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Journal of Neuro-Ophthalmology:
doi: 10.1097/WNO.0b013e31818cba79
Neuro-Ophthalmology At Large

Annual Meeting of the Association for Research in Vision and Ophthalmology (ARVO) Fort Lauderdale, April 27-May 1, 2008

Pomeranz, Howard D MD, PhD; Mudumbai, Raghu MD; Shindler, Kenneth S MD, PhD

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North Shore Long Island Jewish Health System Great Neck, New York

University of Washington Seattle, Washington

Scheie Eye Institute, University of Pennsylvania Philadelphia, Pennsylvania

More than 6,000 abstracts were presented at the annual meeting of the Association for Research in Vision and Ophthalmology (ARVO), Fort Lauderdale, FL, April 27-May 1, 2008. Available at www.arvo.org, the abstracts are referenced by program number.

This year the focus was “Eyes on Innovation.” The keynote address was given by Ray Kurzweil, a leader in groundbreaking technologies such as the CCD flat-bed scanner, omni-font optical character recognition, the print-to-speech reading machine for the blind, and the text-to-speech synthesizer.

The Proctor Medal was awarded to Robert Miller, MD, University of Minnesota, for his work on cell communication mechanisms in the vertebrate retina. Dr. Miller has made seminal discoveries on the basic mechanisms through which nerve cells of the retina communicate. He identified inhibition in the retina, paving the way for new knowledge on the processes of excitation and neurotransmission mediated by peptides. The Weisenfeld Award went to George Waring III, MD, a leader in the field of refractive surgery, who spoke about refractive surgery, visual impairment, and quality of life. The Friedenwald Award winner was Lois Smith, MD, PhD, whose research is directed at understanding the causes of retinopathy of prematurity and on developing methods to prevent it. Dr. Smith has made seminal contributions in promoting understanding of vascular endothelial and insulin-like growth factors in pathologic retinal angiogenesis.

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NEUROPROTECTION

Virus-mediated gene delivery of the normal human complex I subunit ND4, mutations of which are responsible for many forms of Leber hereditary optic neuropathy (LHON), reduced retinal ganglion cell degeneration in a rodent model of LHON (#3239). The gene inserts into the chromosomal DNA and contains a mitochondrial targeting sequence to subsequently direct the normal ND4 to the mitochondria. Initial clinical trials of this therapy in LHON have been approved.

Allotypic expression of a mutant human ND4 subunit of mitochondrial complex I recapitulates the hallmarks of LHON in the mouse, as demonstrated by an induction of optic nerve swelling and apoptosis with a progressive demise of ganglion cells. Superoxide dismutase 2 gene transfer protected against optic neuropathy induced by mutant human ND4 by suppressing reactive oxygen species and providing long-term protection against ganglion cell loss in the retina and axonal loss in the optic nerve (#4359). The study suggests that this form of gene therapy may be useful after the onset of disease in LHON at a time when allotypic normal ND4 was not able to rescue mitochondrial function.

SIRT1 belongs to the family of type III histone deacetylases and is implicated in diverse cellular processes. Nicotinamide adenine dinucleotide (NAD)+dependent protein deacetylase SIRT1 regulates cellular apoptosis. Oral administration of SIRT1-activating compounds attenuated neurodegeneration in a mouse model of multiple sclerosis (#3240). The drug penetrates the eye and prevents retinal ganglion cell loss during acute optic neuritis. It also reduces neurologic dysfunction from spinal cord axonal damage during disease remission.

Injection of granulocyte-macrophage colony-stimulating factor (GM-CSF) into the third brain ventricle significantly attenuated retinal ganglion cell loss in a rat model of ischemic optic neuropathy (#3242). Neuroprotection was conferred with treatment 3 days after ischemic injury and appears to be mediated by increased recruitment of extrinsic macrophages into the optic nerve.

Conditions that allow regeneration of retinal ganglion cell axons after traumatic injury were reported (#3243). Blocking the NOGO receptor, which binds myelin-derived axonal growth inhibitors, allowed sprouting of new axons posterior to the injury site in mutant mice containing increased expression of bcl-2, which promotes axonal growth, and lacking the glial fibrillary acidic protein and vimentin genes required for glial scarring. Results suggest that combining promotion of axonal growth with blocking of growth inhibitors and scarring promoters permits axonal regeneration.

Matrix metalloproteinase-7 (MMP-7) and vascular endothelial growth factor may have important roles in maintaining axonal structure after injury. Optic nerve bundles in MMP-7 knockout mice had irregular shape, organization, and myelination, and traumatic nerve injury resulted in decreased MMP-7 expression and increased VEGF expression (#4356).

NAD may have neuroprotective effects in toxic or inflammatory optic neuropathies. Tumor necrosis factor injection into rodent eyes induced axonal loss, with decreased levels of NAD. Exogenous NAD was able to reduce axonal loss through suppressed activation of microglia (#4358).

The role of the melanopsin pupillary light reflex in patients with retinal photoreceptor disease was studied by using Ganzfeld red and blue stimuli (#3245). The authors were able to demonstrate that patients with rod or cone degeneration had diminished pupil response to red or dim blue light but intact pupillary constriction to bright blue light, which may aid in localization of disease.

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OPTIC NERVE

Peripapillary nerve fiber layer (ppNFL) thickness was measured using Fourier domain optical coherence tomography (FD-OCT) in 39 control subjects and 22 patients with nonarteritic anterior ischemic optic neuropathy (NAION) (#936). The superior and inferior hemisphere average of the automated visual field total deviation and pattern deviation were compared with superior and inferior hemisphere average of the ppNFL thickness. The NAION group had a significantly thinner ppNFL in every quadrant and octant compared with that in the normal group. The relative loss was greatest in the superior quadrant and superior-temporal octant. The most severe hemispheric visual field loss was associated with a residual ppNFL thickness of 32 m. FD-OCT was able to measure ppNFL thickness with excellent reproducibility both in normal subjects and in patients with NAION. Severity and location of visual field defects were significantly correlated with ppNFL thinning.

The ability of optical coherence tomography (OCT), GDx, and Heidelberg retinal tomography (HRTIII) to detect permanent optic nerve damage was assessed in patients with a history of acute unilateral retrobulbar optic neuritis who had complete recovery of visual acuity (#820). The study included 25 patients and 29 control subjects. Both OCT and GDx were good for differentiating optic neuritis and control eyes with a high level of sensitivity and specificity, whereas HRTIII cannot make such a differentiation. There was good correlation between standard visual function tests and retinal nerve fiber layer (RFNL) imaging and visual evoked potential P-100 amplitude.

OCT and GDx were used to study the RNFL of 40 patients evaluated within 21 days of onset of vision loss in a first episode of typical acute optic neuritis (#5389). Swelling or thickening of the RNFL was defined as 3 sectors of ≥10% thickness compared with the unaffected fellow eye. More than 85% of patients had RNFL swelling by OCT measurement. RNFL loss could be observed within 1 month of onset of optic neuritis. There was no correlation between RNFL thickness and the retrobulbar distance of the demyelinating lesion from the globe. The investigators concluded that when demyelinating lesions are distal to the globe, axoplasmic blockade at the site of the lesion and not inflammation of the optic disc region could be the cause of RNFL swelling.

Optic nerve axonal loss was studied prospectively with OCT in 93 consecutive patients with multiple sclerosis (MS) and normal subjects (#1181). The group with MS included 47 patients who had had optic neuritis and 46 who had not. Among the patients with MS, 60 had the relapsing remitting form, 8 had the primary progressive form, and 25 had the secondary progressive form. No significant relationship was found between RNFL thickness and Expanded Disability Status Scale (EDSS) score or MS type. The average RNFL thickness for the whole MS patient group was 90 m compared with 104 m for the healthy group. Average RNFL thickness for patients with MS without previous optic neuritis was 94 m. The investigators concluded that there were highly significant reductions in RNFL thickness in affected eyes of patients (with or without previous acute optic neuritis) compared with control eyes. RNFL thickness as measured by OCT was found to correlate with the level of relative afferent papillary defect measured with neutral density filters (#1182). Frequency domain OCT was used to measure the relative contribution of blood vessels to overall RNFL thickness (#1184). Blood vessels comprised a mean of 7% of RNFL thickness in normal eyes and 12% in areas of major arcuate fiber bundles. In eyes with severe visual field loss, blood vessels comprised a mean of 24% in areas of major arcuate fiber bundles.

OCT thickness of RNFL correlated with clinical grading of optic disc edema, but thickening of only the inferior portion of the optic disc correlated with Humphrey visual field (HVF) mean deviation (#1185).

A study of patients with idiopathic intracranial hypertension (IIH) showed no consistent correlation between RNFL thickness on OCT and visual field loss on HVF, noting that a combination of atrophy and swelling can coexist (#1186). A smaller study did show that improvement in OCT-measured RNFL thickness after acute papilledema in IIH correlated with improvement in HVF mean deviation (#1187). Optic disc area measured by Heidelberg retinal tomography (#1189) demonstrated that Caucasians have smaller discs (2.15 ± 0.58 mm2) than African Americans (2.55 ± 0.51), Asian Americans (2.38 ± 0.54), Filipino Americans (2.48 ± 0.70), and Hispanic Americans (2.57 ± 0.55).

Matrix frequency doubling technology (FDT) 30-2 visual field defects correlated with standard HVF field 30-2 fields in at least 3 quadrants of 71% of patients with a variety of neuro-ophthalmic causes for vision loss (#1192), including cortical, chiasmal, and optic nerve disease.

Average visual field loss in FDT testing as a measure of contrast sensitivity could discriminate patients with Alzheimer disease (AD) from healthy control subjects and patients with mild cognitive impairment (#1194).

FDT matrix visual field testing was more sensitive than earlier versions of FDT and paralleled HVF 24-2 Swedish Interactive Thresholding Algorithm (SITA) Fast testing for detecting visual field loss respecting the vertical midline (#1196).

Anterior optic nerve cross-sectional area measured on MRI did not correlate with visual acuity or color vision loss, but did correlate with HVF mean deviation in patients with optic atrophy (#1197).

A series of 20 patients undergoing evaluation and treatment of pituitary tumors were subjected prospectively to standard automated perimetry (SAP) (24-2 SITA Fast) and Rarebit visual field testing (#1195). The pattern of visual field defects seen on SAP was duplicated by Rarebit in all cases. In 4 patients with normal SAP after pituitary treatment, persistent visual field defects could still be seen in the Rarebit, indicating subclinical pathologic changes. The use of tiny suprathreshold stimuli may be a sensitive way of looking for residual defects seen in patients with chiasmal syndromes.

In a retrospective interventional clinical case study, the records of 7 patients (8 eyes) were reviewed to study the functional and anatomic outcomes of triamcinolone acetonide intravitreal injection for NAION (#6008). Visual acuity improved in 6 (85%) patients with a mean improvement of 3.5 lines. Two patients (25%) had loss of visual acuity with a mean worsening of 4 lines. Among 6 patients with improved acuity, visual field mean deviation improved slightly in one patient (12.5%) and showed no significant overall change in 5 patients (62.5%). The benefit of intravitreal steroid use in NAION could not be clearly demonstrated in this small study.

In an ultrastructural study of induced optic neuropathy in a mouse model (#4362), chloramphenicol administered orally in high doses for 15 days resulted in axonal condensation and nerve fiber degeneration, remyelination, neuroglial reactivity, and cell death. Gliotic changes were the most pronounced morphologic evidence for cell injury as observed by astrocytic hypertrophy and hyperplasia, oligodendrocytic remyelination of demyelinated axons, and apoptotic changes. The increase in the number of mitochondria may be a compensatory reaction to impairment in oxidative phosphorylation induced by chloramphenicol.

An ultrastructural study of the optic nerve was carried out in a mouse model for conditional knockout gene mitofusin 2 (Mfn2) (#5383) associated with mitochondrial fusion, a phenomenon that occurs with remodeling in the cell. Impairment of fusion causes mitochondrial fragmentation. Mouse models of Mfn2 that cause conditional knockout only in the visual system have been developed. This study revealed that axonal profiles of knockout mice show degenerative changes, condensation of axoplasm and mitochondria, an increased number of microglia, a decrease in oligodendrocytes, and the appearance of astrocytes with giant mitochondria. This model may serve as a tool to observe how mitofusins contribute to optic atrophy and to other neurologic disorders associated with aberrant mitochondrial fusion.

Retinal ganglion cells were simultaneously identified and levels of reactive oxygen species were measured in vivo using a dual frequency confocal scanning laser ophthalmoscope (#5384). This information is helpful in studying the mechanisms of apoptosis that occur with retinal ganglion cell injury.

Previous histologic studies have shown optic nerve axonal degeneration in AD. The receptor for advanced glycation end-products (RAGE) is a possible mediator in the pathogenesis of many neurodegenerative diseases. RAGE can play a role in the signal transduction pathways leading to amplification and perpetuation of inflammation. Ten optic nerves from patients who died of AD were examined immunohistochemically (#5385). An increase in RAGE was found in optic nerves in patients with AD compared with those of control subjects. RAGE expression was associated with glial cells in AD optic nerves compared with control nerves. A linear relationship of RAGE expression with age was found in AD optic nerves with increased RAGE expression in AD optic nerve axons and glial cells. RAGE up-regulation in AD is a possible compensatory phenomenon or cellular adaptation. It is not known whether this up-regulation is a cause or consequence of AD.

Brain metabolic changes in cortical gray and normal-appearing white matter (NAWM) were studied with 1H magnetic resonance spectroscopy to determine the prognostic value of metabolic alterations in patients with clinically isolated syndromes (CIS) suggestive of MS and presenting as optic neuritis (#613). Using a 3-T whole body magnetic resonance system, a multisequence conventional MRI protocol, and single voxel proton magnetic resonance spectroscopy of the parietal NAWM, studies were performed in 30 patients presenting with optic neuritis at baseline and 20 control subjects. The metabolic concentrations of N-acetylaspartate (NAA), myoinositol (INS), choline, and creatine were determined at baseline and at 6, 12, 18, and 24 months after the initial demyelinating event. In this study, 11 patients converted to definite MS during the follow-up period. The patients who converted to MS showed significantly lower baseline NAA concentrations (P < 0.01) and higher INS concentrations (P < 0.01) in the NAWM compared with those in nonconverters. No significant difference was observed for creatine and choline in either patient group. No significant differences were observed between any metabolite concentrations from the nonconverted group and control group. The early increase in INS and decrease in NAA may reflect a process of pathogenic importance in MS NAWM. NAA and INS brain concentrations may be a prognostic marker for conversion to early definite MS.

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EYE MOVEMENTS

Mechanically restricting microsaccades, present during normal fixation, with a scleral contact lens (#129) also leads to microsaccade suppression in the contralateral eye. The authors suggested that proprioceptive inputs play a role in suppressing microsaccades in dark conditions.

Examination of prediagnosis carriers of the Huntington gene showed a significant decrease in visual scanning measurements up to 5-6 years before clinical diagnosis of Huntington disease (#131) that may be useful as a biomarker of early disease.

Involuntary version-vergence nystagmus induced by motion stimuli demonstrated that although the vergence and saccadic systems can act separately, they interact, with vergence velocity dependent on saccadic velocity, when both systems are stimulated simultaneously (#134).

Investigators looked at primates with prism-induced strabismus as a surrogate for amblyopia in infantile esotropia in assessing the potential benefit of early intervention. They found that binocular connections between the ocular dominance columns are diminished if primates are subjected to prism-induced strabismus and that sensory and ocular motor defects can be prevented if correction occurs between 3 and 12 weeks (corresponding to 3 and 12 human months). This finding suggests that early intervention in humans may be beneficial for appropriate brain development.

Five adult patients who underwent tenotomy for infantile nystagmus had improved target acquisition times, correlating with subjective improvement in vision (#137).

MRI demonstrated abnormalities in 47 of 48 patients with infantile nystagmus (#138), ranging from signal abnormalities in the white matter (44%), gray matter (42%), and brainstem (44%), to specific cranial anomalies (38%), developmental malformations (35%), cerebral atrophy (17%), and enlarged subarachnoid and Virchow-Robin spaces (35%).

Soft contact lenses were found to dampen the slow phases of infantile nystagmus (#140), possibly by feedback signaling through the fifth cranial nerve, resulting in a wider range and degree of foveation.

Mechanical restriction of eye movements with a handle-held scleral contact lens in one eye of patients with infantile nystagmus resulted in reduced amplitude of nystagmus in both eyes (#141) and may be useful for times when nystagmus needs to be dampened during clinical evaluation.

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ORBIT

Progressive enophthalmos to a degree that the globes lose contact with the eyelids can occur after cerebrospinal fluid (CSF) shunting for acquired hydrocephalus. Based on volumetric image analysis, the results of one study of 4 patients (#6022) suggested that enophthalmos after CSF shunting is secondary to expansion of bony orbital volume that may be due to chronic CSF hypotension. Possible mechanisms for enophthalmos include fat atrophy or tethering of the globes via tension on the optic nerves due to a posterior shift in the position of the brain.

A symposium on thyroid-related orbitopathy (TRO) focused on attempts to translate basic science discoveries into clinical therapy including core components of pathophysiology and valid scales in assessing clinical disease. Orbital fibroblasts may possess unique properties that separate them from other fibroblasts with special roles for insulin-like growth factor (IGF-1) receptor and thyroid-stimulating hormone (TSH) receptor in accelerating fibroblast proliferation and inflammation. The IGF-1 receptor has been identified in patients with TRO but in few patients without disease. This receptor may be overexpressed in orbital tissue; binding of antibody to receptor may lead to altered cell function. The TSH receptor is not always expressed except in specific conditions. Is there a link between TSH and IGF-1 receptors in the orbit? Evidence of their close physical linkage was reviewed along with data suggesting that the receptors may interact with each other. Such interaction suggests the possibility that an initiating event leads to autoantibodies generated against epitopes in the TSH and IGF-1 receptors. Spread could occur so that autoantigens are incorporated in a step-like fashion, leading to generation of cytokines and chemoattractants. There could be overexpression of extracellular matrix and hyaluronic acid until clinical disease is manifested. Although there have been prior classification systems of TRO, such as “NOSPECS,” a newer algorithm called “vision, inflammation, strabismus, appearance/exposure) (VISA) was proposed.

Howard D. Pomeranz, MD, PhD

North Shore Long Island Jewish Health System

Great Neck, New York

Raghu Mudumbai, MD

University of Washington

Seattle, Washington

Kenneth S. Shindler, MD, PhD

Scheie Eye Institute

Philadelphia, Pennsylvania

© 2008 Lippincott Williams & Wilkins, Inc.

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