Pseudodominance in two families with KCNV2 related retinopathy.

PURPOSE: To describe the phenotypic and genotypic characteristics of two families with cone dystrophy with supernormal rod responses (CDSRR) presenting with a pseudodominant inheritance of disease. OBSERVATIONS: Three affected members from each family were ascertained. Family 1 of Egyptian ancestry showed consanguinity, and Family 2 was of Northern Iraqi ancestry. Both families showed pseudodominance in their pedigrees.Individuals presented with reduced visual acuity and nyctalopia. Macular disturbances were present in all, varying from a decreased foveal reflex to geographic atrophy. Electrophysiology showed reduced scotopic b-wave amplitudes and prolonged implicit times, and characteristic elevated b-wave amplitudes with high intensity flashes in all individuals.Genetic analysis of Family 1 identified a complete homozygous deletion of the KCNV2 gene, and in Family 2 a homozygous missense variation of c.562T > A: p.(Trp188Arg). CONCLUSIONS AND IMPORTANCE: To our knowledge this is the first report of pseudodominance of CDSRR, with a novel pathogenic KCNV2 variant present in the second family. Clinicians evaluating these individuals should consider autosomal recessive disease manifesting as pseudodominant inheritance. In such cases, electrophysiology remains essential for making a definitive diagnosis.

A novel rhodopsin point mutation, proline-170-histidine, associated with sectoral retinitis pigmentosa.

Identification and classification of all retinitis pigmentosa (RP) causing mutations contribute to a better understanding of disease variants. In this report we describe a New Zealand family, of European heritage, affected by a sectoral type RP phenotype in association with a novel rhodopsin mutation (proline-170-histidine) in a highly conserved site.

Autoimmune retinopathy associated with carcinoid tumour of the small bowel.

Cancer associated retinopathy (CAR) is an immune mediated paraneoplastic condition associated with vision loss. It has been associated with a variety of systemic malignancies. The primary clinical presentation is rapid, progressive vision loss. Rod and cone dysfunction can cause other associated symptoms, such as nyctalopia. Electrophysiological testing and detection of anti-retinal antibodies are used to confirm the diagnosis. To our knowledge we describe the first patient with CAR associated with a carcinoid tumour of the gastrointestinal system. Auto-antibodies against alpha enolase and carbonic anhydrase II were detected with western blotting. Electroretinogram findings were consistent with rod and cone dysfunction.

Rhodopsin F45L Allele Does Not Cause Autosomal Dominant Retinitis Pigmentosa in a Large Caucasian Family.

PURPOSE: To ascertain the potential pathogenicity of a retinitis pigmentosa (RP)-causing RHO F45L allele in a family affected by congenital achromatopsia (ACHM). METHODS: Case series/observational study that included two patients with ACHM and 24 extended family members. Molecular genetic analysis was performed to identify RHO F45L carrier status in the family and a control population. An adaptive optics scanning light ophthalmoscope (AOSLO) was used to image the photoreceptor mosaic and assess rod and cone structure. Spectral domain optical coherence tomography (SD-OCT) was used to examine retinal lamination. Comprehensive clinical testing included acuity, color vision, and dilated fundus examination. Electroretinography was used to assess rod and cone function. RESULTS: Five carriers of the RHO F45L allele alone (24-80 years) and three carriers in combination with a heterozygous CNGA3 mutant allele (10-64 years) were all free of the classic symptoms and signs of RP. In heterozygous carriers of both mutations, SD-OCT showed normal retinal thickness and intact outer retinal layers; rod and cone densities were within normal limits on AOSLO. The phenotype in two individuals affected with ACHM and harboring the RHO F45L allele was indistinguishable from that previously reported for ACHM. CONCLUSIONS: The RHO F45L allele is not pathogenic in this large family; hence, the two ACHM patients would unlikely develop RP in the future. TRANSLATIONAL RELEVANCE: The combined approach of comprehensive molecular analysis of individual genomes and noninvasive cellular resolution retinal imaging enhances the current repertoire of clinical diagnostic tools, giving a substantial impetus to personalized medicine.

Two-year safety and efficacy of ranibizumab 0.5 mg in diabetic macular edema: interim analysis of the RESTORE extension study.

OBJECTIVE: To evaluate the 2-year safety and efficacy of ranibizumab 0.5 mg in diabetic macular edema (DME). DESIGN: Twenty-four-month, open-label, multicenter, Phase IIIb extension study. PARTICIPANTS: Two hundred forty of 303 patients with visual impairment due to DME who completed the RESTORE core study and entered the extension. METHODS: All patients were eligible to receive ranibizumab 0.5 mg pro re nata (PRN) from month 12 (end of core study) to month 36 based on best-corrected visual acuity (BCVA) stability and disease progression retreatment criteria. Patients were also eligible to receive laser PRN according to Early Treatment Diabetic Retinopathy Study guidelines. A preplanned interim analysis was performed at month 24, stratifying by treatment groups as in the RESTORE core study and referred to as prior ranibizumab, ranibizumab plus laser, or laser groups in the extension. MAIN OUTCOME MEASURES: Incidence of ocular and nonocular adverse events (AEs) and mean change in BCVA. RESULTS: Two hundred twenty patients (92%) completed the month 24 visit. Over 2 years, the most frequent ocular serious AE (SAE) and AE were cataract (2.1%) and eye pain (14.6%), respectively. The main nonocular AEs were nasopharyngitis (18.8%) and hypertension (10.4%). There were no cases of endophthalmitis, and the incidences of nonocular SAEs were low. Of the patients entering the extension, 4 deaths were reported in the second year, none of which were related to study drug or procedure. Mean BCVA gain, central retinal thickness (CRT) decrease, and National Eye Institute Visual Functioning Questionnaire-25 (NEI VFQ-25) composite score observed at month 12 were maintained at month 24 (prior ranibizumab: +7.9 letters, -140.6 µm, and 5.6, respectively; prior ranibizumab plus laser: +6.7 letters, -133.0 µm, and 5.8, respectively), with an average of 3.9 (prior ranibizumab) and 3.5 ranibizumab injections (prior ranibizumab plus laser). In patients treated with laser alone in the core study, the mean BCVA, CRT, and NEI VFQ-25 composite score improved from month 12 to month 24 (+5.4 letters, -126.6 µm, and 4.3, respectively), with an average of 4.1 ranibizumab injections. CONCLUSIONS: Ranibizumab 0.5 mg administered according to prespecified visual stability and disease progression criteria was well tolerated, with no new safety concerns identified over 2 years. Overall, an average of 3.8 ranibizumab injections was sufficient to maintain (prior ranibizumab) or improve (prior laser) BCVA, CRT, and NEI VFQ-25 outcomes through the second year. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Alström syndrome--an uncommon cause of early childhood retinal dystrophy.

Alström syndrome (AS) is a ciliopathy and an uncommon cause of syndromic retinal dystrophy. This case reports findings in a 5-year-old boy with severe early onset retinal dystrophy, and how the recognition of extraocular features with genetic analysis led to the correct diagnosis of AS after 4 years of investigation.

Safety and efficacy of ranibizumab in diabetic macular edema (RESOLVE Study): a 12-month, randomized, controlled, double-masked, multicenter phase II study.

OBJECTIVE: The expression of vascular endothelial growth factor (VEGF) is elevated in diabetic macular edema (DME). Ranibizumab binds to and inhibits multiple VEGF variants. We investigated the safety and efficacy of ranibizumab in DME involving the foveal center. RESEARCH DESIGN AND METHODS: This was a 12-month, multicenter, sham-controlled, double-masked study with eyes (age>18 years, type 1 or 2 diabetes, central retinal thickness [CRT]≥300 µm, and best corrected visual acuity [BCVA] of 73-39 ETDRS letters [Early Treatment Diabetic Retinopathy Study]) randomly assigned to intravitreal ranibizumab (0.3 or 0.5 mg; n=51 each) or sham (n=49). The treatment schedule comprised three monthly injections, after which treatment could be stopped/reinitiated with an opportunity for rescue laser photocoagulation (protocol-defined criteria). After month 1, dose-doubling was permitted (protocol-defined criteria, injection volume increased from 0.05 to 0.1 ml and remained at 0.1 ml thereafter). Efficacy (BCVA and CRT) and safety were compared between pooled ranibizumab and sham arms using the full analysis set (n=151, patients receiving≥1 injection). RESULTS: At month 12, mean±SD BCVA improved from baseline by 10.3±9.1 letters with ranibizumab and declined by 1.4±14.2 letters with sham (P<0.0001). Mean CRT reduction was 194.2±135.1 µm with ranibizumab and 48.4±153.4 µm with sham (P<0.0001). Gain of ≥10 letters BCVA from baseline occurred in 60.8% of ranibizumab and 18.4% of sham eyes (P<0.0001). Safety data were consistent with previous studies of intravitreal ranibizumab. CONCLUSIONS: Ranibizumab is effective in improving BCVA and is well tolerated in DME. Future clinical trials are required to confirm its long-term efficacy and safety.

Drug-induced optic neuropathy-TB or not TB.

Autosomal dominant optic atrophy is an inherited optic neuropathy manifesting with variable penetrance and expressivity. Other genetic and environmental factors are postulated to contribute to more marked visual loss in some affected individuals. Optic neuropathy is also a known adverse effect of ethambutol therapy for tuberculosis. This case report demonstrates an atypical presentation of ethambutol toxicity, with progressive profound loss of vision despite drug cessation. A subsequent diagnosis of autosomal dominant optic atrophy was made when the proband's sons presented with mild visual disturbances and color vision defects, confirmed with electrophysiology and OPA1 gene mutational analysis. This case emphasizes the importance of avoiding potentially neurotoxic therapy in predisposed individuals and the influence of environmental factors in patients with inherited optic neuropathies.

Transient retinal effects of 5,6-dimethylxanthenone-4-acetic acid (DMXAA, ASA404), an antitumor vascular-disrupting agent in phase I clinical trials.

PURPOSE: 5,6-Dimethylxanthenone-4-acetic acid (DMXAA), an anticancer vascular-disrupting agent, has induced transient visual symptoms in some patients. Exploratory investigations were undertaken to characterize the visual disturbances in two consecutive phase I trials. METHODS: Assessments were made in 21 patients before and immediately after a 20-minute IV infusion of DMXAA, including visual acuity, funduscopy, color discrimination, pattern electroretinography (PERG), pattern visual-evoked potentials (VEP), and full-field electroretinography (ERG). Evaluation of late effects was undertaken subsequently in 12 patients before and after 6 weeks of IV DMXAA at one dose per week. RESULTS: Frequency and intensity of transient visual disturbance increased with DMXAA dose, occurring in two thirds of patients at 3000 mg x m(-2). Symptoms included blurring, flickering, fragmentation, alteration of colors, and contrast and mild photosensitivity, starting during the infusion and resolving completely, usually within 60 minutes. Visual acuity was unchanged but color discrimination was perturbed. Dose-dependent increases in PERG P50 implicit time by up to 23 ms returned toward baseline values within 90 minutes. Prominent transient changes on ERG included prolonged scotopic rod and 30-Hz flicker implicit times and reduced 30-Hz flicker amplitude. In the second trial, no clinically significant sustained effects were detected, although an increase in bright flash a-wave implicit time (P = 0.022) was seen on whole-group analysis. In vitro studies showed nonspecific phosphodiesterase inhibition by DMXAA. CONCLUSIONS: DMXAA induced acute, transient disturbance of retinal activity consistent with phosphodiesterase inhibition. No clinically significant cumulative effects were noted and most effects occurred at doses higher than those used in ongoing clinical trials (ClinicalTrials.gov numbers, NCT00856336, NCT00863733, and NCT00003697).

Reversible optic neuropathy due to metronidazole.

Metronidazole is a little known cause of drug-induced optic neuropathy. We report a patient who developed progressive visual loss after an 8-month course of Metronidazole. Electrophysiology confirmed a bilateral optic neuropathy. Her vision improved dramatically with cessation of the drug.

Photodynamic therapy with verteporfin for choroidal neovascularization due to age-related macular degeneration and other causes: a New Zealand outcomes study.

PURPOSE: To assess the efficacy and safety of photodynamic therapy (PDT) for choroidal neovascularization (CNV) secondary to age-related macular degeneration (AMD) and other conditions by analysing visual acuity changes. METHODS: A retrospective review of patients treated with PDT was conducted. CNV was confirmed on fluorescein angiography. Visual acuity outcomes were recorded at 3-monthly intervals to a maximum of 48 months. The primary outcome measure was the proportion of patients avoiding moderate visual loss (losing less than three lines of visual acuity relative to baseline) at 12 months. RESULTS: A total of 343 patients receiving PDT were followed up for a mean of 14.9 months. Two hundred and eighty-five (83%) patients presented with CNV due to AMD and 58 patients (17%) due to other causes. Seventy per cent of patients with CNV secondary to AMD avoided moderate visual loss at both 12 and 24 months. Secondary outcomes (including mean change in visual acuity, proportion of patients with stable or improved vision and proportion of patients with severe vision loss) also compared favourably with the Treatment of Age-Related Macular Degeneration with Photodynamic Therapy (TAP) Investigation. Of patients with CNV secondary to causes other than AMD, 76% avoided moderate visual loss at both 12 and 24 months. The safety profile identified one severe adverse reaction, with development of a serous pigment epithelial detachment and subsequent rip. CONCLUSION: The results of this present retrospective, open-label, clinical practice study in New Zealand are consistent with the findings of multicentre randomized, placebo-controlled trials and confirm the treatment benefit of PDT in a clinical setting.

Randomised controlled trial of prevention of falls in people aged > or =75 with severe visual impairment: the VIP trial.

OBJECTIVES: To assess the efficacy and cost effectiveness of a home safety programme and a home exercise programme to reduce falls and injuries in older people with low vision. DESIGN: Randomised controlled trial. SETTING: Dunedin and Auckland, New Zealand. PARTICIPANTS: 391 women and men aged > or =75 with visual acuity of 6/24 or worse who were living in the community; 92% (361 of 391) completed one year of follow-up. INTERVENTIONS: Participants received a home safety assessment and modification programme delivered by an occupational therapist (n = 100), an exercise programme prescribed at home by a physiotherapist plus vitamin D supplementation (n = 97), both interventions (n = 98), or social visits (n = 96). MAIN OUTCOME MEASURES: Numbers of falls and injuries resulting from falls, costs of implementing the home safety programme. RESULTS: Fewer falls occurred in the group randomised to the home safety programme but not in the exercise programme (incidence rate ratios 0.59 (95% confidence interval 0.42 to 0.83) and 1.15 (0.82 to 1.61), respectively). However, within the exercise programme, stricter adherence was associated with fewer falls (P = 0.001). A conservative analysis showed neither intervention was effective in reducing injuries from falls. Delivering the home safety programme cost NZ650 dollars (234 pounds sterling, 344 euros, US432 dollars) (at 2004 prices) per fall prevented. CONCLUSION: The home safety programme reduced falls and was more cost effective than an exercise programme in this group of elderly people with poor vision. The Otago exercise programme with vitamin D supplementation was not effective in reducing falls or injuries in this group, possibly due to low levels of adherence. Trial registration number ISRCTN15342873.

A CACNA1F mutation identified in an X-linked retinal disorder shifts the voltage dependence of Cav1.4 channel activation.

Light stimuli produce graded hyperpolarizations of the photoreceptor plasma membrane and an associated decrease in a voltagegated calcium channel conductance that mediates release of glutamate neurotransmitter. The Ca(v)1.4 channel is thought to be involved in this process. The CACNA1F gene encodes the poreforming subunit of the Ca(v)1.4 channel and various mutations in CACNA1F cause X-linked incomplete congenital stationary night blindness (CSNB2). The molecular mechanism of the pathology underlying the CSNB2 phenotype remains to be established. Recent clinical investigations of a New Zealand family found a severe visual disorder that has some clinical similarities to, but is clearly distinct from, CSNB2. Here, we report investigations into the molecular mechanism of the pathology of this condition. Molecular genetic analyses identified a previously undescribed nucleotide substitution in CACNA1F that is predicted to encode an isoleucine to threonine substitution at CACNA1F residue 745. The I745T CACNA1F allele produced a remarkable approximately -30-mV shift in the voltage dependence of Ca(v)1.4 channel activation and significantly slower inactivation kinetics in an expression system. These findings imply that substitution of this wild-type residue in transmembrane segment IIS6 may have decreased the energy required to open the channel. Collectively, these findings suggest that a gain-of-function mechanism involving increased Ca(v)1.4 channel activity is likely to cause the unusual phenotype.

Clinical manifestations of a unique X-linked retinal disorder in a large New Zealand family with a novel mutation in CACNA1F, the gene responsible for CSNB2.

PURPOSE: To describe the phenotype in a New Zealand family with an unusual severe X-linked retinal disorder with a novel I745T mutation in CACNA1F, the gene responsible for incomplete congenital stationary night blindness (CSNB2). METHODS: Members of the family tree were invited for clinical, psychophysical and electrodiagnostic evaluation. RESULTS: Male family members had severe non-progressive visual impairment, abnormal colour vision, congenital nystagmus, hyperopia and normal fundi. Some were intellectually disabled. Female family members had congenital nystagmus and decreased visual acuity frequently associated with high myopia. Electroretinograms (ERG) identified reduced rod and cone responses with negative waveform in male and female family members, with atypical features for CSNB2. CONCLUSIONS: Although there were similarities to CSNB2, distinctive features in male family members included severity of phenotype, and association of intellectual disability. Moreover, all female heterozygotes had clinical and ERG abnormalities. CACNA1F encodes the Ca(v)1.4 alpha1 subunit of a voltage-gated calcium channel, which may mediate neurotransmitter release from photoreceptors. Molecular analyses, reported separately, identified a novel I745T CACNA1F mutation that was associated in vitro with major alterations in gating and kinetics of the Ca(v)1.4 channel. It is speculated that the unique phenotype described in this family may reflect similarly altered function of Ca(v)1.4 channel activity in vivo.