Literature Commentary

In this issue of Journal of Neuro-Ophthalmology, M. Tariq Bhatti, MD and Mark L. Moster, MD will discuss the following 6 articles.

Literature Commentary Section Editors: Mark L. Moster, MD M. Tariq Bhatti, MD Literature Commentary In this issue of Journal of Neuro-Ophthalmology, M. Tariq Bhatti, MD and Mark L. Moster, MD will discuss the following 6 articles: 1. Nazarian S, Hansford R, Rahsepar AA, Weltin V, McVeigh D, Gucuk Ipek E, Kwan A, Berger RD, Calkins H, Lardo AC, Kraut MA, Kamel IR, Zimmerman SL, Halperin HR. Safety of magnetic resonance imaging in patients with cardiac devices. N Engl J Med. 2017;377:2555-2564. 2. Martin DR, Kalb B, Mittal A, Salman K, Vedantham S, Mittal PK. No incidence of nephrogenic systemic fibrosis after gadobenate dimeglumine administration in patients undergoing dialysis or those with severe chronic kidney disease. Radiology. 2018;286:113-119. 3. Howard JF Jr, Utsugisawa K, Benatar M, Murai H, Barohn RJ, Illa I, Jacob S, Vissing J, Burns TM, Kissel JT, Muppidi S, Nowak RJ, O'Brien F, Wang JJ, Mantegazza R; REGAIN Study Group. Safety and efficacy of eculizumab in anti-acetylcholine receptor antibody-positive refractory generalized myasthenia gravis (REGAIN): a phase 3, randomized, double-blind, placebo-controlled, multicenter study. Lancet Neurol. 2017;16:976-986. Erratum in: Lancet Neurol. 2017;16:954. 4. Dosunmu EO, Hatt SR, Leske DA, Hodge DO, Holmes JM. Incidence and etiology of presumed fourth cranial nerve palsy: a population-based study. Am J Ophthalmol. 2018;185:110-114. 5. Eade EL, Hardy TG, McKelvie PA, McNab AA. Review of extraocular muscle biopsies and utility of biopsy in extraocular muscle enlargement. Br J Ophthalmol. [published online ahead of print January 19, 2018] doi: 10.1136/bjophthalmol-2017-311147. 6. Nath S, Badhiwala JH, Alhazzani W, et al. Atraumatic versus traumatic lumbar puncture needles: a systematic review and meta-analysis. Lancet. 2018;391:1197-1204. Nazarian S, Hansford R, Rahsepar AA, Weltin V, McVeigh D, Gucuk Ipek E, Kwan A, Berger RD, Calkins H, Lardo AC, Kraut MA, Kamel IR, Zimmerman SL, Halperin HR. Safety of magnetic resonance imaging in patients with cardiac devices. N Engl J Med. 2017;377:2555-2564. Background: Patients who have pacemakers or defibrillators are often denied the opportunity to undergo magnetic resonance imaging (MRI) because of safety concerns, unless the devices meet certain criteria specified by the Food and Drug Administration (termed "MRI-conditional" devices). Methods: We performed a prospective, nonrandomized study to assess the safety of MRI at a magnetic field strength of 1.5 Tesla in 1,509 patients who had a pacemaker (58%) or an implantable cardioverter-defibrillator (42%) that was not considered to be MRI-conditional (termed a "legacy" device). Overall, the patients underwent 2,103 thoracic and nonthoracic MRI examinations that were deemed to be clinically necessary. The pacing mode was changed to asynchronous mode for pacing-dependent patients and to demand mode for other patients. Tachyarrhythmia functions were disabled. Outcome assessments included adverse events and changes in the variables that indicate lead and generator function and interaction with surrounding tissue (device parameters). Results: No long-term clinically significant adverse events were reported. In 9 MRI examinations (0.4%; 95% confidence interval, 0.2-0.7), the patient's device was reset to a backup mode. The reset was transient in 8 of the 9 examinations. In Moster and Bhatti: J Neuro-Ophthalmol 2018; 38: 263-270 one case, a pacemaker with less than 1 month left of battery life reset to ventricular inhibited pacing and could not be reprogrammed; the device was subsequently replaced. The most common notable change in device parameters (.50% change from baseline) immediately after MRI was a decrease in P-wave amplitude, which occurred in 1% of the patients. At long-term follow-up (results of which were available for 63% of the patients), the most common notable changes from baseline were decreases in P-wave amplitude (in 4% of the patients), increases in atrial capture threshold (4%), increases in right ventricular capture threshold (4%), and increases in left ventricular capture threshold (3%). The observed changes in lead parameters were not clinically significant and did not require device revision or reprogramming. Conclusions: We evaluated the safety of MRI, performed with the use of a prespecified safety protocol, in 1,509 patients who had a legacy pacemaker or a legacy implantable cardioverter-defibrillator system. No long-term clinically significant adverse events were reported (Funded by Johns Hopkins University and the National Institutes of Health; ClinicalTrials.gov number, NCT01130896). Anytime we order a magnetic resonance imaging (MRI) study, a critical question for the patient is "Do you have any metal in your body, such as a pacemaker?" Well, based on this study, we may not have to ask that question any longer. One thousand five hundred nine patients with either a legacy system (meaning a non-FDA approved or non MRIconditional) pacemaker (58%) or implantable cardioverter263 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Literature Commentary defibrillator (ICD, 42%) who underwent an MRI (1.5T) for various clinical reasons were evaluated in a prospective fashion to determine if any adverse events or abnormal device parameters developed. There were several exclusion criteria to the study: lead implantation within the previous 4 weeks, permanent surgical epicardial leads or permanent nonfunctional leads, subcutaneous ICD system, and pacingdependent ICD without asynchronous pacing capability. To my surprise, especially given that I was under the impression that these devices are an absolute contraindication to an MRI, there were very few clinically significant adverse events. A total of 2,103 MRIs were performed (594 patients had more than 1 MRI performed) with 52% of the MRIs to the head or neck. Only 1 of 200 MRI examinations (9 events in 8 patients) suffered a "power-on reset," meaning that during this time, there could have been inhibition of pacing output and activation of antitachycardia therapy. None of these events were associated with serious clinical consequences. In fact, of the 9 events, 7 completed the MRI. In terms of device parameter changes, the most common (occurring in only 1% of patients) was a decrease in P-wave amplitude. Five patients had their MRI study aborted due to: bradycardia (,40 beats per minute) that resulted from functional inhibition of pacing with electromagnetic interference (1 patient), frequent, nonsustained ventricular tachycardia (1 patient), and image artifact (3 patients). The authors emphasized the importance of their prespecified safety protocol: • All MRI examinations were supervised by a registered nurse who had experience in cardiac device programming and training in cardiac life support. • Immediate access to an electrophysiologist or electrophysiologist directly supervising. • Baseline and immediately after completion of MRI device parameter measurements: B Battery voltage B Capture thresholds B Pacing lead impedance, and sensing • Device reprogrammed to an asynchronous pacing mode for patients who had an intrinsic heart rate of ,40 beats per minute. An inhibited pacing mode was used for all other patients. • Deactivated the following pacing features and functions to treat tachyarrhythmia: B Magnet mode (a programmable feature in some pacemakers that allows for the disabling of the asynchronous pacing response to magnet application) B Premature ventricular complex detection B Noise discrimination B Rate response, and B Ventricular sense response • After completion of the MRI, devices were reprogrammed to the original settings. 264 When I asked one of my neuroradiology colleagues if Duke would allow MRIs to be performed on patients with a pacemaker or ICD, she answered by saying ".they are still going to be worried about heating, arrhythmia and death. It will involve so much work, getting cardiology involved routinely for monitoring. I don't think it will change in a hurry." -M. Tariq Bhatti, MD It is encouraging that this study did not find any disastrous outcomes from doing MRIs on patients with legacy devices. However, 20% of patients did not have follow-up afterward; so, we do not know whether there are any pacemaker malfunctions in those individuals. In addition, the MRI scans were of 1.5 Tesla strength and many MRI machines currently have stronger magnets. Finally, it will be very difficult for most centers to have the cardiac and electrophysiology support on board that was available in this study. Many, if not most, patients with implanted devices will need MRIs. With the limitations of expertise and cost, it might be best if there are designated centers in each large city specified to perform MRIs on those individuals with implanted devices. -Mark L. Moster, MD Martin DR, Kalb B, Mittal A, Salman K, Vedantham S, Mittal PK. No incidence of nephrogenic systemic fibrosis after gadobenate dimeglumine administration in patients undergoing dialysis or those with severe chronic kidney disease. Radiology. 2018;286:113-119. Purpose: To determine the incidence of nephrogenic systemic fibrosis (NSF) in patients with severe chronic kidney disease (CKD) who underwent a uniform protocol for contrast material-enhanced magnetic resonance (MR) imaging with a gadolinium-based contrast agent (GBCA). Materials and Methods: This retrospective, single-center, institutional review board-approved, HIPAA-compliant study included 3,819 patients with severe (Stage 4 or 5) CKD who underwent gadobenate dimeglumine-enhanced MR imaging as part of a preoperative evaluation for potential renal transplantation from January 2008 to February 2014. After undergoing contrast-enhanced MR imaging, patients were assessed for NSF by means of clinical follow-up, including a full integumentary examination, with a minimum of 6 months between administration of the GBCA and clinical skin examination. Suspicious skin lesions were sampled with deep punch biopsy, and results of pathologic examination were reviewed and categorized. In addition, a search of the institution's pathology database during the time of the study was performed to identify any additional patients with NSF. The proportion of subjects who developed NSF after the administration of gadobenate dimeglumine was calculated, and Clopper-Pearson 95% confidence intervals were determined by using binomial proportions. Results: The average length of follow-up for the patient population was 501 days (range, 186-2,121 days). A total of 219 biopsies were performed, and none of the 3,819 Moster and Bhatti: J Neuro-Ophthalmol 2018; 38: 263-270 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Literature Commentary TABLE 1. MRI contrast agents and nephrogenic systemic fibrosis Gadolinium-Based Contrast Agent Risk of Nephrogenic Systemic Fibrosis Gadodiamide (Omniscan; GE Healthcare) Gadoversetamide (Optimark; Mallinckrodt Inc) Gadopentetate dimeglumine (Magnevist; Bayer Healthcare) Gadobenate dimeglumine (Multihance; Bracco) Gadoxetate disodium (Primovist/Eovist; Bayer Healthcare) Gadofosveset trisodium (Ablavar/Vasovist; Lantheus Medical Imaging) Gadobutrol (Gadovist/Gadavist; Bayer Healthcare) Gadoteridol (Prohance; Bracco) Gadoterate meglumine (Dotarem; Guerbet) High High High Intermediate Intermediate Intermediate Low Low Low patients developed NSF after administration of gadobenate dimeglumine, resulting in a proportion of zero; the exact upper bound of 95% confidence interval was 0.000965 (0.0965%). Conclusions: None of the 3,819 patients with severe CKD developed NSF after undergoing gadobenate dimeglumine- enhanced MR imaging, which suggests that this GBCA may be safely administered in patients with severe CKD, with an immeasurable risk of the subsequent development of NSF. A variety of gadolinium-based contrast agents (GBCAs) are on the market for use with magnetic resonance imaging (MRI) (1). Nephrogenic systemic fibrosis (NSF) has been associated with the use of these agents in patients with acute or chronic severe renal insufficiency (estimated glomerular filtration rate [eGFR] of ,30 mL/min/1.73 m2). One of the risk factors for the development of NSF is the type of GBCA administered (Table 1) (2). In this retrospective study, the incidence of NSF was assessed in patients with severe chronic kidney disease (CKD) undergoing peritoneal dialysis or hemodialysis and Stage 4 and 5 CKD (eGFR ,30 mL/min/1.73 m2) not receiving dialysis. Gadobenate dimeglumine (Multihance; Bracco Diagnostics Inc, Singen, Germany) was administered, at an average volume of 25 mL (range, 3-45 mL; dose of 0.05 mmol/kg for MRI and 0.1 mmol/kg for magnetic resonance angiography). No NSF was noted in the 3,819 patients analyzed with an average of 501 days of follow-up. Although the number of patients (n = 3,819) is quite large in this study, I always remain skeptical when I see such extreme percentages as 0% or 100%. Having said that, I think this study points out that as neuro-ophthalmologists, we should be aware of the type of GBCA being administered and that in our patients with CKD who would benefit from an enhanced MRI, it may be acceptable to proceed with the administration of certain GBCAs. But, of course, I would recommend consulting with the radiologist/neuroradiologist overseeing the study. Here, at Duke, we use gadobenate dimeglumine, which is used in patients with CKD but there must be a consent form signed by the patient and the indication for contrast administration must be very strong. The Duke policy for administering contrast is based on the American College of Radiology guidelines on contrast (3): Moster and Bhatti: J Neuro-Ophthalmol 2018; 38: 263-270 • For patients with eGFR ,15 mL/min/1.73 m2, a discussion of the risks and benefits must be undertaken with the patient (or designee) by a physician member of the Radiology department or the referring clinical team. The patient (or designee) must provide written informed consent. If the consent document is obtained by the referring team but documentation cannot be verified at the time of MRI examination, written consent must be reobtained in MRI before GBCA administration. • Before GBCA administration, the noncontrast portion of the examination must be evaluated by a radiologist to determine whether GBCA administration is necessary. • After the above, if deemed necessary, GBCA may be administered at the lowest reasonable dose that is expected to yield a diagnostic examination and answer the clinical question, as determined by the supervising radiologist. The choice of GBCA will depend on the clinical situation; however, agents with favorable safety profiles (gadobenate dimeglumine, gadoteridol, or gadobutrol) should be used whenever possible. Gadopentetate dimeglumine is contraindicated for patients in this category of renal function, in concordance with the Food and Drug Administration's guidelines. • The radiologist reporting the MRI result must clearly summarize the steps taken above in his/her report, including verification of informed consent (if applicable) and the note from the referring physician. • Although dialysis after GBCA administration has not shown clear benefit, the risks and benefits of dialysis should be considered after GBCA administration to patients who receive dialysis. -M. Tariq Bhatti, MD 1. The Round Table Foundation. Magnetic Resonance: A PeerReviewed, Critical Introduction. Available at: http://www. magnetic-resonance.org/ch/13-01.html. Accessed March 2, 2018. 2. Lohrke J, Frenzel T, Endrikat J, Alves FC, Grist TM, Law M, Lee JM, Leiner T, Li KC, Nikolaou K, Prince MR, Schild HH, Weinreb 265 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Literature Commentary JC, Yoshikawa K, Pietsch H. 25 years of contrast-enhanced MRI: developments, current challenges and future perspectives. Adv Ther. 2016;33:1-28. 3. American College of Radiology. ACR Committee on Drugs and Contrast Media, 2017: ACR Manual on Contrast Media, Version 10.3. Available at: https://www.acr.org/-/media/ACR/Files/ Clinical-Resources/Contrast_Media.pdf. Accessed March 2, 2018. Having no cases of NSF in so many patients with severe kidney disease is reassuring. We have many patients with suspected conditions where contrast studies are important but we do not order the contrast for fear of NSF. We should all be discussing the findings of this study with our radiologists and consider routinely ordering studies with contrast on our CKD patients when it is clinically important. Tariq, first you tell me I can do MRIs on my patients with pacemakers. Now you tell me I can use contrast in patients with severe kidney disease. I am beginning to think you are spreading "fake news!" -Mark L. Moster, MD Look, Mark, I am only here to make neuro-ophthalmology great again! -M. Tariq Bhatti, MD Howard JF Jr, Utsugisawa K, Benatar M, Murai H, Barohn RJ, Illa I, Jacob S, Vissing J, Burns TM, Kissel JT, Muppidi S, Nowak RJ, O'Brien F, Wang JJ, Mantegazza R; REGAIN Study Group. Safety and efficacy of eculizumab in anti-acetylcholine receptor antibody-positive refractory generalized myasthenia gravis (REGAIN): a phase 3, randomized, doubleblind, placebo-controlled, multicenter study. Lancet Neurol. 2017;16:976-986. Erratum in: Lancet Neurol. 2017;16:954. Background: Complement is likely to have a role in refractory generalized myasthenia gravis, but no approved therapies specifically target this system. Results from a Phase 2 study suggested that eculizumab, a terminal complement inhibitor, produced clinically meaningful improvements in patients with anti-acetylcholine receptor antibody-positive refractory generalized myasthenia gravis. We further assessed the efficacy and safety of eculizumab in this patient population in a Phase 3 trial. Methods: We did a Phase 3, randomized, double-blind, placebo-controlled, multicenter study (REGAIN) in 76 hospitals and specialized clinics in 17 countries across North America, Latin America, Europe, and Asia. Eligible patients were aged at least 18 years, with a Myasthenia Gravis-Activities of Daily Living (MG-ADL) score of 6 or more, Myasthenia Gravis Foundation of America (MGFA) Class II-IV disease, vaccination against Neisseria meningitidis, and previous treatment with at least 2 immunosuppressive therapies or one immunosuppressive therapy and chronic intravenous immunoglobulin or plasma exchange for 12 months without symptom control. Patients with a history of thymoma or 266 thymic neoplasms, thymectomy within 12 months before screening, or use of intravenous immunoglobulin or plasma exchange within 4 weeks before randomization, or rituximab within 6 months before screening were excluded. We randomly assigned participants (1:1) to either intravenous eculizumab or intravenous matched placebo for 26 weeks. Dosing for eculizumab was 900 mg on day 1 and at weeks 1, 2, and 3; 1,200 mg at week 4; and 1,200 mg given every second week thereafter as maintenance dosing. Randomization was done centrally with an interactive voice or webresponse system with patients stratified to 1 of 4 groups based on MGFA disease classification. Where possible, patients were maintained on existing myasthenia gravis therapies and rescue medication was allowed at the study physician's discretion. Patients, investigators, staff, and outcome assessors were masked to treatment assignment. The primary efficacy endpoint was the change from baseline to week 26 in MG-ADL total score measured by worst-rank analysis of covariance. The efficacy population set was defined as all patients randomly assigned to treatment groups who received at least one dose of study drug, had a valid baseline MG-ADL assessment, and at least one postbaseline MG-ADL assessment. The safety analyses included all randomly assigned patients who received eculizumab or placebo. This trial is registered with ClinicalTrials.gov, number NCT01997229. Findings: Between April 30, 2014, and February 19, 2016, we randomly assigned and treated 125 patients, 62 with eculizumab and 63 with placebo. The primary analysis showed no significant difference between eculizumab and placebo (least-squares mean rank 56$6 [SEM 4$5] vs 68$3 [4$5]; rank-based treatment difference 211.7, 95% CI 224.3 to 0.96; P = 0.0698). No deaths or cases of meningococcal infection occurred during the study. The most common adverse events in both groups were headache and upper respiratory tract infection (10 [16%] for both events in the eculizumab group and 12 [19%] for both in the placebo group). Myasthenia gravis exacerbations were reported by 6 (10%) patients in the eculizumab group and 15 (24%) in the placebo group. Six (10%) patients in the eculizumab group and 12 (19%) in the placebo group required rescue therapy. Interpretation: The change in the MG-ADL score was not statistically significant between eculizumab and placebo, as measured by the worst-rank analysis. Eculizumab was well tolerated. The use of a worst-rank analytical approach proved to be an important limitation of this study because the secondary and sensitivity analyses results were inconsistent with the primary endpoint result; further research into the role of complement is needed. Eculizumab is a humanized monoclonal antibody that targets complement protein 5 preventing it from being converted into proteins C5a and C5b. The complement system is involved in the pathogenesis of myasthenia gravis (MG). This was a Phase III, randomized, double-blinded, placebo-controlled study that enrolled a total of 125 patients with medically refractive, serology positive generalized MG to receive either eculizumab (62 patients) or placebo (63 patients). The primary outcome was the change in the Myasthenia Gravis-Activities of Daily Living Moster and Bhatti: J Neuro-Ophthalmol 2018; 38: 263-270 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Literature Commentary (MG-ADL) score between baseline and 26 weeks. The MGADL scale is a validated 8-item patient-reported outcome measure that assesses functional disability secondary to ocular (2 items), bulbar (3 items), respiratory (1 item), and gross motor or limb impairment (2 items). These 8 items are not weighted and are individually graded from 0 (normal) to 3 (most severe), providing a total MG-ADL score ranging from 0 to 24 points (1). The primary outcome of the study was not statistically significantly reached (least-squares mean [SEM] rank 56.6 [SEM 4.5] vs 68.3 [4.5]; rank-based treatment difference 211.7 [95% CI 224.3 to 0.96], P = 0.0698). In the discussion, the authors suggest that the method in which they measured the MG-ADL total score may have had something to do with the result. The MG-ADL total score was measured by using the worst-rank analysis of covariance. What that meant was that all patients who did not complete the study (no matter what the reason was for discontinuation) were assigned the lowest score, which may have skewed the results because not all patient discontinuations were due to worsening MG. In fact, of the 7 patients who were discontinued from the study, only 4 were due to MG worsening and the other 3 (all of whom were receiving eculizumab) were showing disease improvement. I am not sure how the designers of the study would have changed the primary outcome measure but, needless to say, I do not think they predicted this and in fact the article alludes to the fact that eculizumab has an application to the FDA pending for the treatment of refractory generalized MG. It is interesting to note that at the end of the discussion, the authors state, "the preplanned analyses and outcomes from REGAIN suggest a potential benefit of eculizumab treatment in patients with anti-acetylcholine receptor antibody-positive refractory generalized myasthenia gravis. These results should stimulate further research into the role of complement in this disease." Although certainly some of the secondary endpoints showed benefit of eculizumab including MG exacerbations (10% patients in eculizumab group vs 24% in the placebo group) and need for rescue therapy (10% in the eculizumab group vs 19% in the placebo group), to me, the authors seem to suggest that maybe other complement targeted medications, not necessarily eculizumab, need to be investigated. My hope is that it will be a similar situation to what we have seen with mycophenolate mofetil in MG. It works well for us clinically, but has failed to show benefit in numerous clinical trials. -M. Tariq Bhatti, MD This population-based study found that fourth nerve palsy occurs in 3.13 per 100,000 per year (95% CI 1.76-4.50) for women and in 8.55 per 100,000 per year (95% CI 5.96-11.14) for men. Congenital fourth nerve palsy was the most common etiology, followed by hypertension and trauma. I have a lot of problems with this study. First, the patients presented between 1978 and 1992; so, all had their diagnosis before high-resolution MRI and some even before MRI. Second, the claim that very few had undetermined etiology is likely related to the falsely high congenital etiology diagnosis by the authors. To diagnose a congenital etiology, only 1 of the following is required: history of infantile onset, documented vertical phoria 1. Wolfe GI, Herbelin L, Nations SP, Foster B, Bryan WW, Barohn RJ. Myasthenia gravis activities of daily living profile. Neurology. 1999;52:1487-1489. Tariq, I agree with your assessment. However, it turns out that besides the 28 other countries which have approved eculizumab, the FDA approved its use for MG in October 2017! This, despite the lack of reaching its primary endpoint in the Phase III trial reported here (more fake news?). Moster and Bhatti: J Neuro-Ophthalmol 2018; 38: 263-270 -Mark L. Moster, MD Dosunmu EO, Hatt SR, Leske DA, Hodge DO, Holmes JM. Incidence and etiology of presumed fourth cranial nerve palsy: a population-based study. Am J Ophthalmol. 2018;185:110-114. Purpose: To determine the incidence of isolated, presumed fourth nerve palsy in a defined population, and to report the frequency of each cause. Design: Retrospective, population-based case series. Methods: A population-based database was used to identify all cases of isolated fourth nerve palsy in Olmsted County, Minnesota, United States, diagnosed over a 15-year period (January 1, 1978-December 31, 1992). The most likely etiology was determined by review of the entire medical record by 2 ophthalmologists. A priori definitions were applied for assigning cause. The incidence of fourth nerve palsy and the frequency of each etiology were calculated. Decade of life at presentation was recorded. Results: Seventy-three patients (74 episodes, 70 [95%] unilateral) were identified. Mean age at presentation was 41.8 (range 3.3-81.6) years. The age- and sex-adjusted annual incidence rate was 5.73 per 100,000 per year (95% confidence interval [CI] 4.31-7.14). The most common etiology was presumed congenital (49%), followed by hypertension (18%) and trauma (18%). One patient (1%) had fourth nerve palsy owing to a known intracranial neoplasm. For 3 patients (4%), the cause of fourth nerve palsy was undetermined. The most common decade of presentation overall was the fourth decade, including for presumed congenital cases. Conclusions: In this population-based study, the majority of isolated fourth nerve palsies were presumed congenital, although they presented throughout adulthood. Other etiologies such as hypertension and trauma were less frequent, and in no case was an isolated fourth nerve palsy the presenting sign of an intracranial tumor. 267 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Literature Commentary (.2 prism diopters) predating diagnosis of fourth nerve palsy, presence of large vertical fusional amplitudes ($5 prism diopters), or history of long-standing head tilt. In addition, a hypertensive etiology required a systolic blood pressure .140 mm Hg, or a diastolic blood pressure .90 mm Hg, requiring treatment, and measured within 1 year of fourth nerve palsy diagnosis. There was no mention of whether the fourth nerve palsy resolved in these patients. A similar requirement for a diabetes etiology within 1 year of onset was used without mention of resolution. There were no cases with fourth nerve palsy as an initial manifestation of an intracranial mass. This alone questions the reliability of the information in this study. I just reviewed my records for the past 8 years. I have diagnosed, as a single practitioner, 15 tumors on the fourth nerve (14 presumptive schwannomas) and 1 meningioma presenting with isolated fourth nerve palsy. -Mark L. Moster, MD I am always interested in understanding the incidence of a particular disease and the frequency of the underlying causes of that particular disease. So, in that context, I found this study very informative, but as you mentioned Mark, there are some significant limitations to the study that cannot be overlooked when considering the relevance of the results. The Rochester Epidemiology Project database contains a treasure trove of information that is being tapped into, but as the authors themselves admit, the population of Olmsted County in Minnesota is predominately white and, therefore, may not be an adequate representation of other areas in the United States that have more ethnic diversity. As you know, I did my fellowship in Atlanta, Georgia, with Nancy J. Newman, a place in which there was a high frequency of sarcoidosis that was not even reported in this study. Also, let me add to what you said about the diagnosis and frequency of congenital fourth nerve palsy in this study. I found it very curious that the fourth decade was the peak decade for the diagnosis of a congenital fourth nerve palsy, followed by the second decade; which to me seems like quite an older population of patients that I typically would consider as having a congenital fourth nerve palsy. The authors hypothesized that this finding might be explained by the loss of the ability to maintain fusion or control of the vertical deviation over time, particularly made worse by presbyopia and looking down through bifocal lenses. One thing that I hoped the authors would have done was to provide us with their thoughts on how a patient with an acute onset isolated fourth nerve palsy should be evaluated. For example, do all these patients need an MRI? Based on your own practice's retrospective study, I am going to bet the farm that you, Mark, are going to say yes! -M. Tariq Bhatti, MD I say "yes" only if it does not spontaneously resolve after 3-6 months. By the way, how many times do you need to 268 remind me that you actually did do a fellowship in neuroophthalmology? -Mark L. Moster, MD Eade EL, Hardy TG, McKelvie PA, McNab AA. Review of extraocular muscle biopsies and utility of biopsy in extraocular muscle enlargement. Br J Ophthalmol. [published online ahead of print January 19, 2018] doi: 10.1136/bjophthalmol-2017-311147. Aims: To review the distribution of pathology in extraocular muscle (EOM) biopsies performed at a tertiary orbital center, identify clinical and imaging features that are associated with benign or malignant diseases, and indicate when biopsy is necessary for EOM enlargement. Methods: Retrospective case series including 93 patients with EOM enlargement who underwent an EOM biopsy. Clinical, radiological, and histopathological information was recorded from the medical records. Statistical analysis was used to compare variables between patients with malignant and benign biopsies. Results: The median age of subjects was 61.1 years. Fortyeight cases (52%) were benign and 45 (48%) were malignant. Those with malignant pathology were significantly older (P , 0.0001). Males were more likely affected by a benign disease and females by a malignancy (P = 0.029). A history of malignancy (P , 0.0001) and diplopia (P = 0.029) were significant factors in predicting a malignancy. Pain (P = 0.005) and eyelid erythema (P = 0.001) were more likely in benign conditions. Idiopathic orbital inflammation was the most common benign diagnosis and lymphoma the most common malignancy. Conclusions: Biopsy is warranted in those with an atypical presentation of EOM enlargement or suspected of having a malignancy. Some features such as age, sex, pain, diplopia, history of malignancy, and eyelid erythema may help indicate a particular diagnosis; however, clinical features and imaging findings are often not pathognomonic of each disease. This retrospective study of extraocular muscle (EOM) biopsies in 93 patients over a 15-year period is quite informative. The goal was to identify possible clinical or radiological markers which indicate that muscle biopsy is warranted and provide guidelines. As mentioned by the authors, the patients may not have typical presentations because they have come to be biopsied. Forty-eight percent of biopsies showed malignancy. Of these, lymphoma was most common (53%), followed by breast cancer (16%), melanoma (9%) carcinoid (5%), and adenocarcinoma (5%). Associated with malignancy were older age, female sex, diplopia, and a previous history of cancer. Of the 52% with benign biopsies, 55% had idiopathic orbital inflammatory disease (IOID), 21% thyroid eye disease (TED), 4% granulomatosis with polyangiitis (GPA), 4% IgG4-related disease, 4% infection, and 1 each had amyloidosis, schwannoma, reactive lymphoid Moster and Bhatti: J Neuro-Ophthalmol 2018; 38: 263-270 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Literature Commentary hyperplasia, cyst, lipoma, and lipogranuloma. Associated with benign pathology were younger age, male sex, lid erythema, and pain. Eight of the patients initially treated with systemic steroids had recurrent episodes. The pathologic diagnoses included 2 with IOID, 2 with lymphoma, and 1 each with GPA, IgG4-related disease, TED, and adenoid cystic carcinoma. What I learned from this article is that biopsy yields many different diagnoses that would change therapies, whether it be for cancer or differing types of inflammation. Although these patients had reasons to be biopsied, it is not possible to glean from this article what was atypical clinically or radiographically that led to the decision to biopsy. -Mark L. Moster, MD As this study has demonstrated, the differential diagnosis of an enlarged EOM is quite extensive and reminds me of a wonderful review article that was written in Survey of Ophthalmology in 1999 with Dr. Rootman as senior author (1). As you know, the diagnosis of TED is often made on clinical grounds with supportive endocrine and radiological findings. Therefore, I found the reasons why the 10 patients with TED were biopsied very interesting: • Unilateral involvement • Focal single EOM involvement • Multiple EOM involvement • Orbital mass adjacent to an enlarged EOM • Euthyroid EOM enlargement • Unilateral involvement of multiple EOMs with history of breast cancer or eosinophilic granuloma. I do not think readers of this article will jump to the conclusion that EOM biopsy should be performed on a routine basis. In fact, the authors make a conclusion that I think has been the paradigm for many decades, which is ".biopsy is required in patients with a suspicion of malignancy or those who present or progress in an atypical fashion." -M. Tariq Bhatti, MD 1. Lacey B, Chang W, Rootman J. Nonthyroid causes of extraocular muscle disease. Surv Ophthalmol. 1999;44:187-213. Nath S, Badhiwala JH, Alhazzani W, et al. Atraumatic versus traumatic lumbar puncture needles: a systematic review and meta-analysis. Lancet. 2018;391:1197-1204. Background: Atraumatic needles have been proposed to lower complication rates after lumbar puncture. However, several surveys indicate that clinical adoption of these Moster and Bhatti: J Neuro-Ophthalmol 2018; 38: 263-270 needles remains poor. We did a systematic review and meta-analysis to compare patient outcomes after lumbar puncture with atraumatic needles and conventional needles. Methods: In this systematic review and meta-analysis, we independently searched 13 databases with no language restrictions from inception to August 15, 2017, for randomized controlled trials comparing the use of atraumatic needles and conventional needles for any lumbar puncture indication. Randomized trials comparing atraumatic and conventional needles in which no dural puncture was performed (epidural injections) or without a conventional needle control group were excluded. We screened studies and extracted data from published reports independently. The primary outcome of postdural-puncture headache incidence and additional safety and efficacy outcomes were assessed by random-effects and fixed-effects meta-analysis. This study is registered with the International Prospective Register of Systematic Reviews, number CRD42016047546. Findings: We identified 20,241 reports; after exclusion, 110 trials conducted between 1989 and 2017 from 29 countries, including a total of 31,412 participants, were eligible for analysis. The incidence of postdural-puncture headache was significantly reduced from 11.0% (95% confidence interval [CI] 9.1-13.3) in the conventional needle group to 4.2% (3.3-5.2) in the atraumatic group (relative risk 0.40, 95% CI 0.34-0.47, P , 0.0001; I2 = 45.4%). Atraumatic needles were also associated with significant reductions in the need for intravenous fluid or controlled analgesia (0.44, 95% CI 0.29-0.64; P , 0.0001), need for epidural blood patch (0.50, 0.33-0.75; P = 0.001), any headache (0.50, 0.43-0.57; P , 0.0001), mild headache (0.52, 0.38-0.70; P , 0.0001), severe headache (0.41, 0.28-0.59; P , 0.0001), nerve root irritation (0.71, 0.54-0.92; P = 0.011), and hearing disturbance (0.25, 0.11-0.60; P = 0.002). Success of lumbar puncture on first attempt, failure rate, mean number of attempts, and the incidence of traumatic tap and backache did not differ significantly between the 2 needle groups. Prespecified subgroup analyses of postdural-puncture headache revealed no interactions between needle type and patient age, sex, use of prophylactic intravenous fluid, needle gauge, patient position, indication for lumbar puncture, bed rest after puncture, or clinician specialty. These results were rated high-quality evidence as examined using the grading of recommendations assessment, development, and evaluation. Interpretation: Among patients who had lumbar puncture, atraumatic needles were associated with a decrease in the incidence of postdural-puncture headache and in the need for patients to return to hospital for additional therapy, and had similar efficacy to conventional needles. These findings offer clinicians and stakeholders a comprehensive assessment and high-quality evidence for the safety and efficacy of atraumatic needles as a superior option for patients who require lumbar puncture. This article is a meta-analysis of randomized controlled trials comparing the complications of lumbar puncture (LP) using the conventional needle with those with the atraumatic needle. Most patients had LP for spinal anesthesia, followed by diagnostic LP and myelography. Previous studies have shown that conventional needles cut through tissues, causing irregular lacerations that can increase the potential for cerebrospinal fluid (CSF) leak. Atraumatic needles separate and dilate dural 269 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Literature Commentary fibers, resulting in a smaller pinpoint opening after needle removal, which limits the CSF leak. The findings in this analysis are compelling. All complications were less with the atraumatic needle. These included a 60% decrease in headache, as well as a decrease in need for intravenous fluids, analgesics, and epidural blood patch. The authors note that many clinicians do not use the atraumatic needles because of lack of awareness of their existence. Although these needles may cost more, they may save money in the long run because of the fewer costly complications. I think it may be worthwhile for those of us doing our own LPs to look into these needles and to make the other practitioners who may be doing LPs on our patients to do the same. Nearly all LPs performed on my patients are performed in the neuroradiology suite (either computed tomography or fluoroscopy guided), mostly because of the technical difficulty of doing the procedure in clinic on patients with suspected idiopathic intracranial hypertension. I have found that it is quite infrequent that my patients require an epidural blood patch for a post-LP headache. The spinal needle used at Duke is an atraumatic spinal needle (Gertie Max spinal needles; International Medical Development, Huntsville, AL). As you said Mark, the results of this systemic review and meta-analysis are quite strong, and writing candidly, I think conventional spinal needles should not be manufactured any longer.how about that for a strong statement! -Mark L. Moster, MD -M. Tariq Bhatti, MD 270 Moster and Bhatti: J Neuro-Ophthalmol 2018; 38: 263-270 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.