Journal of Neuro-Ophthalmology, March 2003, Volume 23, Issue 1

Annual Meeting of the Association for Research in Vision and Ophthalmology

NEURO- OPHTHALMOLOGY AT LARGE Annual Meeting of the Association for Research in Vision and Ophthalmology ( ARVO), Fort Lauderdale, Florida, May 5- 10, 2002 The authors highlight some of the approximately 5,000 abstracts presented at the Annual Meeting of the As­sociation for Research in Vision and Ophthalmology ( ARVO), Fort Lauderdale, Florida, May 5- 10, 2002. The abstracts, published in Investigative Ophthalmology & Visual Science 2002; 43( 4), are referenced by program number (#). NEUROPROTECTION There was a great deal of interest in new approaches to neuroprotection, some of which targeted the optic nerve or the retinal ganglion cells ( RGCs). Neuroprotection re­ferred to anything that might mitigate damage in animal models or humans. Thus, it could range from glaucoma therapy to the use of motorcycle helmets! Brimonidine once again received a great deal of attention. In vitro (# 766) and in vivo work, such as ischemia/ reperfusion (# 764, 765) or optic nerve crush (# 767); rodent models demonstrated re­duction of RGC death with brimonidine. However, there was no clinical trial that demonstrated its efficacy. In fact, in a retrospective review of NAION, the authors (# 243) concluded that topical treatment with brimonidine did not lead to better visual outcome in 14 patients compared with 17 controls, all with acute manifestations. This year's Friedenwald lecture was delivered by Michal Schwartz, PhD, from Rechovot, Israel, who dis­cussed neuroprotective aspects of glaucoma and a therapeu­tic vaccine using copolymer- 1 in a rat model of glau­coma (# 1938). Neuron- specific enolase was found to be a reliable indicator of inner retinal cell damage in a rat model of reti­nal ischemia (# 3614), and erythropoietin seemed to act as a neuroprotective agent (# 1996). MECHANISMS OF RETINAL GANGLION CELL APOPTOSIS There were several poster sessions on retinal gan­glion cell ( RGC) degeneration and neuroprotection (# 745- 767) and retinal ischemia- reperfusion mechanisms of injury and neuroprotection (# 768- 786). The role of mi­tochondrial K ( ATP) channel and Pkc or minocycline and PPAR- 7 ligands to mitigate glutamate neurotoxicity (# 746, 747,748) was explored. Neurotrophic factors and cytokines BDNF, CNTF, and FGF- 2 seemed promising in a variety of in vitro and in vivo studies (# 753, 754, 755, 760). TNF- a, IL- 1, IL- 6 were shown to be proapoptotic; IL- 10 was anti-apoptotic (# 782). Several models to study such agents were also presented (# 757, 761). In some cases, the presence of neurotrophic or chemokine factors was found but not fully identified (# 762). Heat shock protein 25 and other agents were demonstrated to be upregulated in optic nerve injury (# 763). Nonsteroidal anti- inflammatory drugs ( NSAIDS) helped protect RGCs from ischemia- reperfusion (# 770), as did protein kinase B (# 772) and protein kinase C (# 773). COX- 2 is induced by retinal ischemia (# 658) and a COX- 2 inhibitor (# 777); free radical scavengers (# 776) also proved to be protective of neuronal cells in animal models. The upregulation of manganese superoxide dismutase ( MnSOD) in surviving RGCs after optic nerve crush injury suggested that free radical toxicity within mitochondria was critical for RGC survival (# 1991). Other pharmaceutical interventions in a novel rodent model of AION (# 768, 3924) also showed promise. Ex­amples of agents that led to successful reduction in RGC loss included estradiol and nifidepine (# 768). NMD A, known to mediate apoptosis in some settings, was also shown to be pre- apoptotic in others (# 745). LEBER HEREDITARY OPTIC NEUROPATHY Two of the dozen " hot topics and must- sees" related to Leber hereditary optic neuropathy ( LHON). The first (# 234), from the Gainesville group, described the creation of a mouse model of LHON through the use of ribozymes to deplete mitochondrial complex I. The second ARVO neuro- ophthalmic " must- see," presented by one of us ( AAS), entailed a description of a new 300- member ho-moplasmic 11778 LHON pedigree of seven generations found in rural Brazil and the epigenetic factors associated Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. J Neuro- Ophthalmol, Vol. 23, No. 1, 2003 83 JNeuro- Ophthalmol, Vol. 23, No. 1, 2003 NEURO- OPHTHALMOLOGY AT LARGE with disease expression (# 908). Unexpectedly, those carry­ing the mtDNA mutation, or more likely, the associated J-haplogroup, demonstrated a protective effect against car­diovascular disease. Members of this same 11778 pedigree were examined by electrophysiology and found to have, in addition to the prominent VER changes, impairments in their electroretinograms ( ERGs) reflecting cone involve­ment (# 236). This abnormality was also found, in a limited fashion, in nonaffected carriers. Similarly, a rodent model of mitochondrial insufficiency induced by folate deficiency and formate accumulation (# 1173) caused impairments in rod and cone ERGs. Rotenone, a complex I inhibitor, was used to pro­duced a mouse model of LHON and marked thinning of the inner retina (# 235). Chloramphenicol was used to induce a mitochondrial impairment syndrome but the features were closer to Kearns- Sayre Syndrome than LHON (# 232). Op­tic nerves from LHON patients with 11778 and 3460 mtDNA mutations, analyzed by electron microscopy, con­tained mostly large- diameter fibers with evidence of myelin remodeling (# 233). The ANT1 mutant mouse model of mi­tochondrial disease failed to show a decline in retinal func­tion or significant cataracts when compared with age-matched controls (# 1775). OPTIC DISC EDEMA Spontaneous venous pulsations were absent in pa­tients with normal intracranial pressure and unilateral optic disc edema resulting from anterior ischemic optic neurop­athy or optic neuritis (# 244). An epidemiological study of pseudotumor cerebri ( PTC) in Parma, Italy revealed that the incidence of this disease is four times lower than in the United States, perhaps due to the decreased incidence of obesity in women of reproductive age in Italy. One hundred eyes of patients with PTC examined echographically dis­closed 95 with optic nerve sheath distention (# 239). AXONAL TRANSPORT Ninety minutes of retinal ischemia led, after 1- week, to impairments of RGC axonal transport (# 786), the effect being more obvious for retrograde than for antero­grade transport. OPTIC NEUROPATHY A systemic mitochondrial mutation at positions 11778, 3460, or 14484 results in a neuron- specific degen­eration of the optic nerve in LHON. A mutant neuronal pre­cursor cell line, Ntera 2/ D1 ( NT2) containing mutant LHON 11778 and 3460 mitochondria, was used in culture to study the differentiation- specific phenotype of optic neuropathy in LHON. There was a significant increase in the production of reactive oxygen species ( ROS) in the LHON- NT2 neurons when compared with controls. The authors concluded that the LHON degenerative phenotype probably resulted from an increase in mitochondrial super­oxide mediated through neuron- specific alterations in Complex I (# 906). Two large pedigrees of ( Kjer) autosomal dominant optic atrophy were used (# 907) to demonstrate that penetrance is variable and that many afflicted with the disease have normal vision. Also presented were papers dealing with a large pedigree of LHON and an analysis of risk factors (# 908), the use of ERGs to identify patients with optic nerve hypoplasia (# 909), local capillary blood speed characteristics measured by laser Doppler to differentiate optic neuritis from NAION (# 910), and studies of AION and optic disc drusen in regards to visual field changes (# 911,912). Using 11778 LHON cybrid cell lines of the type de­scribed earlier (# 906), and in whom a 60% decrease in ATP production was demonstrated, the corrective ND4 ( of com­plex I) infusion gene was inserted by an adenoviral vector (# 4599), resulting in a complete restoration of normal ATP synthesis. Patients with optic neuritis and Y1 distribution pain or pain with eye movement had involvement of the orbital seg­ment of the optic nerve on magnetic resonance imaging ( MRI), while those without pain were likely to have lesions in the canalicular or intracranial optic nerves (# 2632). Long- term therapy with cyclosporine was associated with optic nerve toxicity (# 2631). RETINAL GANGLION CELL PHYSIOLOGY In humans, monkeys, rats, and mice, there is an ap­proximate age- related 40% loss of retinal ganglion cells ( RGCs) over the lifespan of each respective species (# 984). In human donor eyes with known glaucoma, choroidal gan­glion cells stained with NADPH diaphorase were markedly decreased when compared with age- matched control donor eyes. The mechanism is not known (# 985). Decreased rela­tive optic nerve blood volume, as measured by laser Doppler flowmetry, predicted visual field loss in glauco­ma and may identify patients at risk for future progression (# 989). A new spectrographic digital oxymeter provided reliable evidence of oxygen extraction at the optic nerve head (# 990). A model of partial optic nerve transection in rats showed rapid loss of directly injured RGCs in the superior retina and delayed secondary loss in the inferior retina. This rodent model would be useful to study pharmacological in­terventions against secondary degeneration (# 2181). Heat shock protein HSP70, known for its neuroprotective effect, was not induced enough in RGCs to protect them in the partial crush model of the optic nerve (# 2197). Further, it was suggested that optic nerve crush induced the formation Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. 84 © 2003 Lippincott Williams & Wilkins NEURO- OPHTHALMOLOGY AT LARGE JNeuro- Ophthalmol, Vol. 23, No. 1, 2003 of death- receptor signaling complex, which may participate in apoptosis (# 4054). NEUROANATOMY The central axon density in the mouse optic nerve was significantly greater than in the peripheral region. This may explain the decreased susceptibility of the central axons in high- pressure optic nerve damage (# 4055). Edinger- Westphal ( E- W) preganglionic motoneurons, identified by retrograde labeling in macaque monkeys, were shown to have specific staining characteristics that would be helpful in identifying E- W motoneurons from neighboring cells (# 1488). NERVE FIBER IMAGING Retinal nerve fiber layer analysis was helpful in iden­tifying glaucoma in patients with small optic discs (< 1.1617 mm) whose diagnosis based on ophthalmoscopy often poses a challenge (# 991). Scanning laser polarimetry ( GDx), used to estimate retinal nerve fiber layer ( RNFL) thickness, was found to be a valuable noninvasive clinical tool to assess the optic nerve in patients with central demy-elinating disorders (# 2642). This technique uses birefrin­gence, which is a property of both the cornea and RNFL. The instrument uses a fixed anterior segment compensator resulting in inadequate compensation in about 30% of pa­tients, while an individualized anterior segment compensa­tor lowers the RNFL thickness values and may prove useful in eyes not compensated by the fixed method (# 993). There was a gender and refractive error- related difference in the disc and neural rim area in the normal optic disc in Hispan-ics compared with blacks and whites in the Baltimore Study (# 996). In the presence of a thin nerve fiber layer, optical coherence tomography ( OCT) readings were found to be lower than scanning laser polarimetry ( GDx) read­ings; the reverse was true in the presence of a thick nerve fiber. An equation has been derived for a relation be­tween the readings obtained by these two different tech­niques (# 1004). ELECTROPHYSIOLOGY Multifocal ERG ( MERG) was found to be a useful clinical tool to distinguish diseases of the retina and the op­tic nerve (# 2460) and assessment of retinal function modu­lation by pharmacological substances such as levodopa (# 4701). However, larger population studies need to be per­formed to establish MERG as a reliable diagnostic tool (# 1806). An incorrect refractive compensation may lead to false results in healthy eyes undergoing this technique (# 2011). The MERG data in 10- week- old infants demon­strated immature cone- mediated processes in the central retina, whereas peripheral cone- mediated responses to full field ERG were relatively mature (# 2861). Sweep visual evoked potentials ( VEP) seem to be a useful technique to follow preverbal children with papilledema (# 1807). Low- dose tamoxifen therapy in patients with breast cancer was not associated with a retinotoxic effect, as de­termined by full field and focal ERG (# 1765). FREQUENCY DOUBLING PERIMETRY Frequency doubling perimetry ( FDT) was found to be a faster technique with similar clinical efficacy as Octopus perimetry in detecting visual field loss (# 1801, 2148). GENE THERAPY There were a number of articles in relation to gene therapy strategies mediated by viral ( adenovirus, lentevi-rus) (# 4595, 4618) or nonviral vectors and genoplasty that uses oligonucleotides to repair targeted mutant genes (# 4591) for treatment of ocular disease. Gene therapy re­stored limited retinal function in the RPE65 null mutation dog model of Leber congenital amaurosis as demonstrated by an improvement in functional and ERG waveforms (# 4596, 4601). Restoration of ATP synthesis in cybrid cell lines with the LHON G11778A mutation by recoding of ND4 subunit of mtDNA may be an initial step in the treat­ment of LHON (# 4599). Gene therapy in autoimmune dacryoadenitis could be used as a therapeutic tool. Experimentally induced autoimmune dacryoadenitis (# 3121, 3122) in the lacrimal gland produced apoptosis while an in vivo transduc­tion with TNF- inhibitor gene appeared to suppress the pro­cess (# 3126). ORBITOPATHY Saccade analysis may help in the early identification of patients with Graves orbitopathy. The induction scleral search coil technique in patients with Graves orbitopathy demonstrated specific changes even in those without clini­cal signs (# 1461). The inferior oblique muscle showed evi­dence of focal inflammatory changes similar to those seen in rectus muscles in Graves disease (# 1462). Extraocular muscle injection of Ricin- mAb35, an im-munotoxin, resulted in a greater long- term weakness com­pared with injection of botulinum toxin A. Ricin- mAb35 may become an alternative treatment in patients with stra­bismus (# 1463). Amphotericin B, used by systemic, retro­bulbar and local routes, proved effective and safe in con­trolling orbital fungal infections (# 2637). OCULOMOTOR CONTROL In a study of 14 very low birth weight infants with normal IQs, saccadic control was marked by subtle defects (# 958). Children with cerebellar disorders did surprisingly well with oculomotor control (# 959). Among 137 cases of Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. 85 JNeuro- Ophthalmol, Vol. 23, No. 1, 2003 NEURO- OPHTHALMOLOGY AT LARGE sixth nerve paresis analyzed for etiology, idiopathic causes, followed by hypertension and diabetes, were most com­mon (# 1485). Mitochondrial impairment produces myopathies as well as optic neuropathies. The mRNA expression profile of extraocular muscles ( EOMs) in the rat was found to be high in a number of muscle trophic and regeneration factors (# 1910). Rapid and massive shifts of calcium into rat mito­chondria correlated with muscle activity (# 1911). Immuno-histochemistry was used to identify and count activated sat­ellite cells from normal monkey and human EOMs (# 1912). FACIAL NERVE/ LAGOPHTHALMOS/ NEUROTROPHIC KERATITIS Lagophthalmos resulting from idiopathic and post­traumatic causes had a greater likelihood of spontaneous recovery than lagophthalmos resulting from cerebellopon­tine angle and facial surgery (# 1472). Previously unrecog­nized retinal surgery (# 57) and beta- blocker use (# 58) are etiologically related to neurotrophic keratitis. TRAUMATIC BRAIN INJURY VEPs and event related potentials ( ERPs) were used to objectify deficits in the information processing in patients with traumatic brain injury (# 1803). An amaurotic pupil and a flat flash VEP at the time of presentation of traumatic optic neuropathy in a comatose patient were as­sociated with a poor visual prognosis (# 2635). PARKINSON DISEASE Surgical implantation of a deep brain stimulus elec­trode within the globus pallidus or ventromedial nucleus of the thalamus, used for intractable tremors, resulted in im­provement in head movements and better reading scores in patients with Parkinson disease (# 4671). Alfredo A. Sadun, MD, PhD Los Angeles, California Swaraj Bose, MD Irvine, California Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. 86 © 2003 Lippincott Williams & Wilkins