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Show NEURO- OPHTHALMOLOGY AT LARGE 2009 Annual Meeting of the Association for Research in Vision and Ophthalmology ( ARVO) Fort Lauderdale, Florida May 3- 7, 2009 The focus of the 2009 Association for Research in Vision and Ophthalmology ( ARVO) annual meeting was ‘‘ Reducing Disparities in Eye Disease and Treatment.'' The keynote address was given by Hugh R. Taylor, MD, Melbourne, Australia, who discussed how huge disparities in eye health around the world are being addressed. The Proctor Medal was awarded to Joe G. Hollyfield, PhD, Cleveland Clinic Foundation, for his work in understanding the initiating events in age- related macular degeneration. The Weisenfeld Award went to Alan Bird, MD, FMedSci, University College London, for his seminal work on the biologic treatment of retinal disease. The Friedenwald Award winner was Samuel Miao- Sin Wu, PhD, Baylor College of Medicine, whose research has led to a better understanding of the synaptic organization of the vertebrate retina. NEUROPROTECTION Clinical trials of potential neuroprotective therapies in neurology and ophthalmology have had disappointing results despite potent neuroprotective effects in preclinical models (# 298). Small differences in animal models or conditions used to induce neuronal injury can lead to large differences in outcome. It will probably be important to identify neuroprotective strategies that work in multiple models to increase chances of successful translation. Preclinical studies that focus on keeping retinal ganglion cells ( RGCs) alive are also insufficient, as the remaining cells may not be functional. For example, RGCs in mice lacking Bax, a pro- apoptotic protein, do not die after optic nerve injury but do not function normally and develop suppressed gene expression due to histone deacetylation. Understanding such epigenetic factors that regulate gene expression may lead to novel therapeutic approaches to restore the function of surviving ganglion cells. Critical reevaluation of how to evaluate neuroprotection may lead to new therapeutic strategies for optic neuropathies and other neurodegenerative diseases. Investigators reported promising neuroprotective effects for RGCs in models of glaucoma and traumatic optic nerve injury. For example, several groups showed neuroprotective effects of specific neurotrophic factors and are developing methods for stable long- term delivery. Mesenchymal stem cells ( MSCs) from adult bone marrow that are engineered to express brain- derived growth factor ( BDNF), glial- derived growth factor ( GDNF), or nerve growth factor ( NGF) will integrate into the retina after intravitreal injection and reduce the level of RGC loss after optic nerve transection (# 1673). Another group found that MSCs secreting BDNFor GDNF prevent RGCs from dying in a laser- induced rat model of glaucoma (# 2754). BDNF delivery by an alternate method- transfection of an adeno-associated viral vector expressing BDNF- showed similar neuroprotection of RGCs after nerve transection (# 2757). Consistent with observed effects of BDNF treatment, endogenous up- regulation of BDNF was detected in rat eyes with experimental glaucoma induced by injection of hypertonic saline into episcleral veins (# 2760). Phosphine-borane complexes ( PB- 1 and PB- 2) previously shown to reduce RGC loss after nerve injury were evaluated further to understand how they may protect neurons. In vitro studies revealed that PB- 1 and PB- 2 reduce disulfides and are probably able to cross the blood- brain barrier, but they do not scavenge the damaging reactive oxygen species superoxide (# 3189). PB- 1 was able to reduce proteins isolated from a RGC cell line, suggesting that changes in sulfhydryl oxidation from drug treatment may promote neuronal survival (# 3190). An Optic Nerve Regeneration Symposium (# 272) focused on factors that may move the technology of optic nerve regeneration from theory to practice. It is currently accepted that intrinsic properties of the optic nerve and its environment prevent regeneration. These factors include reactive gliotic scar formation, myelin inhibitory proteins, and macrophage- associated scar retraction. Many factors have been evaluated to encourage re- growth of the RGC axons. One promising factor seems to be Bcl- 2. Neonatal mice overexpressing Bcl- 2 have been shown to be capable of regeneration of the entire length of the optic nerve. Removal of phosphatase and tensin homolog and tuberous sclerosis complex 1, which down- regulate the rapamycin pathway, can lead to protein synthesis helpful in re-generation. Directed growth of damaged axons to the site of 358 J Neuro- Ophthalmol, Vol. 29, No. 4, 2009 injury seems to require EphB3 receptor tyrosine kinase, which does not, however, prevent aberrant growth patterns. Intravitreal placement of factors that may promote photo-receptor regeneration may be the next site of application. It remains to be determined how the complex retinotopic arrangement of RGC axons in the pre- and post- geniculate visual pathways will be re- established with optic nerve regeneration. ASSESSING STRUCTURE- FUNCTION RELATIONSHIPS Pattern electroretinogram ( ERG) amplitude and retinal nerve fiber layer ( RNFL) thickness were diminished in patients with temporal hemianopia due to chiasmal compression (# 929). Swelling of the RNFL from papil-ledema due to intracranial hypertension ( IIH) is better shown by optical coherence tomography ( OCT) than by slit lamp polarimetry ( SLP), whereas SLP may be more useful than OCT to demonstrate axonal dilatation (# 932). RNFL swelling from papilledema was greatest in the superior and inferior quadrants on OCT. There was no correlation between change in RNFL thickness and change in mean deviation on automated perimetry. Forty- seven adult patients with monocular amblyopia ( anisometropia, strabismic, deprivation, or idiopathic) had evidence on pattern visual evoked potentials ( VEPs) of delayed P100 latency ( 118.69 msec) and an increased P100 latency ratio of 1.18 compared with control subjects ( P100 latency [ 103.63 msec] and P100 latency ratio [ 1.03]) (# 4708). Pattern VEPs may be helpful in confirming amblyopia in adults. The RNFL is commonly thickened compared with that in the fellow eye during acute optic neuritis ( ON) even though clinically the optic disc may not appear edematous. One month after the acute episode, most of the RNFL thickening has diminished. Persistent RNFL thickening at 1 month was predictive of poor long- term prognosis for visual recovery with continued RNFL loss progressing over the following 6 months (# 926). Visual loss in patients with multiple sclerosis ( MS) may be present even in the absence of a history of ON. Reductions in low- contrast acuity are associated with RNFL thinning, suggesting that axonal loss may be a significant contributor to visual dysfunction in MS. The rate of chronic axonal loss observed in patients with MS was greater than that seen in healthy patients, regardless of a previous history of ON. Progressive axonal loss can be detected in the optic nerves of patients with MS. Ocular imaging technologies are useful tools to evaluate structural abnormalities in the RNFL and changes over time (# 927, # 928). RNFL birefringence reduction and recovery were studied using GDx in patients with acute ON. The percent change in thickness was calculated for each sector and globally in 10 subjects with the fellow eye as a control. There was acute thickening of the RNFL across all sectors on OCT and subsequent thinning over 6 months. Bi-refringence fell at baseline and recovered over time. Baseline birefringence reduction did not correlate with the 6- month mean deviation on automated perimetry or the amount of RNFL loss on OCT. Most of the birefringence reduction seems to be due to intra- axonal swelling and extra- axonal edema and seems to be recoverable (# 5664). Twenty patients who had recovered from ON underwent multifocal VEP testing (# 5348). Among the areas most commonly affected, the cecocentral and arcuate nerve fiber bundle regions were found to have abnormally prolonged latencies, which correlated with defects seen on standard automated perimetry. The RNFL was longitudinally evaluated in 23 carriers of Leber hereditary optic neuropathy ( LHON) over 4 years (# 934). Forty- eight percent of carriers with subclinical disease showed RNFL loss that was greatest in the superior and inferior quadrants. Subclinical pattern VEP abnormalities with prolonged latencies in P100 and N135 were found in clinically unaffected 11778 LHON carriers (# 5347). Macular thickness and RNFL thickness were both significantly smaller in eyes with band atrophy of the optic nerve compared with healthy control eyes. The macular thickness parameters of the nasal nerve fiber layer were the most predictive for differentiating eyes with band atrophy from control eyes. Macular thickness may have greater potential than RNFL thickness for assessing structure-function relationships in chiasmal disease. Global and sectoral macular and RNFL thickness differed significantly between eyes with band atrophy and healthy control eyes. Correlations were stronger between visual field loss and quadrantic or hemianopic nasal macular thickness than between visual field sector loss and sectoral RNFL thick-ness. The strongest correlation was observed between macular thickness in the inferonasal quadrant and visual field sectoral loss in the superior- temporal central quadrant (# 930). Evaluation of Humphrey matrix frequency doubling technology ( matrix FDT), a newer program that uses smaller spot size than original FDT perimetry, showed a high correlation to defects detected on standard Humphrey visual field ( HVF) perimetry for pre- chiasmal and post-chiasmal visual field loss (# 5352). Prior studies of the original FDT had shown poor correlation for post- chiasmal lesions. Rarebit perimetry, a newer technology that uses supra- threshold small spot sizes 1/ 100 the size of standard HVF testing, was evaluated for its possible role as a bedside test in the inpatient setting (# 5353). Rarebit perimetry was performed using a laptop computer for 29 eyes with visual field loss to test subjects lying in a hospital bed. Each eye also had been tested with the HVF 24- 2 SITA program 359 Neuro- Ophthalmology at Large J Neuro- Ophthalmol, Vol. 29, No. 4, 2009 in a clinic setting. Twenty- one of 29 eyes showed good correlation between rarebit and HVF results. In an addi-tional 5 patients, rarebit perimetry was more sensitive than HVF testing, suggesting that this may be a useful bedside visual field test for inpatients. Trans- synaptic retrograde loss of RGC after retro-geniculate lesions was demonstrated in humans using Stratus OCT to measure peripapillary nerve fiber layer thickness in both eyes (# 5665). Pituitary macroadenoma volume measured on MRI correlated with mean deviation, pattern standard deviation, and number of defective quadrants on Humphrey perimetry in 39 patients (# 931). OPTIC NERVE A retrospective review of visual outcomes in patients with neuromyelitis optica treated with rituximab compared with those of patients treated with other, more conven-tional, immunosuppressive therapies suggested that vision may recover better with rituximab (# 1439). However, only 3 rituximab- treated patients were reported, with all 3 returning to baseline vision within a 6- month to 2- year available follow- up period. A study of optic nerves from 2 brothers affected by LHON showed that decreased optic nerve size seems to predispose to phenotypic expression of LHON and may also be responsible for a more severe level of visual and structural nerve degeneration (# 5350). Analysis of the RNA transcription profile extracted from leukocytes from 4 men with the 11778 LHON mutation who had experienced visual loss many years earlier revealed 137 up- regulated genes and 152 down- regulated genes hypothesized to be involved in cellular transport and transcription. ND4 and other mitochondria- encoded genes were not differentially expressed. The OPA1 gene was down- regulated in each of the 4 patients (# 3468). Axonal mitochondrial DNA copy number was found to be correlated with the pattern of axonal degeneration in histologic analysis of optic nerves from 4 patients with LHON (# 3469). A retrospective review of 7 patients with LHON who were treated with idebenone ( 360- 540 mg/ day for 2 months to 1.5 years), a synthetic analog of coenzyme Q, revealed that 3 patients had significant improvement in visual acuity, visual fields, and color vision (# 1440). Two patients who improved had the 11778 mutation; 1 patient had the 14484 mutation. Stimulation of ATP production by idebenone or other mechanisms may be useful for treating LHON. Related results in a rodent glaucoma model demonstrated that topical coenzyme Q10 administration reduces retinal ganglion cell loss through increased expression of cyclophilin D and cytochrome c oxidase (# 4046), suggesting that coenzyme Q may have benefits for a variety of optic nerve stressors. Studies in a mouse model of LHON demonstrated long- term protection of RGCs and stable expression of ND4 in an AAV2 vector (# 1443). Targeted gene therapy to replace mutant mitochondrial gene products through chromosomal DNA with a mito-chondrial localizing sequence presents another potential strategy for long- term preservation of RGCs in LHON. A study of 4 eyes from 2 Brazilian men with LHON who had the 11778 mutation and 4 age- matched control subjects demonstrated that melanopsin- containing RGCs are partially spared by neurodegeneration in LHON (# 2559). Melanopsin- containing RGCs seems to withstand the degeneration process, consistent with the preservation of the pupillary light reflex and circadian rhythm seen in patients with LHON. Light- induced melatonin suppression after exposure to monochromatic blue light was unaffected in 5 patients with LHON and in 4 patients with dominant optic atrophy compared with control subjects (# 5663). 24S- Hydroxycholestrol, a by- product of enzymatic oxidation of cholesterol in neurons, seems to be a biomarker of some optic neuropathies. Retinal and plasma levels were measured using gas chromatography and mass spectros-copy in an animal model for optic nerve disease. Plasma levels were also monitored in patients with ischemic optic neuropathy ( ION) 1 day- 6 months after onset of visual loss. Plasma levels increased 3- fold in the animal model. Patients with ION showed increased levels compared with those in age- matched control subjects (# 3200). In a novel rat model for ION, erythrosin B dye was activated with a YAG laser at 532 nm for 90 seconds at 200 mV to photochemically induce an ischemic injury 3 mm posterior to the optic disc. There was 50% RGC survival at 4 weeks (# 3198). This paradigm seems to be a good model for posterior ION. Using the photochemical thrombosis mouse model for anterior ION, aB crystallin, a heat shock protein, was up- regulated (# 3463). Exogenously delivered aB crystallin did not increase RGC survival and improved latency but not amplitude in the flash VEP. In a prospective study of 304 asymptomatic morbidly obese patients, screening with nonmydriatic fundus photography for optic disc edema identified only 1 patient (# 4020), suggesting that screening for asymptomatic IIH is not cost- effective in this population. The sensitivity and specificity of ultrasound to detect intraoptic nerve sheath fluid for distinguishing papilledema from pseudopapille-dema in patients with elevated optic disc pressure was examined in a retrospective review of 44 patients (# 4021). Twenty patients had true papilledema, confirmed by elevated opening pressure on lumbar puncture, and 24 had pseudopapilledema. Among the 20 patients with papilledema, 19 ( 95%) had positive fluid signs on ultrasound. Among the 24 patients with pseudopapillede-ma, 10 ( 40%) had positive fluid signs on ultrasound. These results suggest that a negative ultrasound fluid test may be 360 q 2009 North American Neuro- Ophthalmology Society J Neuro- Ophthalmol, Vol. 29, No. 4, 2009 Shindler et al useful to exclude papilledema but that a positive test may falsely suggest papilledema quite often. The ability of a portable home- monitoring device to detect whether patients with nonarteritic anterior ION ( NAION) have obstructive sleep apnea ( OSA) was examined (# 4023). Of 15 patients monitored, 5 ( 33%) were found to have OSA, consistent with published reports that OSA incidence is increased in patients with NAION. Further development of this device may lead to easier and cheaper evaluation for patients by reducing the need for traditional sleep studies. Histologic evaluation of optic nerves from patients with Alzheimer disease ( AD) detected the presence of S- 100 A12 ( calgranulin C) (# 4027). The staining pattern showed a plaque- like structure similar to plaques seen in brain lesions, suggesting that S- 100 A12 plaques can form in optic nerves and may contribute to disease pathology. Further studies by this group identified additional potential pathogenic markers of AD- related optic neuropathy, including the receptor for advanced glycation end products. Detected in microvascular endothelial cells of optic nerves from patients with AD, they are known to bind a variety of ligands, including b- amyloid (# 5345). High- mobility group box 1, a nonhistone DNA binding protein, was found by immunohistochemical analysis in the extracellular matrix of 12 optic nerves from patients with AD but not in the optic nerves of control subjects (# 5351). Whether these proteins play a causative or bystander role is still unknown. Nuclear magnetic resonance- based metabolomic analysis, used to detect metabolites including proteins, amino acids, drug compounds, and lipids, was used to screen blood and spinal fluid samples from patients with a variety of central nervous system ( CNS) diseases (# 4036). Results showed that reproducible disease- specific patterns could be identified, The metabolomic analysis pattern in 21 patients with IIH was 80% sensitive and 80% specific in distinguishing this condition from a full spectrum of CNS diseases, and analysis patterns in 17 patients with MS were also 80% sensitive and specific. Further refinement is needed, but results suggest that this technology will be useful for identifying biomarkers to aid in diagnosis and monitoring of disease. Long- term follow- up of patients who underwent optic nerve sheath fenestration suggested that early inter-vention may be useful to better preserve vision (# 1441). A retrospective review showed that 88% of patients with 20/ 40 or better visual acuity at the time of surgery retained 20/ 40 or better after surgery. Of patients with 20/ 50- 20/ 200 visual acuity, 34% improved to 20/ 40 or better post-operatively, whereas only 9% of patients with visual acuity poorer than 20/ 200 vision improved to 20/ 40 or better and only 5% improved to 20/ 50- 20/ 200. Investigators are using an infrared laser to perform endoscopic optic nerve sheath fenestrations (# 1442) in an attempt to reduce surgical complications. ORBIT Upper eyelid injection of triamcinolone ( 40 mg) to treat lid retraction and orbital swelling (# 650) in patients with thyroid- related orbitopathy was evaluated. Average palpebral height decreased from 9.6 to 8.7 mm in 20 eyes, and 19 of 22 eyes showed improvement in orbital swelling. The only complication was a mild elevation in intraocular pressure in 1 patient. Axial globe position seems to have an effect on eyelid excursion (# 656). In 58 patients, every 1- mm decrease in axial globe position measured by exophthalmometry resulted in a 0.4- mm decrease in levator function, which should be kept in mind when one is evaluating patients for neuromuscular disease. No correlations were found between MRI volumetric analysis of extraocular muscle ( EOM) motility and diplopia as measured by plotting the zone of single binocular vision on Goldmann perimetry (# 1981). A retrospective review of long- term (> 4 year) follow-up data of patients with ocular myasthenia gravis confirmed results of earlier shorter- term studies showing that patients treated with prednisone were less likely to develop gener-alized disease ( GMG) and less likely to have diplopia than patients who did not receive prednisone (# 1436). Of 87 patients, 55 were treated with prednisone, with 13% devel-oping GMG and 27% having diplopia at the last recorded visit ( mean = 7.2 years). In comparison, 50% of the 32 patients not treated with prednisone developed GMG, and 57% had diplopia at the last follow- up ( 4.6 years). In a review of 176 temporal artery biopsies, older age and higher sedimentation rate were correlated with greater likelihood of positive biopsy results in patients. Although women were more likely to undergo biopsy, the likelihood of positive biopsy results was not significantly different from that in men. Longer biopsy specimens were not associated with a higher likelihood of positive pathology. The choice of surgical service to perform the biopsy did not seem to have any correlation to the results of the biopsy (# 4017). Lay observers were evaluated for their ability to detect strabismus in subjects from various ethnic groups in 12 digitally simulated esotropia and exotropia models (# 1993). With 70% as a positive detection rate, the critical magnitude was 18.82 prism- diopters ( PD) for esotropia ( ET) and 16.63 PD for exotropia ( XT). ET was easier to detect than XT among Asians and the opposite was true for Caucasians and African Americans. Eight subjects performed voluntary and ‘‘ visually guided saccades'' while undergoing 3- T functional MRI (# 2879). The superior parietal cortex and the dorsolateral prefrontal cortex seemed to be most involved in vertical saccades. 361 Neuro- Ophthalmology at Large J Neuro- Ophthalmol, Vol. 29, No. 4, 2009 Caffeine increased ocular microtremor and micro-saccades within 30 minutes in 20 healthy subjects given 180 mg of regular coffee but not in subjects given decaffeinated coffee (# 2882). Autopsied EOMs of patients with amyotrophic lateral sclerosis ( ALS) were compared with autopsied control EOMs in a mice model of ALS (# 3038). Decreased expression of gangliosides GD1b and GQ1b/ GT1a and Schwann cell marker S- 100 were noted in patients with ALS. Parvalbumin, believed to be protective for EOMs in patients with early ALS, was diminished in these patients with end- stage ALS. Both patients with ALS and transgenic ALS mice with the D90A mutation had similar changes in the extracellular matrix of EOMs that may make the mouse model useful in evaluating pro-gressive changes in EOMs. VISUAL PATHWAY Eight- three patients have been enrolled in a commu-nity based, multicenter trial evaluating the potential benefit of high- power ( 57 PD) peripheral prism glasses for homonymous hemianopia (# 3210). Peripheral Fresnel prism segments were fitted unilaterally on the side of the field loss. Preliminary results showed that 68% of patients believed that the high- power peripheral prism helped in obstacle avoidance. In another study (# 4734), hemianopic patients were evaluated for scotomas in visual space located at the prism apex with either 40- or 57- PD base out Fresnel prisms. One of 4 patients with 57 PD had binocular ( 10 lateral extent) scotomas. These scotomas are important to recognize in future designs of bilateral prism glasses for hemianopic field expansion. The ability to drive a 14- mile route in an automobile was tested in 30 patients with homonymous hemianopia or quadrantanopia and 30 matched control subjects with normal visual fields 6 months after brain injury (# 3204). Patients with visual field defects were likely to drive more slowly and accelerate less often. These driving character-istics are different from those seen in unsafe drivers. Kenneth S. Shindler, MD, PhD Scheie Eye Institute University of Pennsylvania Philadelphia, Pennsylvania kenneth. shindler@ uphs. upenn. edu Raghu C. Mudumbai, MD Department of Ophthalmology University of Washington Seattle, Washington Howard D. Pomeranz, MD, PhD North Shore Long Island Jewish Health System Great Neck, New York 362 q 2009 North American Neuro- Ophthalmology Society J Neuro- Ophthalmol, Vol. 29, No. 4, 2009 Shindler et al |
