Lucilla Barbano

Objectives: Visual Evoked Potential (VEP) abnormalities in Friedreich Ataxia (FA) may result from dysfunction of retinal ganglion cells (RGC), post-retinal visual pathways, or both. Therefore, we aimed to clarify whether in Friedreich Ataxia (FA), abnormal neural conduction is due to dysfunctional RGC, impaired conduction along the post-retinal visual pathways, or both. The secondary aim of the study was to clarify the relationship between a possible RGC and/or post-retinal dysfunction and the patient’s age, age at disease onset, and disease duration. Method: Fourteen FA patients (14 eyes; mean age 38.64 ± 8.21 years) without functional or structural macular abnormalities, confirmed by multifocal electroretinogram (mfERG) and spectral domain–optical coherence tomography (SD-OCT), and 20 age-matched healthy controls were enrolled. Patients were classified as late-onset (FA1, disease onset > 25 years) or early-onset (FA2, disease onset < 25 years). All participants underwent comprehensive ophthalmological and neurological evaluations. RGC function and visual pathway conduction were assessed through simultaneous pattern electroretinogram (PERG) and VEP recordings using 60′ and 15′ checkerboard stimuli. Retino-cortical time (RCT) was calculated as the difference between VEP P100 and PERG P50 implicit times. Statistical analyses included a general linear model. Results: 60′ PERG amplitude (A) was significantly (p < 0.01) reduced in the FA group compared to the Control group. FA patients showed significantly delayed 60′ and 15′ VEP ITs and significantly increased 60′ and 15′ RCT values, particularly in the FA1 group. In late-onset patients, no significant relationships were found between age at onset of disease and all electrophysiological parameters (60′ and 15′ VEP and PERG ITs and As and RCTs). Conclusions: In our selected FA, RCG function and neural conduction along the post-retinal visual pathways are impaired. The abnormal neuronal conduction is greater in late-onset FA patients and is not related to patients’ age and the age at the onset of the disease. The duration of the disease has a slight effect on the post-retinal neural conduction on small optic nerve fibers.

Objectives: To evaluate the long-term effects on retinal structure and visual function of oral bromelain and curcumin supplementation in patients with inherited retinal dystrophies (IRD) complicated by persistent cystoid macular oedema (CMO). Methods: We retrospectively studied 20 eyes with genetically confirmed IRD complicated by CMO, with refractory to systemic or local treatments performed for 6 months. We collected baseline (V1) and follow-up (V2) data from these IRD-CMO patients, who were continuously supplemented with oral bromelain and curcumin for 12 months. Outcome measures were the Snellen best-corrected visual acuity (BCVA) and central macular thickness (CMT) values, collected by spectral-domain optical coherence tomography (OCT). Based on OCT scans, we classified IRD-CMO as microcystic or macrocystic, performing this sub-grouping in two eye cohorts (n = 10). Baseline median BCVA and CMT differences in both groups were verified (Mann–Whitney test). For both CMO groups, changes from V1 to V2 in median BCVA and CMT values were evaluated (Friedman test). Results: At baseline, both the median BCVA and CMT values were significantly different in both groups (p < 0.01 and p < 0.001). Between V1 and V2, in the microcystic CMO group, a slightly improved median BCVA was found, whereas the median CMT was reduced; however, this did not reach statistical significance (p = 0.6 and p = 0.2, respectively). In the macrocystic CMO group, a significant stable median BCVA was found from V1 to V2, with concomitant significant reduction in median CMT (p < 0.05 for both comparisons). Conclusions: Retinal structural improvement and visual function preservation were observed after oral bromelain and curcumin supplementation in macrocystic IRD-CMO. It is likely that the vasogenic component in macrocystic CMO is more responsive to nutraceutical molecules than the degenerative microcystic component.

Objectives: To evaluate the changes in retinal function and neural conduction along the visual pathways after 12 months of treatment with Citicoline oral solution in patients with open-angle glaucoma (OAG). Methods: In this randomized, prospective, double-blind study, 29 OAG patients were enrolled. Fifteen patients (Citicoline Group, 15 eyes) received Citicoline oral solution (Neurotidine^®, 500 mg/day), and 14 patients (Placebo Group, 14 eyes) received placebo for 12 months. Visual field (VF), pattern electroretinogram (PERG), visual evoked potentials (VEP), and Retinocortical Time (RCT) were assessed at baseline and after 6 and 12 months. Brain Diffusion Tensor Imaging (DTI)-Magnetic Resonance Imaging (MRI) was performed at baseline and at 12 months. Results: PERG, VEP, and RCT baseline values were comparable between groups (p > 0.01) at baseline. After 12 months of Citicoline treatment, significant (p < 0.01) increases in PERG P50–N95 and VEP N75-P100 amplitudes, and significant shortening of PERG P50, VEP P100 implicit times and RCT were observed. VEP implicit times shortening significantly correlated with the changes in VF Mean Deviation, and RCT shortening was associated with changes in DTI-MRI metrics in the lateral geniculate nucleus and on optic radiations, without reaching the level of significance. No significant changes were found in the Placebo Group. Conclusions: In OAG, Citicoline oral solution enhances retinal function likely through neuromodulation processes and changes post-retinal visual pathway connectivity. This could explain the improvement of visual field defects.

Background: Considering the lack of studies regarding the localized evaluation of the macular inner retina in multiple sclerosis patients without optic neuritis (MSnoON eyes), we investigated the structure and function of retinal ganglion cells (RGCs) located in different macular areas. Methods: In 24 MSnoON patients (mean age: 45.22 ± 5.57 years; 14 females and 10 males; mean MS disease duration: 11.07 ± 5.88 years) and in 30 age-similar (mean age: 45.09 ± 5.08 years) control subjects, complete ophthalmological examination, optical coherence tomography (OCT) and multifocal photopic negative response (mfPhNR) were performed. The ganglion cell layer thickness (GCL+-T) via OCT and the response amplitude density (RAD) through mfPhNR were measured from localized macular regions, including rings and Early Treatment of Diabetic Retinopathy Study (ETDRS) sectors. Results: When comparing MSnoON data from all tested areas with respect to the controls, macular GCL+-T and mfPhNR RAD mean values were found to be significantly (ANOVA, p < 0.01) reduced. In the MSonON group, considering both rings and sectors, the GCL+-T values were significantly and linearly correlated (Pearson’s test, p < 0.01) to the mfPhNR RAD values. Conclusions: In MS, even in the absence of optic neuritis, potential primary morpho-functional involvement of the inner macular elements can occur. This impairment widely involves all macular areas and sectors.

O-mannosylation is a post-translational modification required for the proper function of various proteins and critical for development and growth. POMGNT1 encodes the enzyme O-linked-mannose β-1,2-N-acetylglucosaminyltransferase 1, which catalyzes the second step in the synthesis of α-dystroglycan O-mannosyl glycans. Among POMGNT1-related α-dystroglycanopathies, muscle–eye–brain (MEB) disease presents with congenital muscular dystrophy, structural brain abnormalities, and retinal dystrophy. Defects in protein O-mannosylation due to biallelic loss-of-function POMGNT1 mutations produce disturbances in assembling and organizing the basal membrane in the neuroretinal system, involving both the central and peripheral nervous systems. In the retina, POMGNT1 is expressed in photoreceptors and is localized near the photoreceptor cilium basal body, a structure critical for protein transport. Recent studies have reported an isolated degenerative ocular phenotype without any involvement of muscular or neuronal tissues. Here, we report on a family with three siblings affected by an apparently isolated clinically variable retinal disease and sharing biallelic inactivating POMGNT1 variants. Notably, the rod-cone dystrophy phenotype in the three siblings varied significantly in onset, presentation, and severity. These findings provide further evidence of the clinical variability associated with defective POMGNT1 function.

Objectives: This study aimed to study the inner retina functional and morphological impairment of retinal ganglion cells (RGCs) from specific macular rings and sectors to identify whether selective macular regions were more vulnerable than others within the 20 central degrees in patients with open-angle glaucoma (OAG). Methods: In total, 21 OAG patients [mean age 50.19 ± 7.86 years, Humphrey Field Analyzer (HFA) 24-2 mean deviation (MD) between −5.02 and −22.38 dB, HFA 10-2 MD between −3.07 and −17.38 dB], providing 21 eyes, were enrolled in this retrospective case–control study. And 20 age-similar healthy subjects, providing 20 eyes, served as controls. The multifocal photopic negative response (mfPhNR) response amplitude density (RAD) from concentric rings and macular sectors and ganglion cell layer thickness (GCL-T) assessed by Spectral Domain–Optical Coherence Tomography (SD-OCT) was measured. Mean RAD and GCL-T values were compared between OAG and control ones by ANOVA. In OAG eyes, the relationship between mfPhNR and SD-OCT data was examined by linear regression analysis, and Pearson’s correlation coefficients were computed. Results: In considering all rings and sectors, compared to the controls, the OAG group showed a significant (p < 0.01) reduction in mean mfPhNR RAD and in GCL-T values with the greatest reduction in the central area. In OAG eyes, a significant (p < 0.01) correlation between all mfPhNR RAD and GCL-T values, with significant (p < 0.01) correlation coefficients, were found. Conclusions: In OAG eyes, RGC dysfunction was detectable by abnormal mfPhNR responses in localized macular areas, mainly in the central one. Localized macular RGC dysfunction was linearly correlated with the GCL morphological changes.

Bardet–Biedl syndrome (BBS) is a rare recessive multisystem disorder characterized by retinitis pigmentosa, obesity, postaxial polydactyly, cognitive deficits, and genitourinary defects. BBS is clinically variable and genetically heterogeneous, with 26 genes identified to contribute to the disorder when mutated, the majority encoding proteins playing role in primary cilium biogenesis, intraflagellar transport, and ciliary trafficking. Here, we report on an 18-year-old boy with features including severe photophobia and central vision loss since childhood, hexadactyly of the right foot and a supernumerary nipple, which were suggestive of BBS. Genetic analyses using targeted resequencing and exome sequencing failed to provide a conclusive genetic diagnosis. Whole-genome sequencing (WGS) allowed us to identify compound heterozygosity for a missense variant and a large intragenic deletion encompassing exon 12 in BBS9 as underlying the condition. We assessed the functional impact of the identified variants and demonstrated that they impair BBS9 function, with significant consequences for primary cilium formation and morphology. Overall, this study further highlights the usefulness of WGS in the diagnostic workflow of rare diseases to reach a definitive diagnosis. This report also remarks on a requirement for functional validation analyses to more effectively classify variants that are identified in the frame of the diagnostic workflow.

We investigated the potential correlation between morphological and functional parameters describing the rarefaction and dysfunction of retinal ganglion cells (RGCs), located in the macula, in multiple sclerosis eyes with a history of optic neuritis (MS-ON). A total of 19 MS-ON eyes from 19 MS patients (mean age: 44.16 ± 4.66 years; 11 females and 8 males), with a mean disease duration of 10.06 ± 6.12 years and full recovery of visual acuity, and 30 age-similar (mean age: 45.09 ± 5.08 years) healthy eyes were submitted for ophthalmological evaluation using swept-source optical coherence tomography (SS-OCT) and multifocal photopic negative response (mfPhNR) to study the structural and functional features of localized RGCs. Both GCL+ thickness (via SS-OCT) and response amplitude density (RAD) (via mfPhNR) measurements were obtained from annular regions and ETDRS sectors. Morphological and electrophysiological data from the control and MS groups were compared by using an ANOVA test. GCL+ values were correlated with the corresponding RADs derived from almost superimposable areas using Pearson’s tests (p < 0.01). In MS-ON eyes, the mean values of macular GCL+-T and mfPhNR RAD detected in all rings and ETDRS sectors were significantly reduced (p < 0.01) when compared with control ones. In addition, when plotting the GCL+-T and mfPhNR RAD individual data from MS-ON eyes, we found statistically significant linear correlations (p < 0.01) when considering responses from both rings and sectors. In conclusion, in MS-ON eyes, a topographical correlation between structural and functional impairment of macular RGCs occurs.

The aim of this study was to assess the morpho-functional involvement of the retinal ganglion cells (RGCs) and of the visual pathways in patients with superficial (ODD-S) or deep (ODD-D) optic disc drusen. This study enrolled 17 patients with ODD (mean age of 59.10 ± 12.68 years) providing 19 eyes and 20 control subjects (mean age 58.62 ± 8.77 years) providing 20 eyes. We evaluated the following: best-corrected visual acuity, visual field mean deviation (MD), the amplitude (A) of Pattern Electroretinogram (PERG), the implicit time (IT) and A of Visual Evoked Potentials (VEPs), retinal nerve fiber layer thickness (RNFL-T) and ganglion cell thickness (GC-T). In ODD-S eyes, the drusen visible height was measured. ODD-D and ODD-S were detected in 26.3% and 73.7% of ODD eyes, respectively. Significantly (p < 0.01) reduced MD, PERG A, VEP amplitude, RNFL-T and GC-T values and significantly (p < 0.01) increased VEP IT values were found in the ODD Group as compared to the Control one. In the ODD Group, no significant correlation (p > 0.01) between PERG As and VEP ITs was found. In ODD-S, the visible height was significantly correlated (p < 0.01) with reduced MD, PERG As and RNFL-T and with increased PSD and VEP IT values. Our findings suggest that ODD might induce morpho-functional changes in RGCs and their fibers and an unrelated visual pathway dysfunction leading or not leading to visual field defects. The observed morpho-functional impairment should be ascribed to an alteration in retrograde (from the axons to the RGCs) and anterograde (from the RGCs up to the visual cortex) axoplasmic transport. In ODD-S eyes, a minimum visible height of 300 microns represented the threshold for the abnormalities, suggesting that “the higher the ODD, the worse the impairment”.

Friedreich’s ataxia (FRDA) is a rare autosomal recessive neurodegenerative disorder due to the homozygous pathological expansion of guanine-adenine-adenine (GAA) triplet repeats in the first intron of the FXN gene, which encodes for the mitochondrial protein frataxin. In the visual system, the typical manifestations are ocular motility abnormality, optic neuropathy, and retinopathy. Despite the evidence of ophthalmological impairment in FRDA patients, there is a lack of information about the morpho-functional condition of the retina and of the optic pathways in healthy heterozygous carriers of Friedreich’s ataxia (C-FRDA). Ten C-FRDA subjects (providing 20 eyes) and thirty-five Controls (providing 70 eyes) underwent a complete neurological and ophthalmological examination comprehensive of functional (full-field Electroretinogram (ffERG), multifocal Electroretinogram (mfERG), Visual Evoked Potential (VEP), and Pattern Reversal Electroretinogram (PERG)) and morphological assessments (Optical Coherence Tomography, OCT) of the retina, macula, retinal ganglion cells, and visual pathways. The groups’ data were compared using a two-sample t-test. Pearson’s test was used to investigate the morpho-functional correlations. Statistically significant differences (p < 0.01) between C-FRDA and Control eyes for the values of the following parameters were found: ffERG b-wave amplitude, mfERG Response Amplitude Densities, PERG P50 implicit time and P50-N95 amplitude, VEP P100 implicit time, Retinal Nerve Fiber Layer (RNFL) Overall, and Nasal thickness. The values of the OCT macular volume were not statistically different (p > 0.01) between the two Groups. Therefore, our data suggest that, in C-FRDA, a dysfunction of retinal elements without morphological macular impairment may occur. In addition, a morphological impairment of RNFL associated with an abnormal neural conduction along the visual pathways can be also detected.