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Show NEURO- OPHTHALMOLOGY AT LARGE Annual Meeting of the Association for Research in Vision and Ophthalmology, Fort Lauderdale, Florida, April 25- 29, 2004 Approximately 5,600 abstracts were presented at the Annual Meeting of the Association for Research in Vision and Ophthalmology ( ARVO), Fort Lauderdale, FL, April 25 to 29, 2004. The abstracts, available at www. arvo. org, are referenced by program number (#). NEUROPROTECTION: RETINAL GANGLION CELLS New approaches to neuro- protection that target the optic nerve or the retinal ganglion cells ( RGCs) in animal models and of optic nerve damage in patients were the subject of a symposium, platform presentations, and posters. Emphasis was on new mechanisms, new therapies, and clinical trials. In one paper (# 20), activation of caspases and changes in transcription factor expression led to a shift in anti- apoptotic protein levels within hours after axotomy. Insulin- like growth factor and brain- derived neurotrophic factor, erythropoietin, caspase inhibitors, and anti- sense oligos ( such as B AX anti- sense) were found to have neuroprotective activity in this optic nerve injury paradigm. In another study (# 21), a 15- kD rod- dependent cone viability factor expressed in the outer nuclear layer of the normal retina rescued the rdl mutant phenotype mouse ( a model of photoreceptor protection in retinal dystrophies) and increased cone viability in vitro. Although intravitreal injection of neurotrophins such as brain- derived neurotrophic factor can extend the life of RGC neurons, their use is limited because of a short half- life in vitro, adverse effects, and because they are not cell- specific modulators of function. In an experimental study (# 22), signaling pathways stimulated by TrkB, MAP kinase, and AKT kinase appeared to be appropriate targets for neuroprotection. In that study, optic nerve injury led to down- regulation of TrkB receptors in RGCs. Up- regulation of TrkB by adenovirus transfection of RGCs, together with stimulation with brain- derived neurotrophic factor, led to a prolonged life for RGCs. Other neuroprotective agents were found to prevent RGC degeneration or promote survival of retinal cells in animal models (# 827, 832, 835, 838, 843, 873, 881, 884). The agents were citicoline ( cytidine- 5- diphosphocholine), lithium chloride, autocamtide- 2- related inhibitory peptide ( AIP, a specific inhibitor of calcium/ calmodulin- dependent protein kinase II), polyethylene glycol- conjugated superoxide dismutase, Akt activation ( protein kinase B), ciliary-derived neurotrophic factor, calcium channel blockers ( nimodipine, lomerizine, iganidipine), latanoprost, and edara-vone ( 3- methyl- l- phenyl- 5- one, a free radical scavenger). Microglia, the resident immune cells in the brain and the eye, serve immune- related functions. Partial crush injury of the optic nerve leads to primary and secondary degeneration. In this process, T lymphocytes are attracted to the optic nerve. Autoimmune T cells protect neurons from secondary degeneration. In the absence of T cells, elevated intraocular pressure causes a greater loss of neurons. Immunization with retinal proteins that are associated with experimental autoimmune uveitis protects against glutamate toxicity. CD4+ and CD25+ T cells control the ability to elicit an autoimmune response. These findings suggest a rationale for boosting autoimmunity in CNS repair models. One example is the weak agonist activity of a self- antigen such as glatiramer acetate ( Copaxone), a polypeptide used in the treatment of multiple sclerosis. Glatiramer acetate was found to decrease RGC loss in an experimental model of glaucoma (# 23). Glatiramer- activated T cells home to the damaged site, cross- react weakly with retinal antigens, and are locally activated, producing cytokines and neurotrophic factors that enhance microglial uptake of glutamate. Therefore, vaccination with self- antigens such as glatiramer acetate may alter disease progression (# 23). Challenges and issues on the design and conduct of clinical trials of neuroprotections using NMD A, AMP A, beta- 1 antagonists, al-pha- 2 agonists, and nitric oxide synthase inhibitors were discussed (# 24). Other challenges included a lack of validated endpoints, the slow nature of the neurologic disease, and the high costs of trials. OPTIC NEUROPATHY A rat model of anterior ischemic optic neuropathy demonstrated a 42% loss of axons when compared with controls 3 months after application of an argon green laser beam to the optic nerve (# 1585). This study provided a timeline of axonal loss essential to the study of potential neuroprotective agents. In a retrospective review of 32 cases of traumatic optic neuropathy (# 1606), the authors J Neuro- Ophthalmol, Vol. 24, No. 4, 2004 323 JNeuro- Ophthalmol, Vol. 24, No. 4, 2004 Neuro- Ophthalmology at Large concluded that the degree of visual impairment on initial presentation predicted the likelihood of visual improvement. Loss of consciousness was correlated with a lower frequency and extent of visual recovery. Latency from the traumatic event to the initiation of corticosteroid treatment did not appear to significantly affect outcome. In a review of 55 cases of amiodarone- associated optic neuropathy (# 1613), 88% occurred within 12 months of starting amio-darone, 13% were asymptomatic, 40%> presented with sudden vision loss, 47%> had insidious vision loss, 18% progressed to legal blindness ( visual acuity of 20/ 200 or less), 91% had visual field loss, 40%> had color vision loss, and 85% i had disc edema. The authors concluded that amiodarone- associated optic neuropathy can be classified into the following five subtypes in order of decreasing frequency of presentation: insidious onset, acute- onset, retrobulbar, raised intracranial pressure, and delayed progressive onset. Most cases start within 12 months of initiating amio-darone. Visual acuity loss may not be permanent, but visual field loss usually is. RETINAL AND OPTIC NERVE IMAGING There were many presentations on advances in retinal and optic nerve imaging that emphasized improved resolution and speed. The ultrahigh speed spectral domain optical coherence tomography ( OCT) is 75 times faster and has twice the resolution of standard OCT, which allows for comprehensive 3- dimensional volume rendering of the optic nerve and fovea within 10 seconds (# 1139). A new method of stabilized Doppler flowmetry using tracking scanning laser ophthalmoscopy provides dynamic dye- free angiographic images of retinal blood flow in response to visual stimuli (# 1137). Several papers discussed the reproducibility of optic nerve head parameters and retinal nerve fiber layer thickness measurements using the new OCT 3 device (# 1629, 1623), ultrahigh resolution OCT (# 2176), scanning laser polarimetry (# 1625), and Heidelberg Retinal Tomography scanning laser ophthalmoscopy (# 1619, 51). Confocal and multiphoton microscopic imaging techniques were used to obtain new information about the spatial and temporal events that occur during the course of ocular vascular disease (# 486). The first direct visualization of individual RGCs undergoing apoptosis in vivo in the glaucoma primate model ( strautosporine- induced RGC apoptosis) was very elegantly demonstrated using intravitreal fluorescent-labeled annexin- 5 and confocal scanning laser ophthalmoscopy (# 1114). NEUROIMAGING Metabolic imaging with fluorodeoxyglucose positron emission tomography demonstrated functional changes in the primary visual cortex and visual association areas in all eight patients with non- arteritic ischemic optic neuropathy. Treatment with pentoxifylline for 3 months reversed the changes observed in the brain in six of the eight patients (# 249). Brain activation maps measured in nine volunteers using functional magnetic resonance imaging demonstrated that central filling- in of an artificial central scotoma was accompanied by increased neuronal activity in the primary visual cortex, suggesting an active cortical process (# 247). Computed tomography angiography was shown to be an accurate, sensitive, noninvasive test for delineation of high-flow cavernous sinus lesions (# 257). IDIOPATHIC INTRACRANIAL HYPERTENSION Because arachnoid granulations may be the site of outflow resistance of cerebrospinal fluid in idiopathic intracranial hypertension ( IIH), a group of investigators developed an in vitro model using arachnoid cap cells. They used an immunomagnetic technique to separate human arachnoid granulations in culture to study cerebrospinal fluid flow characteristics (# 28). This model successfully obtained pure cultures of pia- arachnoid cells that will allow study of fluid dynamics and the responses of drugs used to treat IIH. The amide II wavelength free electron laser was used to make a 2- mm- diameter optic nerve sheath fenestration in blind patients undergoing enucleation that resulted in cerebrospinal fluid release and an effective optic nerve sheath incision. Tissue glial response was similar to that after incision by scissors. No acute damage or thermal damage to the optic nerve was found (# 45). Heidelberg Retinal Tomography II was used to measure surface topography ( neuroretinal rim and peripapillary surface height), whereas retinal nerve fiber layer thickness was measured using the OCT 3 in 24 eyes of 12 women with IIH. Although the elevation of surface height during optic disc swelling was associated with an increase in nerve fiber layer thickness, the association was weak. Factors other than swelling within the retinal nerve fiber layer must play a role in the elevation of the optic nerve head in IIH (# 1626). NEUROTROPHIC KERATITIS A combination of parameters including central corneal sensation ( measured by the Cochet- Bonnet esthesiom-eter) and aqueous tear production ( measured by the Schirmer test) was found to be useful in assessing the risk and progression of neurotrophic keratitis in 277 patients (# 2955). A distinct variant of neurotrophic keratitis called " noninfectious pseudodendritic keratitis" that resembled dendritic herpes zoster or herpes simplex keratitis was described in nine patients undergoing antiviral therapy. The lesions were located inferiorly in the cornea and demonstrated a rapid response to punctual occlusion (# 2954). 324 © 2004 Lippincott Williams & Wilkins Neuro- Ophthalmology at Large JNeuro- Ophthalmol, Vol. 24, No. 4, 2004 LEBER HEREDITARY OPTIC NEUROPATHY A separate session dedicated to Leber Hereditary Optic Neuropathy ( LHON) detailed the results of a comprehensive 2- year follow- up examination of the 300- member homoplasmic 11778 LHON pedigrees of seven generations in rural Brazil. Ongoing studies with the asymptomatic carriers of 11778 mutation in this pedigree showed that subclinical disease reflects ongoing low- grade degeneration. Decreases in red/ green and blue/ yellow chromatic and luminance spatial contrast sensitivity were observed in 11778 mutation asymptomatic carriers. Cambridge color testing demonstrated that 40% of carriers had loss of color discrimination, mostly in the protan and deutan axes (# 1012). Multifocal ERG studies in 29 asymptomatic carriers and four affected LHON patients showed substantial abnormalities in peripapillary ganglion cell function. Multifocal visual evoked potential ( VEP) abnormalities were subtle and difficult to detect (# 1015). OCT studies on NFL thickness in patients with LHON suggest that the NFL has increased thickness in patients at less than 6 months from the time of acute vision loss (# 1010). In contrast, color vision testing in affected LHON patients demonstrated a profound loss in the red- green system, whereas the blue system ( tri-tan axis) was relatively spared (# 4331). An experimental study designed to investigate the influence of bioenergetic failure in driving the pathway of apoptotic cell death in cybrid cells bearing the LHON mutation revealed that the LHON mutation profoundly impairs complex I- dependent synthesis of ATP and that LHON cybrid apoptotic death in galactose is caspase-independent (# 1624). ELECTROPHYSIOLOGY In an attempt to prevent the posterior ischemic optic neuropathy associated with spine surgery, optic nerve function was evaluated in three patients using intraoperative flash VEPs during spine surgery under total intravenous anesthesia. There was a trend toward increased stability of VEP waveforms in all parts of surgery under total intravenous anesthesia, with all waveforms identifiable throughout the surgery using a certain combination of general anesthetics (# 251). Multifocal VEP recordings showed local delays in 11 of 12 patients with atypical optic neuritis (# 242). This technique was found useful in diagnosing psychogenic static perimetry defects (# 245). PUPIL Forty- nine normal subjects and 46 patients with asymmetric visual field loss caused by prechiasmal defects were used to compare the diagnostic power of timing parameters and the amplitude of pupil contraction (# 230). This study found that the timing of the pupil reflex had greater diagnostic power. In an experimental study on the macaque monkey, melanopsin- containing ganglion cells contributed significantly to light- evoked pupillary responses over much of the photopic range (# 2262). A relative sparing of the pupillary light reflex was seen in seven patients with ischemic optic neuropathy. These results suggested that ganglion cells related to the pupillary reflex were less affected than those related to vision in eyes with ischemic optic neuropathy (# 250). PERIMETRY Subtle visual field defects not detected by conventional perimetry were detected by a recently developed program that uses tiny points of light as stimuli ( RAREBIT). This technology identified the eye with the afferent pupil defect in five of five cases, all of which had normal Humphrey visual field 24- 2 tests (# 234). Among 15 patients with glaucomatous optic neuropathy who underwent Humphrey 24- 2 achromatic automated perimetry, frequency doubling perimetry and multifocal VEP testing detected visual field abnormalities when the standard achromatic 24- 2 test showed no defect. There was only modest agreement between frequency doubling perimetry and multifocal VEP results in eyes without defects in the reference 24- 2 test (# 2121). Another study found that an abnormal result in frequency doubling perimetry showed a high risk of a future scotoma on Humphrey visual field testing 3 years later, even if the original Humphrey visual field showed normal results (# 2129). EXTRAOCULAR MUSCLES/ EYE MOVEMENTS The extraocular muscles in adenine nucleotide trans-locator 1 mutant mice had the typical appearance of mitochondrial myopathy seen in chronic progressive external ophthalmoplegia (# 5009). Latanoprost was no more effective than placebo in the management of benign essential blepharospasm (# 259). Ice pack application in benign essential blepharospasm patients was associated with a 50% o to 66% decrease in blink rate; by comparison, normal subjects and patients with Graves disease had a 10% or less reduction in blink rate (# 260). Botulinum toxin ( Botox, Al-lergan Inc., Irvine, CA) injections ( 8- 10 injections of 50 units/ ml in the upper eyelid above the superior border of the tarsus) in the management of active- phase Graves eyelid retraction caused 77% o percent of the eyelids to return to normal position 1 to 2 mm below the limbus. Approximately half of the patients continued to receive injections every 3 months to maintain the effect. The most common complications were ptosis and lagophthalmos (# 263). 325 JNeuro- Ophthalmol, Vol. 24, No. 4, 2004 Neuro- Ophthalmology at Large ORBIT In a series of 1,264 patients with orbital masses, 64% were benign and 36% malignant, with the percentage of malignant tumors increasing with age (# 4693). A comparison of exophthalmometry readings in 39 normal Asian and 69 normal white adults found significantly lower values in Asians (# 48). In a Japanese study, the degree of proptosis correlated well with the severity of ocular manifestations of dysthyroid ophthalmopathy (# 2717). However, another study showed that higher exophthalmometry readings did not correlate with a higher incidence of compressive optic neuropathy (# 1610). In an attempt to measure the orbital volume deficiency after enucleation, investigators used perforated swimming goggles in 15 patients after enucleation. The difference in the amount of water that could be placed into the goggle- bounded cavity was used to assess the amount of volume replacement in dermis- fat grafting (# 34). A study of the factors that predicted the need for adjuvant radiation therapy after corticosteroid therapy in sclerosing orbital pseudotumor in eight biopsy- proven cases found that neither age nor gender predicted the need for adjuvant radiotherapy (# 269). Swaraj Bose, MD Department of Ophthalmology University of California Irvine, California Howard D. Pomeranz, MD, PhD Department of Ophthalmology University of Minnesota Medical School Minneapolis, Minnesota 326 © 2004 Lippincott Williams & Wilkins |
