Ygal Rotenstreich

Visual acuity loss and clinical observations in a large series of patients with stargardt disease

PURPOSE To assess visual acuity impairment in Stargardt disease. DESIGN Retrospective clinic-based cross-sectional study. PARTICIPANTS Three-hundred sixty-one patients with Stargardt disease. METHODS Clinical findings in 361 patients were analyzed as part of a cross-sectional evaluation. Visual acuity at their most recent visit, fundus photographs, and electroretinographic findings were reviewed, and patients were categorized into four clinical phenotypes. Seventy-three patients with 20/40 or better vision and 38 patients with 20/50 to 20/100 vision in the better seeing eye at their initial visit who were followed for at least 1 year were included in a survival analysis. For analysis purposes, these latter patients were categorized into four 20-year age groups according to their age at initial visit. MAIN OUTCOME MEASURES Best-corrected visual acuity from the eye with better vision on the most recent visit was used in the cross-sectional analysis. For the survival analysis, best-corrected visual acuity was used from the eye with better vision on the initial visit. RESULTS Eighty-two of the 361 patients (23%) had 20/40 or better acuity in at least one eye, 64 (18%) 20/50 to 20/100, and 199 (55%) 20/200 to 20/400, whereas 16 (4%) had worse than 20/400 in each eye at their most recent visit. In the patients with visual acuity of 20/40 or better, 59 (72%) had foveal sparing visible on ophthalmoscopic examination. The median time to develop visual acuity of 20/200 or worse was 22 years for the patients with 20/40 or better visual acuity at their initial visit. Those seen initially in the first two decades of life with this level of acuity showed a median time of 7 years to reach a visual acuity of 20/200 or worse compared with 22 years and 29 years for those who were initially seen at ages 21 to 40 or 41 to 60, respectively. Analyzing by the four 20-year age groups, the log rank statistic indicated significant differences in the survival experience among the four groups (P = 0.004). The median time to develop 20/200 vision or worse was 6 years for the patients with 20/50 to 20/100 visual acuity at their initial visit, and this result, based on the log rank statistic, was independent of age group at initial visit (P = 0.852). CONCLUSIONS In a large cohort of Stargardt patients, a cross-sectional analysis showed that almost a quarter had vision of 20/40 or better, whereas 4% had acuity of worse than 20/400. The presence of foveal sparing ophthalmoscopically was associated with a higher prevalence of 20/40 or better visual acuity. Survival analysis showed that the prognosis of patients who initially were seen with visual acuity of 20/40 or better is related to age at initial visit.

Topical anesthesia using lidocaine gel for cataract surgery.

PURPOSE To assess the safety and efficacy of topical anesthesia using lidocaine gel in cataract surgery. SETTING Department of Ophthalmology, Meir Hospital, Sapir Medical Center, Kfar-Saba, Israel. METHODS One hundred cataract procedures (48 manual extracapsular cataract extraction [ECCE] and 52 phacoemulsification) were performed using lidocaine 2% gel as the sole anesthetic agent. The gel was applied 3 to 5 times prior to surgery. Intraoperative and postoperative data were recorded, and patients were asked to grade the pain on a scale of 0 (no pain) to 10 (unbearable pain). RESULTS Sixty-two percent of patients having manual ECCE and 74% having phacoemulsification reported no pain during surgery (score 0). The mean pain score in the manual ECCE group was 0.99 +/- 1.64 (SD); 3 patients required an additional intracameral lidocaine injection. The mean score in the phacoemulsification group was 0.72 +/- 1.47; no patient required additional anesthesia. CONCLUSIONS Topical application using lidocaine 2% gel is safe and highly effective, especially in clear corneal phacoemulsification. The gel also provides prolonged lubrication, further facilitating surgery.

Mutations in C8orf37, Encoding a Ciliary Protein, are Associated with Autosomal-Recessive Retinal Dystrophies with Early Macular Involvement

Cone-rod dystrophy (CRD) and retinitis pigmentosa (RP) are clinically and genetically overlapping heterogeneous retinal dystrophies. By using homozygosity mapping in an individual with autosomal-recessive (ar) RP from a consanguineous family, we identified three sizeable homozygous regions, together encompassing 46 Mb. Next-generation sequencing of all exons, flanking intron sequences, microRNAs, and other highly conserved genomic elements in these three regions revealed a homozygous nonsense mutation (c.497T>A [p.Leu166(∗)]) in C8orf37, located on chromosome 8q22.1. This mutation was not present in 150 ethnically matched control individuals, single-nucleotide polymorphism databases, or the 1000 Genomes database. Immunohistochemical studies revealed C8orf37 localization at the base of the primary cilium of human retinal pigment epithelium cells and at the base of connecting cilia of mouse photoreceptors. C8orf37 sequence analysis of individuals who had retinal dystrophy and carried conspicuously large homozygous regions encompassing C8orf37 revealed a homozygous splice-site mutation (c.156-2A>G) in two siblings of a consanguineous family and homozygous missense mutations (c.529C>T [p.Arg177Trp]; c.545A>G [p.Gln182Arg]) in siblings of two other consanguineous families. The missense mutations affect highly conserved amino acids, and in silico analyses predicted that both variants are probably pathogenic. Clinical assessment revealed CRD in four individuals and RP with early macular involvement in two individuals. The two CRD siblings with the c.156-2A>G mutation also showed unilateral postaxial polydactyly. These results underline the importance of disrupted ciliary processes in the pathogenesis of retinal dystrophies.

Effect of aspirin intake on bleeding during cataract surgery

Purpose: To study the association between chronic intake of aspirin and intraoperative bleeding during cataract surgery and the effect of discontinuing the medication before surgery. Setting: Department of Ophthalmology, Meir Hospital, Sapir Medical Center, KfarSaba, Israel. Methods: Sixty‐one patients having cataract surgery and receiving aspirin to prevent thromboembolic events were divided into 3 groups: Group A, continuation of the medication; Group B, cessation of aspirin intake for 2 to 5 days before surgery; Group C, cessation of medication for 7 to 10 days before surgery. Blood tests of coagulation parameters, a detailed questionnaire, and 1 day and 1 week follow‐up were evaluated. Results: There were no significant differences in blood tests and the amount and incidence of intraoperative bleeding among the 3 groups. Diathermy was used somewhat more in Group A; however, there was no difficulty stopping the bleeding in any case and discontinuation of the medication had no effect on the intraoperative course or postoperative outcome. Conclusions: Aspirin intake was not associated with significant intraoperative bleeding; thus, discontinuation of aspirin is usually not indicated. Clear corneal phacoemulsification is advantageous in patients receiving antiplatelet therapy.

Treatment of a retinal dystrophy, fundus albipunctatus, with oral 9-cis-β-carotene

Background Fundus albipunctatus is a retinal dystrophy caused by a mutation in the gene encoding 11-cis-retinol dehydrogenase which delays the recovery of rod photoreceptor cells from light stimulation leading to night blindness. A recent study of a mouse model of fundus albipunctatus treated with 9-cis-retinal showed an improvement in visual function and structure. Methods Seven patients with fundus albipunctatus were given a daily food supplement of four capsules containing high-dose 9-cis-β-carotene for 90 days. The subjects were tested before and after treatment by visual field and electroretinogram in both eyes. This non-randomised prospective phase I study was registered at http://www.clinicaltrials.gov (NCT00478530). Results All patients showed significant improvements in peripheral visual field (mean deviation improved from −4.77±2.0 to −3.28±2.28, p=0.009, t test) and a highly significant improvement in rod recovery rates measured electroretinographically (maximal scotopic b-wave amplitude responses, improved from 197±49 μV to 292±48 μV, p<0.001, t test). No complications or side effects were observed. Conclusion Oral treatment with 9-cis-β-carotene led to reversal of a human retinal dystrophy. This potential therapy is readily available and should be evaluated in retinal dystrophies of similar mechanisms such as various types of retinitis pigmentosa.

Short-term inter-visit variability of erg amplitudes in normal subjects and patients with retinitis pigmentosa.

PURPOSE To evaluate the short-term test/retest variability in visually normal subjects and patients with retinitis pigmentosa (RP), and to assess the effect of stimulus intensity and baseline amplitude on electroretinogram (ERG) variability. METHODS Eighteen patients with RP and nine visually normal subjects had a series of three unilateral ERGs, with an inter-visit interval of no less than 2 days and no more than 2 weeks. Responses to dark-adapted and both light-adapted single flash and 32 Hz flicker stimuli were recorded from a dilated eye over a range of stimulus intensities. B-wave amplitudes were compared to baseline amplitudes recorded at initial visit, and the resulting inter-visit percent difference was compared between stimulus intensities. Inter-visit variability was determined by one-way repeated measures analysis of variance using a 95% confidence interval to calculate threshold criteria for significant change. Analysis of variance followed by Bonferroni test for pairwise comparison was used to test for differences in inter-visit variability between two RP patient subgroups (higher versus lower baseline amplitudes) and visually normal subjects. The effect of stimulus intensity on amplitude reproducibility was also assessed. RESULTS Threshold for significant increase or decrease in inter-visit ERG amplitudes at a 95% confidence level for patients with RP and visually normal subjects was often at or above 25% and not infrequently at or above 40% for certain stimuli and test conditions. While no statistical difference in inter-visit variability was demonstrated between visually normal subjects and patients with RP who were arbitrarily categorized as having relatively higher baseline amplitudes, there was a difference between each of these two groups and a smaller group of patients with RP categorized as having lower baseline amplitudes. Although the authors could not demonstrate that percent inter-visit differences varied with stimulus intensity in either controls or patients with RP, the 32 Hz flicker stimulus generally produced less amplitude variability than either dark- or light-adapted single flash stimuli in patients with RP. CONCLUSIONS When using ERG amplitude for monitoring either the natural history of functional loss in retinal disease or as an outcome measure during a therapeutic trial, it becomes vital to define inter-visit variability of ERG amplitudes. These findings suggest that a percentage of patients with RP with appreciably lower baseline ERG amplitudes may manifest greater inter-visit ERG amplitude variability than patients with RP with higher baseline amplitudes or controls. Stimulus intensity had no clinically significant effect on inter-visit amplitude variability.

Primary cataract extraction and intraocular lens implantation in penetrating ocular trauma

PURPOSE To analyze the postoperative outcome and complication rate after cataract extraction or lensectomy with primary intraocular lens (IOL) implantation for penetrating traumatic cataract. DESIGN Retrospective, nonconsecutive, noncomparative case series. METHODS We retrospectively reviewed the files of 21 patients who were admitted to our departments because of traumatic cataract with corneal or scleral laceration caused by penetrating trauma with or without intraocular foreign body (IOFB) from 1992 through 1997. Lens aspiration or manual extracapsular cataract extraction with primary IOL implantation was performed in all patients. Removal of an IOFB was performed in eight patients. MAIN OUTCOME MEASURES Final visual acuity and deviation of actual refraction from emmetropia and from expected postoperative refraction. RESULTS The mean follow-up was 20.4 months. Fourteen eyes (67%) achieved final visual acuity of 20/40 or better, 95% obtained 20/60 or better final visual acuity, and all eyes achieved 20/100 or better final visual acuity. Major causes of limited visual acuity were central corneal scar and central retinal injury. Eleven eyes (57%) experienced secondary cataract and underwent neodymium:yytrium-aluminum-garnet capsulotomy. CONCLUSIONS Primary implantation of posterior chamber lenses after penetrating ocular trauma is associated with favorable visual outcome and a low rate of postoperative complications.

Clinical characteristics of rod and cone photoreceptor dystrophies in patients with mutations in the C8orf37 gene

PURPOSE To provide the clinical features in patients with retinal disease caused by C8orf37 gene mutations. METHODS Eight patients--four diagnosed with retinitis pigmentosa (RP) and four with cone-rod dystrophy (CRD), carrying causal C8orf37 mutations--were clinically evaluated, including extensive medical history taking, slit-lamp biomicroscopy, ophthalmoscopy, kinetic perimetry, electroretinography (ERG), spectral-domain optical coherence tomography (SD-OCT), autofluorescence (AF) imaging, and fundus photography. RESULTS In families A and D, respectively, one and three patients showed a classic RP phenotype with night blindness followed by concentric loss of visual field. Severe visual loss to light perception occurred early in the course of the disease. The symptoms initiated during infancy (family A) or adolescence (family D). Ophthalmoscopy revealed macular atrophy, bone spicules, attenuated vessels, and waxy pale optic discs. SD-OCT showed profound photoreceptor degeneration and AF demonstrated atrophy of the retinal pigment epithelium (RPE). ERG responses were nonrecordable in these patients. In families B and C, the patients were diagnosed with CRD. Initial symptoms were photophobia or loss of visual acuity and occurred during infancy (family B) or adolescence (family C). Ophthalmoscopy and AF revealed profound macular RPE atrophy and SD-OCT demonstrated macular photoreceptor degeneration. ERG responses were severely reduced in a cone-rod pattern or were nonrecordable. Interestingly, both patients in family B demonstrated polydactyly. CONCLUSIONS Mutations in C8orf37 give rise to an early or adolescent-onset autosomal recessive CRD or RP phenotype with early macular atrophy. The occurrence of postaxial polydactyly in one family suggests a syndromic phenotype, which may indicate C8orf37 has a ciliary function.

Effect of Brimonidine Tartrate on Ocular Hemodynamics in Healthy Volunteers

While alpha2-adrenergic agonists, such as brimonidine tartrate, significantly reduce the intraocular pressure (IOP), the presence of vasoconstrictor postsynaptic alpha2 receptors on vascular smooth muscle raise the possibility that brimonidine could potentially compromise ocular blood flow. Consequently, the ocular hemodynamic effects of brimonidine were studied in normal subjects. Twelve healthy volunteers were included in this prospective, double-masked, placebo controlled, crossover-designed clinical trial. They received either brimonidine tartrate 0.2% or placebo b.i.d. for 2 weeks. Goldmann tonometry and color Doppler imaging (CDI) were performed at baseline, at 2 hr, 1 week, and 2 weeks after the treatment. Fundus angiography using a scanning laser ophthalmoscope was performed at baseline and 2 weeks after treatment to determine retinal arteriovenous passage time. Brimonidine lowered IOP at 2 hr, 1 week, and 2 weeks (p = 0.058, p = 0.031, and p = 0.022, respectively). Brimonidine did not affect the retrobulbar arterial velocities measured by CDI, nor retinal arteriovenous passage time. In conclusion, two-week treatment with brimonidine reduces IOP and does not reduce the bulk retinal or retrobulbar arterial perfusion in young healthy volunteers.

Conditional inactivation of the NBS1 gene in the mouse central nervous system leads to neurodegeneration and disorganization of the visual system

Nijmegen breakage syndrome (NBS) is a genomic instability disease caused by hypomorphic mutations in the NBS1 gene encoding the Nbs1 (nibrin) protein. Nbs1 is a component of the Mre11/Rad50/Nbs1 (MRN) complex that acts as a sensor of double strand breaks (DSBs) in the DNA and is critical for proper activation of the broad cellular response to DSBs. Conditional disruption of the murine ortholog of the human NBS1, Nbs1, in the CNS of mice was previously reported to cause microcephaly, severe cerebellar atrophy and ataxia. Here we report that conditional targeted disruption of the murine NBS1 gene in the CNS results in mal-development, degeneration, disorganization and dysfunction of the murine visual system, especially in the optic nerve. Nbs1 deletion resulted in reduced diameters of Nbs1-CNS-Delta eye and optic nerve. MRI analysis revealed defective white matter development and organization. Nbs1 inactivation altered the morphology and organization of the glial cells. Interestingly, at the age of two-month-old the levels of the axonal guidance molecule semaphorin-3A and its receptor neuropilin-1 were up-regulated in the retina of the mutant mice, a typical injury response. Electroretinogram analysis revealed marked reduction in a- and b-waves, indicative of decreased retinal function. Our study points to a novel role for Nbs1 in the development, organization and function of the visual system.