Literature Commentary

Literature Commentary Section Editors: Mark L. Moster, MD M. Tariq Bhatti, MD Literature Commentary Le Page E, Veillard D, Laplaud DA, Hamonic S, Wardi R, Lebrun C, Zagnoli F, Wiertlewski S, Deburghgraeve V, Coustans M, Edan G; COPOUSEP investigators; West Network for Excellence in Neuroscience. Oral versus intravenous high-dose methylprednisolone for treatment of relapses in patients with multiple sclerosis (COPOUSEP): a randomised, controlled, double-blind, non-inferiority trial. Lancet. 2015;386:974-981. Background: High doses of intravenous methylprednisolone are recommended to treat relapses in patients with multiple sclerosis, but can be inconvenient and expensive. We aimed to assess whether oral administration of high-dose methylprednisolone was non-inferior to intravenous administration. Methods: We did this multicentre, double-blind, randomised, controlled, non-inferiority trial at 13 centres for multiple sclerosis in France. We enrolled patients aged 18- 55 years with relapsing-remitting multiple sclerosis who reported a relapse within the previous 15 days that caused an increase of at least one point in one or more scores on the Kurtzke Functional System Scale. With use of a computer-generated randomisation list and in blocks of 4, we randomly assigned (1:1) patients to either oral or intravenous methylprednisolone, 1,000 mg, once a day for 3 days. Patients, treating physicians and nurses, and data and outcome assessors were all masked to treatment allocation, which was achieved with the use of saline solution and placebo capsules. The primary endpoint was the proportion of patients who had improved by Day 28 (decrease of at least one point in most affected score on Kurtzke Functional System Scale), without need for retreatment with corticosteroids, in the per-protocol population. The trial was powered to assess non-inferiority of oral compared with intravenous methylprednisolone with a predetermined noninferiority margin of 15%. This trial is registered with ClinicalTrials.gov, number NCT00984984. Findings: Between January 29, 2008, and June 14, 2013, we screened 200 patients and enrolled 199. We randomly assigned 100 patients to oral methylprednisolone and 99 patients to intravenous methylprednisolone with a mean time from relapse onset to treatment of 7.0 days (SD 3.6) and 7.4 days (3.9), respectively. In the per-protocol population, 66 (81%) of 82 patients in the oral group and 72 (80%) of 90 patients in the intravenous group achieved the primary endpoint (absolute treatment difference 0.5%, 90% CI, 29.5 to 10.4). Rates of adverse events were similar, but insomnia was more frequently reported in the oral group (77 [77%]) than in the intravenous group (63 [64%]). Interpretation: Oral administration of high-dose methylprednisolone for 3 days was not inferior to intravenous administration for improvement of disability scores 1 month Moster and Bhatti: J Neuro-Ophthalmol 2016; 36: 103-109 after treatment and had a similar safety profile. This finding could have implications for access to treatment, patient comfort, and cost, but indication should always be properly considered by clinicians. The optic neuritis treatment trial (ONTT) found that oral (po) prednisone at a dose of 1 mg/kg per day was associated with a 2-fold higher incidence of another attack of optic neuritis compared with po placebo and intravenous (iv) methylprednisolone. As a result of this finding, po prednisone has not only been avoided in treating patients with optic neuritis but also in treating patients with multiple sclerosis (MS) in the midst of an exacerbation. The exact reason for the increased risk of recurrent optic neuritis associated with po prednisone is not known; but based on several smaller studies performed after the ONTT (1), it seems that it was not the route of administration (po or iv) that was the reason for the increased risk of optic neuritis but rather the low dose of po prednisone used (oral bioavailable equivalent of 1,000 mg iv methylprednisolone is 1,250 mg po prednisone). This double-blinded, randomized controlled trial was performed with the research hypothesis being that 1,000 mg/day of po methylprednisolone is not inferior to 1,000 mg/day of iv methylprednisolone (i.e., noninferiority study) in patients being treated for an MS relapse. All patients received 3 days of an iv infusion and 3 days of pills. Half of the patients were given 1,000 mg/day of iv methylprednisolone for 3 days and the other half were given 1,000 mg/day of po methylprednisolone for 3 days. The purpose of the study was very well described and based on a critical appraisal of the literature in a Cochrane review by Burton et al (2). The bottom line of the study was that in terms of primary end point (proportion of patients who improved by day 28 as defined by at least 1 point decrease in the most affected score on the Kurtzke Functional System Scale), po methylprednisolone was not inferior to iv methylprednisolone (81% vs 80%, respectively). In addition, the adverse events were no different between the 2 groups, except that insomnia was more often seen in the po group. Interestingly, epigastric pain and other gastrointestinal problems were not seen more often in the po group. However, a "purist" would argue that based on the ONTT if a patient with optic neuritis is going to be treated, 103 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Literature Commentary the clinical trial regiment must be followed: 250 mg of iv methylprednisolone every 6 hours for 3 days followed by 11 days of po prednisone at a dose of 1 mg/kg per day and then a rapid taper over the next 4 days (20 mg on day 12, 10 mg on day 13, 0 mg day 14 and 10 mg day 15). However, I will admit that I have taken liberties with the ONTT protocol and often treated patients with once-a-day infusion of iv methylprednisolone (1,000 mg/d for 3 days with or without a po prednisone taper) and high-dose oral methylprednisolone (1,000 mg/d) for 3 days. I feel better now having taken those liberties because this study provides Class 1 evidence that 1,000 mg/day of oral methylprednisolone is as effective and safe as 1,000 mg/day of iv methylprednisolone. I asked the Duke Eye Center financial department to provide me with the cost difference between po methylprednisolone vs iv methylprednisolone (including cost of equipment and infusion center facility fees). Taking into consideration regional and insurance rate differences, the cost of po methylprednisolone is approximately $90/day vs $1,200/day for iv methylprednisolone. Finally, from a logistical point of view, in the United States, the highest pill dosage of methylprednisolone is 32 mg, which means that patients would need to take approximately 31.25 pills every day for 3 days. Alternatively, Dr Michael Vaphiades (University of Alabama, Birmingham, AL) suggests 1,000 mg po methylprednisolone powder (before reconstitution), dissolved in a smoothie drink. -M. Tariq Bhatti, MD I agree it is reassuring that high dose po methylprednisolone is not inferior to iv methylprednisolone in improving relapses. However, 2 important ONTT issues that are not addressed by this study are whether the oral treatment postpones further demyelinating events or whether it is associated with more frequent episodes of optic neuritis. -Mark L. Moster, MD REFERENCES 1. Sellebjerg F, Nielsen HS, Frederiksen JL, Olesen J. A randomized, controlled trial of oral high-dose methylprednisolone in acute optic neuritis. Neurology. 1999;52:1479-1484. 2. Burton JM, O'Connor PW, Hohol M, Beyene J. Oral versus intravenous steroids for treatment of relapses in multiple sclerosis. Cochrane Database Syst Rev. 2012;12: CD006921. Lochhead J. SSRI-associated optic neuropathy. Eye (Lond). 29:1233-1235. Epub 2015 July 3. Purpose: We report 5 cases of optic neuropathy (ON) identified over a 2-year period within an island population of 140,000. These cases display characteristics possibly related to long-term treatment with selective serotonin reuptake inhibitors (SSRIs). 104 Methods: Retrospective analysis of casenotes. Each case has been assessed using the Naranjo algorithm to indicate likelihood of adverse drug reaction (ADR). Results: Clinical assessment and investigation confirmed ON in all cases with a vascular origin suspected. SSRI cessation may help protect the unaffected eye and in some cases recovery of vision seems possible. The Naranjo scores indicated possible ADR in 4 cases and probable ADR in 1 case. Conclusions: In 2004, w7% of the UK adult population was receiving SSRI treatment for a range of 4.8-7.7 years. The most common ophthalmic side effect is acute glaucoma. Currently, there remain no reports of SSRI associated ON, although papilloedema has been reported. A potential mechanism for ischaemic optic neuropathy (ION) has been described in relation to raised serotonin levels. A single case of central retinal vein occlusion exists along with reports of deep vein thrombosis (DVT) and ischaemic stroke. We recommend a review of SSRI treatment in cases of acute ON. This article reports 5 cases of optic neuropathy occurring in patients taking serotonin reuptake inhibitors (SSRIs). The authors suggest that in 4 cases there is a possible adverse drug reaction (ADR) and in 1 case a probable ADR based on the Naranjo algorithm (1). They propose a possible contribution of SSRI to ischemia and decreased perfusion and quote previous reports of increased serotonin being associated with decreasing optic nerve perfusion. I have a few problems with this article. First, the clinical presentations were quite varied including 1 with a simultaneous bilateral anterior ischemic optic neuropathy, 2 with gradually progressive bilateral visual loss without optic disc edema, and 2 with a sudden unilateral visual loss with normal disc appearance. Three different presentations of optic neuropathy would be unusual as an ADR. Secondly, when I perform an independent calculation of the Naranjo score, in most of the cases, I got a score lower than reported. For me, all of the cases fall into the "possible" ADR rather than the "probable" ADR range. Despite these criticisms, it seems that an extensive workup for other etiologies was performed as described: "MRI scan, CXR, FBC (full blood count), U (urea) and E (electrolytes), serum B12, coagulopathies, autoimmune serology, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), serum angiotension converting enzyme, fundus fluorescein angiography (FFA), optical coherence tomography, visual fields (VF), electroretinogram (ERG), and visual evoked potentials (VEPs). Leber's mutation and serology for lyme, syphilis and bartonella were also performed where appropriate." However, 4 of the 5 cases had either diabetes, a smoking history, or both. The bottom line for me is that in a patient with an optic neuropathy with no clear diagnosis after evaluation, who is on an SSRI, we should consider whether the SSRI might be playing a role. -Mark L. Moster, MD Moster and Bhatti: J Neuro-Ophthalmol 2016; 36: 103-109 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Literature Commentary I must tell you, Mark, I am not sure what to make of this case series and am very skeptical. I did a bit of research on SSRIs to familiarize myself with their history and side effect profile. The first SSRI to be approved by the US Food and Drug Administration (FDA) was in 1988 (fluxoteine, Prozac; Eli Lilly, Indianapolis, IN). Currently, there about a half a dozen SSRIs on the market in the United States. I looked on the FDA Web site to see whether I could find any information on SSRI and visual loss and found nothing (http://www.fda. gov/Drugs/DrugSafety/InformationbyDrugClass/ucm283587. htm, accessed on November 27, 2015). I find it a bit curious that nearly 3 decades after being introduced on the market and with millions of people prescribed SSRIs, we have our first published case series of possible SSRI-associated optic neuropathy. I think a database registry needs to be created and more information be collected before I am convinced that there is at best an association, let alone a cause and effect. -M. Tariq Bhatti, MD REFERENCE 1. Naranjo CA, Busto U, Sellers EM, Sandor P, Ruiz I, Roberts EA, Janecek E, Domecq G, Greenblatt DJ. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther. 1981;30:239-245. Labarca C, Koster MJ, Crowson CS, Makol A, Ytterberg SR, Matteson EL, Warrington KJ. Predictors of relapse and treatment outcomes in biopsy-proven giant cell arteritis: a retrospective cohort study. Rheumatology (Oxford). 2015. Epub ahead of print. Objective: To evaluate characteristics of relapse, relapse rates, treatment and outcomes among patients with biopsyproven GCA in a large, single-institution cohort. Methods: We conducted a retrospective review of all patients with biopsy-proven GCA from 1998 to 2013. Demographic, clinical, laboratory and treatment data at presentation and during follow-up were collected. Comparisons by relapse rate were performed using x2 tests. Prednisone discontinuation by initial oral dose #40 and .40 mg/d was compared using Cox models. Results: The cohort included 286 patients (74% female, mean age at diagnosis 75.0 years [SD 7.6], median followup 5.1 years). During follow-up, 73 patients did not relapse, 80 patients had 1 relapse and 133 had 2 or more relapses. The first relapse occurred during the first year in 50% of patients, by 2 years in 68% and by 5 years in 79%. More patients with established hypertension (P = 0.007) and diabetes (P = 0.039) at GCA diagnosis were in the high relapse rate group ($0.5 relapses/y) and more females were in the low or high relapse groups than in the no relapse group (P = 0.034). Patients receiving an initial oral prednisone dose .40 mg/day were able to reach a dose of ,5 mg/day (hazard ratio [HR] 1.46 [95% CI, 1.09-1.96]) and discontinue prednisone (HR 1.56 [95% CI, 1.09-2.23]) sooner than patients receiving #40 mg/day without an Moster and Bhatti: J Neuro-Ophthalmol 2016; 36: 103-109 increase in observed glucocorticoid-associated adverse events. Conclusions: Females and patients with hypertension or diabetes at GCA diagnosis have more relapses during followup. Patients treated with an initial oral prednisone dose .40 mg/day achieved earlier prednisone discontinuation. I think it is safe to say that many of us, after having taken care of the acute visual loss or secured the diagnosis of giant cell arteritis (GCA) in a patient without visual loss, are not intimately involved in the long term steroid management and do not follow the specifics regarding the chronic course of the patient's disease. This article provides insight into the challenges of long-term treatment and risk of relapses that may affect how we manage patients with GCA acutely. The authors defined a relapse as any of the following 3 criteria if corticosteroid therapy was increased with subsequent improvement: 1. New onset or reappearance of signs/symptoms compatible with GCA with an associated increase in inflammatory markers 2. New onset or reappearance of signs/symptoms compatible with GCA without an associated increase in inflammatory markers 3. Isolated increase in inflammatory markers without GCA signs/symptoms or other explainable etiology present (particularly infection). Inflammatory marker elevation was defined as a CRP level .8 mg/L and/or ESR by the Westergren method .22 mm/hour for men and .29 mm/hour for women. I realize that in this study there was a relatively small percentage of patients who had visual symptoms (7% with transient visual loss and 5.7% with permanent visual loss), therefore extrapolating these data may not be relevant to the type of patients with GCA we see as neuro-ophthalmologists, but I was struck by several findings that I think are helpful to think about: 1. 213 patients (74%) had a relapse 2. 50% of patients had their first relapse in the first year of treatment 3. 28.6% had laboratory abnormalities as a relapse and 24.2% had positive symptoms indicative of a relapse 4. Cumulative mean dose of glucocorticosteroids was greater in patients who were administered oral prednisone .40 mg/day (10 g) compared with #40 mg/day (8.2 g). However, patients administered . 40 mg/day discontinued steroids sooner than patients administered # 40 mg/day 5. 56% of patients remained on glucocorticosteroids by 5 years 6. 73% of patients experienced adverse events due to glucocorticosteroid by 10 years. 7. 25% of patients had glucocorticosteroid-induced osteoporosis. 105 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Literature Commentary As with any retrospective study, there several inherent biases and limitations that need to be framed within the context of the results. One aspect of this study that I wish the authors had delved into was trying to understand why did so many of the patients have relapses? In addition, it would have been very helpful if the authors would have provided more specific recommendations on how to manage tapering the steroids and guidelines on what not to do! -M. Tariq Bhatti, MD Tariq, in our practice, we do take care of the tapering of steroids for years in those who present with visual loss, so frequently we do deal with the issue of relapses. Because most of our patients with GCA have had significant visual loss by the time we meet them, we do not feel comfortable in having the other specialists taper since they tend to taper more rapidly than we do. In our patients without visual loss, we have the rheumatologists guide the taper. If it is with visual loss, we control the taper, along with rheumatology or the primary care physician. This study is helpful in teaching us that we have to be more aware of the potential for relapses in women and patients with baseline diabetes or hypertension. I think one of the reasons for the high relapse rate is the loose definition of relapse. The authors included patients whose CRP or ESR rose but do not stipulate whether they repeated the testing to verify the rise in the value. To me, that would include many patients who are tapering steroid but have tapered a bit too rapidly and have to raise the steroid dose for a short period. I would not consider that a true relapse. -Mark L. Moster, MD I must commend you, Mark, on your commitment to the long-term treatment of patients with GCA. Given the elderly age of the patients and often comorbid medical conditions, I am not bashful to say that, I do not feel completely equipped to take care of such patients and often hand off the care to the internist or rheumatologist as I continue to follow the patient from an ophthalmic perspective. -M. Tariq Bhatti, MD Callizo J, Feltgen N, Pantenburg S, Wolf A, Neubauer AS, Jurklies B, Wachter R, Schmoor C, Schumacher M, Junker B, Pielen A; European Assessment Group for Lysis in the Eye. Cardiovascular risk factors in central retinal artery occlusion: results of a prospective and standardized medical examination. Ophthalmology. 2015;122:1881- 1888. Purpose: To analyze the underlying risk factors in patients with nonarteritic central retinal artery occlusion (CRAO) in a well-defined and homogenous group of patients enrolled in 106 the European Assessment Group for Lysis in the Eye (EAGLE) study. Design: Analysis of the cardiovascular risk factors in a prospective, randomized clinical trial. Participants: Seventy-seven EAGLE patients with nonarteritic CRAO. Methods: Analysis of vascular risk factors and underlying diseases detected by questionnaire and standardized physical examination within 1 month after occlusion. Main Outcome Measures: The standardized physical examination included carotid Doppler ultrasonography, echocardiography, electrocardiography, blood pressure monitoring, pulse rate, urine analysis, body mass index analysis, and laboratory tests. Results: Seventy-seven of 84 patients had complete datasets for analysis. Fifty-two (67%) patients had cardiovascular risk factors in their medical history, and comprehensive phenotyping identified at least 1 new risk factor in 60 patients (78%; 95% confidence interval, 67%-87%). Thirty-one (40%) had carotid artery stenosis of at least 70%. Eleven patients experienced a stroke, 5 of those within 4 weeks after the CRAO occurred. Arterial hypertension was found in 56 (73%) patients and was newly diagnosed in 12 (16%) study participants. Cardiac diseases were also highly prevalent (22% coronary artery disease, 20% atrial fibrillation, and 17% valvular heart disease). Conclusions: Previously undiagnosed vascular risk factors were found in 78% of all CRAO patients. The most meaningful risk factor was ipsilateral carotid artery stenosis. A comprehensive and prompt diagnostic workup is mandatory for all CRAO patients. Although many articles have reviewed risk factors for central retinal artery occlusion (CRAO), this study benefits from having a standardized evaluation process for a homogeneous study population of patients with acute, angiographically proven CRAO. They had carotid Doppler ultrasonography (more than 70% stenosis was deemed to be clinically significant), echocardiography (transthoracic or transesophageal, depending on the cardiologist's decision), electrocardiography, blood pressure monitoring, pulse rate, urinalysis, body mass index, and laboratory tests for hyperlipidemia and diabetes, and excluded people with elevated ESR and CRP. The evaluations were completed for 77 of the 84 patients in the EAGLE study. Fifty-four patients were men and 23 were women; the mean age was 62.2 years. In 25% with no known risk factors at baseline, a newly diagnosed risk factor was found. In 53% with known risk factors, at least 1 new risk factor was found. In 14% with known risk factors, no new risk factors were found. In total, 71 (92%) patients had cardiovascular risk factors or events, and 60 (78%) patients had more than 1 risk factor or event. The most common new diagnoses were hypercholesterolemia and carotid artery stenosis. In only 1 patient was carotid artery stenosis known, whereas in 29 patients, it was newly diagnosed. Six patients (8%) reported a previous stroke, and 5 patients (6%) had a stroke newly diagnosed in MRI imaging during follow-up. One of those had experienced a silent Moster and Bhatti: J Neuro-Ophthalmol 2016; 36: 103-109 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Literature Commentary stroke, 2 patients experienced a stroke immediately after local intra-arterial fibrinolysis, and 2 others experienced a stroke a few days after conservative treatment. Of those 5 patients, 4 had an ipsilateral carotid artery stenosis. Three patients (4%) had a history of transient ischemic attack (TIA), and a TIA was newly diagnosed in 1 patient. Taken together, 9 patients had a history of stroke or TIA, and 15 patients had a stroke or TIA diagnosis before or after the CRAO event. Although not a surprise, the findings verify frequent cardiovascular risk factors and stroke in patients with CRAO, often not known until after the presentation of CRAO. -Mark L. Moster, MD I appreciate the findings of this report, but as you said, Mark, there is nothing surprising or new about the results, conclusions, or recommendations. In fact, there was an article from the Republic of Korea published in Ophthalmology a few months later that reported similar findings (1). I was taught very early on in my training that patients with a CRAO are at a higher risk of morbidity and mortality from cardiovascular events and that they all require a complete medical evaluation for underlying atherosclerotic disease, risk modification, and stroke/myocardial infarction prevention. The bottom line is that a patient with a CRAO may require treatment for the visual loss, but more importantly needs to counseled on the importance of seeking medical attention for the potential of cerebrovascular and cardiovascular disease. -M. Tariq Bhatti, MD REFERENCE 1. Park SJ, Choi NK, Yang BR, Park KH, Lee J, Jung SY, Woo SJ. Risk and risk periods for stroke and acute myocardial infarction in patients with central retinal artery occlusion. Ophthalmology. 2015;122:2336-2343.e2. Wingerchuk DM, Banwell B, Bennett JL, Cabre P, Carroll W, Chitnis T, de Seze J, Fujihara K, Greenberg B, Jacob A, Jarius S, Lana-Peixoto M, Levy M, Simon JH, Tenembaum S, Traboulsee AL, Waters P, Wellik KE, Weinshenker BG; International Panel for NMO Diagnosis. International consensus diagnostic criteria for neuromyelitis optica spectrum disorders. Neurology. 2015;85:177-189. Abstract: Neuromyelitis optica (NMO) is an inflammatory CNS syndrome distinct from multiple sclerosis (MS) that is associated with serum aquaporin-4 immunoglobulin G antibodies (AQP4-IgG). Prior NMO diagnostic criteria required optic nerve and spinal cord involvement but more restricted or more extensive CNS involvement may occur. The International Panel for NMO Diagnosis (IPND) was convened to develop revised diagnostic criteria using systematic literature reviews and electronic surveys to facilitate consensus. The new nomenclature defines the unifying term NMO spectrum disorders (NMOSD), which is stratified further by Moster and Bhatti: J Neuro-Ophthalmol 2016; 36: 103-109 serologic testing (NMOSD with or without AQP4-IgG). The core clinical characteristics required for patients with NMOSD with AQP4-IgG include clinical syndromes or MRI findings related to optic nerve, spinal cord, area postrema, other brainstem, diencephalic, or cerebral presentations. More stringent clinical criteria, with additional neuroimaging findings, are required for diagnosis of NMOSD without AQP4-IgG or when serologic testing is unavailable. The IPND also proposed validation strategies and achieved consensus on pediatric NMOSD diagnosis and the concepts of monophasic NMOSD and opticospinal MS. I have to give kudos to this international panel of neuromyelitis optica (NMO) experts, in particular to our own Jeff Bennett (University of Colorado Denver, Aurora) and Marco Lana-Peixoto (Federal University of Minas Gerais Medical School, Belo Horizonte, Brazil), for continuing the advancement in our understanding and classification of NMO. I think this article should be on every neuroophthalmologist's "need to read list." I want to highlight a number of key points: 1. Neuromyelitis optica spectrum disorders (NMOSD) is a unifying term that encompasses the classic NMO (bilateral optic neuritis and transverse myelitis) 2. NMOSD can be divided into a. NMOSD aquaporin-4 immunoglobulin antibodies (AQP4-IgG) positive b. NMOSD AQP4-IgG negative 3. The diagnosis of NMOSD can be made in the absence of either optic nerve or spinal cord involvement 4. NMOSD is highly suggestive in patients with the following visual manifestations a. Simultaneous bilateral optic neuritis b. Chiasmal involvement c. Altitudinal visual defect d. Severe (,20/200) visual loss e. Posterior optic nerve or chiasmal enhancement on MRI f. Extensive (.50%) optic nerve enhancement on MRI 5. Alternative diagnosis ("red flags") should be considered for the following findings a. Gradual progressive clinical course b. Time to attack nadir less than 4 hours or continual worsening from onset of attack for more than 4 weeks c. Partial transverse myelitis d. Positive cerebrospinal fluid oligoclonal bands (occur in ,20% with NMOSD) e. Comorbidities such as sarcoidosis, cancer or chronic infection f. MRI features of the brain suggestive of multiple sclerosis (MS) g. Persistent (.3 months) gadolinium enhancement h. ,3 complete vertebral segment lesion i. 70% of spinal cord lesion located in the periphery of the cord 107 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Literature Commentary 6. 60% of NMOSD patients have asymptomatic cerebral white matter lesions and 16% fulfill Barkhof MS MRI criteria 7. Recommend cell-based assay to detect AQP4-IgG 8. Occasionally, some patients with NMOSD will be AQP4-IgG negative and then later become seropositive. -M. Tariq Bhatti, MD As we understand more about NMOSD and the accuracy of that diagnosis, more of our patients will get optimal treatment for their disorder. I agree with kudos to the group and neuro-ophthalmologists in the group, Jeff Bennett and Marco Lana-Peixoto. -Mark L. Moster, MD Schrag M, Youn T, Schindler J, Kirshner H, Greer D. Intravenous fibrinolytic therapy in central retinal artery occlusion: a patient-level meta-analysis. JAMA Neurol. 2015;72:1148-1154. Importance: Central retinal artery occlusion (CRAO) is an ophthalmologic emergency that can result in blindness. At present, no proven therapy for CRAO exists. Treatment with fibrinolytic agents has shown promise but remains of unproven benefit. Objectives: To assess the efficacy of systemic fibrinolytic therapy for patients with CRAO and to define a time window of efficacy. Data Sources: We systematically queried PubMed, Web of Science, and Scopus using the following index terms: "retinal artery occlusion" OR "retinal ischemia" AND "thrombolysis" OR "fibrinolysis" OR "tissue plasminogen activator" OR "streptokinase" OR "urokinase." Search was not limited by year of publication or language and was conducted in August 2014. In addition, we evaluated the references from relevant review articles. Study Selection: We assembled observational studies reporting on visual acuity outcomes after CRAO. Inclusion criteria were complete reporting of visual outcomes after CRAO (with or without fibrinolytic therapy) and a series of more than 5 patients for fibrinolysis treatment or more than 20 cases when untreated or treated with conservative modalities. Data Extraction and Synthesis: Patient-level data were sought for studies reporting outcomes of treatment with fibrinolysis. Summary statistics were obtained for conservative treatment and natural history studies. The studies were weighted by the inverse of variance and merged in a random-effects model. Main Outcomes and Measures: Rate of visual recovery (defined as improvement of visual acuity from 20/200 or worse at presentation to 20/100 or better) was calculated for patients treated with fibrinolytic and conservative therapies and those who received no treatment. Results: We obtained summary statistics from 7 studies that included 396 patients who received no treatment after CRAO and from 8 studies that included 419 patients treated with ocular massage, anterior chamber paracentesis, and/ or hemodilution (conservative treatment). Patient-level data 108 were obtained for 147 patients treated with systemic fibrinolysis. We found that fibrinolysis was beneficial at 4.5 hours or earlier after symptom onset compared with the natural history group (17 of 34 [50.0%] vs 70 of 396 [17.7%]; odds ratio, 4.7 [95% CI, 2.3-9.6]; P , 0.001). Absolute risk reduction was 32.3%, with a number needed to treat of 4.0 (95% CI, 2.6-6.6). We also found that conservative treatment significantly worsened visual acuity outcomes and recovery rates after CRAO compared with the natural history group (31 of 419 [7.4%; 95% CI, 3.7%- 11.1%] vs 70 of 396 [17.7%; 95% CI, 13.9%-21.4%]; P , 0.001; number needed to harm, 10.0 [95% CI, 6.8-17.4]). Conclusions and Relevance: Our analysis suggests that a clinical trial of early systemic fibrinolytic therapy for CRAO is warranted and that conservative treatments are futile and may be harmful. This meta-analysis of available studies for 3 different approaches to treat central retinal artery occlusion (CRAO) compared the rate of visual recovery for no treatment, conservative therapy, and with intravenous (iv) fibrinolytic treatment (t-PA, streptokinase, or urokinase). Conservative therapies included any combination of sublingual isosorbide dinitrate, topical timolol maleate, systemic inhalation of 10% carbon dioxide, hyperbaric oxygen, ocular massage, iv acetazolamide, mannitol, anterior chamber paracentesis, hemodilution, and corticosteroids. The rate of recovery was defined as the % of patients who presented with 20/200 or worse visual acuity who improved to 20/100 or better. The first surprise was that patients with conservative therapies had a decreased rate of recovery compared with those who received no treatment (7.4% vs 17.7%). The most important finding was a higher rate of recovery with iv fibrinolysis within 4.5 hours of symptom onset than no treatment (50% vs 17.7%). Subgroup analysis of the tPA group showed similar findings. Fibrinolysis at later time points was not associated with improvement. Hemorrhagic complications occurred, but only in the streptokinase group, not in the more commonly used tPA. As a meta-analysis, there are the usual methodologic concerns. Studies were all performed differently and analyzed differently. Visual recovery was assessed at the end of an acute hospitalization or "shortly thereafter" without longer term follow up. Time of entry is likely delayed for the some of the "no treatment" groups, since there was no time pressure to enter early for treatment. Despite these limitations, it appears that iv fibrinolysis within 4.5 hours is likely beneficial, and a prospective study assessing this is warranted. This is the same time frame for benefit in most stroke studies and easier to achieve than intra-arterial therapy because there is no need to mobilize an interventional team. Finally, we should consider abandoning our conservative therapies, because our assumption ("it can't hurt") may be wrong. -Mark L. Moster, MD Moster and Bhatti: J Neuro-Ophthalmol 2016; 36: 103-109 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Literature Commentary Before I make my comments on this article, Mark, I want to remind the readers of a systematic review regarding intra-arterial thrombolysis for CRAO by Noble et al (1) that can put into some context systemic fibrinolytic therapy. I take issue with Schrag et al stating "systemic fibrinolytic therapies are simpler and faster to deploy and maybe safer." First, the thrust of this meta-analysis was on vision (improving or worsening). There was very little discussion regarding the adverse events associated with systemic fibrinolytic therapy. All that is stated is: "The adverse effect profile of streptokinase is inferior to that of tPA, particularly regarding hemorrhagic complications. Among the patients treated with streptokinase, 5 serious hemorrhagic complications occurred (4 of them were fatal, including 3 fatal intracerebral hemorrhages and 1 fatal hemorrhage from the liver). No major hemorrhages occurred after administration of urokinase or tPA in this analysis." In the review published in 2007, Biousse et al (2) reported a 12.6% (10 hemorrhages, 2 fatal, and 1 shock) frequency of complications. Second, systemic fibrinolytic therapy may be simpler and faster to deploy than intra-arterial thrombolytic therapy, but it remains a very challenging and daunting process. Several years ago, we reviewed this issue in the context of the Duke University t-PA stroke protocol (3) (See Supplemental Digital Content, Table E1, http://links.lww.com/ WNO/A197). We raised several challenges and issues regarding whether thrombolytic therapy for CRAO is cutting-edge therapy, standard of care therapy, or impractical therapy (3): 1. Development of an organizational infrastructure that facilitates well-tolerated administration of iv thrombolytic therapy, intra-arterial thrombolytic therapy, or both in a timely manner. 2. A systematic institutional approach with integral involvement of ophthalmologists, stroke specialists, emergency physicians, and neuroradiologists. 3. Development of a specific thrombolytic therapy protocol to maximize benefits and minimize complications. 4. A consensus on who will be responsible for the administration of iv thrombolytic therapy (e.g., emergency physician, ophthalmologist, neurologist, etc). Currently, most hospi- Moster and Bhatti: J Neuro-Ophthalmol 2016; 36: 103-109 tals allow emergency physicians to administer iv thrombolytic therapy for an acute ischemic stroke, a situation that may not necessarily be appropriate for patients with CRAO. 5. Medicolegal ramifications of thrombolytic therapy associated with CRAO. 6. Lack of public awareness of CRAO resulting in a delay in seeking medical care. To overcome this problem, extensive public education and awareness programs will be required. 7. The large financial cost of thrombolytic therapy. A recent study showed that the mean hospital cost of not receiving thrombolytic therapy was dramatically less than the hospital cost of thrombolytic therapy ($14,500 vs $32,500-37,800, respectively). -M. Tariq Bhatti, MD Tariq, I agree with all the challenges, potential complications, and cost. Nonetheless, vision loss from CRAO is devastating and in centers that have tPA stroke protocols already in place and ophthalmologists immediately available, there should be further study on the use of iv tPA. -Mark L. Moster, MD Please do not get me wrong, Mark, I am not against a well-designed controlled clinical trial on thrombolysis for CRAO. What I am concerned about is implementing such an intervention in clinical practice at this time. -M. Tariq Bhatti, MD Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the full text and PDF versions of this article on the journal's Web site (www.jneuro-ophthalmology.com). REFERENCES 1. Noble J, Weizblit N, Baerlocher MO, Eng KT. Intra-arterial thrombolysis for central retinal artery occlusion: a systematic review. Br J Ophthalmol. 2008;92:588-593. 2. Biousse V, Calvetti O, Bruce BB, Newman NJ. Thrombolysis for central retinal artery occlusion. J Neuroophthalmol. 2007;27:215-230. 3. Hazin R, Dixon JA, Bhatti MT. Thrombolytic therapy in central retinal artery occlusion: cutting edge therapy, standard of care therapy, or impractical therapy? Curr Opin Ophthalmol. 2009;20:210-218. 109 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.