR), Cornell Medical Center, New York, New York; Department of Ophthalmology and Neurology (JJ-WC), Mayo Clinic, Rochester, New York; Department of Ophthalmology (RCS, MM), Wills Eye Hospital, Philadelphia, Pennsylvania; Department of Ophthalmology & Visual Sciences (CAS), University of British Columbia, Vancouver, British Columbia, Canada; Department of Ophthalmology (RF), Baylor College of Medicine, Houston, Texas; Department of Neurology (MWK), SUNY Upstate Medical University, Syracuse, New York; Department of Ophthalmology (CEF), University of Washington, Seattle, Washington; Department of Ophthalmology (ZRW), Flaum Eye Institute, University of Rochester Medical Center, Rochester, New York; Houston Methodist Ophthalmology Associates (AGL, SY, EP, MR), Houston, Texas; Department of Ophthalmology and Visual Neurosciences (CMM), University of Minnesota, Minneapolis, Minnesota; Department of Neurology and Ophthalmology (BO), Georgetown University, Washington DC; New England Eye Center (TRH), Tufts University, Boston, Massachusetts; Department of Ophthalmology and Neurology (GPVS, IG-B), Washington University, St. Louis, Missouri; and Department of Ophthalmology, University Hospital Virgen de la Victoria, Campus Teatinos, Málaga, Spain. The authors report no conflicts of interest. Address correspondence to Madhura A. Tamhankar, MD, Scheie Eye Institute, 51 N. 39th Street, Philadelphia PA 19104; E-mail: [e-mail] 8 with diplopia from GCA with age-matched controls. Demographic information, review of symptoms, ophthalmic examination, and laboratory data of biopsy-proven patients with GCA were compared with those of age-matched controls presenting with diplopia. Results: A total of 27 patients presented with diplopia from GCA, 19 with constant diplopia, and 8 with transient diplopia. All patients with constant diplopia from GCA were matched with 67 control subjects who had diplopia from other etiologies. Patients with GCA were more likely to describe other accompanying visual symptoms (58% vs 25%, P = 0.008), a greater number of systemic GCA symptoms (3.5, GCA vs 0.6, controls, P , 0.001) such as headache (94% [17/18] vs 39% [23/67]; P , 0.001), jaw claudication (80% [12/15] vs 0% [0/36]; P , 0.001), and scalp tenderness (44% [7/16] vs 7% [3/43]; P , 0.001). Ocular ischemic lesions (26% vs 1%, P , 0.001) were also common in patients with diplopia from GCA. Inflammatory markers were elevated significantly in patients with GCA vs controls (erythrocyte sedimentation rate: 91% [10/11] vs 12% [3/25], P , 0.001; C-reactive protein: 89% [8/9] vs 11% [2/19], P , 0.001). Conclusions: GCA is a rare but serious cause of diplopia among older adults and must be differentiated from other more common benign etiologies. Our study suggests that most patients with diplopia from GCA have concerning systemic symptoms and/or elevated inflammatory markers that should trigger further work-up. Moreover, careful ophthalmoscopic examination should be performed to look for presence of ocular ischemic lesions in older patients presenting with acute diplopia. Journal of Neuro-Ophthalmology 2019;39:8-13 doi: 10.1097/WNO.0000000000000656 © 2018 by North American Neuro-Ophthalmology Society Ross et al: J Neuro-Ophthalmol 2019; 39: 8-13 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution G iant cell arteritis (GCA) is the most common form of systemic inflammatory vasculitis in people older than 50 years and can result in a wide variety of systemic, neurologic, and ophthalmologic complications. The annual incidence of GCA is approximately 19 per 100,000 (1,2). Affected individuals most commonly experience sudden transient or permanent vision loss from optic nerve, retinal, or rarely, intracranial ischemia (3). Diplopia as an initial symptom of GCA is rare and reported to occur in 2%- 15% of patients (3-5). Affected individuals may present with constant or transient diplopia with or without vision loss (3,4,6). The pathophysiology of diplopia in GCA is multifactorial and can occur because of vasculitic occlusion and/or ischemia of the ocular motor cranial nerves, the extraocular muscles, or both (3,7,8). Ischemia due to vasculitis in GCA also may affect brainstem ocular motor nuclei, their fascicles, supranuclear or internuclear pathways associated with ocular motility (9-15). Rarely, inflammatory intracranial aneurysms have been reported in patients with GCA (16). Older patients presenting with isolated diplopia pose a diagnostic challenge because of the complex differential diagnoses that must be considered, including paretic and restrictive causes, neuromuscular conditions, and decompensated strabismus. However, the clinical profile of patients who present with diplopia from GCA is not well described in the literature outside of case reports and small series (3-6,9,11,13,15,17-27). In the absence of clear evidence, clinicians rely on their judgment to exclude GCA by weighing aspects of the clinical history, examination, laboratory studies, and the need for temporal artery biopsy. The objective of our study was to identify clinical findings that would suggest the possibility of GCA while sparing other patients from unnecessary diagnostic studies. This multicenter, retrospective study compared the clinical history, ophthalmic presentation, and laboratory data of patients with diplopia from GCA with matched controls having diplopia from other etiologies. MATERIALS AND METHODS A multicenter retrospective matched case-control study design was used. Institutional review board approval was obtained for each of the study sites, and the study was performed in accordance with health insurance portability and accountability act regulations. The research protocol adhered to the tenets of the Declaration of Helsinki. A total of 551 ophthalmologists, neurologists, and neuro-ophthalmologists practicing in the United States and Canada were initially contacted through email to request their participation in the study. Of the 176 respondents, 152 (86%) declined to participate, citing a lack Ross et al: J Neuro-Ophthalmol 2019; 39: 8-13 of patients as the main reason, whereas 24 investigators from 13 centers enrolled patients. Inclusion criteria were patients 50 years and older presenting with constant or transient diplopia who were subsequently diagnosed with GCA by temporal artery biopsy. Only those patients with biopsy-proven GCA diagnosed at their respective institution were included; those with equivocal pathologic findings were excluded. The patients with constant diplopia from GCA were matched with 2-5 controls that included those with diplopia from other etiologies with similar age (±5 years), race, and strabismus pattern and had at least 6 months of followup or a negative temporal artery biopsy. Because it was not always possible to ascertain the pattern of misalignment among those who described transient diplopia, these patients were not matched with controls but were categorized separately. Demographic information including age, sex, race, and medical history including diabetes mellitus, hypertension, hypercholesterolemia, smoking status of the subjects, and controls was recorded. The initial strabismus pattern, time course of diplopia, and the etiologies of diplopia were collected for patients and controls. Data regarding review of systems including presence or absence of headache, jaw claudication, scalp tenderness, weight loss, malaise, anorexia, myalgia, fever, neck pain, facial pain, and polymyalgia were recorded. The presence of concomitant retinal or optic nerve ischemia such as anterior or posterior ischemic optic neuropathy, retinal vascular occlusions, and choroidal ischemia was determined. Laboratory values for erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), hemoglobin, and platelet count were recorded based on institutional standards. In cases where the standard differed from defined numerical standards at our home institution, the investigators and laboratories were contacted to confirm positive testing. Anemia was defined as a hemoglobin level ,11 gm/dL, and thrombocytosis was defined as a platelet level .450,000/mL. Study data were collected and entered into Redcap electronic data capture tools (28) located at the University of Pennsylvania. Comparisons between patients and controls were analyzed using analysis of variance for continuous characteristics and x2 tests for categorical characteristics. Each characteristic was analyzed separately, and patients in matched sets were used only if the case and at least one of the controls were not missing information of that characteristic. All statistical computations were performed with SAS 9.4 (SAS Inc, Cary, NC). RESULTS The 27 patients who presented with diplopia from GCA were enrolled from 13 centers in the United States and Canada. Nineteen subjects presented with constant diplopia, whereas 8 presented with transient diplopia that had 9 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution resolved before presentation. Patients with constant diplopia from GCA were matched with 67 control subjects who had diplopia from other etiologies including presumed microvascular ischemia (52/67, 78%), cerebrovascular accident (3/67, 4.5%), decompensated strabismus (3/67, 4.5%), myasthenia gravis (2/67, 3%), and undetermined etiologies (7/67, 10%). Of the 67 controls, 2 underwent temporal artery biopsies both of which were normal. Constant Diplopia The demographics and clinical characteristics of patients and controls are shown in Table 1. The majority in the GCA cohort were women (n = 17/19, 89%). Controls were more likely to have diabetes mellitus (P = 0.03), hypertension (P , 0.01), and hyperlipidemia (P = 0.04). Sixth nerve palsy was the most common cause of diplopia in both groups and was seen in 53% of patients in the GCA cohort (10/19) and in 48% of controls (32/67), followed by third nerve palsy (37%, 7/19). One patient (5%) had a fourth nerve palsy from GCA. Approximately 21% of patients with constant diplopia from GCA and 17% of controls described a previous episode of transient diplopia; this did not differ significantly between the 2 groups (P = 0.69). The total duration of diplopia was shorter among patients with GCA, all of whom were treated with corticosteroids. Control subjects may or may not have received treatment depending on the etiology. Patients with GCA were more likely than controls to describe accompanying visual/ophthalmologic symptoms (58% vs 25%, P = 0.008). These included bilateral blurred vision (n = 4), eye pain (n = 3), transient monocular vision loss (n = 2), permanent monocular vision loss (n = 2), photophobia (n = 1), periocular swelling (n = 1), and chronic eye discharge (n = 1). Ocular ischemic lesions were identified more frequently among patients with GCA (26% vs 1%, P , 0.001) included anterior ischemic optic neuropathy (3), choroidal ischemia (1), and cotton wool spots (1). One control patient was suspected of having had an episode of nonarteritic anterior ischemic optic neuropathy in the years before presentation but did not experience new visual symptoms with diplopia and had a negative temporal artery biopsy. Patients with constant diplopia from GCA experienced, on average, a greater number of systemic symptoms of GCA (headache, jaw claudication, scalp tenderness, myalgia, polymyalgia rheumatica, anorexia, weight loss, and neck pain) than controls (3.5, GCA vs 0.6, controls, P , 0.001). All but one patient with GCA had more than one systemic symptom. There was no significant difference in the frequency of malaise, fever, or facial pain between patients with GCA and controls. Elevated ESR (P , 0.001), CRP (P , 0.001), and platelets (P = 0.02) were observed at a significantly higher rate in the GCA cohort vs controls. One patient with constant diplopia from GCA had a normal ESR, CRP, and 10 platelet level and had no evidence of ocular ischemic lesions but reported both headache and jaw claudication. Transient Diplopia Of the 8 patients with transient diplopia from GCA, 6 reported episodes lasting less than 15 minutes intermittently for 4-5 days preceding the diagnosis. Five of the 8 patients had evidence of ocular ischemic lesions including bilateral anterior ischemic optic neuropathy (n = 1), unilateral posterior ischemic optic neuropathy (n = 3), and cotton wool spots (n = 1). Systemic symptoms of GCA also were common among patients with transient diplopia particularly headache, scalp tenderness, jaw claudication, and malaise (Table 1). A single patient with transient diplopia from GCA had no systemic symptoms or evidence of ocular ischemia but had an elevated ESR. Seventy-one percent (5/7) of patients had an elevated ESR level, 83% (5/6) had an elevated CRP, and 40% (2/5) had anemia. A single patient with transient diplopia from GCA had a normal ESR, CRP, and platelet level but reported headaches and weight loss as well as transient vision loss in both eyes, although there was no fundoscopic evidence of ocular ischemia. DISCUSSION Diplopia as an initial manifestation of GCA seems to be rare. Despite conducting an extensive search nationwide of specialists involved in making the diagnosis of GCA, most respondents cited lack of patients as the main reason for their inability to participate in the study. The results of our study indicate that historical information, clinical examination, and laboratory markers are useful in identifying patients who are at risk of GCA vs those that have other etiologies of diplopia. A greater proportion of patients with GCA were women, consistent with a higher female to male ratio of GCA reported in the literature (29,30). In our study, GCA and control patients reported a similar frequency of previous episodes of transient diplopia. This is likely due to patients with decompensated strabismus and myasthenia gravis being in the control group. In a prospective case series of 27 patients with GCA, 9 patients presented with diplopia, and the majority (8/9) described previous episodes of transient diplopia (6). Thus, the literature and our results suggest that this feature occurs at varying rates, making it unreliable as a way of distinguishing GCA from other causes of diplopia. In our study, patients with constant diplopia from GCA also frequently described other visual symptoms (58%), although some were likely unrelated to GCA. The presence of concomitant optic nerve and retinal ischemia seen in our patient cohort with GCA is not surprising, although almost three-quarters of the affected patients with GCA presenting with constant diplopia had no ocular ischemic lesions. The higher prevalence of ocular Ross et al: J Neuro-Ophthalmol 2019; 39: 8-13 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution TABLE 1. Demographic and clinical characteristics of patients with constant diplopia from GCA and controls Age, years Sex (% female) Race (% white) Medical history (%, n/total number) Diabetes mellitus Hypertension Hyperlipidemia Current cigarette smoking Past cigarette smoking Pattern of diplopia (%, n/total number) Third nerve palsy Fourth nerve palsy Sixth nerve palsy Other Duration of diplopia (days) Episodes of transient diplopia (%, n/total number) Visual symptoms Ocular ischemic lesions Average number of systemic symptoms/total number of symptoms Systemic symptoms suspicious for GCA (%, n/total number) Headache Jaw claudication Scalp tenderness Myalgia Polymyalgia rheumatica Anorexia Weight loss Neck pain Malaise Fever Facial pain Laboratory studies Elevated ESR Elevated CRP Thrombocytosis (platelets .450,000 /mL) Anemia (hemoglobin ,11 g/dL) GCA with Constant Diplopia (N = 19) Controls (N = 67) 72.9 (SD ± 6.0) 89 (17/19) 74 (14/19) 73.0 (SD ± 5.9) 49 (33/67) 70 (47/67) 11 (2/18) 33 (6/18) 38 (6/16) 18 (3/17) 0 (0/19) 39 (24/61) 74 (45/61) 67 (36/54) 36 (16/45) 13 (7/52) 37 (7/19) 5 (1/19) 53 (10/19) 5 (1/19) (1 patient: ET) 61 (SD ± 51.7) 21 (4/19) 37 (25/67) 4 (3/67) 48 (32/67) 6 (4/67) (1 patient: INO and skew; 1 patient: RHT & XT; 2 patients: ET) 135.1 (SD ± 128.3) 17 (11/64) P value 0.92 0.002* 0.63 0.03* ,0.001* 0.04* 0.13 0.04* 0.69 58 (11/19) 26 (5/19) 3.5/11 25 (17/67) 1.5 (1/67) 0.6/11 0.008* ,0.001* 0.001* 94 (17/18) 80 (12/15) 44 (7/16) 50 (7/14) 31 (4/13) 33 (4/12) 31 (5/16) 55 (6/11) 31 (4/13) 7 (1/14) 22 (2/9) 39 (23/59) 0 (0/36) 7 (3/43) 4 (2/45) 3 (1/36) 3 (1/37) 7 (3/45) 14 (4/29) 9 (4/43) 3 (1/38) 8 (2/24) ,0.001* ,0.001* ,0.001* ,0.001* 0.004* 0.002* 0.01* 0.008* 0.053 0.42 0.28 91 (10/11) 89 (8/9) 56 (5/9) 12 (3/25) 11 (2/19) 12 (2/17) ,0.001* ,0.001* 0.02 14 (1/7) 15 (2/13) 0.95 *P , 0.05. CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; ET, esotropia; GCA, giant cell arteritis; INO, internuclear ophthalmoplegia; RHT, right hypertropia; XT, exotropia. ischemic lesions seen in those patients with transient diplopia could be due to the fact that monocular visual loss prevented them from experiencing constant double vision. In one report, ocular ischemia was seen in 44% (4/9) of patients with GCA presenting with diplopia (6). Importantly, active signs of ocular ischemia were not found in our control patients, with only 1% (1/67) having an old nonarteritic anterior ischemic optic neuropathy. In our study, most patients with constant diplopia from GCA experienced more than 1 systemic symptom of GCA. Ross et al: J Neuro-Ophthalmol 2019; 39: 8-13 Another study also found that headache, jaw claudication, and scalp tenderness were common in patients with GCA presenting with diplopia (6). However, there are reports of patients without systemic symptoms in whom elevated inflammatory markers alone suggested the diagnosis of GCA: in one prospective study of 109 patients with isolated ocular motor cranial neuropathy, 3 patients had isolated sixth cranial nerve palsy from GCA with elevated inflammatory markers but no systemic symptoms (31). In a case series of 4 patients with third nerve palsies from GCA, all 11 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution described new headache or pain in the brow or periorbital region, but only 2 of 4 had a positive review of other systemic symptoms of GCA (7). The presence of jaw claudication, seen in 80% of our patients with GCA and in none of the controls, is highly suggestive of GCA and may be a sufficient indication to initiate prompt treatment and perform further diagnostic studies. Inflammatory markers were elevated in a significantly greater proportion of patients with constant diplopia from GCA vs controls (91% vs 12%) and in those with transient diplopia (86%) illustrating their value as supportive diagnostic tests. Haering et al (6) found similar results. González-Gay et al (4) reported that patients with visual symptoms from GCA, including diplopia, were less likely to have elevated acute inflammatory markers (4), all but 2 patients in our study (one with persistent diplopia and one with transient diplopia) had elevation of at least 1 acute inflammatory marker, but both described systemic symptoms of GCA. In our study, there were no patients with diplopia from GCA that did not have systemic symptoms of GCA or elevated inflammatory markers (32). Our study had several limitations. Given its retrospective design, data collection was not complete for all patients and controls. Control subjects did not all undergo identical laboratory evaluations, nor did all have temporal artery biopsies; therefore, a minimum of 6 months of follow-up was required to reduce the likelihood of a missed diagnosis of GCA among control patients. Because laboratory testing procedures were not standardized among centers, the treating physician provided an interpretation of the laboratory data that were used in the analyses. The diagnosis of GCA required a positive temporal artery biopsy that was interpreted by a pathologist, but specimens did not undergo a standard histopathologic review process. However, we excluded patients that carried the diagnosis of "possible temporal arteritis" or "healed temporal arteritis" to mitigate the possibility of false-positive diagnoses. We believe that the distribution of etiologies for diplopia among the control population was representative of commonly encountered causes among adults. However, other causes were not represented among controls such as inflammatory, infectious, or neoplastic etiologies that may be expected to share more in common with the clinical presentation of GCA (the presence of constitutional symptoms; elevated inflammatory markers). Thus, the differences identified between patients with GCA and controls may not be generalizable to populations with other causes of diplopia. Last, although it would have been of interest to know the prevalence of diplopia associated with GCA, our study could not provide that data, because of different methodologies that were adopted by institutions to find patients with GCA and match them with controls with double vision. GCA must be considered in the differential diagnosis when an older adult presents with constant or transient diplopia. In our cohort, all patients who presented with 12 diplopia from GCA experienced more than one systemic symptom suggestive of GCA or had at least 1 elevated inflammatory marker. 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