Slope between positive and negative ERG components in patients with open-angle glaucoma.

PURPOSE: To evaluate ERG morphology, in particular the slope between P50 and N95 components of the PERG, as well as between the b-wave and the photopic negative response (PhNR) of the light-adapted (LA) ERG in patients with retinal ganglion cell (RGC) dysfunction due to open-angle glaucoma. METHODS: The PERG and LA-ERG traces of 16 glaucoma patients and 21 age-similar controls were retrospectively analysed. The ERG signal between the peak of the positive component (P50 and b-wave) towards the negative component (N95 and PhNR) was described by a linear regression y = a + bx, where the parameter b indicated the steepness of the P50-N95 and b-PhNR slope. RESULTS: The P50-N95 slope was less steep in glaucoma patients (-0.079 ± 0.034 vs. -0.166 ± 0.050 in controls, p < 0.001), while the b-PhNR slope was not affected (-4.2 ± 2.1 vs. -4.4 ± 1.2, p = NS). The P50-N95 slope showed strong correlation with PhNR and N95 amplitude (r = -0.68 and -0.92, respectively; p < 0.001), while the b-PhNR slope correlated only with b-wave amplitude (r = -0.66, p < 0.001). CONCLUSIONS: The P50-N95 slope is a sensitive indicator of RGC dysfunction in patients with open-angle glaucoma. A similar component of LA-ERG, the b-PhNR slope, is less affected by glaucomatous RGC dysfunction and probably originates from similar retinal mechanisms as the b-wave.

Retinal Ganglion Cell Function and Perfusion following Intraocular Pressure Reduction with Preservative-Free Latanoprost in Patients with Glaucoma and Ocular Hypertension.

(1) Background: Given the global prevalence of glaucoma and the crucial role of intraocular pressure (IOP) reduction in the management of the disease, understanding the immediate effects on retinal structure and function is essential. (2) Methods: This study aimed to assess the effects of preservative-free latanoprost on morphological and functional parameters in treatment-naïve patients with ocular hypertension and open-angle glaucoma. (3) Results: This study showed a significant reduction in IOP by an average of 30.6% after treatment with preservative-free latanoprost. Despite the significant reduction in IOP, no statistically significant changes were observed in the electroretinogram (ERG) nor the optical coherence tomography/angiography (OCT/OCTA) parameters compared to baseline. An exploration of the correlation between IOP changes and various parameters revealed a significant association solely with the macular IPL/INL plexus vessel density (VD) measured with OCTA. (4) Conclusions: This finding suggests a possible association between IOP reduction and changes in the macular microcirculation and provides valuable insights into the differential effects of latanoprost. Acknowledging the study limitations, this study emphasizes the need for larger, longer-term investigations to comprehensively assess the sustained effects of preservative-free latanoprost on both IOP and retinal parameters. In addition, exploring systemic factors and conducting subgroup analyses could improve personalized approaches to glaucoma treatment.

Electroretinographic oscillatory potentials in Leber hereditary optic neuropathy.

PURPOSE: Leber hereditary optic neuropathy (LHON) affects retinal ganglion cells causing severe vision loss. Pattern electroretinogram and photopic negative response (PhNR) of the light-adapted (LA) full-field electroretinogram (ERG) are typically affected in LHON. In the present study, we evaluated dark-adapted (DA) and LA oscillatory potentials (OPs) of the flash ERG in genetically characterized LHON patients to dissociate slow from fast components of the response. METHODS: Seven adult patients (mean age = 28.4 ± 5.6) in whom genetic diagnosis confirmed LHON with mtDNA or nuclear DNAJC30 (arLHON) pathogenic variants were compared to 12 healthy volunteers (mean age = 35.0 ± 12.1). Full-field ERGs were recorded from both eyes. Offline digital filters at 50, 75 and 100 Hz low cutoff frequencies were applied to isolate high-frequency components from the original ERG signals. RESULTS: ERG a-waves and b-waves were comparable between LHON patients and controls, while PhNR was significantly reduced (p = 0.009) in LHON patients compared to controls, as expected. OPs derived from DA signals (75 Hz low cutoff frequency) showed reduced peak amplitude for OP2 (p = 0.019). LA OP differences between LHON and controls became significant (OP2: p = 0.047, OP3: p = 0.039 and OP4: p = 0.013) when the 100 Hz low-cutoff frequency filter was applied. CONCLUSIONS: Reduced OPs in LHON patients may represent disturbed neuronal interactions in the inner retina with preserved photoreceptoral (a-wave) to bipolar cell (b-wave) activation. Reduced DA OP2 and high-cutoff LA OP alterations may be further explored as functional measures to characterize LHON status and progression.

Morphological and Functional Correlations in Acute Central Serous Chorioretinopathy.

PURPOSE: We evaluate morphological and functional correlations in patients with acute central serous chorioretinopathy (CSC). METHODS: A prospective study was conducted on 50 patients with an acute CSC episode lasting less than 3 months. At baseline, assessments included optical coherence tomography (OCT), best-corrected visual acuity (BCVA), contrast sensitivity (CS), microperimetry (MP), and multifocal electroretinography (mfERG). A correlation analysis between OCT morphological parameters (maximal subretinal fluid height (SRF), central retinal thickness (CRT), and macular volume (MV)) and functional parameters was conducted on the affected eye for each patient. RESULTS: Among the morphological parameters, SRF showed the strongest correlations with functional parameters (r absolute value range = 0.10-0.70). Weak correlations were observed between BCVA and morphological parameters (r absolute value range = 0.14-0.26). Average retinal sensitivity (MP-A) was the functional parameter displaying the most robust negative correlation with morphological parameters (r absolute value range = 0.61-0.70). In contrast, average contrast sensitivity (CS-A) and mfERG average amplitude density in the first (mfERG-A1) and second (mfERG-A2) ring showed weak to moderate (r absolute value range = 0.35-0.56) yet statistically significantly nonzero correlations. CONCLUSIONS: SRF and CRT could serve as the most representative morphological proxies for visual function deficit in acute CSC patients. Retinal sensitivity, as measured by MP, may be superior to BCVA in clinical research studies or when an in-depth visual function evaluation is needed.

Leber Hereditary Optic Neuropathy (LHON) in Patients with Presumed Childhood Monocular Amblyopia.

BACKGROUND: Most Leber hereditary optic neuropathy (LHON) cases are bilateral and sequential; however, there are rare unilateral examples, or those in which the delay of onset of vision loss between one and the other eye is longer. In the case of presumed childhood amblyopia in one eye, vision loss in the good eye may be the only symptom of bilateral disease, which was unnoticed in the previously amblyopic eye, or a preexisting episode of LHON in the "amblyopic" eye. The clinical decision in such cases may be difficult and suggestive of other forms of atypical optic neuropathy until confirmed by genetic testing. CASE SERIES: We present three genetically confirmed (MT-ND1:m.3700G>A, MT-ND6:m14484 T>C, and MT-ND4:m.11778G>A) patients with subacute vision loss in the previously good eye, with the other eye believed to be amblyopic from childhood and their features different from what would be expected in true amblyopia. In all, electrophysiology testing showed a bilaterally reduced amplitude of PERG with low VEP P100 wave amplitudes and prolonged peak time in both eyes, also unusual for amblyopia. During follow-up, the pallor of the optic discs progressed in all eyes. Significant thinning of the peripapillary retinal nerve fiber layer (pRNFL; retinal nerve fiber layer around the optic disc) and ganglion cell complex (GCC) in the macular region was present. All three patients had a peculiar history. The first patient was treated for presumed hyperopic amblyopia that did not improve since childhood, experienced visual loss in the good eye at the age of 17, and was negative for the three typical LHON mutations. Extended testing confirmed an atypical pathogenic variant MT-ND1:m.3700G>A in homoplasmy. The second patient with presumed strabismic amblyopia had an unusual presentation of vision loss only at the age of 61, and after the exclusion of other causes, a typical MT-ND4:m.11778G>A pathogenic variant was found in homoplasmy. The third case was peculiar as he had presumed strabismic amblyopia since childhood and had some degree of disc pallor in the amblyopic eye upon presenting with loss of vision in the good eye at the age of 21, and a typical pathogenic variant m14484 T>C, p.Met64Val was subsequently confirmed. However, one year after disease onset, he started to experience significant spontaneous functional improvement in the non-amblyopic up to 1.0 Snellen whilst improvement in the presumed amblyopic eye was modest, suggesting preexisting amblyopia. This interestingly extensive improvement was carefully followed by electrophysiology as well as visual acuity and fields. CONCLUSIONS: This report shows three different scenarios of presentation of LHON in patients with presumed uniocular amblyopia from childhood. In such cases, the diagnosis may be difficult, and detailed structural and functional evaluation of the optic nerve head is necessary to assess whether an earlier LHON episode was misdiagnosed as amblyopia or whether LHON presented bilaterally on both eyes whilst only being noticed in the previously good eye.

Natural History of Stargardt Disease: The Longest Follow-Up Cohort Study.

Long-term natural history studies are important in rare disease research. This study aimed to assess electrophysiological and fundus autofluorescence (FAF) progression rate in 18 genetically confirmed Stargardt disease (STGD1) patients with a minimum follow-up of 10 years. Age at the first and last exams, age at onset, Snellen decimal visual acuity (VA), electroretinography (ERG), and FAF images were evaluated. Patients were classified into four Fishman stages and three electroretinography groups, and areas of definitely decreased autofluorescence (DDAF) were measured. Patients were further substratified based on genotype, and phenotype-genotype correlations were performed. The median follow-up was 18 (range 10-26) years. The median yearly VA loss was 0.009 (range 0.002-0.071), while the median progression rate of the DDAF area was 0.354 (range 0.002-4.359) mm2 per year. Patients harbouring p.(Gly1961Glu) or p.(Asn1868Ile) allele had significantly slower DDAF area progression when compared to patients with other genotypes (0.07 mm2 vs. 1.03 mm2, respectively), as well as significantly later age at onset (20 years vs. 13 years, respectively). Results showed that structural and functional parameters, together with genotype, should be considered when counselling patients regarding prognosis and monitoring disease progression. Patients harbouring hypomorphic variants p.(Gly1961Glu) or p.(Asn1868Ile) presented with overall milder disease than patients with other genotypes.

Analysis of the slope between P50 and N95 waves of the large field pattern electroretinogram as an additional indicator of ganglion cell dysfunction.

AIM: Dysfunction of the retinal ganglion cells (RGC) can be detected by the pattern electroretinogram (PERG) as a reduction of the N95 amplitude, a decrease of the ratio between N95 and P50 amplitude and/or a shortening of P50 peak time. Additionally, the slope from the top of the P50 towards the N95 (P50-N95 slope) is less steep than in control subjects. The aim of the study was to quantitatively evaluate this slope in large field PERGs in controls and patients with RGC dysfunction due to optic neuropathy. SUBJECTS AND METHODS: Large field (21.6°X27.8°) PERGs and optical coherence tomography (OCT) data from 30 eyes of the 30 patients with different types of clinically confirmed optic neuropathies, and with P50 amplitudes within normal limits and abnormal PERG N95 were retrospectively analysed and compared to 30 healthy eyes of 30 control subjects. The P50-N95 slope was analysed with a linear regression from 50 to 80 ms after the stimulus reversal. RESULTS: The patients with optic neuropathy exhibited a significant reduction of the N95 amplitude (p < 0.001) and N95/P50 ratio (p < 0.001), the P50 peak time was mildly shorter (p = 0.03). The P50-N95 slope was significantly less steep in eyes with optic neuropathies (- 0.089 ± 0.029 vs. - 0.220 ± 0.041, p < 0.001). Thickness of temporal RNFL and the P50-N95 slope appeared to be the most sensitive and specific parameters for detecting RGC dysfunction (AUC = 1.0). CONCLUSIONS: The slope between the P50 and N95 waves of a large field PERG is considerably less steep in patients with RGC dysfunction and could thus be an efficient biomarker, particularly in the diagnosis of early or borderline cases.

Leber Hereditary Optic Neuropathy in a Family of Carriers of MT-ND5 m.13042G>T (A236S) Novel Variant.

BACKGROUND: A Slovenian three-generation family with 3 individuals with bilateral optic neuropathy and 2 unaffected relatives with a novel homoplasmic missense variant m.13042G > T (A236S) in the ND5 gene is described. A detailed phenotype at initial diagnosis and a follow-up of bilateral optic neuropathy progression is presented for 2 affected individuals. METHODS: A detailed phenotype analysis with clinical examination in the early and chronic phase with electrophysiology and OCT segmentation is presented. Genotype analysis with full mitochondrial genome sequencing was performed. RESULTS: Two affected male individuals (maternal cousins) had a profound visual loss at an early age (11 and 20 years) with no recovery. The maternal grandmother exhibited bilateral optic atrophy with a history of visual loss at the age 58 years. The visual loss of both affected male individuals was characterized by centrocecal scotoma, abnormal color vision, abnormal PERG N95, and VEP. Later with disease progression, retinal nerve fiber layer thinning was observed on OCT. We observed no other extraocular clinical features. Mitochondrial sequencing identified a homoplasmic novel variant m.13042G > T (A236S) in the MT-ND5 gene, belonging to a haplogroup K1a. CONCLUSIONS: Novel homoplasmic variant m.13042G > T (A236S) in the ND5 gene in our family was associated with Leber hereditary optic neuropathy-like phenotype. However, predicting the pathogenicity of a novel ultra-rare missense variant in the mitochondrial ND5 gene is challenging. Genetic counseling should consider genotypic and phenotypic heterogeneity, incomplete penetrance, haplogroup type, and tissue-specific thresholds.

Correlation between the Serum Concentration of Vitamin A and Disease Severity in Patients Carrying p.G90D in RHO, the Most Frequent Gene Associated with Dominant Retinitis Pigmentosa: Implications for Therapy with Vitamin A.

The pathogenic variant p.G90D in RHO is believed to be responsible for a spectrum of phenotypes, including congenital stationary blindness (for the purpose of this study termed night blindness without degeneration; NBWD), Sector RP, Pericentral RP, and Classic RP. We present a correlation between the serum concentration of vitamin A and disease severity in patients with this variant. This prospective study involved 30 patients from 7 families (17 male; median age 46 years, range 8−73). Full ophthalmological examination including visual acuity, Goldmann perimetry, slit-lamp exam, optical coherence tomography, fundus autofluorescence, and electrophysiology was performed to determine the presenting phenotype. The serum concentration of vitamin A was determined from a fasting blood sample taken on the day of the exam, where it was found that 23.3% (7/30) of patients had NBWD, 13.3% (4/30) had Sector RP, 3.3% (1/30) had Pericentral RP, and 60% (18/30) had Classic RP. Multiple logistic regression revealed a significantly higher probability of having a milder phenotype (NBWD or Sector RP) in association with younger age (p < 0.05) and a higher concentration of vitamin A (p < 0.05). We hypothesize that vitamin A in its 11-cis-retinal form plays a role in stabilizing the constitutively active p.G90D rhodopsin and its supplementation could be a potential treatment strategy for p.G90D RHO patients.

The role of visual electrodiagnostics in management of children with neurofibromatosis type 1.

PURPOSE: To evaluate the role of visual electrodiagnostic testing in children with neurofibromatosis type 1 (NF1) despite improved accessibility to magnetic resonance imaging (MRI). METHODS: The records from 39 children (78 eyes, 15 boys, 24 girls, average age at last visit of 11.5 ± 4.3 years, average follow-up time of 7.8 ± 3.9 years) with genetically confirmed NF1 were retrospectively analysed. They all underwent a thorough ophthalmological investigation, including age-appropriate visual acuity testing, anterior segment evaluation for Lisch nodules and a dilated fundus examination. If children were cooperative enough, colour vision was tested using the Hardy-Rand-Rittler test, visual fields were evaluated with Goldmann perimetry. All performed MRI of the brain and orbits as part of the standard of care protocol. Visual electrodiagnostics included electroretinography (ERG) and visual evoked potentials (VEP) using a standard protocol in older children, whereas with less cooperative children a modified protocol according to the Great Ormond Street Hospital (GOSH protocol) was used. RESULTS: The average visual acuity was 0.8 ± 0.3, colour vision was abnormal in 6%, perimetry in 8%, Lisch nodules were present in 62%, and the optic disc was pale in 66% of all eyes. Plexiform neurofibroma of the eyelid/orbit was present in 4%. Optic pathway glioma (OPG) was detected with MRI in 22 (57%) and in 6/22 treatment was indicated. Other intracranial NF1-related lesions were documented in 70% of children. VEP were abnormal in 16/39 of all children with NF1 (41%) comprising 14/22 (65%) of children with confirmed OPG and 2/17 (12%) of children without OPG. All full-field and pattern ERG responses were within normal limits. All individual VEP results are described and three cases from this cohort of children are presented in detail to illustrate the importance of VEP testing. In Case 1, VEP abnormality suggested subsequent MRI of the brain under general anaesthesia, which was otherwise contraindicated according to normal clinical findings and his young age. In Cases 2 and 3, VEP provided more precise functional information during the follow-up of OPG, while other psychophysical tests remained unchanged. CONCLUSIONS: Electrodiagnostics has multifactorial role and importance in children with NF1, either when visual pathway function is impaired in young children, even before MRI under general anaesthesia and other psychophysical tests can be performed, as well as for a more precise monitoring of the visual pathway function before potential treatment of OPG, or after it, to evaluate its success.

Case report: Long-term follow-up of two patients with LHON caused by DNAJC30:c.152G>A pathogenic variant-case series.

Background: We present the disease course and long-term follow-up of two patients who were phenotypically diagnosed with atypical Leber Hereditary Optic Neuropathy (LHON) 14 and 12 years ago, respectively, whereby whole exome sequencing revealed recently described recessive DNAJC30:c.152G>A 152 A>G (p.Tyr51Cys) homozygous pathogenic variant with significant spontaneous visual acuity recovery in one. Case presentation: Two presented unrelated males with atypical LHON with sequential visual acuity (VA) loss were followed for many years. Both patients had negative family history. At the presentation at ages 17 (Case 1) and 18 years (Case 2), both had reduced visual acuity (Snellen): (Case 1) right eye (RE):CF 3m, left eye (LE):0.6, (Case 2) RE:0.2, LE:0.15; and color vision (Ishihara): (Case 1) 1/15 and 13/15; (Case 2) 2/15 and 3/15. Both had hyperemic optic disks (PNO) and central scotoma in their visual fields. Electrophysiology in the acute phase showed reduced and delayed visually evoked potentials (VEP) P100 in both patients, with reduced N95 amplitude in Case 2, and initially normal N95 amplitude in Case 1. Fluorescein angiography showed no early leakage with some late pooling at optic disks. Extensive clinical workout, including brain magnetic resonance imaging (MRI), aquaporin 4 (Aq4), and anti-myelin oligodendrocyte protein (anti-MOG) antibodies, was negative. Intravenous corticosteroids did not improve vision. Both experienced further deterioration several months after the onset accompanied by thinning of the peripapillary retinal nerve fiber layer (RNFL). Genetic testing for typical LHON pathogenic variants and whole mitochondrial DNA (mtDNA) sequencing was negative. 1 year after the onset, modest VA improvement began in Case 2 and continued over the next 3 years. VA improved bilaterally to 0.7, color vision 15/15, and islands of vision appeared within the visual field scotoma. VEP P100 peak time shortened, and amplitude increased, despite further RNFL thinning on optical coherent tomography (OCT). The patient's visual function remained stable during the entire 12-year follow-up period. Case 1 experienced modest VA improvement to 0.1 with some improvement in the visual field seven years after the disease onset, remaining stable during the entire 14-year follow-up period. VEP P100 wave remained undetectable. Conclusions: Presented are two autosomal recessive LHON (arLHON, OMIM:619382) cases with the same DNAJC30:c.152G>A pathogenic variant and different degrees of spontaneous visual recovery despite progressive RNFL thinning during a long-term follow-up. This mutation should be screened in every atypical LHON patient.

The Relative Preservation of the Central Retinal Layers in Leber Hereditary Optic Neuropathy.

(1) Background: The purpose of this study was to evaluate the thickness of retinal layers in Leber hereditary optic neuropathy (LHON) in the atrophic stage compared with presumably inherited bilateral optic neuropathy of unknown cause with the aim of seeing if any LHON-specific patterns exist. (2) Methods: 14 patients (24 eyes) with genetically confirmed LHON (LHON group) were compared with 13 patients (23 eyes) with negative genetic testing results (mtDNA + WES) and without identified etiology of bilateral optic atrophy (nonLHON group). Segmentation analysis of retinal layers in the macula and peripapillary RNFL (pRNFL) measurements was performed using Heidelberg Engineering Spectralis SD-OCT. (3) Results: In the LHON group, the thickness of ganglion cell complex (GCC) (retinal nerve fiber layer (RNFL)­ganglion cell layer (GCL)­inner plexiform layer (IPL)) in the central ETDRS (Early Treatment Diabetic Retinopathy Study) circle was significantly higher than in the nonLHON group (p < 0.001). In all other ETDRS fields, GCC was thinner in the LHON group. The peripapillary RNFL (pRNFL) was significantly thinner in the LHON group in the temporal superior region (p = 0.001). Longitudinal analysis of our cohort during the follow-up time showed a tendency of thickening of the RNFL, GCL, and IPL in the LHON group in the central circle, as well as a small recovery of the pRNFL in the temporal region, which corresponds to the observed central macular thickening. (4) Conclusions: In LHON, the retinal ganglion cell complex thickness (RNFL-GCL-IPL) appears to be relatively preserved in the central ETDRS circle compared to nonLHON optic neuropathies in the chronic phase. Our findings may represent novel biomarkers as well as a structural basis for possible recovery in some patients with LHON.

The Clinical Spectrum and Disease Course of DRAM2 Retinopathy.

Pathogenic variants in DNA-damage regulated autophagy modulator 2 gene (DRAM2) cause a rare autosomal recessive retinal dystrophy and its disease course is not well understood. We present two Slovenian patients harboring a novel DRAM2 variant and a detailed review of all 23 other patients described to date. Whole exome and whole genome sequencing were performed in the two patients, and both underwent ophthalmological examination with a 2-year follow-up. PubMed was searched for papers with clinical descriptions of DRAM2 retinopathy. Patient 1 was homozygous for a novel variant, p.Met1?, and presented with the acute onset of photopsia and retina-wide retinopathy at the age of 35 years. The patient was first thought to have an autoimmune retinopathy and was treated with mycophenolate mofetil, which provided some symptomatic relief. Patient 2 was compound heterozygous for p.Met1? and p.Leu246Pro and presented with late-onset maculopathy at the age of 59 years. On review, patients with DRAM2 retinopathy usually present in the third decade with central visual loss, outer retinal layer loss on optical coherence tomography and a hyperautofluorescent ring on fundus autofluorescence. Either cone-rod or rod-cone dystrophy phenotype is observed on electroretinography, reflecting the importance of DRAM2 in both photoreceptor types. Non-null variants can result in milder disease.