Visual function in children with Joubert syndrome.

AIM: To describe visual function in children with Joubert syndrome and to investigate its possible association with diagnostic and developmental aspects. METHOD: This retrospective cross-sectional work included 59 patients (33 male; mean age 9 years 2 months, standard deviation 6 years 3 months, range 4 months to 23 years) diagnosed with Joubert syndrome from January 2002 to December 2020. Data about clinical (neurological, neuro-ophthalmological, developmental/cognitive) and diagnostic (e.g. genetic testing, neuroimaging, systemic involvement) evaluations were collected in a data set during a review of medical records. Clinical and diagnostic variables were described in terms of raw counts and percentages. A χ2 test was conducted to investigate their association with neuropsychological skills. RESULTS: Ocular motor apraxia was highly represented in our cohort (75%), with a high prevalence of refractive defects and retinal abnormalities. Developmental delay/intellectual disability was frequent (in 69.5% of the sample), associated with retinal dystrophy (p = 0.047) and reduced visual acuity both for near (p = 0.014) and for far distances (p = 0.017). INTERPRETATION: On the basis of the relevance of oculomotor and perceptual alterations and their impact on overall and cognitive impairment, we encourage early and multidisciplinary assessment and follow-up of visual function in children with Joubert syndrome. This would help in planning a personalized rehabilitation to sustain functional vision. Further studies will be important to explore the link between biological aspects and global functioning in children with Joubert syndrome. WHAT THIS PAPER ADDS: Perceptual deficits and oculomotor impairments frequently coexist in Joubert syndrome. Retinal dysfunction may be present despite the absence of funduscopic abnormalities. Both perceptual and oculomotor impairments negatively affect cognitive development in Joubert syndrome.

Multicenter, Prospective, Randomized, Single Blind, Cross-Over Study on the Effect of a Fixed Combination of Citicoline 500 mg Plus Homotaurine 50 mg on Pattern Electroretinogram (PERG) in Patients With Open Angle Glaucoma on Well Controlled Intraocular Pressure.

Purpose: To evaluate the potential beneficial and synergistic effects of oral intake of a fixed combination of citicoline 500 mg plus homotaurine 50 mg (CIT/HOMO) on retinal ganglion cell (RGC) function in subjects with glaucoma using pattern electroretinogram (PERG) and to investigate the effects on visual field and quality of life. Methods: Consecutive patients with primary open-angle glaucoma with controlled IOP (<18 mmHg) receiving beta-blockers and prostaglandin analogs alone or as combination therapy (fixed or un-fixed); with stable disease (progression no more than -1 dB/year at the visual field MD); and an early to moderate visual field defect (MD < -12 dB) were randomized to: arm A. topical therapy + CIT/HOMO for 4 months, 2 months of wash out, 4 months of topical therapy alone; arm B. topical therapy alone for 4 months, topical therapy + CIT/HOMO for 4 months, 2 months of wash out. All patients underwent 4 visits: complete ocular examination, visual field, PERG and quality of life assessment (NEI-VFQ25) were performed at each visit. Results: Fifty-seven patients completed the study: 26 in group A and 31 in group B. At the end of the intake period, PERG's P50 and N95 waves recorded a greater amplitude. The increase was statistically significant in the inferior and superior P50 waves amplitude: 0.47 µV (95%CI, 0.02-0.93; p = 0.04) and 0.65 µV (95% CI, 0.16-1.13; p = 0.009), respectively, and in the inferior N95 wave amplitude 0.63 µV (95% CI, 0.22-1.04; p = 0.002). A significantly shorter peak time of 3.3 µV (95% CI, -6.01- -0.54; p = 0.01) was observed for the superior P50 wave only. Conclusions: Daily oral intake of the fixed combination CIT/HOMO for 4 months improved the function of inner retinal cells recorded by PERG in the inferior and in the superior quadrants, independently from IOP reduction. This interesting association could represent a valid option for practicing neuromodulation in patients with glaucoma to prevent disease progression.

Neurodevelopmental Profile in Children Affected by Ocular Albinism.

AIM: The aim of this study was to detail the neurodevelopmental profile of subjects affected by ocular albinism (OA) and to collect data on GPR143 gene analysis. DESIGN: The design of the study involves a retrospective longitudinal observational case series. METHODS: We collected data on the neurodevelopmental profile of 13 children affected by OA from clinical annual assessments conducted for a period of 6 years after the first evaluation. We described visual profile, neuromotor development and neurological examination, cognitive profile, communication and language skills and behavioral characteristics. The GPR143 gene analysis was performed as well. RESULTS: Children presented a variable combination of ocular and oculomotor disorders unchanged during the follow-up, a deficit in visual acuity and in contrast sensitivity that progressively improved. Abnormalities in pattern visual evoked potential were found. No deficits were detected at neurological examination and neuromotor development except for a mild impairment in hand-eye coordination observed in five cases. A language delay was observed in five cases, two of whom had also a developmental quotient delay at 2 years evolving to a borderline/deficit cognitive level at preschool age, difficulties in adaptive behavior and autistic-like features were found. Mutations in the GPR143 gene were identified in the two patients who presented the most severe clinical phenotype. CONCLUSION: Children with OA may share, in addition to a variable combination of ocular signs and symptoms, a neurodevelopment impairment regarding mostly the cognitive, communicative, and social area, especially those with GPR143 mutation.

Visual Evoked Potentials in Joubert Syndrome: A Suggested Useful Method for Evaluating Future Approaches Targeted to Improve Visual Pathways' Function.

INTRODUCTION: Joubert syndrome (JS) is a recessive disorder characterized by a congenital malformation of the mid-hindbrain and a large spectrum of clinical features including optic nerve morphologic abnormalities. The function of the visual pathways, including the optic nerve, can be objectively evaluated by visual evoked potential (VEP) recordings. Our work aims to employ VEP to evaluate the neural conduction along the visual pathways in JS patients with or without optic nerve morphologic abnormalities (ONMA). METHODS: In this observational and prospective study, 18 children with genetic diagnosis of JS (mean age 8.78 ± 5.87 years) and 17 healthy age-similar control subjects (control group, 9.05 ± 6.02 years) were enrolled. Based on presence/absence of ONMA at fundus examination, JS patients were divided into two groups: the JS-A group (eight patients with ONMA) and JS-N group (ten patients without ONMA). Following the ISCEV standards, pattern VEPs were recorded in patients and controls in response to 60' and 15' checks to obtain a prevalent activation of large or small axons, respectively. RESULTS: Compared to controls, both the JS-A and JS-N groups showed significant abnormalities in 60' and 15' VEP implicit time and amplitude. Only in the JS-N group were values of 15' VEP implicit significantly correlated with the corresponding values of visual acuity. CONCLUSIONS: Our results suggest that a visual pathways dysfunction (of both large and small axons) detectable by VEP may occur in JS patients regardless of the presence of ONMA. Since clinical trials are envisaged in the near future to address JS-related ocular problems, our results might provide information about the potential usefulness of VEP recordings to assess the efficacy of treatments targeted to improve the visual pathways' function.

Electroretinographic Assessment in Joubert Syndrome: A Suggested Objective Method to Evaluate the Effectiveness of Future Targeted Treatment.

INTRODUCTION: Joubert syndrome (JS) is an autosomal recessive disorder characterized by a congenital malformation of the mid-hindbrain and a large spectrum of clinical features including congenital retinal dystrophy. The function of different retinal elements (rod, cone, bipolar cells) can be objectively evaluated by electroretinogram (ERG) recordings. Our work aims to evaluate the retinal function (by ERG recordings) in patients with JS with or without congenital retinal dystrophy. In addition, since clinical trials should be performed in the near future in JS, our results could provide information about the possible usefulness of ERG recordings in the assessment of the efficacy of treatments targeted to improve the retinal involvement. METHODS: In this observational and prospective study, 24 children with genetic identification for JS (mean age 10.75 ± 6.59 years) and 25 healthy age-similar normal control subjects (control group, mean age 10.55 ± 3.76 years) were enrolled. On the basis of the presence/absence of retinal dystrophy at fundus examination, patients with JS were divided into two groups: patients with JS with retinal dystrophy (16 children, mean age 11.00 ± 6.74 years, providing 16 eyes; JS-RD group) and patients with JS without retinal dystrophy (8 children, mean age 10.50 ± 6.45 years, providing 8 eyes; JS-NRD group). In patients with JS and controls, visual acuity (VA), dark-adapted, light-adapted, and 30-Hz flicker ERGs were performed according to International Society for Clinical Electrophysiology of Vision (ISCEV) standard protocols. RESULTS: When compared to controls, patients in the JS-RD and JS-NRD groups showed significant abnormalities of the values of dark-adapted, light-adapted, and 30-Hz flicker ERG parameters. The ERG and VA changes were not significantly correlated. CONCLUSIONS: Our results suggest that a dysfunction of photoreceptors and bipolar cells occurs in patients with JS with or without retinal dystrophy. The retinal impairment can be detected by ERG recordings and this method should be proposed to evaluate the effectiveness of adequate treatment targeted to improve the retinal impairment in patients with JS.

Morpho-functional survey in children suspected of inherited retinal dystrophies via video recording, electrophysiology and genetic analysis.

PURPOSE: To present a detailed study matching functional response and video imaging with genetic analysis in children suspected of inherited retinal dystrophy (IRD). METHODS: Sixteen children underwent fundus examination via video recording (Heine Omega 500 indirect ophthalmoscope with DV1 camera) and electroretinogram (ERG) under general anesthesia to investigate the cause of suspected low vision. The patients [median age 12 (interquartile range 8-57.5) months] had associated genetic analysis performed with next-generation sequencing or array-comparative genomic hybridization. RESULTS: Four children had potential pathogenic variants in genes involved in Leber congenital amaurosis and Joubert syndrome (NMNAT1, CEP290, KCNJ13, IMPDH1); 1 child had a 16p11.2 microdeletion and 1 in 2q22.1. The ERG was altered in 6 patients, fundus imaging showed serious abnormality matching an IRD in 7 children, and less severe fundus alterations were found in 2 subjects. CONCLUSION: Fundus imaging associated with ERG may be significant in IRD diagnosis and visual impairment prognosis, alongside genetic analysis and therapy in selected cases.

Effect of palmitoylethanolamide on inner retinal function in glaucoma: a randomized, single blind, crossover, clinical trial by pattern-electroretinogram.

Glaucoma is a neurodegenerative disease, our study aimed to evaluate the potential effects of Palmitoylethanolamide (PEA) supplementation on RGCs function by PERG examination, and to record effects on intraocular pressure, visual field and quality of life. It was a single centre, randomized, prospective, single blind, two treatment, two period crossover study on stable glaucoma patients on topical monotherapy comparing current topical therapy alone or additioned with PEA 600 mg one tablet a day. At baseline, at 4 and at 8 months, all patients underwent to complete ophthalmic examination, pattern electroretinogram, visual field, and quality of life evaluation. 40 patients completed the study: mean age 66.6 ± 7.6 years; 21 (52.5%) male; 35 POAG (87.5%). At baseline, most patients had an early visual field defect, the IOP was well controlled. At the end of the PEA 600 mg supplementation, a significantly higher (mean 0.56 µV, 95% CI 0.30-0.73, p < 0.001) in the P50-wave amplitude was observed; in the PEA period a significantly lower IOP (- 1.6 mmHg, 95% CI - 2 to 1.2, p < 0.001) and higher quality of life scores (+ 6.7, 95% CI 4-9.9, p < 0.001) were observed. Our study is the first to show promising effects of PEA on PERG and on quality of life in glaucoma patients.

Surgery for Idiopathic Epimacular Membrane: Morpho-Functional Outcomes Based on the Preoperative Macular Integrity of the Photoreceptoral Junction. A Prospective Pilot Study.

INTRODUCTION: This study aimed to evaluate whether the preoperative integrity of the inner segment (IS) and outer segment (OS) photoreceptoral junction may influence the postoperative visual acuity, the macular morphology [assessed by spectral domain optical coherence tomography (SD-OCT)], and macular function (evaluated by multifocal electroretinogram, mfERG) in patients with idiopathic epimacular membrane (EMM) followed up for 6 months. METHODS: In this observational prospective study, 18 patients with EMM (mean age 72.5 ± 6.87 years) were enrolled. They were divided into two groups according to the preoperative integrity of the SD-OCT IS/OS junction: the EMM-I group with an intact IS/OS junction (11 patients, mean age 72.75 ± 3.49 years, providing 11 eyes) and the EMM-D group with a disrupted IS/OS junction (7 patients, mean age 70.86 ± 10.79 years, providing 7 eyes). For each enrolled patient, visual acuity (VA), mfERG, and SD-OCT were assessed at baseline (preoperative) and after 1, 3, and 6 months of follow-up after surgical treatment for EMM (pars plana vitrectomy with EMM removal and internal limiting membrane peeling). RESULTS: During the whole follow-up, VA was significantly increased in EMM-I eyes and unmodified in EMM-D eyes. In both groups, mfERG responses were not significantly different and not related to VA differences. In EMM-I eyes a significant reduction of central retinal thickness (CRT) was observed; however, it was not correlated with VA changes. In EMM-D eyes CTR was not significantly reduced, whereas macular volume was significantly reduced. These changes were significantly related to the corresponding differences in VA. CONCLUSIONS: Our results suggest that the preoperative evaluation of the integrity of the IS/OS junction is relevant for postoperative outcomes. The recovery in VA was higher in EMM-I eyes than in EMM-D eyes. Postoperative recovery was not associated with morphology of the outer retina (photoreceptor and outer nuclear layer) and the function of preganglionic elements.

Early morpho-functional changes in patients treated with hydroxychloroquine: a prospective cohort study.

PURPOSE: We aimed to find earlier morphological and functional alterations in the retinas of patients treated with hydroxychloroquine (HCQ). This was a prospective cohort study. METHODS: We examined 33 patients (mean age, 57.14 [SD, 11.02] years) who were affected by various types of rheumatic diseases. The mean treatment period was 124.7 [SD, 99.4] months, and the mean total drug intake was 5.41 [SD, 3.34] g daily at baseline. The control group consisted of 28 subjects with a mean age of 61.25 [SD, 2.16 years]. The set of tests encompassed best-corrected visual acuity (BCVA), a multifocal electroretinogram (mfERG), spectral-domain optical coherence tomography (SD-OCT), fundus auto fluorescence (FAF), the 10-2 automated visual field (VF) test (10-2 VF), and frequency-doubling technology (FDT). RESULTS: The mfERG P1 wave density amplitudes decreased in all the rings, from 31.10 to 28.02 (p = 0.008) in the first ring, and from 18.29 to 16.55 [p < 0.001], from 12.050 to 10.91 [p = 0.002], from 9.53 to 8.69 [p = 0.003], and from 8.25 to 7.48 [p = 0.001] nanovolts/degree2 in rings 2, 3, 4, and 5, respectively. A significant reduction was found also in the N1 wave in the second ring. The SD-OCT retinal thickness measurement revealed significant thinning in five sectors, including the outer and inner nasal sectors, the outer and inner temporal sectors, and the inner superior sector. The 10-2 VF mean deviation paradoxically improved, while minimal FAF alterations in the retinal pigment epithelium were found in eight eyes. CONCLUSIONS: mfERGs and SD-OCT were altered in our patients before significant retinal changes occurred.

Macular staphyloma in patients affected by Joubert syndrome with retinal dystrophy: a new finding detected by SD-OCT.

PURPOSE: Joubert syndrome (JS) is an inherited autosomal recessive or X-lined disorder characterized by a congenital malformation of the mid-hindbrain and a large spectrum of clinical features. It is estimated that retinal dystrophy is present in association with the typical neurological findings in about one-third of the patients. The aim of this study is to better characterize the macular region in JS patients with and without retinal dystrophy. METHODS: We describe six individuals affected by JS as demonstrated by the presence of the typical "molar tooth sign" on MRI. The presence of retinal dystrophy was assessed by fundus examination and electrophysiology by means of full-field electroretinogram (ERG) and visual evoked potentials (VEP) at five spatial frequencies (300-15 min of arc). The macular region was examined with spectral domain optical coherence tomography (SD-OCT). All the exams were performed in awake conditions. All the patients underwent next-generation-sequencing analysis of known JS genes. RESULTS: Pathogenic biallelic variants in either the INPP5E gene or the AHI1 gene were detected in two pairs of siblings, all positive for retinal dystrophy. Genetic testing yielded no results in the remaining two patients, one with bilateral coloboma and retinal dystrophy and the other with normal fundus appearance. Decimal best-corrected visual acuity was between 0.1 and 1.0. In the two pairs of siblings, SD-OCT revealed a posterior staphyloma centred on the fovea, in one case associated with cystoid macular oedema. Macular morphology was just slightly altered in the fifth patient and completely normal in the last patient. Refractive error was between + 2.50 diopter sphere (DS) and - 8 DS and - 4 diopter cylinder ax 45°. ERG waves were markedly lower than the normal limits in both scotopic and photopic components in the two pairs of siblings and in the fifth subject, with VEP P100 latencies and amplitudes delayed and reduced in all spatial frequencies. ERG and VEP were within normal limits in the last patient. CONCLUSIONS: To our knowledge, macular staphyloma has not been described before in JS. Further work is warranted to assess the true prevalence of staphyloma in JS and its connection to retinal dystrophy.

Morphologic and functional analysis of the optic nerve in premature and term children with OCT, HRT, and pVEP: a 10-year resurvey.

PURPOSE: Most studies on premature newborns have focused on infants of less than 28 weeks of gestational age (GA) due to their increased risk of developing diseases, such as premature retinopathy. Studies on premature infants born between 28 and 35 weeks GA with normal development are less frequent. The aim of our study was to identify subclinical morphologic or functional defects in these children. METHODS: We evaluated 14 premature newborns at birth (mean gestational age, 33.45 weeks) with a neuro-ophthalmologic examination and patterned visual evoked potentials (pVEP). The same subjects were surveyed when they were young children (mean age, 7.5 ± 0.2 years) using Heidelberg retinal tomography (HRT) and optical coherence tomography (Stratus OCT). The pVEP studies were performed as transient (temporal frequency, 1.96 Hz) and steady-state (7.5-Hz temporal frequency). A complete ophthalmic examination also was performed. The data were compared to those from 15 term newborns who were examined in the same manner (mean age, 9.8 ± 0.3 years). RESULTS: A statistically significant thickening of the macular temporal and inferior nerve fibers was found on OCT in premature newborns. The thickness of the superior and inferior retinal nerve fiber layer (RFNL) also was reduced. A difference also was found in rim area thickness based on HRT. Multiple significant P values were found in the VEP P100 peak time and steady-state amplitudes at the time of birth, but not at the time of morphologic analysis. CONCLUSIONS: Healthy, premature newborns may have morphologic abnormalities of the optic nerve. These abnormalities do not cause visual acuity or functional decreases.

Septo-optic dysplasia in childhood: the neurological, cognitive and neuro-ophthalmological perspective.

AIM: We set out to describe 17 patients with septo-optic dysplasia (SOD), focusing on the little-explored neurological, cognitive, and neuro-ophthalmological components. A further aim was to identify possible clinical correlations and phenotypic characteristics within the diagnostic spectrum. METHOD: We collected clinical-instrumental data (from the history, general and neurological examination, developmental assessment, and neuro-ophthalmological, neuroradiological, neurophysiological, and endocrinological evaluations) on nine males and eight females (mean age 34.4mo, SD 31.6; range 4mo-9y 6mo) diagnosed with SOD who were referred to our Centre of Child Neuro-ophthalmology between 1999 and 2010. RESULTS: We observed a heterogeneous clinical spectrum characterized by nervous system, visual, and endocrine dysfunctions; optic nerve involvement was present in all 17 children, midline brain defects in 14, and cortical developmental malformations in seven. Developmental/cognitive delay and relational and communication difficulties were observed in eight and seven children, respectively, and reduced visual acuity and oculomotor dysfunction were observed in all. Pituitary hormone deficiencies were present in nine children. INTERPRETATION: Nervous system involvement emerged as a key feature of SOD. As part of a holistic approach to the disease, particular attention should be paid to this aspect. The emergence of new clinical correlations and correlations between clinical features and three SOD subtypes opens the way for better clarification of this disease and, therefore, more targeted diagnosis, follow-up, and care of affected children.

Changes in the optic disc excavation of children affected by cerebral visual impairment: a tomographic analysis.

PURPOSE: To obtain quantitative data on the optic disc excavation in children affected by cerebral visual impairment (CVI) by using the Heidelberg Retinal Tomograph (HRT)-II (Heidelberg Engineering, Heidelberg, Germany). METHODS: A total of 24 subjects affected by CVI (mean age, 7.28 years) were examined: 16 in alert conditions and 8 under general anesthesia. The following parameters of the optic nerve head were examined: disc area, cup area, rim area, cup volume, rim volume, cup-to-disc area ratio, mean cup depth, maximum cup depth, cup shape measure, and mean retinal nerve fiber layer (RNFL) thickness. The tomographic results in children with CVI were compared with those of 88 normal, alert subjects of similar age. RESULTS: The optic disc of patients with CVI appeared smaller than normal. Its excavation, however, was more pronounced. Several tomographic parameters were altered in CVI-affected subjects. Statistical analysis showed a highly significant probability in cup-to-disc area ratio (P < 0.01, both eyes), rim area (P < 0.01, both eyes), cup shape measure (P < 0.01, right eye; P < 0.01, left eye), and mean RNFL thickness (P < 0.01, right eye; P < 0.01, left eye). A novel observation was temporal atrophy of the optic nerve head in CVI. CONCLUSIONS: The data provide a tridimensional, objective evaluation of the anatomic alterations of the optic nerve head in children with CVI. Furthermore, tomographic standards for optic disc shape in normal children are set for the first time.