More than 5,000 abstracts were presented at the 2001 Association for Research in Vision and Ophthalmology (ARVO) Annual Meeting, Fort Lauderdale, FL, April 29–May 4, 2001 (Invest Ophthalmol Vis Sci 2001;42 (4). We highlight some of the investigations of interest to neuro-ophthalmologists. Abstracts are referenced by number (#), sections, and symposia by the letter S.
Apoptosis and regeneration
The week began with two symposia, one devoted to molecular mechanisms of apoptosis and cytoprotection and the other to tissue injury, repair, and regeneration. The first symposium was dedicated to Richard Lolley, PhD, former Dean of Research at the USC School of Medicine, and an important contributor to the field of the neurobiology of inherited degenerative disorders who died last year. The symposium reviewed how mouse mitochondrial mutant strains owing to a mitochondrial genome knock-out are used to investigate mitochondrial dysfunction. The pathophysiology of these disorders goes beyond that of energy deficiency to involve problems with reactive oxygen species and the early initiation of apoptosis. In the second symposium, investigators described how cultured neural stem cells are implanted in the mature nervous system to facilitate regeneration. The implantation of these stem cells leads to interactions whereby the host tissues modify the stem cells. Stem cells cause release of factors and alteration of the mature nervous system (S1). Stem cells release factors that alter the environment and interaction with other stems cells and mature neurons.
Cataract and color vision
Nuclear opacification of the crystalline lens is correlated with color vision loss owing to selective wavelength absorption (S7).
Imaging of the optic nerve and the peripapillary nerve fiber layer has improved with technical advances but is still limited in the precise longitudinal analysis of axonal loss. Media clarity, corneal birefringence, an intraocular lens, and ocular movement are confounding factors (S15–S19). The GDx nerve fiber analyzer may not recognize nerve fiber layer swelling when caused by ischemia (#110).
The neural control of eye movements was reviewed in a mini-symposium (S111). The superior colliculus appears to be important in providing a motor map for sequential saccades. Target distance modulates the vestibuloocular reflex. Three short-latency mechanisms normally compensate for subject movement to maintain fixation before the subject is aware of a disturbance in vision.
Aspects of the molecular regulation of nitric oxide synthase 2 expression in astrocytes in the optic nerve head were demonstrated and associated with a number of cellular signals and cytokines (#128). In a rat model of retinal ischemia (high intraocular pressure), systemic administration of brimonidine was more effective than topical administration in mitigating the extent of retinal ganglion cell (RGC) drop out and electroretinogram (ERG) abnormalities (#130). However, as in previous models of central nervous system ischemia, a beneficial effect required that brimonidine be administered at least 1 hour before onset of ischemia. The administration of brain-derived neurotrophic factor could mitigate RGC death after crush injury to the optic nerve in rats (#132). A similar experiment demonstrated the utility of the trophic factor CTNF (#134). The glial-derived neurotrophic factors (GDNF) and glomerular filtration rate (GFRalpha-1), as well as neurturin and brain-derived neurotrophic factor (BDNF), have receptors located on RGCs; these receptors become apparent after axotomy in the rat (#138). Because these are separate receptors, their trophic effects may be additive. A different type of study (#141) demonstrated the neuroprotective effects of memantine in two types of rat models of RGC injury: optic nerve crush injury and RGC ischemic injury through induced intraocular hypertension.
Two months after optic nerve section, the multifocal ERG is unchanged from controls, suggesting RGCs make little or no contribution to this signal (#786).
Frequency doubling perimetry
The danger of accepting new technology uncritically was highlighted in a study showing that frequency doubling time (FDT) perimetry was poor at detecting the visual field defects of brain lesions, especially in the posterior visual pathways (#807). FDT detected fewer than 50% of the quadrantanopic defects detected by Humphrey 24-2 testing. The sensitivity of FDT perimetry can be improved by offsetting the stimulus by 3 degrees from the vertical meridian (#820).
In mice developed with N-methyl d-aspartate (NMDA) receptor subunit knock-out, experimentally induced transient ischemia caused significantly less RGC death than it did in controls, which suggests excitatory amino acid–related injury acts through these receptors (#1055).
In a patient with anticardiolipin antibodies, a central retinal vein occlusion developed despite the patient's being already treated with warfarin (#1270).
Retrograde axonal flow can be demonstrated by careful ophthalmoscopy in retinal artery occlusion. In these cases, swelling and opacification similar to cotton wool spots can be seen. This phenomenon probably accounts for some of the swelling of the optic disk seen with central retinal artery occlusion (#1281).
An intravenous treatment of 50 mg rt-PA followed by eight days of heparin treatment improved the vision in three patients with macula-involving branch artery occlusion of less than 12 hours' duration (#1296).
A mini-symposium discussed progress in gene therapy and the issues facing future development (S302). In a canine model of Leber's congenital amaurosis, the known deleted gene was transfected into three animals using a methodology that not only got the gene into the retinal cells, but altered the promotor region of the existing genes. A functional gene resulted, as evidenced improvement of behavioral vision and the ERG, and a recordable visual evoked potential and pupillary response to light were demonstrated at 2.5 months and maintained for at least nine months (#1624).
Retinal ganglion cells
A mini-symposium on RGCs discussed how glial cells, which provide the normal supportive environment for neurons, can become a destructive influence when reactive astrocytes evolve (S305). The Müller glial cell is particularly important in maintaining RGC function. The notion of selective loss of parvocellular RGCs in early glaucoma was demonstrated to be erroneous.
Increased foveation time followed horizontal rectus tenotomy in 10 adults with congenital nystagmus. Binocular visual acuity improved by five letters or more in three subjects (#1720).
Leber's hereditary optic neuropathy
In a Leber's hereditary optic neuropathy (LHON)/11778 pedigree with 80 members and six generations, environmental factors—particularly tobacco, alcohol, and toxic exposures—increased the disease expression (#1754). Furthermore, this susceptibility to environmental factors was increased in the subset with haplo group J. More than two thirds of 44 patients visually impaired by ethambutol toxicity showed dramatic recovery, but recovery was less likely in older patients (#1755).
Immunofluorescent antibody studies revealed somatostatin receptors on arachnoid granulation and choroid plexus cells. These receptors might play a role in the iatrogenically induced increased intracranial pressure after growth hormone therapy (#1762).
Giant cell arteritis
In a series of patients with giant cell arteritis treated with corticosteroids, reduction of the prednisone dose to 40 mg daily by the fourth week of therapy had a low a rate of drug complications and only one recurrence of giant cell arteritis symptoms. In this single instance, increasing the prednisone dose reversed the symptoms (#1763).
In actively growing goldfish optic nerve axons, mitochondria migrate toward the growth cone, possibly owing to a demand for a high-energy supply (#1779).
In an elderly patient with LHON/3460, there was depletion of Purkinje cells largely limited to the superior cerebellar vermis (#1781). This depletion may reflect the cellular architectural and surface antigen homology between RGCs and Purkinje cells.
Genetic testing for the von Hippel-Lindau gene was negative in 10 patients with an isolated retinal capillary hemangioma, which suggests that this test could be used to screen patients for the complete disorder (#1807). New retinal hemangioblastomas developed in 22% of eyes of 68 patients with the von Hippel-Lindau gene over a median follow-up period of 16 months (#1808).
Functional MRI (fMRI) was used to demonstrate that stereopsis is dependent on a network of functional fields found in the occipital, parietal, and prefrontal cortex regions (#2160). Single fMRI studies inconsistently demonstrated the retinotopic mapping of the V1-V2 border. Signal averaging of repeated measures is necessary to accomplish this (#2192). The voxel (three-dimensional pixel) size needs to be optimized and is an important parameter in detecting brain activation in fMRI with T2-weighted echo-planar imaging (#2197).
A new method for specifying cortical location on MRI used a coordinate system with the fundamental axis in the sagittal plane extending from the anterior corpus callosum to the posterior aspect of the parietooccipital sulcus. This system seemed to be easier to use than previous systems (#2193).
Optic nerve injury
The RGC biologic basis for ischemic injury and neuroprotection was reported. Glutamate-nitric oxide signaling during development may influence the circuitry between RGCs, amacrine cells, and bipolar cells (#2025). Schwann cell-derived neurotrophic agent, administered intraocularly, can protect RGCs from optic nerve crush injury (#2035). Nitric oxide plays a major role in retinal damage after ischemia/reperfusion injury in the rat (#2211). This observation fits well with the report that inhibiting nitric oxide synthase with aminoguanidine partially protected the optic nerve axons after ischemia injury from increased intraocular pressure in the rat eye (#2224).
In an experimental unilateral glaucoma monkey model, the lateral geniculate nucleus developed atrophy not only in layers with connections to the glaucomatous eye, but also in layers receiving input from the unaffected eye. This finding suggests a more complex relationship for glaucomatous progression than merely injury at the ganglion cell level and that still unclear central mechanisms play a role (#2212).
The perceptual completion effect (“filling in”) in a patient with an occipital injury and hemianopic scotoma was demonstrated to be a retinotopic phenomenon and not attributable to inattention (#2776). Completion of filling in also occurs within the scotomas of age-related macular degeneration. Modeling that enlarges the receptive fields of adjacent normal retina appears to account for some of the observed improvement in the field defect, including retention of pattern detection (#2777).
Retinal bipolar cells
A mini-symposium reported that the bipolar cell is the starting point for parallel processing of vision (S519). On bipolar cells have sustained or transient responses as well as on or off responses. These functions are modulated through subtypes of γ-aminobutyric acid receptors. Multiple types of bipolar cells, each with unique axons, provide the basis for complex interactions with photoreceptor input and interaction with amacrine and ganglion cells. Amacrine cells might provide the modulation that results in differential tuning of bipolar cells.
Parkinson's disease causes saccadic multistepping worse with upward saccades. l-dopa significantly reduces this dysfunction (#3353).
Histology of ischemic optic neuropathy
In a well-preserved histopathologic specimen of an optic nerve that had had anterior ischemic optic neuropathy 20 days pre-mortem, there was severe axonal loss but no evidence of an infarct in a single vascular territory (#3360).
Post-operative ischemic optic neuropathy
In a retrospective survey by anesthesiologists of 27 patients with postoperative anterior or posterior ischemic optic neuropathy, visual loss after spinal or cardiac surgery was associated with low intraoperative blood pressure and/or hematocrit, vigorous fluid management to maintain perfusion of the ocular tissues, and patient positioning (#3363).
Leber's congenital amaurosis
Numerous investigators reported progress in uncovering genetic defects in Leber's congenital amaurosis (S640, S644–645).
Brimonidine mitigated the apoptosis induced by tumor necrosis factor (TNF) on retinoblastoma cells in culture, but only in the faster dividing cell lines (#3557). The same dose of brimonidine caused death of some of these cells. Curiously, TNF in conjunction with brimonidine led to less cell death, proving that two wrongs sometimes make a right.
Pupils and retinal ganglion cells
A morphologically distinct RGC type mediated the pupillary light reflex in rhesus monkey (#3639). This finding has interesting clinical implications, explaining perhaps why the pupillary reflexes are spared in some optic neuropathies (see #5020 below).
Thrombolysis of retinal vein occlusion
Direct cannulation of the retinal venous system with infusion of rt-PA via a pars plana approach with vitrectomy was performed in approximately 60 patients with central retinal vein occlusion, most of whom had prolonged reduction central acuity beforehand. The authors claimed three-line improvement in more than 50% and no major complications. Vitreous hemorrhage occurring two months after the procedure cleared spontaneously. One retinal detachment that did not affect the macula was surgically repaired (#3860).
Adenosine A2a and A1 receptors were increased in the inner nuclear layer of the retina six hours after ischemia induced by 45 minutes of elevated intraocular pressure. The A1 receptor is predominantly expressed on ganglion cells; the A2a receptor is predominantly expressed in the nerve fiber layer and ganglion cell layer (#3984).
In a primate model of transient central retinal artery occlusion induced by clamping the CRA for 190 minutes, vitreous sampling failed to demonstrate the expected elevation of glutamate or glycine (#3986).
Pretreatment with carvedilol, a beta blocker that has antiapoptotic properties, and MK-801, an NMDA antagonist, preserves more retinal function than either agent alone (#3993). Pretreatment with trimetazide, an agent used for prophylaxis of angina pectoris, reduced the effects of ischemia on retinal morphology (#3998). In vitro hypothermia (25°C) prevented a drop in adenosine triphosphate levels and reduced morphologic changes in the rat retina (#3998).
Intravitreal administration of homocysteine appears to be toxic to RGCs; the combination of homocysteine and glutamate induces even more ganglion cell loss (#4004).
In a murine knock-out gene model of Batten's disease, the optic nerve develops significant loss of axons (#4112).
A wide-field (57–90 degrees) multifocal ERG can demonstrate loss of peripheral retinal dysfunction in patients on long-term vigabatrin treatment (#4206).
Topical brimonidine causes the pupil to be approximately 1 mm smaller but has no effect on the clinical determination of the pupillary response to light (#4415). A study using computerized infrared pupillography confirmed the clinical observation that a brighter light stimulus produced a greater distinction between normal subjects and patients with unilateral anterior visual pathway lesions (#4518).
MRA and third nerve palsy
A statistical analysis of the literature on magnetic resonance angiography (MRA) in patients with isolated third nerve palsy concluded that MRA is not adequate to rule out an aneurysm in most patients younger than 70 years. However, the authors presented no original data. Their model did not distinguish between extradural and intradural aneurysms or consider MRA that includes high-resolution techniques or review of the source image data (#4531).
If patients with ocular myasthenia gravis are treated with corticosteroids, the development of generalized myasthenia gravis at two years appears to be significantly reduced. In diagnostic intravenous edrophonium testing for myasthenia, most patients require no more than 3 mg to demonstrate an ameliorative effect on ptosis or ocular motor dysfunction (#4532).
Optical coherence tomography
Optical coherence tomography appears to be the best imaging technique to view the nerve fiber layer. Asymmetry analysis of comparable areas in both eyes is useful in overcoming interindividual variations (#4548).
Rat model of ischemic optic neuropathy
A model of nonarteritic ischemic optic neuropathy was created in rats by using a laser activating an injected photosensitizing dye to thrombose small vessels supplying the optic nerve. Pale swelling of the optic disk, reduced visual evoked potentials, and a loss of RGCs were demonstrated (#5019).
Histopathology using Dil, a fluorescent dye, in a patient with LHON demonstrated preservation of optic nerve input to the pretectal region in the brain. This provides anatomic evidence for the clinical observation of relative preservation of the pupillary light response in these patients and supports the notion that some axons in the afferent loop of the pupillary reflex are not related to conscious vision (#5020).