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Show Literature Commentary 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. doi: 10.1001/jamaophthalmol. 2013.7630. [Epub ahead of print]. Importance: We developed a novel strategy for treatment of Leber hereditary optic neuropathy (LHON) caused by a muta-tion in the nicotinamide adenine dinucleotide dehydroge-nase subunit IV (ND4) mitochondrial gene. Objective: To demonstrate the safety and effects of the gene therapy vector to be used in a proposed gene therapy clinical trial. Design and Setting: In a series of laboratory experiments, we modified the mitochondrial ND4 subunit of complex I in the nuclear genetic code for import into mitochondria. The protein was targeted into the organelle by agency of a targeting sequence (allotopic expression). The gene was packaged into adeno-associated viral vectors (AAVVs) and then vitreally in-jected into rodent, nonhuman primate, and ex vivo human eyes that underwent testing for expression and integration by immunohistochemical analysis and blue native polyacrylamide gel electrophoresis. During serial follow-up, the animal eyes underwent fundus photography, optical coherence tomography, and multifocal or pattern electroretinography. We tested for rescue of visual loss in rodent eyes also injected with a mutant G11778A ND4 homolog responsible for most cases of LHON. Exposure: Ocular infection with recombinant AAVVs con-taining a wild-type allotopic human ND4 gene. Main Outcomes and Measures: Expression of human ND4 and rescue of optic neuropathy induced by mutant human ND4. Results: We found human ND4 expressed in almost all mouse retinal ganglion cells by 1 week after injection and ND4 integrated into the mouse complex I. In rodent eyes also injected with a mutant allotopic ND4, wild-type allotopic ND4 prevented defective adenosine triphosphate synthesis, suppressed visual loss, reduced apoptosis of retinal gan-glion cells, and prevented demise of axons in the optic nerve. Injection of ND4 in the ex vivo human eye resulted in expression in most retinal ganglion cells. Primates under-going vitreal injection with the ND4 test article and followed up for 3 months had no serious adverse reactions. Conclusions and Relevance: Expression of our allotopic ND4 vector in the ex vivo human eye, safety of the test article, rescue of the LHON mouse model, and the severe irreversible loss of visual function in LHON support clinical testing with mutated G11778A mitochondrial DNA in our patients. Most patients with Leber hereditary optic neuropathy (LHON) carry the G11778A mutation, which affects the nicotinamide adenine dinucleotide dehydrogenase subunit IV (ND4) gene. The authors packaged "normal" and "mutant" human ND4 genes into an adeno-associated viral vector (AAVV). Either normal ND4 AAVV or control AAVV was injected intravitreally in mouse eyes. Three days later, the mutant ND4 AAVV, which has been shown to cause an optic neuropathy in mice similar to LHON, was injected. Rhesus monkeys underwent injection of control AAVV. Two enucle-ated human received injections of normal ND4 AAVV. Mouse and human eyes showed human ND4 expression in nearly all retinal ganglion cells within a week. Mouse eyes preinjected with normal ND4 AAVV maintained significantly better pattern electroretinogram amplitudes, retinal nerve fiber layer, and adenosine triphosphate synthesis than eyes prein-jected with control AAVV. No complications occurred from control AAVV in primate eyes except a mild vitritis at 1 month. We may be on the cusp of a gene therapy clinical trial for LHON! These viral vectors can deliver the normal genes to retinal ganglion cells leading to production of normal ND4. Treated eyes maintained structural and functional integrity compared with vehicle eyes in this mouse model of LHON. Finally, the viral vector vehicle seemed safe in primate eyes. Although nearly all patients with unilateral LHON develop visual loss in the fellow eye within 1 year, we would only need relatively few patients to show efficacy but assessing safety may require many more. -Michael S. Lee, MD This article describes all the steps that have been taken in animal studies and ex vivo human eyes demonstrating the efficacy of this genetic therapy. No important adverse effects were seen in these animals. The work described should be the justification for proceeding with a phase 1 clinical trial in humans with LHON. Positive results would have more widespread beneficial implications for other diseases with mitochondrial inheritance. -Mark L. Moster, MD Ristori G, Romano S, Cannoni S, Visconti A, Tinelli E, Mendozzi L, Cecconi P, Lanzillo R, Quarantelli M, Buttinelli C, Gasperini C, Frontoni M, Coarelli G, Caputo D, Bresciamorra V, Vanacore N, Pozzilli C, Salvetti M. Effects of Bacille Calmette-Guerin after the first demyelinating event in the CNS. Neurology. 2014;82:41-48. 208 Moster and Lee: J Neuro-Ophthalmol 2014; 34: 208-212 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. Objective: To evaluate Bacille Calmette-Guérin (BCG) ef-fects after clinically isolated syndromes (CIS). Methods: In a double-blind, placebo-controlled trial, partic-ipants were randomly assigned to receive BCG or placebo and monitored monthly with brain MRI (6 scans). Both groups then entered a preplanned phase with IM interferon b-1a for 12 months. From month 18 onward, the patients took the disease-modifying therapies (DMTs) that their neurologist considered indicated in an open-label extension phase lasting up to 60 months. Results: Of 82 randomized subjects, 73 completed the study (33 vaccinated and 40 placebo). During the initial 6 months, the number of cumulative lesions was signifi-cantly lower in vaccinated people. The relative risks were 0.541 (95% confidence interval [CI], 0.308-0.956; P = 0.03) for gadolinium-enhancing lesions (the primary end-point), 0.364 (95% CI, 0.207-0.639; P = 0.001) for new and enlarging T2-hyperintense lesions, and 0.149 (95% CI, 0.046-0.416; P = 0.001) for new T1-hypointense lesions. The number of total T1-hypointense lesions was lower in the BCG group at months 6, 12, and 18: mean changes from baseline were 20.09 ± 0.72 vs 0.75 ± 1.81 (P = 0.01), 0.0 ± 0.83 vs 0.88 ± 2.21 (P = 0.08), and 20.21 ± 1.03 vs 1.00 ± 2.49 (P = 0.02), respectively. After 60 months, the cumulative probability of clinically definite multiple sclerosis was lower in the BCG + DMT arm (hazard ratio = 0.52; 95% CI, 0.27-0.99; P , 0.05), and more vaccinated people remained DMT-free (odds ratio = 0.20; 95% CI, 0.04-0.93; P = 0.04). Conclusions: Early BCG may benefit CIS and affect its long-term course. Classification of Evidence: BCG, as compared with pla-cebo, was associated with significantly reduced develop-ment of gadolinium-enhancing lesions in people with CIS for a 6-month period before starting immunomodulating therapy (Class I evidence). This study of 1 dose of Bacille Calmette-Guérin (BCG) in addition to subsequent disease modifying therapy in pa-tients with clinically isolated syndrome (CIS) found a decrease in active magnetic resonance imaging (MRI) lesions and in subsequent clinical exacerbations. All MRI parameters (gadolinium enhancing T1, T2, and T1 hypo-intense) were better in patients receiving BCG. The number of exacerbations and the rate of conversion to clinically definite MS over 5 years were decreased as well. Although this study provides Class I evidence, having been a randomized double-blind placebo-controlled trial, there are limitations as pointed out by the authors and an accompanying editorial (1). First, the sample size was small. Second, only the first portion of the clinical trial was con-trolled with care after 18 months in the hands of the treat-ing neurologists. Both the authors and editorial writers speculate on what mechanisms may be at play in the immune response to BCG that might provide the clinical benefits seen. If these results are borne out in future studies, BCG will provide a very reasonably priced, reasonably safe, and quite easily tolerated adjunctive treatment for patients with CIS and possibly for patients with clinically definite MS as well. -Mark L. Moster, MD I would like to point out that patients received BCG at baseline and did not start intramuscular interferon b-1a until 6 months. The difference in MRI findings between vaccinated and placebo groups was significant at 6 months and at 18 months, and this suggests a real effect of the BCG on these patients. At 18 months, the article describes the open label extension as "unblinded." I do not know if that means that the investigators, neuroradiologists, and patients were given the treatment allocation. That may make the 60-month data more difficult to trust because of bias. Finally, BCG vaccination gives a fairly characteristic scar and would likely leave unblinded those "in the know." -Michael S. Lee, MD REFERENCE 1. Bourdette D, Naismith RT. BCG vaccine for clinically isolated syndrome and MS: infections and protective immunity. Neurology. 2014;82:15-16. Feil K, Claaßen J, Bardins S, Teufel J, Krafczyk S, Schneider E, Schniepp R, Jahn K, Kalla R, Strupp M. Effect of cholorzoxazone in patients with downbeat nystagmus: a pilot trial. Neurology. 2013;81:1152- 1158. Objective: Downbeat nystagmus (DBN) is the most frequent form of acquired persisting fixation nystagmus with different symptoms such as unsteadiness of gait, postural instability, and blurred vision with reduced visual acuity (VA) and oscillopsia. However, different symptomatic therapeutic principles are required, such as 3,4-diaminopyridine and 4-aminopyridine, that effectively suppress DBN. Chlorzoxazone (CHZ) is a nonselective activator of small conductance calcium-activated potas-sium (SK) channels that modifies the activity of cere-bellar Purkinje cells. We evaluated the effects of this agent on DBN in an observational proof-of-concept pilot study. Methods: Ten patients received CHZ 500 mg 3 times a day for 1 or 2 weeks. Slow-phase velocity of DBN, VA, postural sway, and the drug's side effects were evaluated. Record-ings were conducted at baseline, 90 minutes after first administration, and after 1 or 2 weeks. Results: Mean slow-phase velocity significantly decreased from a baseline of 2.74 ± 2.00 °/s to 2.29 ± 2.12 °/s (mean ± SD) 90 minutes after first administration and to 2.04 ± 2.24 °/s (P , 0.001; post hoc both P = 0.024) after long-term treatment. VA significantly increased, and pos-tural sway in posturography showed a tendency to decrease on medication. Fifty percent of patients did not report any side effects. The most common reported side effect was abdominal discomfort and dizziness. Moster and Lee: J Neuro-Ophthalmol 2014; 34: 208-212 209 Literature Commentary Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Conclusions: The treatment with the SK-channel activator CHZ is a potentially new therapeutic agent for the symp-tomatic treatment of DBN. Classification of Evidence: This study provides Class IV evidence that CHZ 500 mg 3 times a day may improve eye movements and visual fixation in patients with DBN. The authors gave chlorzoxazone (CHZ) 500 mg 3 times daily to 10 patients with downbeat nystagmus (DBN). They measured slow phase velocity (SPV), visual acuity (VA), and postural sway at baseline and after 1-2 weeks of treatment. They found a mean improvement of 44% in SPV, a marginal change in VA, and no change in postural sway. Fifty percent developed abdominal discomfort and dizziness. There is no definitive treatment for DBN, but the aminopyridines, 4-aminopyridine (4-AP), and 3,4- diaminopyridine (3,4-DAP), seem to work the best in many patients. Unfortunately, 3,4-DAP is not commercially avail-able in the United States. Although 4-AP is available, it is hard to come by and costs can be more than 1,000 dollars per month. For patients with DBN who cannot get or afford 4-AP, CHZ may represent another reasonable therapeutic alternative. This study included a very small group of patients, and time will tell if this is truly helpful and whether an alternative dosing schedule could improve outcomes in DBN. -Michael S. Lee, MD A new nystagmus treatment is always welcome, espe-cially one reasonably priced and widely available (CHZ is commonly known in the United States as parafon forte, a muscle relaxant). What is hard to glean from this article, but of utmost importance, is whether the responders felt any symptomatic improvement. The bellyache side effect is not worth it if it does not provide much relief. -Mark L. Moster, MD Avery RA, Hwang EI, Jakacki RI, Packer RJ. Marked recovery of vision in children with optic pathway gliomas treated with bevacizumab. JAMA Ophthalmol. 2014;132:111-114. Importance: Children with optic pathway gliomas (OPGs) frequently experience vision loss from their tumors. Stan-dard frontline treatment using carboplatin-based chemo-therapy typically produces only a modest benefit (e.g., stabilization or 0.2 logMAR improvement) in visual acuity (VA). Bevacizumab is a monoclonal antibody that targets vascular endothelial growth factor and acts primarily as an anti-angiogenic agent. Recent reports suggest a qualitative improvement in vision after bevacizumab-based treatment in children with OPGs. Observations: We report 4 cases of pediatric OPGs (2 neurofibromatosis Type 1-related and 2 sporadic cases) that received treatment with bevacizumab due to progressive VA or visual field (VF) loss despite prior treatment with chemother-apy or proton-beam radiation. All 4 subjects demonstrated a marked improvement in their VA, VF, or both while receiving bevacizumab-based therapy. Three patients had complete resolution of their VA or VF loss in at least 1 eye, 2 of whom had previously received bevacizumab therapy. Conclusions and Relevance: Given that most patients with OPG-related visual impairment will show modest or no visual improvement with standard treatment, the incorporation of bevacizumab in these cases may greatly improve visual outcomes and should be considered in appropriate clinical situations. Although an anecdotal report of 4 patients, this article demonstrates hope for visual recovery in children with optic glioma and progressive visual loss or radiographic enlarge-ment. Particularly encouraging is that the improvement was also seen in 3 children with prior bevacizumab treatment. Two patients had radiation therapy 4 and 7 months before visual deterioration, so it is difficult to distinguish the cause of the deterioration between tumor progression and radiation toxicity. This raises the possibility that IV bevacizumab may benefit patients with radiation toxicity. However, this possibility should be considered in view of conflicting reports that bevacizumab may actually contribute to optic neuropathy in the setting of radiation (1). For time being, it is likely reasonable to try bevacizumab in a child with progressive visual loss from glioma. Where this treatment ultimately fits in in the global treatment of these patients awaits further clinical trials. -Mark L. Moster, MD I think it is unlikely that these 2 patients had radiation injury. One patient presented at 7 months but began to lose vision at 4 months after radiation. Radiation injury typically does not occur this early in the clinical course. The other patient was treated with radiation 4 months prior, because she was losing vision and this was likely progression of that visual loss. In 3 patients, there was new and progressive visual loss (the fourth was asymptomatic, so we do not know the time course). I wonder if the previous bevacizumab therapy was ineffective because there was no active growth of the gliomas; whereas the marked recovery of vision with the current treatment of bevacizumab occurred, because the authors treated at an acute stage of growth. -Michael S. Lee, MD REFERENCE 1. Sherman JH, Aregawi DG, Lai A, Fathallah-Shaykh HM, Bierman PJ, Linsky K, Larner JM, Newman SA, Schiff D. Optic neuropathy in patients with glioblastoma receiving bevacizumab. Neurology. 2009;73:1924-1926. Abegg M, Dysli M, Wolf S, Kowal J, Dufour P, Zinkernagel M. Microcystic macular edema: retrograde maculopathy caused by optic neuropathy. Ophthalmology. 2014;121:142-149. 210 Moster and Lee: J Neuro-Ophthalmol 2014; 34: 208-212 Literature Commentary Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Purpose: To investigate retrograde axonal degeneration for its potential to cause microcystic macular edema (MME), a maculopathy that has been previously described in patients with demyelinating disease. To identify risk factors for MME and to expand the anatomic knowledge on MME. Design: Retrospective case series. Participants: We included 117 consecutive patients and 180 eyes with confirmed optic neuropathy of variable etiology. Patients with glaucoma were excluded. Methods: We determined age, sex, visual acuity, etiology of optic neuropathy, and the temporal and spatial character-istics of MME. Eyes with MME were compared with eyes with optic neuropathy alone and to healthy fellow eyes. With retinal layer segmentation, we quantitatively measured the intraretinal anatomy. Main Outcome Measures: Demographic data, distribution of MME in the retina, and thickness of retinal layers were analyzed. Results: We found MME in 16 eyes (8.8%) from 9 patients, none of whom had multiple sclerosis or neuromyelitis optica. The MME was restricted to the inner nuclear layer (INL) and had a characteristic perifoveal circular distribu-tion. Compared with healthy controls, MME was associated with significant thinning of the ganglion cell layer and nerve fiber layer, as well as a thickening of the INL and the deeper retinal layers. Youth is a significant risk factor for MME. Conclusions: MME is not specific for demyelinating dis-ease. It is a sign of optic neuropathy irrespective of its etiology. The distinctive intraretinal anatomy suggests that MME is caused by retrograde degeneration of the inner retinal layers, resulting in impaired fluid resorption in the macula. In this retrospective study, the authors searched their databases for patients with a history of optic neuropathy who underwent macular optical coherence tomography testing. They found that 16 of 180 eyes had microcystic macular edema (MME) limited to the inner nuclear layer. A striking finding was the perifoveal location of the MME in all eyes. The cause of the optic neuropathy ranged from compressive (n = 9), vascular (n = 3), hereditary (n = 2), and idiopathic (n = 2), and the proportions did not differ from the non-MME eyes. The shortest time to develop MME was 4 months and the longest time was several years. The authors make a compelling argument that this represents a retrograde degenerative process. I actually have seen these changes on optical coherence tomography in patients with optic neuropathy, but did not associate the findings. I had assumed that the patient had developed cystic retinal changes and made a referral to a retinal specialist. Now I know. It has a pretty characteristic appearance, and I would recommend the reader look at the images. -Michael S. Lee, MD This article demonstrates that MME is not likely part of the pathophysiologic process of inflammatory optic neuropathy as previously proposed (first for multiple sclerosis [MS] and then for neuromyelitis optica [NMO]), but a nonspecific secondary change occurring in optic neuropathy. It was seen in compressive, vascular, and hereditary causes of optic neuropathy but further clinical details on these patients were not provided. If it were part of the primary inflammatory process in optic neuritis from MS or NMO, one would not expect to see it in these other optic neuropathies. The authors excluded glaucoma cases "to better match patients with MS in whom MME had been first described." I do not understand how ischemic, com-pressive, and hereditary optic neuropathy are better matches for patients with MS, but that does not detract from the findings in this study. Indeed, MME has now been described in a group of glaucoma patients (1). I agree with Michael that a few years ago, I would send a patient with MME for retinal consultation, but am now comfortable that it is part of the process affecting the optic nerve. -Mark L. Moster, MD REFERENCE 1. Wolff B, Basdekidou C, Vasseur V, Mauget-Faysse M, Sahel JA, Vignal C. Retinal inner nuclear layer microcystic changes in optic nerve atrophy: a novel spectral-domain OCT finding. Retina. 2013;33:2133-2138. Sato DK, Callegaro D, Lana-Peixoto MA, Waters PJ, Jorge FM, Takahashi T, Nakashima I, Apostolos-Pereira SL, Talim N, Simm RF, Lino AM, Misu T, Leite MI, Aoki M, Fujihara K. Distinction between MOG antibody-positive and AQP4 antibody-positive NMO spectrum disorders. Neurology. 2014;82:474-481. Objective: To evaluate clinical features among patients with neuromyelitis optica spectrum disorders (NMOSD) who have myelin oligodendrocyte glycoprotein (MOG) antibodies, aquaporin04 (AQP4) antibodies, or seronegativity for both antibodies. Methods: Sera from patients diagnosed with NMOSD in 1 of 3 centers (2 sites in Brazil and 1 site in Japan) were tested for MOG and AQP4 antibodies using cell-based assays with live transfected cells. Results: Among the 215 patients with NMOSD, 7.4% (16/ 215) were positive for MOG antibodies and 64.7% (139/ 215) were positive for AQP4 antibodies. No patients were positive for both antibodies. Patients with MOG antibodies represented 21.1% (16/76) of the patients negative for AQP4 antibodies. Compared with patients with AQP4 antibodies or patients who were seronegative, patients with MOG anti-bodies were more frequently male, had a more restricted phenotype (optic nerve more than spinal cord), more frequently had bilateral simultaneous optic neuritis, more often had a single attack, had spinal cord lesions distributed in the lower portion of the spinal cord, and usually demon-strated better functional recovery after an attack. Conclusions: Patients with NMOSD with MOG antibodies have distinct clinical features seronegative for both anti-bodies. Moster and Lee: J Neuro-Ophthalmol 2014; 34: 208-212 211 Literature Commentary Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Myelin oligodendrocyte glycoprotein (MOG) antibodies have been seen in patients with numerous demyelinating disorders, such as acute disseminated encephalomyelitis, MS, and adrenoleukodystrophy. This study evaluated MOG antibodies and aquaporin04 (AQP4) antibodies in patients with neuromyelitis optica spectrum disorders (NMOSD). The findings are interesting in that the clinical features were somewhat different for those with MOG, AQP4 or those that were seronegative for both. No patients had both MOG and AQP4 antibodies. Patients who met the diagnostic criteria for definite NMO rarely had MOG antibodies (1/101), whereas 84% (85/101) had AQP4 antibodies. The other variants in the spectrum of NMOSD include longitudinal exten-sive transverse myelitis (LETM) or bilateral simultaneous or recurrent optic neuritis. LETM patients had MOG antibody 6.4% of the time but the optic neuritis group had the highest association, being positive for MOG antibody 27.8% of the time (10/36) with only 30.5% positive for AQP4. Other features associated with MOG antibody was a more likelihood of being male, having better recovery, and having a single rather than multiple attacks. What we do not really know is if these patients are more likely behaving in a better prognostic fashion because they really do have early MS instead of NMO, and their future clinical course and MRI picture will establish this as time goes on. Nonetheless, just as finding AQP4 antibody has improved our understanding and treatment of a subset of optic neuritis patients, finding other associated antibodies may further refine our diag-nostic and therapeutic capabilities. -Mark L. Moster, MD Patients with recurrent or bilateral simultaneous optic neuritis could develop NMO. Based on this article, if the MOG antibody is positive, this indicates a better visual prognosis than those who are NMO positive or seronegative for both. The visual acuity was ,20/200 in 19%, 73%, and 47% of MOG positive, NMO positive, and seronegative patients, respectively. It may be helpful to order this test for prognostic purposes. -Michael S. Lee, MD 212 Moster and Lee: J Neuro-Ophthalmol 2014; 34: 208-212 Literature Commentary Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. |
