Efficacy and Safety of Intravitreal Gene Therapy for Leber Hereditary Optic Neuropathy Treated within 6 Months of Disease Onset.

PURPOSE: To evaluate the efficacy of a single intravitreal injection of rAAV2/2-ND4 in subjects with visual loss from Leber hereditary optic neuropathy (LHON). DESIGN: RESCUE is a multicenter, randomized, double-masked, sham-controlled, phase 3 clinical trial. PARTICIPANTS: Subjects with the m.11778G>A mitochondrial DNA mutation and vision loss ≤6 months from onset in 1 or both eyes were included. METHODS: Each subject's right eye was randomly assigned (1:1) to treatment with rAAV2/2-ND4 (single injection of 9 × 1010 viral genomes in 90 µl) or to sham injection. The left eye received the treatment not allocated to the right eye. MAIN OUTCOME MEASURES: The primary end point was the difference of the change from baseline in best-corrected visual acuity (BCVA) between rAAV2/2-ND4-treated and sham-treated eyes at week 48. Other outcome measures included contrast sensitivity, Humphrey visual field perimetry, retinal anatomic measures, and quality of life. Follow-up extended to week 96. RESULTS: Efficacy analysis included 38 subjects. Mean age was 36.8 years, and 82% were male. Mean duration of vision loss at time of treatment was 3.6 months and 3.9 months in the rAAV2/2-ND4-treated eyes and sham-treated eyes, respectively. Mean baseline logarithm of the minimum angle of resolution (logMAR) BCVA (standard deviation) was 1.31 (0.52) in rAAV2/2-ND4-treated eyes and 1.26 (0.62) in sham-treated eyes, with a range from -0.20 to 2.51. At week 48, the difference of the change in BCVA from baseline between rAAV2/2-ND4-treated and sham-treated eyes was -0.01 logMAR (P = 0.89); the primary end point of a -0.3 logMAR (15-letter) difference was not met. The mean BCVA for both groups deteriorated over the initial weeks, reaching the worst levels at week 24, followed by a plateau phase until week 48, and then an improvement of +10 and +9 Early Treatment Diabetic Retinopathy Study letters equivalent from the plateau level in the rAAV2/2-ND4-treated and sham-treated eyes, respectively. CONCLUSIONS: At 96 weeks after unilateral injection of rAAV2/2-ND4, LHON subjects carrying the m.11778G>A mutation treated within 6 months after vision loss achieved comparable visual outcomes in the injected and uninjected eyes.

Cross-Sectional Analysis of Baseline Visual Parameters in Subjects Recruited Into the RESCUE and REVERSE ND4-LHON Gene Therapy Studies.

OBJECTIVE: This report presents a cross-sectional analysis of the baseline characteristics of subjects with Leber hereditary optic neuropathy enrolled in the gene therapy trials RESCUE and REVERSE, to illustrate the evolution of visual parameters over the first year after vision loss. METHODS: RESCUE and REVERSE were 2 phase III clinical trials designed to assess the efficacy of rAAV2/2-ND4 gene therapy in ND4-LHON subjects. At enrollment, subjects had vision loss for ≤6 months in RESCUE, and between 6 and 12 months in REVERSE. Functional visual parameters (best-corrected visual acuity [BCVA], contrast sensitivity [CS], and Humphrey Visual Field [HVF]) and structural parameters assessed by spectral-domain optical coherence tomography were analyzed in both cohorts before treatment. The cross-sectional analysis of functional and anatomic parameters included the baseline values collected in all eyes at 2 different visits (Screening and Inclusion). RESULTS: Seventy-six subjects were included in total, 39 in RESCUE and 37 in REVERSE. Mean BCVA was significantly worse in RESCUE subjects compared with REVERSE subjects (1.29 and 1.61 LogMAR respectively, P = 0.0029). Similarly, mean CS and HVF were significantly more impaired in REVERSE vs RESCUE subjects (P < 0.005). The cross-sectional analysis showed that the monthly decrease in BCVA, ganglion cell layer macular volume, and retinal nerve fiber layer thickness was much more pronounced in the first 6 months after onset (+0.24 LogMAR, -0.06 mm3, and -6.00 µm respectively) than between 6 and 12 months after onset (+0.02 LogMAR, -0.01 mm3, and -0.43 µm respectively). CONCLUSION: LHON progresses rapidly in the first months following onset during the subacute phase, followed by relative stabilization during the dynamic phase.

Bilateral visual improvement with unilateral gene therapy injection for Leber hereditary optic neuropathy.

REVERSE is a randomized, double-masked, sham-controlled, multicenter, phase 3 clinical trial that evaluated the efficacy of a single intravitreal injection of rAAV2/2-ND4 in subjects with visual loss from Leber hereditary optic neuropathy (LHON). A total of 37 subjects carrying the m.11778G>A (MT-ND4) mutation and with duration of vision loss between 6 to 12 months were treated. Each subject's right eye was randomly assigned in a 1:1 ratio to treatment with rAAV2/2-ND4 (GS010) or sham injection. The left eye received the treatment not allocated to the right eye. Unexpectedly, sustained visual improvement was observed in both eyes over the 96-week follow-up period. At week 96, rAAV2/2-ND4-treated eyes showed a mean improvement in best-corrected visual acuity (BCVA) of -0.308 LogMAR (+15 ETDRS letters). A mean improvement of -0.259 LogMAR (+13 ETDRS letters) was observed in the sham-treated eyes. Consequently, the primary end point, defined as the difference in the change in BCVA from baseline to week 48 between the two treatment groups, was not met (P = 0.894). At week 96, 25 subjects (68%) had a clinically relevant recovery in BCVA from baseline in at least one eye, and 29 subjects (78%) had an improvement in vision in both eyes. A nonhuman primate study was conducted to investigate this bilateral improvement. Evidence of transfer of viral vector DNA from the injected eye to the anterior segment, retina, and optic nerve of the contralateral noninjected eye supports a plausible mechanistic explanation for the unexpected bilateral improvement in visual function after unilateral injection.

Immune Response and Intraocular Inflammation in Patients With Leber Hereditary Optic Neuropathy Treated With Intravitreal Injection of Recombinant Adeno-Associated Virus 2 Carrying the ND4 Gene: A Secondary Analysis of a Phase 1/2 Clinical Trial.

Importance: Intravitreal gene therapy is regarded as generally safe with limited mild adverse events, but its systemic effects remain to be investigated. Objective: To examine the association between immune response and intraocular inflammation after ocular gene therapy with recombinant adeno-associated virus 2 carrying the ND4 gene (rAAV2/2-ND4). Design, Setting, and Participants: This secondary analysis of an open-label, dose-escalation phase 1/2 randomized clinical trial of rAAV2/2-ND4 included data from February 13, 2014 (first patient visit), to March 30, 2017 (last patient visit at week 96), the first 2 years after injection. Patients older than 15 years with diagnosed ND4 Leber hereditary optic neuropathy (LHON) and visual acuity of at least counting fingers were enrolled in 1 of 5 cohorts. Four dose cohorts of 3 patients each were treated sequentially. An extension cohort of 3 patients received the dose of 9 × 1010 viral genomes per eye. Interventions: Patients received increasing doses of rAAV2/2-ND4 (9 × 109, 3 × 1010, 9 × 1010, and 1.8 × 1011 viral genomes per eye) as a single unilateral intravitreal injection. Patients were monitored for 96 weeks after injection; ocular examinations were performed regularly, and blood samples were collected for immunologic testing. Main Outcomes and Measures: A composite ocular inflammation score (OIS) was calculated based on grades of anterior chamber cells and flare, vitreous cells, and haze according to the Standardization of Uveitis Nomenclature. The systemic immune response was quantified by enzyme-linked immunospot (cellular immune response), enzyme-linked immunosorbent assay (IgG titers), and luciferase assay (neutralizing antibody [NAb] titers). Results: The present analysis included 15 patients (mean [SD] age, 47.9 [17.2] years; 13 men and 2 women) enrolled in the 5 cohorts of the clinical trial. Thirteen patients experienced intraocular inflammation after rAAV2/2-ND4 administration. Mild anterior chamber inflammation and vitritis were reported at all doses, and all cases were responsive to treatment. A maximum OIS of 9.5 was observed in a patient with history of idiopathic uveitis. Overall, OIS was not associated with the viral dose administered. No NAbs against AAV2 were detected in aqueous humor before treatment. Two patients tested positive for cellular immune response against AAV2 at baseline and after treatment. Humoral immune response was not apparently associated with the dose administered or with the immune status of patients at baseline. No association was found between OISs and serum NAb titers. Conclusions and Relevance: In this study, intravitreal administration of rAAV2/2-ND4 in patients with LHON was safe and well tolerated. Further investigations may shed light into the local immune response to rAAV2/2-ND4 as a potential explanation for the observed intraocular inflammation.

Non-arteritic ischemic optic neuropathy and supplemental nitric oxide usage.

PURPOSE: To report a case of Non-Arteritic Ischemic Optic Neuropathy (NAION) in a middle-aged bodybuilder in excellent physiological condition without any signs or symptoms of vasculopathy and a history of nitric oxide supplement usage. OBSERVATIONS: The patient had visual acuity of 20/25 in the right eye, and 20/30 in the left eye, with a relative afferent pupillary defect and dyschromatopsia in the right eye. Visual field testing with Humphrey perimetry demonstrated an inferior altitudinal field defect OD. Fundus examination showed a small cupless disc OD with mild pallor, and a small cupless disc OS. He denied usage of sildenafil or other phosphodiesterase (PDE) inhibitor medications but frequently ingested megadoses of nitric oxide (NO) as part of his bodybuilding regimen. CONCLUSIONS: Nitric oxide supplements act through the same pharmacologic pathway as PDE inhibitors, and this case is suggestive that other vasodilating agents may be similarly associated with NAION.

Identification and quantification of thymosin beta4 in human saliva and tears.

Thymosin beta(4) (Tbeta(4)) is a ubiquitous, naturally occurring, 43-amino acid peptide that takes part in several biological activities including angiogenesis, inhibition of inflammation, wound healing, chemotaxis, and endothelial cell migration. Recent studies also indicate that Tbeta(4) accelerates corneal wound healing and downregulates several proinflamatory chemokines and cytokines. In this study, we sought to determine whether Tbeta(4) is naturally occurring in human tears and other human bodily fluids, such as saliva. Tear and saliva samples were analyzed by EIA to identify and quantify the amount of Tbeta(4) present. Around 10-20 samples were collected from each of three different age groups: 15-20, 25-35, and >50 years old with n = 30 and n = 60 for tears and saliva, respectively. Exclusion criteria included the use of any topical ophthalmic or topical oral medication and/or history of ocular or oral surgery within the past 6 months. Tears were collected from both eyes using Schirmer's strips. Saliva samples were collected in sterile tubes and were then centrifuged to remove solid particles. Tbeta(4) was found in tear and saliva samples in all age groups. The concentrations ranged from 0.5-7 mug/mL in tears and 0.2-3.6 mug/mL in saliva. In both fluids, Tbeta(4) concentration varied with age and appeared to peak at ages 25-35 years. Studies are in progress to determine if Tbeta(4) levels in saliva and tears demonstrate a circadian rhythm during a 24-h period, as well as to confirm that they vary with age and to explore if they vary with diseased states. This is the first study to report the presence of Tbeta(4) in human tears and saliva. This finding raises the possibility that Tbeta(4) acts as an endogenous agent contributing to the rapid healing of corneal and oral wounds. Considering that Tbeta(4) facilitates reepithelialization and modulates anti-inflammatory mediators, Tbeta(4) could potentially be used therapeutically in the treatment of (a) ocular surface disease and injury of eye and (b) various oral disorders, such as periodontal disease.

Vascular endothelial growth factor and the potential therapeutic use of pegaptanib (macugen) in diabetic retinopathy.

Both clinical and preclinical findings have implicated vascular endothelial growth factor (VEGF) in the pathophysiology of diabetic macular edema (DME). VEGF is both a potent enhancer of vascular permeability and a key inducer of angiogenesis. VEGF levels are elevated in the eyes of patients with DME, and in animal models of diabetes this elevation coincides with the breakdown of the blood-retinal barrier. Moreover, injection of VEGF (the VEGF165 isoform in particular) into healthy eyes of animals can induce diabetes-associated ocular pathologies.Pegaptanib, a novel RNA aptamer currently used in the treatment of agerelated macular degeneration, binds and inactivates VEGF165 and has been shown in animal models to reverse the blood-retinal barrier breakdown associated with diabetes. These findings formed the basis of a phase II trial involving 172 patients with DME, in which intravitreous pegaptanib (0.3 mg, 1 mg, 3 mg) or sham injections were administered every 6 weeks for 12 weeks, with the option of continuing for 18 more weeks or undergoing laser treatment. Compared to sham, patients receiving 0.3 mg displayed superior visual acuity (p = 0.04) as well as a reduction in retinal thickness of 68 micrometers compared to a slight increase under sham treatment (p = 0.021). These data support the use of pegaptanib in the treatment of DME.

A phase II randomized double-masked trial of pegaptanib, an anti-vascular endothelial growth factor aptamer, for diabetic macular edema.

OBJECTIVE: To evaluate the safety and efficacy of pegaptanib sodium injection (pegaptanib) in the treatment of diabetic macular edema (DME). DESIGN: Randomized, double-masked, multicenter, dose-ranging, controlled trial. PARTICIPANTS: Individuals with a best-corrected visual acuity (VA) between 20/50 and 20/320 in the study eye and DME involving the center of the macula for whom the investigator judged photocoagulation could be safely withheld for 16 weeks. INTERVENTION: Intravitreous pegaptanib (0.3 mg, 1 mg, 3 mg) or sham injections at study entry, week 6, and week 12 with additional injections and/or focal photocoagulation as needed for another 18 weeks. Final assessments were conducted at week 36. MAIN OUTCOME MEASURES: Best-corrected VA, central retinal thickness at the center point of the central subfield as assessed by optical coherence tomography measurement, and additional therapy with photocoagulation between weeks 12 and 36. RESULTS: One hundred seventy-two patients appeared balanced for baseline demographic and ocular characteristics. Median VA was better at week 36 with 0.3 mg (20/50), as compared with sham (20/63) (P = 0.04). A larger proportion of those receiving 0.3 mg gained VAs of > or =10 letters (approximately 2 lines) (34% vs. 10%, P = 0.003) and > or =15 letters (18% vs. 7%, P = 0.12). Mean central retinal thickness decreased by 68 microm with 0.3 mg, versus an increase of 4 microm with sham (P = 0.02). Larger proportions of those receiving 0.3 mg had an absolute decrease of both > or =100 microm (42% vs. 16%, P = 0.02) and > or =75 microm (49% vs. 19%, P = 0.008). Photocoagulation was deemed necessary in fewer subjects in each pegaptanib arm (0.3 mg vs. sham, 25% vs. 48%; P = 0.04). All pegaptanib doses were well tolerated. Endophthalmitis occurred in 1 of 652 injections (0.15%/injection; i.e., 1/130 [0.8%] pegaptanib subjects) and was not associated with severe visual loss. CONCLUSIONS: In this phase II trial, subjects assigned to pegaptanib had better VA outcomes, were more likely to show reduction in central retinal thickness, and were deemed less likely to need additional therapy with photocoagulation at follow-up.

Gaze-evoked amaurosis from vitreopapillary traction.

PURPOSE: We report four patients with gaze-evoked amaurosis attributable to incomplete posterior vitreous detachment and ensuing vitreopapillary traction. We present these cases to illustrate and extend the spectrum of vitreopapillary syndromes and to draw attention to vitreopapillary traction and its expected manifestations in both optic disk appearance and optic nerve and retinal function. DESIGN: This is a retrospective observational case series culled from tertiary neuro-ophthalmology practice. METHODS: Patients were evaluated with direct and indirect ophthalmoscopy, Hruby (precorneal) lens, three-mirror Goldmann contact lens, macular contact lens, formal perimetry, fundus photography, fluorescein angiography, and orbital ultrasound. RESULTS: Four patients with gaze-evoked amaurosis had disk edema associated with a partial posterior vitreous separation. These patients were young and had atypical posterior vitreous detachments characterized by persisting vitreopapillary attachments. CONCLUSIONS: Gaze-evoked amaurosis is a rare visual obscuration precipitated by changes in volitional gaze, usually associated with an underlying orbital mass. We extend its etiologies to implicate the vitreous through traction expressed at the optic disk. In our cases, vitreopapillary traction elevated the nerve head and eye movements precipitated transient visual phosphenes followed by gaze-evoked amaurosis caused by traction transmitted from the vitreous to superficial nerve fibers of the retina and disk.

Neurologic impairment 10 years after optic neuritis.

BACKGROUND: Participants enrolled in the Optic Neuritis Treatment Trial have been observed for more than a decade to assess the relationship between optic neuritis and the development of clinically definite multiple sclerosis. OBJECTIVE: To assess neurologic disability 10 to 12 years after an initial episode of optic neuritis. DESIGN: Longitudinal follow-up of a clinical trial. SETTING: Fourteen Optic Neuritis Treatment Trial clinical centers performed standardized neurologic examinations, including an assessment of neurologic disability. PARTICIPANTS: One hundred twenty-seven patients who had developed clinically definite multiple sclerosis. MAIN OUTCOME MEASURES: Functional Systems Scale and Expanded Disability Status Scale. RESULTS: The disability of most patients was mild, with 65% of patients having an Expanded Disability Status Scale score lower than 3.0. The degree of disability appeared to be unrelated to whether the baseline magnetic resonance imaging scan was lesion-free or showed lesions (P =.51). Among patients with baseline lesions, the degree of disability was unrelated to the number of lesions that were present on the scan (P =.14). Two patients died owing to severe multiple sclerosis, one of whom had no lesions revealed on the baseline scan. CONCLUSION: Most patients who develop clinically definite multiple sclerosis following an initial episode of optic neuritis will have a relatively benign course for at least 10 years.

High- and low-risk profiles for the development of multiple sclerosis within 10 years after optic neuritis: experience of the optic neuritis treatment trial.

OBJECTIVE: To identify factors associated with a high and low risk of developing multiple sclerosis after an initial episode of optic neuritis. METHODS: Three hundred eighty-eight patients who experienced acute optic neuritis between July 1, 1988, and June 30, 1991, were followed up prospectively for the development of multiple sclerosis. Consenting patients were reassessed after 10 to 13 years. RESULTS: The 10-year risk of multiple sclerosis was 38% (95% confidence interval, 33%-43%). Patients (160) who had 1 or more typical lesions on the baseline magnetic resonance imaging (MRI) scan of the brain had a 56% risk; those with no lesions (191) had a 22% risk (P<.001, log rank test). Among the patients who had no lesions on MRI, male gender and optic disc swelling were associated with a lower risk of multiple sclerosis, as was the presence of the following atypical features for optic neuritis: no light perception vision; absence of pain; and ophthalmoscopic findings of severe optic disc edema, peripapillary hemorrhages, or retinal exudates. CONCLUSIONS: The 10-year risk of multiple sclerosis following an initial episode of acute optic neuritis is significantly higher if there is a single brain MRI lesion; higher numbers of lesions do not appreciably increase that risk. However, even when brain lesions are seen on MRI, more than 40% of the patients will not develop clinical multiple sclerosis after 10 years. In the absence of MRI lesions, certain demographic and clinical features seem to predict a very low likelihood of developing multiple sclerosis. This natural history information is a critical input for estimating a patient's 10-year multiple sclerosis risk and for weighing the benefit of initiating prophylactic treatment at the time of optic neuritis or other initial demyelinating events in the central nervous system.

Visual function more than 10 years after optic neuritis: experience of the optic neuritis treatment trial.

PURPOSE: To assess visual function more than 10 years after an episode of optic neuritis in patients enrolled in the Optic Neuritis Treatment Trial. DESIGN: Longitudinal follow-up of a randomized clinical trial. METHODS: Vision testing included measures of visual acuity, contrast sensitivity, and visual field. Quality of life was assessed with the National Eye Institute Visual Function Questionnaire. RESULTS: Examinations were completed on 319 patients. In most patients, visual function test results in the eyes that experienced optic neuritis at study entry ("affected eyes") were normal or only slightly abnormal after 9.9 to 13.7 years. Visual acuity in the affected eyes was >or=20/20 in 74%, 20/25 to 20/40 in 18%, <20/40 to 20/200 in 5%, and <20/200 in 3%. On average, visual function was worse in patients with multiple sclerosis (MS) than in those without MS. Recurrent optic neuritis in either eye occurred in 35% of patients. Such attacks were more frequent in patients with MS (P <.001). The National Eye Institute Visual Function Questionnaire scores were lower when visual acuity was abnormal and when MS was present. CONCLUSIONS: Most patients retained good to excellent vision more than 10 years after an attack of optic neuritis. Recurrences were more frequent in patients with MS.

Pegaptanib sodium for macular edema secondary to central retinal vein occlusion.

OBJECTIVES: To assess the safety and efficacy of intravitreous pegaptanib sodium for the treatment of macular edema following central retinal vein occlusion (CRVO). DESIGN: This dose-ranging, double-masked, multicenter, phase 2 trial included subjects with CRVO for 6 months' or less duration randomly assigned (1:1:1) to receive pegaptanib sodium or sham injections every 6 weeks for 24 weeks (0.3 mg and 1 mg, n=33; sham, n=32). MAIN OUTCOME MEASURE: Visual acuity at week 30. RESULTS: In the primary analysis at week 30, 12 of 33 (36%) subjects treated with 0.3 mg of pegaptanib sodium and 13 of 33 (39%) treated with 1 mg gained 15 or more letters from baseline vs 9 of 32 (28%) sham-treated subjects (P= .48 for 0.3 mg and P= .35 for 1 mg of pegaptanib sodium vs sham). In secondary analyses, subjects treated with pegaptanib sodium were less likely to lose 15 or more letters (9% and 6%; 0.3-mg and 1-mg pegaptanib sodium groups, respectively) compared with sham-treated eyes (31%; P= .03 for 0.3 mg and P= .01 for 1 mg of pegaptanib sodium vs sham) and showed greater improvement in mean visual acuity (+7.1 and +9.9, respectively, vs -3.2 letters with sham; P= .09 for 0.3 mg and P= .02 for 1 mg of pegaptanib sodium vs sham). By week 1, the mean central retinal thickness decreased in the 0.3-mg and 1-mg pegaptanib sodium groups by 269 microm and 210 microm, respectively, vs 5 microm with sham (P< .001). CONCLUSIONS: Based on this 30-week study, intravitreous pegaptanib sodium appears to provide visual and anatomical benefits in the treatment of macular edema following CRVO. APPLICATION TO CLINICAL PRACTICE: Benefits accrued with intravitreous pegaptanib sodium treatment of macular edema following CRVO suggest a role for vascular endothelial growth factor in the pathogenesis of this condition. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00088283.

Gamma knife radiosurgery in neuro-ophthalmology.

PURPOSE OF REVIEW: Following technological advances in imaging and dose planning made in the past decade, gamma knife radiosurgery has become more and more an established treatment for a wide range of indications of interest and import to the neuro-ophthalmology community. These areas include cavernous sinus lesions and sellar lesions (for which radiosurgery can be offered as adjuvant or in certain cases as primary treatment), cavernous sinus fistulae, parasellar syndromes, and pituitary tumors. RECENT FINDINGS: Occurrence of radiation-induced cranial nerve deficits and radiation-induced optic neuropathy are infrequent following radiosurgery to these areas, and perhaps radiation-induced necrosis is less prevalent than in conventional radio therapeutic interventions. SUMMARY: Gamma knife radiosurgery remains a compelling treatment for lesions of the cavernous sinus, pineal, and sellar regions and offers increasing applicability for ocular conditions such as uveal melanoma and glaucoma.

Neuroprotection in glaucoma: a model for neuroprotection in optic neuropathies.

PURPOSE OF REVIEW: Efforts to discover modalities and pathophysiologies that might afford successful neurorescue, neurorestoration, and neuroprotection of cells of the central nervous system have focused on processes that affect the central nervous system proper, that is, the brain. Often overlooked in the search for neural protection is the fact that the mammalian optic nerve behaves in many ways as an integral part of the central nervous system. As such, the eye--the optic nerve and retina--affords an ideal clinical model for neuroprotection and neuroprotective agents. Glaucomatous optic neuropathy is the most prevalent of all adult optic neuropathies, and offers an ideal primate and lower mammalian animal model for investigations of neuroprotection. RECENT FINDINGS: This is especially compelling because while recent studies in glaucoma have shown reduction of intraocular pressure (IOP) to be an effective modality in the treatment of glaucomatous optic neuropathy, not all patients respond to or can achieve meaningful IOP reductions. Therefore much attention has now been focused on neuroprotection as a strategy in therapies for glaucomatous optic neuropathy as a means of preserving retinal ganglion cells and their axonal projections. SUMMARY: This review discusses the latest studies on various mechanisms of neuroprotection in the treatment of glaucomatous optic neuropathy.

Elevated intracranial pressure associated with idiopathic retinal vasculitis, aneurysms, and neuroretinitis syndrome.

The idiopathic retinal vasculitis, aneurysms, and neuroretinitis (IRVAN) syndrome typically occurs in young patients and may produce multiple retinal macroaneurysms, neuroretinitis, and peripheral capillary nonperfusion. Optic disc edema has been described, but elevated intracranial pressure has not been previously documented. We report a case of a 12-year-old girl who presented with bilateral disc swelling and peripapillary hemorrhage. Brain magnetic resonance imaging (MRI) was normal, but lumbar puncture yielded an opening pressure of 360 mm H2O with normal constituents. Fluorescein angiography delineated saccular aneurysms of the retinal arteriolar vasculature, and IRVAN syndrome was diagnosed. MR venography disclosed poor filling of both transverse venous sinuses. Acetazolamide treatment of 14 months did not alter the fundus findings. IRVAN syndrome may present initially with optic nerve swelling and elevated intracranial pressure with subsequent development of the characteristic retinal vascular abnormalities.