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Show Literature Commentary Campbell UB, Walker AM, Gaffney M, Petronis KR, Creanga D, Quinn S, Klein BE, Laties AM, Lewis M, Sharlip ID, Kolitsopoulos F, Klee BJ, Mo J, Reynolds RF. Acute nonarteritic anterior ischemic optic neuropathy and exposure to phosphodiesterase type 5 inhibitors. J Sex Med. 2014. doi: 10.1111/jsm.12726. Epub ahead of print. Introduction: Nonarteritic anterior ischemic optic neuropa-thy (NAION), a rare visual disorder, has been reported in men using phosphodiesterase type 5 inhibitors (PDE5i) for erectile dysfunction. Aim: We examined whether intermittent use of PDE5i is associated with acute NAION onset within approximately 5 half-lives after drug ingestion. Methods: One hundred two ophthalmology centers in the United States and Europe identified potential cases of NAION. An expert adjudication committee conducted a blind review of the records of those with recent PDE5i use to classify cases as Definite, Possible, or not NAION. Subjects provided information on PDEi use through telephone inter-view. Each NAION case's PDE5i exposure immediately before onset was compared against his recent patterns of use in an observational case-crossover design. A sample size of 40 cases with intermittent PDE5i exposure in the 30 days before NAION onset was needed to detect an odds ratio (OR) of 3.0 with 80% power. Main Outcome Measures: The daily relative risk for acute NAION on days within 5 half-lives of PDE5i use vs other days was estimated through an OR obtained from conditional logistic regression. Results: Among 43 Definite NAION cases with PDE5i exposure in the prior 30 days, the OR was 2.15 (95% confidence interval [CI]: 1.06-4.34). When 21 Possible NAION cases were included (n = 64), the OR was 2.36 (95% CI: 1.33-4.19). Conclusions: We found an approximately 2-fold increased risk of acute NAION within 5 half-lives of PDE5i use com-pared with use in a more prior time period. Bias from inaccurate recall of exposure was unlikely to have sub-stantially affected the results. Based on our results, we estimate that weekly use of PDE5i adds 3 NAION cases per 100,000 men of 50 years and older annually. In this study, men with nonarteritic anterior ischemic optic neuropathy (NAION) were asked about their use of phosphodiesterase type 5 inhibitor (PDE5i). Subjects indicated PDE5i use 1 day before the onset of visual symptoms (case) vs 2-30 days before (control). The study also looked at whether there was a difference in PDE5i use in the week before symptom onset vs 2-8 weeks prior. The risk of NAION after PDE5i use in both analyses was increased by more than 100%. Finally, we have a prospective rigorous study that clearly associates PDE5i use with NAION. We should ask all men with NAION about PDE5i use. In the European Union, PDE5i use is not recommended for patients with a history of NAION. If we assume that PDE5i use doubles the risk of fellow eye involvement, which is already around 15%- 25%, then all clinicians should really consider recommend-ing the same for patients with unilateral NAION. -Michael S. Lee, MD This case-crossover design trial came up with 2 different estimates of the number of additional cases of NAION expected from PDE5i use. Estimating a use of 1 in 5 days yields a risk of an additional 3 annual cases of definite NAION per 100,000 patients. However, daily use yields a risk of an additional 34 annual probable or definite cases of NAION per 100,000 patients. This study adds to a controversial literature with claims on the one hand that NAION is caused by PDE5i, but others claiming that NAION is caused by the same risk factors causing erectile dysfunction (ED). Michael, let's not get ahead of ourselves and claim as you have that, "Finally, we have a prospective rigorous study that clearly associates PDE5i use with NAION." I'd ask you to consider the study below published ahead of print in the Journal of Neuro-ophthalmology (JNO) by Nathoo et al (1). That case-control study did not find an increased risk of NAION in patients "prescribed" ED drugs. Of course, there are limitations in the study (e.g., there was no information in this healthcare database on whether some patients may have obtained ED drugs not officially prescribed). So, although there is evidence implicating PDE5i in NAION, the controversy continues!! Stay tuned for the JNO session on this topic at NANOS 2015 in San Diego! -Mark L. Moster, MD Thanks for bringing the Nathoo et al article up. This was a retrospective review of claims data. The cases and controls were significantly different; there was no expert who diagnosed NAION, and use of PDE5i was inferred because prescriptions were filled. They concluded that no association exists between filling a prescription for PDE5i and receiving a diagnostic code for NAION. Mark, the 90 Moster and Lee: J Neuro-Ophthalmol 2015; 35: 90-93 Literature Commentary Section Editors: Mark L. Moster, MD Michael S. Lee, MD Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Nathoo et al article is not prospective, rigorous, or convincing. I stand by my statement. -Michael S. Lee, MD REFERENCE 1. Nathoo NA, Etminan M, Mikelberg FS. Association between Phosphodiesterase-5 inhibitors and nonarteritic anterior ischemic optic neuropathy. J Neuroophthalmol. 2015;35:12-15. Marmor MF, Hu J. Effect of disease stage on progression of hydroxychloroquine retinopathy. JAMA Ophthalmol. 2014;132;1105-1112. Importance: Hydroxychloroquine sulfate retinopathy can prog-ress after the drug is stopped. It is not clear how this relates to the stage of retinopathy or whether early screening with modern imaging technology can prevent progression and visual loss. Objective: To determine the relationship between progression of retinopathy and the severity of disease using objective data from optical coherence tomography and assess the value of early screening for the toxic effects of hydroxychloroquine. Design, Setting, and Participants: Clinical findings in patients with hydroxychloroquine retinopathy were moni-tored with repeated anatomical and functional examinations for 13-40 months after the drug was stopped in a referral practice in a university medical center. Eleven patients par-ticipated, with the severity of toxic effects categorized as early (patchy parafoveal damage shown on field or objective testing), moderate (a 50%-100% parafoveal ring of optical coherence tomography thinning but intact retinal pigment epithelium), and severe (visible bull's-eye damage). Main Outcomes and Measures: Visual acuity, white 10-2 visual field pattern density plots, fundus autofluores-cence, spectral density optical coherence tomography cross sections, thickness (from cube diagrams), and ellipsoid zone length. Results: Visual acuity and visual fields showed no consis-tent change. Fundus autofluorescence showed little or no change except in severe cases in which the bull's-eye dam-age expanded progressively. Optical coherence tomography cross sections showed little visible change in early and moderate cases but progressive foveal thinning (approxi-mately 7 mm/y) and loss of ellipsoid zone (in the range of 100 mm/y) in severe cases, which was confirmed by quan-titative measurements. The measurements also showed some foveal thinning (approximately 4 mm/yr) and deepen-ing of parafoveal loss in moderate cases, but the breadth of the ellipsoid zone remained constant in both early and mod-erate cases. A few cases showed a suggestion of ellipsoid zone improvement. Conclusions and Relevance: Patients with hydroxychloro-quine retinopathy involving the retinal pigment epithelium demonstrated progressive damage on optical coherence tomography for at least 3 years after the drug was discontinued, including loss of foveal thickness and cone structure. Cases recognized before retinal pigment epithe-lium damage retained foveal architecture with little retinal thinning. Early recognition of hydroxychloroquine toxic effects before any fundus changes are visible, using visual fields and optical coherence tomography (along with fundus autofluorescence and multifocal electroretinography as indicated), will greatly minimize late progression and the risk of visual loss. Intuitively, finding hydroxychloroquine toxicity earlier leads to less visual loss. This study verifies that by optical coherence tomography (OCT) measurements of foveal thickness and loss of ellipsoid zone, those who discontinue the medication with early toxicity remain stable, while those with severe involvement continue to have progressive deterioration for the next 3 years. Although the study is very small and follow up only 2 to slightly more than 3 years, it emphasizes the need for appropriate monitoring of patients for early diagnosis and discontinuation of the medication. -Mark L. Moster, MD The fundus autofluorescence and OCT progression are striking for the severe cases of toxicity, and I'm interested to see if longer follow-up will show further progression. For-tunately, the visual acuity and visual fields did not progres-sively worsen in any of the patients for the first 3 years of follow-up, and I think we can reassure patients with toxicity about the functional data. -Michael S. Lee, MD Lee SB, Shin YI, Jo YJ, Kim JY. Longitudinal changes in retinal nerve fiber layer thickness after vitrectomy for epiretinal membrane. Invest Ophthalmol Vis Sci. 2014;55:6607-6611. Purpose: We investigated longitudinal changes in retinal nerve fiber layer (RNFL) thickness after vitrectomy for epiretinal membrane (ERM). Methods: Thirty-one patients who underwent pars plana vitrectomy with internal limiting membrane peeling for ERM were included. Average thickness and 4 quadrants of RNFL thicknesses were determined before and at 1, 3, 6, and 12 months after surgery by spectral domain optical coherence tomography. As macular lesions could affect RNFL thick-ness, we evaluated changes in RNFL thickness by dividing the RNFL into 12 o'clock hourly positions, defining patho-logic area adjacent to the lesion and nonpathologic area. Results: RNFL thickness of the affected eyes increased at 1 month after vitrectomy and later decreased compared with baseline values. Temporal quadrant RNFL thickness was statistically significantly thicker in affected eyes at baseline and at 1 month after surgery and thinner after 12 months than fellow eyes. RNFL thickness in pathologic area decreased after surgery, and the RNFL was statistically significantly thinner at 3, 6, and 12 months postoperatively, compared with the baseline thickness. The RNFL thickness of pathologic area of affected eyes compared with fellow eyes was thicker both at baseline and 1 month after surgery but thinner at 12 months compared with baseline values. Conclusions: Postoperative RNFL thickness after vitrectomy combined with ERM removal tended to decrease postopera-tively. RNFL thicknesses in temporal pathologic area were significantly reduced at 3, 6, and 12 months postoperatively Moster and Lee: J Neuro-Ophthalmol 2015; 35: 90-93 91 Literature Commentary Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. compared with baseline values, whereas RNFL thicknesses in nasal nonpathologic area exhibited no significant postopera-tive changes. We found that ERM itself and the removal procedure resulted in decreased RNFL thickness. Pan BX, Yee KM,Ross-Cisneros FN, Sadun AA, Sebag J. Inner retinal optic neuropathy: vitreomacular surgery-associated disruption of the inner retina. Invest Ophthalmol Vis Sci. 2014;55:6756-6764. Purpose: Macular pucker (MP) and macular hole (MH) are vitreomaculopathies treated by vitrectomy and membrane peel. The complication of postoperative central scotoma can be associated with significant reduction in visual acuity (VA). We seek to determine whether retinal nerve fiber layer (RNFL) disruption is the pathophysiologic basis of this defect. Mitigating clinical circumstances also were sought. Methods: Eleven eyes from 10 pseudophakic patients who had undergone vitrectomy with peeling for either MH or MP were studied with clinical measures, including optical coher-ence tomography (OCT). Membrane specimens were evalu-ated by immunohistochemistry for neurofilament, a marker for the inner retina. Ten eyes from 10 pseudophakic patients who underwent repeat surgery for persistent or recurrent pathology were evaluated to determine the relationship between the timing of reoperation and clinical outcome. Results: Cases with a postoperative central scotoma (N = 4) had worse VA (w20/600) compared with those without (N = 7, w20/30, P = 0.01). Eyes with a central scotoma had significantly reduced RNFL thickness in the temporal quadrant (53.67 vs 72.33 mm, P = 0.05) by OCT. A central scotoma was associated with more disruption of the inner retina on immunohistochemistry (P = 0.03). In patients with persistent or recurrent pathology, waiting 6 months before reoperation resulted in better functional outcomes (P = 0.03). Conclusions: Central scotomata and poor VA were associ-ated with disruption of the RNFL during membrane peeling. Affected patients have RNFL thinning and signs of optic neuropathy, for which we propose the term inner retinal optic neuropathy (IRON). In patients requiring reoperation, waiting 6 months between surgeries may reduce the risk of IRON. It has long been observed that patients can have what looks like an optic neuropathy after vitrectomy. Both of the abstracts above address this issue. In the first study, Lee et al performed prospective pre-operative and postoperative retinal nerve fiber layer (RNFL) thickness measurements on eyes undergoing vitrectomy with internal limiting membrane (ILM) peeling for epiretinal membrane (ERM). The temporal RNFL in the affected eyes was significantly thicker than fellow eyes at baseline and 1 month postoperatively. At 3-, 6-, and 12-month follow-up, the temporal RNFL became much thinner than the fellow eye and baseline values. I assume that the majority of these 31 eyes did not experience significant visual loss despite the significant thinning of the RNFL, but it would have been helpful if they had reported visual acuity data and compared that with the RNFL thickness. In the second study, Pan et al retrospectively looked at various vitrectomies including ERM peeling alone, ILM peeling, and air-fluid exchange for macular hole repair. They compared the visual function and RNFL of eyes that experienced a good visual outcome vs a poor visual outcome and found that eyes with the latter had significantly thinner RNFL. They looked at the timing of repeat vitrectomy and found that repeat surgery ,6 months experienced worse visual outcomes and thinner RNFL compared with eyes with repeat surgery .6 months. This study did not com-pare the RNFL thickness with baseline values or normal eyes. The authors also performed immunohistochemistry on the peeled membranes for the presence of neurofilament and found that eyes with the worst visual acuities were more likely to stain positively. This suggests that the RNFL itself was peeled along with the ERM or ILM during the surgery. From the results of both studies, it appears that the RNFL commonly becomes significantly thinner after all vitrectomies. Eyes with poorer visual outcomes experience substantially more thinning of the RNFL. If an eye needs repeat vitrectomy and ERM peeling, then it may be reasonable to wait 6 months. -Michael S. Lee, MD The first study by Lee et al is limited by lack of information about visual function. Did any of the patients have symptomatic visual loss? If so, was there a difference of RNFL thickness measurements among these patients, as found in the second study. The second study by Pam et al suffers from not having a set time that the optical coherence tomographies were obtained, and there were a lot of different surgical procedures. What these articles seem to be telling us is that the RNFL and optic nerve function are at risk in ERM and pucker surgeries, and there may be ways to reduce this risk. As neuro-ophthalmologists, we often see patients with visual loss after vitrectomy and think about ischemia or damage from intraocular pressure spikes. These reports may be bringing us closer to understanding the underlying pathophysiology. -Mark L. Moster, MD Waugh JL. Education in medical billing benefits both neurology trainees and academic departments. Neurology. 2014;8:1856-1861. Abstract: The objective of residency training is to produce physicians who can function independently within their chosen subspecialty and practice environment. Skills in the business of medicine, such as clinical billing, are widely applicable in academic and private practices but are not commonly addressed during formal medical education. Residency and fellowship training include limited exposure to medical billing, but our academic department's performance of these skills was inadequate; in 56% of trainee-generated outpatient notes, documentation was insufficient to sustain the chosen billing level. We developed a curriculum to improve the accuracy of documentation and coding and introduced practice changes to 92 Moster and Lee: J Neuro-Ophthalmol 2015; 35: 90-93 Literature Commentary Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. address our largest sources of error. In parallel, we developed tools that increased the speed and efficiency of documenta-tion. Over 15 months, we progressively eliminated note deval-uation, increased the mean level billed by trainees to nearly match that of attending physicians, and increased outpatient revenue by $34,313 per trainee per year. Our experience sug-gests that inclusion of billing education topics into the formal medical curriculum benefits both academic medical centers and trainees. In response to billing audits, which found errors in 56% of patient encounters in resident's clinic, the Division of Pedi-atric Neurology at Boston Children's Hospital embarked on a program to train the residents in proper documentation. This included 4 hours of lectures and individualized struc-tured feedback for each resident. Initial errors included in declining order: inadequate review of systems, insufficient documentation to justify billing as a new patient, medical decision making, physical exam, undercoding, overcoding, medical history. After the training, accuracy improved from 44%, sustaining the audit to 93%. Financially, this resulted in an increase in revenue of $34,313 per trainee per year. In addition to the obvious financial benefit to academic departments and medical centers, this type of training will certainly help the transition from training to practice. As the accompanying editorial by Kaminski and Busis emphasized, we best educate residents in the "3 legs that support and health care delivery platform: the art, science and business of medicine." -Mark L. Moster, MD I know that I did not receive any type of billing education in residency, and I had a rude awakening in fellowship and my first job. Our current ophthalmology residents have access to coding courses annually, but very few take advantage of it. Making coding a part of an already crowded curriculum would have great overall value to help the graduate hit the ground running. I think the financial incentive to the departments only applies to those where the residents fill out their own billing. I think it is also harder to make the coding information stick when residents are not part of the billing process. -Michael S. Lee, MD George JS, Leite MI, Kitley JL, James N, Cortes N, Donati M, Mathews BN, Calladine D, Hillier C, Yusuf IH, Munneke R, Patel CK, Palace JA, Elston JS. Opportunistic infections of the retina in patients with Aquaporin-4 antibody disease. JAMA Neurol. 2014;71:1429-1432. Importance: Patients with neuromyelitis optica who have aquaporin-4 antibodies are being identified and receiving immunosuppressant treatment earlier and more aggressively as a result of increasing awareness of the importance of preventing relapses responsible for the high morbidity and mortality associated with the disease. To our knowledge, opportunistic retinal infection in patients with aquaporin-4 antibodies who are receiving immunosuppressants has not been reported to date. Observations: We describe 2 patients with aquaporin-4 antibodies who were receiving conventional doses of first-line immunosuppressive therapy. Both patients presented with vision loss that was initially thought to be optic neuritis attacks. The subsequent diagnoses were ocular toxoplas-mosis and cytomegalovirus retinitis. Conclusions and Relevance: Retinal opportunistic in-fections can occur in patients with aquaporin-4 anti-bodies who are receiving relatively low levels of immunosuppression, may mimic optic neuritis, and are a potentially reversible cause of vision loss when treated promptly. The default diagnosis in a patient with visual loss who has aquaporin-4 antibodies and either classic neuromyelitis optica or a variant would be an episode of optic neuritis. However, this article describes one case of cytomegalovirus retinitis and one of ocular toxoplasmosis and highlights to me the importance of a thorough ophthalmic examination in anyone with visual loss. This is reminiscent of the patient with multiple sclerosis who is on natalizumab and who has what mimics an exacerbation, but really has progressive multifocal leukoencephalopathy. Of course, the treatments in both these situations are dramatically different. On the one hand, an exacerbation of neuromyelitis optica or multiple sclerosis may require treatment with steroids and boosting up the immunosuppression. On the other hand, an infection with progressive multifocal leukoencephalopathy or infectious retinitis must be treated with anti-infectious agents and not increasing the immunosuppression. We must emphasize to our neurology colleagues that anyone with visual loss needs a thorough funduscopic examination. We've likely all had cases called central ret-inal artery occlusion that were retinal detachments or optic neuritis that were central serous retinopathy. -Mark L. Moster, MD I have seen the patient with NMO, treated by the neurologist for presumed optic neuritis. When she did not get better, she was sent for evaluation to find out that she had a retinal detachment. Although statistically vision loss is more apt to be optic neuritis, Hickam's dictum can always rear its head. I think the clinician could also get a good orbital magnetic resonance imaging with fat suppression and gadolinium. The absence of T2 hyperintensity or gadoli-nium enhancement should prompt him/her to seek an ophthalmic consultation because it may not represent optic neuritis. -Michael S. Lee, MD Moster and Lee: J Neuro-Ophthalmol 2015; 35: 90-93 93 Literature Commentary Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. |