Literature Commentary

Literature Commentary Nagane Y, Utsugisawa K, Suzuki S, Masuda M, Shimizu Y, Utsumi H, Uchiyama S, Suzuki N. Topical naphazoline in the treatment of myasthenic blepharoptosis. Muscle Nerve. 2011;44:41-44. Introduction: When treating ocular myasthenia gravis (MG), the risk/benefit profile of corticosteroids is unclear, and acetylcholinesterase inhibitors are not very effective. We examined the efficacy of topical naphazoline in the treatment of myasthenic blephar-optosis. Methods: Sixty MG patients with blepharoptosis (32 with ocular symptoms only and 28 with mild generalized symptoms) were enrolled in a multicenter open trial of topical naphazoline. The effects were reported by patients via a questionnaire and were also confirmed for each patient at the clinic. Results: Among 70 eyes of 60 patients, 20 eyes (28.6%) of 17 patients (28.3%) exhibited a marked response (full eye opening) and 24 eyes (34.3%) of 20 patients (33.3%) showed a good response (adequate but incomplete eye opening). Topical naphazoline was evaluated to be useful in the treatment of myasthenic blepharoptosis by.70% of the patients. Conclusions: Topical naphazoline was found to be an ef-fective supplementary symptomatic treatment for myas-thenic blepharoptosis. This is not a bad idea, especially among those patients with ptosis unresponsive to acetylcholinesterase inhibitors. Ninety percent of these patients achieved maximal response within 15 minutes, and the effect lasted more than 2 hours in three-fourths of the patients. More than three-fourths used the drops between 2 and 6 times daily. I would certainly feel comfortable if a patient chose to use this for brief periods of time, such as a wedding or going out. It lasts longer than phenylephrine and is available over the counter. I am not completely convinced about its long-term use although these patients used topical naphazoline for an average of 7 months. Used for temporary relief of eye redness, naphazoline is an alpha 2-adrenergic receptor agonist that produces va-soconstriction of conjunctival vessels and stimulates Mu¨ller muscle. This article did not comment on any adverse events but reported side effects include headache, drowsiness, nausea, sweating, weakness, dizziness, and rebound redness. The package insert recommends avoiding naphazoline in patients with narrow-angle glaucoma, younger than 6 years, or concurrent use of a monoamine oxidase inhibitor or tricyclic antidepressants. -Michael S. Lee, MD This article reintroduces an interesting approach to treating myasthenic ptosis that of a sympathomimetic ag-onist to stimulate Mu¨ller muscle. The authors postulate an inhibition of Mu¨ller muscle in some patients as a cause of ptosis in MG and quote other articles that have demon-strated antiacetylcholinesterase antibodies (Anti-Ach-E) in myasthenia-which was found more often in ocular than generalized myasthenia-that can cause a block at pre-ganglionic sympathetic terminals (1). Although this might be the case, and the lack of any lid elevation in the control group supports this, perhaps it is a nonspecific stimulation of Mu¨ller muscle that is occurring. Nonetheless, naphazo-line may be a useful adjunct to treatment in the patient with ocular MG with suboptimal response in whom we may be considering steroids or immunosuppressants. -Mark L. Moster, MD REFERENCE 1. Provenzano C, Marino M, Scuderi F, Evoli A, Bartoccioni E. Anti-acetylcholinesterase antibodies associate with ocular myasthenia gravis. J Neuroimmunol. 2010;218:102-106. Clayton LM, De´vile´ M, Punte T, Kallis C, de Haan GJ, Sander JW, Acheson J, Sisodiya SM. Retinal nerve fiber layer thickness in vigabatrin-exposed patients. Ann Neurol. 2011;69:845-854. Objective: Vigabatrin-associated visual field loss (VAVFL) occurs in 25%-50% of exposed patients and is routinely monitored using perimetry, which has inherent limi-tations. Using optical coherence tomography (OCT), ret-inal nerve fiber layer (RNFL) thinning has been described in a small number of vigabatrin-exposed patients. We explored the relationship between RNFL thickness and visual field (VF) size to determine whether OCT is a suit-able tool to use in patients exposed to vigabatrin. Methods: Two hundred one vigabatrin-exposed subjects with epilepsy, divided into 2 groups, and 90 healthy controls participated. VFs were obtained using kinetic perimetry and quantified using mean radial degrees (MRD). RNFL imaging was performed using either spectral-domain OCT (group 1) or time-domain OCT (group 2). Section Editors: Mark L. Moster, MD Michael S. Lee, MD Moster and Lee: J Neuro-Ophthalmol 2011; 31: 285-289 285 Literature Commentary Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Results: Thirty-nine of 201 patients (19.4%) were unable to perform perimetry. Thirteen patients (6.5%) were unable to perform OCT. A total of 51.6% of patients showed VAVFL. Average RNFL thickness was significantly thinner in pa-tients (77.9 mm) compared to healthy controls (93.6 mm) (P , 0.001). There was a strong correlation between MRD and average RNFL thickness for Group 1 (r = 0.768, P , 0.001) and Group 2 (r = 0.814, P , 0.001). OCT RNFL imaging showed high repeatability. Interpretation: OCT provides a useful tool to assess people exposed to vigabatrin and can provide an accurate esti-mate of the extent of VF loss in the absence of a reliable direct measure of the VF. The strong linear relationship found between RNFL thickness and VF size provides some evidence that irreversible VAVFL may be related to loss of retinal ganglion cell axons. The anticonvulsant vigabatrin, which is approved for the treatment of adults with refractory complex partial seizures and children with infantile spasms, has been associated with peripheral VF loss. As neuro-ophthalmologists, we are re-quested to participate in monitoring patients for toxicity. Monitoring adult patients is often complicated by the as-sociated neurologic deficits and drug effects, which limit cooperation and reliability on perimetry, electrophysiologic tests, and imaging studies. Monitoring young children has been even more difficult. This study provides further evi-dence that RNFL is abnormal in these patients, and fur-thermore, thinning correlates with the degree of VF loss. It is the first to use spectral-domain optical coherence to-mography (OCT) and the largest to date on OCT in this group. They found that 19.4% could not adequately per-form kinetic VFs but only 6.5% could not do OCT. This study also supports the notion that there is not just toxicity to photoreceptors but also to the ganglion cell-retinal nerve fiber complex. Otherwise, one would not expect a tight association between RNFL thickness and degree of VF loss. It is likely that similar to hydroxychloroquine toxicity, imaging with OCT will assume an increasing role for monitoring. -Mark L. Moster, MD Electrophysiologic testing is fairly accurate for VAVFL, but repeatability is hard to evaluate and it is more invasive. OCT is quick and easy to perform, seems to correlate well with VF testing, and is fairly repeatable. Electrophysiology measures function while OCT measures structure. While we can doc-ument VF loss, abnormal full-field and multifocal electroret-inography, and thinning of the RNFL, is there a time when we can recognize toxicity, stop vigabatrin, and minimize or even reverse visual loss? At what point do we say that the OCT has progressed and that we should stop vigabatrin and yet still potentially recover VF? Or by the time the OCT has thinned, is it too late? I think OCT is definitely an option to monitor patients who cannot perform VF testing, but I don't think it should replace functional testing, such as perimetry or electro-physiology. If we watch RNFL alone, we may miss an opportunity to catch early VAVFL, where function is im-paired but structure remains intact. -Michael S. Lee, MD Avraham-Lubin BCR, Dratviman-Storobinsky O, Dadon-Bar El S, Hasanreisoglu M, Goldenberg- Cohen N. Neuroprotective effect of hyperbaric oxygen therapy on anterior ischemic optic neuropathy. Front Neurol. 2011;2:1-7. The study investigated the therapeutic effect of hyper-baric oxygen (HBO) on anterior ischemic optic neuropathy in a rodent model (rAION). rAION was laser induced in 1 eye of 63 mice. The fellow (uninjured) eye served as an internal control. Thirty-three mice underwent two 90- minute sessions of 100% oxygen (2 atm) treatment im-mediately following injury and 1 session daily thereafter for up to 14 days. The remaining mice were untreated. Retinas were harvested at different time points, and mRNA levels of various genes were analyzed by real-time polymerase chain reaction and histologic study. Un-treated mice: day 1 post-rAION-SOD-1 (oxidative stress- related) decreased to 82% of control (uninjured eye) levels (P , 0.05), caspase-3 (proapoptotic) decreased to 89%, and Bcl-xL mildly increased (117%; all NS); day 3-HO-1 and endothelial nitric oxide synthase (eNOS; ischemia-related) decreased to 74%, and Bcl-2-associ-ated X protein, caspase-3, and B-cell lymphoma 2 (Bcl-2; apoptotic) increased by 170%, 120%, and 111%, re-spectively (all NS); day 21-HO-1 increased to 222% (NS), and eNOS decreased to 48% (P , 0.05). Treated mice: day 1-SOD-1 and caspase-3 remained unchanged, and Bcl-2 and Bcl-xL mildly increased (112% and 126%, respectively); day 3-HO-1 and eNOS increased, and ap-optosis- related gene decreased; day 21-SOD-1 de-creased, whereas eNOS increased (P , 0.05), and HO-1 increased to a lesser degree than without treatment. None of the oxygen-treated animals had retinal ganglion cell loss or a decrease in Thy-1 expression. In conclusion, HBO treatment after rAION induction influences the ex-pression of apoptosis-related genes as well as oxidative stress-induced and ischemia-related genes and may exert a neuroprotective effect. After induction of rAION, 33 mice had HBO treatment and 30 did not. The authors found significantly less retinal ganglion cell loss in HBO-treated rAION eyes than control eyes and untreated rAION eyes. There were some statisti-cally significant differences in apoptosis-related gene ex-pression levels. However, these likely represented statistical noise. Conceivably, HBO could work based on these data. However, as the authors note, this particular study may not relate clinically since these mice received HBO immediately following the ischemic event. Getting patients therapy within 7 days of symptom onset can represent a substantial challenge. Arnold et al (1) delivered HBO therapy to 20 patients with anterior ischemic optic neuropathy and did not find any benefit compared to a control group. Subgroup 286 Lee and Moster: J Neuro-Ophthalmol 2011; 31: 285-289 Literature Commentary Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. analysis of those patients treated within 9 days of initial symptoms also did not show improved visual outcome. The challenge remains to find the appropriate window where HBO can still improve outcome and to get those patients in the chamber within that likely small time window. -Michael S. Lee, MD Mike, I agree that it is difficult to get to treat patients with nonarteritic anterior ischemic optic neuropathy acutely in time to make a difference. However, if HBO can prove beneficial, it will be a major advance in one of the most frustrating conditions we treat. How often do you have patients seeing you for NAION and when you're all done they are shocked that you aren't going to fix them back to normal? There is a captive audience of patients who we could likely treat within hours if HBO was to prove successful. Those are the patients who have already had a unilateral NAION and are at increased risk for the second eye. They are the most needy for early intervention because it is their second eye and are ‘‘ tuned-in'' to immediate care should they lose vision in the second eye. If we had an acute treatment for NAION (or similarly for CRAO), we can develop an education program similar to the one that has been successful in bringing stroke pa-tients to treatment within minutes to hours: ‘‘Time is Brain.'' We could promote, Time is Sight!!! -Mark L. Moster, MD REFERENCE 1. Arnold AC, Hepler RS, Lieber M, Alexander JM. Hyperbaric oxygen therapy for nonarteritic anterior ischemic optic neuropathy. Am J Ophthalmol. 1996;122:535-541. Lee KM, Woo SJ, Hwang JM. Differentiation of optic nerve head drusen and optic disc edema with spectral-domain optical coherence tomography. Ophthalmology. 2011;118:971-977. Purpose: To evaluate the efficacy of spectral-domain op-tical coherence tomography (SD-OCT) in differentiating optic disc edema (ODE) and optic nerve head drusen (ONHD) and to reveal the differential points. Design: Comparative case series. Participants: Forty-five patients with ONHD, 15 patients with ODE, and 32 normal controls. Methods: SD-OCT was performed with scans on the optic nerve head and measurements of retinal nerve fiber layer thickness. Main Outcome Measures: Qualitative findings of optic nerve head scans and retinal nerve fiber layer thickness profiles on SD-OCT. Results: ONHD was visualized as a focal, hyper-reflective, subretinal mass with a discrete margin on SD-OCT. The retinal nerve fiber layer was deformed and showed pseudoedema and high reflectance. The outer nuclear layer smoothly covered the drusen, which led to a hyporeflective boot-shaped area adjacent to the drusen. In ODE, peripapillary retinal nerve fiber layers were significantly thicker in all sections than ONHD (average thickness of ODE: 174.1 6 53.5 mm vs ONHD: 119.2 6 20.2 mm vs control: 103.4 6 19.1 mm, P , 0.001). Retinal nerve fiber thickness in the nasal section provides a good differential marker for ODE from ONHD (area under receiver operating characteristic curve = 0.866). Conclusions: With the use of SD-OCT, noninvasive and accurate differentiation of ONHD and ODE is possible. This study has many flaws but still provides some useful information. The small group with ODE was very diverse, including 4 with anterior ischemic optic neuropathy, 4 with uveitic disc edema, 1 diabetic papillopathy, 1 with central retinal vein occlusion, and 1 with optic neuritis. Only 4 patients likely had papilledema (idiopathic intracranial hypertension)- the real issue that clinicians are faced with in the differential diagnosis. The populations that were compared were also quite different-the average age of the ONHD group was 13 years, the ODE group was 42 years, and the control group was 12 years. Another problem is that the criterion for diagnosis of ONHD was the direct visualization of ONHD on the OCT. This creates a ‘‘self-fulfilling prophecy'' and hardly tests the ability of the OCT to truly determine the diagnosis. The above limitations make this study powerless in helping to distinguish papilledema from ONHD. However, it is useful in describing some features in the young ONHD group. First, the direct visualization of a lesion between the inner nuclear layer and the RPE with obliteration of the inner segment/outer segment line is helpful. Second, the pattern of thickening of the RNFL-thickened in all areas except inferonasally might be a clue. The information in this study will be a good baseline for a study in the population of patients who present with a differential diagnosis of pap-illedema vs pseudopapilledema. -Mark L. Moster, MD I would agree with you, Mark. The key issue is whether a patient has papilledema from intracranial hypertension or pseudopapilledema from buried optic disc drusen, and unfortunately, this article does not adequately distinguish them using SD-OCT because of the small number of papilledema patients. To me, the best take-home message from this article is the appearance of the buried drusen on SD-OCT. Using the line images through the optic nerve head, the drusen shows a smooth highly reflective area in the outer retina adjacent to the nerve head. Others have shown the appearance of surface drusen using SD-OCT, but the images look significantly different. As to your point of using SD-OCT to define whether an individual has drusen, I think another interesting study Moster and Lee: J Neuro-Ophthalmol 2011; 31: 285-289 287 Literature Commentary Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. would be to compare B-scan ultrasound to SD-OCT in the diagnosis of buried drusen. -Michael S. Lee, MD Lemp MA, Bron AJ, Baudouin C, Benı´tez Del Castillo JM, Geffen D, Tauber J, Foulks GN, Pepose JS, Sullivan BD. Tear osmolarity in the diagnosis and management of dry eye disease. Am J Ophthalmol. 2011;151:792-798. Purpose: To evaluate the use of tear osmolarity in the diagnosis of dry eye disease. Design: A prospective observational case series to de-termine the clinical usefulness of tear osmolarity and commonly used objective tests to diagnose dry eye dis-ease. Methods: A multicenter 10-site study consisting of 314 consecutive subjects between 18 and 82 years of age. Bilateral tear osmolarity, tear film break-up time (TBUT), corneal staining, conjunctival staining, Schirmer test, and meibomian gland grading were performed. Diagnostic performance was measured against a composite index of objective measurements that classified subjects as hav-ing normal, mild or moderate, or severe dry eye. The main outcome measures were sensitivity, specificity, area un-der the receiver operating characteristic curve, and in-tereye variability. Results: Of the 6 tests, tear osmolarity was found to have superior diagnostic performance. The most sensitive threshold between normal and mild or moderate subjects was found to be 308 mOsm/L, whereas the most specific was found at 315 mOsm/L. At a cutoff of 312 mOsm/L, tear hyperosmolarity exhibited 73% sensitivity and 92% specificity. In contrast, the other common tests exhibited either poor sensitivity (corneal staining, 54%; conjuncti-val staining, 60%; meibomian gland grading, 61%) or poor specificity (TBUT, 45%; Schirmer test, 51%). Tear osmo-larity also had the highest area under the receiver oper-ating characteristic curve (0.89). Intereye differences in osmolarity were found to correlate with increasing dis-ease severity (r2 = 0.32). Conclusions: Tear osmolarity is the best single metric to both diagnose and classify dry eye disease. Intereye variability is a characteristic of dry eye not seen in normal subjects. We all see patients sent to the neuro-ophthalmologist with dry eye causing eye pain, monocular diplopia, and transient blurred vision despite eyes that appear white and quiet. While many of these patients may have punctate corneal staining or an early TBUT, these signs are not universally present. The authors in this study used a new test called tearlab (www.tearlab.com). The device is placed in the tear film along the lower lid and then it measures os-molarity within 15 seconds. It appears to have high sensi-tivity and specificity and it renders a rapid quantifiable number to assign to a dry eye patient. For those neuro-ophthalmologists in an eye department, this may represent a reasonable addition to the diagnostic armamentarium. -Michael S. Lee, MD This study demonstrates that tear osmolarity is more sensitive and specific than other available tests for dry eye, a cause of symptoms in some of our neuro-ophthalmologic patients. While on the ‘‘surface'' it is a great technique, there are some barriers to it's use. It is a costly piece of equipment and is considered a laboratory test in the United States by Medicare, which requires Clinical Laboratory Improvement Amendments certification. This will limit access in many of our practices. -Mark L. Moster, MD Schwingenschuh P, Katschnig P, Edwards MJ, Teo JT, Korlipara LV, Rothwell JC, Bhatia KP. The blink reflex recovery cycle differs between essential and presumed psychogenic blepharospasm. Neurology. 2011;76:610-614. Background: Psychogenic blepharospasm is difficult to distinguish clinically from benign essential blepharo-spasm (BEB). The blink reflex recovery cycle measures the excitability of human brainstem interneurons and is abnormal in BEB. We wished to study the blink reflex recovery cycle in patients with atypical (presumed psy-chogenic) blepharospasm (AB). Methods: This was a prospective data collection study investigating the R2 blink reflex recovery cycle at in-terstimulus intervals (ISI) of 200, 300, 500, 1,000, and 3,000 milliseconds in 10 patients with BEB, 9 patients with AB, and 9 healthy controls. All patients had spasm of the orbicularis oculi muscles. To compare individual pa-tients, an R2 recovery index was calculated as average of the recovery values at ISIs of 200, 300, and 500 milli-seconds, with the upper limit of normal defined as mean (control group) + 2 SD. Results: The R2 recovery cycle was significantly dis-inhibited in patients with BEB, whereas patients with AB did not differ from controls on a group level. The upper limit of normal for the R2 recovery index was 61%. The R2 index was abnormal in 9 of 10 patients with BEB and in none of the patients with AB. Conclusions: A normal blink reflex recovery cycle in-dicates normal brainstem interneuron excitability. As-sessment of the R2 recovery cycle may provide a useful diagnostic tool to distinguish patients with psychogenic blepharospasm from those with BEB and is worthy of further study. Patients with BEB have been shown to have an enhanced R2 blink recovery cycle compared with controls. This is an electrophysiologic measure of brainstem excitability shown by EMG recording of the blink reflex in the orbicularis oculi after stimulation of the supraorbital nerve. This study compared patients with atypical psychogenic blepharospasm (AB) with those with BEB and normal controls. The authors estimate that 22% of their patients have blepharospasm on a psychogenic basis. The suspicion of psychogenic blepharospasm was made by the following atypical features: young age, acute onset, constant eye closure, unusual aggravating or relieving factors, or 288 Lee and Moster: J Neuro-Ophthalmol 2011; 31: 285-289 Literature Commentary Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. unusual response (sometimes immediate) to botulinum toxin injections. The findings were robust-all 9 patients with PB had normal R2 recovery cycle and 9 of 10 with BEB had the expected abnormality. Therefore, study of the blink reflex R2 recovery cycle may prove clinically useful in demon-strating that a patient has nonorganic blepharospasm. -Mark L. Moster, MD The investigators recruited all the patients with true BEB and AB from a botulinum toxin injection clinic, and they defined 7 of 9 as ‘‘possible'' or ‘‘probable'' AB and only 2 as ‘‘definite.'' Clinically speaking, the suspicion for AB was underwhelming enough for them that they de-cided to inject these AB patients with botulinum toxin. Although I don't know if the findings would change, it would be better to study more patients with definite AB to know how accurate the normal R2 recovery cycle is in this group of patients. Although they feel confident that they identified AB patients accurately based on R2 recovery, the authors do not comment on how these patients were subsequently managed. Did they keep injecting them with botulinum toxin? What if these patients were doing just fine on botulinum toxin and now they stop receiving it? Should they go for a psychiatric evaluation? Did the authors tell patients that the AB would resolve spontaneously? I'd like to hear if and how they changed management and the outcome. -Michael S. Lee, MD Moster and Lee: J Neuro-Ophthalmol 2011; 31: 285-289 289 Literature Commentary Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.