The 58th Annual Meeting of the American Academy of Neurology San Diego, California April 1-8, 2006

The 58th Annual Meeting of the American Academy of Neurology (AAN) was held in San Diego, California, April 1-8, 2006. There were 1,580 scientific abstracts presented and a very full educational program. Neuro-ophthalmology and neuro-otology courses and scientific presentations were very well attended this year in part as a result of a recent innovation at the AAN: the enhanced vertical integration (EVI) program. This program comprises a day that integrates many aspects of select subspecialties, allowing an AAN attendee the ability to concentrate on that subspecialty for the entire day. In addition to a cluster of courses, the day included a private poster session and a scientific session followed by a more in-depth session and panel discussion. The scientific portion of EVI began with a neuro-otology poster blitz with discussion of the posters by Michael Halmagyi, MD (Sydney, Australia), David Zee, MD (Baltimore, MD), and John Leigh, MD (Cleveland, OH). The scientific platform session, chaired by Kathleen Digre, MD (Salt Lake City, UT) and Mark Moster, MD (Philadelphia, PA), consisted of a presentation of 6 abstracts focused mainly on mitochondrial disorders. This was followed by a session devoted to the mechanisms of optic nerve injury and neuronal death and featured Valerio Carelli, MD (Bologna, Italy) speaking on hereditary optic neuropathies, Leonard Levin, MD (Montreal, Quebec, Canada) speaking on mechanisms of axonal injury, and Robert Weinreb, MD (San Diego, CA) speaking on mechanisms of cell injury in glaucoma. Nancy Newman, MD (Atlanta, GA) chaired the session. Elizabeth Engle, MD (Boston, MA) delivered the Sydney Carter Award Lecture at the presidential plenary session on the subject of ocular motility disorders arising from errors in brainstem motor neuron development. She discussed a classification of these entities as congenital cranial dysinnervation disorders (CCDDs). She described the conditions that primarily affect horizontally acting extraocular muscles, including Duane syndrome, horizontal gaze palsy with progressive scoliosis, and Möbius syndrome. Of the many scientific abstracts presented, the following had particular interest to neuro-ophthalmologists. OPTIC NEURITIS AND MULTIPLE SCLEROSIS Three studies of optical coherence tomography (OCT) in optic neuritis and multiple sclerosis (MS) were reported. A measurement of macular volume and retinal nerve fiber layer (RNFL) thickness with OCT-3 was performed in patients with MS (n = 70 [140 eyes]) and in disease-free controls (n = 29 [58 eyes]). Visual function was tested with low-contrast letter acuity (Sloan charts, 1.25%) and Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity. Total macular volume and RNFL thickness were lower in MS compared with controls (6.48 mm3 vs 6.86 mm3 for macular volume, 88 μm vs 98 μm for RNFL thickness; P < 0.0005) and were reduced even in eyes with no history of optic neuritis (ON). Lower vision scores were associated with reduced macular volumes and RNFL thickness. Measurements of macular volume and RNFL thickness were able to distinguish patients from controls and separate MS eyes with and without an ON history. However, direct correlations of overall RNFL thickness and total macular volume were only within the moderate range (rs = 0.60, P < 0.0001), suggesting to the authors that these two parameters may capture different aspects of the disease (Osborne B, Philadelphia, PA, EV5.006). A study of RNFL thickness using OCT-3 compared 60 patients with a single episode of ON (nonrecurrent ON), 10 patients with recurrent ON, and 27 patients with relapsing-remitting MS (RRMS). Those with recurrent ON had the thinnest RNFL (66 μm), those with RRMS 93 μm, and those with nonrecurrent ON 81 microns in the affected eye and 100 μm in the unaffected eye. Decreased RNFL measurements correlated with poorer visual acuity and worse visual fields (Costello F, Ottawa, Ontario, Canada, EV4.013). Another prospective study found a reduced RNFL thickness, as measured by OCT, in patients with MS with or without a history of ON. This small prospective study evaluated 61 patients with MS and 20 controls every 6 months over an 18-month period. RNFL thickness and the presence of retinal periphlebitis were associated with disease activity in MS as measured by T2 and enhanced T1 MRI. Six (9.8%) of 61 patients developed retinal periphlebitis, which was associated with clinical relapses (P < 0.05). These findings suggest that RNFL thickness and the presence of retinal periphlebitis could be used as substitute markers of disease activity in MS (Villoslada P, Pamplona, Spain, S22.003). A study looked at mitochondrial function in animals with experimental allergic encephalomyelitis, an animal model used to study MS. Oxidative injury to the mitochondrion began 3 days after antigenic sensitization, even before any inflammatory cell infiltration. Reductions in adenosine triphosphate (ATP) synthesis of 94% in retinal ganglion cells were even greater than those associated with mitochondrial diseases. Mice that received intravitreal recombinant AAV-SOD2 to suppress oxidative injury had a rescue of ATP synthesis by 55%, a suppression of myelin fiber injury by 51%, and a fourfold increase in retinal ganglion cell survival 1 year later. This study implicates a mitochondrial process in the axonal and neuronal loss in MS (Qi X, Gainesville, FL, EV5.005). A study of 117 brain biopsies in patients with pathologically proven MS and sufficient cortical tissue for analysis were reviewed for evidence of cortical demyelination. The biopsies were performed for diagnostic purposes within days to weeks of clinical presentation. Cortical demyelination was present in 21% of biopsies. Perivascular T-lymphocyte density was similar in cortical and white matter plaques, but parenchymal T cell density was less. Microglia predominated in all cortical plaques. Early active cortical demyelination characterized by myelin degradation products within macrophages was present in a subset of cases. MS cortical plaques were present in the subpial cortex, within the cortex, and in subcortical white matter. The lesions showed dramatic evidence of inflammation and tissue destruction. These findings contrast with prior reports emphasizing the noninflammatory nature of cortical plaques, but the prior reports may be biased toward patients with longstanding disease (Roemer S, Gottingen, Germany, P02.080). An MRI study of newly enhancing lesions was performed as part of the BECOME study, which compares interferon beta-1b (INFB-1b; Betaseron) with glatiramer acetate (Copaxone) for RRMS and clinically isolated syndromes (CIS). In that study, 406 newly enhancing lesions were identified with a mean of 0.6 per patient per month using a 3-Tesla MRI and triple-dose gadolinium. In 62% of lesions, the enhancement lasted less than 1 month, in 34% for 1 to 3 months, and in 4% for longer than 3 months. Twenty lesions were hypointense on T1 MRI at 3 months. Nineteen of these 20 lesions fulfilled criteria for black holes at 6 months. Larger lesions were more likely to show prolonged enhancement and to progress to black holes (Gomez-Choco MJ, Canary Islands, Spain, P02.093). Eleven patients with diplopia as part of a CIS were reported. Seven patients had sixth cranial nerve palsy, 3 had internuclear ophthalmoplegia, and 1 had partial third cranial nerve palsy. All had MRI lesions consistent with demyelination and negative diffusion-weighted studies but 4 had initially negative reports by the radiologist. All 9 patients followed up for at least 6 months had significant improvement. Three have progressed to clinically definite MS (CDMS) (Pula J, Peoria, IL, P01.027). Prior studies of antimyelin antibodies as a predictor for developing CDMS have had conflicting results. In a study reported here of 51 patients with CIS, 28 (54.9%) had either double or single positivity for antimyelin (anti-MOG or anti-MBP) antibodies. Antibody status significantly predicted development of MS based on Poser (but not McDonald) criteria (P = 0.004) with a higher proportion of patients converting to MS in the antibody-positive group (P = 0.027). However, patients who were anti-MBP-positive developed a significantly higher number of T2-hyperintense lesions than did patients who were anti-MBP-negative (anti-MBP+ 9.28 ± 10.45 vs anti-MBP- 3.96 ± 5.12, P = 0.03) (Tomassini V, Rome, Italy, P02.107). The BENEFIT trial reported the results of 250 μg IFNB1b administered subcutaneously every other day in patients with a clinical demyelinating event and 2 clinically silent MRI lesions. Primary efficacy end points were time to CDMS and time to diagnosis of MS according to the McDonald criteria. IFNB-1b significantly delayed the progression from the first clinical event to CDMS (log-rank test P < 0.0001) and McDonald criteria-defined MS (P < 0.00001). According to proportional hazards regression analysis adjusted for standard baseline covariates, the risk of CDMS in the IFNB-1b group was reduced by 50% (hazard ratio with 95% confidence interval [CI]: 0.50; 0.36-0.70) and for McDonald criteria-defined MS by 46% (0.54; 0.43-0.67), respectively. The Kaplan-Meier estimates of the percentage of patients who fulfilled the criteria for CDMS within 24 months were 45% in the placebo group and 28% in the IFNB-1b group. IFNB-1b prolonged the time to CDMS by 363 days based on the 25th percentiles. The BENEFIT study demonstrates that IFNB-1b administered according to that regimen significantly delays progression to definite MS in patients with a first clinical demyelinating event suggestive of MS (Freedman M, Ottawa, Ontario, Canada, S02.001). Twenty patients with RRMS with acute exacerbations were included in a study of intravenous immunoglobulin (IVIg) vs intravenous methylprednisolone (IVMP). Ten patients received 0.4 g/kg IVIg per day for 5 days and ten patients received 1,000 mg IVMP per day for 3 days. In both groups, the Expanded Disability Status Scale score improved significantly after the treatment of relapse with no difference seen between the two groups. Brain MRI showed significant reduction of T2, FLAIR, and enhanced T1 lesion volumes in the IVIg group, whereas no such finding was observed in the IVMP group. The authors conclude that IVIg is effective and well tolerated in the treatment of acute MS relapses. However, there was no untreated control group in this study (Kuusisto H, Tampere, Finland, P01.069). New sensitive measures of visual function in MS have been evaluated over the past year. Low-contrast letter acuity was used in 2 clinical trials of natalizumab to measure the drug's potential to preserve visual function in patients with MS. 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