Literature Commentary

To compare the incidence of cardiac and cerebrovascular events following non-arteritic anterior ischemic optic neuropathy (NAION) compared to published control data using the Framingham, United Kingdom Prospective Diabetes Study (UKPDS) and the National Vascular Disease Prevention Alliance (NVDPA) data. A retrospective study of all consecutive cases of NAION between 1990 and 2005. Patients were stratified into those with or without prior ischemic events and into diabetics and non-diabetics. Outcome measures included cardiovascular morbidity, cerebrovascular events and the Framingham, UKPDS and NVDPA scores for each patient. According to the NVDPA, the average absolute 5-year risk for cardiovascular disease (CVD) was 8.98, compared to 9 CVD events in our study. In the diabetic patients, 5 (17%) had a cardiac event and 2 (8%) had a cerebral vascular accident (CVA). Based on the UKPDS risk calculator, the average 10-year risk for cardiac events is 21.6%, CVA 26.8%. In the non-diabetics, there were 3 cases (7.5% ) of myocardial infarction, compared to the average 10-year Framingham risk for myocardial infarction or coronary death of 11% (8 SD). Following NAION, the incidence of cardiovascular or cerebrovascular events in patients taking aspirin is not in major excess from that expected in risk-factor agematched controls.

Literature Commentary Hasanreisoglu M, Robenshtok E, Ezrahi D, Stiebel- Kalish H. Do patients with non-arteritic ischemic optic neuritis have increased risk for cardiovascular and cerebrovascular events? Neuroepidemiology. 2013;40:220-224. Objectives: To compare the incidence of cardiac and cerebrovascular events following non-arteritic anterior ische-mic optic neuropathy (NAION) compared to published control data using the Framingham, United Kingdom Pro-spective Diabetes Study (UKPDS) and the National Vascular Disease Prevention Alliance (NVDPA) data. Methods: A retrospective study of all consecutive cases of NAION between 1990 and 2005. Patients were stratified into those with or without prior ischemic events and into diabetics and non-diabetics. Outcome measures included cardiovascular morbidity, cerebrovascular events and the Framingham, UKPDS and NVDPA scores for each patient. Results: According to the NVDPA, the average absolute 5-year risk for cardiovascular disease (CVD) was 8.98, compared to 9 CVD events in our study. In the diabetic patients, 5 (17%) had a cardiac event and 2 (8%) had a cerebral vascular accident (CVA). Based on the UKPDS risk calculator, the average 10-year risk for cardiac events is 21.6%, CVA 26.8%. In the non-diabetics, there were 3 cases (7.5%) of myocardial infarction, compared to the average 10-year Framingham risk for myocardial infarction or coronary death of 11% (±8 SD). Conclusions: Following NAION, the incidence of cardiovas-cular or cerebrovascular events in patients taking aspirin is not in major excess from that expected in risk-factor age-matched controls. Published risk calculators exist for cerebrovascular and cardiovascular events. To compare accurately nonarteritic anterior ischemic optic neuropathy (NAION) patients with these risk calculators, the authors divided NAION patients into 2 groups-those with (Group 1) and without (Group 2) atheroembolic disease. They further subdivided Group 2 into those with (Group 2A) and without (Group 2B) diabetes. They captured cardiovascular and cerebro-vascular events using medical records and telephone inter-views of all patients. Published, validated control data were used to compare risk of events following NAION by group. The number of events did not exceed published risk calculations for any group, suggesting that NAION does not lead to an increased risk of cardiovascular or cerebrovascular event over that expected for patient age or medical history. The authors likely captured all events because they made telephone contact with each patient. I do not like the fact that they compared NAION patients with published controls instead of finding their own. However, based on the assumption that the pathophysiology of NAION is more likely a compartment syndrome, I do not see a strong reason why NAION patients should be at increased risk for vascular events. Personally, I counsel patients that NAION does not, in and of itself, increase their risk of cerebrovas-cular or cardiovascular event over their baseline risk, and this study supports that notion. -Michael S. Lee, MD This study has some encouraging news in that NAION by itself may not be a vascular risk factor rather it may be a consequence of other risk factors. It is consistent with the understanding that NAION is a problem of hypoperfusion and not a thrombotic or embolic phenomenon. Perhaps, in the previous studies showing NAION as a risk factor, it was the other pre-existing factors (e.g., diabetes, hypertension) that increased the risks for stroke and cardiac events. -Mark L. Moster, MD Hougaard A, Amin F, Hauge AW, Ashina M, Olesen J. Provocation of migraine with aura using natural trigger factors. Neurology. 2013;80:428-431. Objective: It is well-known that migraine attacks can be precipitated by various stimuli. More than 50% of patients with migraine with aura (MA) know of at least one stimulus that always or often triggers their MA attacks. The objective of this study was to expose patients with MA to their self-reported trigger factors in order to assess the causal relation between trigger factors and attacks. Methods: We recruited 27 patients with MA who reported that bright or flickering light or strenuous exercise would trigger their migraine attacks. The patients were experimen-tally provoked by different types of photostimulation, strenuous exercise, or a combination of these 2 factors. During and following provocation, the patients would report any aura symptoms or other migraine-related symptoms. Results: Of 27 provoked patients with MA, 3 (11%) reported attacks of MA following provocation. An additional 3 patients reported migraine without aura attacks. Following exercise, 4 out of 12 patients reported migraine, while no patients developed attacks following photostimulation. 198 Moster and Lee: J Neuro-Ophthalmol 2013; 33: 198-201 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. Conclusion: Experimental provocation using self-reported natural trigger factors causes MA only in a small subgroup of patients with MA. Prospective confirmation is important for future studies of migraine trigger factors and in the clinical management of patients with migraine. Previous studies report that most migraineurs can identify environmental triggers that induce their migraine with aura. These include certain foods, sleep deprivation, caffeine withdrawal, emotional stress, physical exertion, or bright light. This study was unable to provoke migraine with aura in most patients who reported an exercise or bright light trigger. Only 17% of those who reported a trigger of physical exercise were able to have this reproduced, and in none of the 26 patients reporting a visual trigger had this reproduced. The authors appropriately suggest that future studies of migraine triggers should not be accepted merely based on the patient's history. These findings have implications for treatment as well. It makes no sense to have a patient avoid exercise if the exercise is not really triggering the migraine. This article reminds us of bias in reporting clinical history and is reminiscent of what we hear from patients "I'm sure the migraine is only in my right eye" without having occluded either eye to test if it's true. -Mark L. Moster, MD The authors acknowledge that migraines triggered by physical exercise in 17% of their patients could have been coincidental. They should have rechallenged those 17% to see if they could trigger another migraine. Interestingly, light could not induce a migraine when patients clearly identify it as a trigger. Perhaps, they needed a different light source or perhaps it really isn't a trigger. -Michael S. Lee, MD Bowers AR, Tant M, Peli E. A pilot evaluation of on-road detection performance by drivers with hemianopia using oblique peripheral prisms. Stroke Res Treat. 2012;2012:176806. Aims: Homonymous hemianopia (HH), a severe visual consequence of stroke, causes difficulties in detecting obstacles on the nonseeing (blind) side. We conducted a pilot study to evaluate the effects of oblique peripheral prisms, a novel development in optical treatments for HH, on detection of unexpected hazards when driving. Methods: Twelve people with complete HH (median 49 years, range 29-68) completed road tests with sham obli-que prism glasses (SP) and real oblique prism glasses (RP). A masked evaluator rated driving performance along the 25-km routes on busy streets in Ghent, Belgium. Results: The proportion of satisfactory responses to unex-pected hazards on the blind side was higher in the RP than the SP drive (80% versus 30%; P = 0.001), but similar for unexpected hazards on the seeing side. Conclusions: These pilot data suggest that oblique periph-eral prisms may improve responses of people with HH to blindside hazards when driving and provide the basis for a future, larger-sample clinical trial. Testing responses to unexpected hazards in areas of heavy vehicle and pedes-trian traffic appears promising as a real-world outcome measure for future evaluations of HH rehabilitation inter-ventions aimed at improving detection when driving. In this study, professional driving evaluators assessed hemi-anopic drivers in a dual-control car around a busy city. They found more satisfactory responses to unexpected hazards on the blind hemianopic side using real prisms compared with sham prisms. None of the patients had an accident, but an intervention (braking, steering) occurred in 29 instances. I have seen 2 patients who did not meet minimum field requirements for licensure in Minnesota. Using these prisms, they experienced sufficient visual field expansion to qualify for a license. Obviously, this doesn't make them safe. I think it is important to realize that this study did not assess whether hemianopic patients using prisms were safe drivers. This was a pilot study to assess the feasibility of performing on-road driving evaluations in preparation for a larger clinical trial. -Michael S. Lee, MD This study is quite important. By placing a hemianopic prism obliquely, it allows for expansion of the visual field (VF) near the horizontal meridian without inducing diplopia. The study also points out that determining safety and legality of driving by a strict rule of VF in the horizontal meridian (e.g., 120 degrees) does not make a lot of sense. Other factors contribute to the relative safety of the driver. These include visual neglect and tendency to scan into the impaired VF and a host of nonvisual issues. Information from such studies will contribute to more valid assessments of driving safety in hemianopic patients in the future. -Mark L. Moster, MD Fernandes DB, Raza AS, Nogueira RG, Wang D, Callegaro D, Hood DC, Monteiro ML. Evaluation of inner retinal layers in patients with multiple sclerosis or neuromyelitis optica using optical coherence tomography. Ophthalmology. 2013;120:387-394. Purpose: To evaluate the thickness of the inner retinal layers in the macula using frequency-domain optical coherence tomography (fd-OCT) in patients with demyelinating diseases. Design: Cross-sectional study. Participants: A total of 301 eyes of 176 subjects were evaluated. Subjects were divided in 5 different groups: controls, neuromyelitis optica (NMO), longitudinally exten-sive transverse myelitis (LETM), multiple sclerosis with a history of optic neuritis (MS-ON), and multiple sclerosis without a history of optic neuritis (MS non-ON). Moster and Lee: J Neuro-Ophthalmol 2013; 33: 198-201 199 Literature Commentary Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Methods: The individual layers from macular fd-OCT cube scans were segmented with an automated algorithm and then manually hand-corrected. For each scan, we deter-mined the thickness of the retinal nerve fiber layer (RNFL), the combined retinal ganglion cell and inner plexiform layers (RGCL+), and the inner nuclear layer (INL). Main Outcome Measures: Macular RNFL, RGCL+, and INL thickness. Results: The RNFL was significantly thinner than in controls for all patient groups (P # 0.01). Macular RGCL+ thickness was significantly thinner than in controls for the NMO, MS-ON, and MS non-ON groups (P , 0.001 for the 3 groups). The INL thickness was significantly thicker than in controls for the patients with NMO (P = 0.003) and LETM (P = 0.006) but not for those with MS-ON or MS non-ON. Although the RNFL and RGCL+ were not significantly different between the NMO and MS-ON groups, the patients with NMO had a significantly thicker INL than the patients with MS-ON (P = 0.02). Conclusions: Macular RNFL and RGCL+ demonstrate axo-nal and neural loss in patients with MS, either with or with-out ON, and in patients with NMO. In addition, the INL thickening occurs in patients with NMO and patients with LETM, and study of this layer may hold promise for differen-tiating between NMO and MS. This study compared the thickness of 3 macular segments (retinal nerve fiber layer [RNFL], retinal ganglion cell layer and inner plexiform layer [RGCL+], and inner nuclear layer [INL]) in multiple sclerosis (MS) and neuromyelitis optica (NMO) patients. There were 4 groups-MS with and with-out optic neuritis, NMO, and longitudinally extensive trans-verse myelitis (LETM). LETM is a disorder on the NMO spectrum, which the authors are considering a possible equiv-alent of NMO without a previous episode of optic neuritis. The findings of RNFL thinning in all 4 patient groups are consistent with previous reports on MS and symptomatic NMO patients. However, it is slightly surprising for LETM, as NMO spectrum patients have been felt not to have subclinical loss of RNFL in the past, the RNFL loss only occurring after a clinical episode of optic neuritis. However, in support of the previous thinking on this issue was the finding that macular RGCL+ was thinner for all groups except the LETM group. This is consistent with retrograde axonal degeneration and ganglion cell death in previous demyelinated optic nerve. What is even more unexpected is the finding that INL was significantly thicker in NMO and LETM patients than in controls or MS patients. The authors speculate that this may be due to intracellular edema with Müller cell dysfunc-tion by virtue of the fact that these cells have Aquaporin4, the target of the NMO antibody. Although this may be a finding that will become clinically useful and helpful in distinguishing differences between MS and NMO, further verification of these findings is necessary. Additionally, although there was a statistically significant difference in INL, the total difference between the NMO/LETM pa-tients and the MS/control patients was less than 2 mm. -Mark L. Moster, MD The RGCL+ and INL are the new hot topics in neurolog-ical diseases. Thankfully, there are only 10 layers of the retina, so we are almost finished segmenting them all and we can move on to something other than optical coherence tomogra-phy (OCT), right? But seriously, I look forward to the day when we can have fully automated segmentation with age-matched controls for the retinal layers. Until then, it can be tedious to hand-correct each OCT for segmentation purposes. My criticism of this study is that we are not given any comparative statistics on how well matched the groups were with regards to age, gender, duration of disease, and time from last attack of optic neuritis. With the small but statistically significant differences, we definitely cannot distinguish NMO from MS based on INL thickness, especially in the acute phase (none of these patients had acute visual loss), which would be of great benefit. -Michael S. Lee, MD Hata M, Miyamoto K, Nakagawa S, Horii T, Yoshimura N. Horizontal deviation as diagnostic and prognostic values in isolated fourth nerve palsy. Br J Ophthalmol. 2013;97:180-183. Background/Aims: To investigate the causes of isolated fourth nerve palsy (IFNP) and the association among etiology, prognosis and ocular deviation. Methods: A total of 126 consecutive cases of IFNP was retrospectively reviewed. According to etiologies, all pa-tients were classified into five groups: microvascular, congenital, decompensation of congenital, traumatic, and others. We investigated the recovery rate of IFNP patients who could be followed for more than 6 months or until they recovered completely. Patients also had the magnitude of vertical and horizontal ocular deviations (prism diopter) measured in the primary eye position on the first visit. Results: Major causes of IFNP were microvascular (47%) and decompensated (33%). The rate of recovery was significantly different between microvascular IFNP and decompensated IFNP (92% vs. 55%, P , 0.001). There were no differences in both age of onset or mean vertical deviation between the two etiologies (68.6 ± 9.8 vs. 65.4 ± 13.3, 5.7 ± 3.3 vs. 7.8 ± 7.9). However, for mean horizontal deviation, there was a sig-nificant difference between microvascular and decompen-sated IFNP (0.4 ± 3.0 vs. 4.9 ± 5.6, P , 0.001). Although the fourth nerve abducts the eyeball, 69 of 126 cases (55%) showed exotropia. The microvascular IFNP group included more cases of exodeviation, while the decompensated IFNP group included more cases of esodeviation (P , 0.001). Conclusions: Contrary to previous thinking, the horizontal deviation of IFNP mainly showed exodeviation, and the degree of horizontal deviation is useful for making a determination between vasculopathic and decompensated IFNP. This differ-entiation could be critical for predicting the outcome. The authors retrospectively identified patients with isolated fourth nerve palsy (IFNP), categorized the etiology, and compared the clinical characteristics. 200 Moster and Lee: J Neuro-Ophthalmol 2013; 33: 198-201 Literature Commentary Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. I have problems with this study beginning with many of the authors' definitions. 1) They define an IFNP by the 3- step test but do not mention how they distinguished these patients from skew deviation, myasthenia, or thyroid eye disease. 2) The only criterion for microvascular IFNP was if the patient had a vascular risk factor. 3) Decompensated IFNP was defined if the patient had a long-standing head tilt. There was no comment about vertical fusional ampli-tudes or other diagnostic criteria. Although the authors found that significantly more patients with decompensated IFNP (73%) had an exotropia compared with microvascular IFNP (37%), I do not agree with the conclusion that the degree of horizontal deviation is useful to differentiate the two (mainly because the definitions are weak). -Michael S. Lee, MD Michael, I agree with all your concerns. I also have some additional issues with this article. First, the authors don't define how they measured the deviation. For instance, if by alternate cover test, they may merely be measuring a con-genital exophoria or esophoria, and if it is with near fixation, perhaps measuring some convergence insufficiency. Addi-tionally, with IFNP, there is not necessarily a specific eso-tropia or exotropia, rather a mild V pattern, with relative esotropia in down gaze, where the superior oblique is max-imally active and where we lose it's tertiary action of abduc-tion in patients with IFNP. -Mark L. Moster, MD Langer-Gould A, Brara SM, Beaber BE, Koebnick C. Childhood obesity and risk of pediatric multiple sclerosis and clinically isolated syndrome. Neurology. 2013;80:548-552. Objective: To determine whether childhood obesity is a risk factor for developing pediatric multiple sclerosis (MS) or clinically isolated syndrome (CIS). Methods: Cases were identified through the Kaiser Perma-nente Southern California (KPSC) Pediatric Acquired Demy-elinating Diseases Cohort between 2004 and 2010. For cases, body mass index (BMI) was obtained prior to symptom onset, for the underlying cohort BMI was obtained through the KPSC Children's health study (n = 913,097). Weight classes of normal weight, overweight, moderate obe-sity, and extreme obesity were assigned based on BMI spe-cific for age and sex. Results: We identified 75 newly diagnosed pediatric cases of MS or CIS, the majority of which were in girls (n = 41, 55%), age 11-18 years (n = 54, 72%). Obesity was asso-ciated with a significantly increased risk of MS/CIS in girls (P = 0.005 for trend) but not in boys (P = 0.93). The adjusted odds ratio and 95% confidence intervals for CIS/MS among girls was 1.58 (0.71-3.50) for overweight compared to normal weight (reference category), 1.78 (0.70-4.49) for moderately obese, and 3.76 (1.54-9.16) for extremely obese. Moderately and extremely obese cases were more likely to present with transverse myelitis com-pared with normal/overweight children (P = 0.003). Conclusion: Our findings suggest the childhood obesity epidemic is likely to lead to increased morbidity from MS/ CIS, particularly in adolescent girls. Two previous studies have suggested an increased risk of MS in young adults with obesity. This population-based study in children found an increased risk of clinically isolated syndrome (CIS) or multiple sclerosis (MS) in obese girls older than 11 years but not in boys or younger girls. The adjusted odds ratio was 1.58 (0.71-3.50) for overweight up to 3.76 (1.54-9.16) for extremely obese teenage girls. Addi-tionally, moderate or severe obesity was associated with a pre-sentation of transverse myelitis compared with normal/ overweight children (P = 0.003). The authors suggest that the increase risk of MS may be related to the combination of a low-grade inflammatory state associated with obesity and the hormonal changes that occur with puberty. According to a recent report in Lancet (1), obesity has overtaken hunger as a global health crisis. In addition to the many known health-related issues with obesity, we may have to add MS to the growing list. -Mark L. Moster, MD We cannot assume causality based on inference or association. When looking at the entire cohort, there was no clear association with BMI. The authors then "arbitrarily" (I say arbitrarily because boys and girls do not reach puberty at the same age) divided patients into younger (2-11 years old) and older (12-18 years old) groups. BMI was not associated with MS/CIS in the younger group. In the older group, there were a total of 54 cases, and only 8 of them were extremely obese. Extreme obesity was associated with an increased odds ratio of MS/CIS in this older group overall and especially for girls but not for boys. Although the adjusted odds ratio among girls seemed to rise with increasing BMI (overweight 1.58, moderate obesity 1.78, extreme obesity 3.76), the confidence intervals in the overweight and moderate obesity groups crossed over 1.00, indicating that they were not statistically significant. Therefore, the obesity association was really based on 8 extremely obese teenage girls. Although obesity is associated with a number of health issues, I don't know that this study clearly identifies an increase in the odds ratio of MS/CIS among these individ-uals. The cohort was very small and the authors created too many subgroups for my liking. -Michael S. Lee, MD REFERENCE 1. Lim SS, et al. A comparative risk assessment of burden of disease and injury attributable to 67 risk factors and risk factor clusters in 21 regions, 1999-2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet. 2012;380:2224-2260. Moster and Lee: J Neuro-Ophthalmol 2013; 33: 198-201 201 Literature Commentary Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.