Journal of Neuro-Ophthalmology, December 2004, Volume 24, Issue 4

The 56th Annual Meeting of the American Academy of Neurology

NEURO- OPHTHALMOLOGY AT LARGE The 56 Annual Meeting of the American Academy of Neurology, San Francisco, California, April 24- 30, 2004 There were 1344 scientific papers and poster presen­tations at the 56th Annual Meeting of the American Acad­emy of Neurology held in San Francisco from April 24 to 30, 2004. The scientific abstracts may be found in Neurol­ogy ( 2004; 62[ Suppl 5]). We have summarized the material most interesting to neuro- ophthalmologists. OPTIC NEURITIS/ MULTIPLE SCLEROSIS A double- blind, randomized, placebo- controlled study of intravenous immunoglobulin ( IVIG) administered within 30 days of onset of optic neuritis ( ON) enrolled 68 patients and studied contrast sensitivity, visual acuity, color vision, visual evoked potential, magnetic resonance imag­ing ( MRI), and relapse rate at 6 months. There was no dif­ference between the two groups in visual parameters at 7 days, 30 days, or 6 months. The authors appropriately con­cluded that IVIG does not affect the course or outcome of acute ON, although the time to recovery was not reported ( Roed HG, Hvidovre, Denmark, S29.005). A study of IVIG in relapsing- remitting multiple scle­rosis ( MS) was performed in patients whose visual acuities were worse than 20/ 200 at 60 to 90 days after an episode of ON, despite an initial course of pulsed intravenous methyl-prednisolone. Patients examined within 3 months of ON on­set were treated with IVIG at 400 mg/ kg per day for 5 con­secutive days, followed by monthly IVIG at the same dose for five additional monthly infusions while continuing pre­vious immune therapy. Patients examined after 3 months after ON onset were followed clinically while maintaining previous therapy. Six months after onset of IVIG therapy, 21 of 23 patients improved in visual acuity to 20/ 30 or bet­ter. In five patients, visual evoked potential also showed reversal of previous delayed conduction. In the untreated group, only 3 of 24 patients improved in visual acuity to 20/ 70 or better. In six patients, visual evoked potential re­peated more than 6 months after onset showed no signifi­cant improvement in PlOO latencies. Although this study suggests that IVIG may help refractory ON, the results must be interpreted in the context of a nonrandomized, open-label study ( Khan O, Detroit, Michigan, P02.121). For patients with ON and other clinically isolated de-myelinating syndromes, the brain MRI is known to be a predictor of the development of future neurologic events consistent with MS. Although brain atrophy was not evi­dent by MRI at baseline among patients in the Controlled High- Risk Avonex MS Prevention Study ( CHAMPS), fol­low- up analyses of treated ( interferon B- 1 a) and placebo pa­tients have demonstrated that brain atrophy does develop within 5 years after first demyelinating events ( including ON). The median baseline brain parenchymal fraction ( BPF, brain volume/[ brain + cerebrospinal fluid volume]) in CHAMPS was 0.857. BPF decreased by 1.146% between the 6- month and 5- year follow- up assessments. Although this rate of change is significant, it is less than that reported previously in cohorts of patients with relapsing- remitting MS in phase III clinical trials, suggesting a potential benefit of early immunomodulatory therapy in reducing the devel­opment of brain atrophy, which is an imaging marker for axonal/ neuronal loss. Baseline T2 lesion volume was an in­dependent predictor of decline in BPF, emphasizing the value of early MRI findings in determining prognosis ( Kinkel R, Boston, Massachusetts, S46.002). The risk of progressing to MS was described for a prospective cohort of patients with ON recruited in 1969 to 1981 ( before MRI) and followed- up for up to 31 years or until MS was diagnosed. MRI, cerebrospinal fluid exami­nation, and HLA typing were performed. The estimated 15- year risk of MS was 40% ( confidence interval [ CI]: 31%>- 52% o). In most cases ( 60% o), MS developed within 3 years. Among factors present at onset, inflammatory cerebral spi­nal fluid findings significantly increased the risk ( P = 0.02) from 23% ( CI: 12%- 44%) to 49% ( CI: 38%- 65%). Recur­rence of ON similarly elevated the risk significantly ( P < 0.001). Younger patients and those with winter onset had greater risk. The presence of HLA DR2 did not increase the risk significantly. After 19 to - 31 years, two or more MRI lesions suggestive of demyelinating disease were detected in 20 of 30 individuals in whom no clinical manifestations of MS had occurred. Although the authors point out that the 15- year risk of MS in this cohort was only 40% o, this study was initiated in the pre- MRI era, when diagnoses of AION and neuroretinitis were not common. These cases may therefore have accounted for a substantial proportion of pa­tients purported to have ON. Inclusion of these patients may, therefore, have artificially decreased the reported rate of conversion to MS ( Sandberg- Wollheim M, Lund, Swe­den, S40.003). CHAMPS was a randomized, double- blind, placebo-controlled trial of interferon beta ( IFNb)- la30 ug intramus­cularly once weekly in patients who experienced a first J Neuro- Ophthalmol, Vol. 24, No. 4, 2004 327 JNeuro- Ophthalmol, Vol. 24, No. 4, 2004 Neuro- Ophthalmology at Large clinical demyelinating event. Results showed that IFNb- la significantly slowed the rate of development of clinically definite MS ( CDMS) and new MRI abnormalities over 2 years compared with placebo. The study was continued as an open- label extension study ( CHAMPIONS). CHAMPS patients were offered intramuscular IFNb- la for up to 5 years ( timed from randomization into CHAMPS) and were followed- up every 6 months. Patients who received placebo in CHAMPS were considered the delayed treatment ( DT) group and patients who received IFNb- la in CHAMPS were considered the immediate treatment ( IT) group. Out­comes included rate of development of CDMS, relapses, measures of disability, and MRI measures. Seventy percent ( 203/ 290) of patients from 32 participating sites were en­rolled in CHAMPIONS ( n = 100, IT group; n = 103, DT group). Overall, 36%> of the IT group and 48%> of the DT group had CDMS by 5 years. Mean number of relapses over 5 years (± SD) was 0.9 (± 1.3) in the IT group compared with 1.7 (± 2.7) in the DT group ( P = 0.008), representing a 47% reduction in the IT group. In both groups combined, 13% of patients had an Expanded Disability Status Scale score of 3.0 or more at their 5- year visit ( IT group 11%, DT group 14%). The median number of new or enlarging T2 lesions at 5 years was significantly lower in the IT group than in the DT group ( 3.5 vs. 6.0, P = 0.05). Initiation of IM IFNb- la at the time of a first clinical demyelinating event slowed the rate of conversion to CDMS over 5 years compared with therapy initiated a median of 2.5 years later. These results support the recommendation to initiate disease- modifying therapy in high- risk patients at the time of a first demyelin­ating event ( Kinkel RP, Boston, Massachusetts, S29.006). To assess the bioavailability of oral high- dose pred­nisone, 16 MS patients were randomized to receive 1 g in­travenous methylprednisolone ( IVMP) or 1,250 mg of oral prednisone. Serum prednisolone and methylprednisolone levels were determined at 0,1,2,4, 8,24, and 48 hours after the first dose. There was no statistically significant differ­ence in corticosteroid serum levels at 24 or 48 hours, but there was at 8 hours, consistent with an earlier peak in the intravenous group. This small study suggests that there is no substantial difference in the bioavailability of methylpred­nisolone and prednisolone at 24 hours after intravenous or oral dosing. Results are consistent with previous studies that have shown no differences in visual outcome but indi­cated reasonable tolerability for high- dose oral steroids as an alternative to IVMP ( Morrow SA, London, Ontario, Canada, P02.117). A 5- year study to determine whether regular pulses of IVMP affect the evolution of T2 lesions into confluent T2 lesions was undertaken. Eighty- eight relapsing- remitting MS patients were randomly assigned to regular pulses of IVMP ( 1 g/ d for 5 days with an oral prednisone taper) or TVMP at the same dose schedule administered only for re­lapses. The patients were not treated with other disease-modifying drugs. Confluent T2 lesions were defined as le­sions larger than 20 mm in strategically important areas of the brain or areas of white matter abnormalities consist­ing of two or more than two interconnected T2 lesions. Pa­tients who received TVMP pulses every 4 to 6 months for 5 years had significantly fewer confluent T2 lesions ( 105 ver­sus 270, P < 0.0001) and fewer large T2 lesions (> 10 mm) ( 165 vs. 541, P < 0.00001) compared with those who re­ceived IVMP for relapses alone ( Zivadinov R, Buffalo, New York, P04.035). To evaluate the effects of neutralizing antibodies ( NAbs) on the clinical efficacy of IFNb during treatment of MS, an open- label study of 78 patients prescribed any of the three main IFNb medications were studied. Of 78 patients enrolled in the study, 13 ( 17%) had persistent NAbs. The incidence of persistent Nab- positive patients was 35% o for IFNb- lb, 20% for IFNb- la- Rebif, and 3% for IFNb- la- Avonex. NAb+ and NAb~ patients showed reductions from baseline in relapse rate over the 3- year follow- up period. However, this reduction was not significant in NAb+ pa­tients ( 25%, P = 0.053) but was highly significant ( 67%; P < 0.0001) in NAb~ patients. In addition, the mean relapse rate was significantly higher ( P = 0.039) and the mean time between first and second relapse was significantly shorter ( 13 vs. 21 months; P = 0.0064) in NAb+ compared with NAb~ patients. The probability of being relapse- free was significantly lower ( P = 0.08) in NAb+ than in NAb~ pa­tients. A significantly higher percentage of NAb+ patients had worsening of Expanded Disability Status Scale scores during follow- up ( P = 0.013). Results of this study, funded by various health foundations, indicate that Nab testing should be considered in patients with continued relapses or progression despite therapy with IFNb ( Malucchi S, Torino, Italy, P02.125). Apo E is involved in the transport of lipids necessary for membrane repair in neuronal cells. Carriage of the Apo E4 allele has been associated with unfavorable outcomes in head trauma and stroke and is considered a risk factor for early- onset Alzheimer disease. The relation of Apo E4 to MS risk and disease progression, however, remains contro­versial. Patients with MS ( n = 364) and monosymptomatic ON ( n = 72) in Copenhagen, Denmark were examined for Apo E genotype, as well as Expanded Disability Status Scale score, disease duration, and disease progression. Fre­quencies of the Apo E4 allele were similar to those found in the general Danish population, but patients with the Apo E4 allele and MS for less than 10 years had signifi­cantly greater rates of disease progression than did those who lacked that allele. Apo E genotype may thus be among the many factors that influence neurologic prognosis in 328 © 2004 Lippincott Williams & Wilkins Neuro- Ophthalmology at Large JNeuro- Ophthalmol, Vol. 24, No. 4, 2004 patients with ON and MS ( Laustrup J, Copenhagen, Den­mark, P06.070). Balance dysfunction secondary to involvement of the brainstem vestibular pathways is a common manifestation of MS. Forty- four patients who completed an 8- week spe­cialized vestibulo- ocular retraining program ( consisting of repetitive practice of vestibular ocular reflex and visual ex­ercise) demonstrated significant improvement in walking tasks as assessed by the Dynamic Gait Index as compared with a control group ( n = 35) that completed an 8- week program of therapeutic exercise without specific balance re- training. Because patients who completed the special­ized training demonstrated improvement compared with control subjects, results of this study suggest that systematic programs of vestibular rehabilitation are effective not only in patients with peripheral vestibular dysfunction but also in patients with MS and other disorders of the brainstem ves­tibular pathways ( Bennett S, Buffalo, New York, P06.007). NEUROMYELITIS OPTICA Neuromyelitis optica ( NMO) is an inflammatory de-myelinating disease characterized by selective involvement of the optic nerves and spinal cord. A recent analysis com­paring cerebral spinal fluid immunologic markers in NMO patients, MS patients, and healthy controls provided further evidence that a major humoral immune response occurs in the cerebral spinal fluid of patients with NMO. Production of anti- myelin oligodendrocyte glycoprotein IgM and acti­vation of eosinophils were factors more associated with NMO than MS or control subjects. The potential role for these findings in the pathogenesis of NMO remains to be investigated ( Correale J, Buenos Aires, Argentina, P06.072). Two studies demonstrated potential roles for helper T cell- attracting chemokines as well as activation of type 1 and type 2 helper T cells in the cerebral spinal fluid of patients with relapsing NMO ( Narikawa K, Sendai, Japan, P05.048; Misu R, Miyagi, Japan, P05.049). The known role of anti- myelin humoral immune re­sponses in NMO and MS provides a rationale for therapies directed at depleting B cells. The safety and tolerability of rituximab, a monoclonal B cell- depleting antibody that has been used successfully to treat rheumatoid arthritis, was re­cently investigated in patients with NMO and MS patients with progressive relapsing myelitis. Intravenous infusions of rituximab ( 375 mg/ m2 weekly for 4 weeks) were well-tolerated, successfully reduced B cell counts to 0, and were associated with recovery of the ability to ambulate and im­provement of visual acuity in two of four NMO patients. These results suggest a potential role for rituximab in pa­tients with NMO and MS with a rapidly progressive course. Clinical trials are underway to examine the safety and effi­cacy of this new therapy in primary progressive MS ( Cree B, San Francisco, California, P06.090). GENETIC OPTIC NEUROPATHIES In Leber Hereditary Optic Neuropathy ( LHON), damage by reactive oxygen species is believed to play a pivotal role in cellular injury. Intravitreal injection of SOD2, a gene that detoxifies reactive oxygen species, was recently shown to suppress apoptosis of retinal ganglion cells and degeneration of optic nerve fibers in a mouse model ( Qi X, Gainesville, Florida, S03.005). Progressive degeneration of retinal ganglion cells is also a prominent feature of autosomal dominant optic atrophy ( ADOA). Most patients with this disorder have a mutation in the OPA1 gene with resulting dysfunction of mitochondrial morphology and ATP synthesis. A recent study confirmed the central role of mitochondrial dysfunction in the patho­physiology of ADOA using near infrared muscle spectros­copy in vivo ( Lodi R, Bologna, Italy, S03.006). Collec­tively, these studies suggest a potential future role for gene therapy in patients with hereditary optic neuropathies. In addition to the three most common mitochondrial DNA ( mtDNA) mutations that occur in patients with LHON, novel mutations are frequently sought in sporadic cases and in familial cases in which known mutations are not identified. Novel, rare pathogenic mutations have been reported within the ND6 subunit of the mitochondrial ge­nome; now, a mtDNA point mutation ( 3733G> A transition that induces an E143K amino acid change) within the NDl subunit gene has been discovered. In these analyses, a 3733G> A nucleotide change was identified in one sporadic case of LHON and in a family with six maternally related affected individuals. All of these patients were negative for known LHON mutations. Findings from this investigation provide evidence that the NDl subunit represents a second " hot spot" ( in addition to ND6) for mtDNA mutations in patients and families with LHON that may be targeted for genetic testing ( Valentino M, Bologna, Italy, POL 101). Investigation of the processes by which mutations in mtDNA lead to apoptotic cell death in LHON is important in demonstrating potential targets for neuroprotective therapies. Two groups in Italy recently showed that LHON mutations profoundly impair ATP synthesis in mitochon­dria ( Carelli V, Bologna, Italy, POL 102), and that the apo­ptotic process induced by oxidative stress primarily in­volves alterations in mitochondrial membrane permeability ( Battisti C, Siena, Italy, POL 103). Based on a model of ap­optosis using cells cultured in galactose- containing rather than glucose- containing medium ( cells with mtDNA muta­tions at positions 11778, 3460, and 14484), Carelli et al demonstrated that impairment of ATP synthesis may be more relevant than previously thought in the process of reti­nal ganglion cell death. In peripheral blood lymphocytes from six patients with LHON, Battisti et al investigated the potential role of 2- deoxy- d- ribose ( a factor that alters redox 329 JNeuro- Ophthalmol, Vol. 24, No. 4, 2004 Neuro- Ophthalmology at Large homeostasis) on the apoptotic response. The rationale for this study was based on the fact that, given the incomplete penetrance of the LHON phenotype ( optic neuropathy de­velops in only 10% of women and 50% of men with the three most common mutations), additional genetic or envi­ronmental factors ( such as oxidative stress affecting mito­chondrial function) are likely to be important modulators of phenotype expression. Based on these investigations, agents that reverse or prevent effects of oxidative stress or that enhance ATP synthesis represent potential therapeutic strategies for preventing cell death in LHON and other mi­tochondrial disorders. The feasibility and timing of such fu­ture therapies remain to be established. A retrospective review of 100 cases of optic nerve hypoplasia ( ONH) studied the frequency of coexisting neu­rologic and endocrine abnormalities. There were 64 men and 36 women, 75%> with bilateral ONH, 21% with prema­ture birth, 9%> with fetal alcohol syndrome, and 7%> with maternal diabetes. All patients had impaired vision or stra­bismus. There was a clinical neurologic abnormality in 57%> of bilateral ONH patients and 32% o of unilateral ONH pa­tients and endocrine abnormalities in 6%> of all patients combined. Developmental delay was present in 32% o, cere­bral palsy in 13%, and seizures in 12%. Of 65 patients with imaging studies, 60% o had abnormalities, including 29%> with dysplasia of the ventricles or white or gray matter, 16% with dysplasia of the corpus callosum, 10% with septo-optic dysplasia, and 8%> with hydrocephalus ( Rothner AD, Cleveland, Ohio, P01.125). MIGRAINE Vestibular dysfunction is now recognized as a fre­quent cause of symptoms in patients with migraine. Docu­mentation of clinical findings in these patients, however, has been largely limited to asymptomatic periods between migraine episodes, making the diagnosis of vestibular migraine one of exclusion. A recent series of 26 patients, examined during or immediately after an acute attack, dem­onstrated the occurrence of nystagmus in the setting of acute or subacute vestibular migraine. Although clinical descriptions of the nystagmus were variable, eye move­ment recordings showed consistent patterns suggesting a central origin that were readily distinguishable from be­nign paroxysmal positional vertigo. Same- day examina­tion of patients with recurrent intermittent positional ver­tigo is a useful strategy for diagnosis ( Hartman S, Atlanta, Georgia, S03.001). Some insights into the mechanism of prolonged mi­graine aura were gained from a study of two patients who had a 1- week aura. The first patient had Sturge- Weber syn­drome in addition to migraine and presented with prolonged aura of left homonymous hemianopia lasting 1 week. Neu-roimaging studies during the aura showed focal hyperemia in the right occipital cortex on single photon emission com­puted tomography, augmented gadolinium leakage from the leptomeningeal angiomatosis along the sulci of the right occipital cortex on enhanced MRI, and retention of the con­trast material in the leptomeningeal vessels of the right me­dial occipital cortex on CT angiography. The neuroimaging findings resolved with the clinical symptoms. The second patient, who had hemiplegic migraine presenting with right hemiparesis, confusion, and global aphasia as a prolonged aura, underwent neuroimaging studies that showed wide­spread hyperemia in the left cerebral hemisphere on single photon emission computed tomography, vasodilatation of the left middle cerebral artery on MRA, and gadolinium enhancement of the cerebral spinal fluid in the sulci of the left parieto- occipito- temporal cortex on delayed enhanced fluid- attenuated inversion recovery images obtained 2 hours after gadolinium administration. The authors suggest that vasogenic leakage from the leptomeningeal vessels, possibly associated with trigeminovascular activation, may delay the process of spontaneous recovery or prolong the state of neuronal suppression in patients with prolonged mi­graine aura ( Iizuka T, Sagamihara, Japan, P01.152). IDIOPATHIC INTRACRANIAL HYPERTENSION A retrospective study of 77 idiopathic intracranial hy­pertension ( IIH) patients in Detroit found that 92% o were female, 88%> were obese, 65% o were black, and 31% were white. The most common presentation was isolated head­ache ( 28.6%); 24.7% of patients were asymptomatic ( Van Stavern GP, Detroit, Michigan, ( P01.098). The features of 20 IIH patients without papilledema ( 6% of a total of 3 53 patients) were compared with the other 94% who did have papilledema. Eighteen were women, 84% were overweight, and 90% o had headaches. When com­pared with those with papilledema, the patients without papilledema had fewer transient visual obscurations, intra­cranial noises, and diplopia. Visual acuity was similar in both groups. Automated visual field tests showed similar mean deviations in both groups, but there were more psy­chogenic visual field defects in those without papilledema. Opening pressures tended to be lower in IIH without papil­ledema ( 312 mmH20 vs. 373 mmH20, P < 0.01) ( Naka-moto BK, Salt Lake City, Utah, P01.099). Nine patients with severe rapid visual loss from IIH (" malignant IIH") were presented. All were women with a mean age of 23 years. Six were obese, and none was ane­mic. All had had acute, severe headaches as an initial symp­tom, prompting rapid evaluation and diagnosis of papille­dema from raised ICP. Visual acuity was 20/ 200 or worse in at least one eye at initial presentation. All had severe, bilat­erally constricted visual fields and bilateral disc edema. All patients underwent at least one lumbar puncture and were 330 © 2004 Lippincott Williams & Wilkins Neuro- Ophthalmology at Large JNeuro- Ophthalmol, Vol. 24, No. 4, 2004 treated with acetazolamide ( 1,000 to 2,000 g/ day) early in the course with progressive worsening of visual function despite treatment. All underwent emergent optic nerve sheath fenestration ( unilateral in four, bilateral in three) or lumbo- peritoneal shunting ( five). Visual function im­proved in all patients but details were not given. The authors conclude that medical management alone may be in­adequate and that prompt surgical intervention may be in­dicated to preserve vision ( Thambisetty M, Atlanta, Geor­gia, POL 100). In advance of an IIH treatment trial, baseline and 6- month follow- up information was collected on 109 pa­tients with newly diagnosed IIH at multiple centers. Median age at presentation was 30 years ( range 13- 52 years), 93% were women, 83% were white, and 13% were black. Symp­toms were headache ( 44%), visual loss ( 29%), transient vi­sual obscurations ( 10%), diplopia ( 4%), or other ( 3%). Forty- two eyes ( 19%) had visual acuity worse than 20/ 25 at baseline and 24 eyes ( 11%) had visual acuity worse than 20/ 25 at follow- up. Abnormal visual fields were found in 67% of eyes at baseline and 50% o of eyes at follow- up. The average Humphrey mean deviation at baseline was - 3.11 dB OD and - 3.03 dB OS. At follow- up, the average mean deviation was significantly improved at - 2.18 dB OD and - 2.62 dB OS ( P = 0.02). There was a high correlation be­tween the mean deviation at baseline and at follow- up ( Pearson r = 0.85 for OD and r = 0.78 for OS) ( Friedman, DI, Rochester, New York, P01.097). CEREBROVASCULAR DISORDERS A report compared 290 patients with unruptured in­tracranial arteriovenous malformation ( AVM) treated with surgery, embolization, or radiation to 108 patients with AVM that was not treated. Incomplete AVM treatment in­creased the risk of symptomatic hemorrhage and acute clinical worsening compared with no treatment. Complete lesion removal resulted in a 5- year risk of bleeding equiva­lent to that of untreated patients. The authors rightfully sug­gest that their findings support the need for a randomized trial for treatment of unruptured brain AVMs ( Mohr JP, New York, New York, S13.003). Traditional teaching is that dolichoectatic aneurysms caused by atherosclerosis are not associated with subarach­noid hemorrhage. In a review gathered from the experience of five major hospitals in a recent 5- year period, six elderly patients were identified with subarachnoid hemorrhage caused by rupture of dolichoectatic basilar artery aneu­rysms. Symptoms of aneurysm growth or clot formation within the dolichoectasia ( because of compression or brain­stem ischemia) preceded its rupture in most cases and the outcome was invariably fatal ( Michel P, Utrecht, The Neth­erlands, S13.004). To further clarify the relationship of headache and stroke, a prospective cohort study of 39,754 women health professionals participating in the Women's Health Study was performed. Migraine, aura symptoms, and headache were accepted as self- reported, but incidence of self-reported ischemic and hemorrhagic stroke was confirmed after medical record review. During an average of 9 years of follow- up, 385 strokes ( 309 ischemic, 72 hemorrhagic, and 4 undefined) occurred. Compared with non- migraineurs, participants who reported migraine without aura had no in­creased risk for ischemic or hemorrhagic stroke. Those who reported migraine with aura had a significant increase in risk for stroke, with an adjusted hazards ratio ( HR) of 1.53 ( 95% confidence interval [ CI]: 1.01- 2.30) for the hemor­rhagic and ischemic stroke combined and 1.70 ( 95% o CI: 1.10- 2.64) for ischemic stroke alone. Participants who were younger than age 55 years had the greatest increased risk of total ( HR 1.74; 95% CI: 1.01- 3.00) and ischemic ( HR 2.25; 95% CI: 1.30- 3.90) stroke. There was no in­crease in the risk of hemorrhagic stroke among migraineurs. Compared with participants without a reported history of any headache, non- migraine headache was not associated with an increased risk of hemorrhagic and ischemic stroke combined ( HR 0.99; 95% CI: 0.73- 1.33), ischemic stroke alone ( HR0.91; 95% CI, 0.64- 1.28), or hemorrhagic stroke alone ( HR 1.27; 95% CI, 0.67- 2.40). It appears that mi­graine with aura is associated with an increase in hemor­rhagic and ischemic stroke combined and ischemic stroke alone, particularly among young women. Migraine without aura and non- migraine headache are not associated with in­creased risk of stroke. Migraine with aura was not associ­ated with an increased risk of hemorrhagic stroke ( Kurth T, Germany, S24.001). To determine the accuracy of CT angiography for evaluation of carotid stenosis compared with conventional digital subtraction angiography ( DS A), two masked readers retrospectively evaluated 81 arteries in consecutive TIA and stroke patients who had undergone both studies over a 32- month period. Using a 70% o stenosis cut- off value, CTA and DSA were in agreement in 78/ 81 ( 96.3%) of vessels. The negative predictive value of a CTA demonstrating less than 70% stenosis was 100%. Three of 81 ( 3.7%) vessels evaluated by CTA as greater than 70% o were found to be less than 70% by DSA. One vessel was overcalled by CTA sec­ondary to calcification. The authors appropriately suggest that CTA is a valid screening tool for significant carotid stenosis and can be used in the initial evaluation of stroke ( Josephson SA, San Francisco, California, S16.003). In North Carolina, a survey of stroke mortality rates at all 128 hospitals showed that care in a basic or advanced stroke center significantly decreased mortality ( Camilo O, Durham, North Carolina, P03.074). 331 JNeuro- Ophthalmol, Vol. 24, No. 4, 2004 Neuro- Ophthalmology at Large To assess whether retinal vascular disease consisting of arteriosclerosis, exudates, or hemorrhages was associ­ated with subsequent myocardial infarction or stroke, 20- year follow- up data of 4,753 adults aged 25 to 74 years who participated in the First National Health and Nutrition Ex­amination Survey ( NHANES) was reported. Of the 4753 participants, 935 ( 20%) had baseline retinal vascular dis­ease on funduscopic examination. At an average of 16.1 years of follow- up, the rate of cardiovascular diseases was 35% in patients with retinal vascular disease and 18% in patients without retinal vascular disease. After adjusting for differences in age, race, sex, systolic blood pressure, smok­ing habit, serum cholesterol levels, body mass index, and diabetes mellitus, the risk of all cardiovascular diseases was increased in persons with retinal vascular disease ( relative risk[ RR], 1.2; 95% CI: 1.0- 1.3). The age- adjusted and sex-adjusted risk of myocardial infarction ( RR 1.1; 95% o CI: 1.0- 1.4) and ischemic stroke ( RR 1.3; 95% CI: 1.0- 1.6) was higher among persons with retinal vascular disease ( Qureshi A, Newark, NJ, P03.131). A retrospective, multicenter study of 90 consecutive cases with isolated Horner syndrome from internal carotid artery dissection was undertaken, with a median follow- up of 2 years. Horner syndrome was painless in 8 and painful in 82 patients. After onset of Horner syndrome, the 2- year risk of transient ischemic attack and stroke was 17%>, and the risk of stroke alone was 12% o. Eleven middle cerebral artery strokes occurred, 10 within the first 15 days and36% o within the first 24 hours. Five patients with stroke had DSA, all demonstrating fibromuscular dysplasia ( de Bray JM, Zu­rich, Switzerland, P03.137). SPORTIF V was a double- blind trial of 3922 patients with non- valvular AF and at least one stroke risk factor who were randomized to treatment with fixed- dose oral ximela-gatran ( 36 mg twice daily) or adjusted- dose warfarin ( target INR 2.0- 3.0). The primary endpoints were stroke and sys­temic emboli. Fixed- dose, oral ximelagatran without co­agulation monitoring was found to be at least as effective as warfarin in prevention of stroke and systemic emboli, and was associated with less bleeding, confirming the results of the earlier open- label SPORTIF III trial. This might im­prove the compliance and ability to anticoagulate patients because INR does not have to be followed ( Albers GW, Palo Alto, California, PL01.003). VENOUS SINUS THROMBOSIS Patients with venous sinus thrombosis generally un­dergo extensive evaluation for hypercoagulable factors. A recent case series revealed that elevated levels of yet an­other prothrombotic factor, lipoprotein ( a) [ Lp( a)], may be associated with venous sinus thrombosis. Lp( a) is an inher­ited prothrombotic lipid fraction and has been demonstrated in patients with accelerated atherosclerosis and venous thromboembolism. Elevated levels of Lp( a) were noted in 9 of 15 patients with non- obstructive ( non- compressive) ve­nous sinus thrombosis, but five of these patients also had coexistent hypercoagulable disorders, including antiphos-pholipid antibodies, anti- B( 2)- glycoprotein- I antibodies, and heterozygosity for the factor V Leiden mutation. These results provide some evidence, however, that measurement of Lp( a) level should be added to the hypercoagulable as­sessment in patients with venous sinus thrombosis and other thrombo- embolic disorders. Further investigation of this prothrombotic lipoprotein may reveal a potential role for therapy with agents used to treat hyperlipidemia ( Lie-beskind D, Philadelphia, Pennsylvania, P06.027). A case- control study of 45 Mexican patients with ce­rebral venous thrombosis and 90 control subjects measured plasma levels of homocysteine ( fasting and after methio­nine load), folate, and vitamin B12. Genotyping of the methylene tetrahydrofolate reductase ( MTHFR) gene was also performed. High plasma concentrations of homocys­teine and low plasma folate levels were associated with an increased risk of cerebral venous thrombosis in this popu­lation whose low socioeconomic status and deficient nutri­tion may be contributory. Although there was a higher in­cidence of MTHFR mutation in cerebral venous thrombosis patients ( 22% o vs. 10%>), the difference did not reach statis­tical significance ( Cantu C, Mexico, P01.052). HEADACHE Chronic cluster headache ( CCH) is the most severe form of chronic headache. Positron emission tomography studies have shown posterior hypothalamic hypermetabo­lism during attacks. Two studies of hypothalamic stimula­tion for intractable CCH were presented. In the first study, 14 CCH patients ( 12 men, 2 women, mean age 41.4 years, range 25- 63 years), received hypothalamic stimulation. At a mean follow- up of 15 months, nine patients were pain-free, and three others had more than 80% o reduction in at­tacks. In one patient, the stimulator was switched off eight times and the mean time of return of headache to pain- free state was 7.6 days ( range 2- 29 days). The authors con­cluded that continuous stimulation of the postero- inferior hypothalamus is an effective, safe, and well- tolerated treat­ment of intractable CCH ( Leone M, Milano, Italy, S43.001). A second study of hypothalamic stimulation for CCH included five patients ( four men). Four of five patients experienced major improvement, which persisted after a mean follow- up of 8 months. One patient remained attack-free, one experienced two brief relapses that could be con­trolled by increasing stimulation parameters, and one still presented some scattered attacks, but frequency was re­duced by 85% o. In the latter two CCH patients, remaining attacks were well- controlled by oxygen or sumatriptan and none required drug prophylaxis. The fifth patient had a fatal 332 © 2004 Lippincott Williams & Wilkins Neuro- Ophthalmology at Large JNeuro- Ophthalmol, Vol. 24, No. 4, 2004 intracranial hemorrhage 4 hours after the surgical electrode implantation, a reminder that this intervention is not en­tirely benign ( Vandenheede M, Liege, Belgium, S43.002). Short- lasting unilateral neuralgiform headache at­tacks with conjunctival injection and tearing ( SUNCT) syn­drome is a rare, usually drug- refractory headache. Pain at­tacks occur hundreds of times per day, last a few seconds, are experienced along the first branch of the trigeminal nerve, and are accompanied by autonomic phenomena such as lacrimation, eye reddening, rhinorrhea, nasal stuffiness, and facial flashing. Based on similarities to cluster head­aches and a previous report of functional MRI demonstrat­ing ipsilateral hypothalamic activation, a patient with SUNCT received ipsilateral hypothalamic deep brain stimulation. Pain attacks gradually decreased. Four months after implantation, the patient was pain- free ( Leone M, Pa-dova, Italy, S43.003). An open- label trial of botulinum- A toxin in the treat­ment of trigeminal neuralgia, idiopathic stabbing head­aches, and SUNCT was presented. Three of seven patients with trigeminal neuralgia became pain- free after 15 days, two had an 85% reduction of symptoms, and two did not improve at all. Three of four patients with idiopathic stab­bing headaches were pain- free 15 days after the injections. At the 3- month follow- up, one had pain recurrence at an­other site. The single SUNCT patient reported worsening in the three first postinjection days, with a 70% reduction of symptoms after 21 days ( Piovesan EJ, Parana, Brazil, P02.105). Results ofthis study suggest that botulinum toxin may be effective in the symptomatic treatment of some headache syndromes. There have been previous reports of SUNCT second­ary to an underlying lesion, mostly in the posterior fossa. A 69- year- old woman who had 50 to 70 lancinating right or­bital pain attacks per day lasting 1 to 2 minutes would some­times have conjunctival injection, profuse ipsilateral lacri­mation, ptosis, rhinorrhea, and eyelid edema. Neurologic and ophthalmologic examination between attacks was nor­mal. A gradually enlarging right orbital lesion was found. The symptoms then became contralateral and a left orbital lesion was found. Metastatic bronchial carcinoid was diag­nosed, but biopsy was not performed on the orbital lesions ( Black DF, Scottsdale, Arizona, p04.159). MYASTHENIA GRAVIS Although patients with ocular myasthenia gravis ( OMG) do not experience the potentially life- threatening manifestations of bulbar and respiratory muscle weakness, diplopia and ptosis may be disabling. Systemic corticoste­roids are known to produce clinical improvement in pa­tients with generalized MG, but their efficacy as compared with pyridostigmine for treating OMG has not been estab­lished. Areview of clinical data from 88 OMG patients who received oral prednisone ( 50- 60 mg/ d with gradual taper) or pyridostigmine ( 180 mg/ d with dose escalation as toler­ated) in a non- randomized fashion showed a significant benefit for corticosteroids in reducing diplopia and ptosis. The proportion of patients experiencing diplopia in primary gaze decreased within 1 month of treatment from 94.6% o to 26.5% in the prednisone group; this effect was sustained for at least 2 years in 70% o of patients. The pyridostigmine group, in contrast, mamfested diplopia in primary gaze in 85.3% at baseline and in 93.1% at 1 month. Prednisone therapy also demonstrated reduced ptosis significantly more often than did pyridostigmine. Although patients in this study were not randomized to treatment groups, the re­sults provide evidence in support of future randomized tri­als to examine tolerability and efficacy of corticosteroids in patients with OMG. The potential for corticosteroids to de­lay or prevent the onset of generalized MG in OMG patients will also be investigated in upcoming trials ( Kupersmith M, New York, New York, S03.004). In contrast to previous reports, a Japanese study found that only 9 ( 26%) of 35 acetylcholine receptor anti­body ( AChRAb)- negative MG patients to be muscle-specific tyrosine kinase ( MuSK) Ab- positive. MuSK is a surface membrane enzyme that is essential in aggregating AChR during the development of the neuromuscular junc­tion. All nine patients were women and symptoms were dysphagia, neck muscle weakness, and respiratory failure, with little ocular or limb muscle weakness. Four of these nine patients experienced myasthenic crisis and none had thymoma. Repetitive nerve stimulation showed mild decre­ment ( from 0%> to 17%) despite severe symptoms. MuSK Ab- positive patients had only mildly decreased AChR den­sity and two of six had immune complex deposition at the motor end- plates, which was different than that of the MuSK Ab- positive patients. Based on these contrasts, the authors suggest that the pathogenesis of AChRAb- negative MG may be a different form of MG that AChRAB- positive MG ( Shiraishi H, Nagasaki, Japan, S22.003). Congenital myasthenic syndromes comprise a het­erogeneous group of rare disorders arising from genetic de­fects in presynaptic, synaptic, or postsynaptic proteins at the neuromuscular junction. Most AChR- deficient patients have AChR- e subunit mutations, but recently mutations in the endplate AChR clustering protein, rapsyn, have been shown to be an additional cause, being associated with two distinct phenotypes: early- onset and late- onset. Twenty-eight early- onset AChR- deficient patients were described, 14 with AChR- e mutations and 14 with rapsyn mutations. All had symptoms from birth or infancy. Ptosis, severe oph­thalmoplegia, and generalized weakness were associated with AChR- e mutations. By contrast, mutated rapsyn pa­tients did not have ophthalmoplegia but rather arthrogrypo­sis multiplex congenita ( n = 10), marked bulbar weakness 333 JNeuro- Ophthalmol, Vol. 24, No. 4, 2004 Neuro- Ophthalmology at Large requiring nasogastric feeding ( n = 8), and life- threatening exacerbations during early childhood ( n = 11). Many had normal strength between attacks and marked spontaneous improvement later in life ( n = 9). Response to anticholinest­erase medication was excellent in those with rapsyn muta­tions but incomplete in the AChR- e group. A decrement of less than 10% on repetitive nerve stimulation at 2 to 3 Hz in at least one muscle was demonstrated in 12 of 13 patients with AChR- e mutations but only in 4 of 12 in the rapsyn group. Although both disorders result in AChR deficiency, phenotypic differences are striking. Rapsyn mutations are associated with full eye movements, arthrogryposis, dra­matic fluctuations in strength, a good response to anticho­linesterase medication, and good prognosis. Mutated AChR- e is associated with ophthalmoplegia, a partial re­sponse to anticholinesterase medication, and less long- term improvement. The authors suggest that awareness of these phenotypic features should facilitate targeted genetic diag­nosis and enable rapid introduction of treatment that, in some infants, could be life- saving ( Burke G, London, On­tario, Canada, S42.001). INHERITED ATAXIAS Mutations in CACNA1A, the gene encoding the hu­man P/ Q- type voltage- gated calcium channel alpha 1A sub-unit, cause episodic ataxia type 2 with interictal nystag­mus and other symptoms including hemiplegic migraine, progressive ataxia, epilepsy, and fluctuating weakness. A novel type of episodic ataxia type 2- causing CACNA1A mutation affecting the splice donor site at intervening sequence + 3 was described ( Jen JC, Los Angeles, Califor­nia, P01.005). Three cases were reported of ataxia- ocular apraxia 2 ( AOA2), a new autosomal recessive ataxia linked to a gene localized to 9q34 and encoding for a protein called sena-taxine. The disease presented with progressive ataxia and areflexia between ages 16 and 19 and, in one patient, ocular motor apraxia. Alpha- feto protein was elevated, electromyography showed an axonal neuropathy, and MRI revealed cerebellar atrophy ( Fleury M, Strasbourg, France, POLO 14). In another series, AOA1 and AOA2 accounted for 5% to 10% of 154 patients ( 77 families) with non- Friedreich autosomal recessive cerebellar ataxia. There were five different truncating/ missense mutations in AOA1, and four missense mutations in AOA2. AOA1 was characterized by an early mean age of onset ( 6.8 ± 4.8), cerebellar ataxia with brain atrophy on MRI, frequent marked choreic movements at onset ( 80%), and severe ax­onal sensorimotor neuropathy that led to considerable neu­rologic disability in the late stage of the illness. AOA2 was characterized by a higher mean age at onset ( 15.1 ± 3.8 years), less frequent chorea ( 44%), and less severe neurop­athy. Biological markers, as well as oculographic patterns, were useful to distinguish these overlapping phenotypes. Although ocular motor apraxia is a common feature of both disorders, differences in the age at onset, as well as the fre­quency and severity of associated signs and biologic fea­tures, allow distinction between AOA1 and AOA2 ( Durr A, Illkirch, France, P01.061). A genotype- phenotype correlation of 100 cases of spinocerebellar atrophy ( SCA) in Brazilian families was re­ported. Sixty five percent had identifiable mutations. Two groups with neuro- ophthalmologic findings were reported. All SCA 2 patients ( 8% of total) had cerebellar ataxia with slow saccades and hyporeflexia in upper limbs; all cases of SCA 7 ( 5% of total) had cerebellar ataxia and decreased visual acuity ( Teive GH, San Paolo, Brazil, P01.020). A study comparing SCA2 patients to those with SCA6 and episodic ataxia type 2 was performed. Although all these patients have a similar type of ataxia, only SCA2 patients have slow saccades. This finding was correlated with significant atrophy of the pons in SCA2. All three groups had atrophy of the cerebellar flocculus ( Ying SH, Los Angeles, California, POL 106). The visual and oculomotor features of 14 patients with late- onset Tay- Sachs disease were described. There were eight men and six women between 24 and 53 years of age. Afferent visual function and funduscopic examination was normal. Most often there was saccadic hypometria, al­though hypermetria sometimes occurred. Saccades also showed prolonged duration and decreased peak velocity. Large saccades showed " discrete decelerations," during which eye velocity had transient decreases. Slowing of sac­cades was present both horizontally and vertically, but was usually not conspicuous during bedside examination. There was decreased horizontal and vertical smooth pursuit gain. Vestibular ocular reflex and vergence movements were pre­served and there was no nystagmus ( Rucker JC, Cleveland Ohio, POL 105). DEGENERATIVE DISEASES Two patients presented with a focal tumor- like MRI lesion whose biopsy result was typical for Alzheimer dis­ease. Their subsequent clinical course was also consistent with Alzheimer disease ( Strand NH, Scottsdale, Arizona, P04.060). A study of retinal nerve fiber layer thickness by opti­cal coherence tomography in Parkinson disease ( PD) was reported. Retinal nerve fiber layer thickness was signifi­cantly thinner in the inferior retinal quadrant of PD patients ( 146.6 ± 19.7 urn) than in controls ( 165.1 ± 15.7 urn, P = 0.032). Within the inferior quadrant, the inferio- temporal part was the thinnest as compared with controls ( P = 0.01), 334 © 2004 Lippincott Williams & Wilkins Neuro- Ophthalmology at Large JNeuro- Ophthalmol, Vol. 24, No. 4, 2004 followed by the mid- inferior part ( P = 0.044). The infero-nasal part was preserved ( P > 0.1). Retinal nerve fiber layer thickness was not correlated with disease duration or age. This non- invasive test might be used potentially for follow- up of PD progression ( Inzelberg R, Hadera, Is­rael, P04.067). The physiologic basis for " freezing" episodes in some patients with PD is not well understood. A study recently demonstrated that abnormalities of visual con­trast sensitivity may contribute to the phenomenon of freezing, and that a relative hypersensitivity to low spatial frequency visual stimuli in the everyday visual environ­ment may represent an important factor. Alternatively, findings of abnormal visual contrast sensitivity at low spatial frequencies and marked gait freezing may repre­sent end- stage signs of dopamine deficiency in the visual and other central nervous system pathways in patients with Parkinson disease ( Kraakevik JA, IA City, Iowa, P04.150). Progressive ataxia with palatal myoclonus is a re­cently described clinical syndrome. The first pathologic case was presented and showed the expected olivary hyper­trophy but also accumulation of intracytoplasmic tau in the dentate- rubral system, sparing the rest of the brain. This may be related to other degenerative " tau- opathies." These are patients without previous stroke or radiation to the brainstem ( Zoltan M, Bethesda, Maryland, P01.062). OCULAR MOTOR DISORDERS Saccadic adaptation refers to the ability to modify the amplitude of a saccade in the midst of performing that sac-cade. It may be tested by having a target move to a new location in the middle of a saccade. This paradigm was used to test if children had this ability, a function of a mature cerebellum. In a study of 39 boys and girls aged 8 to 19 years, all had saccadic adaptation ( Salman MS, Toronto, Ontario, Canada, POL108). To support their claim that isolated congenital facial palsy and Mobius syndrome are different entities, a group of investigators performed pathologic examinations on three members of a family with autosomal dominant con­genital facial palsy. There was a marked decrease in the number and size of neurons in the facial motor nucleus with corresponding small facial nerve remnants. Neuronal de­generation, necrosis with neuronal loss, gliosis, or calcifi­cations was not present. The corticospinal long tracts were fully developed and no abnormalities of the rhombencepha­lon and its associated structures were observed. In contrast, Mobius syndrome is known to have hypoplasia of the entire brainstem, including the traversing long tracts, and other congenital brain abnormalities ( Verzijl HTFM, Nijmegen, The Netherlands, P01.126). The same group reported absence of the facial nerve on MRI in six patients with Mo­bius syndrome despite some residual facial function. This finding suggested that other cranial nerves might be inner­vating the facial muscles ( Verzijl HTFM, Amsterdam, The Netherlands, POL127). VESTIBULO- AUDITORY DISORDERS To assess the long- term efficacy of the canalith repo­sitioning procedure, 460 patients with benign paroxysmal positional vertigo were studied. Of 405 patients who were followed- up for an average of 39 months, 88% had com­plete recovery ( Tzagournissakis M, Heraklion, Crete, Greece, P01.109). Autoimmune inner ear disease, characterized by rap­idly progressive sensorineural hearing loss, is associated with autoimmune disease such as systemic lupus, pol­yarteritis nodosa, and Cogan syndrome. Two cases asso­ciated with reactive arthritis were described. Reactive arthritis is an aseptic arthritis triggered by an acute gastro­intestinal or genitourinary infection strongly associated with HLA B27. Steroids were not helpful in treating au­toimmune inner ear disease. Histopathologic examination of the cristae and maculae obtained at the time of surgery in one patient showed round cell infiltration and loss of hair cells in the cochlear and vestibular end organs consistent with a cell- mediated immune response ( Cha YH, San Fran­cisco, California, P01.110). The pathogenicity of tRNASer mitochondrial DNA mutations is generally low, usually resulting in relatively mild neurologic dysfunction ( ataxia, dysarthria). A family with more severe findings related to this mutation and a mutation in A7472C was recently reported. Clinical fea­tures in a 72- year- old mother included a 20- year history of progressive weakness associated with deafness. Her 53- year- old daughter had exercise intolerance associated with progressive weakness, deafness, and stroke, whereas her 50- year- old son had a more than 20- year history of progres­sive weakness requiring the use of a motorized scooter. Thus, the phenotype of tRNASer may be influenced by other mutations in the mitochondrial genome ( Haller RG, Dallas, Texas, POL 134). A new, dominantly inherited audio- vestibular syn­drome was described. Affected family members experi­enced slowly progressive hearing loss beginning in their late 30s and progressive imbalance in their early 70s. Three of four affected individuals had episodes of vertigo, typi­cally lasting minutes and occurring several times per year. Auditory and vestibular function testing documented a slowly progressive loss of auditory and vestibular function. Postmortem examination showed a loss of hair cells in the cochlea and vestibular receptor organs ( Ishiyama G, Los Angeles, California, P01.107). 335 JNeuro- Ophthalmol, Vol. 24, No. 4, 2004 Neuro- Ophthalmology at Large MISCELLANEOUS A personal account of sleep- related alterations asso­ciated with Wallenberg syndrome was given by a 67- year-old sleep physiologist and psychiatrist who had been a vic­tim of this stroke. He described insomnia for the first 10 days after the stroke. Complex visual and vestibular hallu­cinations occurred on eye closure during the awake state. Commonly prescribed hypnotics ( benzodiazepines, Zolpi­dem, antihistamines) provided little relief, increased hallu­cinations, and led to a few dissociative episodes. Sleep pro­gressively improved from day 10 to 40 after the stroke with slow resumption of dreaming ( Silvestri RC, Boston, Mas­sachusetts, P01.093). In an attempt to determine whether an electroretino-gram can be manipulated to simulate organic disease, five normal subjects were asked to be noncompliant while per­forming the test. Although abnormalities were noted, none simulated organic retinal disease ( Reiss A, Atlanta, Geor­gia, P01.104). Mark L. Moster, MD Albert Einstein Medical Center Wills Eye Hospital Philadelphia, Pennsylvania Laura J. Baker, MD, MSCE University of Pennsylvania School of Medicine Philadelphia, Pennsylvania 336 © 2004 Lippincott Williams & Wilkins