Gene therapy for Leber hereditary optic neuropathy.

INTRODUCTION: Leber hereditary optic neuropathy (LHON) is among the most frequent inherited mitochondrial disease, causing a severe visual impairment, mostly in young-adult males. The causative mtDNA variants (the three common are m.11778 G>A/MT-ND4, m.3460 G>A/MT-ND1, and m.14484T>C/MT-ND6) by affecting complex I impair oxidative phosphorylation in retinal ganglion cells, ultimately leading to irreversible cell death and consequent functional loss. The gene therapy based on allotopic expression of a wild-type transgene carried by adeno-associated viral vectors (AVV-based) appears a promising approach in mitochondrial disease and its efficacy has been explored in several large clinical trials. AREAS COVERED: The review work employed basic concepts in mitochondrial diseases, LHON, and gene therapy procedures. Reports from completed trials in LHON (i.e. RESCUE) were reviewed and critically compared. EXPERT OPINION: New challenges, as the improvement of the contralateral untreated eye or the apparently better outcome in patients treated in later stages (6-12 months), were highlighted by the latest gene therapy trials. A better understanding of the pathogenetic mechanisms of the disease together with combined therapy (medical and gene therapy) and optimization in genetic correction approaches could improve the visual outcome of treated eyes.

Cardiac Wolframinopathies: A Case Report of Myocarditis and a Literature Review of Cardiac Involvement in Wolfram Syndrome 1.

Purpose: Myocarditis is frequently a sporadic disease, but may also occur in the context of genetic disorders which may increase susceptibility to cardiac inflammation. Cardiac involvement in Wolfram syndrome type 1 (WS1) has been scarcely characterized. To our knowledge, no cases of virus-negative myocarditis have been reported in the WS1 pediatric population. Methods: We report the description of a pediatric case of acute myocarditis in the context of WS1, followed by a literature review of cardiovascular involvement associated with wolframin variants, and discuss potential pathophysiological mechanisms and therapeutic options. Results: A young patient with WS1, treated with insulin and liraglutide, was admitted for acute chest pain. Cardiac magnetic resonance and endomyocardial biopsy were performed to confirm the clinical suspicion of myocarditis. While congenital heart diseases and arrhythmias have been described previously in patients with WS1, this is the first description of virus-negative myocarditis. Conclusions: Myocarditis may represent a possible manifestation of cardiovascular involvement in WS1. Cardiovascular screening may be considered in patients with WS1.

AFG3L2 and ACO2-Linked Dominant Optic Atrophy: Genotype-Phenotype Characterization Compared to OPA1 Patients.

PURPOSE: Heterozygous mutations in the AFG3L2 gene (encoding a mitochondrial protease indirectly reflecting on OPA1 cleavage) and ACO2 gene (encoding the mitochondrial enzyme aconitase) are associated with isolated forms of Dominant Optic Atrophy (DOA). We aimed at describing their neuro-ophthalmological phenotype as compared with classic OPA1-related DOA. DESIGN: Cross-sectional study. METHODS: The following neuro-ophthalmological parameters were collected: logMAR visual acuity (VA), color vision, mean deviation and foveal threshold at visual fields, average and sectorial retinal nerve fiber layer (RNFL), and ganglion cell layer (GCL) thickness on optical coherence tomography. ACO2 and AFG3L2 patients were compared with an age- and sex-matched group of OPA1 patients with a 1:2 ratio. All eyes were analyzed using a clustered Wilcoxon rank sum test with the Rosner-Glynn-Lee method. RESULTS: A total of 44 eyes from 23 ACO2 patients and 26 eyes from 13 AFG3L2 patients were compared with 143 eyes from 72 OPA1 patients. All cases presented with bilateral temporal-predominant optic atrophy with various degree of visual impairment. Comparison between AFG3L2 and OPA1 failed to reveal any significant difference. ACO2 patients compared to both AFG3L2 and OPA1 presented overall higher values of nasal RNFL thickness (P = .029, P = .023), average thickness (P = .012, P = .0007), and sectorial GCL thickness. These results were confirmed also comparing separately affected and subclinical patients. CONCLUSIONS: Clinically, DOA remains a fairly homogeneous entity despite the growing genetic heterogeneity. ACO2 seems to be associated with an overall better preservation of retinal ganglion cells, probably depending on the different pathogenic mechanism involving mtDNA maintenance, as opposed to AFG3L2, which is involved in OPA1 processing and is virtually indistinguishable from classic OPA1-DOA.

Association of Circulating Antiretinal Antibodies With Clinical Outcomes in Retinitis Pigmentosa.

Purpose: To determine if circulating antiretinal antibodies (ARAs) differ between patients affected by retinitis pigmentosa (RP) and control participants and to assess whether ARAs are associated with clinical outcomes in patients with RP. Methods: Cross-sectional study involving a group of patients clinically diagnosed with RP and a control group of healthy participants. Serum autoantibodies against enolase, heat shock protein 70 (HSP70), and carbonic anhydrase II (CAII) were tested in all participants using Jess capillary Western blot. We compared ARA prevalence between the RP and control groups and investigated the association of serum ARA positivity with macular edema and vitreomacular disorders in patients affected by RP. Results: Thirty-six patients affected by RP and a control group of 39 healthy individuals were included. Overall, at least one ARA positivity was detected in 89% and 80% of participants in the RP and control groups, respectively. We observed a similar prevalence of anti-CAII and anti-enolase ARA between patients and controls (P = 0.87 and P = 0.35, respectively). Sera from patients with RP tested positive for anti-HSP70 ARAs more frequently than those from controls (53% vs. 36%), albeit without reaching statistical significance (P = 0.29). Among the 72 eyes with RP, 25% presented with macular edema (most often bilateral) and 33% with epiretinal membrane and/or lamellar macular hole. None of the three ARAs was associated with an increased risk of any macular complications in eyes affected by RP (all P > 0.05). Conclusions: The prevalence of circulating ARAs against enolase, HSP70, and CAII is similar between patients affected by RP and healthy individuals. Our results provide evidence against the association of ARAs with macular edema and vitreomacular interface disorders in RP.

Capturing the Transition From Intermediate to Neovascular AMD: Longitudinal Inner Retinal Thinning and Factors Associated With Neuronal Loss.

Purpose: To estimate the impact of transition from intermediate to exudative neovascular age-related macular degeneration (AMD) on the inner retina and to assess the relationship of clinical characteristics and optical coherence tomography (OCT) findings with inner retinal changes. Methods: A total of 80 participants (80 eyes) with intermediate AMD at baseline who developed neovascular AMD within 3 months were included in the analysis. OCT scans at follow-up visits (after transition to neovascular AMD) were compared with values at the latest visit with evidence of intermediate AMD to quantify longitudinal inner retinal changes. OCT images were also reviewed for qualitative features reflecting distress of the outer retina or retinal pigment epithelium and for the presence and characteristics of exudation. Results: The parafoveal and perifoveal inner retinal thicknesses were 97.6 ± 12.9 µm and 103.5 ± 16.2 µm, respectively, at baseline, and a significant increase in values was detected at the visit with first evidence of neovascular AMD (parafoveal: 99.0 ± 12.8 µm, P = 0.040; perifoveal: 107.9 ± 19.0 µm, P = 0.0007). Conversely, the inner retina was significantly thinner at the 12-month follow-up visit after initiation of the anti-vascular endothelial growth factor therapy (parafoveal: 90.3 ± 14.8 µm, P < 0.0001; perifoveal: 92.0 ± 21.3 µm, P < 0.0001). At the 12-month follow-up visit, OCT evidence of alterations of the external limiting membrane and history of previous intraretinal fluid were associated with a greater inner retinal thinning. Conclusions: The development of exudative neovascularization is associated with significant neuronal loss that may be detected once the exudation is resolved. OCT analysis demonstrated a significant relationship between morphological alterations detected using structural OCT and the amount of inner neuronal loss.

Peripapillary hyperreflective ovoid mass-like structures (PHOMS): OCTA may reveal new findings.

PURPOSE: Peripapillary hyperreflective ovoid mass-like structures (PHOMS) are novel and not well characterized findings occurring in several disorders of the optic nerve. The aim of this study is to present two cases of tilted disc syndrome (TDS) and one case with optic disc drusen undergoing a multimodal imaging approach. METHODS: In this case series, a qualitative evaluation of the OCTA findings in regions with PHOMS was performed. RESULTS: Structural OCT revealed the presence of PHOMS. OCTA identified the presence of a vascular complex within this hyperreflective structure. CONCLUSIONS: Assuming that PHOMS are thought to correspond to herniating nerve fibers or be secondary to axoplasmic stasis, this vascular complex may represent a displacement of the deeper vessels deputed at the irroration of the optic nerve into the retina or, alternatively, might be secondary to an increase in vascular endothelial growth factor (VEGF) levels and a subsequent development of neovessels.

Macular Microcysts in Mitochondrial Optic Neuropathies: Prevalence and Retinal Layer Thickness Measurements.

PURPOSE: To investigate the thickness of the retinal layers and to assess the prevalence of macular microcysts (MM) in the inner nuclear layer (INL) of patients with mitochondrial optic neuropathies (MON). METHODS: All patients with molecularly confirmed MON, i.e. Leber's Hereditary Optic Neuropathy (LHON) and Dominant Optic Atrophy (DOA), referred between 2010 and 2012 were enrolled. Eight patients with MM were compared with two control groups: MON patients without MM matched by age, peripapillary retinal nerve fiber layer (RNFL) thickness, and visual acuity, as well as age-matched controls. Retinal segmentation was performed using specific Optical coherence tomography (OCT) software (Carl Zeiss Meditec). Macular segmentation thickness values of the three groups were compared by one-way analysis of variance with Bonferroni post hoc corrections. RESULTS: MM were identified in 5/90 (5.6%) patients with LHON and 3/58 (5.2%) with DOA. The INL was thicker in patients with MON compared to controls regardless of the presence of MM [133.1±7µm vs 122.3±9µm in MM patients (p<0.01) and 128.5±8µm vs. 122.3±9µm in no-MM patients (p<0.05)], however the outer nuclear layer (ONL) was thicker in patients with MM (101.4±1mµ) compared to patients without MM [77.5±8mµ (p<0.001)] and controls [78.4±7mµ (p<0.001)]. ONL thickness did not significantly differ between patients without MM and controls. CONCLUSION: The prevalence of MM in MON is low (5-6%), but associated with ONL thickening. We speculate that in MON patients with MM, vitreo-retinal traction contributes to the thickening of ONL as well as to the production of cystic spaces.

Natural course of symptomatic focal choroidal excavation.

A 32-year-old man was referred to the authors' department for nonspecified macular dystrophy with persistent metamorphopsia in the right eye diagnosed 10 years before and followed using optical coherence tomography. The patient underwent a comprehensive ocular examination, including multimodal imaging evaluation and electrofunctional testing. The diagnosis was consistent with nonconforming focal choroid excavation. Over 10 years, no complications occurred, visual acuity was stable, and optical coherence tomography showed no progression of the lesion during follow-up. In this case, nonconforming symptomatic focal choroid excavation was a nonprogressive condition with good long-term visual outcome.

Changes in macular function after ozurdex for retinal vein occlusion.

PURPOSE: To investigate changes in macular function after intravitreal dexamethasone implant (Ozurdex) for macular edema (ME) secondary to retinal vein occlusion (RVO). METHODS: Nineteen treatment-naive patients with RVO-related ME were treated with intravitreal Ozurdex and followed up to 6 months to evaluate functional outcomes, by means of best-corrected visual acuity, microperimetry, and multifocal electroretinography, and their correlations with morphological parameters by enhanced depth imaging optical coherence tomography. RESULTS: Nineteen eyes of 19 patients were included for analysis. At 1 month, mean best-corrected visual acuity, retinal sensitivity, and central macular thickness (CMT) improved from 0.50 ± 0.34 LogMAR, 10.51 ± 4.31 dB, and 762 ± 259 µm (baseline) to 0.38 ± 0.34 LogMAR (p = 0.043), 12.28 ± 5.06 dB (p = 0.025), and 385 ± 191 µm (p = 0.001), respectively. At 3 months, improvement of mean retinal sensitivity and CMT was still significant (11.62 ± 5.05 dB [p = 0.047] and 518 ± 251 µm [p = 0.006]). Multifocal electroretinography measurements also showed (nonsignificant) improvement. No significant changes in choroidal thickness were recorded. Improvements recorded during the first 3 months were no longer significant from month 4. At each time point, we found a negative significant correlation between CMT and retinal sensitivity. Interestingly, 7 eyes did not undergo retreatment of less than 6 months; these eyes showed a significantly better baseline retinal sensitivity than eyes requiring retreatment of less than 6 months (12.27 ± 3.52 dB vs. 9.48 ± 4.53 dB [p = 0.038]). CONCLUSIONS: In eyes with ME secondary to RVO, intravitreal dexamethasone implant provides functional benefits as soon as 1 month after treatment. In most cases, the optimum retreatment interval is less than 6 months from first intravitreal Ozurdex. Microperimetry is a very useful tool to characterize macular function. Baseline macular sensitivity may predict the need for early (<6 months) retreatment.

Fluorescein angiography and spectral-domain optical coherence tomography for monitoring anti-VEGF therapy in myopic choroidal neovascularization.

AIM: To evaluate the agreement between fluorescein angiography (FA) and spectral-domain optical coherence tomography (SD-OCT) in detecting myopic choroidal neovascularization (CNV) activity during bevacizumab treatment. METHODS: Thirty-four patients with subfoveal myopic CNV were prospectively enrolled. FA and SD-OCT were performed at baseline and at all planned monthly visits. After the first injection, additional treatments were administered following detection of fluid on SD-OCT and/or leakage on FA. κ-Analysis was performed to examine the agreement between FA and SD-OCT. RESULTS: At baseline, FA and SD-OCT agreed in 26/34 cases (κ=0.23); sensitivity and specificity were 77.4 and 66.7%, respectively. Seven eyes presented leakage on FA with no fluid on SD-OCT, 1 case showed intraretinal fluid on SD-OCT and no leakage on FA. At the 1-month examination, specificity and κ-value improved, and 30/34 cases showed complete concordance. At the 3- and 4-month examinations, a discordance was noted in 6 cases. From the 5-month examination on, a correspondence was achieved in at least 30/34 cases and reached a perfect match in 11 sessions. CONCLUSIONS: Our study confirms the key role of FA in diagnosing myopic CNV. It seems possible there may be a role for SD-OCT in assisting FA to monitor the myopic CNV activity during anti-vascular endothelial growth factor antibody treatment.

Natural course of photic maculopathy secondary to uncomplicated cataract surgery.

We report on a 36-year-old man who developed photic maculopathy in the left eye shortly after uncomplicated cataract surgery. The visual acuity (VA) of the left eye was 6/39 and spectral domain optical coherence tomography (SD-OCT), performed one week after surgery, revealed a hyporeflective space in the outer retina (a 'partial-thickness hole') at the fovea. Microperimetry showed a relative central scotoma and multifocal electroretinogram (ERG) showed reduced responses within the central 10°. Two months later, VA in the felt eye improved to 6/6 and SD-OCT showed an almost complete resolution of the 'partial-thickness hole'. Microperimetry showed the resolution of the relative scotoma at the fovea and multifocal ERG showed improved responses within the central 10°. SD-OCT, microperimetry and multifocal ERG are useful tools in the diagnosis and follow-up of photic maculopathy after uncomplicated cataract surgery. Its natural history may be characterised by resolution of both morphological and functional changes shortly after surgery.

Intravitreal Ranibizumab for myopic choroidal neovascularization after pars plana vitrectomy and silicone oil tamponade.

PURPOSE: To report on intravitreal Ranibizumab for intervening myopic choroidal neovascularization (CNV) in a case of retinal detachment successfully repaired with pars plana vitrectomy and silicone oil tamponade. METHODS: Intravitreal ranibizumab was performed in a 67-year-old woman with CNV complicating pathologic myopia. The patient had previously undergone vitrectomy and silicone oil tamponade for retinal detachment. RESULTS: At 2 months from intravitreal ranibizumab, best-corrected visual acuity (BCVA) improved from count fingers to 20/100, and intraocular pressure (IOP) was 16 mm Hg. Fluorescein angiography (FA) and spectral-domain optical coherence tomography (SD-OCT) showed resolution of late leakage and subretinal/intraretinal fluid, respectively. CONCLUSIONS: Administration of intravitreal anti-V EGF in patients with silicone oil as intraocular tamponade may represent an intriguing treatment option. Our results suggest that intravitreal injections of Ranibizumab may lead to a rapid improvement in both functional (BCVA) and morphologic (FA and SD-OCT) parameters of CNV activity, without significant rise in IOP, in eyes with silicone oil as intraocular tamponade.

Intravitreal ranibizumab versus bevacizumab for treatment of myopic choroidal neovascularization.

PURPOSE: To compare intravitreal bevacizumab (IVB) and intravitreal ranibizumab (IVR) in the treatment of subfoveal choroidal neovascularization associated with pathologic myopia. METHODS: Fifty-five patients fulfilling inclusion and exclusion criteria were randomized either to IVB or to IVR. After the first injection, re-treatments were performed on a pro re nata basis in monthly examinations over an 18-month follow-up. Primary outcome measures were the change in mean best-corrected visual acuity and the proportion of eyes improving in best-corrected visual acuity by >1 and >3 lines at the 18-month examination. RESULTS: Forty-eight eyes received the treatment and were subsequently included in the analysis. At the 18-month examination, a significant improvement of 1.7 lines and 1.8 lines compared with baseline were noticed in the IVR and IVB subgroups, respectively. The difference in the final mean best-corrected visual acuity between the groups was not significant. A 3-line gain or higher was noted in 30% of eyes in the IVR subgroup and 44% of eyes in the IVB subgroup. Although both groups attained a significant improvement in central macular thickness, the IVR subgroup achieved a faster central macular thickness reduction. A significantly lower number of injections were administered in the IVR subgroup (2.5) compared with the IVB subgroup (4.7; P < 0.001). CONCLUSION: Intravitreal ranibizumab and IVB are effective in the treatment of subfoveal myopic choroidal neovascularization. Intravitreal ranibizumab achieved greater efficacy than IVB in terms of the mean number of injections administered.

Intravitreal dexamethasone implant in patients with persistent diabetic macular edema.

PURPOSE: To evaluate the effects of a single injection of Ozurdex over 6 months in eyes with persistent diabetic macular edema (DME). METHODS: In this retrospective interventional study, 9 patients with decreased visual acuity, as a result of persistent DME, received Ozurdex (intravitreal dexamethasone implant 0.7 mg). Main outcome measures included changes in best-corrected visual acuity (BCVA) and central retinal thickness (CRT). RESULTS: Nine eyes of 9 patients (5 males, 4 females; mean age 58 years) were included in the analysis. The mean duration of DME was 49.9 months (range 24-85). All patients had undergone previous treatments for DME (intravitreal injection of anti-vascular endothelial growth factor, steroids or laser photocoagulation) before entering the study. At baseline, the mean BCVA was 0.74 ± 0.33 logMAR, and the mean CRT was 502 ± 222.16 µm. The mean BCVA was unchanged on the third day (0.74 ± 0.38 logMAR, p = 0.5), improved to 0.62 ± 0.32 logMAR (p = 0.02), 0.59 ± 0.26 logMAR (p = 0.02) and 0.63 ± 0.38 logMAR (p = 0.6) after the first, third and fourth months, respectively, and decreased again to 0.73 ± 0.35 logMAR (p = 0.4) at 6 months. The mean CRT improved to 397 ± 115.31 µm (p = 0.17), 271 ± 99.97 µm (p = 0.007), 325 ± 133.05 µm (p = 0.03) and 462 ± 176.48 µm (p = 0.36) on the third day and after 1, 3 and 4 months of follow-up and then increased again to 537 ± 265.42 µm (p = 0.33) at 6 months. Eight patients needed retreatments in the sixth month. One eye developed a transient intraocular pressure (IOP) increase 1 month after injection, which was successfully managed with topical IOP-lowering medication. CONCLUSION: In eyes with persistent DME, Ozurdex produces improvement in BCVA and CRT as soon as the first days after the injection. Such improvement is maintained until the fourth month.

Intravitreal bevacizumab in a patient with a macular star in malignant hypertension.

PURPOSE: To report a case of retinopathy secondary to malignant hypertension showing a macular star, which responded favorably to a single intravitreal injection of bevacizumab (IVB). METHODS: A 46-year-old man with malignant hypertension showing incomplete macular star in his right eye with best-corrected visual acuity (BCVA) of 20/32 underwent IVB. RESULTS: Subsequent examinations revealed a progressive resolution of the macular star with functional recovery over the follow-up. In particular, at the 9-month examination BCVA was 20/20, fundus biomicroscopy disclosed resolution of the macular star, and the retinal sensitivity improved remarkably. CONCLUSIONS: Intravitreal injection of bevacizumab can be a useful approach to treat the exudative manifestations of malignant hypertension.

Sequential anterior ischemic optic neuropathy and central retinal artery and vein occlusion after ranibizumab for diabetic macular edema.

PURPOSE: To describe a rare adverse event characterized by anterior ischemic optic neuropathy (AION) associated with central retinal artery occlusion (CRAO) followed by central retinal vein occlusion (CRVO) secondary to treatment with intravitreal injection of ranibizumab for diabetic macular edema (DME). METHODS: A patient with DME refractory to focal grid laser photocoagulation in the left eye was prospectively followed and treated with intravitreal injection of ranibizumab. Over a 12-month period and after 4 injections, best-corrected visual acuity (BCVA) improved from 20/63 to 20/50 (Snellen equivalent) and central retinal thickness (CRT) reduced from 551 to 279 µm. In July 2009, BCVA dropped to 20/100 with CRT of 421 µm due to the recurrence of DME and a further injection was administered. RESULT: One month later, the left eye showed a sudden visual acuity loss. Best-corrected visual acuity was 20/400 and the fundus examination revealed a hyperemic and swollen optic disc, with several retinal hemorrhages. Retina at the posterior pole was pale, with attenuation and sheathing of arterial vessels. Fluorescein angiography showed a delayed optic disc and arterial filling with retinal ischemia involving both posterior pole and periphery and confirmed the diagnosis of AION associated with CRAO. One month later, the BCVA decreased to 20/800, and fundus examination evidenced a CRVO with diffuse retinal hemorrhages in the 4 quadrants, congestion, and tortuosity of the retinal veins. CONCLUSIONS: Although severe ocular adverse events are generally rare, patients receiving intraocular anti-vascular endothelial growth factor injection should be monitored carefully for the development of vascular complications.

Bevacizumab vs photodynamic therapy for choroidal neovascularization in multifocal choroiditis.

OBJECTIVE: To compare the effectiveness of photodynamic therapy (PDT) vs intravitreal bevacizumab injection in patients with subfoveal choroidal neovascularization (CNV) secondary to multifocal choroiditis (MC). METHODS: Patients affected by subfoveal CNV associated with MC referred for clinical evaluation from March 1, 2005, to July 31, 2008, were considered for this pilot randomized clinical trial. Twenty-seven patients were included in the study and followed up from March 15, 2005, through April 30, 2009. After randomization, patients receiving PDT were treated according to the Treatment of Age-Related Macular Degeneration With Photodynamic Therapy protocol, whereas patients receiving intravitreal bevacizumab injection, after a loading phase of 3 monthly injections, were examined monthly and re-treated on the basis of detection of fluid on optical coherence tomography and/or leakage on fluorescein angiography. MAIN OUTCOME MEASURES: The primary outcome measure was the 5- and 15-letter change on the Early Treatment of Diabetic Retinopathy Study charts at 12-month examinations compared with baseline. Secondary outcomes included central macular thickness changes. RESULTS: Thirteen and 14 patients were randomized to PDT and bevacizumab treatment, respectively. At the 12-month examination, 5 of 14 eyes treated with bevacizumab and 0 of 13 eyes treated with PDT experienced a best-corrected visual acuity gain of greater than 3 lines (P = .04). Twelve eyes in the bevacizumab group and 6 eyes in the PDT group gained more than 1 line (P = .04). The central macular thickness showed a progressive reduction in both subgroups without a significant difference compared with the baseline values. CONCLUSIONS: Greater beneficial effects can be achieved using intravitreal bevacizumab injection rather than PDT for the treatment of subfoveal CNV secondary to MC. Larger multicenter investigations are needed to confirm our preliminary results. Application to Clinical Practice Currently, there is no precise indication regarding the best therapeutic approach to subfoveal CNV secondary to MC. This investigation was designed to verify whether intravitreal bevacizumab injection has a more beneficial effect with respect to PDT.