Journal of Neuro-Ophthalmology, September 2012, Volume 32, Issue 3

Treatment of Acute Visual Loss in Giant Cell Arteritis: Should We Prescribe High-Dose Intravenous Steroids or Just Oral Steroids?

Treatment of Acute Visual Loss in Giant Cell Arteritis: Should We Prescribe High-Dose Intravenous Steroids or Just Oral Steroids? Sohan Singh Hayreh, MD, MS, PhD, DSc, FRCS, FRCOphth (Hon), Valérie Biousse, MD A 76 year-old Caucasian woman presents to her ophthal-mologist with acute visual loss in her right eye. She has a medical history of hypertension well-controlled with one medication, diet-controlled borderline diabetes mellitus, hysterectomy, and cholecystectomy. She takes one aspirin 81 mg per day. She is mildly overweight and denies smoking or drinking alcohol. She had cataract extractions in both eyes 10 years previously, and she only wears reading glasses. One day ago, she noticed a "shadow" in her right eye while vision seemed normal in the left eye. Her ophthal-mologist documented visual acuities of hand motion in the right eye and 20/25 in the left eye. Color vision was normal in the left eye. There was a large right relative afferent pupillary defect. Fundus examination showed diffuse, pallid right optic disc edema with attenuated arteries and a few cotton wool spots in the peripapillary area. In the left eye, the optic nerve was normal with a cup-to-disc ratio of 0.3, with mild retinal arterial attenuation and a few macular drusen. Suspicious that the patient may have arteritic ische-mic optic neuropathy (AION), the ophthalmologist obtained an erythrocyte sedimentation rate (ESR) and C-reactive pro-tein (CRP), which came back "very high" the following morning. The patient denied headache, scalp tenderness, jaw claudication or diplopia, but mentioned an episode of blurry vision in the right eye 2 days before permanent visual loss. The diagnosis of arteritic-AION secondary to giant cell arteritis (GCA) was considered very likely. Aware of your expertise in GCA, the ophthalmologist calls the following day upon reviewing the laboratory results, asking whether the patient should be sent to the local hospital for high-dose intravenous (IV) methylprednisolone or rather begin treat-ment with oral prednisone 1 mg/kg per day. What do you recommend and why? IV corticosteroids are not more effective than oral corticosteroids to treat patients with acute visual loss sec-ondary to GCA. Oral steroids should be given to GCA patients with acute visual loss: Sohan Singh Hayreh, MD, MS, PhD, DSc, FRCS, FRCOphth (Hon) First of all, I would like to comment on the management of the narrated case, by the referring ophthalmologist. It is stated: "he obtained ESR (erythrocyte sedimentation rate) and CRP (C-reactive protein), which came back "very high" the following morning." Having dealt with giant cell arteritis (GCA) cases for more than 40 years, I am very concerned about this statement for the following 2 reasons. 1. The ophthalmologist described ESR and CRP as "very high." When a referring physician tells me that the ESR and/or CRP are "normal", "high," or "very high", I always ask for the exact values, because these descriptive terms are subjective and meaningless in the management of a case of GCA. 2. The ophthalmologist reported that ESR and CRP came back "very high" the "following morning." Kearns (1) rightly stressed that GCA "ranks as the prime medical emergency in ophthalmology, there being no other disease in which the prevention of blindness depends so much on prompt recognition and early treatment." To wait for the ESR and CRP results until "the following morning" is unacceptable, in my opinion. I do not let my patients leave the clinic until I have the results, which I get within 1-1½ hours-CRP much earlier than ESR. If those tests indicate the possibility of GCA, then I imme-diately start the patient on high-dose corticosteroid therapy to prevent visual loss or further visual loss. This is an emergency and there is NO safe period between diagnosis and start of corticosteroid therapy to prevent visual loss. Department of Ophthalmology and Visual Sciences (SSH), College of Medicine, University of Iowa, Iowa City, Iowa; Departments of Ophthalmology and Neurology (VB), Emory University School of Medicine, Atlanta, Georgia; and Emory University School of Medi-cine (VB), Emory Eye Center, Atlanta, Georgia. Supported in part by a departmental grant (Department of Oph-thalmology, Emory University School of Medicine) from Research to Prevent Blindness, Inc, New York, New York, and by a core grant P30-EY06360 (Department of Ophthalmology, School of Medicine, Emory University) and supported by grants EY-1151 and RR-59 from the National Institutes of Health, Bethesda, Maryland (Department of Ophthalmology, University of Iowa). Address correspondence to Sohan S. Hayreh, MD, MS, PhD, DSc, FRCS, FRCOphth (Hon), Department of Ophthalmology and Visual Sciences, College of Medicine, University of Iowa, 200 Hawkins Drive, Iowa City, Iowa 52242-1091; E-mail: [e-mail] 278 Hayreh and Biousse: J Neuro-Ophthalmol 2012; 32: 278-287 Point Counter-Point Section Editors: Andrew G. Lee, MD Valérie Biousse, MD Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Role of IV vs oral corticosteroid therapy in prevention of visual loss due to GCA The primary concern in the management of GCA is visual loss. I have reviewed the conflicting literature on this subject (2). The use of IV vs oral corticosteroids in the management of GCA has been reported, but these studies are mostly based on only a few patients (3-8). In addition, progressive visual loss has been described in GCA, despite corticosteroid therapy (IV or oral) (6,7,9). I investigated the question whether IV megadose corticosteroid therapy was more effective than oral therapy in the prevention of visual loss (2). A total of 144 consec-utive patients fulfilled the criteria for the study. All patients had temporal artery biopsy positive for GCA. At their first visit, 53 patients had no visual loss, whereas 91 had a vari-able degree of visual loss in one or both eyes. Initially, 96 patients were treated by high-dose (80-120 mg) oral prednisone only and 48 with IV megadose of corticosteroid therapy; the treatment regimen for IV therapy was usually 150 mg dexamethasone every 8 hours for 1-3 days, followed by high-dose oral prednisone. During the initial stages of the study, because of the prevalent impression that IV therapy was better than the oral therapy, IV treatment was generally given to patients with visual loss and also to some patients without visual loss. Later on, with greater experience, my criteria for initial IV therapy became: 1) history of amaurosis fugax but no visual loss; 2) complete or marked loss of vision (judged by both visual acuity and visual fields) in one eye; and 3) early signs of involvement of the second eye. Tapering of the oral corticosteroid therapy was done very gradually, guided only by the levels of ESR and CRP (10). The results of this study showed that 13% of those on IV corticosteroid therapy had visual deterioration compared with 3% on oral corticosteroid therapy. This indicated that IV megadose corticosteroid therapy was no more effective than oral therapy in preventing visual deterioration. The following GCA case with positive temporal artery biopsy is an instructive example. A 78-year-old Caucasian man noticed blurred vision in the left eye when he awoke one morning, which progressively worsened during the day (Day 1). That day his ophthalmologist recorded visual acuity of hand motions in the left eye and normal acuity in the right eye. On the second day (Day 2) he was seen in my clinic, with visual acuity of hand motions in a temporal island of visual field in the left eye and 20/20 in the right eye. Fundus examination revealed chalky white left optic disc swelling (classic finding of arteritic AION (11)), and a normal right fundus. He was admitted to hospital and immediately started on IV dexamethasone 150 mg every 8 hours. Beginning on Day 3, he was switched to 120 mg oral prednisone daily. Vision in both eyes was stable until Day 6 (while still in hospital), when he awoke with visual acuity of counting fingers at 2½ feet in the right eye and light perception in the left eye. The right optic disc now had chalky white swelling. IV dexamethasone 150 mg was again started immediately and repeated every 6 hours 4 times that day. The following morning (Day 7), his visual acuity was hand motions in the right eye and no light perception in the left eye. So, despite IV megadose cortico-steroid therapy, the patient suffered progressive visual loss in both eyes. For that reason, I felt that IV corticosteroid therapy was not helping him, so he was switched to 120 mg prednisone orally. On Day 8, visual acuity in the right eye was bare light perception and in the left it no light perception. On Day 9, it was no light perception in both eyes and remained unchanged on follow-up. Despite inten-sive IV and oral corticosteroid therapy, there was relentless visual deterioration in both eyes. Role of IV vs oral corticosteroid therapy in visual improvement in visual loss due to GCA A review of the literature reveals disagreement on the effect of IV vs oral corticosteroid therapy on visual improvement in GCA. The majority of the reported patients with visual loss due to GCA in these studies initially were started on IV corticosteroids, followed by oral therapy. Some authors (3,12,13) claimed that IV corticosteroid therapy improved vision (based on only a total of 4 anecdotal cases). These 3 reports (3,12,13) require comment. In 2 cases (12,13), improved visual acuity without concomitant improvement in visual fields probably represented the patients' learning to fixate eccentrically (see below). The report by Matzkin et al (3) illustrates another problem with visual improvement during corticosteroid therapy in GCA. These authors reported visual improvement with megadose IV methyl-prednisolone in 2 eyes diagnosed with "central retinal artery occlusion." My review of these cases offers a different inter-pretation. One of the 2 eyes had a cilioretinal artery occlu-sion and NOT central retinal artery occlusion. Our natural history study of 61 eyes with cilioretinal arterial occlusion showed marked spontaneous improvement in visual acuity (14). Similarly, our natural history study of 260 eyes with central retinal artery occlusion showed evidence of sponta-neous improvement in visual acuity (15). It seems that the improvement in visual acuity claimed by Matzkin et al (3) in 2 cases simply represented natural history rather than the effect of the megadose IV methylprednisolone. Clearkin (16,17), on review of reports in the literature that have claimed visual improvement with IV megadose corticoste-roid therapy, rightly pointed out that these claims were not justified and concluded that oral therapy is safer and just as efficacious. I agree with these conclusions. Liu et al (5) retrospectively reviewed the records of 41 GCA patients with visual loss. IV methylprednisolone was given to 25 patients, while the rest received oral prednisone alone. These authors reported that in the 41 patients with visual loss, there was visual improvement in 39% after IV treatment vs 28% on oral therapy. They claimed that Hayreh and Biousse: J Neuro-Ophthalmol 2012; 32: 278-287 279 Point Counter-Point Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. "visual loss due to giant cell arteritis had a 34% chance for some improvement in visual function after corticosteroid treatment"; however, this is not supported by other pro-spective studies (see below). In view of this controversy, we investigated the useful-ness of IV vs oral systemic corticosteroid therapy in visual improvement in 84 consecutive patients with visual loss due to biopsy-proven GCA (18). The regimen of IV and oral corticosteroid therapy was the same as described above. Visual loss was due to arteritic AION (91%), central retinal artery occlusion (10.5%), cilioretinal artery occlusion (10%), and/or posterior ischemic optic neuropathy (4%) alone or in various combinations. Visual improvement was seen in 7% of 41 patients treated initially with IV corticosteroids vs 5% of 43 patients treated with oral corti-costeroids (P = 0.672). This study did not support IV megadose corticosteroid therapy as being more effective than oral therapy in leading to visual improvement. Com-parison of patients with visual improvement in both visual acuity and fields vs those with no improvement suggested a shorter (P = 0.065) interval between onset of visual loss and start of therapy in the improved patients. The data suggested early diagnosis and immediate start of corticoste-roid therapy give a better chance of visual improvement. Overall, only 4% of eyes with visual loss due to GCA improved, judging from improvement in both visual acuity and central visual field (by kinetic perimetry and Amsler grid). Similarly, Danesh-Meyer et al (9), in a series of 34 consecutive biopsy-proven GCA patients, found that only 5% had improvement in both visual acuity and visual field. These 2 studies contradict the finding of Liu et al (5) that 34% of patients had improvement in visual function after corticosteroid treatment. It is important to stress that reported "improvement in visual acuity" does not always reflect genuine visual improve-ment, as shown by my various studies (14,15,18-20) and by others (9). Genuine visual improvement involves improve-ment in both visual acuity and central visual field. Improvement in visual acuity alone, without correspond-ing improvement in the central visual field, usually repre-sents the patient's learning to see better by eccentric fixation. My studies (2,18) in GCA patients demonstrated no difference in effectiveness between IV vs high-dose oral corticosteroid therapy in the prevention or improvement of visual loss (2,18). Based on my studies, my current recom-mendations for corticosteroid therapy in GCA are as follows (10). For all patients, with or without vision loss, I initially begin with a dose of at least 80 mg oral prednisone daily, except in the following 3 situations. 1) A history of amaurosis fugax but no visual loss; amaurosis fugax is an ominous sign of impending visual loss. 2) Complete or marked (judged by both visual acuity and visual field- particularly the latter) loss of vision in one eye. 3) Early signs of involvement of the second eye. In these conditions, it is essential to act urgently to achieve high levels of corti-costeroid concentration in the circulation as soon as possi-ble. Oral corticosteroid therapy takes some time to achieve high levels in the circulation. Therefore, in these patients, I initially give one megadose of IV corticosteroid (as an out-patient) and immediately start the patient on at least 80 mg oral prednisone daily. What I have learned from my expe-rience in dealing with GCA patients over the past 4 decades is that it is most important to play the game according to the situation at hand, and not believe "one size fits all patients." I think it is relevant to point out that about a year ago I was diagnosed with GCA, without any loss of vision. My ESR was .140 mm/hour (my normal value usually about 10 mm/hour) and CRP was 17.1 mg/dL (normal value ,0.5 mg/dL) with a positive temporal artery biopsy. I wanted to be treated the way I had treated my patients because if the treatment is appropriate for them, it is also appropriate for me. I asked my treating physician to start me immediately on 80 mg oral prednisone daily. With this treatment my ESR dropped to 8 mm/hour and CRP to ,0.5 mg within 3 weeks. I experienced no visual problems. Since then, I have been slowly tapering my prednisone, guided exclusively by the levels of ESR and CRP (10). In light of all this information, my recommendation for the management of the patient in question is as follows. The patient had "hand motion" vision in the involved eye. Therefore, this patient falls in one of my 3 "emergency" situations, discussed above, that is, complete or marked loss of vision in one eye. One has to try to reduce the risk of visual loss in the fellow eye. Therefore, as stated above, I would initially give her one megadose of IV corticosteroids and immediately start her on 80 mg prednisone daily. I would regulate the tapering of her therapy based only on the levels of ESR and CRP (10). IV steroids should be given to GCA patients with acute visual loss: Valérie Biousse, MD Visual loss is the most feared complication of GCA and was noted in 30%-60% of patients with GCA before the era of corticosteroid treatment (21). Despite the widespread use of corticosteroids in the modern era, devastating visual loss may still occur in 14%-20% of patients (21-24). GCA encompasses a broad spectrum of clinical subtypes: cranial arteritis with severe ischemic complications, such as visual loss and cerebral ischemia; large vessel arteritis causing subclavian and axillary artery stenosis, and aortitis leading to aortic dissection, aneurysm, and aortic rupture; and 280 Hayreh and Biousse: J Neuro-Ophthalmol 2012; 32: 278-287 Point Counter-Point Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. a systemic inflammatory syndrome with nonstenosing vasculitis; and "isolated" polymyalgia rheumatica (PMR) with myalgias, fatigue, anorexia, and subclinical systemic vas-culitis (22-24). Few studies have evaluated treatment proto-cols by individual GCA subtype. Instead, studies examining treatment protocols for GCA are influenced by the patient populations from which they draw. Those performed by ophthalmologists and researchers in tertiary care centers have generally recommended more aggressive treatment measures, sustained for longer periods of time, than population-based studies and those by rheumatologists (10-25). Rheumatolo-gists, for example, may use low-dose oral prednisone to treat isolated PMR, while neuro-ophthalmologists often use high-dose IV methylprednisolone to treat patients with acute visual loss or brain ischemia (22). The treatable nature of GCA and the devastating visual consequences of a delayed diagnosis make identification and treatment of this disorder a true medical emergency (26,27). However, delays in recognition and management of GCA still occur. In a recent study (28) of 65 GCA patients in the United Kingdom, mean time from symptom onset to diag-nosis (and therefore, to treatment) was 35 days! This delay likely explains the high rate of irreversible visual complica-tions in many series. Even a short delay of 24 hours in treatment seen in the case presented above is unacceptable and the timing of steroid therapy is probably more impor-tant than the dose or route of administration. Once a patient has lost vision in one eye, the risk of GCA-related visual loss in the fellow eye is highest within hours to days (10). Delaying steroid treatment by 24 hours not only reduces the chances of visual improvement but also places the patient at risk for fellow eye involvement, which occurs in more than 50% of cases. Although the visual outcome of arteritic AION is poor, immediate treatment with steroids might result in some visual improvement, and rarely, even complete visual recovery (5,21). There is universal agreement that corticosteroids are the mainstay of treatment for GCA and should be initiated immediately and aggressively, with the goal of suppressing inflammation and disease activity, preventing further visual loss in the involved eye, preventing visual loss in the fellow eye, and possibly restoring vision (26,27). The initial start-ing dose, method of delivery, and duration of therapy are still matters of debate but depend largely upon the patient's potential for visual loss (26,27). What does the literature tells us? Oral prednisone is the first-line therapy for GCA in most cases. The initial starting dose used to control GCA varies widely in the literature, from 20 mg per day in a mixed population of patients with either GCA or PMR, but with strictly constitutional signs and symptoms (29), to more than 100 mg per day in a high-risk neuro-ophthalmic pop-ulation with recent or impending visual loss (10). Selection bias during enrollment influences the conclusions of these studies; rheumatologic reports often combine GCA with PMR and neuro-ophthalmic reports often enroll patients with severe visual loss and occult GCA. Although no con-sensus exists for initial dose of prednisone, the majority of patients respond to a dose of 1 mg/kg per day (22-24). Higher doses of 80-100 mg per day often are given to patients with visual or neurological symptoms (10,30). IV pulse methylprednisolone is frequent induction therapy when vision is at risk. Four studies have examined IV steroid therapy in GCA, 2 of which were prospective randomized controlled trials (Table 1). The study by Che-valet et al (31) showed no benefit for a single induction dose of IV methylprednisolone (250 mg) in reducing cumulative steroid dose at 1 year. Mazlumzadeh et al (32) found that a 3-day course of induction IV methylprednisolone at a much higher dose of 15 mg/kg per day allowed more rapid weaning from oral prednisone than placebo and also reduced the cumulative steroid dose at Week 78. Interest-ingly, the benefits of pulse steroid therapy in this study only became obvious later in the course of the disease. Chan et al (33) evaluated IV steroids in exclusively high-risk patients- those with biopsy-proven GCA and recent or impending visual loss-and found improvement of visual acuity in significantly more patients treated with induction IV ste-roids compared with oral steroids alone. A study by Hayreh et al (18) did not show any obvious benefit of high-dose IV steroids, but the patients were not randomized and the group of patients treated with IV steroids tended to have greater vision loss at presentation as were those reported by Gonzales-Gay et al (21). After the initiation of corticosteroid treatment, no matter what the route, systemic symptoms of GCA disappear rapidly and dramatically over hours to days in nearly all patients (22-24,26,27). Improvement of visual loss is much less frequent, occurring in only 4%-34% of affected eyes (Table 2). Visual improvement, when it occurs, is mild, with persistent and often severe visual field defects (5,9,21,34-36). There does not seem to be any major dif-ference in terms of visual outcome based on whether patients receive induction IV bolus steroids initially or whether they are treated with oral steroids alone. However, when treatment is initiated within 24 hours of visual loss, 58% of patients have visual improvement compared with the 6% of patients who improve after a delay in treatment (21). This trend toward better visual outcomes when ste-roids are commenced early after visual loss has been docu-mented in other studies (18) (Table 2). While published case reports also suggest occasional dramatic improvement of visual function in rare patients receiving high-dose IV methylprednisolone (3,13,16,21), it is impossible to draw conclusions from isolated cases. Despite treatment with high-dose corticosteroids, both oral and IV, bilateral vision loss or worsening of unilateral vision loss may sometimes occur, usually within the first 5 days of treatment (2,6,37). While there are reports of Hayreh and Biousse: J Neuro-Ophthalmol 2012; 32: 278-287 281 Point Counter-Point Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. TABLE 1. Therapeutic trials of intravenous methylprednisolone for GCA Authors Design N Population Intervention Primary Endpoint Outcome Chevalet et al (31) 3-armed RCT 164 GCA without ocular or cerebrovascular involvement Pulse of 240 mg IV methylprednisolone followed by 0.7 mg/kg oral prednisone Cumulative steroid dose at 1 year No benefit with IV vs oral steroids Pulse of 240 mg IV methylprednisolone followed by 0.5 mg/kg oral prednisone Oral prednisone 0.7 mg/kg Chan et al (33) Retrospective 73 Vision loss from biopsy-proven GCA High-dose IV methylprednisolone (w1,000 mg/d for 3 d), followed by oral prednisolone at 75 mg/d Significant improvement in visual acuity on Snellen chart Benefit for IV vs oral steroids (40% vs 13%; P = 0.01) Oral prednisolone alone at w75 mg/d Hayreh et al Longitudinal observational 145 Biopsy-proven GCA (96 with visual loss; 49 without visual loss) "Megadose" IV dexamethasone (up to 450 mg/d for 1-3 d) followed by oral prednisone at 80-120 mg/d Visual outcome; cumulative steroid dose No benefit with IV vs oral steroids Oral prednisone alone 80-120 mg/d Mazlumzadeh et al (32) 2-armed RCT 27 GCA without ocular or cerebrovascular involvement Oral prednisone 40 mg/d followed by a systematic taper at Week 4, plus an "induction" dose of IV methylprednisolone 15 mg/kg/d for 3 d (about 1,000 mg/d) and placebo Prednisone dose of no more than 5 mg/d at 36 wk Benefit for IV vs oral steroids (71% vs 15%; P = 0.003) GCA, giant cell arteritis; IV, intravenous; RCT, randomized controlled trial. 282 Hayreh and Biousse: J Neuro-Ophthalmol 2012; 32: 278-287 Point Counter-Point Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. TABLE 2. Studies of visual recovery in giant cell arteritis patients treated with corticosteroids Authors Design N (All With Permanent Visual Loss) Steroid Regimen Findings Liu et al (5) Retrospective 41 patients (63 eyes) 25 patients received IV methylprednisolone followed by oral prednisone; 20 patients received 60-100 mg oral prednisone alone 34% of patients with visual loss had visual improvement with IV or oral corticosteroids. More benefit was seen in the patients who received IV treatment. More fellow eye involvement while receiving oral steroids than IV steroids Gonzales-Gay et al (21) Retrospective 34 patients 10 with severe visual loss received 1 g IV methylprednisolone · 3 d, followed by oral prednisone; 24 patients received 45-80 mg oral prednisone alone Early treatment (within 24 hours) was the only predictor of recovery of VA. No significant difference between IV and PO treatment (but all patients treated with IV steroids had severe visual loss) Kupersmith et al (35) Prospective 7 patients (9 eyes) 3 patients received 1g IV methylprednisolone with oral prednisone; 6 patients received 40-200 mg oral prednisone 44% of eyes had improved VA within 1 month of starting treatment with steroids Hayreh et al (18) Retrospective 84 patients (114 eyes) 41 patients received "Megadose" IV dexamethasone (up to 450 mg/d for 1-3 d) followed by oral prednisone at 80-120 mg/d; 43 patients received oral prednisone alone 80-120 mg/d 4% of eyes had improvement of both VA and central VF on treatment. A trend toward improvement was seen with immediate treatment. No difference in outcomes between IV and oral steroids Foroozan et al (36) Retrospective 32 patients (39 eyes) All patients received 1 g IV methylprednisolone for 3 d followed by oral prednisone 1 mg/kg/d 13% of patients had improvement of VA with treatment (time from onset of symptoms not specified), but none showed significant improvement in VF Danesh-Meyer et al (9) Prospective 34 patients All patients received 1 g IV methylprednisolone for 3 d followed by oral prednisone 1-3 mg/kg/d Patients received treatment within 10 d after onset of visual loss (mean 2 d). 15% of patients had improvement of VA of 2 or more lines IV, intravenous; VA, visual acuity; VF, visual field. Hayreh and Biousse: J Neuro-Ophthalmol 2012; 32: 278-287 283 Point Counter-Point Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. GCA patients progressively losing vision while on oral steroids, and then stabilizing with high-dose pulse IV methylprednisolone, Hayreh and Zimmerman (2) reported a higher incidence of visual deterioration in patients receiv-ing high-dose IV methylprednisolone (in 6 of 48 patients) than in those treated with oral steroids (in 3 of 97 patients). However, Hayreh emphasized that high-dose IV steroids are often prescribed to those patients with severe unilateral or bilateral visual loss at the time of diagnosis, hence suggesting a bias toward treating more severe forms of GCA with IV steroids (2,10). I always recommend IV steroids for patients with acute visual loss and presumed GCA for the following reasons: 1. It is essential to administer steroids as soon as possible when GCA is suspected. Usually, I send the patient directly from my office to the Emergency Department (ED) where IV methylprednisolone can be started immediately. This is much more efficient than sending an anxious and sick patient home with a prescription for oral prednisone. It also guaranties immediate patient compliance with treatment. The GCA population is by definition older, often with numerous comorbidities, and have difficulties with transportation. These factors, which may lead to delay in treatment, are mitigated by referral to the ED. When a patient is seen a few days after visual loss and is already on oral prednisone or does not have any visual symptoms, outpatient oral steroids are appropriate. 2. Recommending IV steroids allows me to admit the patient to the hospital for at least 48 hours. Comorbid-ities such as hypertension, heart disease, and diabetes mellitus increase the risk of life-threatening complica-tions of steroids. A short admission to hospital ensures that IV steroids are well tolerated, and any other medical conditions are properly managed. It facilitates obtaining all necessary tests, such as temporal artery biopsy, brain and orbital imaging in some cases, evaluation of vascular risk factors and osteoporosis, and patient education regarding long-term steroid use and prevention of complications. The patient is usually discharged from hospital after 3 days of IV methylprednisone with a pre-scription for oral prednisone and adjunctive treatments to prevent osteoporosis and other complications of long-term steroid treatment, recommendations from a nutri-tionist, and follow-up appointments. 3. Most medications act faster and have a more potent effect when administrated IV rather than taken orally. This is why IV therapy is chosen over oral prednisolone in a variety of clinical settings including organ transplant rejection, severe systemic lupus erythematosus, acute glo-merulonephritis, and other autoimmune and systemic vasculitides (38,39). Corticosteroids mediate their function in part by binding to glucocorticoid receptors present in the cell cytoplasm. After binding, the glucocorticoid receptors are translocated to the nucleus and modulate gene expression, resulting in the up- or downregulation of specific genes affecting the expression of several cytokines and/or adhesion molecules. In addition, glucocorticoid receptors regulate the inflammatory response through interference with numerous transcription factors. These properties of glucocorticoid receptors are known as "genomic effects" and can be seen as early as 30 minutes after drug administration, as opposed to " nongenomic effects," which are detected in seconds to minutes (39). While a dose of 30-100 mg oral prednisolone results in 100% glucocorti-coid receptor saturation, administration of IV pulse methyl-prednisolone at doses greater than 250 mg may enhance clinical effects by additional nongenomic mechanisms. In addition, IV pulse methylprednisolone has a longer duration of action than oral prednisolone and may have greater anti-inflammatory and immunosuppressive effects (39). This is clearly desirable in the initial treatment of ischemic complica-tions of GCA including visual loss. IV pulses of methylpred-nisolone are generally greater than 10 mg/kg (frequently a dose of 1,000 mg is used) and given daily for 3 days (oral prednisone equivalent: 1,250 mg). This dose was adapted TABLE 3. British Society of Ophthalmology guidelines regarding the initial dose and route of steroids to treat GCA (adapted from Dashgupta (27)) Uncomplicated GCA (no jaw claudication or visual disturbance) 40-60 mg oral prednisone daily (not less than 0.75 mg/kg daily) Evolving visual loss (recent onset visual symptoms over 6-12 h) or transient visual loss Intravenous methylprednisolone 500-1,000 mg daily for 3 d before oral steroids Established visual loss At least 60 mg prednisone daily, to protect the contralateral eye Patients should also receive bone protection with weekly biphosphonate and calcium/vitamin D supplementation. Proton pump inhibitors for gastrointestinal protection should be considered, especially if low-dose aspirin is also prescribed. The symptoms of GCA should respond rapidly to high-dose glucocorticosteroid treatment, followed by resolution of the inflammatory response. Failure to do so should raise the question of an alternative diagnosis. The initial dose of steroids should be continued for 3-4 weeks and reduced in the absence of any clinical symptoms or any laboratory abnormalities suggestive of ongoing active disease. The steroid tapering should be gradual, provided there is no relapse. GCA, giant cell arteritis. 284 Hayreh and Biousse: J Neuro-Ophthalmol 2012; 32: 278-287 Point Counter-Point Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. from treating graft rejection in renal transplant recipients with supporting evidence from animal experiments (38,39). It has been suggested that 500 mg per day may be as effective as 1 g per day for severe systemic lupus erythematosus (40) and such a dose also might be considered for GCA, particularly in patients with hypertension, heart disease, or diabetes mellitus. 4. IV high-dose pulse methylprednisolone seems to be as well tolerated as oral prednisone. It does increase the risk of osteoporotic fractures and avascular necrosis, but its use may lead to a reduction of total steroid dose, expos-ing the patient to fewer long-term side-effects of steroid therapy (32). In conclusion, symptoms of GCA are exquisitely sensitive to corticosteroid therapy. Administering high-dose steroids as quickly as possible after the onset of visual loss is essential to suppress inflammation, prevent further visual loss, prevent visual loss in the fellow eye, and possibly restore vision. IV pulse methylprednisolone at a dose of 500-1,000 mg per day is a relatively easy and safe way to treat GCA patients and should be recommen-ded in patients with acute visual loss. This statement is in accordance with the guidelines from the British Society of Ophthalmology and the British Society of Rheumatology (Table 3) (26,27). Rebuttal: Sohan Singh Hayreh, MD, MS, PhD, DSc, FRCS, FRCOphth (Hon) I conducted studies on various aspects of GCA for approximately 40 years as a part of the prospective studies on ocular vascular occlusive disorders funded by the National Institutes of Health. Thus, the comment by Dr Biousse that my studies were retrospective is not correct. One has to be extremely careful in accepting claims of visual improvement with IV corticosteroid therapy vs oral therapy based simply on visual acuity improvement. My various studies on visual outcome (14,15,18-20) consis-tently have shown that unless there is a corresponding improvement in central visual field, better visual acuity alone simply represents a patient learning to see better by eccentric fixation. In light of this important fact, I find the information in Dr Biousse's table 2 misleading. Gonzales-Gay et al (21) in their retrospective chart review were able to obtain detailed data on both therapy and visual acuity outcome in only 29 patients with visual loss-10 patients treated with IV pulse methylprednisolone and 19 with oral prednisone. There was no difference in the visual acuity outcome between the 2 groups (P = 0.26). They found that those who were treated within 24 hours had better chance of visual improvement but the therapeutic regimen did not influence the visual outcome (odds ratio, 0.6; 95% confi-dence interval, 0.1-40.8). In the studies by Kupersmith et al (35) and Foroozan et al (36), there was no visual field improvement corresponding to improved visual acuity improvement. The study by Kupersmith et al (35) had multiple other problems as discussed elsewhere (41). In the prospective study by Danesh-Meyer et al (9), only 5% of GCA patients had improvement in both visual acuity and visual field when treated with IV corticosteroid therapy. Similarly, in our prospective (not retrospective) study (18), only 4% showed improvement in both visual acuity and visual field. Dr Biousse commented that our study (18) did not show any obvious benefit of high-dose IV steroids because the group of patients treated with IV steroids tended to have worse visual loss at presentation. This is contradicted by the fact that visual improvement in our study (84 patients, 114 eyes) (18) and in that of Danesh-Meyer et al. (34 patients, 40 eyes) (9) was similar, that is, 4% and 5%, respectively. The report of visual improvement in 34% of GCA patients by Liu et al (5) was based only on visual acuity. Cornblath and Eggenberger (6) found that results of high-dose IV methylprednisolone treatment of patients with visual loss from GCA were similar to the results of treatment with oral corticosteroid therapy. Salvarani et al (42) found no evidence that IV methylprednisolone was better than oral therapy. As regards Table 1, Chan et al (33) conducted a retro-spective study and noted visual improvement based only on visual acuity and the authors stated: "intravenous steroids may offer a greater prospect of improvement compared with oral steroids." Yet, they concluded: "A prospective trial comparing intravenous with oral steroid is needed to vali-date these finding." The study by Mazlumzadeh et al (32) (rheumatologists) needs to be put in perspective in relation to visual outcome and relapses of GCA. In that study, 14 patients received a 3-day course of IV methylpredniso-lone plus oral prednisone and 13 received only oral predni-sone. The oral prednisone dose was 40 mg daily initially. Then the dose was reduced successively every 2 weeks to daily 30, 25, 20, then by 2.5 to 10 mg, and thereafter by 1 mg every 2 weeks. No information regarding visual acuity was included. My studies show that this treatment regimen was totally inadequate to prevent visual loss in GCA. It is not surprising that in the oral group there were 37 relapses, which also can put a GCA patient at risk for visual loss. There were no relapses at all in my studies. There is not a single large comprehensive study that has shown signifi-cantly better visual improvement with IV corticosteroid therapy compared with adequate oral corticosteroid therapy. Dr Biousse has cited much rheumatologic literature about the management of GCA. As I have stressed previously (10), rheumatologists and ophthalmologists have different perspectives on GCA (22,42). Rheumatologists Hayreh and Biousse: J Neuro-Ophthalmol 2012; 32: 278-287 285 Point Counter-Point Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. deal essentially with patients with rheumatologic manifes-tations, while ophthalmologists see GCA patients with visual loss or patients with occult GCA (43) who may lose vision without any rheumatologic or systemic symptoms. For the ophthalmologist, GCA is a blinding disease with tragic consequences; for the rheumatologist it is a disease with mainly systemic complaints, with less severe medical consequences. Salvarani et al (rheumatologists) (22,42) have given a "cookbook" regimen of corticosteroid therapy in GCA, which may be adequate to manage rheumatologic symptoms but is inadequate to prevent visual loss. Similarly, Mazlumzadeh et al (32) (rheumatologists), as discussed above, recommended a course of corticosteroid therapy that is inadequate to prevent visual loss, as is evident from mul-tiple relapses in their patients. My studies have shown that a "one-size-fits all" regimen is totally inadequate to prevent visual loss. There is marked interindividual variation in the dose and duration of corticosteroid therapy required to con-trol GCA and prevent visual loss. Rheumatologists advocate corticosteroid therapy to be guided by systemic symptoms, which is not effective to prevent visual loss (41). Levels of ESR and CRP are the only reliable methods to regulate treatment in GCA. Rheumatologists believe that GCA burns itself out in approximately 2 years and there is no need to continue corticosteroid therapy. I have seen patients whose rheumatologists stopped corticosteroid therapy, who then lost vision. Finally, Dr Biousse proposes admitting a patient to hospital for "a 3-day course of induction intravenous meth-ylprednisolone," as also was done by Mazlumzadeh et al (32), Danesh-Meyer et al (9), and advocated by the British Society of Ophthalmology (26). But there is no scientific study showing that such an inpatient "3-day course" is superior to outpatient management; therefore, to hospitalize patients for 3 days is not justified in my experience. Dr Biousse also stated that that hospitalization enabled brain and orbital imaging in some cases and the evaluation of vascular risk factors and osteoporosis. In my experience, neurological and orbital findings are extremely rare in GCA and I see no justification for admitting a patient for evalu-ation of vascular risk factors and osteoporosis. I have not admitted a GCA patient to the hospital in approximately 30 years. In the University of Iowa Hospitals and Clinics, the cost of 3-day hospitalization and IV medication is approximately $15,000. As I have discussed, when IV corticosteroid therapy is indicated, giving one IV dose as an outpatient costs approximately $500. In my opinion, not only is hospitalization an unnecessary inconvenience and possibly traumatic to the patient; it is a totally unnecessary medical expense. Rebuttal: Valérie Biousse, MD I completely agree with Dr Hayreh regarding the unaccept-able delay in treating the patient under discussion. Most troubling is that the ophthalmologist waited until the next day to check the results of the ESR and CRP and not initiate steroid therapy immediately. A 24-hour delay in treatment is still within the window of time for "acute visual loss," and the patient is at very high risk for worsening vision in the involved eye and for loss of vision in the fellow eye. This is why, despite Dr Hayreh's statement, I still would not hesitate to recommend immediate administra-tion of pulse IV methylprednisolone (500 or 1,000 mg) and admission to hospital for close observation and further testing as detailed above. I am pleasantly surprised to see that Dr Hayreh recommends giving one initial bolus of IV methylprednisolone in this setting to acutely achieve higher levels of corticosteroids. However, unlike Dr Hayreh, I would then keep the patient in the hospital for 2 more days and repeat the bolus of IV methylprednisolone so that the patient receives 1,000 mg of methylprednisolone per day for 3 days before being discharged on 1 mg/kg per day of oral prednisone. 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