Scotopic Electroretinogram Research Articles

Long-term Retinal Function and Structure Rescue Using Capsid Mutant AAV8 Vector in the rd10 Mouse, a Model of Recessive Retinitis Pigmentosa

The retinal degeneration 10 (rd10) mouse is a well-characterized model of autosomal recessive retinitis pigmentosa (RP), which carries a spontaneous mutation in the β subunit of rod cGMP-phosphodiesterase (PDEβ). Rd10 mouse exhibits photoreceptor dysfunction and rapid rod photoreceptor degeneration followed by cone degeneration and remodeling of the inner retina. Here, we evaluate whether gene replacement using the fast-acting tyrosine-capsid mutant AAV8 (Y733F) can provide long-term therapy in this model. AAV8 (Y733F)-smCBA-PDEβ was subretinally delivered to postnatal day 14 (P14) rd10 mice in one eye only. Six months after injection, spectral domain optical coherence tomography (SD-OCT), electroretinogram (ERG), optomotor behavior tests, and immunohistochemistry showed that AAV8 (Y733F)-mediated PDEβ expression restored retinal function and visual behavior and preserved retinal structure in treated rd10 eyes for at least 6 months. This is the first demonstration of long-term phenotypic rescue by gene therapy in an animal model of PDEβ-RP. It is also the first example of tyrosine-capsid mutant AAV8 (Y733F)-mediated correction of a retinal phenotype. These results lay the groundwork for the development of PDEβ-RP gene therapy trial and suggest that tyrosine-capsid mutant AAV vectors may be effective for treating other rapidly degenerating models of retinal degeneration.

Nifedipine alters the light-rise of the electro-oculogram in man

To determine if the L-type calcium channel participates in the generation of the light-rise of the electro-oculogram (EOG) in man. The aim was to use nifedipine, a specific, L-type calcium channel inhibitor and determine the effects on the light-rise of the EOG in healthy participants. The EOG was recorded in 14 participants before and after a 10 mg oral dose of fast-acting nifedipine. The Arden index, time to peak of the EOGs and pulse were recorded before and after ingestion of nifedipine. The test-retest variability of the EOG's light-rise in the absence of nifedipine was performed on 11 of the participants. The mean ± SEM oral dose was 147 ± 9 μg/kg. Scotopic electroretinograms (ERGs) were recorded at four intensities (0.0067, 0.0849, 0.364 and 1.140 cd.s.m⁻²) in six participants before and after a 10 mg oral dose of nifedipine. The light-rise of the EOG was significantly reduced in five participants by -22.80 ± 5.6% (p = 0.021), whilst in four of the participants the light-rise increased by +15.7 ± 1.9% (p = 0.033). The results of the test-retest EOGs showed a range of -9.1 to +9.8% Arden index in the absence of nifedipine. Thus, the responses of five participants were not included in the analysis, as the change in the EOG with nifedipine was within this range. The differences in the time to peak of the light-rise were not significantly different in those that showed an increase (p = 0.33) or a decrease (p = 0.87) in the EOG after nifedipine. Pulse rate was not significantly different after nifedipine in the group that showed an increased light-rise (p = 0.77) or in those whose light-rise fell after nifedipine (p = 0.33). No significant effect was observed on the a- and b-wave amplitudes and implicit times for the scotopic components of the scotopic ERG. The L-type calcium channel contributes to the light-rise of the EOG in man.

High correlation of scotopic and photopic electroretinogram components with severity of central retinal artery occlusion

PurposeThe aim of this study was to determine whether a significant correlation exists between the scotopic and photopic components of electroretinograms (ERGs) and the degree of circulation disturbances caused by a central retinal artery occlusion (CRAO).DesignObservational clinical study.ParticipantsSixteen patients with a CRAO (16 eyes).MethodsThe circulatory disturbance in eyes with CRAO was graded as mild (group 1) when the arm-to-retina transmission time was <30 sec and severe (group 2) when the arm-to-retina transmission time was ≥30 sec. Scotopic and photopic ERG components in eyes with CRAO were compared with those in healthy fellow eyes with respect to the degree of circulation disturbance.ResultsThe scotopic and photopic b-waves were significantly reduced only in group 2, whereas the amplitudes of the photopic negative response (PhNR) of the photopic cone ERGs were significantly reduced in both groups. The amplitudes of each ERG component, except for the a-wave of the mixed rod-cone ERG, were significantly smaller in group 2 than in group 1.ConclusionsThe PhNR was reduced even in group 1 with minimal circulatory disturbance and thus may be a good functional indicator.

Morphological and functional evaluation of an animal model for the retinal degeneration induced byN-methyl-N-nitrosourea

The retinal degeneration (RD) is a general cause of blindness. To study its pathophysiology and evaluate the effects of new therapeutic agents before clinical trials, it is essential to establish reliable and stable animal models. This study evaluated a RD animal model in which blindness was induced by N-methyl-N-nitrosourea (MNU), a potent retinotoxin leading to apoptosis of photoreceptors. MNU was applied to the Sprague-Dawley rats by a single intraperitoneal injection in different doses (40, 50, and 60 mg/kg). The retinal functions were examined at 1 week after MNU injection by electroretinogram (ERG). Afterwards, each retina was examined by hematoxylin and eosin stain and immunohistochemistry with anti-glial fibrillary acidic protein antibody. Upon MNU injection of 40, 50 and 60 mg/kg, the ERG amplitude of a-waves showed significant reductions of 7, 26, and 44%, respectively, when compared to that of normal a-waves. The b-wave amplitudes were about 89, 65, and 58% of normal b-waves in the response to scotopic light stimulus. At 1 week, 2 weeks, and 4 weeks after MNU injection (50 mg/kg), all scotopic ERG components decreased progressively. In addition, degeneration of retinal neurons was observed in a time- and dose-dependent manner after MNU injection. Taken together, functional reduction following RD induced by MNU correlates with morphological changes. Thus, this RD rat model may be a useful model to study its pathophysiology and to evaluate the effects of new therapeutic agents before clinical trials.

Restoration of Cone Vision in the CNGA3−/− Mouse Model of Congenital Complete Lack of Cone Photoreceptor Function

Congenital absence of cone photoreceptor function is associated with strongly impaired daylight vision and loss of color discrimination in human achromatopsia. Here, we introduce viral gene replacement therapy as a potential treatment for this disease in the CNGA3(-/-) mouse model. We show that such therapy can restore cone-specific visual processing in the central nervous system even if cone photoreceptors had been nonfunctional from birth. The restoration of cone vision was assessed at different stages along the visual pathway. Treated CNGA3(-/-) mice were able to generate cone photoreceptor responses and to transfer these signals to bipolar cells. In support, we found morphologically that treated cones expressed regular cyclic nucleotide-gated (CNG) channel complexes and opsins in outer segments, which previously they did not. Moreover, expression of CNGA3 normalized cyclic guanosine monophosphate (cGMP) levels in cones, delayed cone cell death and reduced the inflammatory response of Müller glia cells that is typical of retinal degenerations. Furthermore, ganglion cells from treated, but not from untreated, CNGA3(-/-) mice displayed cone-driven, light-evoked, spiking activity, indicating that signals generated in the outer retina are transmitted to the brain. Finally, we demonstrate that this newly acquired sensory information was translated into cone-mediated, vision-guided behavior.

Choroideremia in a woman with ectodermal dysplasia and complex translocations involving chromosomes X, 1, and 3

Background: Choroideremia is an X-linked recessive disorder characterized by vision loss with progressive atrophy of the retinal photoreceptors, retinal pigment epithelium (RPE), and choriocapillaris. Ectodermal dysplasia is a heterogeneous group of disorders characterized by a deficiency of two or more ectodermal derivatives. We report on the phenotypic and genetic characteristics of a 29-year-old woman with both choroideremia and ectodermal dysplasia.Materials and Methods: Observational case report with physical and ophthalmic examination, fluorescein angiography (FA), visual field testing, electroretinography, and cytogenetic analysis. This study adhered to the tenets of the Declaration of Helsinki and The New York Eye and Ear Infirmary Institutional Review Board guidelines.Results: Physical and ocular examination revealed hypotrichosis, hypohidrosis, full dentures, meibomian gland hypoplasia, and a decrease in corneal tear film. Visual acuity was hand motions in the right eye and 20/50 in the left eye. Fundus examination and fluorescein angiography were consistent with advanced choroideremia and revealed diffuse bilateral RPE and chorioretinal atrophy with sparing of the fovea. Visual field testing had less than 10-degree central islands in both eyes. Scotopic electroretinogram (ERG) was flat with a small flicker response. Cytogenetic analysis showed a complex translocation involving chromosomes X, 1, and 3: 46,X,t(X;1;3)(q13;q24;q21),inv(9)(p11q13). Selective inactivation of the normal X chromosome was present in blood and skin. Chromosomal analyses of the proband’s family (mother and two brothers) were normal.Conclusion: An X-autosome chromosomal translocation combined with non-random inactivation of the normal X-chromosome in a woman resulted in the phenotypic findings of choroideremia and ectodermal dysplasia.

Retinal and cortical functions in adult mice lacking cannabinoid receptors

Abstract Purpose Cannabinoid receptor type 1 (CB1R) has been localized in the adult retina of rodents. It is expressed in cones, horizontal, bipolar, some amacrine and ganglion cells. The expression of the cannabinoid receptor type 2 (CB2R) mRNA in the retina of adult rats was also reported. The goal of the present study was to investigate the functional roles of CB1R and CB2R in the retina by comparing retinal electrophysiological responses and cortical optical signals in normal and genetically modified mice. Methods Experiments were conducted on four different groups of C57BL/6 mice: CB1R wild type (WT), CB1R knockout (KO), CB2R WT and KO. Scotopic electroretinograms (ERG) luminance‐response functions and photopic ERGs were recorded. In a subset of CB1 groups, intrinsic signals acquired by optical brain imaging were used to determine spatial frequency, contrast sensitivity and retinotopic maps in the visual cortex. Results The CB1R KO retina showed a stronger photopic response. No differences were observed for scotopic responses. For the CB2R groups, the scotopic b‐wave response was stronger in the KO mice. No differences could be seen between visual cortices maps with respect to SF and contrast sensitivity. Retinotopic maps differed only along the azimuth. Significant differences were observed between hemodynamic response functions. Conclusion These results indicate that CB receptors can play a regulatory effect on the neurovascular coupling at the retinal and cortical levels and on the functional organization of the mice visual cortex along the azimuth Axis.(NSERC)

Effects of the AMPA Antagonist ZK 200775 on Visual Function: A Randomized Controlled Trial

BackgroundZK 200775 is an antagonist at the α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptor and had earned attention as a possible neuroprotective agent in cerebral ischemia. Probands receiving the agent within phase I trials reported on an alteration of visual perception. In this trial, the effects of ZK 200775 on the visual system were analyzed in detail.MethodologyIn a randomised controlled trial we examined eyes and vision before and after the intravenous administration of two different doses of ZK 200775 and placebo. There were 3 groups of 6 probands each: Group 1 recieved 0.03 mg/kg/h, group 2 0.75 mg/kg/h of ZK 200775, the control group received 0.9% sodium chloride solution. Probands were healthy males aged between 57 and 69 years. The following methods were applied: clinical examination, visual acuity, ophthalmoscopy, colour vision, rod absolute threshold, central visual field, pattern-reversal visual evoked potentials (pVEP), ON-OFF and full-field electroretinogram (ERG).Principal FindingsNo effect of ZK 200775 was seen on eye position or motility, stereopsis, pupillary function or central visual field testing. Visual acuity and dark vision deteriorated significantly in both treated groups. Color vision was most remarkably impaired. The dark-adapted ERG revealed a reduction of oscillatory potentials (OP) and partly of the a- and b-wave, furthermore an alteration of b-wave morphology and an insignificantly elevated b/a-ratio. Cone-ERG modalities showed decreased amplitudes and delayed implicit times. In the ON-OFF ERG the ON-answer amplitudes increased whereas the peak times of the OFF-answer were reduced. The pattern VEP exhibited lower amplitudes and prolonged peak times.ConclusionsThe AMPA receptor blockade led to a strong impairment of typical OFF-pathway functions like color vision and the cone ERG. On the other hand the ON-pathway as measured by dark vision and the scotopic ERG was affected as well. This further elucidates the interdependence of both pathways.Trial RegistrationClinicalTrials.gov NCT00999284

Autosomal-Recessive Early-Onset Retinitis Pigmentosa Caused by a Mutation in PDE6G, the Gene Encoding the Gamma Subunit of Rod cGMP Phosphodiesterase

Retinitis pigmentosa (RP) is the most common form of hereditary retinal degeneration, with a worldwide prevalence of 1 in 4000. Over 30 genes and loci have been implicated in nonsyndromic autosomal-recessive (ar) RP. Genome-wide homozygosity mapping was conducted in two sibships from an extended consanguineous Muslim Arab Israeli family segregating ar severe early-onset RP. A shared homozygous region on chromosome 17q25.3 was identified in both sibships, with an overlap of 4.7 Mb. One of the genes located in this interval is PDE6G, encoding for the inhibitory gamma subunit of rod photoreceptor cyclic GMP-phosphodiesterase. Mutations in the genes encoding for the catalytic subunits of this holoenzyme, PDE6A and PDE6B, cause arRP. Sequencing of all coding exons, including exon-intron boundaries, revealed a homozygous single base change (c.187+1G>T) located in the conserved intron 3 donor splice site of PDE6G. This mutation cosegregated with the disease in the extended family. We used an in vitro splicing assay to demonstrate that this mutation leads to incorrect splicing. Affected individuals had markedly constricted visual fields. Both scotopic and photopic electroretinograms were severely reduced or completely extinct. Funduscopy showed typical bone spicule-type pigment deposits spread mainly at the midperiphery, as well as pallor of the optic disk. Macular involvement was indicated by the lack of foveal reflex and typical cystoid macular edema, proved by optical coherence tomography. These findings demonstrate the positive role of the gamma subunit in maintaining phosphodiesterase activity and confirm the contribution of PDE6G to the etiology of RP in humans.

A Novel Nonsense Mutation inCEP290Induces Exon Skipping and Leads to a Relatively Mild Retinal Phenotype

PURPOSE. To identify the genetic defect in a family with variable retinal phenotypes. The proband had a diagnosis of Leber congenital amaurosis (LCA), whereas her two cousins had an early-onset severe retinal dystrophy (EOSRD) with useful vision. A distant family member had retinitis pigmentosa (RP). METHODS. DNA samples of the affected family members were genotyped with 250 K genome-wide SNP microarrays. Genetic defects were localized by linkage analysis and homozygosity mapping, and candidate genes were analyzed by sequencing. Patients underwent a full ophthalmic examination. RESULTS. Compound heterozygous mutations in CEP290 were identified in the proband and her two cousins: the frequent c.2991+1655A>G founder mutation and a novel nonsense mutation in exon 7 (c.451C>T, p.Arg151X). The proband had nystagmus, hyperopia, a flat electroretinogram (ERG), and decreased visual acuity (20/250) from birth. The two cousins had minimal scotopic ERG responses at the age of 2. In one of these patients, visual acuity had reached a level of 20/32 at age 5, which is high for patients with CEP290 mutations. Analysis of the CEP290 mRNA in affected individuals revealed altered splice forms in which either exon 7 or exons 7 and 8 were skipped. In both mutant cDNA products, the open reading frame was not disrupted. Furthermore, homozygosity mapping and mutation analysis in the distant family member affected by RP revealed a homozygous mutation in MERTK, but no CEP290 mutations. This MERTK mutation was heterozygously present in the most severely affected (LCA) patient, but was absent in the two more mildly affected cousins. CONCLUSIONS. A novel nonsense mutation in CEP290 results in nonsense-associated altered splicing. That the remaining open reading frame is intact may explain the less severe phenotype observed in the two affected cousins. The additional heterozygous mutation in MERTK may clarify the more severe phenotype in the proband. This study extends the phenotypic spectrum of CEP290-associated diseases at the mild end.

Nonclassic retinitis pigmentosa: A challenging clinical diagnosis solved by pedigree analysis and electrodiagnostic testing

Purpose The aim of this study was to describe a case of nonclassic retinitis pigmentosa, to highlight ancillary testing tools for proper diagnosis, and to differentiate between common hereditary fundus dystrophies. Methods Methods used in this study included complete ophthalmologic evaluation, optical coherence tomography, visual field testing, pedigree analysis, and electrodiagnostic testing. Results Reduced vision and photopsia were the initial complaints of a patient who had an overall normal ocular appearance. However, a strong family history of retinitis pigmentosa and depressed scotopic and photopic electroretinograms confirmed the diagnosis of autosomal dominant retinitis pigmentosa. Conclusion In cases of atypical-appearing retinitis pigmentosa, both pedigree analysis and electrodiagnostic testing are fundamental in correct diagnosis of this multifaceted hereditary fundus disorder.

Prolonged blockade of VEGF receptors does not damage retinal photoreceptors or ganglion cells

It has recently been reported that relatively short-term inhibition of vascular endothelial growth factor (VEGF) signaling can cause photoreceptor cell death, a potentially clinically important finding since VEGF blockade has become an important modality of treatment of ocular neovascularization and macular edema. However, in a set of studies in which we achieved extended and complete blockage of VEGF-induced vascular leakage through retinal expression of a VEGF binding protein, we did not observe any toxicity to retinal neurons. To follow-up on these apparently discrepant findings, we designed a set of experiments with the kinase inhibitor SU4312, which blocks phosphorylation of VEGF receptors, to look directly for evidence of VEGF inhibition-related retinal toxicity. Using transgenic mice with sustained expression of VEGF in photoreceptors, we determined that periocular injection of 3 microg of SU4312 every 5 days markedly suppressed subretinal neovascularization, indicating effective blockade of VEGF signaling. Wild-type mice given periocular injections of 5 microg of SU4312 every 5 days for up to 12 weeks showed normal scotopic and photopic electroretinograms (ERGs), no TUNEL stained cells in the retina, and no reduction in outer nuclear layer thickness. Incubation of cultured ganglion cells or retinal cultures containing photoreceptors with high doses of SU4312 did not reduce cell viability. These data suggest that blocking VEGF signaling in the retina for up to 12 weeks does not damage photoreceptors nor alter ERG function and should reassure patients who are receiving frequent injections of VEGF antagonists for choroidal and retinal vascular diseases.

Circadian variation in the electroretinogram and the presence of central melatonin

The light/dark cycle is the most important circadian clock synchronizer for mammals and humans. Circadian rhythms of dopamine and melatonin production in the retina have been reported to follow the light and dark cycle, but their impact on rod and cone functioning is not clear. The purpose of this study was to assess diurnal variations (morning vs. evening) in retinal function as measured with the photopic and scotopic electroretinogram (ERG). We also tried to correlate our results with the presence or absence of melatonin secretion in the saliva. Photopic and scotopic luminance-response functions were obtained in 29 participants at 11:00 (when melatonin should not be present) and 23:00 (when melatonin should be present). From the luminance-response function, Vmax, log K and slope parameters were derived. In scotopic condition, a significant increase of 6% in Vmax amplitude was observed in evening compared to morning (P = 0.03) along with a prolonged b-wave implicit time of 8% (P = 0.01) and an increase in rod sensitivity in evening compared to morning (P = 0.02). As expected, these changes in rod function were accompanied by a higher concentration of melatonin in saliva samples in the evening (P = 0.01). In photopic condition, only a prolonged a-wave implicit time of 5% was observed in evening when compared to morning (P = 0.02). Our findings suggest that the rod system is favored during night time, when circulating melatonin is present. Although statistically significant changes were observed, the day vs. night difference observed in the present study appears to be too small to impact significantly upon clinical assessment of retinal function.

Effects of hypercapnia on the electroretinogram in sevoflurane and isoflurane anaesthetized dogs

To evaluate the effects of induced hypercapnia on the electroretinogram (ERG) in beagle dogs anaesthetized with isoflurane and sevoflurane. Binocular, full-field flash photopic and scotopic ERGs were obtained from six healthy neutered female beagle dogs. In order to determine Vmax and the photopic negative response (PhNR), photopic ERG luminance-response curves were generated with 17 different light stimuli. Photopic flicker ERGs were obtained at 30-Hz temporal frequency. Scotopic ERGs were recorded after 35 min of dark adaptation. For all animals, this procedure was performed once in four different sessions: isoflurane + end-tidal [CO(2)] at 35 mmHg +/- 3 mmHg (ISON), isoflurane + end-tidal [CO(2)] at 65 mmHg +/- 3 mmHg (ISOH), sevoflurane + end-tidal [CO(2)] at 35 mmHg +/- 3 mmHg (SEVON), isoflurane + end-tidal [CO(2)] at 65 mmHg +/- 3 mmHg (SEVOH). In photopic conditions, b-wave amplitudes were significantly smaller in hypercapnic groups (ISON = 170.6 +/- 12.1 microV; ISOH = 132.6 +/- 24.9 microV; SEVON = 170.9 +/- 14.4 microV; SEVOH = 130.2 +/- 22.8 microV). Similarly, in scotopic conditions, b-wave amplitudes were significantly decreased when CO(2) was increased (ISON = 89.4 +/- 14.7 microV; ISOH = 58.2 +/- 17.6 microV; SEVON = 93.4 +/- 24.1 microV; SEVOH = 56.2 +/- 22.2 microV). Flicker peak times were significantly increased in hypercapnic groups (ISON = 25.9 +/- 0.4 ms; ISOH = 27.7 +/- 1.2 ms; SEVON = 25.9 +/- 1.5 ms; SEVOH = 27.2 +/- 0.7 ms). Our results clearly indicate that induced hypercapnia significantly alters the genesis of the electroretinogram at level of ON-pathway and suggest that OFF-pathway is unaffected and that ERGs obtained from isoflurane or sevoflurane anaesthetized dogs are almost identical. Control of hypercapnia must be taken into consideration when ERGs are performed under inhaled anaesthesia in dogs.

“CONE DYSTROPHY WITH SUPERNORMAL ROD ELECTRORETINOGRAM”: A COMPREHENSIVE GENOTYPE/PHENOTYPE STUDY INCLUDING FUNDUS AUTOFLUORESCENCE AND EXTENSIVE ELECTROPHYSIOLOGY

The purpose of this study was to characterize the clinical, electrophysiologic, and genetic features in "cone dystrophy with supernormal rod electroretinogram (ERG)." Twenty-four cases between 5 and 59 years of age were ascertained. Full-field ERGs, incorporating the international standards, were used to derive intensity-ERG response functions. ON-OFF ERGs were performed. Fundus autofluorescence imaging was performed on 15 subjects. Deoxyribonucleic acid was available in 18 cases and was screened for a mutation in KCNV2. Photophobia and nyctalopia were common. Autofluorescence was variable but often showed a ring-like area of high density that in middle-aged individuals, usually surrounded by an area of macular retinal pigment epithelial atrophy. Scotopic ERG amplitudes overlapped with the normal range but had characteristic a- and b-wave intensity-response functions; all had a broadened a-wave to the brightest flash. Photopic ERGs were abnormal; there was a delay in some ON and most OFF responses. Mutations in KCNV2 were detected in 18 cases, including 4 with novel mutations. Individuals with mutations in KCNV2 manifest a wide range of macular and autofluorescence abnormalities. A ring-like area of parafoveal high density autofluorescence is common. ERG amplitudes are variable, but the intensity-ERG response functions and bright flash ERG waveforms are pathognomonic.

Postnatal hyperoxia and the developing rat retina: beyond the obvious vasculopathy

Although a great deal of emphasis has been placed on the vasculopathy that is associated with oxygen-induced retinopathy (OIR), our studies also revealed significant and irreversible structural (retinal histology) and functional (scotopic and photopic electroretinograms) impairments that were significantly more severe in pigmented Long-Evans rats compared to the more commonly used albino Sprague Dawley rats. In the following pages, we will highlight what we have learned about the retinal pathophysiological processes of OIR taking place in strains of both rats with the hope that this will trigger investigations into new therapeutic strategies to complement those geared at preventing the vasculopathy.

Long-term follow-up of a family with dominant X-linked retinitis pigmentosa

To document the progression of disease in male and female members of a previously described family with X-linked dominant retinitis pigmentosa (RP) caused by a de novo insertion after nucleotide 173 in exon ORF15 of RPGR. The clinical records of 19 members of family UTAD054 were reviewed. Their evaluations consisted of confirmation of family history, standardised electroretinograms (ERGs), Goldmann visual fields, and periodic ophthalmological examinations over a 23-year period. Male members of family UTAD054 had non-recordable to barely recordable ERGs from early childhood. The males showed contracted central fields and developed more severe retinopathy than the females. The female members showed a disease onset delayed to teenage years, recordable but diminishing photopic and scotopic ERG amplitudes in a cone-rod pattern, progressive loss and often asymmetric visual fields, and diffuse atrophic retinopathy with fewer pigment deposits compared with males. This insertion mutation in the RPGR exon ORF15 is associated with a RP phenotype that severely affects males early and females by 30 years of age, and is highly penetrant in female members. Families with dominant-acting RPGR mutations may be mistaken to have an autosomal mode of inheritance resulting in an incorrect prediction of recurrence risk and prognosis. Broader recognition of X-linked RP forms with dominant inheritance is necessary to facilitate appropriate counselling of these patients.

The mysterious a‐wave

Abstract Purpose The electroretinogram (ERG) waveform usually consists of two major components, the a‐ and b‐waves. Exceptions to the above rule are scotopic ERGs evoked to dim flashes, where only b‐waves are recorded. The aim of this study was to examine if the no a‐wave ERG was a feature of scotopic ERG only and try to explain why it occurs. Methods Photopic (background: 30 cd.s.m‐2; flash:‐1.81 to 2.84 log cd.s.m‐2 in 0.2 log unit steps) and scotopic (‐5.01 to ‐0.96 log cd.s.m‐2 in 0.4 log unit steps) ERG luminance‐response functions were obtained from normal human subjects (n=30) and Long‐Evans (n=8) and Sprague‐Dawley (n=8) rats (scotopic ERGs only). Results Human photopic ERG waveform always included an a‐wave. With flash luminance, its peak time first increased, reached a maximal value and then decreased progressively and could be fitted to a fourth order polynomial function. In contrast, scotopic a‐waves appeared only in ERGs evoked to flashes equal to or brighter than ‐3.01 log cd.s.m‐2. With increasing intensity, the peak time of the a‐wave shortened following a linear model.On average, for each log‐unit of flash attenuation, the scotopic a‐wave shortened by more than 10 ms compared to 1.4 ms for the photopic one. Of interest, in rat scotopic ERGs evoked to the dimmest intensities the a‐wave appeared to be replaced by a group of short latency oscillations that were best seen in recordings where the low frequency cut‐off had been raised to 100 Hz. Conclusion The a‐b‐wave rule seems to apply only to photopic ERGs where an a‐wave was still identifiable in ERGs smaller than 1% of maximal amplitude. One wonders if the submicrovolt oscillations occurring prior to the onset of the b‐wave of rat scotopic ERGs evoked to dim flashes could represent remnant of the original a‐wave. Funded by CIHR

Melatonin modulates visual function and cell viability in the mouse retina via the MT1 melatonin receptor.

A clear demonstration of the role of melatonin and its receptors in specific retinal functions is lacking. The present study investigated the distribution of MT1 receptors within the retina, and the scotopic and photopic electroretinograms (ERG) and retinal morphology in wild-type (WT) and MT1 receptor-deficient mice. MT1 receptor transcripts were localized in photoreceptor cells and in some inner retinal neurons. A diurnal rhythm in the dark-adapted ERG responses was observed in WT mice, with higher a- and b-wave amplitudes at night, but this rhythm was absent in mice lacking MT1 receptors. Injection of melatonin during the day decreased the scotopic response threshold and the amplitude of the a- and b-waves in the WT mice, but not in the MT1(-/-) mice. The effects of MT1 receptor deficiency on retinal morphology was investigated at three different ages (3, 12, and 18 months). No differences between MT1(-/-) and WT mice were observed at 3 months of age, whereas at 12 months MT1(-/-) mice have a significant reduction in the number of photoreceptor nuclei in the outer nuclear layer compared with WT controls. No differences were observed in the number of cells in inner nuclear layer or in ganglion cells at 12 months of age. At 18 months, the loss of photoreceptor nuclei in the outer nuclear layer was further accentuated and the number of ganglion cells was also significantly lower than that of controls. These data demonstrate the functional significance of melatonin and MT1 receptors in the mammalian retina and create the basis for future studies on the therapeutic use of melatonin in retinal degeneration.

Microwave = Thermal Balloon Endometrial Ablation

The electroretinogram (ERG) is an electrical response of the retina to photic stimulation. A flash of light or bright appearance of a pattern elicits a biphasic negative/positive waveform. The a-wave originating in the receptor level of rods and cones is the initial large negative wave. The b-wave originating in the midretina is the following large positive component. Protocols include full-field and multifocal ERGs. Full-field ERGs are recorded if one is most interested in the global health of the retina, such as in retinitis pigmentosa. A limitation of the full-field ERG is that the recording is a massed potential from the whole retina. Multifocal ERGs can map small scotomas in the central 40 + degrees of visual field. Abbreviated methods are used with infants and in the operating room as part of an exam under anesthesia. The effects of toxic medications can be detected and quantified using ERGs. The ERG is useful to assess cases of retinal foreign bodies and trauma to estimate the extent of retinal dysfunction. Foreign bodies affect retinal function depending on the extent of trauma to the retina and the location and composition of the object. Systemic metabolic disorders usually reduce ERG b-wave amplitudes, particularly the scotopic dim flash ERGs.