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Show NEURO- OPHTHALMOLOGY AT LARGE 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 Mobius 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 | Jim vs 98 | Jim 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 | Jim), those with RRMS 93 | Jim, and those with nonrecurrent ON 81 microns in the affected eye and 100 | Jim in the unaffected eye. Decreased RNFL measurements correlated with poorer visual acuity and worse visual fields ( Costello F, Ottawa, Ontario, Canada, EV4.013). J Neuro- Ophthalmol, Vol. 26, No. 3, 2006 223 J Neuro- Ophthalmol, Vol. 26, No. 3, 2006 Moster and Osborne 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 Tl 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 demyelin-ation. 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- lb ( INFB- lb; 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 Tl 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 | JLg IFNBlb 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- lb 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- lb 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- lb group. IFNB- lb prolonged the time to CDMS by 363 days based on the 25th percentiles. The BENEFIT study demonstrates that IFNB- lb 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 224 © 2006 Lippincott Williams & Wilkins Neuro- Ophthalmology at Large J Neuro- Ophthalmol, Vol. 26, No. 3, 2006 ( 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 Tl 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 natahzumab to measure the drug's potential to preserve visual function in patients with MS. The AFFIRM ( natahzumab vs placebo) and SENTINEL ( natahzumab plus interferon beta la vs placebo plus interferon beta la) were multicenter, randomized, double- blind trials in patients with RRMS. Although high- contrast letter acuity was not able to show a treatment effect after 24 months, low- contrast letter acuity testing ( 1.25% and 2.5% Sloan charts) showed sustained reductions in vision loss in the AFFIRM ( hazard ratio: 0.73, CI: 0.58- 0.91, P = 0.006) and SENTINEL ( hazard ratio: 0.75, CI: 0.61- 0.92, P = 0.007) trials ( Balcer LJ, Philadelphia, PA, S32.004). Another aim of the AFFIRM and SENTINEL trials was to measure the effect of the medications on quality of life in patients with MS. The Multiple Sclerosis Quality of Life Inventory ( MSQLI) and Visual Analog Scale ( VAS) were used to measure quality of life and well- being, respectively. Patients on natahzumab therapy over 2 years in both the AFFIRM and SENTINEL trials demonstrated statistically significant improvement in quality of life and well- being compared to those on placebo or 30 meg interferon ( 3- la intramuscularly weekly ( Rudick RA, Cleveland, OH, S52.005). The incidence of neutralizing antibodies and their potential clinical effect were investigated in the AFFIRM and SENTINEL trials. Nataluzimab is a humanized monoclonal antibody against VLA- 4, an integrin receptor that blocks T cell egress from the circulation into the central nervous system. Over a 2- year period, 6% of patients in the AFFIRM trial were found by enzyme- linked immunosorbent assay to have positive antinataluzimab antibodies at more than 2 time points separated by at least 6 weeks (" persistently positive"). Patients with persistent antibodies demonstrated a reduced clinical benefit by 6 months and a higher incidence of adverse reactions from infusion ( Calabresi PA, Baltimore, MD, S42.007). The most severe adverse reaction associated with natahzumab is the development of progressive multifocal leukoencephalopathy ( PML). To find predictors of which treated patients are at risk for developing PML, investigators compared the cerebrospinal fluid ( CSF) cell counts in patients with MS treated with natahzumab, untreated patients with MS, patients with HIV, and patients with other neurologic diseases. Also, PCR for JC virus DNA was performed on the CSF and peripheral blood. The patients with MS on natahzumab therapy had a low CD4: CD8 ratio in the CSF similar to the patients with HIV, whereas untreated patients with MS and patients with other neurologic diseases had normal CD4: CD8 ratios. The CSF CD4: CD8 ratio returned to normal in the treated patients with MS 6 months after discontinuing therapy with nataluzimab. These results suggest that the lowered CSF CD4: CD8 ratio in treated patients was the result of the natahzumab giving a similar immunologic profile as patients with HIV The effect of natahzumab on the CD4: CD8 ratio may be a risk factor for developing PML, but further research is necessary to test this hypothesis ( Stuve O, Dallas, TX, S32.001). A study of how glatiramer acetate dosing affects MRI included a randomization of 90 patients with RRMS to 40 mg subcutaneously per day or 20 mg subcutaneously per day. At 7, 8, and 9 months after treatment was begun, the 40- mg dose demonstrated a 38% reduction in enhancing MRI lesions compared with the 20- mg dose; this difference did not, however, reach statistical significance ( P = 0.0898). The adverse reactions were similar in both groups ( Cohen JA, Cleveland, OH, S61.001). Mitoxantrone treatment for progressive MS has been associated with the development of acute myelogenous leukemia. In one clinical center, among 111 patients with MS treated with mitoxantrone, 3 developed acute myelogenous leukemia. This was a higher incidence than the 0.25% previously reported ( Lynn DJ, Columbus, OH, POL074). The mechanisms of action of FTY720, a new medication to treat MS, were demonstrated in several papers. FTY720 is an oral agent that binds with high affinity to sphingosine 1- phosphate receptors. The drug has already shown effectiveness in reducing MRI activity and relapse rate over a 6- month period in a phase II trial of 281 patients with RRMS. Patients in another study demonstrated decreases in their peripheral lymphocyte counts at both tested doses ( 1.25 mg and 5 mg orally per day) beginning at week 1 and lasting until week 24 ( Schmidli H, Basel, Switzerland, S32.003). In a murine model, FTY720 prevented peripheral lymphocytes from leaving lymphoid tissue, decreasing their transit into other tissues and into the central nervous system. In addition, the murine model showed that FTY720 prevented vascular endothelial growth factor- induced leakage across the blood- brain barrier ( Brinkmann V, Basel, Switzerland, P03.175). Another study of FTY720 administered 2 to 4 weeks after onset of experimental allergic encephalomyelitis in 225 J Neuro- Ophthalmol, Vol. 26, No. 3, 2006 Moster and Osborne mice showed normalization of somatosensory evoked potentials within 2 weeks. Neurologic deficits in the animals were improved by 4 weeks and histopathologic studies at autopsy showed no active inflammatory lesions. If it shows significant efficacy in its phase III trial, FTY720 could potentially be the first oral immunomodulatory agent for MS ( Foster CA, Vienna, Austria, P05.193). NEUROMYELITIS OPTICA Neuromyelitis optica ( NMO) is a syndrome consisting of ( usually bilateral) ON and transverse myelitis. According to the most recent diagnostic criteria, the brain MRI should be normal. However, recent studies have shown that patients with NMO may have some typical abnormalities on brain MRI. MRI abnormalities in the hypothalamus and periventricular area have been shown to colocalize with areas of aquaporin- 4 ( AQP4), the predominant water channel protein in the central nervous system. The NMO- IgG antibody binds selectively to AQP4. Studies have shown that AQP4 is most highly concentrated in the astrocytic foot processes forming the blood- brain barrier around the hypothalamus and the periventricular areas. A study looked at 130 patients clinically diagnosed with NMO whose serum was positive for the NMO antibody. Nine of these patients had abnormal T2 signal in the hypothalamic and periventricular areas corresponding the localization of AQP4, although no autopsy studies were performed to verify this histologically. Future studies will be needed to further elaborate the relationship of the aquaporin water channel protein with the MRI abnormalities and the clinical manifestations of NMO ( Pittock SJ, Rochester, MN, S22.004). The NMO antibody was studied in two small cohorts of children with clinical NMO. In one cohort, all 4 children ( girls) were positive for the NMO antibody. Three of the patients had ON followed by transverse myelitis and 3 also had supratentorial lesions on MRI. One of the patients had lupus ( Moein M, Dallas, TX, P05.045). In the second cohort, a retrospective analysis of patients with MS who presented between 2002 and 2005 found 3 who met the diagnostic criteria for NMO. All 3 were women; 2 tested positive for the NMO antibody with the serology on the third patient pending. Common findings were an initial presentation suggestive of acute disseminated encephalomyelitis and a significant clinical response to rituximab without significant side effects ( McClinskey N, Huntington, NY, P05.198). INTRACRANIAL HYPERTENSION A small prospective trial of endovascular venous sinus stenting was reported in patients with intracranial hypertension secondary to dural venous sinus obstruction. Ten patients had papilledema, elevated CSF pressures ranging from 270 to 450 mm H20, and venous sinus obstruction demonstrated by retrograde cerebral venography and manometry. After stent placement, all patients had reduced sinus pressures and normalized CSF pressures at 3 months. Four patients became asymptomatic, 5 improved, and 1 remained unchanged. At 6 months after the procedure, 7 patients had repeat venography that showed no stent thrombosis. Future larger trials of this intervention may validate it as another treatment option besides optic nerve sheath fenestration and ventricular shunting for patients who have dural venous sinus obstruction and whose elevated intracranial pressure is refractory to medical therapy ( Donnet A, Marseille, France, S35.004). The Useful Field of View test is a composite measure of visual attention that has been used mainly to predict driving abilities. It assesses the area from which one can extract visual information from competing visual stimuli using a brief glance without head or eye movement. The limits of this area are reduced by poor vision, difficulty dividing attention and/ or ignoring distraction, and slower processing ability. A study of the Useful Field of View compared normal subjects with patients who had extra-striate lesions in the temporo- occipital (" what" pathway) or the parieto- occipital (" where" pathway) region. Both groups performed poorly compared with normal subjects but the test did not distinguish between the two patient groups ( Philippi CL, Iowa City, IA, P01.032). Data were presented on the benefits of vision restoration therapy ( VRT) for patients with different types of field loss. In one study, 302 patients with field defects resulting from various etiologies ( stroke, traumatic brain injury, ischemic optic neuropathy, tumor) were retrospectively evaluated by suprathreshold perimetry after 6 months of daily VRT. Treated patients were able to detect 17.2% more stimuli within their original field defect at the end of the 6 month period ( P < 0.001) and improvements were seen in 70.9% of patients independent of variables such as the age or cause of the visual field defect ( Sabel BA, Magdeburg, Germany, S48.008). Another study reported the long- term stability of visual field improvement after VRT. Twenty- four patients with visual field defects from stroke or traumatic brain injury underwent VRT for 6 ( 15 patients) or 12 ( 9 patients) months and had follow- up suprathreshold high- resolution perimetry and standard near threshold perimetry an average of 46 months after completion of VRT. On average, the initial gains on either 6- month or 12- month protocols were maintained at follow up. This correlated with patients' subjective assessment of their performance on activities of daily living ( Sabel BA, Germany, P01.033). A report presented results related to improving medical student and resident training in performance of confrontation visual fields. The study surveyed neurologists and neuro- ophthalmologists on their preferred technique, 226 © 2006 Lippincott Williams & Wilkins Neuro- Ophthalmology at Large J Neuro- Ophthalmol, Vol. 26, No. 3, 2006 reviewed neurology and neuro- ophthalmology textbooks, and reviewed 120 charts on a medical consultation service. The clinicians and textbooks agreed on the importance of this task and on methods of testing. The chart review revealed little routine use of confrontation visual fields by trainees. Additionally, the homonymous hemianopias found by the attending physician on 2 patients were not elicited by the trainees. A more thorough study of how medical schools are teaching confrontation visual fields appears to be warranted ( Glick TH, Boston, MA, P01.013). RETINA A possible association of patent foramen ovale ( PFO) with retinal ischemia was presented. In a database of 158 patients with clinical episodes of cerebral or retinal ischemia and a PFO found on transesophageal echocardiography, 13 ( 8%) had cryptogenic retinal ischemia with no cause other than the PFO. Mean age was 57 years ( range, 17- 80 years). Eight ( 62%) patients had vascular risk factors. Seven patients had retinal infarcts of which 2 were bilateral. Six patients had transient monocular blindness. Five patients had prior or subsequent cerebral infarcts. One episode was present on awakening and the others occurred during daily activities. Five patients ( 38%) had symptoms develop at the time of Valsalva maneuver. The authors reasonably concluded that cryptogenic retinal ischemia may be caused by paradoxic embolization by a PFO. Support for this mechanism includes an absence of vascular risk factors in some patients, relatively young age, and symptoms occurring during activity ( Thaler D, Boston, MA, P01.050). Alpha- interferons have been associated with retinopathy. Two cases of patients with MS treated with beta-interferons ( one with INFB- lb, one with INFB- la) were reported to have asymptomatic retinopathy consisting of cotton wool spots noted within 4 to 6 months of beginning therapy. One was taken off therapy with resolution of the cotton wool spots. Further reports are needed to determine if the findings are therapy- related or coincidental ( Roberts JK, New York, NY, P01.076). Recent reviews have reported permanent visual loss in retinal migraine ( RM). This and other inconsistencies in prior reports prompted a review of the literature on RM to see whether reported cases meet the International Headache Society criteria of " at least two attacks of fully reversible monocular visual disturbance associated with migraine headache within sixty minutes of the visual event." Only 7 cases had clinical manifestations consistent with RM and only 3 met the strict criteria of RM. The authors concluded that migraine as a cause of transient monocular blindness is rare. This is an important contribution, because many patients have visual loss diagnosed as migraine when other etiologies should be pursued ( Hill D, Atlanta, GA, P01.035). GENETICS In a study of 35 Saudi patients with a presentation resembling Leber hereditary optic neuropathy ( LHON) who had no family history of LHON, only 6 had the primary LHON mutations. Fourteen patients had novel nonsynonymous mtDNA changes. Sixteen of 19 patients had evidence of mitochondrial respiratory dysfunction. Further study will determine the pathogenicity of these mutations ( Bosley T, Camden, NJ, EV5.003). A patient with episodic ataxia, seizures, migraine, and alternating hemiplegia was found to have a heterozygous mutation in SLC1A3 not present in his asymptomatic parents and controls. The mutation alters an amino acid residue strictly conserved in all glutamate transporters and in all organisms ( down to bacteria). The transporter is important in removing glutamate from the synaptic cleft. This adds an additional mutation to CACNA1A and ATP1A2 as causes of this syndrome ( Wan J, Los Angeles, CA, EV4.006). A study of mitochondrial ATP synthesis in skeletal muscles of patients with dominant optic atrophy ( DOA) with or without the OPA1 gene mutation was reported. Using MR spectroscopy, the calf muscles were studied at rest, during aerobic exercise, and during recovery. Various mutations in the OPA1 gene were associated with deficits in ATP synthesis, but patients without OPA1 mutations were similar to controls. These data support the role of mitochondrial dysfunction in OPA1- related DOA ( Lodi R, Bologna, Italy, EV5.002). Nine patients with LHON with monocular visual loss for less than 6 months and normal visual function in the fellow eye were followed prospectively for up to 2 years in an open- label, nonrandomized pilot study of topical brimonidine purite as prophylactic treatment after first eye involvement in LHON. Despite normal visual acuity at baseline in all patients, 7 patients had minimal changes in the central visual field of the " uninvolved" fellow eye. All patients had subsequent deterioration of visual acuity, visual field mean deviations, and foveal sensitivity in the fellow eye. The earliest pattern of visual field abnormality was typically a cecocentral defect enlarging to become a central defect often with a superior or inferior predilection. The visual field defects in the two eyes of any given patient were remarkably similar. LHON may be a bilateral condition at onset more frequently than appreciated ( Newman NJ, Atlanta, GA, EV5.004). Although retinal ganglion cell loss is seen in DOA and LHON, the underlying defects are dissimilar. DOA is caused by mutations in OPA1, which encodes a mitochondrial dynamine- related GTPase implicated in maintenance of the mitochondrial network; LHON is caused by mtDNA mutations affecting complex 1. Respiratory function and mitochondrial network were studied in fibroblasts from 227 J Neuro- Ophthalmol, Vol. 26, No. 3, 2006 Moster and Osborne patients with DOA and patients with LHON. Galactose medium forced mitochondrial respiration in LHON leading to loss of ATP content and ultimately to cell death. A perinuclear mitochondrial fragmentation, as typically seen in apoptosis, was also evident in LHON. The cell phenotype of DOA fibroblasts in galactose medium differed from LHON being mainly characterized by rearrangement of mitochondrial network and maintenance of cell viability ( Carelli V, Bologna, Italy, EV4.001). In a review of 74 patients with LHON mutations at positions 11778 and 3460, 54 had nonocular manifestations. These included an MS- like disorder, Parkinsonism, tremor, myoclonus, brisk deep tendon reflexes, syncope, hypoacusis, migraine, epilepsy, psychiatric disorders, cramps, cardiologic abnormalities, and other miscellaneous findings. There was no mutation or haplogroup- specific prevalence for any non-ocular feature and no differences in serum lactic acid levels. Mitochondrial proliferation was a compensatory change in skeletal muscle. Family clustering of 2 or more individuals with the same nonocular feature was frequently observed. Approximately half of patients with nonocular features were asymptomatic carriers ( Morgia CL, Bologna, Italy, EV4.010). Horizontal gaze palsy with progressive scoliosis ( HGPPS) is a syndrome of absent conjugate horizontal gaze and severe progressive scoliosis starting in infancy. The corticospinal tract and the dorsal column- medial lemniscal pathway fail to cross in the medulla in patients with HGPPS, contributing to deep fissures in the medulla with an abnormal butterfly- like appearance. Most patients have come from consanguineous kindreds. In a study of 3 nonconsanguineous families, distinct novel compound heterozygous ROB03 mutations were found altering highly conserved residues or resulting in a premature stop codon. All newly identified mutations are located in the extracellular domains of ROB 03 as are the majority of previously reported ROB03 mutations ( Jen JC, Toronto, Ontario, Canada, EV4.009). A new genetic mutation for early- onset Parkinson disease was discovered in the gene for polymerase gamma ( POLG- 1). POLG- 1 is a mitochondrial protein encoded in nuclear DNA, which has previously been implicated in progressive external ophthalmoplegia and infantile hepatocerebral Alpers syndrome. Two sisters were found to have a levodopa- responsive syndrome consisting of action tremor, bradykinesia, hypomimia, and stooped posture. Both sisters did not have either ptosis or any evidence of external ophthalmoplegia. This discovery adds to the breadth of clinical manifestations of POLG- 1 mutations ( Davidzon G, New York, NY, S40.003). TACTILE PERCEPTION IN BLINDNESS Blindness is associated with superior tactile perceptual abilities. A functional MRI study examined the differences between 7 blind and 7 sighted subjects during an encoding/ retrieval test of touching and recalling the pattern on sandpaper surfaces. Although the recognition memory scores were not significantly different, the blind subjects had activation of bilateral secondary visual areas ( BA 18, 19), whereas sighted subjects activated the right inferior parietal cortex and left superior parietal area in both the encoding and retrieval tasks. Crossmodal plasticity may underlie superior tactile perceptual abilities in blind people ( Dorsch A, Bethesda, MD, P02.109). STROKE Intravenous tissue plasminogen activator ( tPA) is used in treatment of ischemic stroke of 3 hours'duration or less. An optimal patient for intravenous tPA is one with a stroke occurring within the hospital. A review of patients in one university hospital over 3M> years found that of 52 ischemic strokes occurring in the hospital, 35 had an absolute contraindication to treatment with tPA. Of the other 17, none received thrombolytic therapy mainly because of a delay in neurologic consultation and/ or CT scanning ( El- Zammar ZMK, Dorchester, MA, PO 1.046). Methamphetamine abuse has been reported as a cause of stroke. Possible mechanisms include acute hypertension, vascular toxicity, and vasculitis. Two cases of internal carotid artery dissection were reported in young women. Both had middle cerebral artery ( MCA) distribution infarcts. No other risk factors were found ( Mcintosh A, Aliso Viejo, CA, PO 1.066). EYE MOVEMENTS Prior studies have shown that the area around the intraparietal sulcus of the posterior parietal cortex is important in maintaining spatial constancy around saccades whenever nonvisual information ( or efference copy) is required. To determine a perceptual correlate of this, post-saccadic localization of a target was studied in patients with right parietal lesions. During a visually guided saccade, the target was blanked for 200 msec and then displaced right or left. Subjects were asked to determine the direction of displacement. Normal subjects performed well and patients performed at chance in identifying the direction of target displacement. This study demonstrated that the perception of target displacement is impaired based on deficient use of efference copy ( Heide W, Niedersachsen, Germany, EV4.007). VESTIBULAR DISEASE Fourteen patients with unilateral vestibular failure resulting from vestibular neurectomy performed optokinetic eye movements during functional MRI. Compared with controls, patients had less activation of area MT/ V5 228 © 2006 Lippincott Williams & Wilkins Neuro- Ophthalmology at Large J Neuro- Ophthalmol, Vol. 26, No. 3, 2006 bilaterally. The authors proposed that this phenomenon may be an adaptive mechanism for eliminating oscillopsia in vestibular loss and may contribute to a decreased sensitivity for slow visual motion ( Deutschlander A, Munich, Germany, EV4.003). Three women with chronic exposure to JP- 8 jet fuel developed vestibulopathy. They had chronic complaints of dizziness, headache, fatigue, and imbalance. The first patient had performed fuel- tank maintenance for the Air National Guard for over a decade. The second and third patients had worked for several years as administrators in a small, poorly ventilated building near the flight line. Exposure to toxic hydrocarbons was substantiated by the presence of n- hexane in human blood specimens and n- undecane, n- dodecane, n- tridecane, n- tetradecane, and toluene in the building carpet analyses. The probable states of JP- 8 during exposure were vapor, liquid, and aerosol. Quantitative vestibular tests in 2 patients revealed markedly diminished caloric and rotational responses consistent with bilateral vestibular paresis. One patient demonstrated borderline low rotational responses and left caloric weakness. Bilateral vestibular loss may be caused by chronic exposure to JP- 8 jet fuel ( Robb MJA, Phoenix, AZ, EV4.008). Nystagmus produced by head shaking (" head-shaking nystagmus" [ HSN]) is a common finding in unilateral peripheral vestibulopathy. In a study of HSN in 16 patients with dorsolateral medullary infarcts ( Wallenberg syndrome), 14 patients had HSN with a fast- phase ipsilateral to the lesion. This type of nystagmus was seen even in the 8 patients with spontaneous contralesional nystagmus. Visual fixation and baclofen treatment reduced the HSN. The authors proposed that the HSN is generated by asymmetric velocity storage as a result of impaired unilateral nodulouvular inhibition on velocity storage ( Choi K, Seongnam, South Korea, EV4.004). A retrospective study looked at the prevalence of stroke among patients presenting to the emergency room with dizziness, vertigo, or imbalance. Among 1,666 patients identified over 2M> years, 53 ( 3.2%) were diagnosed with stroke ( mostly ischemic) or transient ischemic attack. If the patient had only 1 of the 3 symptoms, a mere 9 ( 0.7%) of 1,297 were diagnosed with stroke. Imbalance was more likely to be a stroke symptom that dizziness or vertigo ( Kerber KA, Ann Arbor, MI, EV4.001). MYASTHENIA GRAVIS Approximately 10% to 15% of patients with generalized myasthenia gravis ( MG) and 50% of patients with ocular MG are characterized as seronegative. To better define and characterize " seronegative" MG, all patients with MG examined over a 13- year period were retrospectively studied. Of the patients initially defined as seronegative with characteristic weakness and electromyographic findings and absent acetylcholine binding, modulating and striational antibodies, 17.4% converted to seropositivity on retesting 12 months later. Of those who remained seronegative, anti- MuSK antibodies were found in 38%. The authors proposed that the use of the term " seronegative MG" be reserved for patients with clinical and electromyographic findings consistent with MG who have persistently negative modulating, striational, and binding acetylcholine antibodies and negative anti- MuSK antibodies for at least 12 months ( Chan KH, Rochester, MN, S36.002). Pupillary abnormalities are not commonly reported in MG. However, research using infrared dynamic pupillom-etry demonstrated pupillary dysfunction in a cohort of 42 patients with MG as compared with 93 healthy control subjects. The reflex amplitude was smaller, constriction velocity was slower and latency was longer in patients than in control subjects ( P < 0.001). The investigators also found that generalized, nonthymectomized or symptomatic patients showed more significant differences in reflex amplitude constriction velocity and latency than did ocular myasthenics, thymectomized, or asymptomatic patients with generalized MG as compared with control subjects ( P < 0.001). These findings suggest there is mild " laboratory" pupillary dysautonomia in MG, but no comment was made about whether the dysautonomia was clinically evident ( Chemali KR, Cleveland, OH, P05.014). A new animal model for ocular MG used different HLA- transgenic mice ( HLA- DQ8, DR3, and B6) to investigate variable susceptibilities to developing ocular MG after being immunized with an Escherichia coli plasmid expressing recombinant human AchR subunits. Some 89% of HLA- DQ8 mice and 65%> of the HLA- B6 mice developed ocular MG, whereas only 3% of the HLA- DR3 mice were susceptible. Ocular MG was diagnosed by observing ptosis, ophthalmoplegia through videooculagraphy, and the absence of generalized weakness ( Christadoss P, Galveston, TX, S36.003). A review of repetitive nerve stimulation ( RNS) results in subsets of patients with MG was performed. Results of RNS in the facial nerve and orbicularis oculi muscle were compared in patients with positive AChRAb, positive anti- MuSK Ab, and negative in both. Sixteen MuSK Ab-positive patients were abnormal ( 89%), 93 AchRAb-positive patients were abnormal ( 59%) and 27 Ab- negative patients were abnormal ( 33%). For RNS with ulnar nerve stimulation, the MuSK group was abnormal 87.5% of the time, the AchRAb group 80% of the time, and the negative group 80% of the time. The findings on facial stimulation go along with the common clinical involvement of facial muscles in anti MuSK- positive patients ( Young AM, Birmingham, AL, POL 195). 229 J Neuro- Ophthalmol, Vol. 26, No. 3, 2006 Moster and Osborne HEADACHE A prospective study of 141 patients with migraine ( with and without aura) used transcranial Doppler to look for a right- to- left shunt as evidence of a PFO. This patient population was compared with 130 young ( mean age, 33.8 years) and 200 older ( mean age, 61.5 years) patients having sustained a stroke. A significantly higher incidence of PFO was found in patients with migraine with aura than without aura ( 51.7% vs 33.7%, P < 0.001). Interestingly, the incidence of PFO was also significantly higher in migraine with aura patients than in young ( 33.8%) and elderly ( 20.5%) patients having sustained a stroke. In patients with cryptogenic stroke, the incidence of PFO was 41.1% in the young and 25% in the elderly ( Artal F, Brasilia, Brasil, P03.195). The MIST trial was a prospective, randomized, double- blind, placebo- controlled study to test whether PFO closure with the STARFlex Septal Repair Implant vs a sham procedure would stop headaches in migraineurs with aura and with moderate to large intracardiac shunts as measured by transthoracic echocardiography. Selected patients had to have a minimum of 5 headache days per month and be refractory to prophylactic medications. The study found a 60.2% incidence of PFO in migraine with aura patients, 6 times greater than in the general population. Of the patients with shunts, 62.7% had a moderate- to- large-sized PFO. In this study, 74 patients were randomized to receive PFO closure and 73 to receive a sham procedure. The study failed to reach its primary end point of elimination of migraine headache. However, 42% of the patients treated with the PFO closure experienced greater than 50% reduction in headache frequency and the procedure was well tolerated ( Dowson AJ, London, UK, S61.002). MIST 2, a larger prospective trial, recruiting patients in North America, will be starting soon. NEUROSARCOIDOSIS There were two reports of novel therapies for patients with refractory neurosarcoidosis. A case report was presented of a 40- year- old woman with progressive vision loss over several years and biopsy- proven sarcoidosis refractory to corticosteroids and cyclophosphamide. She developed worsening headaches, neck and back pain. A brain MRI showed leptomeningeal enhancement. The patient was started on 100 mg thalidomide per day and titrated up to 450 mg per day ( higher doses caused excess sedation). The patient's vision stabilized and MRI enhancement was significantly reduced. The presenters noted that patients with pulmonary and cutaneous sarcoidosis have been reported in small case series to have clinical responses to thalidomide and suggested that this agent could be a potential treatment for neurosarcoidosis ( Newton HB, Columbus, OH, P03.135). A series of 14 patients with biopsy- proven neurosarcoidosis showed a positive response to therapy with infliximab. The patients had been refractory to corticosteroid treatment. After treatment with 5 mg/ kg intravenous infliximab monthly for 3 to 6 months, 13 patients showed clinical improvement and 8 of 9 patients who underwent MRI scanning showed improvement on the scans. Only one patient had a significant adverse reaction ( mild hypotension) ( Aksamit AJ, Rochester, MN, P03.139). Mark L. Moster, MD Department of Neurology Albert Einstein Medical Center Wills Eye Hospital Philadelphia, Pennsylvania Benjamin Osborne, MD Department of Neurology University of Pennsylvania Philadelphia, Pennsylvania 230 © 2006 Lippincott Williams & Wilkins |
