Publications by authors named "Ido Perlman"

43 Publications

ISCEV extended protocol for the S-cone ERG.

Doc Ophthalmol 2020 04 20;140(2):95-101. Epub 2019 Nov 20.

National University of Singapore, Singapore, Singapore.

The International Society for Clinical Electrophysiology of Vision (ISCEV) standard for full-field electroretinography (ERG) describes a minimum procedure for testing generalized retinal function but encourages more extensive testing. This extended protocol describes a method of assessing the function of the short-wavelength-sensitive cone (S-cone) retinal pathway, using a short-wavelength flash superimposed on a background that saturates the rods and adapts the L/M-cones to elicit a response, known as the S-cone ERG. Stimulus parameters such as the strength and luminance of the flash and background, respectively, and their spectral and temporal characteristics are specified. As a complement to the ISCEV standard, testing the S-cone ERG enables further characterization of light-adapted retinal function and may refine diagnosis of some retinal disorders. Typical applications are described including use in the diagnosis of rod monochromacy and S-cone monochromacy, identification and investigation of cone On-bipolar cell dysfunction and use of the technique to confirm the diagnosis of enhanced S-cone syndrome.
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http://dx.doi.org/10.1007/s10633-019-09730-6DOI Listing
April 2020

PRCD is concentrated at the base of photoreceptor outer segments and is involved in outer segment disc formation.

Hum Mol Genet 2019 12;28(24):4078-4088

Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.

Mutations of the photoreceptor disc component (PRCD) gene are associated with rod-cone degeneration in both dogs and humans. Prcd is expressed in the mouse eye as early as embryonic day 14. In the adult mouse retina, PRCD is expressed in the outer segments of both rod and cone photoreceptors. Immunoelectron microscopy revealed that PRCD is located at the outer segment rim and that it is highly concentrated at the base of the outer segment. Prcd-knockout mice present with progressive retinal degeneration, starting at 20 weeks of age and onwards. This process is reflected by a significant and progressive reduction of both scotopic and photopic electroretinographic responses and by thinning of the retina, and specifically of the outer nuclear layer, indicating photoreceptor loss. Electron microscopy revealed severe damage to photoreceptor outer segments, which is associated with immigration of microglia cells to the Prcd-knockout retina and accumulation of vesicles in the inter-photoreceptor space. Phagocytosis of photoreceptor outer segment discs by the retinal pigmented epithelium is severely reduced. Our data show that Prcd-knockout mice serve as a good model for retinal degeneration caused by PRCD mutations in humans. Our findings in these mice support the involvement of PRCD in outer segment disc formation of both rod and cone photoreceptors. Furthermore, they suggest a feedback mechanism which coordinates the rate of photoreceptor outer segment disc formation, shedding and phagocytosis. This study has important implications for understanding the function of PRCD in the retina, as well as for future development of treatment modalities for PRCD deficiency in humans.
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http://dx.doi.org/10.1093/hmg/ddz248DOI Listing
December 2019

Verifying complaints of difficulties in night vision using electroretinography and dark adaptation tests.

Doc Ophthalmol 2020 04 16;140(2):169-180. Epub 2019 Oct 16.

Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.

Purpose: To determine the electroretinographical and psychophysical parameters that can help to verify patients' complaints of reduced night vision.

Methods: We tested 275 consecutive patients with normal appearing fundi, complaining of visual difficulties at night, using flash electroretinography (ERG) and dark adaptation (DA) test. Two ERG parameters were used to assess a scotopic retinal function: the amplitude of the response to dim blue flash (the rod response) and the b-wave ratio (measured/expected). Dark adaptation was measured with green- and red-light stimuli after exposure to a bright, bleaching light. The psychophysical parameter of night vision was defined as the threshold for detection of the blue-green stimulus that was measured after 40-45 min in complete darkness.

Results: Fifty-five patients were excluded from the analysis because of a discrepancy between the two ERG parameters in assessment of scotopic retinal function. The remaining 220 patients were divided into 4 groups: (1) normal ERG and normal DA, (2) subnormal ERG and subnormal DA, (3) normal ERG and subnormal DA and (4) subnormal ERG and normal DA. The ERG and DA tests supported the complaint of visual difficulties at night in 67 patients (group 2), while 34 patients were characterized as having normal scotopic visual function (group 1). The other 119 patients (groups 3 and 4) presented a diagnostic dilemma because one test (ERG or dark adaptation) showed normal scotopic function, while the other indicated subnormal scotopic function.

Conclusion: Our findings indicate that ERG is an essential, but not sufficient test for verifying patient's complaint on visual difficulties in the dark. We suggest using both electroretinography and psychophysical dark adaptation to test patients complaining of reduced night vision.
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http://dx.doi.org/10.1007/s10633-019-09729-zDOI Listing
April 2020

A nationwide genetic analysis of inherited retinal diseases in Israel as assessed by the Israeli inherited retinal disease consortium (IIRDC).

Hum Mutat 2020 01 15;41(1):140-149. Epub 2019 Sep 15.

Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.

Inherited retinal diseases (IRDs) cause visual loss due to dysfunction or progressive degeneration of photoreceptors. These diseases show marked phenotypic and genetic heterogeneity. The Israeli IRD consortium (IIRDC) was established in 2013 with the goal of performing clinical and genetic mapping of the majority of Israeli IRD patients. To date, we recruited 2,420 families including 3,413 individuals with IRDs. On the basis of our estimation, these patients represent approximately 40% of Israeli IRD patients. To the best of our knowledge, this is, by far, the largest reported IRD cohort, and one of the first studies addressing the genetic analysis of IRD patients on a nationwide scale. The most common inheritance pattern in our cohort is autosomal recessive (60% of families). The most common retinal phenotype is retinitis pigmentosa (43%), followed by Stargardt disease and cone/cone-rod dystrophy. We identified the cause of disease in 56% of the families. Overall, 605 distinct mutations were identified, of which 12% represent prevalent founder mutations. The most frequently mutated genes were ABCA4, USH2A, FAM161A, CNGA3, and EYS. The results of this study have important implications for molecular diagnosis, genetic screening, and counseling, as well as for the development of new therapeutic strategies for retinal diseases.
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http://dx.doi.org/10.1002/humu.23903DOI Listing
January 2020

[THE ISRAELI INHERITED RETINAL DISEASES CONSORTIUM (IIRDC)- CLINICAL-GENETIC MAPPING AND FUTURE PERSPECTIVES].

Harefuah 2019 Feb;158(2):91-95

Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa.

Introduction: The sense of vision is highly important for humans and its loss markedly affects function and quality of life. Many inherited retinal diseases (IRDs) cause visual loss due to dysfunction or progressive degeneration of photoreceptor cells. These diseases show clinical and genetic heterogeneity.

Aims: The Israeli IRD consortium (IIRDC) was established with the goal of performing clinical and genetic mapping of IRDs in the Israeli population.

Methods: Clinical evaluation is carried out at electroretinography (ERG) centers and ophthalmology departments, where the patients undergo a comprehensive eye exam, including testing of visual acuity, refractive error, imaging techniques and ERG tests. Genetic analysis is performed using Sanger sequencing, analysis of founder mutations, and whole exome sequencing.

Results: We recruited over 2,000 families including more than 3,000 individuals with IRDs. The most common inheritance pattern is autosomal recessive (65% of families). The most common retinal phenotype is retinitis pigmentosa (RP- 45% of families), followed by cone/cone-rod dystrophy, Stargardt Disease and Usher syndrome. We identified the cause of disease in 51% of families, mainly due to mutations in ABCA4, USH2A, FAM161A, CNGA3, and EYS. IIRDC researchers were involved in the identification of 16 novel IRD genes. In parallel, IIRDC members are involved in the development of therapeutic modalities for these currently incurable diseases.

Conclusions: IIRDC works in close collaborative efforts aiming to continue and recruit for the genotype - phenotype study from the vast majority of Israeli IRD families, to identify all disease-causing mutations, and to tailor therapeutic interventions to each IRD patient.
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February 2019

Retinal Toxicity of Intravitreal Injection of Ziv-Aflibercept in Albino Rabbits.

Transl Vis Sci Technol 2018 Nov 7;7(6):23. Epub 2018 Dec 7.

Department of Ophthalmology, Tel-Aviv Sourasky Medical Center, Tel-Aviv, Israel.

Purpose: To evaluate retinal toxicity of ziv-aflibercept, a drug that had been approved for use for patients with colon cancer.

Methods: Twenty-two albino rabbits were injected intravitreally with 0.1 mL of ziv-aflibercept solution into the experimental eye and 0.1-mL saline into the control eye. Twelve were used for electroretinogram (ERG) at 4-weeks follow-up. An additional 10 rabbits were used for testing penetration of ziv-aflibercept into the retina during follow-up. The visual-evoked potential (VEP) was recorded after 4 weeks of ERG follow-up. Glial fibrillary acidic protein (GFAP) immunocytochemistry and retinal histology were performed after the termination of the follow-up period.

Results: The ERG responses of the experimental eyes did not show signs of permanent functional damage. The VEP responses of the experimental eyes were of normal pattern and amplitude, and were similar to those recorded by stimulation of the control eyes. Histologic studies of both experimental and control eyes did not show signs of structural damage. However, GFAP expression was increased in retinal Müller cells of the experimental eyes and not of the control eyes. Retinal penetration of ziv-aflibercept, as indicated by positive antihuman immunoreactivity, was observed 1 day postinjection and was strengthened during the next 7 days. At 14 days postinjection, ziv-aflibercept was not detected.

Conclusions: Ziv-aflibercept was found to be nontoxic to the retina of rabbits based on electrophysiologic testing and histologic examination. However, GFAP immunocytochemistry suggests mild retinal stress caused by the drug.

Translational Relevance: If proven safe, ziv-aflibercept may be a new affordable treatment option in conditions involving neovascularization and macular edema.
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http://dx.doi.org/10.1167/tvst.7.6.23DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6287445PMC
November 2018

Intravitreal Trimethoprim and Sulfamethoxazole Toxicity to the Retina of Albino Rabbits.

Transl Vis Sci Technol 2018 Nov 14;7(6). Epub 2018 Nov 14.

Ruth & Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology and the Rappaport Institute, Haifa, Israel.

Purpose: To evaluate retinal toxicity of intravitreal trimethoprim-sulfamethoxazole (TMP-SMX) in an albino rabbit model.

Methods: Albino rabbits ( = 10) were treated in the right eye with the maximum intravitreal dose of TMP-SMX mixture (1600 μg/8000 μg /0.1 mL), while 0.1 mL saline was injected into the vitreous of the left eye. Clinical examination and electrophysiological (electroretinogram [ERG] and visual evoked potentials [VEPs]) testing were conducted before injection, 3 days, 1, 2, and 4 weeks postinjection. Retinal structure and expression of glial fibrillary acidic protein (GFAP) were assessed from histology and immunocytochemistry respectively at the end of the follow-up period.

Results: Clinical examination was normal throughout the follow-up period. ERG responses from the experimental eyes were similar to those recorded from the control eyes, but the sum of oscillatory potentials decreased in the experimental eyes at 2 weeks postinjection. The VEP responses, elicited by stimulation of the experimental eyes, were abnormal having reduced amplitude and prolonged implicit time. Histological damage in the experimental eyes was expressed by thickness reduction of whole, outer, and inner nuclear layers. GFAP was expressed in retinal Müller cells of all experimental eyes, but none of control eyes.

Conclusions: A single intravitreal injection of TMP-SMX mixture (1600 μg/8000 μg, respectively) causes functional and structural damage to the inner retina and retinal output. Signs of retinal stress were also evident by GFAP expression in retinal Müller cells of all experimental eyes. Therefore, the use of TMP-SMX via intravitreal administration should be done with caution.

Translational Relevance: These findings highlight the risk of retinal toxicity after intravitreal injection of trimethoprim-sulfamethoxazole and emphasize that this treatment should be carefully considered.
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http://dx.doi.org/10.1167/tvst.7.6.2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6238985PMC
November 2018

ISCEV extended protocol for the dark-adapted red flash ERG.

Doc Ophthalmol 2018 06 22;136(3):191-197. Epub 2018 Jun 22.

UCL Institute of Ophthalmology, London, UK.

The International Society for Clinical Electrophysiology of Vision (ISCEV) standard for full-field electroretinography (ERG) describes a minimum procedure, but encourages more extensive testing. This ISCEV extended protocol describes an extension to the ERG standard, namely the dark-adapted (DA) red flash ERG. The DA red flash ERG can be incorporated conveniently within the ISCEV standard ERG protocol after a minimum of 20-min DA and recorded after the DA 0.01 ERG to a flash strength of 0.3 phot cd s m, eliciting a waveform with two positive peaks in healthy individuals. The first positive component is the cone-mediated x-wave with a peak at 30-50 ms; the second is a rod-mediated b-wave with a peak time of approximately 100 ms. Shorter DA times may be desirable to shorten the recording time or to alter the prominence of the early cone-mediated x-wave relative to the rod-mediated b-wave. The DA red flash ERG is used to aid the diagnosis of achromatopsia (rod monochromacy), cone dystrophy and other forms of cone system dysfunction, including "Bradyopsia" (RGS9/R9AP-retinopathy), when the DA red flash ERG x-wave is preserved in the absence of ISCEV standard LA ERGs. The DA red flash ERG can also help determine the origin of residual DA ERGs in cases of severe rod dysfunction, for example in disorders such as vitamin A deficiency, fundus albipunctatus (RDH5-retinopathy), Oguchi disease (SAG- or GRK1-retinopathy) and some rod-cone dystrophies. To shorter DA periods, the x-wave may be elicited without the following rod b-wave, shown to be helpful in abbreviated protocols for children.
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http://dx.doi.org/10.1007/s10633-018-9644-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6061112PMC
June 2018

ATF3 Regulates the Expression of AChE During Stress.

Front Mol Neurosci 2018 6;11:88. Epub 2018 Apr 6.

Department of Neuroscience, Ruth & Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology and The Rappaport Institute, Haifa, Israel.

Acetylcholinesterase (AChE) expresses in non-cholinergic cells, but its role(s) there remain unknown. We have previously attributed a pro-apoptotic role for AChE in stressed retinal photoreceptors, though by unknown mechanism. Here, we examined its promoter only to find that it includes a binding sequence for the activating transcription factor 3 (ATF3); a prototypical mediator of apoptosis. This suggests that expression of AChE could be regulated by ATF3 in the retina. Indeed, ATF3 binds the AChE-promoter to down-regulate its expressions . Strikingly, retinas of "blinded" mice display hallmarks of apoptosis, almost exclusively in the outer nuclear layer (ONL); coinciding with elevated levels of AChE and absence of ATF3. A mirror image is observed in the inner nuclear layer (INL), namely prominent levels of ATF3 and lack of AChE as well as lack of apoptosis. We conclude that segregated patterns of expressions of ATF3 reflect its ability to repress apoptosis in different layers of the retina-a novel mechanism behind apoptosis.
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http://dx.doi.org/10.3389/fnmol.2018.00088DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5897425PMC
April 2018

Infliximab exerts a dose-dependent effect on retinal safety in the albino rabbit.

Doc Ophthalmol 2017 12 19;135(3):175-185. Epub 2017 Aug 19.

Department of Ophthalmology, Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.

Purpose: To assess the retinal toxicity of an intravitreal injection of infliximab, a monoclonal antibody to tumor necrosis factor α, in a rabbit model.

Materials And Methods: Two groups of adult albino rabbits (n = 5) received intravitreal injections of infliximab (0.1 ml) in the study eye and balanced salt solution (BSS, 0.1 ml) in the control eye at baseline. Group 1 was administered with 1.5 mg/0.1 ml, and group 2 was injected with 7.5 mg/0.1 ml of infliximab solution. Electroretinography (ERG) was performed at baseline and at 1, 7, 30, and 45 days after the injection. Visual evoked potentials (VEPs) were recorded at 7 and 45 days after the injection. After the last electrophysiological assessment, the rabbits were euthanized and retinal histopathology and immunhistochemistry for glial fibrillary acidic protein (GFAP) were performed.

Results: ERG responses demonstrated no significant deficit in retinal function in eyes injected with infliximab. Mean dark-adapted a-wave and b-wave maximal amplitude and semi-saturation constant values at baseline and throughout the 45 days of follow-up after the injection indicated no remarkable difference in outer retinal function between the control and experimental eyes. VEP responses were similar at each time point (7 and 45 days). No difference was seen in retinal histopathology and immunocytochemistry sections in eyes receiving the 1.5 mg/0.1 ml dose compared to the control eyes. However, increased GFAP labeling in retinal Müller cells was detected in rabbit eyes treated with the 7.5 mg/0.1 ml dose.

Conclusions: Intravitreal injection of 1.5 mg/0.1 ml infliximab dose has no toxic effect on the integrity (functional or structural) of the retina in rabbits. A higher dose of 7.5 mg/0.1 ml may be slightly toxic as suggested by positive Müller cell GFAP expression. Additional studies of retinal toxicity at higher doses and after multiple injections are needed to establish the retinal safety of intravitreal infliximab therapy in humans.
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http://dx.doi.org/10.1007/s10633-017-9606-xDOI Listing
December 2017

The role of nitric oxide in spectral information processing in the distal turtle retina.

Vision Res 2018 10 18;151:69-77. Epub 2017 Sep 18.

Department of Physiology & Biophysics, Ruth & Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology and Rappaport Institute for Biomedical Research, Haifa, Israel. Electronic address:

Chromaticity type horizontal cells (C-type HCs) are the first retinal neurons exhibiting spectral information processing in cold-blooded vertebrates. The simple input of hyperpolarizing responses of cone photoreceptors is transformed in the C-type HCs into spectral opponent output. Nitric oxide (NO), a known background neuromodulator in the distal retina, was tested here for its effects upon spectral information processing by C-type HCs in the retina of turtle. Photoresponses were intracellularly recorded from C-type HCs, using light stimuli of different wavelength, applied over backgrounds of different wavelengths, and changing retinal NO level. Raising retinal level of NO in darkness by adding the precursor for its synthesis (l-Arginine) augmented the depolarizing photoresponses elicited by long-wavelength light stimuli, and reduced the hyperpolarizing photoresponses elicited by short-wavelength light stimuli. Lowering retinal level of NO by l-NAME, an inhibitor of NO synthesis, induced the opposite effects. However, the total voltage range of operation remained constant regardless of the level of NO. Qualitatively similar effects were observed under background illuminations regardless of background strength and wavelength. Altering retinal level of NO exerted a small effect upon the null wavelength. Our findings are consistent with the known effects of NO upon turtle distal retinal neurons, with the addition of NO strengthening the negative feedback pathway from L-type horizontal cells onto medium-wavelength cones.
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http://dx.doi.org/10.1016/j.visres.2017.07.010DOI Listing
October 2018

Safety of intravitreal clindamycin in albino rabbit eyes.

Doc Ophthalmol 2017 10 25;135(2):133-146. Epub 2017 Jul 25.

Division of Ophthalmology, Tel Aviv Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.

Purpose: To study the potential toxic effects of intravitreal clindamycin on the retina of albino rabbits, by assessing functional and morphological retinal changes.

Methods: Eight albino rabbits were included in the study. In each rabbit, 1 mg/0.1 ml clindamycin was injected into the vitreous of the right (experimental) eye, and 0.1 ml saline was injected into the vitreous of the left (control) eye. The electroretinogram (ERG) was recorded before injection, 3 days, 1, 2, and 4 weeks post-injection. The visual evoked potential (VEP) was recorded 4 weeks post-injection. Clinical examination was conducted at all time points. The eyes were enucleated at the termination of the follow-up period in order to prepare the retinas for histology in order to assess retinal structure.

Results: ERG and VEP responses that were recorded from the experimental eye at different times following intravitreal clindamycin injection were very similar to the corresponding responses that were recorded from the control eyes. Clinical examination was normal in all eyes, and no histological damage was observed.

Conclusions: Intravitreal injection of 1 mg clindamycin does not cause functional or morphological signs of retinal toxicity in albino rabbits, during a period of 4 weeks post-injection. These findings support the clinical use of 1 mg intravitreal clindamycin.
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http://dx.doi.org/10.1007/s10633-017-9599-5DOI Listing
October 2017

Light Modulates Ocular Complications in an Albino Rat Model of Type 1 Diabetes Mellitus.

Transl Vis Sci Technol 2017 Jul 3;6(4). Epub 2017 Jul 3.

The Ruth and Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel.

Purpose: The purpose of the study was to assess potential interactions of light exposure and hyperglycemia upon ocular complications in diabetic rats.

Methods: Streptozotocin-induced (STZ-induced) diabetic rats ( = 39) and non-diabetic rats ( = 9) were distributed into eight groups according to the irradiance and color of the light phase during the 12/12-hour light/dark regime. Follow-up lasted 90 days and included assessment of cataract development and electroretinogram (ERG) recordings. Stress to the retina was also assessed by glial fibrillary acidic protein immunocytochemistry.

Results: Cataract development was fast in diabetic rats that were exposed to unattenuated white light or to bright colored lights during the light phase. Diabetic rats that were kept under attenuated brown or yellow light during the light phase exhibited slower rate of cataract development. Electroretinogram responses indicated very severe retinal damage in diabetic rats kept under bright colored lights in the blue-yellow range or bright white light during the light phase. Electroretinogram damage was milder in rats kept under bright red light or attenuated yellow or brown light during the light phase. Glial fibrillary acidic protein expression in retinal Müller cells was consistent with ERG assessment of retinal damage.

Conclusions: Attenuating white light and filtering out short wavelengths have a protective effect on the eyes of diabetic rats as evident by slower rate of cataract formation and a smaller degree of retinal damage.

Translational Relevance: Our findings suggest that special glasses attenuating light exposure and filtering out short wavelengths (400-530 nm) may be beneficial for diabetic patients.
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http://dx.doi.org/10.1167/tvst.6.4.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5497601PMC
July 2017

Homozygosity for a Recessive Loss-of-Function Mutation of the NRL Gene Is Associated With a Variant of Enhanced S-Cone Syndrome.

Invest Ophthalmol Vis Sci 2016 Oct;57(13):5361-5371

Ruth & Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel.

Purpose: To investigate the genetic basis for severe visual complaints by Bukharan Jewish patients with oculopharyngeal muscular dystrophy (OPMD).

Methods: Polymerase chain reaction amplification and direct sequencing were used to test for NRL, PABPN1, and NR2E3 mutations. Complete ophthalmic examination included best-corrected visual acuity, biomicroscopic examination, optical coherence tomography, and fundus autofluorescence. Detailed electroretinography (ERG) testing was conducted including expanded International Society for Clinical Electrophysiology of Vision protocol for light-adapted and dark-adapted conditions, measurements of S-cone function, and ON-OFF light-adapted ERG.

Results: The index patients were homozygotes for both a dominant mutation of the PABPN1 gene, (GCN)13, and a recessive mutation of the NRL gene, p.R31X, on chromosome 14q11.1, leading to early-onset OPMD accompanied by night blindness and reduced visual acuity. No mutations were found in the NR2E3 gene. Both patients were of Bukharan Jewish origin, but from unrelated families. Electroretinography responses of both patients were dominated by short-wavelength-sensitive mechanisms, with no detectable rod function, similar to the ERG responses of individuals with enhanced S-cone syndrome (ESCS) due to NR2E3 mutations. Heterozygotes for the PABPN1 and NRL mutations demonstrated normal fundi and ERG responses.

Conclusions: Homozygosity for the recessive NRL mutation described here appears to be associated with a distinct retinal phenotype, demonstrating ERG characteristics similar to those of ESCS patients. This report expands the spectrum of NRL recessive mutations, as well as the genetic spectrum of ESCS, and indicates a new syndrome of OPMD with an ESCS-like phenotype.
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http://dx.doi.org/10.1167/iovs.16-19505DOI Listing
October 2016

An intronic deletion in the PROM1 gene leads to autosomal recessive cone-rod dystrophy.

Mol Vis 2015 8;21:1295-306. Epub 2015 Dec 8.

Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.

Purpose: To investigate the genetic basis for autosomal recessive cone-rod dystrophy (CRD) in a consanguineous Israeli Jewish family.

Methods: Patients underwent a detailed ophthalmic evaluation, including eye examination, visual field testing, optical coherence tomography (OCT), and electrophysiological tests, electroretinography (ERG) and visual evoked potential (VEP). Genome-wide homozygosity mapping using a single nucleotide polymorphism (SNP) array was performed to identify homozygous regions shared among two of the affected individuals. Mutation screening of the underlying gene was performed with direct sequencing. In silico and in vitro analyses were used to predict the effect of the identified mutation on splicing.

Results: The affected family members are three siblings who have various degrees of progressive visual deterioration, glare, color vision abnormalities, and night vision difficulties. Visual field tests revealed central scotomas of different extension. Cone and rod ERG responses were reduced, with cones more severely affected. Homozygosity mapping revealed several homozygous intervals shared among two of the affected individuals. One included the PROM1 gene. Sequence analysis of the 26 coding exons of PROM1 in one affected individual revealed no mutations in the coding sequence or in intronic splice sites. However, in intron 21, proximate to the intron-exon junction, we observed a homozygous 10 bp deletion between positions -26 and -17 (c.2281-26_-17del). The deletion was linked to a known SNP, c.2281-6C>G. The deletion cosegregated with the disease in the family, and was not detected in public databases or in 101 ethnically-matched control individuals. In silico analysis predicted that this deletion would lead to altered intron 21 splicing. Bioinformatic analysis predicted that a recognition site for the SRSF2 splicing factor is located within the deleted sequence. The in vitro splicing assay demonstrated that c.2281-26_-17del leads to complete exon 22 skipping.

Conclusions: A novel and unique intronic mutation of PROM1, underlying autosomal recessive CRD in a consanguineous Israeli family, was found. This report expands the spectrum of pathogenic mutations of PROM1 and further demonstrates the importance of intronic mutations.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4676936PMC
September 2016

Müller cells separate between wavelengths to improve day vision with minimal effect upon night vision.

Nat Commun 2014 Jul 8;5:4319. Epub 2014 Jul 8.

Department of Physiology and Biophysics, Ruth & Bruce Rappaport Faculty of Medicine, Rappaport Institute, Technion-Israel Institute of Technology, Haifa 31096, Israel.

Vision starts with the absorption of light by the retinal photoreceptors-cones and rods. However, due to the 'inverted' structure of the retina, the incident light must propagate through reflecting and scattering cellular layers before reaching the photoreceptors. It has been recently suggested that Müller cells function as optical fibres in the retina, transferring light illuminating the retinal surface onto the cone photoreceptors. Here we show that Müller cells are wavelength-dependent wave-guides, concentrating the green-red part of the visible spectrum onto cones and allowing the blue-purple part to leak onto nearby rods. This phenomenon is observed in the isolated retina and explained by a computational model, for the guinea pig and the human parafoveal retina. Therefore, light propagation by Müller cells through the retina can be considered as an integral part of the first step in the visual process, increasing photon absorption by cones while minimally affecting rod-mediated vision.
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http://dx.doi.org/10.1038/ncomms5319DOI Listing
July 2014

Retinal toxicity of intravitreal rituximab in albino rabbits.

Retina 2013 Mar;33(3):649-56

Department of Ophthalmology, Tel-Aviv Medical Center, Sackler Faculty of Medicine, Tel-Aviv University, Tel Aviv, Israel.

Purpose: To evaluate retinal toxicity of intravitreal rituximab.

Methods: Twelve albino rabbits were included in the study. 1 mg/0.1 mL of rituximab was injected to the right (experimental) eye of each rabbit, and 0.1 mL of saline was injected into the left (control) eye. Electroretinogram was recorded before injection and 3 hours, 4 days, 1 week, 2 weeks and 4 weeks after injection (12 rabbits), and visual evoked potential was recorded before injection and 4 weeks after injection (10 rabbits). Histology and glial fibrillary acidic protein immunocytochemistry (12 rabbits) were performed at 4 weeks after injection. Clinical examination was conducted at all time points in all rabbits.

Results: The average dark-adapted electroretinogram b-wave Vmax ratios, and the average light-adapted b-wave amplitude ratios were approximately 1, and the average log σ difference was around zero throughout the follow-up period. The average visual evoked potential amplitude ratio and the average visual evoked potential implicit time difference were approximately 1 and 0, respectively. No histologic damage was seen, but glial fibrillary acidic protein was mildly expressed in 6 of 12 experimental eyes. Results of clinical examination were normal in all the eyes.

Conclusion: Intravitreal injection of 1 mg rituximab does not cause functional or histologic signs of retinal toxicity in albino rabbits. Mild glial fibrillary acidic protein expression in Müller cells probably indicates a mild degree of retinal stress.
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http://dx.doi.org/10.1097/IAE.0b013e318263d14fDOI Listing
March 2013

Physiological and toxicological effects of cefuroxime on the albino rabbit retina.

Invest Ophthalmol Vis Sci 2012 Feb 21;53(2):906-14. Epub 2012 Feb 21.

Ophthalmology Department, Tel Aviv Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.

Purpose: Intracameral cefuroxime was found to lower the risk of endophthalmitis after cataract surgery. The purpose of this study was to evaluate the retinal toxicity of cefuroxime in a rabbit model.

Methods: Twenty-two albino rabbits were divided into two cefuroxime groups: low-dose (1mg/0.1 mL, n = 9) and high dose (10 mg/0.1 mL, n = 13). The right eye of each rabbit was injected with 0.1 mL cefuroxime solution (experimental eye) and the left eye with 0.1 mL saline (control eye). Electroretinogram (ERG) responses were recorded at 3 hours, 4 days, and 1, 2, and 4 weeks after injection. After 4 weeks, the rabbits were euthanized, the eyes were enucleated, and the retinas were prepared for histologic evaluation and GFAP immunostaining.

Results: No functional (ERG) or histologic damage was found in rabbits in the low-dose group. In the high-dose group, a significant decrease in the ERG amplitudes of the experimental eyes was seen 3 hours after injection, followed by partial recovery during 4 weeks of follow-up. Retinal histology of experimental eyes revealed marked damage. GFAP immunoreactivity in Müller cells was expressed in rabbits belonging to both groups, although it was more extensive in the high-dose group.

Conclusions: ERG and histologic findings indicated that a dose of 1 mg cefuroxime, administered intravitreally, was not toxic to the rabbit retina. A dose of 10 mg, injected intravitreally, induced transient physiological effects, and was toxic to the rabbit retina, as was evident by the permanent reduction in the ERG responses and by the structural damage to the retina with signs of glial activation.
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http://dx.doi.org/10.1167/iovs.11-8053DOI Listing
February 2012

Safety of intravitreal bevacizumab in the developing rabbit retina.

Retina 2011 Oct;31(9):1885-95

Department of Ophthalmology, Tel Aviv Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.

Purpose: The purpose of this was to study the long-term effects of a single intravitreal dose of bevacizumab injected at different postnatal age on retinal function and development of retinal blood vessels in the adult albino rabbit.

Methods: Bevacizumab was injected into the right eye of newborn rabbits, aged 11 days to 25 days, whereas the left eye of each rabbit was injected with identical volume of saline and served as control. The electroretinogram was recorded 1 week and 10 weeks after injection. Visual evoked potentials were recorded 10 weeks after injection. At termination of the follow-up period, the rabbits were killed and the retinas were prepared for histopathologic studies at the light microscopic level, for glial fibrillary acidic protein immunoreactivity, and for reduced form of nicotinamide adenine dinucleotide phosphate diaphorase histochemistry to assess the integrity of the retinal vascular system.

Results: The electroretinogram responses demonstrated normal retinal function in adult rabbits injected at postnatal age of 11 days to 25 days. Mean Vmax and σ values calculated for each group of rabbits, 10 weeks after bevacizumab injection, indicated similar retinal function of the experimental and control eyes. Visual evoked potentials recorded by stimulating each eye separately were also similar. The histopathologic studies yielded similar results; no structural retinal damage was observed in the experimental eyes compared with the control eyes of rabbits from all age groups, and no increased glial fibrillary acidic protein immunoreactivity in Müller cells was observed in the experimental eyes. Staining of blood vessels with reduced form of nicotinamide adenine dinucleotide phosphate diaphorase revealed decreased branching of the capillary network in the experimental eyes compared with the control eyes in all age groups.

Conclusion: The electroretinographic and morphologic data showed no deleterious effects of a single intravitreal dose of bevacizumab, injected during the first 30 days postnatally, on the structural and functional integrity of the sensory retina in the adult rabbit. Even partial blockage of vascular endothelial growth factor with bevacizumab applied during retinal development seems to interfere with the development of the retinal vascular system in the albino rabbit. However, extrapolation from rabbits to humans should be made with caution.
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http://dx.doi.org/10.1097/IAE.0b013e31821a88e2DOI Listing
October 2011

Normal physiological and pathophysiological effects of trypan blue on the retinas of albino rabbits.

Invest Ophthalmol Vis Sci 2010 Aug 5;51(8):4187-94. Epub 2010 Mar 5.

Department of Ophthalmology, Tel Aviv Medical Center, Tel Aviv, Israel.

Purpose: To determine whether intravitreal injection of trypan blue is toxic to the retina of the albino rabbit.

Methods: Sixteen albino rabbits were studied for the effects of intravitreal trypan blue (eight with 0.06% solution and eight with 0.15% solution). Saline was injected into the fellow control eye of all rabbits. The electroretinogram and visual evoked potentials were recorded from each rabbit at different time intervals after injection. The rabbits were killed at the termination of the follow-up period, and their retinas were prepared for histologic examination under light microscopy.

Results: In all rabbits, short-term follow-up showed significant reduction of ERG responses in the experimental eye, with the b-wave more affected than the a-wave. Partial to complete recovery was observed during follow-up. After 4 weeks, negligible ERG deficit was observed in the rabbits treated with 0.06% trypan blue, whereas significant ERG deficit was measured in rabbits tested by the 0.15% trypan blue. No differences in flash VEP responses between experimental and control rabbit eyes were found. Light microscopy showed no significant histologic effects in the retinas exposed to the 0.06% solution. Marked disorganization of all retinal layers was observed in areas close to the site of injection in the rabbits injected with the 0.15% solution.

Conclusions: Trypan blue exerts transient physiological effects on the distal retina of the rabbit, but in concentrations of 0.15% it can induce permanent toxic effects. Therefore, caution should be used when using this dye in vitreoretinal surgery.
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http://dx.doi.org/10.1167/iovs.09-4675DOI Listing
August 2010

Safety evaluation of repeated intravitreal injections of bevacizumab and ranibizumab in rabbit eyes.

Retina 2010 Apr;30(4):671-81

Department of Ophthalmology, Tel Aviv Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.

Purpose: Repeated intravitreal injections of ranibizumab or bevacizumab are a common treatment for several retinal diseases. The aim of the present study was to evaluate the long-term retinal toxicity of repeated injections of ranibizumab and bevacizumab in rabbits.

Methods: Albino rabbits were injected intravitreally with ranibizumab (1 mg/0.1 mL) or bevacizumab (2.5 mg/0.1 mL) into the right eye, whereas the left eye of each rabbit was injected with saline. Nine consecutive injections were administered at 14-day intervals. Electroretinographic responses and flash visual-evoked potentials were recorded periodically. After 18 weeks of follow-up, the rabbits were killed, and the retinas were prepared for morphologic examination and for immunocytochemistry for glial fibrillary acidic protein.

Results: Electroretinographic and visual-evoked potential responses of the experimental and control eyes were similar in amplitude and pattern throughout the follow-up period. The histopathologic studies yielded similar results. No retinal damage was observed in the experimental and control eyes of all rabbits. Glial fibrillary acidic protein immunoreactivity showed staining only in retinal astrocytes but not in Müller cells in all rabbits.

Conclusion: The electrophysiological tests and the morphologic data indicate that the repeated intravitreal injections of ranibizumab or bevacizumab have no cumulative long-term toxic effect on the retina in rabbits.
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http://dx.doi.org/10.1097/IAE.0b013e3181c0858cDOI Listing
April 2010

The developing mammalian retina is partially protected from gentamicin toxicity.

Exp Eye Res 2009 Jun 13;88(6):1152-60. Epub 2009 Feb 13.

Department of Ophthalmology, Tel Aviv Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.

Gentamicin retinal toxicity was tested in numerous studies on adult animal models, but not in the developing retina. Since differentiating cells and developing tissues may exhibit different degrees of sensitivity to toxic drugs, we aimed here to test the susceptibility of the developing mammalian retina to the toxic action of gentamicin. Gentamicin was injected in the right eye of newborn rabbits, aged 11-38 days. The left eye of each rabbit was injected with saline. Eight weeks after injection, electroretinographic (ERG) responses were recorded in the dark- and light-adapted states. The rabbits were then sacrificed, and the retinas were prepared for morphological examination and immunostaining for Glial Fibrillary Acidic Protein (GFAP) and Protein Kinase C (PKC). The ERG responses demonstrated practically no functional damage to the retina of rabbits injected at postnatal age of 11 and 13 days, and a gradually increasing severity of functional damage with increasing postnatal age of intravitreal gentamicin injection. The histopathological studies yielded similar results. GFAP immunoreactivity showed staining in Müller cells only in retinas that exhibited functional and structural damage. PKC immunoreactivity indicated lesser damage to the rod-bipolar cells compared to the photoreceptors. The ERG data and morphological observations suggest that processes involved in development of the rabbit retina, such as outer segment elongation may provide partial or even complete protection to the retina from toxic insults such as a single dose of gentamicin.
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http://dx.doi.org/10.1016/j.exer.2009.02.002DOI Listing
June 2009

Testing retinal toxicity of drugs in animal models using electrophysiological and morphological techniques.

Authors:
Ido Perlman

Doc Ophthalmol 2009 Feb 9;118(1):3-28. Epub 2008 Nov 9.

Department of Physiology and Biophysics, Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology and Rappaport Institute, P.O. Box 9649, Haifa, 31096, Israel.

Drugs are frequently tested for retinal toxicity in animal models in order to address applied and basic research questions. When a retinal toxicity study is designed, the researcher needs to consider several factors depending on his/her research questions. Among the factors that need to be addressed before a toxicity study is conducted are: the animal species to be used, choice of experimental (functional and/or morphological) techniques, procedure of testing, period of follow-up, and modes of data analysis. This review is a summary of 20 years' experience of studying retinal toxicity of different drugs in rabbits and rats. The use of the electroretinogram and the visual evoked potential for assessment of outer and inner retinal function, respectively, is described as well as the use of morphological techniques (histology, histochemistry, and immunocytochemistry). The advantages and limitations of functional and morphological techniques are discussed with specific examples from my experience. Recommendations for future drug toxicity studies are summarized.
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http://dx.doi.org/10.1007/s10633-008-9153-6DOI Listing
February 2009

Retinal toxicity of commercially available intravitreal ketorolac in albino rabbits.

Retina 2009 Jan;29(1):98-105

Department of Physiology and Biophysics, Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology and the Rappaport Institute, Haifa, Israel.

Purpose: To determine whether intravitreal injection of a commercially available ketorolac tromethamine preparation causes retinal toxicity in albino rabbits.

Methods: Nine albino rabbits were injected intravitreally with ketorolac tromethamine (3 mg; 0.1 mL) in one eye and saline (0.1 mL) in the fellow eye. Six of the rabbits received a single injection of ketorolac, and the other three rabbits underwent biweekly injection for a total of four injections. Electroretinography testing was performed on both eyes at different time intervals during 4 weeks of follow-up in the single injection group, and during 12 weeks of follow-up in the multiple injection group. Visual evoked potentials were recorded from each rabbit using monocular and binocular stimulation at the end of the follow-up period. Animals were then killed, and the retinas were prepared for morphologic examination at the light microscope level and for immunostaining for glial fibrillary acidic protein, as a marker of retinal damage.

Results: The electroretinography responses from the control and experimental eyes were similar throughout the follow-up period in all rabbits of both experimental groups. There were no differences in the flash visual evoked potential responses between experimental and control eyes in the single injection group, while in the repeated injection group, statistically significant differences were found. Light microscopy did not identify significant histologic differences between the retinas from control and experimental eyes after a single dose. However, after repeated dosing, two of three eyes showed histologic evidence of local toxicity. Immunocytochemical analysis showed no glial fibrillary acidic protein staining in Muller (glial) cells throughout the retina in the single injection group. Slight glial fibrillary acidic protein staining was detected in only one of the three retinas from rabbits in the repeated injection group.

Conclusions: Commercially available ketorolac tromethamine was found to be toxic to the retinas of albino rabbits following multiple intravitreal injections at a dose of 3 mg while no electrophysiologic toxicity was found. Therefore, the use of commercially available ketorolac containing alcohol, for intravitreal injection is not recommended.
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http://dx.doi.org/10.1097/IAE.0b013e31817d8c09DOI Listing
January 2009

Retinal toxicity of intravitreal kenalog in albino rabbits.

Retina 2007 Jul-Aug;27(6):778-88

Department of Ophthalmology, Ha'Emek Medical Center, Afula, Israel.

Purpose: To evaluate possible toxicity of intravitreal Kenalog (commercial triamcinolone acetonide) to the retina of albino rabbits.

Methods: Forty-three albino rabbits were injected intravitreally with 0.1 mL of experimental solution to the right eye and 0.1 mL of saline to the left eye (control). Rabbits in Group A (n=28) were injected with 4 mg/0.1 mL of Kenalog suspension; rabbits in Group B (n=8) were injected with 0.1 mL of Kenalog vehicle; and rabbits in Group C (n=7) were injected with 4 mg/0.1 mL of triamcinolone acetonide. Rabbits were examined ophthalmoscopically and by electroretinogram (ERG) recordings before and at different time intervals after injection. At the end of follow-up, animals were killed and the retinas were prepared for light microscopy.

Results: Thirty-eight rabbits completed 4 weeks of follow-up. Follow-up for 8 and 17 weeks was completed by 29 and 3 rabbits, respectively. Intravitreal commercial Kenalog or its vehicle alone caused approximately 50% reduction in the ERG b-wave amplitude at the end of follow-up. Pure triamcinolone acetonide caused only mild (up to 14%) reduction of the ERG b-wave amplitude. Histologic examination of retinas exposed to Kenalog or its vehicle showed severe damage to all retinal layers in areas close to the site of Kenalog injection.

Conclusions: Intravitreal injection of 4 mg Kenalog suspension is retinotoxic to albino rabbit eyes. The vehicle of Kenalog is probably the main cause of this toxicity.
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http://dx.doi.org/10.1097/IAE.0b013e318030c517DOI Listing
August 2007

A novel isoform of acetylcholinesterase exacerbates photoreceptors death after photic stress.

Invest Ophthalmol Vis Sci 2007 Mar;48(3):1290-7

Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology and the Rappaport Institute, Haifa, Israel.

Purpose: To study the involvement of stress-induced acetylcholinesterase (AChE) expression in light-induced retinal damage in albino rats.

Methods: Adult albino rats were exposed for 24 hours to bright, damaging light. AChE expression was monitored by in situ hybridization, by histochemistry for AChE activity, and by immunocytochemistry. An orphan antisense agent (Monarsen; Ester Neurosciences, Ltd., Herzlia Pituach, Israel) was administered intraperitoneally to minimize light-induced AChE expression. The electroretinogram (ERG) was recorded to assess retinal function.

Results: Twenty-four-hour exposure to bright light caused severe reduction in the ERG responses and augmented expression of mRNA for the "read-through" variant of AChE (AChE-R) in photoreceptor inner segments (IS), bipolar cells, and ganglion cells. AChE activity increased in IS. The expressed AChE protein was a novel variant, characterized by an extended N terminus (N-AChE). Systemic administration of the orphan antisense agent, Monarsen, reduced the photic induction of mRNA for AChE-R, and of the N-AChE protein. Rats exposed to bright, damaging light and treated daily with Monarsen exhibited larger ERG responses, relatively thicker outer nuclear layer (ONL), and more ONL nuclei than did rats exposed to the same damaging light but treated daily with saline.

Conclusions: The findings indicate that the photic-induced novel variant of AChE (N-AChE-R) may be causally involved with retinal light damage and suggest the use of RNA targeting for limiting such damage.
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http://dx.doi.org/10.1167/iovs.06-0847DOI Listing
March 2007

Evaluation of intravitreal kenalog toxicity in humans.

Ophthalmology 2007 Apr 16;114(4):724-31. Epub 2007 Jan 16.

Department of Ophthalmology, Ha'Emek Medical Center, Afula, Israel.

Objective: To evaluate possible functional toxicity of intravitreal Kenalog (commercial triamcinolone acetonide) in patients' retinas.

Design: Observational case series.

Participants: Thirty-two phakic eyes of 16 patients who had nonproliferative diabetic retinopathy and bilateral macular edema refractory to laser therapy, which had no other eye disorder and no previous ophthalmic operation.

Intervention: Kenalog (4 mg/0.1 ml) was injected intravitreally to one eye, whereas the second eye served as the control. The experimental eye was chosen as the eye with worse visual acuity (VA).

Main Outcome Measures: Deterioration of electroretinogram parameters of the study eye measured at 3 months of follow-up when compared with the electroretinogram responses of the fellow, control eye and when compared with electroretinogram responses obtained before injection. Visual acuity, intraocular pressure (IOP), and eventual complications were assessed. No improvement or deterioration of VA or any increase in IOP was regarded as a secondary outcome.

Results: Average maximal response amplitude ratios of the dark-adapted b-wave (treated/control eyes) of the electroretinogram were 0.93 before (P = 0.221) and 0.94 (P = 0.387) 3 months after Kenalog injection. Average ratios of the light-adapted b-wave amplitude (treated/control eyes) of the electroretinogram were 1.04 (P = 0.702) before and 0.86 (P = 0.138) 3 months after Kenalog injection. No significant differences (P>0.05) were found between the electroretinogram parameters obtained from all eyes before and 3 months after Kenalog injection. Average VAs in the treated eyes were 1.08, 0.8, and 1.0 logarithm of the minimum angle of resolution units before and 2 and 4 months after injection, respectively. Temporary elevation of IOP was found in 4 treated eyes of 4 patients (25%).

Conclusions: No electroretinographic evidence of a retinotoxic effect of intravitreal Kenalog was found in our patients.
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http://dx.doi.org/10.1016/j.ophtha.2006.08.044DOI Listing
April 2007

Hypotrichosis with juvenile macular dystrophy: clinical and electrophysiological assessment of visual function.

Ophthalmology 2006 May;113(5):841-7.e3

Department of Ophthalmology, Rambam Medical Center, Haifa, Israel.

Purpose: To evaluate retinal function in subjects suffering from hypotrichosis with juvenile macular dystrophy (HJMD).

Design: Retrospective case-control study.

Participants: Sixteen HJMD patients belonging to 2 genetic groups and 20 control subjects.

Methods: The HJMD patients underwent clinical ophthalmological examination and electrophysiological testing for a period of as many as 14 years. The electroretinogram (ERG), electro-oculogram (EOG), and visual evoked potential (VEP) were recorded serially to assess visual function and to follow possible progression of the disease.

Main Outcome Measures: Amplitudes and implicit times of ERG and VEP, and Arden ratio of EOG.

Results: Fundus examination revealed pigmentary abnormalities with atrophic changes at the posterior pole extending to regions beyond the macular area. A slow and time-dependent decline in visual acuity was noted. The ERG responses were subnormal in amplitude. The ERG deficit was similar for light- and dark-adapted responses. There was a gradual but consistent decrease in the ERGs with time. The EOG measurements were within the normal range. Pattern reversal VEPs were very subnormal, even in patients with mild deterioration of visual acuity. The flash VEPs were of slightly subnormal amplitudes and implicit times in the upper limit of the normal range.

Conclusions: The fundus pictures and electrophysiological tests were consistent with retinal involvement extending beyond the macular region. Follow-up of visual acuity and ERG testing indicated a slowly progressing retinal disorder affecting cone-mediated vision as well as rod-mediated vision. Therefore, we suggest that a more appropriate name for this syndrome is hypotrichosis with cone-rod dystrophy.
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http://dx.doi.org/10.1016/j.ophtha.2005.10.065DOI Listing
May 2006