Robert A. Sisk

Human Cone Visual Pigment Deletions Spare Sufficient Photoreceptors to Warrant Gene Therapy

Human X-linked blue-cone monochromacy (BCM), a disabling congenital visual disorder of cone photoreceptors, is a candidate disease for gene augmentation therapy. BCM is caused by either mutations in the red (OPN1LW) and green (OPN1MW) cone photoreceptor opsin gene array or large deletions encompassing portions of the gene array and upstream regulatory sequences that would predict a lack of red or green opsin expression. The fate of opsin-deficient cone cells is unknown. We know that rod opsin null mutant mice show rapid postnatal death of rod photoreceptors. Using in vivo histology with high-resolution retinal imaging, we studied a cohort of 20 BCM patients (age range 5-58) with large deletions in the red/green opsin gene array. Already in the first years of life, retinal structure was not normal: there was partial loss of photoreceptors across the central retina. Remaining cone cells had detectable outer segments that were abnormally shortened. Adaptive optics imaging confirmed the existence of inner segments at a spatial density greater than that expected for the residual blue cones. The evidence indicates that human cones in patients with deletions in the red/green opsin gene array can survive in reduced numbers with limited outer segment material, suggesting potential value of gene therapy for BCM.

Combined phacoemulsification and sutureless 23-gauge pars plana vitrectomy for complex vitreoretinal diseases

Background To evaluate the safety and visual outcomes of combined phacoemulsification and sutureless 23-gauge vitrectomy for concomitant cataract and vitreoretinal diseases. Methods Retrospective consecutive interventional case series. 114 eyes of 111 patients underwent combined sutureless 23-gauge vitrectomy and phacoemulsification surgery between 1 January 2006 and 1 March 2009. Main outcome measures were visual acuity and perioperative complications. Results All patients had at least 3 months follow-up (mean 263 days). The main vitreoretinal surgical indications were intractable cystoid macular oedema, epiretinal membrane and retinal detachment. Mean logMAR visual acuity improved from baseline 20/192 to 20/129 at 3 months (p=0.005). Mean intraocular pressure (IOP) increased from baseline 15.8 mm Hg to 17.7 mm Hg (p=0.033) on postoperative day 1 and then decreased by postoperative month 3 to 14.8 mm Hg (p=0.019). 110 (96.5%) eyes had significant pre-existing macular disease, and 93 (81.6%) received preoperative treatments. 82 (71.9%) patients required supplemental treatment(s) at a mean of 91.5 days, most commonly intravitreal injections to reduce vascular leakage or YAG capsulotomy. Hypotony, defined as IOP <5, was observed in four (3.5%) patients, and no patient developed endophthalmitis. Capsular tears were more frequent in eyes with a history of previous radiation or vitrectomy. Conclusions Combined phacoemulsification and sutureless 23-gauge vitrectomy surgery was safely and effectively used for cataracts and a variety of complex vitreoretinal diseases.

Gene therapy for Leber congenital amaurosis: advances and future directions

BackgroundLeber congenital amaurosis (LCA) is a congenital retinal dystrophy that results in significant and often severe vision loss at an early age. Comprehensive analysis of the genetic mutations and phenotypic correlations in LCA patients has allowed for significant improvements in understanding molecular pathways of photoreceptor degeneration and dysfunction. The purpose of this article is to review the literature on the subject of retinal gene therapy for LCA, including historical descriptions, preclinical animal studies, and human clinical trials.MethodsA literature search of peer-reviewed and indexed publications from 1996–2011 using the PubMed search engine was performed. Key terms included “Leber congenital amaurosis”, LCA, RPE65, ”cone-rod dystrophy”, “gene therapy”, and “human trials” in various combinations. Seminal articles prior to 1996 were selected from primary sources and reviews from the initial search. Articles were chosen based on pertinence to clinical, genetic, and therapeutic topics reviewed in this manuscript. Fundus photographs from LCA patients were obtained retrospectively from the clinical practice of one of the authors (R.A.S).ResultsHerein, we reviewed the literature on LCA as a genetic disease, the results of human gene therapy trials to date, and possible future directions towards treating inherited retinal diseases at the genetic level. Original descriptions of LCA by Theodor Leber and subsequent research demonstrate the severity of this disease with early-onset blindness. Discoveries of the causative heritable mutations revealed genes and protein products involved in photoreceptor development and visual transduction. Animal models have provided a means to test novel therapeutic strategies, namely gene therapy. Stemming from these experiments, three independent clinical trials tested the safety of subretinal delivery of viral gene therapy to patients with mutations in the RPE65 gene. More recently, efficacy studies have been conducted with encouraging results.ConclusionsInitial safety studies indicated promising results of subretinal delivery of viral vector with subclinical immunologic or surgical sequelae. Overall, these initial studies demonstrate that viral vector gene therapy results are very promising, safe, and effective. Future studies measuring potential improvement in photoreceptor function may rely on recent advances in retinal imaging and electrophysiologic testing.

Neuropathy target esterase impairments cause Oliver–McFarlane and Laurence–Moon syndromes

Background Oliver–McFarlane syndrome is characterised by trichomegaly, congenital hypopituitarism and retinal degeneration with choroidal atrophy. Laurence–Moon syndrome presents similarly, though with progressive spinocerebellar ataxia and spastic paraplegia and without trichomegaly. Both recessively inherited disorders have no known genetic cause. Methods Whole-exome sequencing was performed to identify the genetic causes of these disorders. Mutations were functionally validated in zebrafish pnpla6 morphants. Embryonic expression was evaluated via in situ hybridisation in human embryonic sections. Human neurohistopathology was performed to characterise cerebellar degeneration. Enzymatic activities were measured in patient-derived fibroblast cell lines. Results Eight mutations in six families with Oliver–McFarlane or Laurence–Moon syndrome were identified in the PNPLA6 gene, which encodes neuropathy target esterase (NTE). PNPLA6 expression was found in the developing human eye, pituitary and brain. In zebrafish, the pnpla6 curly-tailed morphant phenotype was fully rescued by wild-type human PNPLA6 mRNA and not by mutation-harbouring mRNAs. NTE enzymatic activity was significantly reduced in fibroblast cells derived from individuals with Oliver–McFarlane syndrome. Intriguingly, adult brain histology from a patient with highly overlapping features of Oliver–McFarlane and Laurence–Moon syndromes revealed extensive cerebellar degeneration and atrophy. Conclusions Previously, PNPLA6 mutations have been associated with spastic paraplegia type 39, Gordon–Holmes syndrome and Boucher–Neuhäuser syndromes. Discovery of these additional PNPLA6-opathies further elucidates a spectrum of neurodevelopmental and neurodegenerative disorders associated with NTE impairment and suggests a unifying mechanism with diagnostic and prognostic importance.

Visual and Anatomic Outcomes With or Without Surgery in Persistent Fetal Vasculature

PURPOSE To determine visual and anatomic outcomes for patients with persistent fetal vasculature (PFV) observed or treated with surgery. DESIGN Retrospective interventional consecutive case series. PARTICIPANTS A total of 165 eyes of 150 patients diagnosed with PFV between January 1, 1983, and December 31, 2006, at the Bascom Palmer Eye Institute. INTERVENTION Patients with media opacity, progressive glaucoma, or retinal detachment who were deemed to have visual potential underwent lensectomy, 3-port vitrectomy, or both, through a limbal or pars plicata/plana approach. MAIN OUTCOME MEASURES Vision, postsurgical retinal attachment, lens status, need for eye removal, and rate of complications. RESULTS Of the 81 eyes that underwent surgical repair, 70 had at least 6 months of follow-up (median 47 months) and 49 (70.0%) had form vision, defined as finger counting, fix-and-follow, or better. Twenty (95.2%) of 21 eyes without form vision had a significant posterior component of PFV (P < 0.001). Forty eyes had limbal incisions, and 30 eyes had pars plicata incisions. The choice of surgical approach did not have a statistically significant effect on final visual acuity or rate of complications (P=0.43). Postoperative events occurred in 28 eyes (40.0%). Retinal attachment was achieved in 54 eyes (77.1%), and 61 eyes (87.1%) were left aphakic. Eighty-four eyes were not offered surgery, of which 78 eyes (92.9%) had a posterior component of PFV. The median age at diagnosis was greater compared with the surgical group (197 vs. 67.5 days, P=0.00545). Fifty-eight eyes (69.0%) lacked form vision, and 39 eyes (46.4%) had no light perception. Posterior manifestations of PFV, bilaterality, and microphthalmia were associated with poorer visual outcomes (P < 0.001, 0.041, and 0.002, respectively). CONCLUSIONS The majority of patients receiving surgical intervention for PFV achieved form vision. Posterior disease, microphthalmia, glaucoma, and amblyopia limited visual acuity outcomes even after aggressive intervention. The choice of limbal versus pars plicata approach produced similar visual and anatomic outcomes without a significant difference in rate of complications. FINANCIAL DISCLOSURE(S) The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Valproic acid treatment may be harmful in non-dominant forms of retinitis pigmentosa.

I read with great excitement the article ‘Therapeutic Potential of Valproic Acid for Retinitis Pigmentosa’, by Clemson et al .1 Patients who received oral valproic acid (VPA) were reported to have improvement in Goldmann visual field performance and best-corrected visual acuity (BCVA) measurements after a mean 4 months of treatment. The current standard of care, vitamin A palmitate, has not been associated with any regression of disease or improvement in visual function in patients with retinitis pigmentosa (RP).2 Rather, a subgroup of patients may experience a decreased rate of cone amplitude degradation, which has been used as a surrogate marker for visual function. Therefore, this seminal work has sparked off a multicentre, prospective, randomised, controlled phase II clinical trial with the aim to evaluate the safety and efficacy of oral VPA in patients with dominant forms of RP.3 The study is currently enrolling patients, and the results will not be known until one year after the final patient is recruited. Shortly after its publication, the study by Clemson et al was criticised for its study design, short mean follow-up …

Outcomes of 25-gauge pars plana vitrectomy in the surgical management of proliferative diabetic retinopathy.

BACKGROUND AND OBJECTIVE To report outcomes and complications of 25-gauge pars plana vitrectomy (PPV) for patients with complications of proliferative diabetic retinopathy (PDR). PATIENTS AND METHODS Retrospective, interventional, consecutive case series of 174 eyes undergoing primary 25-gauge PPV for PDR from 2006 to 2009. Primary outcomes were visual acuity changes and rates of postoperative complications. RESULTS Visual acuity improved from 20/187 before to 20/69 after surgery (P < .0001). Postoperative vitreous hemorrhage occurred in 38.7% of eyes and 10.4% of all eyes required another PPV for non-clearing vitreous hemorrhage. Complications included limited choroidal effusion (5.2%), rhegmatogenous retinal detachment (4.6%), hypotony, rubeosis, and ocular hypertension (4.1%), neovascular glaucoma (2.3%), hyphema (1.2%), and phthisis bulbi (0.6%). CONCLUSION The authors found 25-gauge PPV to be effective for vitreous removal and membrane dissection. The spectrum and frequency of complications were similar to those reported for 20-gauge PPV for PDR. In the surgical management of PDR, 25-gauge PPV is an alternative.

Multimodal imaging and multifocal electroretinography demonstrate autosomal recessive Stargardt disease may present like occult macular dystrophy.

Purpose: To describe multimodal imaging and electrophysiologic characteristics of an unusual subset of patients with genetically confirmed autosomal recessive Stargardt disease (STGD1) who exhibited a central form of cone dysfunction resembling occult macular dystrophy that preceded the development of lipofuscin flecks, atrophy of retinal pigment epithelium (RPE), or full-field electroretinography abnormalities. Methods: Retrospective, observational descriptive case series. Results: Five patients with compound heterozygous ABCA4 mutations presented with bilateral visual acuity reduction, normal-appearing fundi, and blocked choroidal fluorescence on fluorescein angiography. One sibling each of two probands with identical genotypes was also included for analysis. Full-field electroretinography testing was normal in all patients, but multifocal electroretinography demonstrated centripetally depressed amplitudes exceeding areas of fundus autofluorescence, infrared imaging, and spectral domain optical coherence tomography abnormalities. Spectral domain optical coherence tomography initially revealed disruption of the inner segment ellipsoid band accompanying an ovoid hypofluorescent foveolar lesion. Progression to later stages was accompanied by the loss of the foveal photoreceptor outer segments, creating foveal cavitation with preservation of the RPE. Fundus autofluorescence and infrared imaging demonstrated corresponding bulls eye lesions. Over time, the foveal potential space on spectral domain optical coherence tomography collapsed, and three patients developed RPE atrophy and visible lipofuscin flecks. The flecks were detectable by fundus autofluorescence and infrared imaging earlier than by biomicroscopy. From these findings, a staging system for this subset of Stargardt disease presenting with central cone dysfunction was developed and presented herein. Conclusion: Autosomal recessive Stargardt disease may present as a central cone dysfunction syndrome before the development of lipofuscin flecks, atrophy of RPE, or full-field electroretinography abnormalities. If emerging therapies for Stargardt disease succeed, early recognition and treatment of patients with preserved foveal photoreceptor and RPE cell bodies may yield a more favorable visual prognosis.

Analysis of Outcomes for Intravitreal Bevacizumab in the Treatment of Choroidal Neovascularization Secondary to Ocular Histoplasmosis

PURPOSE To assess the long-term outcomes of intravitreal bevacizumab (IVB) in the treatment of choroidal neovascularization (CNV) secondary to presumed ocular histoplasmosis syndrome (POHS). DESIGN Retrospective, comparative case series. PARTICIPANTS Interventional series of 150 eyes in 140 patients treated for subfoveal or juxtafoveal CNV secondary to POHS from January 2006 to January 2010. INTERVENTION Intravitreal bevacizumab monotherapy or combination IVB and verteporfin photodynamic therapy (IVB/PDT). MAIN OUTCOME MEASURES Visual acuity (VA) at 12 and 24 months was analyzed. Secondary outcome measures included the number of injections per year and treatment-free intervals. RESULTS A total of 117 eyes received IVB monotherapy, and 34 eyes underwent combination IVB/PDT treatment. For all patients, the average pretreatment logarithm of minimum angle of resolution (logMAR) was 0.63 (Snellen equivalent 20/86) with a 12-month logMAR VA of 0.45 (Snellen equivalent 20/56) and a 24-month logMAR VA of 0.44 (Snellen equivalent 20/55). The mean follow-up was 21.1 months with an average of 4.24 IVB injections per year. There was no significant difference in initial VA, VA at 12 months, VA at 24 months, or number of eyes with a 3-line gain between the IVB monotherapy and IVB/PDT groups. Thirty-eight percent (39/104) of eyes gained 3 lines or more, and 81.2% (84/104) of subjects had maintained or improved their starting VA at 1 year. The proportion of subjects maintaining a 3-line gain in VA was relatively preserved at 2 years (29.8%, 17/57) and 3 years (30.3%, 10/32) follow-up. There was no increase in the proportion of subjects losing 3 lines or more over 3 years of follow-up. CONCLUSIONS There is no significant difference in VA outcomes between IVB monotherapy versus IVB/PDT combination therapy. The use of IVB alone or in combination with PDT results in significant visual stabilization in the majority of patients with CNV secondary to POHS.

Comparative Effectiveness of the Dexamethasone Intravitreal Implant in Vitrectomized and Non-vitrectomized Eyes With Macular Edema Secondary to Central Retinal Vein Occlusion

BACKGROUND AND OBJECTIVE To compare duration and efficacy of the dexamethasone (DEX) intravitreal implant in vitrectomized (pars plana vitrectomy [PPV] group) and non-vitrectomized eyes (control group) with macular edema related to central retinal vein occlusion (CRVO). PATIENTS AND METHODS Eyes that received the DEX implant for CRVO related to macular edema were included in a retrospective chart review. Outcomes measured were best-corrected visual acuity (BCVA) and central macular thickness (CMT). RESULTS Fifteen eyes were included in the study. Eight of 15 eyes had prior vitrectomy. Mean BCVA was 20/160 in both groups. Baseline mean CMT was 550 μm (PPV group) and 556 μm (control group, P = .70), and improved to 307.5 μm (PPV group) and 316.3 μm (control group) (P = .90) after implant. The BCVA was 20/125 (PPV group) and 20/200 (control group) (P = .60). Time to next procedure was similar in both groups. CONCLUSIONS This retrospective study shows similar CMT reductions with DEX implant treatment for CRVO-related macular edema in vitrectomized and non-vitrectomized eyes.