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To report a case series of neuro-ophthalmic sarcoidosis manifestations from a predominantly Caucasian Midwest population.Retrospective non-comparative case series and literature review.Twenty patients with biopsy proven sarcoidosis cases and neuro-ophthalmic manifestations.We reviewed 67 consecutive charts with the clinical diagnosis of neurosarcoidosis at the University of Iowa Hospital and Clinics (UIHC) Department of Ophthalmology database in Iowa City, Iowa, seen from 1984 to 2006.Charts were reviewed for the following: 1) demographic information; 2) neuro-ophthalmic findings; 3) biopsy location and results; 4) pre-existing sarcoidosis; 5) neuroimaging studies (e.g., cranial magnetic resonance imaging and computed tomography scans); 6) cerebrospinal fluid results; 7) sarcoid related testing (serum angiotensin converting enzyme, chest radiograph, chest computed tomography scans, Gallium scan, bronchoalveolar lavage, pulmonary function testing); 8) treatment; and 9) course of disease.Twenty of the 67 charts (30%) had biopsy proven sarcoidosis and neuro-ophthalmic manifestations. Of the 20 included cases, 4 (20%) were men and 16 (80%) were women. Six (30%) patients were African-American and 14 (70%) were Caucasian. The average age at diagnosis was 43.1 years with a standard deviation of 14.1 and a range of 22 to 80 years. Neuro-ophthalmic manifestations included optic neuropathy (14), cranial neuropathy (4), Horner's Syndrome (1), tonic pupil (1), and optic tract involvement (1). Of the 14 patients presenting with optic neuropathy, 8 had optic disc edema, 5 had optic disc pallor and 1 had an optic disc granuloma. Contrast cranial magnetic resonance imaging (MRI) showed pathologic contrast enhancement (16 of 19 cases) involving optic nerve (9), optic chiasm (1), optic radiations (1), cavernous sinus (1), leptomeninges (3), and cerebral parenchyma (3). Chest imaging was abnormal in the course of disease for 12 of 18 and serum angiotensin-converting enzyme was only elevated in 5 of 15 patients tested. All 20 patients were treated with corticosteroids but five required additional immunosuppressive therapy to control disease activity. The neuro-ophthalmic course was relapsing and remitting in 8 cases, stable or resolved in 7, and chronic in 5 patients. After treatment of patients with optic neuropathy, visual acuity at last follow-up visit was improved in 5, worsened in 5, and stable (i.e., within one Snellen acuity line of baseline) in 4.In our Midwest retrospective case series of biopsy proven neuro-ophthalmic sarcoidosis, patients were predominately white females with a wide age range. Consideration for the diagnosis of neurosarcoidosis should therefore not be limited by age, gender, or race. Optic neuropathy was the most common manifestation, typically presenting with optic disc edema and severe visual loss. No light perception vision was relatively common and should be considered a "red flag" for the diagnosis. Contrast cranial MRI frequently shows pathologic enhancement of the visual pathway. Serum angiotensin converting enzyme and chest radiography had relatively poor sensitivity for detecting biopsy proven disease in our study and therefore additional testing for tissue diagnosis might still be necessary for extrapulmonary neuro-ophthalmic sarcoidosis. Corticosteroids are the mainstay of therapy but some patients may require additional immunosuppressive therapy.

Progressive external ophthalmoplegia (PEO), with ptosis and weakness of extraocular muscles, is a common manifestation of mitochondrial diseases and is often associated with multisystem involvement.1 Progressive external ophthalmoplegia is best classified based on genetic transmission into sporadic, maternally inherited, or mendelian traits. Sporadic cases include Kearns-Sayre syndrome and adult-onset PEO with myopathy. In Kearns-Sayre syndrome, PEO is the clinical hallmark, together with pigmentary retinopathy and onset before the age of 20 years.2 Additional symptoms include ataxia and defects of cardiac conduction. Adult-onset PEO is characterized by the exclusive or prevalent involvement of skeletal muscle, although other clinical features may include deafness and cataracts. These patients harbor single heteroplasmic deletions of mitochondrial DNA (mtDNA). Patients with maternal inheritance have point mutations in mtDNA, most commonly the A3243G transition, typically seen in mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes.1 The mendelian forms of PEO can be autosomal dominant or recessive, occur in about 15% of all cases, and are associated with multiple mtDNA deletions that are due to nuclear gene mutations.3,4 Autosomal dominant PEO has been associated with mutations in genes encoding adenine nucleotide translocator 1 (ANT1)5 and Twinkle, a putative mtDNA helicase (PEO1).6 Both protein products are involved in mtDNA maintenance. Mutations in the polymerase γ (polγ) gene (POLG), encoding the α subunit of mtDNA polγ, were identified in patients with either autosomal dominant PEO or autosomal recessive PEO,7,8 but approximately one-fourth of patients with PEO and multiple deletions do not have a positive family history of PEO. Of these sporadic cases, only 36% carry mutations in 1 of the 3 genes associated with familial autosomal recessive PEO or autosomal dominant PEO, and the remaining cases have no recognized molecular defect.9 Herein, we describe a sporadic adult patient with an unusual clinical history characterized by PEO, hearing loss, macrocytic anemia, hypogonadism, central vision loss, and mild ataxia. Skeletal muscle histochemistry revealed variation in fiber size because of the presence of atrophic fibers. There were no ragged-red fibers, but several fibers had no cytochrome-c oxidase activity. Because we detected multiple mtDNA deletions in muscle, we looked for a mutation in ANT1, PEO1, and POLG1 (the gene encoding the catalytic subunit of polγ) but found none. Genetic testing for Leber hereditary optic neuropathy excluded the typical mtDNA mutations. The recent report10 of a similar patient harboring a single mutation in the gene encoding the accessory subunit (p55) of polγ (POLG2) prompted us to sequence this gene: we identified a different heterozygous mutation, which, however, did not significantly impair enzyme function. We, therefore, sequenced OPA1, which encodes a dynamin-related GTPase, and identified a novel heterozygous missense mutation that better explains this patient’s features.

Hydroxyamphetamine eyedrops are used to help localize the lesion in Horner's syndrome. Because normal variability in the response to the eyedrops may influence the interpretation of test results in patients with Horner's syndrome, we studied both the interocular variability of the drug's mydriatic effect within each normal subject and the variation between individuals. We used photographs to document the variability among 26 normal subjects. Hydroxyamphetamine hydrobromide 1% eyedrops (Paredrine) were placed in both eyes of normal subjects in the same way that patients with Horner's syndrome are tested. The drug produced a mean increase in pupil size of 1.96 mm (+/- 0.61 S.D.) in the 52 eyes tested. In normal subjects, the mydriatic effect of hydroxyamphetamine was symmetric in each pair of eyes. The mean interocular asymmetry of mydriasis as measured by the difference in dilation (right eye dilation minus left eye dilation) was -0.087 mm (+/- 0.29 S.D.). Thus, the variability of hydroxyamphetamine mydriasis from one eye to the other in a single subject was much lower than the variability between subjects.

We studied hydroxyamphetamine hydrobromide 1% (Paredrine) mydriasis in 54 patients with Horner's syndrome to determine its effectiveness in distinguishing preganglionic lesions from postganglionic lesions. The difference in pupillary dilation between the unaffected and affected sides was used as a measure of the hydroxyamphetamine effect. We found that patients who had clinical evidence of damage to the postganglionic neuron of the oculosympathetic pathway had less pupillary dilation on the affected side. In contrast, almost all patients judged to have clinical evidence of preganglionic lesions dilated more on the affected side. We determined the probability that a given difference in pupillary dilation between the involved and uninvolved side is the result of a postganglionic lesion.

Horner syndrome may indicate a serious disorder such as carotid dissection, Pancoast tumour or medullary infarction. Autonomic headache syndromes such as cluster headache and hemicrania continua may also cause Horner syndrome.1 Absence of ptosis and pupillary miosis may delay the diagnosis and lead to grave consequences. We present a patient with painful Horner syndrome initially masked by Visine (tetrahydrozoline) use. A 46-year-old man developed sudden-onset, severe right periorbital aching for 8 weeks. The pain was constant with intermittent exacerbations. He noted ptosis of the right upper lid and red eye for 1 week. He subsequently used Visine (tetrahydrozoline HCl 0.05%) several times daily in …

An optimal 3-D graph search approach designed for simultaneous multiple surface detection is extended to allow for varying smoothness and surface interaction constraints instead of the traditionally used constant constraints. We apply the method to the intraretinal layer segmentation of 24 3-D optical coherence tomography (OCT) images, learning the constraints from examples in a leave-one-subject-out fashion. Introducing the varying constraints decreased the mean unsigned border positioning errors (mean error of 7.3 ± 3.7 µm using varying constraints compared to 8.3 ± 4.9 µm using constant constraints and 8.2 ± 3.5 µm for the inter-observer variability).

While it is often said that structural damage due to glaucoma precedes functional damage, it is not always clear what this statement means. This review has two purposes: first, to show that a simple linear relationship describes the data relating a particular functional test (standard automated perimetry (SAP)) to a particular structural test (optical coherence tomography (OCT)); and, second, to propose a general framework for relating structural and functional damage, and for evaluating if one precedes the other. The specific functional and structural tests employed are described in Section 2. To compare SAP sensitivity loss to loss of the retinal nerve fiber layer (RNFL) requires a map that relates local field regions to local regions of the optic disc as described in Section 3. When RNFL thickness in the superior and inferior arcuate sectors of the disc are plotted against SAP sensitivity loss (dB units) in the corresponding arcuate regions of the visual field, RNFL thickness becomes asymptotic for sensitivity losses greater than about 10 dB. These data are well described by a simple linear model presented in Section 4. The model assumes that the RNFL thickness measured with OCT has two components. One component is the axons of the retinal ganglion cells and the other, the residual, is everything else (e.g. glial cells, blood vessels). The axon portion is assumed to decrease in a linear fashion with losses in SAP sensitivity (in linear units); the residual portion is assumed to remain constant. Based upon severe SAP losses in anterior ischemic optic neuropathy (AION), the residual RNFL thickness in the arcuate regions is, on average, about one-third of the premorbid (normal) thickness of that region. The model also predicts that, to a first approximation, SAP sensitivity in control subjects does not depend upon RNFL thickness. The data (Section 6) are, in general, consistent with this prediction showing a very weak correlation between RNFL thickness and SAP sensitivity. In Section 7, the model is used to estimate the proportion of patients showing statistical abnormalities (worse than the 5th percentile) on the OCT RNFL test before they show abnormalities on the 24-2 SAP field test. Ignoring measurement error, the patients with a relatively thick RNFL, when healthy, will be more likely to show significant SAP sensitivity loss before statistically significant OCT RNFL loss, while the reverse will be true for those who start with an average or a relatively thin RNFL when healthy. Thus, it is important to understand the implications of the wide variation in RNFL thickness among control subjects. Section 8 describes two of the factors contributing to this variation, variations in the position of blood vessels and variations in the mapping of field regions to disc sectors. Finally, in Sections 7 and 9, the findings are related to the general debate in the literature about the relationship between structural and functional glaucomatous damage and a framework is proposed for understanding what is meant by the question, ‘Does structural damage precede functional damage in glaucoma?’ An emphasis is placed upon the need to distinguish between “statistical” and “relational” meanings of this question.

We present a method for the incorporation of regional image information in a 3-D graph-theoretic approach for optimal multiple surface segmentation. By transforming the multiple surface segmentation task into finding a minimum-cost closed set in a vertex-weighted graph, the optimal set of feasible surfaces with respect to an objective function can be found. In the past, this family of graph search applications only used objective functions which incorporated "on-surface" costs. Here, novel "in-region" costs are incorporated. Our new approach is applied to the segmentation of seven intraretinal layer surfaces of 24 3-D macular optical coherence tomography images from 12 subjects. Compared to an expert-defined independent standard, unsigned border positioning errors are comparable to the inter-observer variability (7.8 ± 5.0 µm and 8.1 ± 3.6 µm, respectively).

Obesity and weight gain are known risk factors for idiopathic intracranial hypertension (IIH; or pseudotumor cerebri). The authors examined profiles of body mass index (BMI) and patterns of weight gain associated with IIH. They also examined vision-specific health-related quality of life (HRQOL) in newly diagnosed IIH patients and explored the relative contribution of obesity and weight gain to overall HRQOL in this disorder.Matched case-control study.Female patients with newly diagnosed IIH (n = 34) and other neuro-ophthalmologic disorders (n = 41) were enrolled in a case-control study to assess patterns of self-reported weight gain. The HRQOL was examined using the 25-Item National Eye Institute Visual Function Questionnaire (NEI-VFQ-25) and the SF-36 Health Survey (Physical Components Summary and Mental Components Summary [MCS]).Higher BMIs were associated with greater risk of IIH (P = .003, logistic regression analysis adjusting for case-control matching), as were higher percentages of weight gain during the year before symptom onset (P = .004). Moderate weight gain (5% to 15%) was associated with a greater risk of IIH among both obese and nonobese patients. Obesity and weight gain influenced the relation between HRQOL and IIH only for subscale scores reflecting mental health (SF-36 MCS). The NEI-VFQ-25 and SF-36 subscale scores were lower in IIH compared with other neuro-ophthalmologic disorders and published norms.Higher levels of weight gain and BMI are associated with greater risk of IIH. Even nonobese patients (BMI30) are at greater risk for IIH in the setting of moderate weight gain. Vision-specific and overall HRQOL are affected to a greater extent in IIH than in other neuro-ophthalmologic disorders.

This paper presents a new Independent Component Analysis algorithm (ICA-P) for modeling and measuring physiological responses to optical stimulation from a new, non-invasive optical imaging device. The ICA-P algorithm uses prior information on the visual stimulus to provide improved detection performance. In comparison with other methods that were considered (JADE, Infomax, SOBI, ESD, and Fast-ICA), ICA-P is shown to achieve significantly improved performance in detecting the retinal response to visual stimuli. Results from simulations show that we can estimate retinal reflectance changes as small as 0.01% (?40 dB, 10 dB lower than the other considered methods).

Irene E. Loewenfeld, PhD has devoted a long and vigorous professional life to understanding the workings of the pupil of the human eye. Her interest in the pupil began in 1940 when she went to work as a technician in the pupillography laboratory of Professor Otto Lowenstein at New York University. It culminated in her widely admired textbook The Pupil, published in 1993. Among her many contributions, Loewenfeld provided rigorous observations about Adie tonic pupil, anisocoria in optic tract lesions, Argyll Robertson pupil, oculomotor paresis with cyclic spasms, and innovations in electronic recordings of pupil movement.

Purpose The goal of this study was to describe the detailed localization of the novel oxygen-binding molecules, neuroglobin (Ngb) and cytoglobin (Cygb), in mammalian retinas and to determine whether Ngb and Cygb are neuronal or glial proteins in the retina. Methods Antibodies directed against Ngb and Cygb were used to examine their patterns of distribution in normal canine retinas. Immunoblot analysis was performed to verify antibody specificity and the presence of Ngb and Cygb in canine tissues. Double-labeling immunohistochemistry was performed with the Ngb and Cygb antibodies along with antibodies against neuronal (MAP-2, class III beta-tubulin (TUJ1), PKCalpha, and calretinin) and glial antigens (vimentin and CRALBP). Tissue sections were analyzed with light and confocal microscopy. Results Ngb and Cygb proteins were observed in different retinal cells. Cygb (but not Ngb) was also present in canine kidney, liver, lung, and heart tissue. Immunohistochemical analysis of canine retinas demonstrated Ngb immunoreactivity (IR) in the ganglion cell layer (GCL), inner (INL) and outer (ONL) nuclear layers, inner (IPL) and outer plexiform (OPL) layers, photoreceptor inner segments (IS), and retinal pigment epithelium (RPE). Ngb IR was localized within retinal neurons, but not in glia. Cygb IR was found in neurons and their processes in the GCL, IPL, INL, and OPL and within the RPE, but not in glia. Conclusions Ngb and Cygb are widely distributed in retinal neurons and RPE, but not in glial cells of the canine retina. Their structure and distribution is suggestive of a possible role in oxygen transport in the mammalian retina.

Imaging studies from anesthetized feline, primate, and human retinas have revealed near-infrared fundus reflectance changes induced by visible light stimulation. In the present study, the spatial and temporal properties of similar changes were characterized in normal, awake humans.Five normal human subjects were studied. A modified fundus camera was used to image changes in retinal reflectance of 780-nm near-infrared light imaged onto a 12-bit charge-coupled device (CCD) camera in response to a green (540 nm) visual stimulus. During 60 seconds of recording (frame rate, 3 Hz) 10 cycles were recorded, during each of which 3 seconds of blank and then 3 seconds of either vertical bar or blank stimulus was projected. The change in the average near-infrared reflectance of the stimulated retinal region relative to an equal-sized nonstimulated region (r is the ratio of reflectance between the two retinal areas) was analyzed with a mixed model for repeated measures.The mixed model showed a significant average decrease in r of 0.14% (95% CI, -0.25 to -0.03) over all subjects induced by bar stimulus cycles, with a gradual return to baseline after stimulus offset, compared with only a 0.04% (95% CI, -0.11-+0.20) decrease in r induced by blank, nonstimulated cycles. The mixed model for individuals showed a decreasing linear trend in r over time during bar stimulation, but no decrease for blank cycles in three of five subjects.There was a localized decrease in reflectance in response to 780-nm near-infrared light in the retinal region exposed to a visual stimulus, which was significant in three of five subjects. It is presumed that the reflectance change represents the functional activity of the retina in response to a visual stimulus.

Purpose To define the prevalence, natural history, treatment, and prognosis of papilledema-related juxtapapillary subretinal neovascular membranes (SRNVMs). Design Retrospective observational case series. Methods We conducted a retrospective chart review. Results Of 1140 cases of idiopathic intracranial hypertension, six patients had juxtapapillary SRNVM. Three patients were observed, and their final visual acuities were 20/20, 20/50, and 20/200. Three SRNVM involved the fovea; two of the cases were treated with argon laser therapy, and one case was treated with photodynamic therapy. Conclusion SRNVM in idiopathic intracranial hypertension is rare (0.53%). Most cases of juxtapapillary SRNVM are self-limited and regress, can be observed, and have a favorable visual prognosis. The progression of the SRNVM ophthalmoscopically or angiographically toward the fovea, however, might be an indication for laser treatment. Once subfoveal extension occurs, the visual outcome tends to be unfavorable. No patients had recurrence of SRNVM after the resolution of the papilledema.

Purpose To describe the pregnancy outcomes after the use of acetazolamide in pregnant patients with idiopathic intracranial hypertension (IIH). Design Observational case series. Methods setting: Two tertiary care academic neuro-ophthalmology units. patient population: Patients with IIH treated with acetazolamide. observation procedure: Documentation of pregnancy outcome. main outcome measures: Normal pregnancy, fetal loss, or congenital malformation. Results Twelve patients were treated with acetazolamide for IIH during pregnancy, and there were no adverse pregnancy outcomes. A critical review of the English language literature on the subject failed to demonstrate any convincing evidence for any adverse effect on pregnancy for acetazolamide. Conclusions Acetazolamide at high doses may produce birth defects in animals, but there is little clinical or experimental evidence to support any adverse effect of the drug on pregnancy outcomes in humans. If the clinical situation warrants the use of acetazolamide in IIH, then the drug probably can be offered after appropriate informed consent.

To compare the variation in thickness and reflectivity of the retinal nerve fibre layer (RNFL), circumferentially and on repeated testing.In 24 normal eyes and 38 eyes with different optic neuropathies or retinopathies, third-party optical coherence tomography (OCT) software defined the RNFL border based on the reflectivity pattern across the retina and also provided measurements of the mean reflectivity and total retinal thickness in addition to RNFL thickness. A new Gaussian filtering method was implemented so that the weight of the applied filter was varied for each of five individually repeated scans until an optimum weight filter was determined.The scans requiring the highest weight filter could be identified as 'outlier' scans that contained measurement or alignment artifacts. There was no difference in the weights of filtering needed for normal and abnormal eyes. The RNFL thickness and reflectivity, and retinal thickness were highly correlated with one another in normal and abnormal eyes.A new Gaussian filtering routine was devised that not only defined the most reproducible substructure of the RNFL for a given patient's eye, but also provided a new method of quantifying measurement variability and identification of scans with measurement or alignment artifacts.

Purpose To compare quantitatively visual field (VF) results obtained using a new standardized semiautomated kinetic perimetry (SKP) with those obtained by conventional Goldmann manual kinetic perimetry (MKP) in patients with advanced VF loss. Design Prospective, single-center, observational comparative case series. Subjects and Methods Seventy-seven eligible patients (36 suffering from advanced retinal nerve fiber layer loss, 20 with concentric constriction of the VF, and 21 with hemianopia) were included in the study. One eye of each patient was examined on the same day with MKP and SKP. Three isopters, identical in both tests, were chosen to assess the extent of the VF loss. To compare the location and size of the corresponding isopters obtained with MKP and SKP, intersection areas of superimposed isopters were expressed as a percentage of union areas. Main Outcome Measures The area and position of isopters for a defined stimulus condition obtained with both methods were compared. Test duration and patients' preference were also evaluated. Results Isopters obtained with Goldmann MKP enclosed areas smaller by 20% (confidence interval [CI], 12%–27%). The mean intersection area of Goldmann and SKP VFs was 1763.1 square degrees (CI, 1558.6–1967.7) smaller than the union for stimulus III4e over all groups of patients. Semiautomated kinetic perimetry was preferred by 60% of patients with concentric constriction of the VF. Median duration of the examination was 15 minutes and did not differ significantly between the 2 methods. Conclusions Our results indicate that SKP isopter shape and size were very comparable to those obtained on the same eyes with MKP. Semiautomated kinetic perimetry may represent a more standardized method of kinetic perimetry, which still takes advantage of perimetrist-patient interaction to diagnose and monitor advanced VF loss in clinical practice.

Purpose/Methods Bilateral visual field defects resembling an hourglass could be produced by bilateral lateral geniculate lesions. We recently encountered such deficits in a 37-year-old woman after an episode of central pontine myelinolysis. Results/Conclusions Automated static perimetry demonstrated the congruous visual field defects to involve both halves of the visual field. They were confirmed with kinetic perimetry, and they remained stable for four years. Magnetic resonance imaging demonstrated enhancing lesions characteristic of myelinolysis in each lateral geniculate.

Purpose. To functionally characterize the rat retina and optic nerve after chronic elevation of the intraocular pressure (IOP) using electroretinography (ERG) and computerized pupillometry. Methods. Chronic elevation of the IOP was induced in Brown Norway rats by combined injection of indocyanine green dye (ICG) into the anterior chamber and diode laser treatment, followed by ERG and pupil light reflex (PLR) monitoring. Results. Laser treatment induced significant elevation of the IOP in operated eyes for 6 weeks, with maximal values observed 14 days postoperatively (ctrl ¼ 18·4 ^ 2·4 and operated ¼ 35 ^ 8·4 mmHg; mean ^ SD). Preoperative values for the PLRratio were 68·5 ^ 4% (mean ^ SEM; %). Three days postoperatively the PLRratio decreased to 60·3 ^ 10·3%, but was not significantly different compared to preoperative values (p . 0·05; Kruskal-Wallis non-parametric test with Dunn’s post-test). However, 7, 14 and 21 days postoperatively the PLR function dramatically decreased to 14·6 þ 8·6, 11·5 ^ 6·7 and 12·6 ^ 4%, respectively, and was significantly smaller compared to preoperative values ðp , 0·01Þ: At day 28 the PLR significantly recovered and was not significantly different compared to preoperative values (PLRratio ¼ 38·5 ^ 8·6, p . 0·05). However, 35 days after surgery the PLR started to decrease once again in the operated eyes (PLRratio ¼ 17·2 ^ 7·4%) and was significantly smaller again compared to preoperative values ðp , 0·05Þ: The PLR values continued to decrease until the end of experiment (60 days postoperatively). ERG analysis of operated eyes revealed significantly decreased amplitudes of a- and b-waves 10d postoperatively, while oscillatory potentials (OPs) and flicker ERG (flERG) amplitudes were not detectable. However, 28 days postoperatively OPs significantly, but temporarily recovered, while a-wave, b-wave and flERG amplitudes did not significantly change compared to values observed 10d postoperatively. The ERG analysis of the operated eyes revealed significantly reduced amplitudes 60 days postoperatively. Histological analysis revealed degeneration of all retina layers and optic nerve axons. Conclusions. Chronic ocular hypertension in rats produces dramatic damage to all retinal layers and optic nerves observed by morphological and functional methods which significantly correlate with the IOP elevation. Outer retina of glaucomatous rats seems to be more susceptible to the damage due to chronic elevation of the IOP. Chronic hypertensive rat eyes have capacity to temporarily recover function of the inner retina and optic nerve. q 2004 Elsevier Ltd. All rights reserved.

To characterize the pupil light reflex (PLR), electroretinographic (ERG) and tonometric parameters which might be of importance for the in vivo characterization of mouse models of chronic ocular hypertension.C57/BL6 mice were used for experiments. The PLR was evaluated with a computerized pupillometer (n = 14), ERGs were recorded simultaneously from both eyes (n = 23) and IOP was measured with a modified Goldmann tonometer (n = 23).The analysis of the PLR parameters confirmed the consensual PLR did not have significantly different amplitude (p0.1) and latency time (p0.1) compared to the direct PLR. However, PLR velocity (p = 0.004) was significantly smaller in the consensual PLR. Electroretinography revealed a-wave amplitude of 168.3 +/- 9.6 microV with latency of 27.5 +/- 0.6 ms and b-wave 403 +/- 28.8 microV with latency of 22.7 +/- 0.6 ms. The flicker ERG recording revealed amplitudes of 20.6 +/- 2.4 microV. Tonometry experiments revealed that modified Goldmann tonometer measurements correlated well with invasive manometry (r(2) = 0.89). The mean IOP of the mouse was 15.3 +/- 0.6 mmHg.Consensual PLR in mice is relatively slower than the direct PLR, but retains the same degree of constriction comparing to the direct PLR. A modified Goldmann tonometer seems to be a reliable non-invasive tool for IOP measurements in mice.

To evaluate visual function in rats with chronic elevation of intraocular pressure (IOP).Chronic ocular hypertension was induced in the left eye of 14 adult Brown Norway rats by cauterizing 3 vortex veins and 2 major episcleral veins; the right eye served as a non-operated control. A control group (n=5) was sham operated on the left eye. Prior to surgery, the IOP was measured with a Tonopen, the pupil light reflex (PLR) evaluated with a custom-made computerized pupillometer and electroretinograms (ERGs) were recorded simultaneously from both eyes post surgically: IOP was measured on weeks 1, 3, 5 and 8 post-operatively, pupil light reflexes on weeks 1, 4 and 8 post-operatively, and ERGs on weeks 4 and 8 post-operatively. Sixty five days postoperatively, rats were euthanized and optic nerves and eye globes were prepared for histological analysis.Seven days after surgery 5/14 rats developed significant elevation of the IOP in operated eyes (control eyes: 25.1+/-0.5mmHg; operated eyes: 34.1+/-0.6mmHg; mean+/-SEM; p=0.0004; Paired t-test). Elevation of the IOP was sustained at 3 (p=0.002) and 5 (p=0.007) weeks postoperatively. However, IOP values did not significantly differ between control and operated eyes 8 weeks postoperatively (p=0.192, Paired t-test). Sham operated animals showed no elevation of the IOP 7 days postoperatively. When the ratio between consensual and direct PLR (PLR(ratio)=consensual/direct PLR; pupil of unoperated eye recorded) was examined in rats which developed elevation of the IOP, preoperative values were 92.2+/-4% (mean+/-SEM), 1 week postoperatively 65+/-4% (significantly different from preoperative values, p0.05 Repeated Measures ANOVA with Dunnett's Multiple Comparison test, n=5), 4 weeks postoperatively 60.6+/-3.2% (p0.01, n=5). By 8 weeks postoperatively, pupil responses had essentially recovered 75.4+/-6.9% (p0.05, n=5). Rats whose IOP values did not rise after surgery and sham operated rats did not develop pupil deficits 4 weeks postoperatively. Rats with elevated IOP displayed a significant decrease in ERG amplitudes in operated eyes at 4 weeks (a-wave(operated)/a-wave(control) (a-wave ratio)=42+/-14% (mean+/-SEM); b-wave(operated)/b-wave(control) (b-wave ratio)=43+/-16%) but not at 8 weeks postoperatively (a-wave ratio=88+/-8.4%; b-wave ratio=82.9+/-9%). Sham operated and rats whose IOP values remained non-elevated after surgery did not develop ERG deficits 4 weeks after surgery. Histological analysis did not reveal any damage in the eyes of animals with elevated intraocular ocular pressure with the exception of one rat, which still had ERG and pupil deficits at the end of experiment.Development of ERG and PLR deficits are proportional to the elevation of the IOP in the rat model of chronic ocular hypertension. Functional monitoring of the ERG and PLR are useful objective techniques for the detection of retina and optic nerve deficits.

PURPOSE. To functionally characterize the status of the rat retina and optic nerve after acute elevation of intraocular pressure (IOP) and to determine the dynamics of the pathologic changes in the ischemic retina and optic nerve. METHODS. Retinal ischemia was induced in rats by acutely increasing the IOP (110 mm Hg/60 minutes). Direct and indirect pupil light reflexes (PLRs) were recorded from the noninjured eye, and electroretinograms (flash and flicker ERG) were recorded from the injured and control eyes before and after surgery. Amplitudes and latencies were calculated for each recording session. RESULTS. Preoperative PLRratios (indirect/direct PLR) were 76.7 2.6 (mean SEM). Twenty-four hours after surgery the PLRratio was 15.2 12.8, 10 days after surgery, 11.6 9.8; 20 days after surgery, 26.5 8.0; and 28 days after surgery, 33.27 9.3. However, at day 35, the PLR had significantly recovered (41.1 7.3) when compared with the 24-hour postoperative ratios (P 0.01, repeated-measures ANOVA). Forty-two days after surgery, the PLRratio started to decrease once again in the injured eyes (28.7 5.9). Electroretinographic amplitudes (full-field flash ERG) followed a similar pattern. Cone responses (flicker ERG) were measured 42 days after surgery and revealed defects in injured eyes (control eyes: 46.6 2.9 V, injured eyes: 3.4 1.7 V). Histologic analysis revealed ischemic damage to all retinal layers, with the primary defects localized to the central retina. CONCLUSIONS. Acute ocular ischemia causes a significant decrease in retinal function, as measured by PLR and ERG, although over time the rat retina and optic nerve show partial regain of function. (Invest Ophthalmol Vis Sci. 2003;44: 2597‐2605) DOI:10.1167/iovs.02-0600

An optical imaging device of retina function (OID-RF) has been developed to measure changes in blood oxygen saturation due to neural activity resulting from visual stimulation of the photoreceptors in the human retina. The video data that are collected represent a mixture of the functional signal in response to the retinal activation and other signals from undetermined physiological activity. Measured changes in reflectance in response to the visual stimulus are on the order of 0.1% to 1.0% of the total reflected intensity level which makes the functional signal difficult to detect by standard methods since it is masked by the other signals that are present. In this paper, we apply principal component analysis (PCA), blind source separation (BSS), using Extended Spatial Decorrelation (ESD) and independent component analysis (ICA) using the Fast-ICA algorithm to extract the functional signal from the retinal videos. The results revealed that the functional signal in a stimulated retina can be detected through the application of some of these techniques.

PURPOSE To investigate the clinical usefulness of the latency of the pupil light reflex by optimizing its measurement, characterizing its variability, and determining the sensitivity of pupil latency as a function of stimulus input in normal subjects. METHODS Computerized binocular infrared pupillography was performed in 14 eyes of seven healthy subjects. Pupils were recorded simultaneously at 60 and 1000 Hz. Each eye was alternatively stimulated eight times for 50 ms every 2.5 seconds, increasing by 0.5 log units over a 2.0-log-unit range. To determine intersubject and intereye variability, 98 eyes of 49 healthy subjects were recorded at 60 Hz over a 3.0-log-unit range (15 degrees radius stimulation, four repetitions at each intensity). RESULTS Accuracy and resolution of latency were limited by the number of light reflexes used to estimate the average latency and were significantly affected by sampling rate when the number of reflexes recorded was fewer than four. Binocular recording and interpolation of the 60-Hz recording to 300 Hz added resolution to the latency. Biological variability contributed more to interindividual variability than did measurement variability. The range of intereye afferent asymmetry of latency in normal subjects was only between 8.3 and 35 ms-less with brighter stimulus intensity. CONCLUSIONS An optimal method for determination of the onset of the pupil light reflex was devised that consisted of filtering, interpolation of pupil recordings, and analysis of the first and second derivative of the pupil movement. Most of the variability in latency as a function of intensity in normal subjects was due to interindividual variation and latency was well matched between the two eyes of the subjects.

Objectives To determine the prognosis of internuclear ophthalmoplegia (INO) caused by infarction. Design Multicenter, retrospective observational case series. Participants Thirty three patients with ischemic-related INO. Methods Chart review of clinical details. Main outcome measure Resolution of diplopia in primary position. Results Of the group, 78.8% demonstrated resolution of diplopia in primary position with an average time to resolution of 2.25 months. The presence of associated neurologic symptoms (vertigo, ataxia, dysarthria, facial palsy, pyramidal tract signs) correlated with a worse prognosis for resolution of diplopia. When performed magnetic resonance imaging (MRI) demonstrated the causative infarct in only 52% of cases; the presence of an MRI-demonstrable lesion was not significantly associated with prognosis for resolution. Conclusions Similar to ischemic ocular motor palsies, most ischemic-based INO become asymptomatic in primary position over 2 to 3 months. The presence of associated features correlated with persistent diplopia. MRI has limited yield in demonstrating the causative infarct.

(1) To report the incidence and extent of visual improvement achieved by high-dose systemic corticosteroid treatment in eyes with visual loss due to giant-cell arteritis (GCA). (2) To understand the cause of the discrepancies between visual improvement revealed by routine visual acuity (VA) and by the central visual field in kinetic perimetry. (3) To review critically the contradictory literature on the effectiveness of corticosteroid therapy on visual recovery in GCA and to attempt to reconcile differences in the reported results.Clinical data were collected systematically on 84 consecutive patients (114 eyes) with visual loss, all of whom had GCA confirmed by temporal artery biopsy and treated by us with high-dose systemic corticosteroid therapy. The patients were treated between 1974 and 1999 and data were compiled retrospectively. All patients underwent a detailed visual and ophthalmic evaluation at the initial visit and at every follow-up. This included visual field testing (with a Goldmann perimeter). All were treated with systemic corticosteroid therapy (intravenous followed by oral in 41 patients and oral only in 43 patients).Visual loss was due to anterior ischaemic optic neuropathy (91%), central retinal artery occlusion (10.5%), cilioretinal artery occlusion (10%), and/or posterior ischaemic optic neuropathy (4%), either alone or in different combinations. Improvement in both VA (or= 2 lines) and central visual field was found in only five (4%) eyes of five patients (three treated with intravenous and two with oral steroid therapy). Improvement in VAor= 2 lines but not in the central visual field was found in seven eyes (in six patients). Visual improvement was seen in 7% of 41 patients treated initially with intravenous steroids versus 5% (p = 0.672) of 43 patients treated with oral steroids only. Comparison of patients with visual improvement in both VA and fields versus those with no improvement suggested a shorter interval (p = 0.065) between onset of visual loss and start of therapy in the improved patients.In our study, only 4% of eyes with visual loss due to GCA improved, as judged by improvement in both VA and central visual field (by kinetic perimetry and Amsler grid). The data also suggest that there is a better (p = 0.065) chance of visual improvement with early diagnosis and immediate start of steroid therapy. Improvement in VA without associated improvement in the central visual field or Amsler grid may simply represent a learned ability to fixate eccentrically with more effective use of remaining vision: this factor could help explain a number of reported cases in the literature of improved VA after steroid treatment for GCA. To prevent further visual loss in either eye and for management of systemic manifestations of GCA, all patients must be treated on a long-term basis with adequate amounts of systemic corticosteroids.

An optical imaging device of retina function (OID-RF) has been constructed to record changes in reflected 700-nm light from the fundus caused by retinal activation in response to a visual 535-nm stimulus. The resulting images reveal areas of the retina activated by visual stimulation. This device is a modified fundus camera designed to provide a patterned, moving visual stimulus over a 45-degree field of view to the subject in the green wavelength portion of the visual spectrum while simultaneously imaging the fundus in another, longer wavelength range. Data was collected from 3 normal subjects and recorded for 13 seconds at 4 Hz; 3 seconds were recorded during pre-stimulus baseline, 5 seconds during the stimulus, and 5 seconds post-stimulus. This procedure was repeated several times and, after image registration, the images were averaged to improve signal to noise. The change in reflected intensity from the retina due to the stimulus was then calculated by comparison to the pre-stimulus state. Reflected intensity from areas of stimulated retina began to increase steadily within 1 second after stimulus onset and decayed after stimulus offset. These results indicated that a functional optical signal can be recorded from the human eye.

Purpose Peripheral neuropathy has been shown to exist in prediabetic and diabetic patients and animal models. However, the development of peripheral neuropathy in prediabetes and posthyperglycemia is likely different. The purpose of this study was to examine the progression of peripheral neuropathy in diet-induced obese rats and high-fat-fed rats treated with a low dose of streptozotocin, a model for type 2 diabetes, using standard endpoints as well as corneal sensitivity and innervation. Methods Diet-induced obese rats and high-fat/low-dose streptozotocin diabetic rats were used to examine standard peripheral neuropathy endpoints and innervation of the cornea and corneal epithelium using corneal and standard confocal microscopy, respectively, and corneal sensitivity using a Cochet-Bonnet esthesiometer at three different time points. Results Obese rats and to a greater extent diabetic rats were insulin resistant. Obese and diabetic rats had developed sensory nerve deficits, but only diabetic rats had motor nerve dysfunction as determined by measuring nerve conduction velocity, thermal nociception, and intraepidermal nerve fiber density. In the cornea there was a decrease in corneal nerve fiber length, innervation of the corneal epithelium, and corneal sensitivity in both diet-induced obese and diabetic rats. Conclusions These studies demonstrate that changes in corneal nerve innervation and sensitivity occur in both obese and type 2 diabetic rat models that are consistent with development of peripheral neuropathy. Examination of corneal nerve changes may be valuable endpoints for exploring potential treatments for peripheral neuropathy in both prediabetes with insulin resistance and diabetes.

Frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), characterized by an autosomal dominant inheritance pattern, has recently been recognized as a distinct entity that can display a confusingly broad clinical phenotype. The pallido-ponto-nigral degeneration (PPND) variant is the prototypical example of the parkinsonism-predominant pattern of FTDP-17. A longitudinal videotape demonstration of the clinical progression of this entity in a single individual, along with brief videotape segments from three additional affected individuals, is presented in order to facilitate recognition of this disorder.

PURPOSE: To describe a case of myositis in the presence of a Baerveldt glaucoma implant. METHOD: Case report. RESULTS: A 41-year-old black woman developed myositis after placement of a Baerveldt glaucoma implant. Echography demonstrated migration of the seton plate against the medial rectus muscle insertion. Myositis resolved after removal of the Baerveldt glaucoma implant. CONCLUSION: The Baerveldt glaucoma implant may have precipitated myositis in this patient.

· Background: The relative afferent pupillary defect (RAPD) is an important parameter for quantifying the loss of neuronal function in asymmetric optic nerve disease. We wanted to assess its correlation with retinal ganglion cell loss, estimated from visual field defects, using a recently described method. · Methods: In 36 patients with unilateral optic nerve disease, the RAPD was measured using an automated, computerized infrared pupillometer. The percentage of ganglion cell loss was estimated with clear templates. · Results: We found a highly significant correlation between the RAPD and estimated ganglion cell loss. The correlation was higher for Humphrey visual fields than for Goldmann visual fields measured with the I4e and I2e stimulus. · Conclusion: The RAPD correlates well with estimated retinal ganglion cell loss in optic nerve disease. Humphrey visual fields seem to reflect the ganglion cell loss better than Goldmann visual fields. The spatial distribution of pupillomotor retinal ganglion cells seems to be proportional to the distribution of light-sensitive ganglion cells projecting to the lateral geniculate nucleus.

Purpose To report the clinical and immunologic features of two patients with progressive retinal degeneration and circulating antiretinal antibodies without systemic malignancy. Methods Two patients were followed up for 5 to 7 years. Comprehensive medical and ophthalmic examinations and visual function testing included manual perimetry and standardized electroretinography. Patient sera were tested for anti-retinal antibodies by Western blot and immunoperoxidase indirect cytochemistry techniques. Results Two patients had family history of autoimmune disease. Each had severe monocular visual loss with photopsia, a ring scotoma, and abnormal electroretinogram despite a normal-appearing ocular fundus. One had a flat electroretinogram; the other had inner retina dysfunction, with selective b-wave loss and abnormal oscillatory potentials. Both patients' sera had antiretinal antibodies that specifically labeled the inner plexiform layer of donor retina by indirect immunoperoxidase testing. Neither had any sign of cancer. Conclusions In two patients without systemic malignancy, the symptoms, perimetric findings, and normal fundus appearance resembled cancer-associated retinopathy. Electroretinography and antibody findings indicating dysfunction of the inner retina are distinct from those of cancer-associated retinopathy. These two cases raise the possibility of an autoimmune mechanism for retinal degeneration that is not cancer associated. Further study is necessary to determine the role of antiretinal antibodies in these patients.

Optical coherence tomography is routinely used clinically for the detection and management of ocular diseases as well as in research where the studies may involve animals. This routine use requires that the developed automated segmentation methods not only be accurate and reliable, but also be adaptable to meet new requirements. We have previously proposed the use of a graph-theoretic approach for the automated 3-D segmentation of multiple retinal surfaces in volumetric human SD-OCT scans. The method ensures the global optimality of the set of surfaces with respect to a cost function. Cost functions have thus far been typically designed by hand by domain experts. This difficult and time-consuming task significantly impacts the adaptability of these methods to new models. Here, we describe a framework for the automated machine-learning based design of the cost function utilized by this graph-theoretic method. The impact of the learned components on the final segmentation accuracy are statistically assessed in order to tailor the method to specific applications. This adaptability is demonstrated by utilizing the method to segment seven, ten and five retinal surfaces from SD-OCT scans obtained from humans, mice and canines, respectively. The overall unsigned border position errors observed when using the recommended configuration of the graph-theoretic method was 6.45 ± 1.87 μm, 3.35 ± 0.62 μm and 9.75 ± 3.18 μm for the human, mouse and canine set of images, respectively.

Purpose Scanning laser polarimetry (SLP) reveals abnormal retardance of birefringence in locations of the edematous peripapillary retinal nerve fiber layer (RNFL), which appear thickened by optical coherence tomography (OCT), in nonarteritic anterior ischemic optic neuropathy (NAION). We hypothesize initial sector SLP RNFL abnormalities will correlate with long-term regional visual field loss due to ischemic injury. Methods We prospectively performed automated perimetry, SLP, and high definition OCT (HD-OCT) of the RNFL in 25 eyes with acute NAION. We grouped visual field threshold and RNFL values into Garway-Heath inferior/superior disc sectors and corresponding superior/inferior field regions. We compared sector SLP RNFL thickness with corresponding visual field values at presentation and at >3 months. Results At presentation, 12 eyes had superior sector SLP reduction, 11 of which had inferior field loss. Six eyes, all with superior field loss, had inferior sector SLP reduction. No eyes had reduced OCT-derived RNFL acutely. Eyes with abnormal field regions had corresponding SLP sectors thinner (P = 0.003) than for sectors with normal field regions. During the acute phase, the SLP-derived sector correlated with presentation (r = 0.59, P = 0.02) and with >3-month after presentation (r = 0.44, P = 0.02) corresponding superior and inferior field thresholds. Conclusions Abnormal RNFL birefringence occurs in sectors corresponding to regional visual field loss during acute NAION when OCT-derived RNFL shows thickening. Since the visual field deficits show no significant recovery, SLP can be an early marker for axonal injury, which may be used to assess recovery potential at RNFL locations with respect to new treatments for acute NAION.

PURPOSE We determined the effect of entrance pupil size on retinal illumination. The influence of unilateral miosis on the magnitude of the pupil light reflex was studied to ascertain how a clinically significant anisocoria influences the relative afferent pupil defect (RAPD). METHODS Miosis was induced by topical 1% pilocarpine in the right eye of 14 healthy subjects with normal eyes. The interocular difference in retinal illumination was assessed by computerized pupillometry from the stimulus response curve of the right and left eyes. The main outcome measure was the RAPD, determined by computerized pupillography, at baseline and after pilocarpine-induced anisocoria. RESULTS Induced anisocoria produced a significant change in RAPD from baseline (mean = 1.60 dB in the miotic eye, P = 0.007). However, anisocoria correlated with RAPD only in subjects with darkly pigmented irides (Pearson correlation coefficient 0.793, P = 0.05). CONCLUSIONS In darkly pigmented eyes, entrance pupil size significantly influenced the retinal illumination. However, retinal illumination of lightly pigmented eyes is relatively independent of entrance pupil size, presumably due to extrapupillary transmission of light through the iris and sclera. This has important implications in understanding the potential influence of anisocoria on the RAPD and also greater susceptibility of lightly pigmented eyes to light toxicity.

Purpose To evaluate retina and optic nerve damage following experimental blast injury. Methods Healthy adult mice were exposed to an overpressure blast wave using a custom-built blast chamber. The effects of blast exposure on retina and optic nerve function and structure were evaluated using the pattern electroretinogram (pERG), spectral domain optical coherence tomography (OCT), and the chromatic pupil light reflex. Results Assessment of the pupil response to light demonstrated decreased maximum pupil constriction diameter in blast-injured mice using red light or blue light stimuli 24 hours after injury compared with baseline in the eye exposed to direct blast injury. A decrease in the pupil light reflex was not observed chronically following blast exposure. We observed a biphasic pERG decrease with the acute injury recovering by 24 hours postblast and the chronic injury appearing at 4 months postblast injury. Furthermore, at 3 months following injury, a significant decrease in the retinal nerve fiber layer was observed using OCT compared with controls. Histologic analysis of the retina and optic nerve revealed punctate regions of reduced cellularity in the ganglion cell layer and damage to optic nerves. Additionally, a significant upregulation of proteins associated with oxidative stress was observed acutely following blast exposure compared with control mice. Conclusions Our study demonstrates that decrements in retinal ganglion cell responses can be detected after blast injury using noninvasive functional and structural tests. These objective responses may serve as surrogate tests for higher CNS functions following traumatic brain injury that are difficult to quantify.

A wealth of new information has recently come to light concerning the pupillary response to various types of visual input. Much of this information is recent, and has either been published in the last year, is in press, or has just been reported at meetings. This new information is important because it is resulting in reexamination of the pupillary input pathways and the clinical role for using pupillary movements to understand the physiology and pathology of the visual system. This review will focus on this new information and its clinical implication. The review is organized in the following sections: 1) the pupillary response to full-field, global light stimuli; 2) "pupil perimetry" or the pupillary response to focal light stimuli; 3) the pupillary response to isoluminant stimuli, eg, color spatial frequency, motion; 4) receptive field organization in the pupillary light reflex pathway.

To assess the role of digitalis in the development of visual symptoms severe enough to warrant ophthalmologic consultation in patients who received digitalis and who had no other clinical or laboratory evidence of digitalis toxicity.Clinical case study.Neuro-ophthalmology referral practice.Six elderly patients (aged 66 to 85 years) who received digitalis were referred to ophthalmologists for evaluation of photopsia (five patients) or decreased visual acuity (one patient). No patient had chromatopsia or nonvisual clinical manifestations of digitalis intoxication at the time of examination.All patients had serum digitalis concentrations within or below the therapeutic range. In most patients, the electroretinographic cone b-wave implicit time was longer than normal.Discontinuation of digitalis therapy, which was possible in five patients, was followed by resolution of visual symptoms and by shortening of the b-wave implicit time. Characteristic features of digitalis-induced photopsia were its dependence on illumination and its tendency to be localized in peripheral visual fields.In an elderly patient receiving digitalis, the development of photopsia characterized by innumerable points of light in the peripheral visual fields or a decrease in visual acuity raises the possibility that the patient's visual disturbance may have been digitalis induced. Digitalis-induced visual disturbances other than chromatopsia or disturbances of color vision may occur in elderly patients who have no other clinical manifestations of digitalis intoxication and who have a serum digitalis concentration within or below the therapeutic range.

A man with acquired immune deficiency syndrome suddenly developed bilateral complete ptosis and minor vertical gaze limitation. Magnetic resonance imaging revealed a lesion in the midbrain surrounding the sylvian aqueduct in addition to bilateral masses in the caudate nuclei. Pathologic examination showed that the caudate lesions were central nervous system lymphoma of B cell origin, but the midbrain lesion contained only signs of AIDS encephalopathy. The periaqueductal lesion involved the caudal central subnucleus and probably also the subnuclei of the superior and inferior recti of the oculomotor nuclear complex bilaterally.

Glaucoma is the second leading cause of visual impairments and blindness worldwide, affecting approximately 70 million people, and is the leading cause of blindness among African Americans in the United States.1 Primary open-angle glaucoma (POAG) is the most common form, accounting for approximately 70% of all cases worldwide. It is characterized by progressive loss of retinal ganglion cell (RGC) axons and irreversible loss of vision,2 which is often associated with elevated intraocular pressure (IOP). Although the exact mechanisms that lead to elevated IOP are poorly understood, an increased resistance to outflow of aqueous humor through the drainage structures in the iridocorneal angle (the trabecular meshwork and Schlemm's canal) is thought to be the major cause of IOP elevation in POAG. Mutations in the myocilin gene (MYOC) are the most common known genetic causes of glaucoma.3–5 These mutations, which cause elevated IOP, are responsible for approximately 4% of POAG, and most cases of autosomal dominant juvenile-onset open-angle glaucoma.5,6 Myocilin is expressed in many ocular tissues including the TM cells.5,7–9 The physiological function of myocilin is not completely understood, although recent reports suggested a possible role in cell–matrix interaction.5,9–11 Myocilin knock-out and -in mouse studies have indicated that wild-type myocilin is not necessary for the physiological regulation of IOP and supports the hypothesis that glaucoma associated with the myocilin mutation is the result of an abnormal property of mutant myocilin.7–9,12 In vitro studies suggest that glaucoma-causing myocilin mutants are misfolded and detergent resistant and do not degrade properly.9,13 Several studies have demonstrated that disease-causing myocilin mutants are secretion incompetent,14–16 accumulate in the endoplasmic reticulum (ER) and induce ER stress.13,17–19 However, in vivo mechanistic studies in a myocilin mouse model that faithfully replicates the human disease have not been available. We have recently generated a transgenic mouse model (Tg-MYOCY437H) that expresses human MYOC containing the Y437H mutation under the control of the CMV promoter within relevant eye tissues including TM.19 Of note, adult Tg-MYOCY437H mice have elevated IOP and show functional and structural loss of RGCs as well as optic nerve degeneration closely resembling those seen in POAG patients with myocilin mutations. Furthermore, we have demonstrated that ER stress plays a key role in the development of elevated IOP in Tg-MYOCY437H mice.19 Sodium 4-phenylbutarate (PBA) is a small chemical chaperone approved for clinical use in patients with urea cycle disorders and has been shown to reduce protein mislocalization and ER stress in different diseases.20–29 A well-known example of this mechanism is the restoration of the cell surface expression and function of the mutant cystic fibrosis transmembrane conductance regulator protein (CFTR) by PBA.20,29 Several studies have suggested that myocilin-associated glaucoma is a protein-misfolding disease and that chemical chaperones can be used to correct myocilin misfolding. Consistent with this hypothesis, in another study, we demonstrated that systemic PBA prevents glaucoma in Tg-MYOCY437H mice.19 Since PBA is approved by the U.S. Food and Drug Administration (FDA) for oral use in urea cycle disorders and has a good safety profile,30,31 we sought to evaluate whether a topical form of this drug, administered as an eye drop could be used for treatment of glaucoma. The purpose of the present study was to determine whether topical ocular PBA treatment would reduce glaucomatous damage in Tg-MYOCY437H mice.

PURPOSE To develop an automated system that analyzes digital fundus images for staging and monitoring of optic disc edema (i.e., papilledema), due to raised intracranial pressure. METHODS A total of 294 retrospective, digital photographs of the right and left eyes of 39 subjects with papilledema acquired over the span of 2 years were used. Software tools were developed to analyze three features of papilledema from digital fundus photographs: (1) sharpness of the optic disc border, (2) discontinuity along major vessels overlying the optic nerve, and (3) texture properties of the peripapillary retinal nerve fiber layer (RNFL). A classifier used these features to assign a grade of papilledema according to a standard protocol used by an expert neuro-ophthalmologist (RK). RESULTS The algorithm showed substantial agreement (κ = 0.71, P < 0.001) with the neuro-ophthalmologist when grading papilledema per patient. Vessel features showed statistical significance (P < 0.05) in differentiating grades 0, 1, and 2 from grades 3 and 4, whereas disc obscuration differentiated grades 0 or 1 from the rest (P < 0.05). CONCLUSIONS These results show that this algorithm can be used to automatically grade papilledema. The algorithm provides objective and quantitative assessment of the stage of papilledema with accuracy that is comparable to grading by a neuro-ophthalmologist. One application is in rapid assessment of digital optic nerve photographs acquired in clinical, intensive care, and emergency response settings by nonophthalmologists to evaluate for the presence and severity of papilledema, due to intracranial hypertension.

PURPOSE. To examine the biomechanical deformation of load bearing structures of the optic nerve head (ONH) resulting from raised intracranial pressure, using high definition optical coherence tomography (HD-OCT). The authors postulate that elevated intracranial pressure induces forces in the retrolaminar subarachnoid space that can deform ONH structures, particularly the peripapillary Bruch's membrane (BM) and RPE layers. METHODS. The authors compared HD-OCT optic nerve and peripapillary retinal nerve fiber layer (RNFL) findings in eyes with papilledema caused by raised intracranial pressure to findings in eyes with optic disc swelling caused by optic neuritis and nonarteritic anterior ischemic optic neuropathy (NAION), conditions without intracranial hypertension. The authors measured average thickness of the RNFL and the angle of the RPE/BM at the temporal and nasal borders of the neural canal opening. The angle was measured as positive with inward (toward the vitreous) angulation and as negative with outward angulation. RESULTS. Of 30 eyes with papilledema, 20 eyes (67%) had positive RPE/BM rim angles. One of eight optic neuritis (12%) eyes and 1 of 12 NAION (8%) eyes had positive angulation. In five eyes with papilledema, RNFL thickening increased, three of which developed positive RPE/BM angles. On follow-up, 22 papilledema eyes had a reduction of RNFL swelling, and 17 of these eyes had less positive RPE/BM angulation. CONCLUSIONS. In papilledema, the RPE/BM is commonly deflected inward, in contrast to eyes with NAION or optic neuritis. The RPE/BM angulation is presumed to be caused by elevated pressure in the subarachnoid space, does not correlate with the amount of RNFL swelling, and resolves as papilledema subsides.

Detection of light serves many tasks. Independent of form vision, the detection of brightness (irradiance) is used to regulate pupil size,1 entrain circadian rhythms to the day-night cycle,2 and modulate endocrine function.3 Irradiance information is transmitted to central nuclei by a specialized subset of intrinsically photosensitive retinal ganglion cells (ipRGCs).4,5 The response of ipRGCs to light is a composite of their intrinsic melanopsin-generated activity and rod-cone photoreceptor-dependent activation mediated by interneurons of the inner retina.6 However, morphologic and functional specialization among ipRGCs has been identified, and these “ipRGC types” show variation in their projections to central nuclei.7–10 How these differences in ipRGC form, function, and central projections relate to a given irradiance response is not well understood. For instance, the pupillary light reflex and negative masking (a suppression of activity by light) both respond to “lights on” in an irradiance-dependent manner.1,11 However, the effect of outer retina degeneration differs dramatically between these irradiance responses, with a paradoxical enhancement of irradiance sensitivity in negative masking12 and a severe loss of sensitivity in the pupillary light reflex.1,13,14 At the level of the retina, such phenotypic variability could arise from secondary effects of outer retina disease on ipRGCs or from differences in rod-cone input to the different ipRGC types. Although inner retinal circuitry is diverse, all vertical transmission of rod and cone signals to ganglion cells is, at some point, mediated by bipolar cells (BCs).15 Therefore, differences between responses could arise from specificity in bipolar cells mediating rod-cone input. The aim of this study was to determine whether there are differences in inner retinal pathways mediating rod-cone input to functionally distinct irradiance responses and whether such differences could contribute to the divergent effects of outer retinal disease on the different irradiance responses. Negative masking and pupillary light reflex were compared between mice with intact inner-retinal circuitry (wild-type), mice selectively lacking the ON-BC pathway of rod-cone input (Nob4), and mice with degenerate rods and cones (rd1), effectively lacking input to both ON- and OFF-BCs (Fig. 1). Figure 1. Vertical transmission of rod-cone input to ganglion cells. Green: ON pathways. Blue: OFF pathways. Loss of function is indicated by gray shading or cell absence. (A) When rods and cones respond to light, metabotropic or ON-BCs depolarize, and ionotropic ...