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Show Literature Commentary Tamhankar M, Biousse V, Ying G, Prasad S, Subramanian P, Lee M, Eggenberger E, Moss H, Pinelas S, Bennett J, Osborne B, Volpe N, Liu G, Bruce B, Newman N, Galetta S, Balcer L. Isolated third, fourth, and sixth cranial nerve palsies from presumed microvascular versus other causes a prospective study. JAMA Ophthalmol. 2013;120:2264-2269. Purpose: To estimate the proportion of patients presenting with isolated third, fourth, or sixth cranial nerve palsy of presumed microvascular origin vs other causes. Design: Prospective, multicenter, observational case series. Participants: A total of 109 patients aged 50 years or older with acute isolated ocular motor nerve palsy. Testing: Magnetic resonance imaging (MRI) of the brain. Main Outcome Measures: Causes of acute isolated ocular motor nerve palsy (presumed microvascular or other) as determined with early MRI and clinical assessment. Results: Among 109 patients enrolled in the study, 22 had cranial nerve III palsy, 25 had cranial nerve IV palsy, and 62 had cranial nerve VI palsy. A cause other than presumed microvascular ischemia was identified in 18 patients (16.5%; 95% confidence interval, 10.7-24.6). The presence of 1 or more vasculopathic risk factors (diabetes, hypertension, hyper-cholesterolemia, coronary artery disease, myocardial infarc-tion, stroke, and smoking) was significantly associated with a presumed microvascular cause (P ¼ 0.003, Fisher exact test). Vasculopathic risk factors were also present in 61% of patients (11/18) with other causes. In the group of patients who had vasculopathic risk factors only, with no other signifi-cant medical condition, 10% of patients (8/80) were found to have other causes, including midbrain infarction, neoplasms, inflammation, pituitary apoplexy, and giant cell arteritis (GCA). By excluding patients with third cranial nerve palsies and those with GCA, the incidence of other causes for isolated fourth and sixth cranial nerve palsies was 4.7% (3/64). Conclusions: In our series of patients with acute isolated ocular motor nerve palsies, a substantial proportion of patients had other causes, including neoplasm, GCA, and brainstem infarction. Brain MRI and laboratory workup have a role in the initial evaluation of older patients with isolated acute ocular motor nerve palsies regardless of whether vascular risk factors are present. This is a thought-provoking article, which calls into question the common practice of following elderly patients with presumed vasculopathic ocular motor cranial nerve palsies without neuroimaging. Although on initial calculation, 16.5% had a non-microvascular cause, the authors claim that for those with third nerve palsy, there is little controversy and most neuro-ophthalmologists will agree on imaging. In analyzing the message of this article, we should concentrate on where there is controversy (fourth and sixth nerve palsies), that 3/64 patients were found to have structural lesions. Let us see what difference it would have made had they not been immedi-ately imaged. The first was a patient with vasculopathic risk factors and a midbrain infarct in whom the treatment of risk factors is identical with or without a small, likely lacunar, infarct. The second was a woman with petroclival meningi-oma subsequently treated with surgery. In her case, when the diplopia did not resolve in a few months, she could have been imaged and subsequently treated with surgery. The third case was a man with lymphoma. He too could have been diagnosed when he worsened or did not recover within the following few months. One could make the case that in this 1 patient of 64 who had imaging, earlier treatment might have made a difference. I would like to question the authors who saw these 3 patients to see if there was any clue in the face-to-face history and examination of a non-microvascular diagnosis. As an author of this article, Michael, you may know the answer to this. One valid point the authors make is that demyelinating disease may present with a cranial neuropathy. Because we are seeing patients with multiple sclerosis (MS) older than 50 years, those of us who are comfortable following elderly patients without imaging may want to begin scanning patients who are below 60 years old. The authors point out the importance of MRI in reassuring those who want to know there is no lesion. Although this is true, there is an approach to patients who want reassurance that they do not need an MRI. Explaining to them that there is a small risk of a lesion and that I am willing to follow them and not obtain an MRI also reassures this patient population. In my 30 years in the neuro-ophthalmology world, I cannot recall a patient with a fourth or sixth palsy where the delay in imaging made a difference in outcome. So for me, I will likely scan a few more patients and perhaps follow only those a little older, but not yet ready to get MRI on all patients. -Mark L. Moster, MD Like you, Mark, I was trained to follow patients with vascular risk factors who have complete third nerve palsies Moster and Lee: J Neuro-Ophthalmol 2014; 34: 87-91 87 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. with pupil sparing and fourth and sixth nerve palsies. If the patient did not show improvement in 6 weeks, I would scan them. I have not run into trouble with this practice, but I have not been practicing for 30 years! More and more, I am moving toward ordering neuro-imaging for the patient with complete third nerve palsy and pupil sparing. Interestingly, in this article, a patient such as this had pituitary apoplexy. I also have a lower threshold for imaging the patient with an isolated fourth or sixth because of the easy availability of neuroimaging and the patient-centered environment in which we exist. I think about other cranial nerve issues that we encounter such as trigeminal neuralgia (10% have compressive lesions) and hemifacial spasm (1% have a neoplastic cause). My practice has been to image these patients, and I believe that most literature supports that recommendation. The question is "What is our threshold for fourth and sixth nerve palsies?" I think it is both reasonable to image and also reasonable to hold off initial imaging for the patient with an isolated fourth or sixth nerve palsy. I agree with you that much of it depends on the face-to- face interaction in obtaining a detailed history and per-forming a careful neuro-ophthalmic examination. -Michael S. Lee, MD Friedman DI, Liu GT, Digre KB. Revised diagnostic criteria for the pseudotumor cerebri syndrome in adults and children. Neurology. 2013;81: 1159-1165. The pseudotumor cerebri syndrome (PTCS) may be primary (idiopathic intracranial hypertension) or arise from an identifiable secondary cause. Characterization of typical neuroimaging abnormalities, clarification of normal open-ing pressure in children, and features distinguishing the syndrome of intracranial hypertension without papilledema from intracranial hypertension with papilledema have furthered our understanding of this disorder. We propose updated diagnostic criteria for PTCS to incorporate ad-vances and insights into the disorder realized over the past 10 years. The authors propose updated criteria for the probable and definite diagnosis of PTCS. I think the most striking findings from this article include the following: 1. PTCS without papilledema is a definite diagnosis only if the patient has a sixth nerve palsy (and meets the rest of the Dandy criteria). 2. If the patient does not have a sixth nerve palsy, PTCS without papilledema is probable if the patient has at least 3 neuroimaging findings such as flattened globes, par-tially empty sella, narrowed transverse sinuses, and wid-ened perioptic subarachnoid space (and meets the rest of the Dandy criteria). 3. The threshold for opening pressure in sedated or obese children (280 mm H2O) may be higher than adults (250 mm H2O). Interestingly, the authors suggest that a gadolinium-enhanced brain MRI alone is adequate in typical (female and obese) patients to rule out intracranial causes. They note that a brain MRV is only required for atypical patients to rule out cerebral venous sinus thrombosis (CSVT). I tend to order both brain MRI and MRV for all patients including the obese woman because they can also have CSVT. In one study (1), 10 of 106 patients with presumed PTC were found to have CSVT, and 4 of those patients were obese women. The question is whether it is cost-effective to order an MRV in all patients, and I fall on the side that it is. Overall, I think this represents a critically important and sensible update to the diagnostic criteria. -Michael S. Lee, MD I agree that the diagnostic criteria proposed make sense. Any diagnostic criteria for PTCS are somewhat arbitrary, because there is no biomarker for PTCS. Opening pressure on LP is just one measurement in time, and papilledema is not always present. I also order MRVs on typical PTC patients who are young and obese, but many patients have already had an MRI withoutMRV when I initially evaluate them. In these patients, I am comfortable with the authors' guidelines and often will not order an MRV. Nonetheless, when an MRV has not been performed, it is important that the radiologist has looked for signs of venous sinus thrombosis on the MRI. The following 2 statements in the article, taken together, were of particular interest to me and raise a controversial question, deserving of study 1. "Notably, LP is always required in the workup of a patient considered to have PTCS." 2. "The occasional patient with a significant tonsillar descent and an otherwise typical presentation of PTCS may be at high risk for herniation with LP and therefore can be diagnosed with PTCS presumptively." If some patients can presumptively be diagnosed with PTCS, then perhaps others can as well. The study that I think needs to be performed is looking at all the CSF examination in typical PTC patients, who are young obese women with a typical history and normal MRI and MRV. We need to know in what percent of these typical patients a diagnosis other than PTC was made and whether there are clinical clues in those patients suggesting an alternative diagnosis. That will help determine if our current rule that all patients receive an LP will "hold water" (that is, cm H2O). -Mark L. Moster, MD 88 Moster and Lee: J Neuro-Ophthalmol 2014; 34: 87-91 Literature Commentary Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. REFERENCE 1. Lin A, Foroozan R, Danesh-Meyer HV, De Salvo G, Savino PJ, Sergott RC. Occurrence of cerebral venous sinus thrombosis in patients with presumed idiopathic intracranial hypertension. Ophthalmology. 2006;113:2281-2284. Deschamps R, Deschamps L, Depaz R, Coffin- Pichonnet S, Belange G, Jacomet P, Vignal C, Benillouche P, Herdan M, Putterman M, Couvelard A, Gout O, Galatoire O. High prevalence of IgG4-related lymphoplasmacytic infiltrative disorder in 25 patients with orbital inflammation: a retrospective case series. Br J Ophthalmol. 2013;97:999-1004. Aims: To evaluate retrospectively the prevalence of positive IgG4-immunostaining in orbital tissue of patients with idio-pathic orbital inflammation and to compare the clinical, radiographic, and pathologic features among patients with and without IgG4-positive cells. Patients and Methods: Twenty-five patients with biopsy-proven idiopathic orbital inflammation examined from Jan-uary 2006 through December 2011 were included. Immu-nohistochemistry with IgG and IgG4 immunostaining from biopsy specimens of all patients was performed. Tissue with more than 10 IgG4-positive plasma cells per high-power field and with a ratio of IgG4+/IgG+ plasma cells of more than 40% was scored as positive. Histopathologic features, demographic and clinical data, radiologic findings, and treatment and follow-up information for each patient were analyzed. Results: Immunohistochemical staining showed 10 cases (40%) were IgG4 positive. The symptoms and signs included eyelid or periocular swelling/mass in all, pain (3/10), extraocular muscle restriction (3/10), proptosis (5/10), and/or decreased vision (4/10). Demographic and clinical findings of these patients did not differ from those with IgG4-negative cells. The presence of positive IgG4- immunostaining in orbital tissue was significantly asso-ciated with characteristic pathological features (more background fibrosis, lymphoid hyperplasia, plasma cells, and phlebitis). Conclusions: Finally, 40% of patients with biopsy-proven orbital inflammation were classified as IgG4-RD, with typical histological features, but without specific clinical or radio-logical findings. This article points out that orbital IgG4-related disease (IgG4RD) may present in an identical fashion to idiopathic orbital inflammatory syndrome (IOIS). A problem with interpreting the findings is the lack of a standard definition for IgG4 positivity. This article used the criteria of more than 10 IGG4+ cells per high-power field and a ratio of IgG4+/IgG+ cells of 40%. Although others have used this cutoff in the literature, it is somewhat arbitrary. In fact, if a more stringent cutoff of .100 IgG4+ cells per high-power field had been applied, would have only been one case considered positive. Additionally, in this retrospective series, serum IgG4 levels were not available, which, if obtained, would help support the diagnosis. We often use pain as a criterion distinguishing IOIS from lymphoma and other infiltrative lesions. It is surpris-ing to see such a low percentage of patients with pain in both the IgG4+ (30%) and IgG42 (33%) groups in this series. It is also surprising to see a similar number of bilateral cases, regardless of IgG4 status. I would have expected more bilateral cases with IgG4 positivity. This article does not add much definitive knowledge to the literature. However, because IgG4RD has systemic ramifications and the presentation seems identical to IOIS in many cases, this report will decrease my threshold for ordering serum IgG4 levels in future patients with orbital disease. -Mark L. Moster, MD So, IgG4RD did not differ clinically from the non- IgG4RD. Regardless of that, I have begun ordering serum IgG4 levels on patients with orbital inflammation. Hope-fully, as we move forward in our understanding of the disease, we can identify more targeted ways to manage these patients beyond systemic corticosteroids. The authors do not indicate whether patients had corticosteroid treatment before the biopsy, which ought to affect the biopsy results. It seems likely that all of the patients had corticosteroids before the biopsy and that many more could have had IgG4RD than reported here. -Michael S. Lee, MD Bowers A, Keeney K, Peli E. Randomized crossover clinical trial of real and sham peripheral prism glasses for hemianopia. JAMA Ophthalmol. [published ahead of print November 7, 2013] doi: 10.1001/jamaophthalmol 2013.5636. Importance: There is a major lack of randomized controlled clinical trials evaluating the efficacy of prismatic treatments for hemianopia. Evidence for their effectiveness is mostly based on anecdotal case reports and open-label evalua-tions without a control condition. Objective: To evaluate the efficacy of real relative to sham peripheral prism glasses for patients with complete hom-onymous hemianopia. Design, Setting, and Participants: Double-masked random-ized crossover trial at 13 study sites, including the Peli laboratory at Schepens Eye Research Institute, 11 vision rehabilitation clinics in the United States, and 1 in the United Kingdom. Patients were 18 years or older with complete homonymous hemianopia for at least 3 months and without visual neglect or significant cognitive decline. Intervention: Patients were allocated by minimization into 2 groups. One group received real (57-prism diopters [PD]) oblique and sham (,5-PD) horizontal prisms; the other received real horizontal and sham oblique, in counter-balanced order. Each crossover period was 4 weeks. Main Outcomes and Measures: The primary outcome was the overall difference, across the 2 periods of the cross-over, between the proportion of participants who wanted to Moster and Lee: J Neuro-Ophthalmol 2014; 34: 87-91 89 Literature Commentary Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. continue with (said yes to) real prisms and the proportion who said yes to sham prisms. The secondary outcome was the difference in perceived mobility improvement between real and sham prisms. Results: Of 73 patients randomized, 61 completed the crossover. A significantly higher proportion said yes to real than sham prisms (64% vs 36%; odds ratio, 5.3; 95% confidence interval, 1.8-21.0). Participants who continued wear after 6 months reported greater improvement in mobil-ity with real than sham prisms at crossover end (P = 0.002); participants who discontinued wear reported no difference. Conclusions and Relevance: Real peripheral prism glasses were more helpful for obstacle avoidance when walking than sham glasses, with no differences between the horizontal and oblique designs. Peripheral prism glasses provide a simple and inexpensive mobility rehabilitation intervention for hemianopia. This was a prospective, multicentered, double-masked randomized crossover trial comparing patient satisfaction using sector, high-power, peripheral prism glasses vs sham among patients with complete homonymous hemianopia. The real prisms were 57-prism diopters (PD) oriented either base out or obliquely on the spectacle lens ipsilateral to the hemianopia. The sham prism was 5-PD and coated to mimic the blurring from the 57-PD prism. Subjects wore either real or sham prisms for 4 weeks, and then crossed over to the opposite prism for 4 weeks. At the end of each period, the subjects were asked to assess mobility and interest in continuing prisms. When forced to choose, 60% chose the real prism, but more than 1/3 chose the sham prism, which highlights the effects of placebo and the need for a control group. In this study, only limited training was provided and 12 patients (16%) withdrew from the study and 35 (48%) discontinued prism use at the end of the study. This could represent lack of training vs lack of efficacy. I have had some success with the 57-PD oblique prisms in patients with complete homonymous hemianopia. There is definitely a learning curve to using them, and I have patients visit with an occupational therapist to provide extensive training. To me, patient training seems to make a big difference, but obviously this factor needs to be studied. -Michael S. Lee, MD Surprisingly after the first period, when some had only sham prism and some real prism-58% endorsed a desire to continue wearing the real prism and 46% the sham prism- not a significant or a whole lot of difference. However, by the end of the second period, when the patients had expe-rience with both a real and a sham prism, 71% wanted to continue the real prism and only 27% the sham prism. The main outcome of the study was whether patients self-reported a desire to continue wearing prism and the secondary outcome was a self-reported benefit in mobility. With that goal, this study does demonstrate that prisms do benefit, but follow-up should reveal how much benefit and what kind of difference it makes in daily activities. The authors acknowledged that "we were unable to ensure total masking of data collectors" which is of concern. -Mark L. Moster, MD Pfeffer G, Burke A, Yu-Wai-Man P, Compston OA, Chinnery PF. Clinical features of MS associated with Leber hereditary optic neuropathy mtDNA mutations. Neurology. 2013 Nov 6 (epub ahead of print). Objective: To determine whether the association between MS and Leber hereditary optic neuropathy (LHON) (known as "Harding disease") is a chance finding, or the 2 disor-ders are mechanistically linked. Methods: We performed a United Kingdom-wide prospec-tive cohort study of prevalent cases of MS with LHON mito-chondrial DNA (mtDNA) mutations. The new cases were compared with published cases, enabling a comprehensive clinical description. We also performed a meta-analysis of studies screening patients with MS for LHON mtDNA mu-tations to find evidence of a genetic association. Results: Twelve new patients were identified from 11 pedigrees, and 44 cases were identified in the literature. The combined cohort had the following characteristics: multiple episodes of visual loss, predominance for women, and lengthy time interval before the fellow eye is affected (average 1.66 years), which is very atypical of LHON; conversely, most patients presented without eye pain and had a poor visual prognosis, which is unusual for optic neuritis associated with MS. The number of UK cases of LHON-MS fell well within the range predicted by the chance occurrence of MS and the mtDNA mutations known to cause LHON. There was no association between LHON mtDNA mutations and MS in a meta-analysis of the published data. Conclusions: Although the co-occurrence of MS and LHON mtDNA mutations is likely to be due to chance, the resulting disorder has a distinct phenotype, implicating a mechanistic interaction. Patients with LHON-MS have a more aggressive course, and prognostication and treatment should be guarded. This study has limitations of being based on a survey of neurologists voluntarily responding with reports of both LHON and MS in the same patient. Therefore, it may underestimate the number of cases. Nonetheless, based on the rarity of the association, it provides support to the notion that LHON does not cause an MS-like illness, but rather that the relatively common illness of MS occurs in some patients who also have LHON. Intriguing are the phenotypic features that are different from either MS or LHON and in some ways an average of both. For instance, the ratio of women to men 2.1/1 is much greater than in LHON but less than in MS. The visual loss had features of both LHON and MS but not typical for either. Four of 12 patients had pain, 5 patients 90 Moster and Lee: J Neuro-Ophthalmol 2014; 34: 87-91 Literature Commentary Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. had more than 2 episodes of visual decline, and 4 patients had some degree of recovery. Half the patients ended with visual acuity less than 20/400. One patient had bilateral simultaneous visual loss. When sequential visual loss occurred, the interval was more than 1 year in 7 patients and up to 17 years in 1 patient. The authors concluded that the LHON-MS phenotype, which is distinct from either disorder, may have several possible causes. One possibility is that having the mtDNA mutation modifies the MS phenotype. The other is that the genetic and environmental factors that predispose to MS precipitates acute LHON in carriers, mostly women, who would have otherwise remained asymptomatic. -Mark L. Moster, MD Despite the suggested reasonable proposals for the atypical phenotype, the authors do not describe the orbital MRI findings, which could separate out these possibilities. Optic nerve enhancement on the MRI would strongly suggest optic neuritis, and lack of enhancement would more likely indicate LHON. This may help us understand why these patients lose vision, but it does not change the fact that patients with LHON and concomitant MS tend to be young women with painless sequential visual loss sometimes separated by years and they have a poor visual prognosis. -Michael S. Lee, MD Tanda ML, Piantanida E, Liparulo L, Veronesi G, Lai A, Sassi L, Pariani N, Gallo D, Azzolini C, Ferrario M, Bartalena L. Prevalence and natural history of Graves' orbitopathy in a large series of patients with newly diagnosed Graves' hyperthyroidism seen at a single center. J Clin Endocrinol Metab. 2013;98:1443-1449. Background: The prevalence and natural history of Graves' orbitopathy (GO) are poorly documented. Methods: A large series of 346 patients with newly diagnosed and recent onset Graves' hyperthyroidism seen at a single (nontertiary referral) center over an 8-year period were enrolled in an observational prospective study and evaluated for GO activity and severity according to the EU-GOGO (European Group on Graves' Orbitopathy) criteria. After excluding patients immediately treated for moderate-to- severe GO, patients undergoing total thyroidectomy or radioactive iodine treatment, and patients lost to follow-up, 237 patients were submitted to antithyroid drug (ATD) treatment, with ocular evaluation at 6, 12, and 18 months. Results: Among the whole cohort, at presentation 255 (73.7%) had no ocular involvement, 70 (20.2%) had mild and inactive GO, 20 (5.8%) had moderate-to-severe and active GO, and 1 (0.3%) had sight-threatening GO with dysthyroid optic neuropathy. Of the 237 patients who com-pleted the 18-month follow-up during or after ATD treatment, 194 (81.9%) had no GO at baseline. Progression to moderate-to-severe GO occurred in 5 (2.6%) of these pa-tients. Of the 43 (18.1%) patients with mild and inactive GO at baseline, 1 (2.4%) progressed to moderate-to-severe GO, and 25 (58.1%) experienced complete remission. Conclusions: Most patients with newly diagnosed Graves' disease have no ocular involvement. Moderate-to-severe and active GO or sight-threatening GO are rare at pre-sentation and rarely develop during ATD treatment. Most patients (.80%) with no GO at baseline do not develop GO after an 18-month follow-up period. Remission of mild GO occurs in the majority of cases. It is often quoted that approximately 50% of patients with Graves' disease will develop ocular involvement. In this relatively large prospective cohort of patients with newly diagnosed Graves' disease at a nontertiary care facility, the authors found moderately smaller numbers. At presenta-tion, 26% of patients had evidence of thyroid eye disease (TED). Of these, 21 patients (6%) had moderate-to-severe TED. Of the patients without TED at baseline, 13% devel-oped TED over 18 months of follow-up. Of the patients who completed follow-up, 6 (3%) developed moderate-to-severe disease. Interestingly, 58% of those with mild TED at baseline experience remission. I believe these data are helpful when counseling patients with Graves' disease, because we often do not get to see these patients unless they develop eye findings. We can tell our patients that less than 15% of those without TED at baseline go on to develop it and less than 5% develop moderate-to-severe disease in the first 18 months. If one has mild TED at baseline, there may be a fair chance that it might resolve spontaneously. -Michael S. Lee, MD Michael, I am not so reassured because 26% already had TED at presentation and another 13% developed TED within 18 months. We have all seen patients with TED years after the original diagnosis of Graves' disease, and we do not know how many more would have been diagnosed with further follow-up. Another concern I have with this article is that the screening for TED was by an endocrinologist, which is less accurate than if an ophthalmologist were screening. Having less expertise in the examination can contribute to both falsely low or falsely high numbers in this study-particularly in the mild cases that resolved. -Mark L. Moster, MD Moster and Lee: J Neuro-Ophthalmol 2014; 34: 87-91 91 Literature Commentary Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. |