The 57th Annual Meeting of the American Academy of Neurology, Miami, Florida, April 9-16, 2005

There were 1,405 scientific papers and poster presentations at the 57th Annual Meeting of the American Academy of Neurology held in Miami Beach, Florida from April 9 to 16, 2005. Abstracts are published in Neurology 2005;64:Suppl 1. We have summarized the material of most interest to neuro-ophthalmologists. OPTIC NEURITIS AND MULTIPLE SCLEROSIS Brain MRI is an established biomarker of disease in multiple sclerosis (MS), and data on the impact of MS and acute optic neuritis on retinal nerve fiber layer (RNFL) thickness, as measured by optical coherence tomography (OCT), are beginning to emerge. A recent investigation examined the relation of visual function to RNFL thickness and brain MRI parameters in an MS cohort. Scores for low-contrast letter acuity (Sloan charts) and contrast sensitivity (Pelli-Robson), the leading candidates for visual components for inclusion in the MS functional composite, were significant predictors of average overall RNFL thickness (P < 0.001) and of lesion burden on T2-weighted MRIs (P = 0.001 for Sloan charts; P = 0.03 for Pelli-Robson) accounting for age. The greatest reductions in RNFL thickness were noted among eyes of MS patients with a history of acute optic neuritis. However, MS eyes without an optic neuritis history also demonstrated abnormalities. These results not only confirm a role for axonal loss in the anterior visual pathways of MS patients but demonstrate correlations of low-contrast letter acuity and contrast sensitivity with structural biomarkers, supporting their validity as clinical trial outcome measures (Wu GF, Philadelphia, PA, P01.025). Visual dysfunction is a common manifestation of MS and may therefore have important effects on health-related quality of life (HRQOL). The 25-Item National Eye Institute Visual Function Questionnaire (VFQ-25) has been used in a variety of ocular conditions and ophthalmic clinical trials. A study was performed to examine whether a 10-Item Neuro-Ophthalmic Supplement could increase the capacity of the VFQ-25 to capture self-reported visual dysfunction in patients with neuro-ophthalmic disorders, particularly those associated with diplopia or optic neuropathy. Patients included those with optic neuritis, MS, idiopathic intracranial hypertension, ischemic optic neuropathy, ocular myasthenia gravis, thyroid eye disease, and ocular motor palsies. Scores for the VFQ-25 + 10-Item Neuro-Ophthalmic Supplement (combined scores) had a greater capacity to distinguish neuro-ophthalmically impaired patients from disease-free controls (receiver operating characteristic[ROC] curve area, 0.77) than did the VFQ-25 alone (ROC curve area, 0.73; P = 0.001). VFQ-25 + Supplement scores correlated significantly with binocular and with worse eye visual acuities (rs = 0.38 - 0.41; P < 0.0001), and Neuro-Ophthalmic Supplement items demonstrated appropriate levels of reliability. The 10-Item Supplement is a valid measure of self-reported visual dysfunction in neuro-ophthalmically impaired patients. This new scale captures symptoms and limitations related to diplopia and will be used to complement the VFQ-25 in clinical trials and other research (Balcer LJ, Philadelphia, PA, P01.031). Sixty MS patients were studied to establish the relationship of infections to MS exacerbations. MS attacks occurring between two weeks before and five weeks after an infection were considered temporally related to infection. A total of 127 infections were recorded in 53 patients, and 124 exacerbations occurred in 49 of the 53 patients. There was an increased risk of relapses temporally related to infection (odds ratio, 3.2; P < 0.0001). Exacerbations that were temporally related to infection were more frequently associated with severe and sustained deficits than those that were not temporally related to infection. The number of Gd-enhancing lesions was higher during exacerbations temporally related to infection than in those that were not temporally related to infection. This study demonstrates a significant association between systemic infection, risk of MS clinical relapse, and degree of MRI activity (Correale JD, Buenos Aires, Argentina, P03117). NEUROMYELITIS OPTICA Neuromyelitis optica (NMO) is a severe inflammatory central nervous system (CNS) disorder with a predilection for the optic nerves and spinal cord. Because of the potential overlap with MS with regard to clinical and neuroimaging findings, the diagnostic criteria for NMO have been recently re-examined and revised. These new criteria have modified those published in 1999 (Wingerchuk et al., Neurology 1999;53:1107-14) to update MRI findings and to incorporate a novel serum autoantibody marker, NMO-immunoglobulin (Ig)G. Investigations for these studies calculated sensitivities and specificities for each component of the 1999 NMO diagnostic criteria using a new 118-patient cohort. Combinations of individual criteria, including NMO-IgG, were tested to optimize the potential for correct diagnosis. Among patients with NMO (n = 84) versus MS (n = 34), criteria that had the greatest capacity to distinguish NMO from MS were the presence of NMO-IgG (sensitivity, 75.3%; specificity, 93.3%) and spinal cord T2-lesion length extending beyond three vertebral segments (sensitivity, 97.0%; specificity, 79.0%). Neurological symptoms indicating disease outside the optic nerves and spinal cord were seen in 17 NMO patients (20.2%). Based on these findings, the authors suggested criteria for diagnosis of NMO. Absolute criteria: presence of optic neuritis and acute myelitis (but disease in other areas of CNS allowed); supportive criteria: 1) spinal cord MRI with lesion(s) extending over three or more vertebral segments or 2) NMO-IgG seropositivity (Wingerchuk DM, Scottsdale, AZ, P01.033). As emphasized by studies refining the diagnostic criteria for NMO (P01.033 above), an NMO diagnosis is no longer precluded by the presence of clinical or imaging abnormalities outside the optic nerves or spinal cord as long as the patient meets the new NMO criteria described the previous paragraph. Importantly, the former (1999) criteria required a normal brain MRI. The brain MRI findings for 60 patients who met revised criteria for NMO (P01.033 above) were described in a recent study. In 26 (43%) of 60 patients, brain MRI was normal at a median of 1.6 years (range, 0-29 years) after the onset of symptoms. Seventeen patients (28%) had non-specific abnormalities that were generally located in the deep white matter and few in number (only four [6.5%] patients had more than four high T2 signal foci). Typical MS-like lesions were found in only six patients (10%), five of whom were seropositive for NMO-IgG. The remaining 11 patients (19%) had MRI findings considered atypical for MS; brainstem lesions were seen mostly among children. Because brain MRI abnormalities were noted among ~50% of patients who otherwise had classic findings for NMO, diagnostic criteria have been revised to allow for brain involvement (Pittock SJ, Scottsdale, AZ, P01.036). Because brain MRI techniques have continued to evolve, atypical findings have been noted more frequently in the brains of NMO patients. Given the contiguity of the hypothalamic regions to the anterior visual pathways, hypothalamic involvement in patients with NMO is perhaps not unexpected. Two patients with otherwise classic features of NMO were described as having hypersomnolence, hyponatremia, and hypothermia. MRI scans revealed new areas of hyperintense signal in the hypothalamus in the absence of other brain parenchymal lesions. Additional similar cases were identified from the literature, and this series again supports revision of the NMO diagnostic criteria to include involvement beyond the optic nerves and spinal cord (Poppe AY, Montreal, QC, Canada, P01.037). GENETIC OPTIC NEUROPATHIES Patients with Friedreich ataxia (FA) develop optic neuropathies, most frequently after development of gait and limb dysfunction. Sixteen molecularly defined Italian FA patients with quantified GAA were assessed with visual acuity, fundus photos, 30-degree Humphrey visual field, Ishihara color plates, OCT, visual evoked potentials (VEP), and electroretinography (ERG). All patients showed optic nerve damage as assessed by OCT and visual fields. Fiber loss was typically peripheral; decreased visual acuity was present only when central fibers were lost. VEP was altered in eight (56%) of the patients. In six, they were significantly delayed with reduced amplitudes; in three, the responses were absent. ERGs were normal in all patients. The degree of fiber loss, expressed as thickness of the nerve fiber layer as measured by OCT, was significantly correlated with the GAA expansion in the smaller allele of the frataxin gene (P = 0.002; r = −0.69 for the peripheral sectors). OCT was the most sensitive test in showing optic neuropathy (Fortuna F, Milan, Italy, S01.003). Investigators designed a battery of clinical measures that may be used for outcomes assessment in FA therapeutic trials. FA candidate performance measures, including the timed 25-foot walk, 9-hole peg test, low-contrast letter acuity, and PATA test (a test of speech) were evaluated in a cohort of 131 FA patients at six academic medical centers. Scores for individual components (including vision) and for the combination of performance measures correlated significantly with neurologic disability, activities of daily living, and disease duration (rs = 0.40 - 0.89; P < 0.0001). Visual function scores were also found to be lower in the FA cohort compared with disease-free controls, further supporting the inclusion of low-contrast letter acuity in an FA outcomes assessment battery. Given the high proportion of FA patients who progress to a non-ambulatory status in adulthood, inclusion of measures that capture vision, arm function, and speech will ensure sensitivity and applicability throughout the course of disease (Lynch DR, Philadelphia, PA, P01.104). To further development of an animal model for Leber Hereditary Optic Neuropathy (LHON), mice received intraocular injections of an adeno-associated virus-ribozyme directed against the murine mitochondrial ND4 subunit of complex I. Their ganglion cells showed hyperchromatic cytoplasm and nuclear condensation suggestive of apoptosis. Optic nerves showed secondary demyelination with axonal loss. Transmission electron microscopy revealed swelling and vacuolization of mitochondria with dissolution of cristae. Allotopic expression of a mutant R340H ND4 results in histopathology similar to that of patients with LHON harboring the G11778A mutation in mitochondrial DNA (mtDNA). This is a step further in development of an animal model of LHON (Qi X, Gainesville, FL, S01.001). In addition to the three most common mtDNA mutations that occur in patients with LHON, novel pathogenetic mutations continue to be discovered. Overlap with other mitochondrial disease phenotypes, such as mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS), has also been described for mutations involving the ND5 subunit of complex I. An Italian family with a maternally inherited LHON phenotype demonstrated an ND5 mtDNA mutation (G13042A/ND5) that was pathogenetic for LHON yet had been previously described in a case of MELAS. This report underscores the potentially variable clinical expression that may occur in the setting of mtDNA mutations and reinforces the need for consideration of a variety of mutations in patients with optic neuropathies consistent with LHON (Valentino ML, Bologna, Italy, P01.029). An attempt to use neuroprotection to prevent second eye involvement with LHON was reported. In an open-label prospective pilot study, nine patients with one-eye vision loss for less than six months and normal visual function in the other eye were treated with brimonidine purite 0.15% (Alphagan P) four times daily in the unaffected eye for up to two years. Visual acuity was the primary outcome measure. Secondary measures included changes on automated perimetry and quantification of the relative afferent pupillary defect. There were eight men and one woman enrolled, aged 13-54 years (mean, 32 years); eight had the 11,778 mtDNA mutations, and one the 3,460 mutations. Despite normal visual acuity and visual field mean deviations at baseline, seven patients had minimal changes in the central visual field of the study eye. All patients had deterioration of their second eye vision. Topical brimonidine purite in this dosage was unsuccessful in preventing second-eye involvement (Newman NJ, Atlanta, GA, S01.002). 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