Arden Ratios Research Articles

A novel variant of autosomal recessive best vitelliform macular dystrophy and management of early-onset complications

To report an adult with autosomal recessive Best vitelliform macular dystrophy with a new homozygous BEST1 mutation, the management of a cystoid macular edema with intravitreal aflibercept in the proband, and the findings in the parents, carriers of heterozygous BEST1 mutations. A 28-year-old female presented with blurry andreduced vision in her both eyes with bilateral vitelliform macular lesions. The patient's parents were also examined. Examinations included electrooculogram (EOGs), imaging studies, and BEST1 gene testing. Interventions included treatment with intravitreal aflibercept for both eyes. The patient presented with visual acuity of 20/20 OD 20/30 OS, RPE changes, multifocal subretinal yellowish deposits resembling vitelliform deposits and subretinal fluids. Cystoid macular edema developed after one month, causing vision reduction (20/28 OD 20/30 OS). Visual acuity recovered to 20/20 OU after serial intravitreal aflibercept injections. The proband showed subnormal EOG Arden ratios. Molecular testing showed the homozygous missense variant c.695T>G p. (IIe232Ser) In exon 6 of the BEST1 mutations and to the best of our knowledge, this variant, which was confirmed by conventional Sanger sequencing, has neither been annotated in databases nor been described in the literature so for (Human Genome Molecular Database 2018.1). In the heterozygous parents, EOGs were subnormal, and minimal autofluorescence changes were seen.Clinical Relevance:Prompt recognition and treatment of cystoid macular edema management effectively restore vision. Awareness and recognition of recessive inheritance permit correct diagnosis and counseling.

Multimodal Imaging Features of Bilateral Choroidal Ganglioneuroma

Purpose Bilateral choroidal ganglioneuroma is extremely rare, and no cases have been described in the literature. Multimodal images are crucial for its diagnosis. Here, we evaluated multimodal images in the early stage of choroidal ganglioneuroma. Methods A 6-year-old boy was recruited who had experienced gradually progressive vision loss and rapidly progressive myopia in both eyes over the past 2 years. His eyes were comprehensively evaluated via slit-lamp microscopy, ultrasound biomicroscopy, swept-source optical coherence tomography (SS-OCT), fundoscopy, fundus fluorescein angiography, indocyanine green angiography (ICGA), ultrasound B scanning, and magnetic resonance imaging. Electrophysiological examinations included electrooculography and electroretinography. Choroid biopsy and pathological examination were performed. Results Over the past 2 years, the patient's best-corrected visual acuity had gradually decreased to hand motions at 10 cm in the right eye and 20/63 in the left, with axial length growth to 25.89 mm in the right and 28.99 mm in the left. Diffuse thickening in bilateral eyewalls was depicted in B scanning and magnetic resonance imaging. Secondary exudative retinal detachment was evident in SS-OCT and B scanning. SS-OCT depicted low optical reflections in the choroidal layer, revealing a lack of choroidal vasculature. Diffuse hypofluorescence in ICGA photography confirmed extensive loss of choroidal vasculature. In electrophysiological function investigations, electrooculography revealed remarkable bilateral low Arden ratios, with almost extinguished electroretinogram in the right eye. Right-eye choroid biopsy was performed, resulting in a histological diagnosis of choroidal ganglioneuroma. Conclusion Choroidal ganglioneuroma is rare. To our knowledge, no bilateral cases have been described in the literature. Major clinical features include a rapid increase in axial length, diffuse choroidal thickening, hyper-reflectivity in the choroid on optical coherence tomography, and loss of choroidal vasculature on ICGA. The current report provides multimodal imaging of choroidal ganglioneuroma for the first time and can be valuable for early diagnosis.

NOVEL BEST1 MUTATIONS DETECTED BY NEXT-GENERATION SEQUENCING IN A CHINESE POPULATION WITH VITELLIFORM MACULAR DYSTROPHY.

To characterize novel BEST1 mutations and the phenotype-genotype correlations in vitelliform macular dystrophy in a Chinese population. Seventeen individuals affected by vitelliform macular dystrophy underwent detailed ophthalmic examinations, including a best-corrected visual acuity test, slit-lamp biomicroscopy, fundus photography, spectral-domain optical coherence tomography, fundus autofluorescence, fluorescein angiography, and optical coherence tomography angiography. Next-generation sequencing was used to screen 790 genes frequently involved in common inherited nonsyndromic eye diseases in all participants. Sanger sequencing was used to identify possible disease-causing variants. The mean ± SD age of the patients was 44.20 ± 15.09 (range: 16-69) years. Seven novel BEST1 mutations were identified: six heterozygous missense (p.Thr307Asn, p.Ile295The, p.Leu75Pro, p.Thr2Ser, p.Ser79Tyr, and p.Val81Leu) and one frameshift (p.Glu115GlufsX120) mutation. Choroidal neovascularization was detected in two probands. One individual presented with subfoveal focal choroidal excavation. Arden ratios obtained by electrooculography were less than the 1.5 cutoff value in 7 patients. No mutations were identified in 2 patients, one of whom had a fundus appearance typical of vitelliform macular dystrophy and a decreased Arden ratio (1.2/1.2). Patients with the same heterozygous BEST1 mutations exhibited varying phenotypes. Our results have expanded the BEST1 mutation spectrum in a Chinese population with vitelliform macular dystrophy.

Novel BEST1 Mutations and Special Clinical Features of Best Vitelliform Macular Dystrophy

Purpose: To describe the clinical features and to analyze BEST1 mutations in patients with Best vitelliform macular dystrophy (BVMD). Methods: Thirteen individuals affected by BVMD from 6 unrelated Chinese families were studied. Complete ophthalmological examinations were performed, and the BEST1 gene was screened in all participants and 100 controls. Follow-ups were arranged within 12 months. Results: All 6 probands showed typical fundus appearances of BVMD. One of the 6 had a history of angle closure glaucoma, and another showed a unilateral focal choroidal excavation on optical coherence tomography. One patient experienced progression of the macular lesion during the follow-up. The asymptomatic mutation carriers had normal fundus but abnormal Arden ratios on electro-oculograms. Besides 4 previously reported mutations (p.Ser16Phe, p.Ser144Asn, p.Glu292Lys, p.Glu300Lys), 2 novel disease-causing mutations (p.Thr307Asp, p.Arg47His) were identified, of which p.Arg47His has been reported in adult-onset vitelliform macular dystrophy. Conclusions: Our findings have expanded the mutational and clinical spectrum of BVMD in a Chinese population. Clinical presentations of angle closure glaucoma and/or focal choroidal excavation may be related to BVMD, underlining the necessity of multimodal studies and risk assessment of angle closure glaucoma in BEST1 mutation carriers. BVMD and adult-onset vitelliform macular dystrophy may share a common etiology in some cases.

Ophthalmological assessment of cannabis-induced persisting perception disorder: is there a direct retinal effect?

Cannabis is a psychotomimetic agent that induces impairment of sensory perception. We present detailed clinical and electrophysiological data of patients with hallucinogen persisting perception disorder (HPPD) after marijuana consumption. A HPPD patient and four heavy cannabis smokers with no visual disturbances (controls) underwent complete ophthalmological examination including psychophysical tests (visual acuity, color vision, visual field, and dark adaptation) and detailed electrophysiological examinations, including extended Ganzfeld ERG, multifocal ERG, and electrooculography (EOG). Furthermore, electrically evoked phosphene thresholds (EPTs) were measured to further evaluate retinal function. Ophthalmological and most electrophysiological examinations were within normal limits for the HPPD patient and for all control subjects. Interestingly, EOG results of the HPPD patient showed a slightly reduced fast oscillation ratio, diminished standing potentials of the slow oscillations, and a light peak within normal range resulting in higher Arden ratios. The EPTs of the patient were reduced, in particular for pulses with long durations (50ms) causing visual sensations even at lowest possible currents of the neurostimulator. The control subjects did not reveal such alterations. Our findings suggest a direct effect of cannabinoids on the retina and retinal pigment epithelium function, which may be involved in disturbances of the visual function experienced after drug consumption. The observations presented here may contribute to the elucidation of the detailed mechanism. Furthermore, EOG and EPT measurements may be useful tools to demonstrate long-term retinal alterations in cannabis-induced HPPD in patients.

A Homozygous Frameshift Mutation inBEST1Causes the Classical Form of Best Disease in an Autosomal Recessive Mode

Best disease is a monogenic macular degeneration caused mainly by heterozygous mutations in the BEST1 gene. The objective was to characterize the molecular and clinical features of patients with the classical form of Best disease that is inherited in an autosomal recessive mode. Clinical evaluation included detailed family history, a full ophthalmologic examination, electro-oculography (EOG), electroretinography, color vision testing, and ocular imaging. Mutation analysis was performed by direct sequencing of PCR products. Two young siblings affected by Best disease, as confirmed by funduscopy, retinal imaging, and electrophysiologic assessment, were recruited for the study. Molecular analysis revealed a novel homozygous deletion (c.1415delT) in the BEST1 gene leading to a frameshift followed by a premature stop codon, which cosegregated with the disease in a recessive mode. The heterozygous parents had normal visual acuity, retinal appearance, and function. The two heterozygous grandmothers, ages 61 and 62, also had normal Arden ratios on EOG, but one of them manifested moderate-to-severe dry non-neovascular age-related macular degeneration. We show here that the typical vitelliform phenotype of Best disease, usually transmitted in an autosomal dominant fashion, can be inherited as an autosomal recessive disease due to homozygosity for a frameshift mutation.

Autosomal Recessive Best Vitelliform Macular Dystrophy

To report a child with early-onset autosomal recessive Best vitelliform macular dystrophy and compound heterozygous BEST1 mutations, the management of a choroidal neovascular membrane with intravitreal bevacizumab in the proband, the benefits of amblyopia therapy in the fellow eye, and the findings in the parents, carriers of heterozygous BEST1 mutations. A 5-year-old white girl presented with monocular visual acuity loss and bilateral vitelliform macular lesions. Her parents were also examined. Examinations included electro-oculograms (EOGs), electroretinograms, imaging studies, and BEST1 gene testing. Interventions included off-label treatment with intravitreal bevacizumab in the left eye and amblyopia therapy in the right eye. The proband presented with visual acuity of 20/200 OD with an atypical subfoveal vitelliform scar and 20/16 OS with asymptomatic vitelliform deposits. Subfoveal choroidal neovascularization developed at age 6 years, causing marked vision loss (20/200 OS). Visual acuity recovered to 20/20 OS after serial intravitreal bevacizumab injections. Amblyopia therapy improved visual acuity to 20/50 OD. The proband showed subnormal EOG Arden ratios and mild electroretinogram changes. Molecular testing showed missense BEST1 mutations (R141S and R141H) in the proband. Unlike dominant Best vitelliform macular dystrophy, in the heterozygous parents EOGs were normal and minimal autofluorescence changes were seen. Choroidal neovascularization treatment with bevacizumab was associated with vision restoration. Amblyopia treatment also yielded significant benefit. Patients presenting with vitelliform lesions should be screened for BEST1 mutations, even when parents have normal EOG and imaging results. Prompt recognition and treatment of choroidal neovascularization and amblyopia management effectively restores vision. Awareness and recognition of recessive inheritance permits correct diagnosis and counseling.

Systematic Screening of BEST1 and PRPH2 in Juvenile and Adult Vitelliform Macular Dystrophies: A Rationale for Molecular Analysis

To evaluate a genetic approach of BEST1 and PRPH2 screening according to age of onset, family history, and Arden ratio in patients with juvenile vitelliform macular dystrophy (VMD2) or adult-onset vitelliform macular dystrophy (AVMD), which are characterized by autofluorescent deposits. Clinical, electrophysiologic, and molecular retrospective study. The database of a clinic specialized in genetic sensory diseases was screened for patients with macular vitelliform dystrophy. Patients with an age of onset less than 40 years were included in the VMD2 group (25 unrelated patients), and patients with an age of onset more than 40 years were included in the AVMD group (19 unrelated patients). Clinical, fundus photography, and electro-oculogram (EOG) findings were reviewed. Mutation screening of BEST1 and PRPH2 genes was systematically performed. Relevance of age of onset, family history, and Arden ratio were reviewed. Patients with VMD2 carried a BEST1 mutation in 60% of the cases. Seven novel mutations in BEST1 (p.V9L, p.F80V, p.I73V, p.R130S, pF298C, pD302A, and p.179delN) were found. Patients with VMD2 with a positive family history or a reduced Arden ratio carried a BEST1 mutation in 70.5% of cases and in 83% if both criteria were fulfilled. Patients with AVMD carried a PRPH2 mutation in 10.5% of cases and did not carry a BEST1 mutation. The probability of finding a PRPH2 mutation increased in the case of a family history (2/5 patients). Electro-oculogram was normal in 3 of 15 patients with BEST1 mutations and reduced in the 3 patients with PRPH2 mutations. Age of onset is a major criterion to distinguish VMD2 from AVMD. Electro-oculogram is not as relevant because decreased or normal Arden ratios have been associated with mutations in both genes and diseases. A positive family history increased the probability of finding a mutation. BEST1 screening should be recommended to patients with an age of onset less than 40 years, and PRPH2 screening should be recommended to patients with an age of onset more than 40 years. For an onset between 30 and 40 years, PRPH2 can be screened if no mutation has been detected in BEST1. The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Effect of docosahexaenoic acid supplementation on the macular function of patients with Best vitelliform macular dystrophy: randomized clinical trial

Objective: Best disease is a slowly progressive macular dystrophy that typically has an onset in early childhood. Multiple lines of evidence suggest that dietary docosahexaenoic acid (DHA) protects against the development of macular degeneration. Our trial tested the effect of an oral supplement of DHA on visual function in patients with Best disease. Design: Double-masked, randomized, placebo-controlled, crossover clinical trial. Participants: Eight patients with Best disease. Methods: Patients were given either an oral supplement of DHA (20 mg/kg daily) or placebo. Primary outcome measures were the multifocal electroretinogram (mfERG) and electro-oculogram (EOG). Plasma DHA was tracked along with visual acuity (Early Treatment Diabetic Retinopathy Study chart), VF-14 scores, and Humphrey visual fields. Results: All 8 patients had increased plasma DHA levels (2–3 fold) during periods of DHA supplementation compared with periods without supplementation. Differences in visual acuity, VF-14 scores, and EOG Arden ratios during periods with and without DHA supplementation were all statistically insignificant. A positive correlation was found between the plasma concentration of DHA and mfERG amplitudes, but amplitude changes during the treatment periods were not significant. A carryover effect of DHA supplementation was a confounding error. Conclusions: Our pilot trial of DHA supplementation in 8 patients with Best disease did not demonstrate an improvement in macular function. An expanded trial would be needed to examine the full effects of DHA supplementation on visual function in Best disease.

Retinal Function in X-linked Ocular Albinism (OA1)

Purpose: To characterize retinal function in human recessive X-linked ocular albinism (OA1) across the normal lifespan. Methods: Retinal function was evaluated in 14 OA1 patients (ages 11 to 71 years) and five obligate carriers (ages 41 to 50 years) and compared to normal controls using full-field and multi-focal electroretinograms (ERG and mERG, respectively) and electro-oculography (EOG). Results: No consistent differences in ERG response parameters were observed when OA1 patients were compared as a group to normal controls. A trend in the direction of better correlations of response parameters with age was, however, observed in OA1. EOG Arden ratios were normal or hypernormal for all patients, but were uncorrelated with age. Central retinal function measured with the mERG suggested a flat response topography with depressed macular function compared to normal controls. Conclusions: Panretinal function in OA1 is within normal limits at all ages, consistent with previous reports in generalized albinism. The stronger correlations with age in OA1 may suggest a different rate of age-related change in OA1 compared to normal populations, but the precise nature of this change must await an appropriate prospective study. The topography of mERG amplitudes in OA1 is relatively flat across the central retina with a reduction in amplitude in the macular region consistent with anatomical studies demonstrating an underdeveloped macular region in albinism.

Is there a dysfunction in the visual system of depressed patients?

BackgroundThe aim of the current study was to identify a possible locus of dysfunction in the visual system of depressed patients.Materials and MethodsFifty Major Depressive patients aged 21–60 years and 15 age-matched controls took part in the study The diagnosis was obtained with the SCAN v 2.0. The psychometric assessment included the HDRS, the HAS, the Newcastle Scales, the Diagnostic Melancholia Scale and the GAF scale. Flash Electroretinogram and Electrooculogram were performed in all subjects. The statistical analysis included ANCOVA, Student's t-test and Pearson Product Moment Correlation Coefficient were used.ResultsThe Electro-oculographic findings suggested that all subtypes of depressed patients had lower dark trough and light peak values in comparison to controls (p < 0.001), while Arden ratios were within normal range. Electroretinographic recordings did not reveal any differences between patients and controls or between subtypes of depression.DiscussionThe findings of the current study provide empirical data in order to assist in the understanding of the international literature and to explain the mechanism of action of therapies like sleep deprivation and light therapy.

Electro-Oculography in Pigment Dispersion Syndrome

Clinical data and the common embryological origin of the pigment epithelium of the iris and retinal pigment epithelium suggest that the latter may be involved in the pigment dispersion syndrome (PDS). In our study functional changes of the retinal pigment epithelium were evaluated by electro-oculography in 10 PDS patients, 10 patients with chronic open-angle glaucoma (COAG) and 10 normal subjects. The mean dark-trough latency and Arden ratio for the PDS group were significantly lower than those of the COAG and control groups. Analysis of the Arden ratios based on the Kruskall-Wallis test revealed that 30% of the PDS values were subnormal with respect to the control group mean –1 SD. These results indicate primary involvement of the retinal pigment epithelium in PDS.

Electrophysiology of type II mesangiocapillary glomerulonephritis with associated fundus abnormalities.

The retinal electrophysiology is reported in four patients with type II mesangiocapillary glomerulonephritis and partial lipodystrophy with associated fundus abnormalities and no visual symptoms. The histological hallmark of the condition is that of widespread electron dense deposits in the renal glomerulus and in the choriocapillaris and Bruch's membrane of the eye. Three of the four patients had the typical fundal appearance of multiple, yellow, drusen-like lesions at the posterior pole of the eye with normal visual acuity. These three patients had abnormally low Arden ratios on electro-oculography with normal electroretinography responses. This is the first clinical model of disease known to be isolated to the choriocapillaris and Bruch's membrane causing an electro-oculographic abnormality without any clinically detectable deficit in visual function.

Studies on the stability of the clinical electro-oculogram.

The electro-oculogram is variable as a clinical test, but the recording technique has not been standardized, and differences in the protocols for adaptation and stimulation among laboratories may contribute to the variability. To analyze some of these factors, we performed more than 100 electro-oculograms on a single subject under different conditions. Both the Arden ratio and the ratio of light peak amplitude to a stable dark-adapted baseline were independent of pupillary dilation but linearly related to retinal illumination measured in trolands. Between 3.0 and 4.0 log trolands, the values began to level off, but they were difficult to interpret because of subject discomfort above 3.5 log trolands. The Arden ratios were influenced by preadaptation light levels and were roughly 20% higher above 90 cd/m2 than below 45 cd/m2. There was a circadian rhythm in dark trough, baseline and light peak values, but the composite Arden ratio and light peak/baseline ratio showed little circadian effect. The light peak/baseline ratios were slightly more stable than the Arden ratios; the variability (defined as [standard deviation x 100]/mean) was 6.6% and 12.5%, respectively. Our results suggest that stimulus intensities for clinical electro-oculographic testing should be between 3.0 and 3.5 log trolands; pupil dilation is optional. This translates into light levels of 141-447 cd/m2 for a 3-mm pupil and 20-63 cd/m2 for an 8-mm pupil. The reduction in variability and independence from preadaptation achieved by using the light peak/baseline ratio instead of the Arden ratio must be weighed against the time required to achieve a stable dark baseline.

Low electrooculographic ratios in patients with seasonal affective disorder

Changes in retinal sensitivity to light have been hypothesized as etiological in seasonal affective disorder. This study was undertaken to investigate sensitivity to light in seasonal affective disorder using electrooculography (EOG), an objective measure of retinal light response. In a mood disorders clinic, 19 depressed, drug-free patients with seasonal affective disorder, diagnosed by DSM-III-R criteria, were compared with 19 age- and sex-matched normal comparison subjects. All subjects had identical EOG testing performed during the winter. EOG (Arden) ratios were calculated from the EOG data. RESULTS According to multivariate analysis of variance, the EOG ratios in the patients with seasonal affective disorder were significantly lower than those of the normal comparison subjects, although there was considerable overlap in EOG ratios between patients and comparison subjects. These results suggest that seasonal affective disorder is associated with subtle retinal abnormalities at the level of the photoreceptor/retinal pigment epithelium complex, consistent with subsensitivity to light. A limitation of this study is that the retinal origins of the EOG response are nonspecific and still not completely elucidated.

Depression, electrooculograms (EOG), and arden ratios: Differential response to light and dark : Meir Steiner, M.D., Ph.D., Harriet MacMillan, M.D., Jo Seggie, Ph.D. Department of Psychiatry, McMaster University, Clinical Studies Program, St. Joseph's Hospital, Hamilton, Ontario L8N 4A6, Canada

Depression, electrooculograms (EOG), and arden ratios: Differential response to light and dark : Meir Steiner, M.D., Ph.D., Harriet MacMillan, M.D., Jo Seggie, Ph.D. Department of Psychiatry, McMaster University, Clinical Studies Program, St. Joseph's Hospital, Hamilton, Ontario L8N 4A6, Canada

Early physiological effects of lithium treatment: electrooculographic and adaptometric findings in patients with affective and schizoaffective psychoses.

Electrooculography allows to measure the fundocorneal potential, a standing potential of the eye, under the conditions of light and dark adaptation. The results are expressed as the so-called Arden ratio. As was demon-strated by others in healthy volunteers, the Arden ratio, on the average, de-creases under Lithium treatment. However, in individual cases it can also remain unchanged or even rise. We have performed electrooculographic and adaptometric examinations in ten patients with affective disorders (DSM-III, 296. XX) and schizoaffective psychoses (DSM-III, 295.70). The criteria for the assignment of patients to lithium treatment were derived from a study by Angst. Arden ratios were determined six times, respectively, before lithium application and after a therapeutic lithium serum level (0.6-0.8 mmol/l) had been reached (cf. 5). The values observed during lithium treatment were significantly lower than those measured before lithium application. Dark adaptation, as measured using an adaptometer according to Goldmann-Weekers, was disturbed under lithium. The potential predictor function of these findings with regard to the lithium response is being investigated by means of a prospective study.

Peripheral retinal function in age-related macular degeneration.

Aging changes are seen histopathologically outside the central retina, but have not been correlated with the presence of age-related macular degeneration (AMD). We studied 21 patients with drusen and AMD to see if peripheral retinal function changes are correlated with changes in the central retina. Electrooculogram Arden ratios were normal. Intensity-response analysis of dark-adapted electroretinogram b-waves and analysis of flicker electroretinograms were normal except for a small sensitivity loss presumed to reflect aging and lens yellowing. There was no difference between patients' severely involved AMD eye and their fellow eye with only drusen. Static perimetry showed sensitivity loss in the central 20 degrees, but normal thresholds peripheral to this. These results suggest that retinal function abnormalities in AMD are confined to the central retina, and the small age-related peripheral changes found do not correlate with the degree of AMD.

Vitelliform macular lesions.

Two patients with vitelliform macular lesions, normal EOG Arden ratios, and no family history of Best's vitelliform dystrophy are presented. Their findings are compared with those in 10 similar reported cases, and a common, nongenetic aetiology is suggested for all. The several names given to this identical fundus picture by different authors are examined and are seen to be inappropriate. A common, descriptive terminology for all such lesions is suggested.