|Creator||Moster, Mark L; Bhatti, M Tariq|
Literature Commentary Section Editors: Mark L. Moster, MD M. Tariq Bhatti, MD Literature Commentary In this issue of the Journal of Neuro-Ophthalmology, M. Tariq Bhatti, MD and Mark Moster, MD discuss the following 6 articles: 1. Feuer WJ, Schiffman JC, Davis JL, Porciatti V, Gonzalez P, Koilkonda RD, Yuan H, Lalwani A, Lam BL, Guy J. Gene therapy for Leber hereditary optic neuropathy: initial results. Ophthalmology. 2016;123:558-570. 2. Raftopoulos R, Hickman SJ, Toosy A, Sharrack B, Mallik S, Paling D, Altmann DR, Yiannakas MC, Malladi P, Sheridan R, Sarrigiannis PG, Hoggard N, Koltzenburg M, Gandini Wheeler-Kingshott CA, Schmierer K, Giovannoni G, Miller DH, Kapoor R. Phenytoin for neuroprotection in patients with acute optic neuritis: a randomised, placebo-controlled, phase 2 trial. Lancet Neurol. 2016;15:259-269. 3. Guo Y, Johnson MA, Mehrabian Z, Mishra MK, Kannan R, Miller NR, Bernstein SL. Dendrimers target the ischemic lesion in rodent and primate models of nonarteritic anterior ischemic optic neuropathy. PLoS One. 2016;11:e0154437. 4. Liguori C, Palmieri MG, Pierantozzi M, Cesareo M, Romigi A, Izzi F, Marciani MG, Oliva C, Mercuri NB, Placidi F. Optic nerve dysfunction in obstructive sleep apnea: an electrophysiological study. SLEEP. 2016;39:19-23. 5. Eraslan M, Cerman E, Yildiz Balci S, Celiker H, Sahin O, Temel A, Suer D, Tuncer Elmaci N. The choroid and lamina cribrosa is affected in patients with Parkinson's disease: enhanced depth imaging optical coherence tomography study. Acta Ophthalmol. 2016;94:e68-e75. 6. Kleiter I, Gahlen A, Borisow N, Fischer K, Wernecke KD, Wegner B, Hellwig K, Pache F, Ruprecht K, Havla J, Krumbholz M, Kümpfel T, Aktas O, Hartung HP, Ringelstein M, Geis C, Kleinschnitz C, Berthele A, Hemmer B, Angstwurm K, Stellmann JP, Schuster S, Stangel M, Lauda F, Tumani H, Mayer C, Zeltner L, Ziemann U, Linker R, Schwab M, Marziniak M, Then Bergh F, Hofstadt-van Oy U, Neuhaus O, Winkelmann A, Marouf W, Faiss J, Wildemann B, Paul F, Jarius S, Trebst C; Neuromyelitis Optica Study Group. Neuromyelitis optica: evaluation of 871 attacks and 1,153 treatment courses. Ann Neurol. 2016;79:206-216. Feuer WJ, Schiffman JC, Davis JL, Porciatti V, Gonzalez P, Koilkonda RD, Yuan H, Lalwani A, Lam BL, Guy J. Gene therapy for Leber hereditary optic neuropathy: initial results. Ophthalmology. 2016;123:558-570. Purpose: Leber hereditary optic neuropathy (LHON) is a disorder characterized by severe and rapidly progressive visual loss when caused by a mutation in the mitochondrial gene encoding NADH:ubiquinone oxidoreductase subunit 4 (ND4). We have initiated a gene therapy trial to determine the safety and tolerability of escalated doses of an adenoassociated virus vector (AAV) expressing a normal ND4 complementary DNA in patients with a G to A mutation at nucleotide 11778 of the mitochondrial genome. Design: In this prospective open-label trial (NCT02161380), the study drug (self-complementary AAV [scAAV]2 (Y444,500,730F)-P1ND4v2) was intravitreally injected unilaterally into the eyes of 5 blind participants with G11778A LHON. Four participants with visual loss for more than 12 months were treated. The ﬁfth participant had visual loss for less than 12 months. The ﬁrst 3 participants were treated at the low dose of vector (5 · 10(9) vg), and the fourth participant was treated at the medium dose (2.46 · 10(10) vg). The ﬁfth participant with visual loss for less than 12 months received the low dose. Treated participants were followed for 90-180 days and underwent ocular and systemic safety assessments along with visual structure and function examinations. 334 Participants: Five legally blind patients with G11778A LHON. Main Outcome Measures: Loss of visual acuity. Results: Visual acuity as measured by the Early Treatment Diabetic Retinopathy Study (ETDRS) eye chart remained unchanged from baseline to 3 months in the ﬁrst 3 participants. For 2 participants with 90-day follow-up, acuity increased from hand movements to 7 letters in 1 and by 15 letters in 1, representing an improvement equivalent to 3 lines. No one lost vision, and no serious adverse events were observed. Minor adverse events included a transient increase of intraocular pressure (IOP), exposure keratitis, subconjunctival hemorrhage, a sore throat, and a transient increase in neutralizing antibodies (NAbs) against AAV2 in 1 participant. All blood samples were negative for vector DNA. Conclusions: No serious safety problems were observed in the ﬁrst 5 participants enrolled in this Phase I trial of virusbased gene transfer in this mitochondrial disorder. Additional study follow-up of these and additional participants planned for the next 4 years is needed to conﬁrm these preliminary observations. Mark, if you will allow me to depart from the typical comments that I make, I would like to brieﬂy share the backstory of gene therapy for Leber hereditary optic neuropathy (LHON). But before I do, I need to disclose 2 items. The ﬁrst is that I am the chair for the Data Safety and Monitoring Board for this study. The second is that Moster and Bhatti: J Neuro-Ophthalmol 2016; 36: 334-340 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Literature Commentary John Guy was my mentor and teacher when I was an ophthalmology resident at the University of Florida (UF), a colleague of mine when I was a faculty member at UF for nearly 8 years and, most importantly, we are friends. The short version of the story begins in the 1980s when John and Bill Hauswirth, PhD, were evaluating a family with LHON at UF, but before they could publish their observations, Doug Wallace, PhD, published his groundbreaking article that described a single-nucleotide change due to a mitochondrial DNA mutation at the 11778 position as a cause of LHON (1). From 2000 to 2001, John took 2 six-month sabbaticals from UF and worked in Eric A. Schon's laboratory at Cornell University in New York to learn about mitochondrial DNA. While there, he helped with the publication of the ﬁrst paper that described the successful implementation of allotopic expression (a technique that uses the nuclear version of a mitochondrial gene to express it in the nucleus, translate it on cytoplasmic polyribosomes, and then import the protein into the mitochondria) to overcome the biochemical defect of mammalian cells with a mitochondrial DNA point mutation at the 8993 position responsible for neuropathy, ataxia, and retinitis pigmentosa (NARP), and maternally inherited Leigh syndrome (2). With this new knowledge, John returned to UF and wrote the seminal paper that demonstrated the restoration of adenosine triphosphate synthesis in G11778A cybrids by using allotopic expression, thereby beginning the era of gene therapy as a potential treatment for LHON (3). But as is the case in most research, John faced a big obstacle based on work published by others that stated allotopic expression does not work and is toxic (4,5)! However, in 2008, a group from Paris, France independently duplicated John's ﬁndings from 2002 by showing that, in a rat model, allotopic expression is an effective strategy to treat LHON (6). Of course, the story doesn't end here. May more years of bench and animal research were needed to show that the recombinant adenoassociated virus was safe and a potentially efﬁcacious vector for allotopic expression (7). I joke with John and tell him that I deserve credit for all that he has done for the advancement of gene therapy for LHON because while he was on his sabbaticals learning about mitochondria, I continued to see his patients in clinic. But the truth be told, all credit has to go to John and his amazing group for truly being the model of what many of us dream of-which is translational medicine-going from benchtop to bedside! -M. Tariq Bhatti, MD REFERENCES 1. Singh G, Lott MT, Wallace DC. A mitochondrial DNA mutation as a cause of Leber's hereditary optic neuropathy. N Engl J Med. 1989;18:1300-1305. 2. Manfredi G, Fu J, Ojaimi J, Sadlock JE, Kwong JQ, Guy J, Schon EA. Rescue of a deﬁciency in ATP synthesis by transfer of Moster and Bhatti: J Neuro-Ophthalmol 2016; 36: 334-340 3. 4. 5. 6. 7. MTATP6, a mitochondrial DNA-encoded gene, to the nucleus. Nat Genet. 2002;30:394-399. Guy J, Qi X, Pallotti F, Schon EA, Manfredi G, Carelli V, Martinuzzi A, Hauswirth WW, Lewin AS. Rescue of a mitochondrial deﬁciency causing leber hereditary optic neuropathy. Ann Neurol. 2002;52:534-542. Oca-Cossio J, Kenyon L, Hao H, Moraes CT. Limitations of allotopic expression of mitochondrial genes in mammalian cells. Genetics. 2003;165:707-720. Bokori-Brown M, Holt IJ. Expression of algal nuclear ATP synthase subunit 6 in human cells results in protein targeting to mitochondria but no assembly into ATP synthase. Rejuvenation Res. 2006:455-469. Ellouze S, Augustin S, Bouaita A, Bonnet C, Simonutti M, Forster V, Picaud S, Sahel JA, Corral-Debrinski M. Optimized allotopic expression of the human mitochondrial ND4 prevents blindness in a rat model of mitochondrial dysfunction. Am J Hum Genet. 2008;83:373-387. Koilkonda RD, Yu H, Chou TH, Feuer WJ, Ruggeri M, Porciatti V, Tse D, Hauswirth WW, Chiodo V, Boye SL, Lewin AS, Neuringer M, Renner L, Guy J. Safety and effects of the vector for the Leber hereditary optic neuropathy gene therapy clinical trial. JAMA Ophthalmol. 2014;132:409-420. We are in the infancy of genetic treatment for neuroophthalmic disorders and it is very encouraging that this Phase 1 trial demonstrated safety and 2 of the 5 patients had improvement of visual acuity. For full disclosure, I'm also a friend of John Guy and go back further with him, as we were both neuroophthalmology fellows at Wills Eye Hospital. So I join you in congratulating him on laying the groundwork for this major advance and thank you for your role in this story. For fuller disclosure, I'm also an investigator in the ongoing Phase 3 RESCUE and REVERSE studies of GS010- a formulation for allotopic expression of ND4 from the French group you mentioned. In the Phase 1/2a trial of GS010 yet to be published, safety was demonstrated and there was a trend toward improvement in those treated less than 2 years from the onset. It is extremely exciting that we have multiple ongoing trials for genetic therapy in LHON, which may ultimately lead to treatments to prevent visual loss before it occurs. -Mark L. Moster, MD Raftopoulos R, Hickman SJ, Toosy A, Sharrack B, Mallik S, Paling D, Altmann DR, Yiannakas MC, Malladi P, Sheridan R, Sarrigiannis PG, Hoggard N, Koltzenburg M, Gandini Wheeler-Kingshott CA, Schmierer K, Giovannoni G, Miller DH, Kapoor R. Phenytoin for neuroprotection in patients with acute optic neuritis: a randomised, placebo-controlled, phase 2 trial. Lancet Neurol. 2016;15:259-269. Background: Acute demyelinating optic neuritis, a common feature of multiple sclerosis, can damage vision through neurodegeneration in the optic nerve and in its ﬁbres in the retina. Inhibition of voltage-gated sodium channels is neuroprotective in preclinical models. In this study we 335 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Literature Commentary aimed to establish whether sodium-channel inhibition with phenytoin is neuroprotective in patient with acute optic neuritis. Methods: We did a randomised, placebo-controlled, doubleblind phase 2 trial at two UK academic hospitals in London and Shefﬁeld. Patients with acute optic neuritis aged 18-60 years, presenting within 2 weeks of onset, with visual acuity of 6/9 or worse, were randomly assigned (1:1) by minimisation via a web-based service to oral phenytoin (maintenance dose 4 mg/kg per day if randomised before or on July 16, 2013, and 6 mg/kg per day if randomised on or after July 17, 2013) or placebo for 3 months, stratiﬁed by time from onset, centre, previous multiple sclerosis diagnosis, use of disease-modifying treatment, and use of corticosteroids for acute optic neuritis. Participants and treating and assessing physicians were masked to group assignment. The primary outcome was retinal nerve ﬁbre layer (RNFL) thickness in the affected eye at 6 months, adjusted for fellow-eye RNFL thickness at baseline, analysed in a modiﬁed intentionto-treat population of all randomised participants who were followed up at 6 months. Safety was analysed in the entire population, including those who were lost to follow-up. The trial is registered with ClinicalTrials.gov, number NCT01451593. Findings: We recruited 86 participants between February 3, 2012, and May 22, 2014 (42 assigned to phenytoin and 44 to placebo). 29 were assigned to phenytoin 4 mg/kg and 13 to phenytoin 6 mg/kg. Five participants were lost to followup, so the primary analysis included 81 participants (39 assigned to phenytoin and 42 to placebo). Mean 6-month RNFL thickness in the affected eye at 6 months was 81.46 mm (SD 16.27) in the phenytoin group (a mean decrease of 16.69 mm [SD 13.73] from baseline) versus 74.29 mm (15.14) in the placebo group (a mean decrease of 23.79 mm [13.97] since baseline; adjusted 6-month difference of 7.15 mm [95% CI 1.08-13.22]; P = 0.021), corresponding to a 30% reduction in the extent of RNFL loss with phenytoin compared with placebo. Treatment was well tolerated, with ﬁve (12%) of 42 patients having a serious adverse event in the phenytoin group (only one, severe rash, was attributable to phenytoin) compared with two (5%) of 44 in the placebo group. Interpretation: These ﬁndings support the concept of neuroprotection with phenytoin in patients with acute optic neuritis at concentrations at which it blocks voltage-gated sodium channels selectively. Further investigation in larger clinical trials in optic neuritis and in relapsing multiple sclerosis is warranted. The "holy grail" of neurotherapeutics is neuroprotection-neurorestoration. Unfortunately, despite promising results in animal models, the ability for neuroprotection-neurorestoration has fallen disappointedly short in human trials (1). In this Phase II clinical trial, Raftopoulos et al set out to see if phenytoin (a voltage-gated sodium channel inhibitor) provides neuroprotection for the optic nerve in patients with optic neuritis. Eighty-six patients were enrolled (42 to the phenytoin group [29 received 4 mg/kg and 13 received 6 mg/kg] and 44 to the control group) within 2 weeks of symptom onset. The primary outcome of the study was mean reduction in retinal nerve 336 ﬁber layer (RNFL) thickness in the affected eye at 6 months (other outcomes analyzed included macular volume, visual acuity, Farnsworth-Munsell [FM] 100 hue test, visual evoked potential [VEP], optic nerve cross sectional area, and lesion length). Eighty-one of the 86 patients completed the study. Ten patients in the phenytoin group discontinued treatment due to adverse events. In terms of primary outcome, the placebo group had a 30% reduction in RNFL compared to the phenytoin group. Macular volume loss was 34% greater in the placebo group compared to the phenytoin group. There was no statistical difference between the 2 groups in terms of optic nerve cross-sectional area, VEP, FM 100 hue total, and visual acuity. The editorial that accompanied the article summarized the limitations of the study nicely (2): 1. Absence of regular and early OCT outcome measures 2. Small sample size 3. Baseline mean RNFL thickness discrepancy between the 2 groups 4. RNFL thickness (as compared to macular volume) more sensitive to effects of edema 5. Absence of ganglion cell + inner plexiform layer thickness analysis. -M. Tariq Bhatti, MD REFERENCES 1. Brew BJ. Lost in translation: again, another failed neuroprotection trial. Neurology. 2007;69:1308-1309. 2. Saidha S, Calabresi PA. Phenytoin in acute optic neuritis: neuroprotective or not? Lancet Neurol. 2016;15:233-235. I share the concerns about study limitations that you and the editorial have raised. In particular, I'm concerned that the RNFL at 6 months being 7.15 mm thinner with placebo than treatment is not much different when you consider that it started out 5.42 mm thinner. I am less concerned that visual acuity didn't improve because even with RNFL thinning most patients improve signiﬁcantly. However, I would expect some improvement in VEP amplitude if axons were preserved. Hopefully, these results are truly valid and, if so, would provide extra reserve for future injuries to the optic nerve. -Mark L. Moster, MD Guo Y, Johnson MA, Mehrabian Z, Mishra MK, Kannan R, Miller NR, Bernstein SL. Dendrimers target the ischemic lesion in rodent and primate models of nonarteritic anterior ischemic optic neuropathy. PLoS One. 2016;11:e0154437. Introduction: Polyamidoamine dendrimer nanoparticles (w4 nm) are inert polymers that can be linked to Moster and Bhatti: J Neuro-Ophthalmol 2016; 36: 334-340 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Literature Commentary biologically active compounds. These dendrimers selectively target and accumulate in inﬂammatory cells upon systemic administration. Dendrimer-linked compounds enable sustained release of therapeutic compounds directly at the site of damage. The purpose of this study was to determine if dendrimers can be used to target the optic nerve (ON) ischemic lesion in our rodent and nonhuman primate models of nonarteritic anterior ischemic optic neuropathy (NAION), a disease affecting .10,000 individuals in the US annually, and for which there currently is no effective treatment. Methods: NAION was induced in male Long-Evans rats (rNAION) and in one adult male rhesus monkey (pNAION) using previously described procedures. Dendrimers were covalently linked to near-infrared cyanine-5 ﬂuorescent dye (D-Cy5) and injected both intravitreally and systemically (in the rats) or just systemically (in the monkey) to evaluate D-Cy5 tissue accumulation in the eye and optic nerve following induction of NAION. Results: Following NAION induction, Cy-5 dendrimers selectively accumulated in astrocytes and circulating macrophages. Systemic dendrimer administration provided the best penetration of the ON lesion site when injected shortly after induction. Systemic administration 1 day postinduction in the pNAION model gave localization similar to that seen in the rats. Conclusions: Dendrimers selectively target the ischemic ON lesion after induction of both rNAION and pNAION. Systemic nanoparticle-linked therapeutics thus may provide a powerful, targeted and safe approach to NAION treatment by providing sustained and focused treatment of the cells directly affected by ischemia. I think you would agree with me, Mark, that nonarteritic anterior ischemic optic neuropathy (NAION) is a very frustrating disorder not only for the patient but also for us as neuro-ophthalmologists because there is no known effective treatment. I was really intrigued by this article because Guo et al were able to show that dendrimers (nanoparticles of approximately 4 nm) injected systemically could be traced to areas of ischemic damage of the optic nerve. The particles did not cross an intact blood-brain barrier and were not detectable in healthy optic nerves. I realize that this is very early in the process and that the report describes the feasibility of applying nanotechnology to NAION in rodent and primate models; but can you imagine if one day we could attach a therapeutic agent to a nanoparticle, inject it into the eye or vein, and have it go directly to the site of damage in the optic nerve to restore vision! Liguori C, Palmieri MG, Pierantozzi M, Cesareo M, Romigi A, Izzi F, Marciani MG, Oliva C, Mercuri NB, Placidi F. Optic nerve dysfunction in obstructive sleep apnea: an electrophysiological study. Sleep. 2016;39:19-23. Study Objectives: The aim of this study was to evaluate the integrity of the visual system in patients affected by obstructive sleep apnea (OSA) by means of electroretinogram (ERG) and visual evoked potential (VEP). Methods: We performed electrophysiological study of the visual system in a population of severe OSA (apneahypopnea events/time in bed $30/h) patients without medical comorbidities compared to a group of healthy controls similar for age, sex, and body mass index. Patients and controls did not have visual impairment or systemic disorders with known inﬂuence on the visual system. ERG and VEP were elicited by a reversal pattern generated on a television monitor at low (559 ) and high (159 ) spatial frequencies stimulation. Daytime sleepiness was assessed using the Epworth Sleepiness Scale (ESS) in both patients and controls. Results: In comparison with healthy controls (n = 27), patients with OSA (n = 27) showed a signiﬁcant latency delay coupled with a signiﬁcant amplitude reduction of P100 wave of VEP at all spatial frequencies in both eyes. No signiﬁcant differences between groups were detected as concerning ERG components. No correlations were found between polygraphic parameters, ESS scores, or VEP and ERG components in OSA patients. Conclusions: This study documented that patients with OSA, without medical comorbidities, present VEP alteration as documented by lower amplitude and longer latency of the P100 component than healthy controls. These altered electrophysiological ﬁndings may be the expression of optic nerve dysfunction provoked by hypoxia, acidosis, hypercarbia and airway obstruction, frequently observed in patients with OSA. Hence, we hypothesize that OSA per se may impair optic nerve function. Yes, Tariq, I agree NAION is one of the most frustrating diagnoses we deal with, as patients are referred with an expectation that we will make them better. This dendrimer technology offers hope not only for NAION but optic neuritis, orbital inﬂammatory diseases, and many other conditions. We're accustomed to considering sleep apnea as a risk factor for nonarteritic anterior ischemic optic neuropathy, papilledema, or progression of normal tension glaucoma. In this report, visually asymptomatic patients with severe obstructive sleep apnea (OSA) had electroretinogram (ERG) and visual evoked potential (VEP) studies and were compared with normal controls. Although they report the study as ERG, it actually was a pattern ERG that was recorded. The results were that the ERGs were similar in both populations but the VEPs were both delayed and decreased in amplitude in patients with OSA (14 milliseconds delay and 50% reduction in amplitude). This is evidence that OSA by itself can affect optic nerve function. Perhaps, this dysfunction may predispose to damage by the mechanisms of ischemia or pressure changes intracranially or intraocularly. -Mark L. Moster, MD -Mark L. Moster, MD -M. Tariq Bhatti, MD Moster and Bhatti: J Neuro-Ophthalmol 2016; 36: 334-340 337 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Literature Commentary I am not sure I share your enthusiasm regarding this study as conclusive evidence that OSA itself results in optic nerve dysfunction. The authors suggest that VEP is a very sensitive test of optic nerve function but fail to acknowledge that it has limitations and can deliver ﬂawed results based on technical issues. I am also bothered by the fact there is absolutely no clinical visual data on any of the patients. I am also trying to understand why there were no ERG changes despite the fact that OSA causes systemic hypoxia and other studies (as acknowledged by the authors) have shown OSA-related retinal abnormalities. -M. Tariq Bhatti, MD Eraslan M, Cerman E, Yildiz Balci S, Celiker H, Sahin O, Temel A, Suer D, Tuncer Elmaci N. The choroid and lamina cribrosa is affected in patients with Parkinson's disease: enhanced depth imaging optical coherence tomography study. Acta Ophthalmol. 2016;94:e68-e75. Purpose: To compare lamina cribrosa (LC) and choroidal thicknesses using enhanced depth imaging optical coherence tomography (EDI-OCT) in patients with Parkinson's disease (PD) and healthy controls. Methods: A total number of 44 eyes of 22 patients with PD and 50 eyes of 25 healthy subjects were utilized in this institutional cross-sectional study. After a complete ophthalmic examination, all eyes were imaged with OCT (RTVue-100 version 5.1 Fourier-domain optical coherence tomography; Optovue Inc, Fremont, CA); LC and choroidal thicknesses were assessed. Results: The mean LC thicknesses were 209.4 ± 40.2 mm in patients with PD and 292.5 ± 33.7 mm in control subjects. There was a signiﬁcant difference in the mean LC thickness between the groups (P , 0.0001). The choroidal thickness measurements of the PD group at the subfoveal region and 1.5 mm temporal and 1.5 mm nasal to the fovea were 228.1 ± 44.3, 193.2 ± 41.4, and 188.4 ± 49.0 mm, respectively, whereas measurements for the controls were, respectively, 246.5 ± 38.2, 227.3 ± 34.7, and 216.7 ± 51.4 mm. The choroid was signiﬁcantly thinner in eyes of the PD group compared to that of the controls (P = 0.001, P , 0.001, and P = 0.006). There was no signiﬁcant correlation between the disease severity and OCT parameters. The duration of the disease showed a statistically signiﬁcant negative correlation with LC (rs = 0.700, P , 0.001) and average subfoveal and temporal and nasal choroid thicknesses (rs = 0.282, P = 0.006; rs = 0.324, P = 0.001; rs = 0.240, and P = 0.020, respectively). Conclusions: Regardless of the disease severity, PD may cause atrophy and volume loss in the lamina cribrosa and choroid. An enhanced depth imaging technique may be used as an additional modality in the diagnosis and follow-up of patients with PD. 338 Despite the minor afferent clinical symptoms in patients with Parkinson disease (PD), many retinal abnormalities have been described. This is partly related to dopaminecontaining cells, such as amacrine cells. Clinically diminished contrast sensitivity and color vision may occur. Abnormal visual evoked potential and electroretinographic measurements have been observed, indicating retinal ganglion cell (RGC) damage. This study found reduced thickness of both the lamina cribrosa (LC) and the choroid in patients with PD. Duration of disease negatively correlated with thickness of LC and choroid but severity did not. The authors postulate a few theories about the reason for these ﬁndings. First, deposition of abnormal proteins leads to LC damage similar to what may occur in glaucoma. The LC damage then decreases transmission of neurotrophic factors coming from the lateral geniculate nucleus to the RGC, causing the retinal nerve ﬁber layer thinning that has been seen in PD. The choroidal thinning is proposed to be related to lower ocular perfusion pressure from hypotension sometimes associated with PD or metabolic changes from damaged RGCs or from vascular effects of dopaminergic medications. I doubt that looking for LC or choroidal thickness will be helpful in diagnosing PD. It is likely a nonspeciﬁc ﬁnding because choroidal thinning has been previously reported in Alzheimer disease. Whether it can become a biomarker for clinical trials along with other ocular measurements will likely soon be determined. -Mark L. Moster, MD This is an interesting study, but frankly I am not sure what to make of the results and I am dubious that these ﬁndings will lead to a better understanding of PD. As you mentioned (and so do the authors in their discussion), choroid and LC thinning have been shown in patients with Alzheimer disease. Therefore, it is most likely a nonspeciﬁc ﬁnding, and I would not be surprised if future studies of other neurodegenerative disorders report similar ﬁndings. I don't have much experience with enhanced depth imaging optical coherence tomography, but just looking at Figure 1, it seems to me that it is not easy to detect the outer border of the choroid (chorioscleral junction), and depending on where you place the vertical line to measure the thickness, it can give signiﬁcantly variable measurements. I also noted that the legends for Figures 1 and 2 were unintentionally reversed (Figure 1 legend refers to the images for Figure 2, and Figure 2 legend refers to the images for Figure 1). -M. Tariq Bhatti, MD Moster and Bhatti: J Neuro-Ophthalmol 2016; 36: 334-340 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Literature Commentary Kleiter I, Gahlen A, Borisow N, Fischer K, Wernecke KD, Wegner B, Hellwig K, Pache F, Ruprecht K, Havla J, Krumbholz M, Kümpfel T, Aktas O, Hartung HP, Ringelstein M, Geis C, Kleinschnitz C, Berthele A, Hemmer B, Angstwurm K, Stellmann JP, Schuster S, Stangel M, Lauda F, Tumani H, Mayer C, Zeltner L, Ziemann U, Linker R, Schwab M, Marziniak M, Then Bergh F, Hofstadt-van Oy U, Neuhaus O, Winkelmann A, Marouf W, Faiss J, Wildemann B, Paul F, Jarius S, Trebst C; Neuromyelitis Optica Study Group. Neuromyelitis optica: evaluation of 871 attacks and 1,153 treatment courses. Ann Neurol. 2016;79:206-216. Objective: Neuromyelitis optica (NMO) attacks often are severe, are difﬁcult to treat, and leave residual deﬁcits. Here, we analyzed the frequency, sequence, and efﬁcacy of therapies used for NMO attacks. Methods: A retrospective review was made of patient records to assess demographic/diagnostic data, attack characteristics, therapies, and the short-term remission status (complete remission [CR], partial remission [PR], no remission [NR]). Inclusion criteria were NMO according to Wingerchuk 2006 criteria or aquaporin-4 antibody-positive NMO spectrum disorder (NMOSD). Remission status was analyzed with generalized estimating equations (GEEs), a patient-based statistical approach. Results: A total of 871 attacks in 185 patients (142 NMO/ 43 NMOSD, 82% female) were analyzed. The 1,153 treatment courses comprised high-dose intravenous steroids (HD-S; n = 810), plasma exchange (PE; n = 192), immunoadsorption (IA; n = 38), other (n = 80), and unknown (n = 33) therapies. The ﬁrst treatment course led to CR in 19.1%, PR in 64.5%, and NR in 16.4% of attacks. Second, third, fourth, and ﬁfth treatment courses were given in 28.2%, 7.1%, 1.4%, and 0.5% of attacks, respectively. This escalation of attack therapy signiﬁcantly improved outcome (P , 0.001, Bowker test). Remission rates were higher for isolated optic neuritis versus isolated myelitis (P , 0.001), and for unilateral versus bilateral optic neuritis (P = 0.020). Isolated myelitis responded better to PE/IA than to HD-S as ﬁrst treatment course (P = 0.037). Predictors of CR in multivariate GEE analysis were age (odds ratio [OR] = 0.97, P = 0.011), presence of myelitis (OR = 0.38, P = 0.002), CR from previous attack (OR = 6.85, P , 0.001), and ﬁrst-line PE/IA versus HD-S (OR = 4.38, P = 0.006). Interpretation: Particularly myelitis and bilateral optic neuritis have poor remission rates. Escalation of attack therapy improves outcome. PE/IA may increase recovery in isolated myelitis. This study is a retrospective analysis of the treatment of 871 neuromyelitis optica (NMO)/NMO spectrum disorder (NMOSD) attacks in 185 patients in the Neuromyelitis Optica Study Group registry at 22 clinical sites in Europe. In addition to information on treatment efﬁcacy, it provides useful clinical information about NMO. One hundred forty-nine patients (81%) had at least 1 attack of optic neuritis (ON), and 178 patients (96%) had 1 or more Moster and Bhatti: J Neuro-Ophthalmol 2016; 36: 334-340 attacks of myelitis. Episodes of isolated myelitis (59.4%) were more frequent than isolated ON (28.4%), simultaneous myelitis and ON (10.2%). ON was unilateral in 81.6% and bilateral in 17.5% of cases. Other manifestations included 1 with nausea/vomiting/vertigo and 9 with other brainstem or cerebral symptoms. Complete remissions were higher for isolated ON than isolated myelitis or combined ON and myelitis, regardless of treatment regimen. Remissions were also greater for unilateral than bilateral ON. Of the 1,153 treatment courses, high-dose steroids (HD-S) were the most commonly used therapy (70.3%) followed by apheresis therapies (91.9%), such as plasma exchange (PE) or immunoadsorption (IA). Other therapies included intrathecal steroids, intravenous immunoglobulin, immunosuppressants, antibiotics, and oral low-dose steroids. Forty-two attacks remained untreated. The frequency of attacks treated with a second, third, fourth, and ﬁfth treatment course was 28.2%, 7.1%, 1.4%, and 0.5%, respectively. Therapeutic strategies varied, with 54 combinations identiﬁed. The most common therapeutic strategies were high-dose intravenous steroids alone (57.4%), 1 course of HD-S followed by PE (8.0%), 2 courses of HD-S (7.1%), PE alone (6.0%), 2 courses of HD-S followed by PE (2.7%), and 1 course of HD-S followed by IA. One of the important results is that adding treatment courses yielded more remissions. Escalation of therapy is strongly recommended when ﬁrst or second treatment courses of NMO attacks do not induce satisfactory recovery. What I wonder is whether we should be more aggressive in our patients with isolated atypical ON who have not been diagnosed with multiple sclerosis but are slow to recover initially with similar escalations of therapy. -Mark L. Moster, MD The authors of this study deserve a lot of credit for analyzing a tremendous amount of data in a very heterogeneous disease with multiple variations of therapies. There is a lot of very valuable information in this retrospective study, which required me to read it over several times. The ﬁgures are very good but I must admit I had to review them many times to understand what I was looking at and I still don't think I have a full understanding of all the ﬁndings. This study conﬁrms that NMO/NMOSD is a devastating disease with an overall complete remission rate of only 20% despite treatment! As a neuro-ophthalmologist, I was very interested in the ON data. As you mentioned, complete remissions were most frequent for patients with isolated ON (35.9%) but also were more frequent in patients who had unilateral ON (in fact patients with bilateral ON had a nearly 2-fold higher risk of no remissions). It should be noted that deﬁned criteria for a complete, incomplete, or no remission in the context of ON were not provided. It is difﬁcult to 339 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Literature Commentary make speciﬁc therapeutic conclusions based on the ﬁndings because the study was not designed to answer such a question. If you just look at the isolated ON group, there was a moderate improvement of complete remission rates with therapy escalation (33.2% after ﬁrst, 34.5% after second, 35.3% after third, and 35.7% after fourth). In addition, the complete remission rate of isolated ON was no 340 different between patients who received HD-S therapy compared to PE/IA (Fig. 5E). However, only 12 attacks were treated with PE/IA compared to 198 attacks treated with HD-S. Unfortunately, this study does not help me decide which intervention(s) to best treat my patients with ON due to NMOSD. -M. Tariq Bhatti, MD Moster and Bhatti: J Neuro-Ophthalmol 2016; 36: 334-340 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.
|Publisher||Lippincott, Williams & Wilkins|
|Source||Journal of Neuro-Ophthalmology, September 2016, Volume 36, Issue 3|
|Relation||NOVEL: Journal of Neuro-Ophthalmology Collection|
|Rights Management||© North American Neuro-Ophthalmology Society|
|Publication Type||Journal Article|