View details for DOI 10.1018/j.jpeds.2022.09.023

View details for Web of Science ID 000903976100005

Abstract

BACKGROUND: Risdiplam is an orally administered therapy that modifies pre-mRNA splicing of the survival of motor neuron 2 (SMN2) gene and is approved for the treatment of spinal muscular atrophy. The FIREFISH study is investigating the safety and efficacy of risdiplam in treated infants with type 1 spinal muscular atrophy versus historical controls. The primary endpoint of part 2 of the FIREFISH study showed that infants with type 1 spinal muscular atrophy attained the ability to sit without support for at least 5 s after 12 months of treatment. Here, we report on the safety and efficacy of risdiplam in FIREFISH part 2 over 24 months of treatment.METHODS: FIREFISH is an ongoing, multicentre, open-label, two-part study. In FIREFISH part 2, eligible infants (aged 1-7 months at enrolment, with a genetically confirmed diagnosis of spinal muscular atrophy, and two SMN2 gene copies) were enrolled in 14 hospitals in ten countries across Europe, North America, South America, and Asia. Risdiplam was orally administered once daily at 0·2 mg/kg for infants between 5 months and 2 years of age; once an infant reached 2 years of age, the dose was increased to 0·25 mg/kg. Infants younger than 5 months started at 0·04 mg/kg (infants between 1 month and 3 months old) or 0·08 mg/kg (infants between 3 months and 5 months old), and this starting dose was adjusted to 0·2 mg/kg once pharmacokinetic data were available for each infant. The primary and secondary endpoints included in the statistical hierarchy and assessed at month 12 have been reported previously. Here we present the remainder of the secondary efficacy endpoints that were included in the statistical hierarchy at month 24: the ability to sit without support for at least 30 s, to stand alone, and to walk alone, as assessed by the Bayley Scales of Infant and Toddler Development, third edition gross motor subscale. These three endpoints were compared with a performance criterion of 5% that was defined based on the natural history of type 1 spinal muscular atrophy; the results were considered statistically significant if the lower limit of the two-sided 90% CI was above the 5% threshold. FIREFISH is registered with ClinicalTrials.gov, NCT02913482. Recruitment is closed; the 36-month extension period of the study is ongoing.FINDINGS: Between March 13 and Nov 19, 2018, 41 infants were enrolled in FIREFISH part 2. After 24 months of treatment, 38 infants were ongoing in the study and 18 infants (44% [90% CI 31-58]) were able to sit without support for at least 30 s (p<0·0001 compared with the performance criterion derived from the natural history of untreated infants with type 1 spinal muscular atrophy). No infants could stand alone (0 [90% CI 0-7]) or walk alone (0 [0-7]) after 24 months of treatment. The most frequently reported adverse event was upper respiratory tract infection, in 22 infants (54%); the most common serious adverse events were pneumonia in 16 infants (39%) and respiratory distress in three infants (7%).INTERPRETATION: Treatment with risdiplam over 24 months resulted in continual improvements in motor function and achievement of developmental motor milestones. The FIREFISH open-label extension phase will provide additional evidence regarding long-term safety and efficacy of risdiplam.FUNDING: F Hoffmann-La Roche.

View details for DOI 10.1016/S1474-4422(22)00339-8

View details for PubMedID 36244364

View details for DOI 10.1016/j.jpeds.2022.09.023

View details for PubMedID 36152687

Abstract

PURPOSE: To investigate retinal fluid features and ellipsoid zone (EZ) integrity dynamics on spectral-domain OCT (SD-OCT) in eyes with diabetic macular edema (DME) treated with intravitreal aflibercept injection (IAI) in the VISTA-DME study.DESIGN: A post hoc subanalysis of a phase III, prospective clinical trial.PARTICIPANTS: Eyes received either IAI 2 mg every 4 weeks (2q4) or every 8 weeks after 5 initial monthly doses (2q8).METHODS: All eyes from the VISTA Phase III study in the IAI groups imaged with the Cirrus HD-OCT system (Zeiss, Oberkochen, Germany) were included. The OCT macular cube datasets were evaluated using a novel software platform to generate retinal layer and fluid boundary lines that were manually corrected for assessment of change in EZ parameters and volumetric fluid parameters from baseline. The retinal fluid index (i.e., proportion of the retinal volume consisting of cystic fluid) was also calculated at each time point.MAIN OUTCOME MEASURES: The feasibility of volumetric assessment of higher-order OCT-based retinal parameters and its correlation with best-corrected visual acuity (BCVA).RESULTS: Overall, 106 eyes of 106 patients were included. Specifically, 52 eyes of 52 patients were included in the IAI 2q4 arm, and 54 eyes of 54 patients were included in the IAI 2q8 arm. Ellipsoid zone integrity metrics significantly improved from baseline to week 100, including central macular mean EZ to retinal pigment epithelium (RPE) thickness (2q4: 26.6 mum to 31.6 mum, P < 0.001; 2q8: 25.2 mum to 31.4 mum, P < 0.001). At week 100, central macular intraretinal fluid volume was reduced by >65% (P < 0.001) and central macular subretinal fluid volume was reduced by >99% in both arms (P < 0.001). Central macular retinal fluid index (RFI) significantly improved in both arms (2q4: 17.9% to 7.2%, P < 0.001; 2q8: 19.8% to 4.2%, P < 0.001). Central macular mean EZ-RPE thickness (i.e., a surrogate for photoreceptor outer segment length) and central RFI were independently correlated with BCVA at multiple follow-up visits.CONCLUSIONS: Intravitreal aflibercept injection resulted in significant improvement in EZ integrity and quantitative fluid metrics in both 2q4 and 2q8 arms and correlated with visual function.

View details for DOI 10.1016/j.oret.2019.06.010

View details for PubMedID 31473172

Abstract

Purpose: To describe new cases of sclopetaria and evaluate the risk factors, management, and visual prognosis of all reported cases in the literature.Observations: We performed a retrospective, observational case series. This study included six cases (median age 23, interquartile range 33) of sclopetaria. Additionally, literature searches were conducted in the PubMed and Cochrane Library databases to uncover risk factors associated with all published cases of sclopetaria. Main outcome measure was best corrected visual acuity (BCVA) worse than 20/20. Sixty-seven cases (71 eyes) of sclopetaria have been reported, of which 59 cases (61 eyes) met inclusion criteria in this study. Most were young (median age 19.5 years) men (51/59, 88.1%). Thirty-seven eyes were observed while 24 underwent immediate surgery including six pars plana vitrectomies and three scleral buckles. Compared to initial presentation, BCVA improved in 31/48 (64.6%) eyes, remained stable in 12/48 eyes (25.0%), and worsened in 5/48 eyes (10.4%). Ten patients (16.4%) achieved a final BCVA of 20/20 with median follow up time of seven months. In a multivariate model, location of sclopetaria in the macula, temporal retina, or immediate orbital foreign body removal predicted poor final BCVA with an area under receiver operating characteristic curve of 0.767.Conclusions and importance: Traumatic chorioretinitis sclopetaria is rare, but reports have increased dramatically over the past two decades. While pars plana vitrectomy may be required for the management of retinal detachments and non-clearing vitreous hemorrhage, close observation is appropriate in most cases. Visual prognosis is poor with most patients attaining 20/200 vision or worse.

View details for PubMedID 30834355

Abstract

Purpose: To report a case of presumed bilateral chorioretinitis secondary to alendronate therapy.Observations: A 71-year-old female presented to the clinic in July 2017 with six months history of difficulty in reading along with floaters in both eyes which were more severe in the right eye. Past medical and surgical history revealed a history of hypertension, gout, hyperthyroidism, osteoporosis, and humerus fracture. She was started on alendronate three months before developing ocular symptoms. On ocular examination, best corrected visual acuity was 20/30 in the right and 20/25 in the left eye. Slit-lamp examination demonstrated normal anterior chamber examination in both eyes. Dilated fundus examination revealed geographic chorioretinal lesions around the optic nerve head in both eyes, more extensively in the right eye; and superior and temporal to the macula in the right eye. Past ocular records in February 2015 did not reveal any such findings. Fundus autofluorescence demonstrated hyper-autofluorescence in the peripapillary lesions in both eyes. The lesion adjacent to the macula in right eye displayed mixed hyper and hypo-autofluorescence. Fluorescein angiography showed combined hyper- and hypo-fluorescence compatible with window defect, staining and blockage. However, no leakage was appreciated in the macula, peripapillary, and peripheral lesions in both eyes. Optical coherence tomography scan showed septate hyporeflective intraretinal spaces in the right eye.Conclusion and importance: The index report underscore the importance of considering alendronate as an etiologic cause of chorioretinitis, especially in subjects with atypical lesions developing after alendronate therapy. We, therefore, recommend discontinuation of this medication in subjects who develop chorioretinitis after employing this medication.

View details for PubMedID 30809598

Abstract

Purpose: Clinical OCT angiography (OCTA) of the retinal microvasculature offers a quantitative correlate to systemic disease burden and treatment efficacy in sickle cell disease (SCD). The purpose of this study was to use the higher resolution of adaptive optics scanning light ophthalmoscopy (AOSLO) to elucidate OCTA features of parafoveal microvascular compromise identified in SCD patients.Design: Case series of 11 SCD patients and 1 unaffected control.Participants: A total of 11 eyes of 11 SCD patients (mean age, 33 years; range, 23-44; 8 female, 3 male) and 1 eye of a 34-year-old unaffected control.Methods: Ten sequential 3 * 3 mm parafoveal OCTA full vascular slab scans were obtained per eye using a commercial spectral domain OCT system (Avanti RTVue-XR; Optovue). These were used to identify areas of compromised perfusion near the foveal avascular zone (FAZ), designated as regions of interest (ROIs). Immediately thereafter, AOSLO imaging was performed on these ROIs to examine the cellular details of abnormal perfusion. Each participant was imaged at a single cross-sectional time point. Additionally, 2 of the SCD patients were imaged prospectively 2 months after initial imaging to study compromised capillary segments across time and with treatment.Main Outcome Measures: Detection and characterization of parafoveal perfusion abnormalities identified using OCTA and resolved using AOSLO imaging.Results: We found evidence of abnormal blood flow on OCTA and AOSLO imaging among all 11 SCD patients with diverse systemic and ocular histories. Adaptive optics scanning light ophthalmoscopy imaging revealed a spectrum of phenomena, including capillaries with intermittent blood flow, blood cell stasis, and sites of thrombus formation. Adaptive optics scanning light ophthalmoscopy imaging was able to resolve single sickled red blood cells, rouleaux formations, and blood cell-vessel wall interactions. OCT angiography and AOSLO imaging were sensitive enough to document improved retinal perfusion in an SCD patient 2 months after initiation of oral hydroxyurea therapy.Conclusions: Adaptive optics scanning light ophthalmoscopy imaging was able to reveal the cellular details of perfusion abnormalities detected using clinical OCTA. The synergy between these clinical and laboratory imaging modalities presents a promising avenue in the management of SCD through the development of noninvasive ocular biomarkers to prognosticate progression and measure the response to systemic treatment.

View details for DOI 10.1016/j.xops.2022.100196

View details for PubMedID 36531581

Abstract

Choroideremia is an X-linked, blinding retinal degeneration with progressive loss of photoreceptors, retinal pigment epithelial (RPE) cells, and choriocapillaris. To study the extent to which these layers are disrupted in affected males and female carriers, we performed multimodal adaptive optics imaging to better visualize the in vivo pathogenesis of choroideremia in the living human eye. We demonstrate the presence of subclinical, widespread enlarged RPE cells present in all subjects imaged. In the fovea, the last area to be affected in choroideremia, we found greater disruption to the RPE than to either the photoreceptor or choriocapillaris layers. The unexpected finding of patches of photoreceptors that were fluorescently-labeled, but structurally and functionally normal, suggests that the RPE blood barrier function may be altered in choroideremia. Finally, we introduce a strategy for detecting enlarged cells using conventional ophthalmic imaging instrumentation. These findings establish that there is subclinical polymegathism of RPE cells in choroideremia.

View details for DOI 10.1038/s42003-022-03842-7

View details for PubMedID 36100689

Abstract

To describe the reflectance adaptive optics scanning laser ophthalmoscopy (AOSLO) findings in different stages of Vogt-Koyanagi-Harada (VKH) disease and correlate them to visual gain post treatment. Confocal (cAOSLO) and non-confocal split-detector AOSLO (sdAOSLO) were used to assess longitudinally the status of the photoreceptors in a patient with VKH managed on corticosteroid and immunomodulatory therapy.A 32-year-old Japanese American female presented with a 2-week history of blurred vision in both eyes (OU) and worsening headache previously diagnosed as a case of VKH and treated with high dose oral prednisone. At the time of presentation, though vision was improving, and frank serous retinal detachments were absent, spectral domain optical coherence tomography (SD-OCT) showed presence of residual subretinal fluid with disruption of the photoreceptor inner segments and outer segments (IS/OS) involving OU. The photoreceptor mosaic at the foveal center appeared very sparse with large areas devoid of visible photoreceptors on cAOSLO, in agreement with the SD-OCT data. sdAOSLO imaging over the same location shows a higher number of contiguous photoreceptors. After imaging, the patient was started on mycophenolate mofetil as steroid-sparing long-term therapy. Three months later, visual acuity improved to 20/20 OU, and SD-OCT showed almost complete resolution of subretinal fluid with significant improvement of the IS/OS SD-OCT signal, OU. cAOSLO imaging revealed a contiguous photoreceptor mosaic without gaps and of normal appearance.VKH patients may demonstrate transient photoreceptor abnormalities on SD-OCT and cAOSLO imaging. sdAOSLO imaging revealed intact photoreceptor segments in areas that appeared as voids on cAOSLO, which later showed structural recovery on SD-OCT and cAOSLO. Therefore, sdAOSLO may predict potential for improvement in patients wherein there appears to be photoreceptor loss in cAOSLO and/or SD-OCT.

View details for DOI 10.1016/j.ajoc.2022.101660

View details for PubMedID 35880207

View details for PubMedCentralID PMC9307596

Abstract

The failure of adult CNS neurons to survive and regenerate their axons after injury or in neurodegenerative disease remains a major target for basic and clinical neuroscience. Recent data demonstrated in the adult mouse that exogenous expression of Sry-related high-mobility-box 11 (Sox11) promotes optic nerve regeneration after optic nerve injury, but exacerbates the death of a subset of retinal ganglion cells, alpha-RGCs. During development, Sox11 is required for RGC differentiation from retinal progenitor cells (RPCs), and we found that mutation of a single residue to prevent sumoylation at lysine 91 (K91) increased nuclear localization and RGC differentiation in vitro Here we explored whether this Sox11 manipulation similarly has stronger effects on RGC survival and optic nerve regeneration. In vitro, we found that non-SUMOylatable Sox11K91A leads to RGC death and suppresses axon outgrowth in primary neurons. We furthermore found that Sox11K91A more strongly promotes axon regeneration but also increases RGC death after optic nerve injury in vivo in adult mouse. RNA sequence data showed that Sox11 and Sox11K91A increase the expression of key signaling pathway genes associated with axon growth and regeneration but downregulated Spp1 and Opn4 expression in RGC cultures, consistent with negatively regulating the survival of alpha-RGCs and ipRGCs. Thus Sox11 and its sumoylation site at K91 regulate gene expression, survival and axon growth in RGCs and may be explored further as potential regenerative therapies for optic neuropathy.Significance Statement Sox11 expression promotes optic nerve regeneration but also increases RGC death after optic nerve injury. Here we demonstrate that mutation of a single SUMOylation site on Sox11 (Sox11K91A) leads to stronger effects in vivo RNA sequencing analysis reveals that Sox11 and Sox11K91A differentially regulate downstream gene expression related to axon growth and guidance. Understanding these effects of post-translational modification of Sox11 in regulating regeneration in vivo suggests a potent therapeutic strategy for vision restoration in optic neuropathies.

View details for DOI 10.1523/ENEURO.0358-20.2020

View details for PubMedID 33441400

Abstract

PURPOSE: Understanding molecular changes is essential for designing effective treatments for nonarteritic anterior ischemic optic neuropathy (AION), the most common acute optic neuropathy in adults older than 50years. We investigated changes in the mitogen-activated protein kinase (MAPK) pathway after experimental AION and focused on dual specificity phosphatase 14 (Dusp14), an atypical MAPK phosphatase that is downstream of Kruppel-like transcription factor (KLF) 9-mediated inhibition of retinal ganglion cell (RGC) survival and axonal regeneration.MATERIALS AND METHODS: We induced severe AION in a photochemical thrombosis model in adult C57BL/6 wild-type and Dusp14 knockout mice. For comparison, some studies were performed using an optic nerve crush model. We assessed changes in MAPK pathway molecules using Western blot and immunohistochemistry, measured retinal thickness using optical coherence tomography (OCT), and quantified RGCs and axons using histologic methods.RESULTS: Three days after severe AION, there was no change in the retinal protein levels of MAPK ERK1/2, phosphorylated-ERK1/2 (pERK1/2), downstream effector Elk-1 and phosphatase Dusp14 on Western blot. Western blot analysis of purified RGCs after a more severe model using optic nerve crush also showed no change in Dusp14 protein expression. Because of the known importance of the Dusp14 and MAPK pathway in RGCs, we examined changes after AION in Dusp14 knockout mice. Three days after AION, Dusp14 knockout mice had significantly increased pERK1/2+, Brn3A+ RGCs on immunohistochemistry. Three weeks after AION, Dusp14 knockout mice had significantly greater preservation of retinal thickness, increased number of Brn3A+ RGCs on whole mount preparation, and increased number of optic nerve axons compared with wild-type mice.CONCLUSIONS: Genetic deletion of Dusp14, a MAPK phosphatase important in KFL9-mediated inhibition of RGC survival, led to increased activation of MAPK ERK1/2 and greater RGC and axonal survival after experimental AION. Inhibiting Dusp14 or activating the MAPK pathway should be examined further as a potential therapeutic approach to treatment of AION.Abbreviations: AION: anterior ischemic optic neuropathy; Dusp14: dual specific phosphatase 14; ERK1/2: extracellular signal-regulated kinases 1/2; Elk-1: ETS Like-1 protein; GCC: ganglion cell complex; GCL: ganglion cell layer; inner nuclear layer; KO: knockout; MAPK: mitogen-activated phosphokinase; OCT: optical coherence tomography; RGC: retinal ganglion cell; RNFL: retinal nerve fiber layer.

View details for DOI 10.1080/02713683.2020.1826976

View details for PubMedID 33107352

Abstract

Dedicator of cytokinesis 10 (Dock10) is a guanine nucleotide exchange factor for Cdc42 and Rac1 that regulates the JNK (c-Jun N-terminal kinase) and p38 MAPK (mitogen-activated protein kinase) signaling cascades. In this study, we characterized the roles of Dock10 in the myocardium. In vitro: we ablated Dock10 in neonatal mouse floxed Dock10 cardiomyocytes (NMCMs) and cardiofibroblasts (NMCFs) by transduction with an adenovirus expressing Cre-recombinase. In vivo, we studied mice in which the Dock10 gene was constitutively and globally deleted (Dock10 KO) and mice with cardiac myocyte-specific Dock10 KO (Dock10 CKO) at baseline and in response to two weeks of Angiotensin II (Ang II) infusion. In vitro, Dock10 ablation differentially inhibited the α-adrenergic stimulation of p38 and JNK in NMCM and NMCF, respectively. In vivo, the stimulation of both signaling pathways was markedly attenuated in the heart. The Dock10 KO mice had normal body weight and cardiac size. However, echocardiography revealed mildly reduced systolic function, and IonOptix recordings demonstrated reduced contractility and elevated diastolic calcium levels in isolated cardiomyocytes. Remarkably, Dock10 KO, but not Dock10 CKO, exaggerated the pathological response to Ang II infusion. These data suggest that Dock10 regulates cardiac stress-related signaling. Although Dock10 can regulate MAPK signaling in both cardiomyocytes and cardiofibroblasts, the inhibition of pathological cardiac remodeling is not apparently due to the Dock10 signaling in the cardiomyocyte.

View details for DOI 10.3390/ijms23179616

View details for Web of Science ID 000851094300001

View details for PubMedID 36077014

View details for PubMedCentralID PMC9455810

Abstract

The pleiotropic Ca2+/calmodulin-dependent phosphatase calcineurin is a key regulator of pathological cardiac myocyte hypertrophy. The selective activation of hypertrophic calcineurin signaling under stress conditions has been attributed to compartmentation of Ca2+ signaling in cardiac myocytes. Here, perinuclear signalosomes organized by the scaffold protein muscle A-Kinase Anchoring Protein beta (mAKAPbeta/AKAP6beta) are shown to orchestrate local Ca2+ transients, inducing calcineurin-dependent NFATc nuclear localization and myocyte hypertrophy in response to beta-adrenergic receptor activation. Fluorescent biosensors for Ca2+ and calcineurin and protein kinase A (PKA) activity, both diffusely expressed and localized by nesprin-1alpha to the nuclear envelope, are used to define an autonomous mAKAPbeta signaling compartment in adult and neonatal rat ventricular myocytes. Notably, beta-adrenergic-stimulated perinuclear Ca2+ and PKA and CaN activity transients depended upon mAKAPbeta expression, while Ca2+ elevation and PKA and CaN activity in the cytosol were mAKAPbeta independent. Buffering perinuclear cAMP and Ca2+ prevented calcineurin-dependent NFATc nuclear translocation and myocyte hypertrophy, without affecting cardiac myocyte contractility. Additional findings suggest that the perinuclear Ca2+ transients were mediated by signalosome-associated ryanodine receptors regulated by local PKA phosphorylation. These results demonstrate the existence of a functionally independent Ca2+ signaling compartment in the cardiac myocyte regulating hypertrophy and provide a premise for targeting mAKAPbeta signalosomes to prevent selectively cardiac hypertrophy in disease.

View details for DOI 10.1016/j.yjmcc.2022.07.007

View details for PubMedID 35952391

Abstract

To determine the prevalence of SARS-CoV-2 in tear samples and to investigate whether it correlates with ocular findings and patients' prognosis in Brazil.Tears were collected using Schirmer strips (SS) and conjunctival swabs (CS) from patients hospitalized with laboratory-confirmed SARS-CoV-2 infection. Samples were analyzed using qRT-PCR. Demographic and clinical data, ocular symptoms, and Schirmer tests (ST) were collected from patients. Charlson Comorbidity Index (CCI) was used to rate comorbidities, and patients were monitored until hospital discharge or death.There were 61 hospitalized patients, 33 of which were diagnosed with COVID-19. Within the confirmed COVID-19 patients, SARS-CoV-2 was detected in 18.2% (n = 6) of CS and 12.1% (n = 4) of SS samples. Subjective and objective parameters for dry eye syndrome (e.g., ST COVID-19: 8.3 ± 6.4mm, non-COVID-19: 8.9 ± 6.6mm, p > 0.05) were comparable between COVID-19 (n = 33) and non-COVID-19 patients (n = 28). Among the 16 COVID-19 patients exhibiting ocular symptoms, only tearing was reported significantly more frequently when tear samples were positive for SARS-CoV-2 (p < 0.05). Strikingly, patients whose tears tested positive for SARS-CoV-2 had significantly inferior CCI (pos.: 34.0 ± 31.8%, neg.: 67.6 ± 36.4%, p < 0.05) and higher mortality rates (pos.: 50.0%, neg.: 7.4%, p < 0.01).SARS-CoV-2 was detected with a prevalence of 18.2% on the ocular surface. Decreased CCI and increased mortality rate in the positive tear group suggests that viral detection may relate to prognosis and highlight the need of personal protective measures for healthcare professionals. Most of the patients, regardless of COVID-19 diagnosis, had low tear production and eye discomfort, possibly pointing to the need for artificial tear use during hospitalization.

View details for DOI 10.3390/jcm11236929

View details for PubMedID 36498504

Abstract

INTRODUCTION: Leber congenital amaurosis (LCA) type 2, due to disease-causing variants in RPE65, is characterized by severe visual loss in early infancy. Current treatments include voretigene neparvovec-rzyl (VN) for RPE65-associated LCA. Herein, we present the long-term follow-up of a patient treated with VN using quantitative autofluorescence (488nm excitation).CASE REPORT: A 9-year-old girl with a diagnosis of LCA with biallelic variants in RPE65 presented for evaluation. The patient underwent VN treatment at the age of 11. The patient returned to clinic at age of 19 at which time imaging revealed evidence of chorioretinal atrophy. Quantitative autofluorescence performed prior to gene therapy and at 6- and 8-year follow-up revealed a central area of fundus autofluorescence.DISCUSSION: This case report demonstrates acquisition of fundus autofluorescence at 6- and 8-year follow-up despite the development of chorioretinal atrophy.

View details for DOI 10.1002/mgg3.2038

View details for PubMedID 36225124

Abstract

This protocol describes an exvivo model to quantify enzymatic effects on vitreous liquefaction using porcine eyes in a transwell-plate system via induced syneresis. It provides a standardized dissection process and performs critical steps for gel-liquid separation with high precision, minimal tissue loss, and scalability. The protocol can be applied to other studies investigating vitreous liquefaction or gelatinous tissue analysis and can also serve to study vitreous liquefaction invivo as it may occur during aging or disease progression.

View details for DOI 10.1016/j.xpro.2022.101754

View details for PubMedID 36208453

Abstract

The accuracy of International Classification of Diseases (ICD) codes for identifying cases of acute optic neuritis (aON) is not known. A prior study reported 61% accuracy for ICD code plus MRI consistent with aON within 2 months. This study determined accuracy for ICD code plus MRI within 2 months regardless of results.Retrospective chart review was conducted using a medical record research repository of a tertiary care institution from 1998 to 2019. Subjects with ICD-9/10 codes for ON and an MRI brain and/or orbits within 2 months of earliest (initial) ICD code were included. MRI was classified as positive or negative for aON based on report noting gadolinium-contrast enhancement. Clinical diagnosis at the time of initial code was classified as aON, prior ON, considered ON, alternative diagnosis, or unknown based on review of physician authored clinical notes within 7 days of the initial code. Accuracy of ICD code for aON, acute or prior ON, and acute, prior, or considered ON were calculated for all subjects and stratified based on MRI result.Two hundred fifty-one subjects had MRI results within 2 months of their initial ON ICD code (49 positive MRI [previously reported]; 202 negative MRI). Among those with negative MRI, 32 (16%) had aON, 40 (20%) had prior ON, 19 (9%) considered ON as a diagnosis, 92 (46%) had other confirmed diagnoses, and 19 (9%) had unknown diagnosis at time of code. Considering all subjects, accuracy for ICD code was 25% for acute ON, 41% for acute or prior ON, and 48% for acute, prior, or considered ON. Positive MRI, increased number of ON ICD codes, a code given by an ophthalmologist or neurologist within 2 months, and the presence of a neurology encounter within 2 months were associated with an increased accuracy for clinical aON diagnosis.In the setting of an MRI within 2 months, ICD codes for ON have low accuracy for acute ON and only slightly better accuracy for acute or prior ON. Accuracy is higher for cases with a positive MRI than those with a negative MRI, suggesting positive MRI in conjunction with ICD codes may help more accurately identify cases. Reliance on ICD and Current Procedural Terminology codes alone to identify aON cases may introduce substantial misclassification bias in claims-based research.

View details for DOI 10.1097/WNO.0000000000001805

View details for PubMedID 36696226

Abstract

Neurocysticercosis (NCC) is the most common parasitic infection of the central nervous system and is typically diagnosed through visualization of the cysts in the cerebral parenchyma by neuro-imaging. However, neuro-imaging may not detect extraparenchymal neurocysticercosis (EPNCC), which is a rare manifestation of the disease involving the subarachnoid, meningeal, and intraventricular spaces. We report 2 cases of extraparenchymal neurocysticercosis, and discuss the diagnostic challenges and management of this entity.Two cases were identified through clinical records.Both patients had an insidious onset with slow progression of disease, and presented with papilledema and cerebrospinal fluid (CSF) eosinophilia. One case was diagnosed with spinal cord biopsy. The other was diagnosed with CSF serology and next-generation sequencing-based pathogen analysis. Both patients were treated with ventriculoperitoneal shunt, systemic antiparasitic agents, and immunosuppression.EPNCC is less common than parenchymal NCC. A high level of clinical suspicion is required given its rarity, long incubation period, and slow progression. Diagnosis and treatment can be challenging and requires a multidisciplinary approach.

View details for DOI 10.1097/WNO.0000000000001782

View details for PubMedID 36637411

Abstract

BACKGROUND: Wyburn-Mason syndrome (WMS) is a neurocutaneous disorder consisting of vascular malformations of the brain, eye, and skin. These include characteristically high-flow intracranial and intraorbital arteriovenous malformations (AVMs) that present commonly with visual deterioration, headache, and hemiplegia. Complete removal of these lesions is challenging. Most patients are followed closely, and intervention occurs only in the setting of worsening symptoms secondary to AVM growth or hemorrhage. Here the authors present the first known case of a patient with WMS and a pituitary macroadenoma.OBSERVATIONS: A 62-year-old man with a 30-year history of WMS with right basal ganglia and orbital AVMs and right eye blindness presented for new-onset left-sided vision loss. A pituitary adenoma was identified compressing the optic chiasm and left optic nerve. Magnetic resonance imaging and digital subtraction angiography studies were obtained for surgical planning, and the patient underwent an endoscopic transnasal transsphenoidal resection, with significant postoperative vision improvement.LESSONS: Given the variable presentation and poor characterization of this rare syndrome, patients with WMS presenting with new symptoms must undergo evaluation for growth and hemorrhage of known AVMs, as well as new lesions. Further, in patients undergoing intracranial surgery, extensive preoperative imaging and planning are crucial for safe and successful procedures.

View details for DOI 10.3171/CASE22236

View details for PubMedID 36572974

View details for DOI 10.1021/acs.jpcb.2c04154AJ

View details for Web of Science ID 000842923500001

Abstract

While color fundus photos are used in routine clinical practice to diagnose ophthalmic conditions, evidence suggests that ocular imaging contains valuable information regarding the systemic health features of patients. These features can be identified through computer vision techniques including deep learning (DL) artificial intelligence (AI) models. We aim to construct a DL model that can predict systemic features from fundus images and to determine the optimal method of model construction for this task. Data were collected from a cohort of patients undergoing diabetic retinopathy screening between March 2020 and March 2021. Two models were created for each of 12 systemic health features based on the DenseNet201 architecture: one utilizing transfer learning with images from ImageNet and another from 35,126 fundus images. Here, 1277 fundus images were used to train the AI models. Area under the receiver operating characteristics curve (AUROC) scores were used to compare the model performance. Models utilizing the ImageNet transfer learning data were superior to those using retinal images for transfer learning (mean AUROC 0.78 vs. 0.65, p-value < 0.001). Models using ImageNet pretraining were able to predict systemic features including ethnicity (AUROC 0.93), age > 70 (AUROC 0.90), gender (AUROC 0.85), ACE inhibitor (AUROC 0.82), and ARB medication use (AUROC 0.78). We conclude that fundus images contain valuable information about the systemic characteristics of a patient. To optimize DL model performance, we recommend that even domain specific models consider using transfer learning from more generalized image sets to improve accuracy.

View details for DOI 10.3390/diagnostics12071714

View details for PubMedID 35885619

View details for DOI 10.1016/j.oret.2017.03.002

View details for DOI 10.1016/j.bspc.2022.104406

Abstract

To describe the characteristics and prevalence of strabismus and nystagmus in children diagnosed with cataracts using a national insurance claims database.Population-based retrospective cohort study METHODS: Patients <13 years diagnosed with cataracts (traumatic cataracts excluded) and enrolled continuously in their healthcare program for ≥5 years after their first cataract diagnosis were identified in a retrospective review of 66 million charts in Optum's de-identified Clinformatics Data Mart Database between 2003 and 2015. Patients were categorized based on age of their first diagnosed cataract, and if cataract surgery was performed. Clinical and demographic factors associated with the occurrence of strabismus and nystagmus were evaluated.Of 1,636 children diagnosed with cataract, 434 (26.5%) and 109 (6.7%) were diagnosed with strabismus and nystagmus, respectively. Both strabismus and nystagmus were more common in those who underwent cataract surgery (P <0.001) and in patients diagnosed with cataract ≤ 12 months of age (P <0.001). Survival analysis demonstrated that strabismus and nystagmus may be diagnosed 8 years following the initial cataract diagnosis. Cox proportional hazard regression analyses revealed strabismus was associated with cataract surgery, nystagmus, and the diagnosis with cataract ≤ 12 months and cataract surgery > 12 months.As strabismus and nystagmus occur more frequently in children diagnosed with cataracts necessitating cataract surgery, regular long-term follow-up is crucial for these children to monitor for the development of strabismus and nystagmus.

View details for DOI 10.1016/j.ajo.2022.11.014

View details for PubMedID 36410473

Abstract

PURPOSE: To evaluate the time course of improvements in clinical convergence measures for children with symptomatic convergence insufficiency treated with office-based vergence/accommodative therapy.METHODS: We evaluated convergence measures from 205, 9- to 14-year-old children with symptomatic convergence insufficiency randomised to office-based vergence/accommodative therapy in the Convergence Insufficiency Treatment Trial - Attention and Reading Trial (CITT-ART). Near-point of convergence (NPC) and near-positive fusional vergence (PFV) were measured at baseline and after 4, 8, 12 and 16weeks of therapy; mean change in NPC and PFV between these time points were compared using repeated measures analysis of variance. Rates of change in NPC and PFV from: (1) baseline to 4weeks and (2) 4-16weeks were calculated. For each time point, the proportion of participants to first meet the normal criterion for NPC (<6cm), PFV blur (break if no blur; >15Delta and >2 times the exodeviation) and convergence composite (NPC and PFV both normal) were calculated.RESULTS: The greatest change in NPC and PFV (7.6cm and 12.7 Delta) and the fastest rate of improvement in NPC and PFV (1.9cm/week and 3.2 Delta/week, respectively) were both found during the first 4weeks of therapy, with both slowing over the subsequent 12weeks. After 12weeks of therapy, the NPC, PFV and convergence composite were normal in 93.2%, 91.7% and 87.8% of participants, respectively, and normalised with another 4weeks of therapy in 4.4%, 2.0% and 4.4% of participants, respectively.CONCLUSION: Although the greatest improvements in NPC and PFV occurred in the first 4weeks of therapy, most participants had weekly improvements over the subsequent 12weeks of treatment. While most children with convergence insufficiency obtained normal convergence following 12weeks of therapy, an additional 4weeks of vergence/accommodative therapy may be beneficial for some participants.

View details for DOI 10.1111/opo.13062

View details for PubMedID 36271753

Abstract

BACKGROUND: RPGR mutations are the most common cause of X-linked retinitis pigmentosa (XLRP). High myopia has been described as a very frequent feature among affected female carriers of XLRP. However, the clinical phenotype of female patients presenting with X-linked RPGR-related high myopia has not been well described.MATERIALS AND METHODS: Retrospective case series of four female patients with RPGR mutations and a diagnosis of high myopia, who presented to two academic eye centers. Clinical data, including age, family history, visual acuity, refractive error, dilated fundus exam, fundus photography, optical coherence tomography, electroretinography, and results of genetic testing, were collected.RESULTS: Three RPGR variants identified in the present study have not been previously associated with myopia in female carriers. One variant (c.2405_2406delAG, p.Glu802Glyfs *32) has been previously associated with a myopic phenotype in a female patient. Patients became symptomatic between the first and sixth decades of life. Myopia-associated tilted optic discs and posterior staphyloma were present in all patients. Two patients presented with intraretinal migration of the retinal pigment epithelium.CONCLUSION: RPGR-related high myopia has been associated with mutations in exons 1-14 and ORF15 in heterozygous females. There is a wide range of visual function among carriers. Although the exact mechanism of RPGR-related high myopia is still unclear, continued molecular diagnosis and description of phenotypes remain a crucial step in understanding the impact of RPGR mutations on visual function in female XLRP carriers.

View details for DOI 10.1080/13816810.2022.2113544

View details for PubMedID 36017691

Abstract

Short-term use of the Balance Goggles System in glaucoma patients was not associated with observable changes in conventional OCT imaging but metabolic imaging using peripapillary flavoprotein fluorescence may represent a useful adjuctive investigation.To determine whether the intraocular pressure (IOP)-lowering effects of the Balance Goggles System (BGS) are accompanied by changes in retinal thickness measured by ocular coherence tomography, retinal vascular density measured by OCT-angiography, or novel peripapillary metabolic profiling using flavoprotein fluorescence (FPF) measured by a fundus camera.Prospective comparative case-series.8 eyes from 8 patients with open-angle glaucoma ranging from mild to severe.In this prospective, single-center, open-label, non-randomized, single-arm study patients received a baseline evaluation including retinal imaging, then one hour of negative pressure application through the BGS, followed by repeat retinal imaging. Participants then used the BGS at home for 1 month and underwent a repeat evaluation at the conclusion of the trial.Changes in nerve fiber layer thickness, OCTA vascular parameters and FPF scores.Mean baseline IOP was 18.0±3.1 mmHg and there was no significant change in IOP at follow-up. At 1 month compared to baseline, there was a statistically significant improvement in FPF optic nerve head rim scores (12.7±11.6 to 10.5±7.5; P=0.04). Additionally, there was there was a trend towards an increase in RNFL thickness after 1 month (69.5±14.2 to 72.0±13.7; P=0.1), but there were no statistically significant differences observable with any of the OCTA vascular parameters either at 1 hour or after 1 month.There were no significant changes observable using conventional OCT imaging following short-term use of the BGS, although metabolic imaging using FPF may be a useful potential biomarker to complement existing investigations. Additional studies are warranted to further investigate these changes.

View details for DOI 10.1097/IJG.0000000000002066

View details for PubMedID 35696700

Abstract

To review the pathway to care for treatment and management of patients receiving visual and vestibular rehabilitation after mild traumatic brain injury (mTBI).English scientific peer-reviewed articles from PubMed, CINAHL, Embase, and PsycINFO between 2000 and 2020 were first screened by title and abstract, then those selected underwent full-text review and analysis.The database search yielded 1640 results and after title and abstract review, 75 articles were selected for full-text screening, from which 8 were included in the qualitative synthesis. Current evidence includes a limited number of retrospective cohort studies and case studies.Many patients with visual and vestibular deficits following mTBI do not receive rehabilitation services until months following their injury as there is no standardized pathway to care for patients for visual and vestibular rehabilitation. Barriers to establishing a standardized pathway are the lack of natural history data for visual and vestibular function following mTBI and the lack of randomized clinical trials establishing the efficacy of rehabilitation in patients following mTBI.

View details for DOI 10.1080/02699052.2022.2105399

View details for PubMedID 35918848

View details for Web of Science ID 000844437004144

Abstract

Controlled breathwork practices have emerged as potential tools for stress management and well-being. Here, we report a remote, randomized, controlled study (NCT05304000) of three different daily 5-min breathwork exercises compared with an equivalent period of mindfulness meditation over 1 month. The breathing conditions are (1) cyclic sighing, which emphasizes prolonged exhalations; (2) box breathing, which is equal duration of inhalations, breath retentions, and exhalations; and (3) cyclic hyperventilation with retention, with longer inhalations and shorter exhalations. The primary endpoints are improvement in mood and anxiety as well as reduced physiological arousal (respiratory rate, heart rate, and heart rate variability). Using a mixed-effects model, we show that breathwork, especially the exhale-focused cyclic sighing, produces greater improvement in mood (p < 0.05) and reduction in respiratory rate (p < 0.05) compared with mindfulness meditation. Daily 5-min cyclic sighing has promise as an effective stress management exercise.

View details for DOI 10.1016/j.xcrm.2022.100895

View details for PubMedID 36630953

View details for DOI 10.1016/j.expneurol.2022.114256

View details for PubMedID 36457222

Abstract

Visual impairment caused by retinal ganglion cell (RGC) axon damage or degeneration affects millions of individuals throughout the world. While some progress has been made in promoting long-distance RGC axon regrowth following injury, it remains unclear whether RGC axons can properly reconnect with their central targets to restore visual function. Additionally, the regenerative capacity of many RGC subtypes remains unknown in part due to a lack of available genetic tools. Here, we use a new mouse line that labels On direction-selective RGCs (oDSGCs) and characterize the survival and regenerative potential of these cells following optic nerve crush (ONC). In parallel, we use a previously characterized mouse line to answer these same questions for M1 intrinsically photosensitive RGCs (ipRGCs). We find that both M1 ipRGCs and oDSGCs are resilient to injury but do not display long-distance axon regrowth following Lin28a overexpression. Unexpectedly, we found that M1 ipRGC, but not oDSGC, intraretinal axons exhibit ectopic branching and are misaligned near the optic disc between one- and three-weeks following injury. Additionally, we observe that numerous ectopic presynaptic specializations associate with misguided ipRGC intraretinal axons. Taken together, these results reveal insights into the injury response of M1 ipRGCs and oDSGCs, providing a foundation for future efforts seeking to restore visual system function following injury.

View details for DOI 10.1016/j.expneurol.2022.114176

View details for PubMedID 35870522

Abstract

Purpose: The purpose of this study was to determine whether glaucoma in human patients produces preferential damage to OFF visual pathways, as suggested by animal experimental models, patient electroretinogram (ERG), and retinal imaging data.Methods: Steady-state visual evoked potentials (SSVEPs) were recorded monocularly from 50 patients with glaucoma and 28 age-similar controls in response to equal Weber contrast increments and decrements presented using 2.73 hertz (Hz) sawtooth temporal waveforms.Results: The eyes of patients with glaucoma were separated into mild (better than -6 decibel [dB] mean deviation; n = 28) and moderate to severe (worse than -6 dB mean deviation, n = 22) groups based on their Humphrey 24-2 visual field measurements. Response amplitudes and phases from the two glaucoma-severity groups were compared to controls at the group level. SSVEP amplitudes were depressed in both glaucoma groups, more so in the moderate to severe glaucoma group. The differences between controls and the moderate-severe glaucoma groups were more statistically reliable for decrements than for increments. Mean responses to decremental sawtooth stimuli were larger than those to increments in controls and in the mild glaucoma but not in the moderate to severe glaucoma group at the first harmonic. OFF/decrement responses at the first harmonic were faster in controls, but not in patients.Conclusions: The observed pattern of preferential loss of decremental responses in human glaucoma is consistent with prior reports of selective damage to OFF retinal ganglion cells in murine models and in data from human ERG and retinal imaging. These data motivate pursuit of SSVEP as a biomarker for glaucoma progression.

View details for DOI 10.1167/iovs.63.11.16

View details for PubMedID 36264656

Abstract

Artificial orthographies have long been used in studies of verbal learning and reading. These orthographies, also known as pseudo or false fonts, are designed to match the letters of an existing alphabet on a range of visual features, isolating effects of orthography from those owing to lexical processing. In a parallel line of research, there has been much interest in the design of optotypes for measuring visual acuity that have good properties in terms of character complexity and graceful degradation under blur. Here we merge these two traditions by designing a fully scalable pseudofont, "PseudoSloan," that is based on the design rubric of the widely used Sloan optotypes. The font includes 26 Latin letters as well as two sets of letter-like symbols matching the Latin alphabet on a letter-by-letter basis. Quantitative matching of the pairs of Sloan and PseudoSloan glyphs is done on the basis of ink area and perimetric complexity. We provide the installable PseudoSloan font in TrueType and OpenType formats, plus a large number of PseudoSloan glyphs in .svg format that vary over wide ranges in their perimetric complexity and ink area (https://osf.io/qhj2b/).

View details for DOI 10.1167/jov.22.10.7

View details for PubMedID 36074477

View details for Web of Science ID 000844401306115