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Show NEURO- OPHTHALMOLOGY AT LARGE 127th Annual Meeting of the American Neurological Association, New York, New York, October 13- 16, 2002 The 127th annual meeting of the American Neurological Association was held in New York City from October 13 to 16, 2002.1 attended the half- day plenary session consisting of nine oral presentations on October 15th and report my observations. Publications of the presentations are referenced. Leading off the session was an oral presentation on the use of gene therapy to reverse the mitochondrial deficiency of Leber Hereditary Optic Neuropathy ( LHON) in cultured cells. The authors used a recombinant adeno-associated virus ( AAV) as a vector to deliver a normal ND4 subunit gene of complex I to cybrid cells containing the G11778A mutation in mitochondrial DNA in a neutral nuclear background. The Gl 1778A mutation in mitochondrial DNA is responsible for approximately half of all LHON cases. The AAV- delivered ND4 subunit gene was specially constructed for expression in the nucleus. Because of the partially different genetic codes between the nucleus and mitochondria, a mitochondrial gene encoding a normal ND4 subunit gene could not be used for gene expression outside the mitochondria. To import the normal ND4 protein, generated by the nuclear encoded ND4 gene from the cytoplasm into the mitochondria, a mitochondrial targeting sequence was added to the beginning of the gene. Next, to visualize the ND4 imported into mitochondria, a short FLAG epitope tag was added to the end of the nuclear- encoded ND4 gene. The FLAG- labeled ND4 was then detected with an antibody against the FLAG. Cells infected with AAV containing this ND4FLAG gene had restored to normal levels the 60% decrease in ATP synthesis found in these cybrid LHON cells, even in the presence of the mutated mitochondrial DNA ( 1). The technology to deliver DNA directly to mitochondria still does not exist. The allotopically expressed ND4 is the next best alternative for the treatment of LHON. In fact, 85% of all mitochondrial proteins are expressed in this fashion. While allotopic gene therapy seems promising, the next step would be to test its effects in an animal model of LHON. Unfortunately, none exists. Therefore, it is not possible to test this new treatment avenue, or more importantly, to study the mechanisms of visual loss in LHON. A complete review of ocular models of mitochondrial diseases has recently been published ( 2). It is unclear whether neuronal cell bodies, such as the ganglion cells of the retina, or their axons are the initial targets of diseases such as LHON. The second oral presentation helped address the issue of whether the axon or the cell body is the target tissue. Glass et al grew dissociated dorsal root ganglion neurons in special designed chambers that allowed isolated exposure of either axons or their cell bodies, but not both, to the neurotoxin vincristine ( 3). They found that axons exposed to the neurotoxin had a progressive reduction in axon length. However, the same dose of neurotoxin did not affect survival of neurons. These results suggest that axons rather than neurons can be the targets of disease, at least that disease induced by a neurotoxin in the peripheral nervous system. Perhaps to address the issue with LHON, parallel studies can be conducted using the model system of Leonard Levin, MD; axo-tomized retinal ganglion cells ( 4) without axotomy. By using the complex I inhibitor rotenone as the neurotoxin, one could then test whether optic nerve axons or retinal ganglion cells are the targets of experimentally induced mitochondrial deficiency. The third oral presentation dealt with the mechanisms of progression of single seizures to status epilepticus. Was-terlain et al showed a five- fold increase in NMDA receptors 40 to 70 minutes after experimentally induced seizures ( 5). This resulted in status epilepticus that was refractory to standard anticonvulsants, but was quickly abolished by the use of NMDA antagonists such as ketamine. These results suggest a new treatment avenue for refractory seizures and status epilepticus ( 6). The fourth oral presentation elegantly used magnetic resonance imaging ( MRI) and positron- emission tomography ( PET) to study the role of suicide gene therapy in eight patients with glioblastoma multiforme. The authors, all from Germany, introduced the herpes simplex virus gene thymidine kinase directly into the tumor by continuous infusion, then performed PET after injection of the tracer [ 124I] 2'- fluoro- 2' deoxy- l- B- D- arabinofuranosyl- 5- iodo-uracil ( FIAU) as a specific marker substrate for herpes simplex virus thymidine kinase. To kill the tumor cells expressing herpes thymidine kinase, they began treatment with ganciclovir 4 days after infusion of this suicide gene. In only one of eight patients did they find colocalization of FIAU ( the marker of herpes thymidine kinase gene Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. 236 JNeuro- Ophthalmol, Vol. 23, No. 3, 2003 Annual Meeting of the American Neurological Association JNeuro- Ophthalmol, Vol. 23, No. 3, 2003 © @ FIG. 1. Allotopic expression. Adeno- associated virus vectors deliver the ND4 subunit gene to the nucleus. This results in transcription of mRNAs that diffuse into the cytoplasm. Translation of the ND4 protein with a mitochondrial targeting sequence directs the import of the ND4 with FLAG epitope tag into the mitochondria that also contains the mutant G11778A mt DNA. expression) to the areas of tumor necrosis imaged by PET as showing decreased tumor uptake of 18F fluorodeoxyglu-cose or ( 11) C methionine. While the gene expression was not seen in the entire tumor bed, I believe this patient had the longest survival ( 8 or 9 months). Although the neuroimaging was striking, the gene therapy did not appear to substantially increase patient survival ( 7- 9). However, the series was small and each of the patients enrolled in this open- ended study had already failed the standard treatments for glioblastoma multiforme. Because gene therapy is not 100% efficient ( it more closely approximates 50%), perhaps this form of treatment would have been more effective had it been done more than once, even though the authors used an infusion rather than simply an injection of the suicide gene. Perhaps repeated cycles of infusion of the gene, followed by ganciclovir administration, will be needed to completely eradicate the tumor. The seventh oral presentation studied the defects of coenzyme Q10 in slowing the functional decline associated with early Parkinson disease. Shults et al ( 10) randomly assigned patients to receive either placebo or oral treatment with coenzyme Q10 at 300 mg, 600 mg or 1200 mg/ day for 16 months. They found a clinically significant treatment effect that was greatest at the higher doses. Although Parkinson disease is not caused by mutated mitochondrial DNA ( 11), complex I activity is markedly reduced in this disorder ( 12). The higher doses of coenzyme Q10 used in this study of Parkinson disease may also be applicable to the treatment of other disorders with complex I dysfunction, such as LHON and MELAS ( 13). Probably all of us have already tried much lower doses of coenzyme Q10 ( the standard 25 mg capsule) without effect in our LHON patients. The results of this study in Parkinson disease suggest that maybe we should be using high doses of coenzyme Q10 in treating LHON. Among over 300 poster presentations, here are the highlights: In poster No. 30, Dceda et al ( 14) from Japan used a novel neuroprotective compound T- 588 to rescue motor neurons of the facial nerve after nerve avulsion. Rats treated orally with his compound for 1 to 4 weeks after facial nerve avulsion had less histopathologic degeneration and better motor neuron function than did placebo- treated rats. The authors have already shown this compound to be effective in a mouse model of motor neuron degeneration, but perhaps this could be applied to some patients with facial nerve paralysis after neurosurgery for large acoustic neuromas. Alternately, most neuroprotective agents have failed miserably in clinical trials ( 15- 17). Poster No. 45 studied the role of alcohol in dementia. Truslen et al ( 18) from Denmark found that beer was associated with an increased risk of dementia, and wine with a decreased risk; spirits had no effect on risk. Perhaps we should all be switching to a good wine. In poster No. 88, Toosy et al ( 19) used photic stimulated functional MRI to study cortical activation in eight patients who had recovered from optic neuritis. All subjects had normal visual acuity and color vision. They found that whereas visual cortex activation was reduced, extra-occipital activation was increased. They concluded that this " adaptive reorganization" may contribute to the visual recovery classically attributed to remyelination of the optic nerve. This work seems to support Sabel's ( 20) hypothesis that brain plasticity can provide the substrate for restoration of vision. His work claims to show that visual field defects caused by irreversible optic neuropathy can be improved by using repetitive cortical stimulation of partially damaged areas with daily computer- based visual restitution training. He claimed that enlargements in the visual field were significant and that they were maintained after the training was stopped. Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. 237 JNeuro- Ophthalmol, Vol. 23, No. 3, 2003 Guy Poster No. 90 examined mtDNA mutations in Devic disease. Although Kalman et al ( 21) detected several homoplastic variants, these were felt to represent polymorphisms that were also present in their control populations with and without multiple sclerosis ( MS). However, the authors did find a common genetic background, a shared hap-lotype between some patients with MS and Devic disease. Poster No. 93 tested a new avenue for MS treatment based on the EAE animal model. Using an antibody against macrophage migration inhibition factor ( MIF), Ogata et al ( 22) reduced the severity of EAE. They also found higher levels of MIF in active lesions of MS brains obtained at autopsy. Macrophages are the effector cells in both MS and EAE. These phagocytic cells strip and ingest myelin. Blocking the effects of MIF may add significantly to MS treatment. The recent approval of natalizumab ( Antegren R) ( 23,24) to block inflammatory cell migration across the blood- brain barrier may also have comparable impact. However, the side effects of infection may turn out to be less with MIF as it only affects leukocytes associated with chronic disease- macrophages rather than polymorphonuclear leukocytes. Natalizumab affects migration of both kinds of white blood cells. Poster No. 97 described a new antiinflammatory peptide, RDP 58, as a potential therapy for multiple sclerosis. RDP58 is a 10- amino acid peptide with multiple antiinflammatory activities ( 25,26). It inhibits proinflam matory cytokines such as tumor necrosis factor and interferon^, while at the same time upregulating defenses ( heme oxygenase- 1) against immune mediators. RDP58 reduced EAE disease activity best when given 10 days after antigenic sensitization. While this appears promising for the treatment of MS, a major drawback is that the peptide was given by intracerebral ventricular injection. In addition, tumor necrosis factor inhibitors actually increased MS disease activity when tested in clinical trials ( 27), though they suppressed EAE ( 28). In poster No. 146, Mastronardi et al ( 29) found that adding vitamin B12 supplementation ( 15 mg/ kg) to interferon therapy had a greater suppressive effect on EAE ( 70- 80%) than using interferon ( 30%) or vitamin B12 ( 20%) alone. These results are very encouraging, as combination therapy with Copaxone and interferon have not had a synergistic effect, even though the mechanisms of disease suppression are different for each agent. Posters No. 213 and 210 examined the role of molecular mimicry as a cause of neurologic diseases. Molecular mimicry is characterized by an immune response to an exogenous agent that cross- reacts with a host antigen such that the resultant autoimmune reaction causes disease. Of ten patients who developed neurologic impairment after vaccination for Lyme disease, four had homology between the Lyme outer surface protein A ( 0SP A) and human neural tissue. In addition, HTLV- 1 patients also developed antibodies to neurons. The human heterogeneous nuclear ribonuclear protein- A1 ( hnRNP- Al) was found to be cross-reactive with the human T- lymphotropic virus type 1 associated with myelopathy/ tropical spastic paraparesis, a disease that can be indistinguishable from MS. Although deletion of the cross- reactive sequences from future vaccines might prevent the neurologic complications associated with Lyme vaccination, the search for the agent responsible for molecular mimicry in multiple sclerosis continues. Herpes virus is considered a prime candidate ( 30). In poster No. 211, intravenous immunoglobulin therapy ( 25- 30 mg/ kg/ d for 4 days) was used to treat two patients with Susac Syndrome who did not respond to high-dose corticosteroids. 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