Gene Therapy for LHON
Leber hereditary optic neuropathy (LHON) is a disorder characterized by severe, rapidly progressive, and usually bilateral vision loss. Feuer et al. present their findings from the first 5 patients who participated in a gene therapy trial to assess the safety and tolerability of escalating doses of an adeno-associated virus (AAV2) vector that expresses normal ND4 complementary DNA in patients with a G to A mutation at nucleotide 11778 of the mitochondrial genome.
The 5 patients were legally blind individuals with LHON. Four had vision loss for more than 12 months, while the fifth had vision loss for less than 12 months. They each received a unilateral injection of the study drug. The first 3 participants received a low dose of the study drug; the fourth patient (loss for more than 12 months) received a medium dose, and the fifth participant (loss for less than 12 months) received a low dose. Treated participants were observed for 90 to 180 days and underwent ocular and systemic safety assessments along with visual structure and function examinations. The main outcome measure was loss of visual acuity (VA), which was assessed using the Early Treatment Diabetic Retinopathy Study (ETDRS) eye chart.
VA remained unchanged from baseline to 3 months in the first 3 participants. In 2 participants (number 4, medium dose; and number 5, low dose), VA increased from hand motions to 7 ETDRS letters and by 15 letters, respectively. No patients lost vision, and no serious adverse events occurred. Minor adverse events included a transient increase in IOP, exposure keratitis, subconjunctival hemorrhage, sore throat, and a transient increase in neutralizing antibodies against AAV2 in 1 study participant. All blood samples were negative for vector DNA. Follow-up will continue on these patients, and the researchers plan to add more participants over the next 4 years.
Precision Pulse Capsulotomy: Preclinical Safety and Performance Assessment
Chang et al. described a new method, called precision pulse capsulotomy (PPC), for making anterior capsulotomies using a disposable handheld instrument that is integrated into the conventional phacoemulsification surgical sequence. According to the authors, this device produces a fast, highly focused, multipulse low-energy discharge to create a perfectly round anterior capsulotomy instantaneously and simultaneously along all 360 degrees.
In a preclinical safety and performance study, the researchers used human cadaver eyes and New Zealand white rabbits. Miyake-Apple imaging and scanning electron microscopy (SEM) were performed in the human cadaver eyes. Surgical, postoperative slit-lamp, and histopathologic assessments of PPC were performed in 20 live rabbits and were compared with manual continuous curvilinear capsulorrhexis (CCC) in the fellow eye.
The main outcome measures were capsulotomy edge circularity, SEM morphologic features, and zonular movement with PPC in human cadaver eyes. Additional measures included anterior chamber temperature during PPC and grading of ocular inflammation, corneal endothelial damage, anterior capsular opacification (ACO), and posterior capsular opacification (PCO) in the rabbits.
Miyake-Apple imaging revealed minimal zonular stress, and thermocouple measurements showed negligible anterior chamber temperature changes during PPC. The technique also produced round and complete capsulotomies in all 20 rabbit eyes, allowing successful in-the-bag IOL implantations.
In slit-lamp exams at 3 days and at 1, 2, and 4 weeks after surgery, the researchers found no significant differences between PPC and CCC in corneal edema, anterior chamber inflammatory reaction, capsular fibrosis, ACO, or PCO. Postmortem studies also revealed no differences in the corneal endothelium. All IOLs were well centered in the PPC eyes, and histopathologic analysis revealed no greater amount of inflammatory infiltrates.
The authors concluded that PPC is a new way to automate the consistent creation of a perfectly circular anterior capsulotomy using an instrument that can be incorporated into standard phacoemulsification surgery.
Antiplatelet/Anticoagulant Drugs and Risk of Retinal or Subretinal Hemorrhage
Ying et al. examined the use of antiplatelet and anticoagulant medications among participants in the Comparison of Age-Related Macular Degeneration (AMD) Treatments Trials (CATT). The aim of this study was to assess the risk of retinal and subretinal hemorrhage in participants with untreated neovascular AMD in the CATT population.
In this cohort study, participants were interviewed about their use of antiplatelet or anticoagulant drugs. Trained readers evaluated photographs for the presence and size of retinal or subretinal hemorrhages at baseline, year 1, and year 2.
Among 1,165 study participants with gradable photographs, 724 (62.1%) had a retinal or subretinal hemorrhage at baseline. Of these hemorrhages, 84.4% were 1 disc area (DA) or less, 8.1% were 1 to 2 DA, and 7.5% were larger than 2 DA. At baseline, 608 participants (52.2%) were taking antiplatelet or anticoagulant medications or both.
At baseline, hemorrhage was present in 64.5% of antiplatelet or anticoagulant users and in 59.6% of nonusers. The researchers found no association between the presence or size of baseline hemorrhage and the type, dose, or duration of antiplatelet or anticoagulant use. Among 1,078 participants photographed at year 1 or year 2, 44 additional hemorrhages (occurring in 4.1%) were detected. These hemorrhages were not associated with antiplatelet or anticoagulant use at baseline or during follow-up. However, among participants with hypertension, antiplatelet or anticoagulant use was found to be associated with a higher rate of hemorrhage at baseline (66.8%), but it was not associated with the size of hemorrhage.
The authors commented that various studies have examined the question of association between retinal and subretinal hemorrhages and use of antiplatelet or anticoagulant drugs, and the results have been mixed. In this study, they found no significant associations overall, though the subgroup of patients with hypertension did have a 1.5-fold increased risk of hemorrhage. The authors concluded that nonhypertensive patients with AMD could continue taking needed antiplatelet or anticoagulant drugs without fear of increased risk of visual loss from hemorrhage. However, among AMD patients with hypertension, antiplatelet or anticoagulant use was associated with 1.5-fold increased risk of retinal or subretinal hemorrhage; thus, blood pressure status should be considered when such drugs are prescribed in this population.
Automated Perimetry and Visual Dysfunction in Blast-Related TBI
With more than 330,000 U.S. military personnel diagnosed with traumatic brain injury (TBI) since the year 2000, blast-related neurotrauma is a significant challenge in this population. Cockerham et al. evaluated the reliability and results of performing automated perimetry on veterans affected by blast neurotrauma.
The authors described the effects of blast forces, which include a supersonic overpressure wave along with embedded shear and stress waves and rapid acceleration and deceleration. These forces can disrupt internal eye tissues without penetrating or rupturing the eye wall, and several studies suggest that blast exposure can cause subtle damage throughout the ocular system and may compromise vision. Although automated visual field (VF) testing has the potential to play an important role in evaluating the visual pathways in patients with TBI, challenges to test reliability in this population include impaired concentration, rapid onset of fatigue, or poor control of fixation.
This prospective longitudinal, observational case series included 61 participants (109 study eyes) in a Veterans Affairs Polytrauma Center who had been diagnosed with TBI due to combat blast exposure. These participants underwent automated perimetry at baseline (median interval, 2 months after injury), and 36 were followed up at a median interval of 10 months from baseline. The main outcome measure was global VF indices (mean deviation and pattern standard deviation).
Reliable VF tests were obtained in 48 participants (79%) and in 78 eyes (72%). Loss of fixation was identified in 32 eyes (29%) in the initial testing. Nine study participants (15%) demonstrated hemianopia or quadrantanopia, and an additional 36% had an abnormal global VF index.
The authors concluded that reliable automated perimetry measurement can be obtained in most patients with TBI resulting from blast exposure. Automated perimetry also revealed a high incidence of VF deficits, which indicates that blast forces can significantly affect the eye and visual pathways. The authors noted that more than 80% of veterans diagnosed with TBI are rated as having mild TBI. However, because VF abnormalities were noted at all levels of TBI severity, they recommended automated perimetry for all patients with TBI who are capable of performing the test. Further, they suggested that the SITA Fast protocols are particularly useful in patients with acquired brain injury.
Ophthalmology summaries are written by Marianne Doran and edited by Susan M. MacDonald, MD.
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American Journal of Ophthalmology