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Show Literature Commentary Jacob S, Viegas S, Leite MI, Webster R, Cossins J, Kennett R, Hilton-Jones D, Morgan BP, Vincent A. Presence and pathogenic relevance of antibodies to clustered acetylcholine receptor in ocular and generalized myasthenia gravis. Arch Neurol. 2012:1-8. Background: Clustered acetylcholine receptor antibodies (clustered AChR-Abs) have been detected in a proportion of patients with previously "seronegative" (SN) generalized myasthenia gravis (GMG), but their presence in patients with ocular MG (OMG) and their pathogenicity in vivo are unknown. Objective: To test the presence of clustered AChR-Abs and their pathophysiologic properties in patients with SNMG. Design: Screening and diagnostic tests. Setting: Regional specialist myasthenia center and clinical laboratory. Patients: Serum samples from 16 patients with SN and OMG were tested for binding to clustered AChRs. Results from 28 further SN patients (14 OMG) were correlated with their single fiber electromyography values. Main outcome measures: Presence, complement-fixation capacity, correlation with neurophysiologic changes, and in vivo pathogenicity of clustered AChR-Abs. Results: Up to 50% of patients with previous SN-OMG had complement-fixing IgG1 clustered AChR-Abs. IgG binding (n = 28) and complement deposition (n = 21) each correlated with the mean consecutive difference (jitter) on single-fiber electromyography. Injection of purified IgG from 2 patients with clustered AChR-Abs into wild-type or complement regulator-deficient mice reduced miniature end plate potential amplitudes to an extent similar to that found with AChR-Abs, and complement was deposited at the end plates. A trend was noted toward an increase in the number of packets of acetylcholine released (quantal content). Conclusions: A proportion of patients with SN-GMG or OMG have clustered AChR-Abs that correlate with their electro-physiologic features. Clustered AChR-Abs can passively transfer disease to mice, demonstrating their pathogenicity, and the mechanisms seem similar to those of patients with typical AChR-Abs. Approximately 50% of patients with ocular myasthenia gravis (OMG) are seronegative (SN) for the 3 most common acetylcholine receptor antibodies (AchRAb): binding, blocking, and modulating. Of these, very few demonstrate antibodies to muscle-specific kinase (MuSK), which makes a serologic diagnosis more challenging. Jacob et al describe a new assay, clustered AchRAb, which potentially could improve detection. They call it clustered because they transfect human embryonic kidney cells with AchR's and then add a protein, rapsyn, which causes these AchR to cluster densely together on the cell surface. The authors incubate these cells with the patient sera, wash, and fix them, and then add monoclonal Ab for detection of human immunoglobulin G (IgG) and IgM Ab. Eight of 16 patients with SN-OMG showed clustered AchRAbs. Because MG results in complement-mediated damage to neuromuscular junctions, the authors also assessed complement activation by detecting membrane attack complexes. Ten of 16 SN-OMG patients were pos-itive for complement activation. Finally, the authors injected purified IgG from patient sera into complement regulator deficient mice and found electrophysiologic and histopathologic changes consistent with MG. There is no obvious difference in disease activity or response to treatment among patients with Ab-positive or Ab-negative OMG. This paper suggests that the current commercially available assays are incapable of detecting the Ab to the AchR among those SN patients rather than true absence of these Abs. Indeed, the techniques described here were able to detect clustered AchRAb in only 50% of the OMG patients. Further room for improvement may be possible, but the current data are encouraging. -Michael S. Lee, MD In contrast to anti-MuSK antibodies, which are rarely positive in the 50% of OMG patients "seronegative" by the conventional AchRAb patients, it is helpful to have a test that is positive in 50% of those patients. If used clinically, this leaves only 25% requiring further diagnos-tic testing (i.e., single fiber electromyography). What remains to be seen is the sensitivity and specificity in larger populations and whether this test becomes com-mercially available. -Mark L. Moster, MD Bujak MC, Leung AK, Kisilevsky M, Margolin E. Monovision correction for small-angle diplopia. Am J Ophthalmol. 2012;154:586-592. Purpose: To assess quantitatively the efficacy of mono-vision correction in the treatment of acquired small-angle binocular diplopia in adult patients. Design: Prospective, interventional case series. Methods: Twenty patients with symptomatic diplopia were enrolled in a prospective treatment trial at a tertiary university neuro-ophthalmology practice. All had stable deviations of 10 prism diopters or less for more than 3 months. Each received monovision spectacles, contact lenses, or both with distance correction in the dominant Moster and Lee: J Neuro-Ophthalmol 2012; 32: 379-383 379 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. eye. Half received a +3.00-diopter add and the others received +2.50 diopters. The validated and standardized Diplopia Questionnaire and Amblyopia and Strabismus Questionnaire were used to quantify the efficacy of mono-vision correction for diplopia by measuring the functional impact on vision-specific quality of life. Results: primary outcome: Based on the results of the Diplopia Questionnaire, 85% of patients experienced significant improvement in diplopia symptoms after mono-vision correction. There was a statistically significant 58.6% improvement in the Diplopia Questionnaire score in our patients (P , .0001). secondary outcome: The Amblyopia and Strabismus Questionnaire scores demon-strated improved quality of life and daily function after monovision correction (P = .03), especially in the areas of double vision (P = .0003) and social contact and appearance (P = .0002). Conclusions: Monovision decreased the frequency of diplo-pia and improved subjects' quality of life. Monovision may be a feasible alternative for presbyopic diplopic patients who are dissatisfied with other conservative treatment options. The treatment of patients with diplopia is a challenge, with many having persistent symptoms despite prescription of prisms, botulinum toxin injections, and strabismus surgery. This prospective study of monovision to treat small-angle diplopia enrolled presbyopic patients older than 45 years with symptomatic diplopia greater than 50% of the time who were not considered surgical candidates because of the small angle of deviation. Some patients had difficulty with adapting to monovision or reported worsened stereoacuity. Nonetheless, at least half the patients had significant improvement. Monovision is a welcome additional thera-peutic option in patients with diplopia. -Mark L. Moster, MD This is not something that I would have considered, but it certainly makes sense. Sometimes I will prescribe a high plus lens in one eye to adequately blur out the second image. But as this article points out, why not make use of the "blurred" image! I cannot help but think this could also apply to patients with deviations greater than 10 prism diopters who cannot fuse with prisms or following eye muscle surgery. -Michael S. Lee, MD Hariri A, Lee SY, Ruiz-Garcia H, Nittala MG, Heussen FM, Sadda SR. Effect of angle of incidence on macular thickness and volume measurements obtained by spectral-domain optical coherence tomography. Invest Ophthalmol Vis Sci. 2012;53:5287-5291. Purpose: Evaluation of the effect of angle of incidence on macular thickness and volume measurements obtained by spectral-domain optical coherence tomography (OCT). Methods: A total of 30 eyes from 15 healthy young subjects underwent macular cube volume scans (512 · 128 protocol) following dilation using the Cirrus spectral domain OCT. For each eye, scans were obtained by positioning the scanning beam in the center of the dilated pupil, as well as in four eccentric positions (approximately 3 mm from the center), superior, inferior, nasal, and temporal to the pupillary center, to create oblique angles of incidence between the light beam and retina. In all cases, the region scanned by the volume cube was centered on the fovea. Macular thickness and vol-ume measurements were computed for volume scan acquis-itions, and differences in values between eccentric scans and the central scan were analyzed. Results: Retinal thickness and volume values were observed to increase significantly in all subfields for all eccentrically-obtained scans compared to scans obtained through the center of the pupil. The mean increase in thickness for the various scan positions and subfields ranged from 3.76 to 11.38. Scans that were displaced temporally consistently showed the greatest increase in thickness and volume, whereas nasally positioned scans showed the least increase. The increase in retinal thickness for all subfields correlated significantly with angle of inclination or tilting of the retina. Conclusions: Macular thickness and volume measurement results may be affected significantly by positioning of the scanning beam in the pupil and resultant angle of incidence on the retina. These findings suggest that care should be taken to position the scanning beam consistently in the center of the pupil to achieve reliable measurements. Nearly all (note that I said "nearly all," not "all") neuro-ophthalmologists use optical coherence tomography (OCT) to some extent, whether it is to measure retinal nerve fiber layer (RNFL) or to look for macular edema. In some cases, we follow serial measurements to determine progression or stability. The OCT machines typically are equipped with automated algorithms to calculate measurements, and these measurements are predicated upon b-scans taken through the center of the pupil and centered on the fovea or the optic disc. The authors compared the OCT retinal thick-ness of normal volunteers aimed eccentrically through the pupil vs centrally through the pupil with both centered on the fovea. The eccentric entry generates a tilted b-scan meaning either the left or right side of the scan is higher than the opposite side. They found that eccentric OCT scans showed thicker maculae than centered ones. The max-imal difference was 30 mm or 10% of retinal thickness. Before you say, "this is so unlikely to happen," I spoke with my photography team and they mentioned they some-times shoot eccentrically through the pupil if some central lens or corneal opacity precludes a high-quality image. Intu-itively, this would be the same for the RNFL, where the tilted image would show a "thicker" RNFL compared with the en face one. This may be an issue to discuss with whoever does OCT scanning in the office. Also, we should proceed with caution when interpreting an OCT that shows a tilted b-scan. -Michael S. Lee, MD This article points out one important technical factor affecting thickness measurements in macular OCT. For an individual patient in a single study, the amount of change 380 Moster and Lee: J Neuro-Ophthalmol 2012; 32: 379-383 Literature Commentary Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. noted would not likely alter a clinical diagnosis (e.g., a 5 mm center subfield difference when normal is close to 300 mm). However, in following changes in a patient's clinical course or in clinical trials monitoring change over time, it would be important to keep the angle of incidence similar each time. -Mark L. Moster, MD McClelland C, Van Stavern GP, Shepherd JB, Gordon M, Huecker J. Neuroimaging in patients referred to a neuro-ophthalmology service. The rates of appropriateness and concordance in interpretation. Ophthalmology. 2012;119:1701-1704. Objective: Neuroimaging studies frequently are ordered to investigate neuro-ophthalmic symptoms. When misused, these studies are expensive and time consuming. This study describes the type and frequency of neuroimaging errors in patients referred to an academic neuro-ophthalmology service and measures how frequently these neuroimaging studies were reinterpreted. Design: Prospective cohort study. Participants: Eighty-four consecutive patients referred to an academic neuro-ophthalmology practice. Methods: From November 2009 through July 2010, 84 con-secutive new patients who had undergone a neuroimaging study in the last 12 months specifically to evaluate their presenting neuro-ophthalmic symptoms were enrolled prospectively. Participants then underwent a complete neuro-ophthalmic evaluation, followed by a review of prior neuroimaging. Questions regarding appropriateness of the most recent imaging, concordance of radiologic interpreta-tion, and re-evaluation of referring diagnoses were answered by the attending physician. Main outcome measures: The frequency and types of errors committed in the use of neuroimaging and the frequency of reinterpretation of prereferral neuroimaging studies after neuro-ophthalmic history and examination. Results: Most study participants (84.5%; 71/84) underwent magnetic resonance imaging before referral; 15.5% (13/84) underwent only computed tomography. The rate of suboptimal neuroimaging studies was 38.1% (32/84). The 3 most common reasons for suboptimal studies were incomplete area of imaging (34.4%; 11/32), wrong study type (28.1%; 9/32), and poor image quality (21.9%; 7/32). Twenty-four of 84 subjects (28.6%) required additional neuroimaging. The authors agreed with the radiology interpretation of the prior neuroimaging studies in most patients (77.4%; 65/84). The most common anatomic locations for discordance in inter-pretation were the intraorbital optic nerve (35%; 7/20) and the brainstem (20%; 4/20). Conclusions: There was a high rate of suboptimal neuro-imaging studies performed in patients referred for neuro-ophthalmology examination. These findings have significant implications given the increasing attention to resource use currently and in the near future. Early in my career, when magnetic resonance imaging (MRI) emerged, there were predictions that the field of neuro-ophthalmology would become obsolete and replaced by neuroimaging ordered by referring clinicians. A few years later, we were receiving many consultations of asymptom-atic patients based on abnormalities found on neuroimaging that needed clinical correlation. As the authors point out, their study is limited by small sample size, inherent subjectivity in defining appropriate-ness, and inherent bias in reinterpretation of imaging. Nonetheless, the findings are similar to previous reports and collective clinical experience that neuroimaging performed before neuro-ophthalmic consultation is often suboptimal in numerous ways. My own sense is that when patients come in with a neuroimaging diagnosis, the diagnosis is changed approximately 20% of the time after reviewing the studies in the context of the clinical findings. In addition to the neuroimaging issue, the authors found that when patients arrived with a referring diagnosis, the diagnosis was changed 69% of the time following neuro-ophthalmic consultation. The training and ongoing experience of neuro-ophthalmologists and other subspecialists add value to patient care and is crucial for appropriate allocation of resources. A combination of diagnostic modalities with a skilled clinician guiding the testing yields the best results. -Mark L. Moster, MD This comes as no surprise to the neuro-ophthalmologist. As Mark alludes to, this study tells us what we already know. I think the big question is why? The current paper references the study of Elmalem et al (1), which focused on imaging of aneurysmal third nerve palsies. If an aneu-rysm was not diagnosed, the authors assumed this would be due to suboptimal scans. Rather, they found contrib-uting factors included that the wrong diagnosis was given to the radiologist and the radiologist lacked neuroradiol-ogy training. In the current paper by McClelland et al, the authors acknowledge the inability to gather this information. So what are the causes of suboptimal neuroimaging in patients that we see in consultation? Is most of the problem ignorance on the part of the referring clinician? Or is it because the support staff (secretary, nurse, or ophthalmic technician) fills out the imaging request? Is it because the radiology protocols for an orbital MRI do not have fat suppressed images or the clinician did not order an orbital MRI? Did the radiologist have too many films to read that day or lack of information or proper training? If we could dig deep and determine the answer(s), then perhaps we, as a neuro-ophthalmic community, could help improve the cost-effectiveness of imaging studies for our patients. -Michael S. Lee, MD 1. Elmalem VI, Hudgins PA, Bruce BB, Newman NJ, Biousse V. Underdiagnosis of posterior communicating aneurysm in noninvasive brain vascular studies. J Neuroophthalmol. 2011;31:103-109. Moster and Lee: J Neuro-Ophthalmol 2012; 32: 379-383 381 Literature Commentary Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Maralani PJ, Hassanlou M, Torres C, Chakraborty S, Kingstone M, Patel V, Zackon D, Bussière M. Accuracy of brain imaging in the diagnosis of idiopathic intracranial hypertension. Clin Radiol. 2012;67:656-663. Aim: To investigate the accuracy of individual and combi-nations of signs on brain magnetic resonance imaging (MRI) and magnetic resonance venography (MRV) in the diagnosis of idiopathic intracranial hypertension (IIH). Materials and methods: This study was approved by the institutional research ethics board without informed consent. Forty-three patients and 43 control subjects were retrospec-tively identified. Each patient and control had undergone brain MRI and MRV. Images were anonymized and reviewed by three neuroradiologists, blinded to clinical data, for the presence or absence of findings associated with IIH. The severity of stenosis in each transverse sinus was graded and summed to generate a combined stenosis score (CSS). The sensitivity, specificity, and likelihood ratios (LR) were calcu-lated for individual and combinations of signs. Results: Partially empty sella (specificity 95.3%, P , 0.0001), flattening of the posterior globes (specificity 100%, P , 0.0001), and CSS ,4 (specificity 100%, P , 0.0001) were highly specific for IIH. The presence of one sign, or any com-bination, significantly increased the odds of a diagnosis of IIH (LR+ 18.5 to 46, P , 0.0001). Their absence, however, did not rule out IIH. Conclusions: Brain MRI with venography significantly increased the diagnostic certainty for IIH if there was no evidence of a mass, hydrocephalus, or sinus thrombosis and one of the following signs was present: flattening of the posterior globes, partially empty sella, CSS ,4. How-ever, absence of these signs did not exclude a diagnosis of IIH. I know this has come up before and may seem like old news, but I was at a meeting where I presented a complicated case of idiopathic intracranial hypertension (IIH). A senior neuro-ophthalmologist commented that the diagnosis was a bit questionable because the patient did not have a partially empty sella. I did not know the pertinent data and could not definitively say how right or wrong he/she was. Additionally, most papers on this subject determine the sensitivity and specificity of either magnetic resonance imaging (MRI) or magnetic resonance venography (MRV) findings in IIH, whereas the current study looks at both studies together. Maralani et al retrospectively identified patients with IIH and a control group without IIH who underwent brain MRI and MRV. They assessed the studies in a masked fashion for 10 different features. There were significantly more women in the IIH group, but otherwise the groups were similar. The sensitivity of having any one of the 3 most specific findings (empty sella, flattened globe, narrow transverse sinus) was 86%. The sensitivity of an empty sella alone was 65%. If any 2 of the 3 features were present, the specificity was 100%. So, I think my colleague at that meeting might have had the numbers crossed. If you see an empty sella, the specificity approaches 95%. In patients with IIH, only about two-thirds have an empty sella. In either case, I just kept my mouth shut! -Michael S. Lee, MD This is another paper which confirms that patients with IIH have the findings of empty sella, flattening of the posterior globe and compression of the venous sinuses. Over the past few years, with numerous reports of neuro-imaging testing in IIH in the literature, I have seen a large increase in MRI (and CT) reports that comment "findings consistent with elevated intracranial pressure (ICP) as seen in IIH." These radiology reports result in referrals and phone consults which often are in patients without symp-toms or examination findings of elevated ICP. A study that can truly tell us the specificity of these findings in the broad-er population would be helpful. -Mark L. Moster MD Kennedy F, Lanfranconi S, Hicks C, Reid J, Gompertz P, Price C, Kerry S, Norris J, Markus HS, on behalf of the CADISS Investigators. Antiplatelets vs anticoagulation for dissection. CADISS nonrandomized arm and meta-analysis. Neurology. 2012;79:686-689. Objective: To present the results of the nonrandomized arm of the Cervical Artery Dissection in Stroke Study (CADISS-NR) trial, comparing anticoagulation and antiplatelets for prevention of recurrent stroke after carotid and vertebral dissection, and perform a meta-analysis of these results with previously published studies comparing the 2 thera-peutic strategies. Methods: A total of 88 patients from 22 centers with extracranial carotid and vertebral dissection were recruited within 1 month of symptom onset. The primary endpoint was recurrent stroke at 3 months. A systematic review was performed, and results of published studies included in a metaanalysis with the CADISS-NR results. Results: In CADISS-NR, one patient in each group had recurrent ischemic stroke (antiplatelet 1/59 [1.69%], anti-coagulation 1/28 [3.57%]). At the primary endpoint of 3 months, 3 (5.08%) antiplatelet patients had recurrent TIA, compared with none in the anticoagulation group. For metaanalysis, there were data from 40 nonrandomized studies including 1,636 patients. There was no significant difference between the 2 treatments in recurrent stroke risk (antiplatelet 13/499 [2.6%], anticoagulant 20/1,137 [1.8%], odds ratio [OR] 1.49) or risk of death (antiplatelet 5/499 [1.00%], anticoagulant 9/1,137 [0.80%], OR 1.27). Conclusion: There is no evidence for superiority of anti-coagulation or antiplatelet therapy in prevention of stoke after carotid and vertebral artery dissection; however, all data are from nonrandomized studies and randomized studies are required. The nonrandomized CADISS data show a lower rate of recurrent stroke than reported in some previous studies. Traditional teaching in neuro-ophthalmology has been to treat all suspected cervical dissections with anticoagulation, 382 Moster and Lee: J Neuro-Ophthalmol 2012; 32: 379-383 Literature Commentary Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. based on a high risk of impending stroke. However, there has been a move toward antiplatelet agents, particularly in patients seen following some time delay after initial symptom onset. The Cervical Artery Dissection in Stroke Study (CADISS) is an ongoing randomized trial comparing antiplatelet therapy with anticoagulation for cervical artery dissection. Inclusion criteria are imaging evidence of extracranial carotid or vertebral dissection presenting with ipsilateral TIA or stroke (including retinal ischemia), ipsilateral Horner syndrome, headache or neck pain, with known date of onset. Evidence of dissection must be on magnetic resonance imaging/magnetic resonance angiog-raphy, computed tomographic angiography or catheter angiography. The current study reviews the nonrandomized arm of patients not selected based on exclusion criteria, mainly a delay of .7 days (CADISS-NR). It compares treatment with antiplatelet agents vs warfarin, which was chosen at the discretion of the treating neurologist. The study found no difference in stroke between antiplatelet agents and antico-agulation (1.69% and 3.57%, respectively). However TIA was more frequent in the antiplatelet group (5.08% vs 0%). The authors also report a meta-analysis of the literature and found no difference in outcomes of antiplatelet vs antico-agulation treatment. Although this study supports the use of antiplatelet agents for cervical dissections, the limitations include its nonrandomized nature, the low recurrence rate compared with other studies (attributed partly to the delayed recruitment of 10.8 days on average), and the lack of a standardized treatment regimen for both antiplatelet agents and anticoagulation. The CADISS is ongoing with 250 patients randomized and treated within 7 days of onset and should provide more valuable data in the near future. -Mark L. Moster, MD I think it is important to note that CADISS and CADISS-NR are open label, so there are inherent biases on the part of the investigators and patients when it comes to symptoms of TIA. The primary objectives of CADISS, which the authors describe as a feasibility study include "(a) There are sufficient clinical endpoints to provide the power to determine treatment effect. (b) Ade-quate numbers of patients can be recruited." The authors are attempting to generate data to determine their power calculations and it is uncertain if they can recruit enough patients. This helps explain why the patients receive vary-ing antiplatelet agents and doses at the discretion of the physician in both CADISS and CADISS-NR. So, while I agree that CADISS will provide further information on this issue of antiplatelets vs anticoagulants in dissection, it would not supply the final conclusion until a double-masked trial with standardized dosing takes place. -Michael S. Lee, MD Moster and Lee: J Neuro-Ophthalmol 2012; 32: 379-383 383 Literature Commentary Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. |
