Green synthesis of neuroprotective spirocyclic chalcone derivatives and their role in protecting against traumatic optic nerve injury.

For clinically prevalent traumatic optic neuropathy (TON) and other retinal and optic nerve injuries lacking effective therapeutic agents, there is an urgent clinical demand for developing highly efficient and safe neuroprotective agents. Here, we have integrated naturally sourced chalcone with isatin through a catalyst-free green synthesis method, reporting a series of spirocyclic chalcone derivatives with significantly lower cytotoxicity than chalcone itself. Following in vitro cell protection assays in models of hydrogen peroxide and glutamic acid-induced damage, multiple active compounds capable of combating both forms of damage were identified. Among these, candidate compound X38 demonstrated promising neuroprotective prospects: in vitro, it attenuated glutamate-induced cell apoptosis, while in vivo, it effectively ameliorated retinal thinning and loss of optic nerve electrophysiological function induced by optic nerve injury. Preliminary mechanistic studies suggest that X38 exerts its neuroprotective effects by mitigating intracellular ROS accumulation, inhibiting JNK phosphorylation, and alleviating oxidative stress. Additionally, acute toxicity studies (intraperitoneal injection, 500 mg/kg) underscored the favorable in vivo safety profile of X38. Taken together, this study has designed a class of safe, neuroprotective spirocyclic chalcone derivatives that can be synthesized using green methods, offering an attractive candidate for treating retinal and optic nerve injuries.

Computed Tomography Optic Nerve Sheath Diameter-to-Eyeball Transverse Diameter Ratio as a Novel Noninvasive Parameter for Prognostication in Traumatic Brain Injury.

Background Traumatic brain injury (TBI) remains a foremost cause of death and disability globally, with elevated intracranial pressure (ICP) being a crucial factor in patient outcomes. While invasive monitoring is the gold standard for assessing ICP, it carries risks and is not always feasible. This study proposes a novel noninvasive parameter using computed tomography (CT) imaging. Aims and objectives The study aims to determine the efficacy of the optic nerve sheath diameter (ONSD)-to-eyeball transverse diameter (ETD) ratio from CT scans in predicting TBI patients' prognosis. The primary objective is to study the ONSD/ETD ratio's efficacy in assessing TBI's severity. The secondary objective is to correlate the ONSD/ETD ratio with the Glasgow Coma Scale (GCS) and Rotterdam computed tomography scoring (RCTS) and assess its clinical benefit. Materials and methods This combined retrospective and prospective analytical study included 308 consecutive patients who underwent CT imaging for TBI at a tertiary care center with a dedicated trauma and neurosurgical unit. We evaluated bilateral ONSD and ETD using axial CT scans. The ONSD/ETD ratio correlated with the GCS, RCTS, and clinical outcomes. Results The cut-off values for elevated ICP were ONSD of >5.17 mm, ETD of <22.2 mm, and ONSD/ETD ratio of >0.21. Variables between GCS (<12 and >12) and the ONSD/ETD ratio (<0.21 and >0.21) were statistically significant (chi-square {χ2} = 18.52, p = 0.000). The ONSD shows a strong positive correlation with RCTS (r = 0.82, p = 0.01), ETD shows a moderate negative correlation with RCTS (r = -0.50), and the ONSD/ETD ratio shows a strong negative correlation with GCS (r = -0.783, p = 0.01). The area under the curve for the ONSD/ETD ratio (0.920) was higher than that for ONSD (0.932) and ETD (0.490). The ONSD/ETD ratio's sensitivity, specificity, positive predictive value, and negative predictive value were 100%, 95.6%, 72.0%, and 100%, respectively, demonstrating that it is an excellent predictor of raised ICP. Conclusion The CT-ONSD/ETD ratio correlates with the severity of TBI as assessed by GCS and RCTS. It could serve as a noninvasive parameter for monitoring ICP and guiding the need for sequential CT in TBI patients, potentially aiding in prognostication and clinical management.

Relationship between optic nerve length and interoptic angle in the prediction of optic chiasm location.

INTRODUCTION AND OBJECTIVES: The sellar region is an area in the base of the skull that is among the most common sites for tumors of the central nervous system. Surgical interventions are currently performed via different routes. While the optic chiasm occupies its expected position in 70% of the population, it can deviate from this position. In such cases, surgery involving this region becomes more difficult as the known surgical routes are narrowed. Advance awareness of these variations can help surgeons to identify the optimal route for safe surgical intervention in the sellar region. By performing simple measurements of both the lengths of the optic nerves and the angle between them, a surgeon can predict the location of the chiasm. MATERIALS AND METHODS: Twenty specimens collected from autopsies performed at Bursa Forensic Medicine Institute were examined to determine the optic chiasm types and the relationships between the surrounding subchiasmal structures. RESULTS: Among the 20 specimens, we found two prefixed (10%), 10 normo-fixed (50%), and eight postfixed chiasms (40%). The mean interoptic angle was 81.03 (±17.41)°. Prefixed chiasms had angles in the range 115.36°-124.76 ° (mean 120.06 [±6.65]°), normo-fixed chiasm angles were between 83.11° and 97.53 ° (mean 86.07 [±6.73]°), and postfixed chiasms ranged between 53.01 ° and 78.71 ° (mean 69.20 [±9.13]°). The length of the right optic nerve ranged between 6.95 and 13.83 mm (mean 10.25 [±1.81] mm), and the length of the left between 7.25 and 12.51 mm (mean 10.40 [±1.47] mm). Obtuse angles indicated that the chiasm was prefixed, and acute angles were indicative of a postfixed chiasm. There was a strong negative correlation between optic nerve lengths and the interoptic angle; thus, as the length of the nerves increases, the interoptic angle becomes more acute. CONCLUSIONS: We have proposed a simple measurement of the optic nerve lengths and the angle between them to predict the relative location of the OC, which can be done easily on MRI.

The optic nerve sheath in hypertensive disorders of pregnancy and perinatal outcomes: a cohort study.

BACKGROUND: Preeclampsia is implicated in 14% of maternal deaths worldwide, mostly due to complications such as intracranial hemorrhage and cerebral edema. Cerebral edema increases intracranial pressure, which can be predicted by ultrasonographic measurement of the optic nerve sheath diameter (ONSD). Greater diameters have been reported in women with preeclampsia and eclampsia; however, data are lacking on the possible association with maternal and neonatal adverse outcomes. This study aimed to determine whether there is an association between hypertensive disorders of pregnancy and the ONSD, and between this measurement and maternal and neonatal adverse outcomes. METHODS: This was a cohort study involving 183 women in the third trimester of pregnancy or within 24 h following childbirth, distributed as follows: control group (n = 30), gestational hypertension (n = 14), chronic hypertension (n = 12), preeclampsia without severe features (n = 12), preeclampsia with severe features (n = 62), superimposed preeclampsia (n = 23) and eclampsia (n = 30). The participants underwent ocular ultrasonography, and data on maternal and neonatal outcomes were collected from the medical records. To compare the groups, analysis of variance was used for the normally distributed numerical variables and the Kruskal-Wallis test was used for variables with non-normal distribution. Two-tailed p-values ≤ 0.05 were considered statistically significant. RESULTS: Overall comparison between the seven groups showed no statistically significant difference in the mean ONSD (p = 0.056). Nevertheless, diameters were significantly greater in the eclampsia group compared to the control group (p = 0.003). Greater diameters were associated with maternal admission to the intensive care unit (ICU) (p < 0.01) and maternal near miss (p = 0.01). There was no association between ONSD and admission to the neonatal ICU (p = 0.1), neonatal near miss (p = 0.34) or neonatal death (p = 0.26). CONCLUSIONS: No association was found between ONSD and the hypertensive disorders of pregnancy in the overall analysis; however, ONSD was greater in women with eclampsia compared to controls. Greater diameters were associated with maternal admission to the ICU and maternal near miss. These findings suggest a potential use for bedside ultrasound as an additional tool for stratifying risk in patients with hypertensive disorders of pregnancy.

Treatment of isolated pediatric optic nerve glioma: A nationwide retrospective cohort study and systematic literature review on visual and radiological outcome.

BACKGROUND: Progressive isolated optic nerve glioma (ONG) in children is a rare disease, treated with various modalities. A global treatment consensus is not available. METHODS: We conducted a national retrospective multicenter cohort study (1995-2020) to investigate how different treatment strategies impact outcome for ONG in children, by assessing treatment responses to systemic anticancer therapy (SAT), surgery, and radiotherapy for ONG. The primary endpoints included changes in best-corrected visual acuity (BCVA) and tumor volume (TV) on MRI, both evaluated at the start and end of therapy and at long-term follow up. RESULTS: A total of 21 ONGs (20 patients) received SAT (n = 14 (66.7%)), surgery (n = 4 (19.0%)), and radiotherapy (n = 3 (14.3%)). After SAT BCVA stabilized or improved in 66.6% (n = 4) and the TV decreased by a median of 45.1% (range: -88.6% to +31.5%) (n = 13). Before resection two eyes were already blind. After resection BCVA decreased to blindness in one eye. In total all four eyes were blind after resection. After first-line RT BCVA decreased in 66.7% of ONG to counting fingers or less, TV increased <3 months after RT by a median of 47.3% (range: -42.8% to +245.1%) (n = 3), followed by a long-term decrease of 94.4 and 13.8% (n = 2), respectively. CONCLUSION: SAT appears to be the preferred modality for progressive ONG in case of potential rescue of visual functions. Complete resection of ONG appears effective to reduce proptosis in case of preexisting blindness. The use of radiotherapy requires careful consideration due to the risk of severe visual impairment and secondary disease.

Recognizing Leber's Hereditary Optic Neuropathy to avoid delayed diagnosis and misdiagnosis.

Leber's Hereditary Optic Neuropathy (LHON) is a maternally inherited optic nerve disease primarily caused by mutations in mitochondrial DNA (mtDNA). The peak of onset is typically between 15 and 30 years, but variability exists. Misdiagnosis, often as inflammatory optic neuritis, delays treatment, compounded by challenges in timely genetic diagnosis. Given the availability of a specific treatment for LHON, its early diagnosis is imperative to ensure therapeutic appropriateness. This work gives an updated guidance about LHON differential diagnosis to clinicians dealing also with multiple sclerosi and neuromyelitis optica spectrtum disorders-related optic neuritis. LHON diagnosis relies on clinical signs and paraclinical evaluations. Differential diagnosis in the acute phase primarily involves distinguishing inflammatory optic neuropathies, considering clinical clues such as ocular pain, fundus appearance and visual recovery. Imaging analysis obtained with Optical Coherence Tomography (OCT) assists clinicians in early recognition of LHON and help avoiding misdiagnosis. Genetic testing for the three most common LHON mutations is recommended initially, followed by comprehensive mtDNA sequencing if suspicion persists despite negative results. We present and discuss crucial strategies for accurate diagnosis and management of LHON cases.

Axon guidance during mouse central nervous system regeneration is required for specific brain innervation.

Reconstructing functional neuronal circuits is one major challenge of central nervous system repair. Through activation of pro-growth signaling pathways, some neurons achieve long-distance axon regrowth. Yet, functional reconnection has hardly been obtained, as these regenerating axons fail to resume their initial trajectory and reinnervate their proper target. Axon guidance is considered to be active only during development. Here, using the mouse visual system, we show that axon guidance is still active in the adult brain in regenerative conditions. We highlight that regenerating retinal ganglion cell axons avoid one of their primary targets, the suprachiasmatic nucleus (SCN), due to Slit/Robo repulsive signaling. Together with promoting regeneration, silencing Slit/Robo in vivo enables regenerating axons to enter the SCN and form active synapses. The newly formed circuit is associated with neuronal activation and functional recovery. Our results provide evidence that axon guidance mechanisms are required to reconnect regenerating axons to specific brain nuclei.

Emergency Endoscopic Endonasal Optic Nerve Decompression for Graves' Orbitopathy.

Graves' orbitopathy (GO) is a rare autoimmune disease that affects patients in their fourth to sixth decade, resulting in retro-orbital inflammation and hypertrophy of extraocular muscles and orbital fat. It is the most common disease affecting the orbit globally, and treatment options vary depending on the severity and activity status of the affection, ranging from local measures such as lubricating eye drops and patching, glucocorticoid eye drops, mydriatics, nonsteroid anti-inflammatory medications to systemic glucocorticoids, and emergency orbital decompression surgery. Immunotherapy and orbital radiation may as well be used as a treatment option even though their efficiency remains controversial. This paper presents the cases of two patients with GO who underwent endoscopic endonasal decompressive surgery. These patients' medical records, including symptoms and duration, clinical examination, imaging results, preoperative preparation, surgery steps, and postoperative course and outcomes, were collected from various specialties, including ophthalmologists and endocrinologists. We highlight the importance of a multidisciplinary approach to managing GO and its complications, with endoscopic endonasal techniques emerging as a minimally invasive and effective way to treat compressive optic nerve forms of the disease. However, the timing of decompression remains crucial, and early intervention is recommended to avoid sight-threatening ophthalmopathy when medical therapies are ineffective.

Investigating Optic Nerve Sheath Diameter in Prone Position Spinal Surgery Patients: A Pilot Study.

Purpose: This study aimed to evaluate the effect of intraoperative positioning and ocular immobility on the amount of cerebrospinal fluid around the optic nerve in patients undergoing prone spinal surgery by measuring the optic nerve sheath diameter (ONSD) using ultrasound. Methods: Consecutive participants (n = 15 patients, 30 eyes) were scanned preoperatively, intraoperatively approximately 20 minutes before the end of the surgery, and postoperatively in the post-anesthesia care unit at least 10 min after the completion of the surgery at one academic hospital. Results: On average, patients who underwent prone spinal surgery had a 21% increase in ONSD intraoperatively, with a positive time-dependent relationship with the overall length of surgery (P < 0.001). ONSDs postoperatively returned to baseline and were not significantly different from preoperative measurements. Conclusion: Our findings suggest pooling and inadequate clearance of perioptic cerebrospinal fluid during prone spinal surgery that improves following termination of the procedure and return of the patient to an upright position.

CHARGE syndrome in a child with a CHD7 variant and a novel pathogenic SOX2 variant: A case report.

CHARGE syndrome is a clinically heterogeneous condition that typically presents with a loss-of-function mutation in CHD7. SOX2 anophthalmia syndrome is a rare condition associated with hypogonadism and hearing loss. Herein, we describe the case of a Japanese boy presenting with a micropenis, bilateral cryptorchidism, cupped ear, right facial nerve palsy, and bilateral hearing loss, clinically meeting the diagnostic criteria for CHARGE syndrome, but with optic nerve hypoplasia, which is atypical for the syndrome. Therefore, a genetic analysis (next-generation sequencing) was performed. In addition to the missense variant p.[Arg1940Cys] in CHD7, a novel nonsense variant, p. [Tyr110*] in SOX2 was identified. Although most features, including genital abnormalities and hearing loss, were clinically compatible with CHARGE syndrome caused by a CHD7 variant, optic nerve hypoplasia may have been caused by a pathogenic SOX2 variant. Prior research has shown that SOX2 is related to the development of male genitalia and the inner ear. Therefore, the genital abnormalities and hearing loss in this patient may be attributed to both the CHD7 and SOX2 variants. Furthermore, the interactions between SOX2 and CHD7 may have affected symptoms independently or reciprocally.

Prevalence and associations of parapapillary scleral ridges: the Beijing Eye Study.

PURPOSE: To explore the prevalence and associated factors of parapapillary scleral ridges (PSRs). METHODS: Out of the cohort of the population-based Beijing Eye Study (n=3468 participants), the study included all eyes with an axial length of ≥25 mm and a randomised sample of eyes with an axial length of <25 mm. Using optical coherence tomographic (OCT) images and fundus photographs, we examined the presence and height of PSRs, defined as a ridge-like structure located on the OCT scans in the parapapillary region. RESULTS: The study cohort consisted of 366 eyes (314 individuals; mean age: 63.7±9.7 years). PSR prevalence increased from 0% in the non-myopic group to 3.8% (95% CI 0.3%, 7.3%) in moderately myopic group and 29.2% (95% CI 15.7%, 42.5%) in the highly myopic group. All PSRs were located in the temporal parapapillary gamma zone and corresponded to an ophthalmoscopically visible demarcation line running almost parallel to the optic disc border. Higher PRS prevalence correlated with longer axial length (OR 2.98; 95% CI 1.99, 4.46; p<0.001), female sex (OR 6.48; 95% CI 1.56, 27.0; p=0.01) and older age (OR 1.09; 95% CI 1.01, 1.18; p=0.02). Axial length had the strongest influence (beta: 0.48), followed by sex (beta: 0.20) and age (beta: 0.14). If age was dropped from the multivariable model, myopic maculopathy prevalence (OR 10.0; 95% CI 1.41,70.9; p=0.02) and stage (OR 3.57; 95% CI 1.21, 10.6; p=0.02) became significantly correlated with higher PSR prevalence. CONCLUSIONS: With a PSR prevalence of >60% in eyes with an axial length of >28 mm, PSRs are a common morphological feature of high myopia, with age and female sex as additional associated factors. PSRs may be due to a biomechanical interplay between the optic nerve and the posterior ocular segment of markedly axially elongated eyes.

Differences and Similarities Between Primary Open Angle Glaucoma and Primary Angle-Closure Glaucoma.

Glaucoma is the leading cause of irreversible blindness worldwide. It is an ocular disease characterized by an increase in intraocular pressure or, in some cases, normal intraocular pressure, which leads to optic nerve damage and progressive constriction of the visual field (VF). Primary Open-Angle Glaucoma (POAG) and Primary Angle-Closure Glaucoma (PACG) represent the predominant forms of glaucoma. Numerous hypotheses have been posited to elucidate the pathogenic mechanisms underlying these conditions. There is an emerging understanding of the distinct pathological processes that differentiate the various types of glaucoma. While some similarities in the mechanisms between PACG and POAG have been suggested, evidence indicates that there are also significant differences between the two. This review synthesizes the similarities and differences in the etiology of optic neuropathy caused by POAG and PACG, considering their respective pathophysiological mechanisms, the morphology of the optic disc and surrounding tissues, genetic characteristics, optical coherence tomography angiography, optical coherence tomography, and structural and functional features from VF examinations. These characteristics may contribute to a deeper comprehension of the underlying pathogenesis of glaucoma and enhance the management of different types of this ocular condition.

The Neuroprotective Effect of Erythropoietin on the Optic Nerve and Spinal Cord in Rats with Experimental Autoimmune Encephalomyelitis through the Activation of the Extracellular Signal-Regulated Kinase 1/2 Signaling Pathway.

Experimental autoimmune encephalomyelitis is a demyelinating disease that causes paralysis in laboratory rats. This condition lacks treatment that reverses damage to the myelin sheaths of neuronal cells. Therefore, in this study, treatment with EPO as a neuroprotective effect was established to evaluate the ERK 1/2 signaling pathway and its participation in the EAE model. EPO was administered in 5000 U/Kg Sprague Dawley rats. U0126 was used as an inhibitor of the ERK 1/2 pathway to demonstrate the possible activation of this pathway in the model. Spinal cord and optic nerve tissues were evaluated using staining techniques such as H&E and the Luxol Fast Blue myelin-specific technique, as well as immunohistochemistry of the ERK 1/2 protein. The EPO-treated groups showed a decrease in cellular sampling in the spinal cord tissues but mainly in the optic nerve, as well as an increase in the expression of the ERK 1/2 protein in both tissues. The findings of this study suggest that EPO treatment reduces cellular death in EAE-induced rats by regulating the ERK pathway.

Optic Nerve Microvascular Decompression for Carotid Dolichoectasia.

Vascular compression of the optic nerve in a patient with rapid monocular vision loss with otherwise negative diagnostic workup is a rare, but controversial dilemma. The literature is conflicted, advocating for either timely surgical decompression to preserve vision1-6 or observation only given the prevalence of asymptomatic vascular compression and observed arrest of visual decline.7-10 The most frequently reported sources of symptomatic compression are unruptured aneurysms and dolichoectatic vasculature,1-6 with recent consensus reached over a need for extensive perioperative ophthalmologic evaluations and follow-up. We present an illustrative case for microvascular decompression of the prechiasmatic optic nerve. Video footage of the operative management of microvascular optic nerve compression is exceedingly rare.5,6 A 50-year-old man with a past medical history of hypertension and substance use presented with a 1-week history of progressive right nasal hemianopsia (Video 1). After a negative stroke workup, magnetic resonance imaging of the brain showed prechiasmatic displacement of the right optic nerve by the right supraclinoid internal carotid artery. Formal cerebral arteriography showed a left-sided fetal posterior cerebral artery and patent vasculature without a causative lesion. Given isolated right eye symptoms and rapid progression, a right orbitozygomatic craniotomy for microvascular decompression was recommended. The patient consented to the procedure and to the publication of his image. Intraoperatively, a right calcified dolichoectatic supraclinoid internal carotid artery was found to be severely displacing and tethering its ipsilateral optic nerve. Optic canal deroofing, detethering of the optic nerve, and polytetrafluoroethylene (Teflon) patch placement was performed to achieve this decompression. His postoperative course was uncomplicated; only mild improvement of his visual symptoms was noted at 1- and 3-month follow-up. Formal acuity and computerized assessments of vision and extensive follow-up are critical for evaluating the true clinical outcome of patients with microvascular optic nerve compression.

Morphological comparison of astrocytes in the lamina cribrosa and glial lamina.

Purpose: Although the mechanisms underlying glaucomatous neurodegeneration are not yet well understood, cellular and small animal models suggest that LC astrocytes undergo early morphologic and functional changes, indicating their role as early responders to glaucomatous stress. These models, however, lack the LC found in larger animals and humans, leaving the in situ morphology of LC astrocytes and their role in glaucoma initiation underexplored. In this work, we aimed to characterize the morphology of LC astrocytes in situ and determine differences and similarities with astrocytes in the mouse glial lamina (GL), the analogous structure in a prominent glaucoma model. Methods: Astrocytes in the LCs of twenty-two eyes from goats, sheep, and pigs were stochastically labeled via Multicolor DiOlistics and imaged in situ using confocal microscopy. 3D models of DiOlistically-labeled LC astrocytes and hGFAPpr-GFP mouse GL astrocytes were constructed to quantify morphological features related to astrocyte functions. LC and GL astrocyte cross-pore contacts, branching complexity, branch tortuosity, and cell and branch span were compared. Results: LC astrocytes displayed distinct spatial relationships with collagen, greater branching complexity, and higher branch tortuosity compared to GL astrocytes. Despite substantial differences in their anatomical environments, LC and GL astrocytes had similar cell and branch spans. Conclusions: Astrocyte morphology in the LC was characterized through Multicolor DiOlistic labeling. LC and GL astrocytes have both distinct and shared morphological features. Further research is needed to understand the potentially unique roles of LC astrocytes in glaucoma initiation and progression.

Retinal damage promotes mitochondrial transfer in the visual system of a mouse model of Leber hereditary optic neuropathy.

Lenadogene nolparvovec is a gene therapy which has been developed to treat Leber hereditary optic neuropathy (LHON) caused by a point mutation in the mitochondrial NADH dehydrogenase 4 (ND4) gene. Clinical trials have demonstrated a significant improvement of visual acuity up to 5 years after treatment by lenadogene nolparvovec but, surprisingly, unilateral treatment resulted in bilateral improvement of vision. This contralateral effect - similarly observed with other gene therapy products in development for MT-ND4-LHON - is supported by the migration of viral vector genomes and their transcripts to the contralateral eye, as reported in animals, and post-mortem samples from two patients. In this study, we used an AAV2 encoding fluorescent proteins targeting mitochondria to investigate whether these organelles themselves could transfer from the treated eye to the fellow one. We found that mitochondria travel along the visual system (optic chiasm and primary visual cortex) and reach the contralateral eye (optic nerve and retina) in physiological conditions. We also observed that, in a rotenone-induced model of retinal damage mimicking LHON, mitochondrial transfer from the healthy to the damaged eye was accelerated and enhanced. Our results thus provide a further explanation for the contralateral beneficial effect observed during clinical studies with lenadogene nolparvovec.

Outcomes of five cases of retinoblastoma with optic nerve invasion on imaging.

PURPOSE: To investigate the timing of enucleation, treatment course, and outcome for retinoblastoma (RB) with optic nerve (ON) invasion on imaging. STUDY DESIGN: Retrospective clinical study. METHODS: Of the 160 patients with RB who presented to the National Center for Child Health and Development in Japan between 2005 and 2022, ON invasion on imaging at the initial presentation was seen in five patients. The clinical, computed tomography (CT), and magnetic resonance imaging (MRI) findings, and treatment courses were reviewed retrospectively. RESULTS: MRI showed ON invasion in all five patients (three with unilateral RB, 2 with bilateral RB); in two patients CT detected no invasion. Enucleation was performed in four patients, three of whom underwent neoadjuvant therapy and one had a positive ON resection margin following the enucleation as initial treatment. One patient did not undergo enucleation due to cerebrospinal fluid dissemination. All enucleated patients underwent adjuvant chemotherapy. Four patients underwent radiotherapy. During follow-up (mean, 89.4 months), four patients survived and one died. CONCLUSION: MRI is recommended to evaluate ON invasion and determine the timing of enucleation for RB. The appropriate choice of neoadjuvant or adjuvant therapy would be helpful to avoid radiotherapy for RB with ON invasion on imaging.

Gene and cell-based therapies for retinal and optic nerve disease.

Leading causes of blindness worldwide include neurodegenerative diseases of the retina, which cause irreversible loss of retinal pigment epithelium (RPE) and photoreceptors, and optic neuropathies, which result in retinal ganglion cell (RGC) death. Because photoreceptor and RGCs do not spontaneously regenerate in mammals, including humans, vision loss from these conditions is, at present, permanent. Recent advances in gene and cell-based therapies have provided new hope to patients affected by these conditions. This chapter reviews the current state and future of these approaches to treating ocular neurodegenerative disease. Gene therapies for retinal degeneration and optic neuropathies primarily focus on correcting known pathogenic mutations that cause inherited conditions to halt progression. There are multiple retinal and optic neuropathy gene therapies in clinical trials, and one retinal gene therapy is approved in the United States, Canada, Europe, and Australia. Cell-based therapies are mutation agnostic and have the potential to repopulate neurons regardless of the underlying etiology of degeneration. While photoreceptor cell replacement is nearing a human clinical trial, RPE transplantation is currently in phase I/II clinical trials. RGC replacement faces numerous logistical challenges, but preclinical research has laid the foundation for functional repair of optic neuropathies to be feasible.

Comparing continuum and direct fiber models of soft tissues. An ocular biomechanics example reveals that continuum models may artificially disrupt the strains at both the tissue and fiber levels.

Collagen fibers are the main load-bearing component of soft tissues but difficult to incorporate into models. Whilst simplified homogenization models suffice for some applications, a thorough mechanistic understanding requires accurate prediction of fiber behavior, including both detailed fiber-level strains and long-distance transmission. Our goal was to compare the performance of a continuum model of the optic nerve head (ONH) built using conventional techniques with a fiber model we recently introduced which explicitly incorporates the complex 3D organization and interaction of collagen fiber bundles [1]. To ensure a fair comparison, we constructed the continuum model with identical geometrical, structural, and boundary specifications as for the fiber model. We found that: 1) although both models accurately matched the intraocular pressure (IOP)-induced globally averaged displacement responses observed in experiments, they diverged significantly in their ability to replicate specific 3D tissue-level strain patterns. Notably, the fiber model faithfully replicated the experimentally observed depth-dependent variability of radial strain, the ring-like pattern of meridional strain, and the radial pattern of circumferential strain, whereas the continuum model failed to do so; 2) the continuum model disrupted the strain transmission along each fiber, a feature captured well by the fiber model. These results demonstrate limitations of the conventional continuum models that rely on homogenization and affine deformation assumptions, which render them incapable of capturing some complex tissue-level and fiber-level deformations. Our results show that the strengths of explicit fiber modeling help capture intricate ONH biomechanics. They potentially also help modeling other fibrous tissues.

Impact of elevated IOP on lamina cribrosa oxygenation; A combined experimental-computational study on monkeys.

Purpose: Our goal is to evaluate how lamina cribrosa (LC) oxygenation is affected by the tissue distortions resulting from elevated IOP. Design: Experimental study on monkeys. Subjects: Four healthy monkey eyes with OCT scans with IOP of 10 to 50 mmHg, and then with histological sections of LC. Methods: Since in-vivo LC oxygenation measurement is not yet possible, we used 3D eye-specific numerical models of the LC vasculature which we subjected to experimentally-derived tissue deformations. We reconstructed 3D models of the LC vessel networks of 4 healthy monkey eyes from histological sections. We also obtained in-vivo IOP-induced tissue deformations from a healthy monkey using OCT images and digital volume correlation analysis techniques. The extent that LC vessels distort under a given OCT-derived tissue strain remains unknown. We biomechanics-based mapping techniques: cross-sectional and isotropic. The hemodynamics and oxygenations of the four vessel networks were simulated for deformations at several IOPs up to 60mmHg. The results were used to determine the effects of IOP on LC oxygen supply, assorting the extent of tissue mild and severe hypoxia. Main Outcome Measures: IOP-induced deformation, vasculature structure, blood supply, and oxygen supply for LC region. Result: IOP-induced deformations reduced LC oxygenation significantly. More than 20% of LC tissue suffered from mild hypoxia when IOP reached 30 mmHg. Extreme IOP(>50mmHg) led to large severe hypoxia regions (>30%) in the isotropic mapping cases. Conclusion: Our models predicted that moderately elevated IOP can lead to mild hypoxia in a substantial part of the LC, which, if sustained chronically, may contribute to neural tissue damage. For extreme IOP elevations, severe hypoxia was predicted, which would potentially cause more immediate damage. Our findings suggest that despite the remarkable LC vascular robustness, IOP-induced distortions can potentially contribute to glaucomatous neuropathy.